Peripheral Nerve Injury Anatomical PDF

Peripheral Nerve Injury
An Anatomical and Physiological Approach

for Physical Therapy Intervention
Stephen J. Carp, PT, PhD, GCS

Doctor of Physical Therapy Program
Temple University
College of Public Health
2560_FM_i-xii.indd i 3/17/2015 4:21:06 PM

Process CyanProcess
CyanProcess MagentaProcess
MagentaProcess YellowProcess
YellowProcess Black
F. A. Davis Company
1915 Arch Street
Philadelphia, PA 19103
www.fadavis.com
Copyright © 2015 by F. A. Davis Company
Copyright © 2015 by F. A. Davis Company. All rights reserved. This product is protected by copyright. No part
of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic,
mechanical, photocopying, recording, or otherwise, without written permission from the publisher.
Printed in the United States of America
Last digit indicates print number: 10 9 8 7 6 5 4 3 2 1
Senior Acquisitions Editor: Melissa Duffield
Developmental Editor: Andrea Edwards
Director of Content Development: George Lang
Design and Illustration Manager: Carolyn O’Brien
As new scientific information becomes available through basic and clinical research, recommended treatments
and drug therapies undergo changes. The author(s) and publisher have done everything possible to make this
book accurate, up to date, and in accord with accepted standards at the time of publication. The author(s),
editors, and publisher are not responsible for errors or omissions or for consequences from application of the
book, and make no warranty, expressed or implied, in regard to the contents of the book. Any practice described
in this book should be applied by the reader in accordance with professional standards of care used in regard to
the unique circumstances that may apply in each situation. The reader is advised always to check product
information (package inserts) for changes and new information regarding dose and contraindications before
administering any drug. Caution is especially urged when using new or infrequently ordered drugs.
Library of Congress Control Number: 2015935849
Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients,
is granted by F. A. Davis Company for users registered with the Copyright Clearance Center (CCC)
Transactional Reporting Service, provided that the fee of $.25 per copy is paid directly to CCC, 222 Rosewood
Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license by CCC, a
separate system of payment has been arranged. The fee code for users of the Transactional Reporting Service is:
978-0-8036-2560-0/15 + $.25.
2560_FM_i-xii.indd ii 3/17/2015 4:21:07 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
Process YellowProcess
YellowProcess Black
For Diane, Julia, Jennifer, and Emily.
Thank you for a lifetime of love
I wish to thank all my teachers and mentors—

especially Dick Williams, Carole Steinruck,
Mark McCandless, Emily Keshner, and Mom
and Dad. Your dedication to my education is
as responsible for this publication as was my
writing. A special thanks to all my students
and especially to Dr. Michael O’Hara for his
editorial assistance. Lastly, a thank you to
Melissa Duffield who believed in my writing
before I did.
2560_FM_i-xii.indd iii 3/17/2015 4:21:07 PM

Process CyanProcess
YellowProcess Black
PREFACE
Sadly, and for a multitude of reasons, the incidence and responses to positional change and exercise. There may
prevalence of peripheral neuropathy in the United be delayed healing, loss of toenails and fingernails, and
States and around the world continue to increase. We trophic skin changes.
are all well aware of the number of Americans affected Peripheral Nerve Injury: An Anatomical and Physio-
by diabetes mellitus and one of its most common com- logical Approach to Pathology and Intervention is the first
plications, peripheral neuropathy. Another complica- comprehensive textbook written for rehabilitation
tion of diabetes mellitus is chronic kidney disease. professionals—physical therapists, occupational thera-
Kidney disease, separate from diabetes, is in itself an pists, physical therapy assistants, occupational therapy
indirect cause of peripheral neuropathy. As the number assistants, physician assistants, nurse practitioners, ath-
of HIV infections continues to increase worldwide, we letic trainers, and orthotists/prosthetists—with content
are seeing an increasing number of patients with HIV- related to the etiology and intervention of diagnoses of
related neuropathic complications. Peripheral neuropa- peripheral neuropathy. In addition, primary care physi-
thy is a common side effect of scores of prescribed cians, nurses, vocational rehabilitation specialists, and
(and illegal) drugs. Cancers and their sequelae— insurance providers may find the text helpful with their
paraneoplastic syndrome, complications of chemother- practices.
apy and surgeries, and space-occupying tumors—often The textbook is divided into five content areas:
lead to peripheral neuropathy. Nerve injuries may result
from low-force, high-repetition activities such as key- 1. Overview of the peripheral nervous system and
board typing, overhead work, and musical instrument biomechanics of peripheral nerve: This section
playing. Exposure to environmental toxins such as lead, includes chapters related to the anatomy and
mercury, and arsenic, prevalent in some areas of the physiology of the peripheral nerve, the
United States and the world, may cause nerve injury. biomechanics of healthy and damaged nerve,
A common risk factor for falls is lower extremity neu- and the pathophysiology of the peripheral
ropathy. The list goes on and on. Peripheral neuropathy nervous system. This section contains a focused
is becoming a very common presenting and comorbid blueprint of the impact of the inflammatory
diagnosis for rehabilitation professionals. cascade on peripheral nerves associated with
Peripheral neuropathy may affect motor neurons, injury and illness.
sensory neurons, and regulatory (autonomic) neurons. 2. Etiologies of peripheral nerve injury: This
The functional impact may range from minimal to section examines common pathologies that
severe. The spectrum of motor neuropathy may range either directly or indirectly injure peripheral
from weakness of muscles within the myotomal distri- nerves. Pathologies examined include vasculitic,
bution of one nerve (mononeuropathy) to weakness of connective tissue, and seronegative
many muscles innervated by many nerves (systemic spondyloarthropathies; environmental toxins;
polyneuropathy). The severity of weakness may range critical illness myopathy/polyneuropathy;
from subclinical to flaccid paralysis. The spectrum of diabetes mellitus; infection; nutritional
sensory loss is even greater than that of motor neu- deficiencies; chronic kidney disease; and
ropathy. There may be positive (additive) signs such as neuropathic complications of common
paresthesia, radicular pain, and multisegmental pain. medications.
There may be negative signs such as loss of tactile, 3. Evaluation of a patient with suspected
temperature, pain, somatosensory (proprioception and peripheral nerve injury: This section includes
kinesthesia), vestibular, and vibratory senses. Lastly, chapters on the physical examination of
pathology of the regulatory neurons may lead to aber- individuals with suspected peripheral
rant and inappropriate blood pressure and cardiac neuropathy, the use of laboratory tests and
iv
2560_FM_i-xii.indd iv 3/17/2015 7:02:52 PM

Process CyanProcess
YellowProcess Black
Preface v
measures in the investigation of suspected care specialist. She currently maintains a clinical prac-
neuropathy, and an overview of tice in Philadelphia.
electroneurodiagnostic testing. Stephan Whitenack, MD, PhD, a graduate of
4. Evidenced-based interventions for individuals Thomas Jefferson Medical College, Thomas Jefferson
with peripheral nerve injury: These chapters University, Philadelphia, is board certified in general
provide a clear summary of the rehabilitative surgery, thoracic surgery, and vascular surgery and is a
modalities and interventions that may be used preeminent researcher, writer, lecturer, diagnostician,
to treat patients. In addition, chapters describe and surgeon in the field of brachial plexopathies.
manual therapy techniques, the role of physical Emily A. Keshner, PT, EdD, received her Certificate
agents, and orthotic fabrication for use with in Physical Therapy at the College of Physicians and
these patients. This section ends with a chapter Surgeons, Columbia University, New York, New York.
on behavioral modification techniques used by She received her doctoral degree in Movement Science
health care practitioners to address functional at Teachers College, Columbia University. She then
loss and chronic pain syndromes. pursued postdoctoral fellowships at the University of
5. Current “hot topics” related to peripheral nerve Oregon, Eugene, Oregon, and the University Hospital
injury: The topics addressed in this section in Basel, Switzerland, both in the area of postural
include brachial plexus syndromes, Guillain- control in healthy and vestibular-deficient adults. Sub-
Barré syndrome, neuropathies associated with sequently she was a Research Associate in the Depart-
athletics, entrapment neuropathies in the upper ment of Physiology, Northwestern University, Chicago,
and lower extremity, and neuropathic processes Illinois, where she performed animal and human
associated with HIV disease. research. She then worked as a research scientist in the
Sensory Motor Performance Program at the Rehabili-
I authored half the chapters. The other half were tation Institute of Chicago with a faculty position in
authored by many who are national and international the Department of Physical Medicine and Rehabilita-
experts in their unique content areas. tion at Northwestern University until she came to
Mary F. Barbe, PhD, Professor of Anatomy and Temple University in 2006. Dr. Keshner has been
Cell Biology at Temple University School of Medi- continuously funded from the National Institutes of
cine, Philadelphia, Pennsylvania, is one of the leading Health since 1989. She currently teaches in the PhD
researchers in the growing field of repetitive strain program in the Department of Physical Therapy. In
injury. For the past 10 years, she has been involved in addition to her appointment at Temple University,
neurobiological, cell, and molecular biological studies Dr. Keshner is Adjunct Professor, Department of
examining the effects of repetition and force on mus- Physical Medicine and Rehabilitation, Feinberg School
culoskeletal and neural systems and on sensorimotor of Medicine, Northwestern University and Director of
function with a research colleague, Ann E. Barr, PT, the Virtual Environment and Postural Orientation
PhD (now at Pacific University, Portland, Oregon). Laboratory at Temple Univeristy. Dr. Keshner has
Drs. Barbe and Barr developed a unique voluntary authored more than 100 peer-reviewed publications.
rat model of work-related musculoskeletal disorders Jill Slaboda, PhD, at the time this article was written,
(also known as repetitive strain injury and overuse was a post-doctoral research fellow in Dr. Keshner’s
injury) with varying levels of repetition and force and laboratory. Currently, she is with the Geneva
have been working to characterize the short-term Foundation.
effects. They have now expanded to examining the James W. Bellew, PT, PhD, is an associate professor
long-term effects of repetitive and forceful tasks on at the Kranert School of Physical Therapy at the
musculoskeletal and nervous system pathophysiology, University of Indianapolis, Indianapolis, Indiana. Dr.
focusing on injury and inflammation and how these Bellew has published more than 50 peer-reviewed sci-
processes induce degenerative tissue changes and sen- entific articles and abstracts in the areas of exercise
sorimotor dysfunction. Dr. Barbe is currently exploring training, balance, and muscle physiology and is the
inflammation-induced catabolic tissue changes versus co-author of the textbook Modalities for Therapeutic
mechanical overload–induced tissue disruption using Intervention, 5th ed., published by FA Davis Company.
pharmaceutical methods to block inflammatory pro- Edward Mahoney, PT, DPT, CWS, is currently Assis-
cesses. This work is currently funded by the National tant Professor at Louisiana State University Health in
Institute for Occupational Safety and Health and Shreveport Louisiana. He obtained his Doctorate of
National Institute of Arthritis and Musculoskeletal Physical Therapy from Louisiana State University
and Skin Diseases. Health Sciences Center in Shreveport and his Master’s
Susan Bray, MD, Clinical and Associate Professor in Science of Physical Therapy from Sacred Heart Uni-
in the Division of Nephrology at Drexel University versity. He has published extensively in the areas of
College of Medicine, Philadelphia, is a much honored wound healing and therapeutic modalities for tissue
clinical nephrologist, internist, author, and palliative healing. He is a member of the American Board of
2560_FM_i-xii.indd v 3/17/2015 4:21:07 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
vi Preface
Wound Management as well as a site reviewer for the analgesics discovery group at Johnson & Johnson and
American Board of Physical Therapy Residency and was involved in the elucidation of the mechanism of
Fellowship Education. action of tramadol. He is co-holder of several patents,
Roberta A. Newton, PT, PhD, FGSA, an interna- including the combination of tramadol with acetamin-
tionally recognized expert in fall prevention pro- ophen. Dr. Raffa is the co-author or editor of several
gramming for older adults and the author of 53 books on pharmacology, including Netter’s Illustrated
peer-reviewed publications, 5 books, and 16 book Pharmacology and Principles in General Pharmacology
chapters. At the time of the authorship of this chapter, and Drug-Receptor Thermodynamics, and has published
Dr. Newton was professor of Physical Therapy and more than 150 articles in refereed journals and more
Clinical Professor of Medicine at Temple University. than 70 abstracts and symposia presentations. He is
Past posts at Temple have included director for the co-founder and editor of the journal Reviews in Anal-
Institute on Aging, and regional coordinator and direc- gesia and was an associate editor of the Journal of Phar-
tor of education of the Gerontology Education Center. macology and Experimental Therapeutics. Dr. Raffa is
Newton was also a tenured associate professor at the active in several professional societies and is a past
Department of Physical Therapy, School of Allied president of the Mid-Atlantic Pharmacology Society.
Health Professions, Medical College of Virginia of He is the recipient of the Hofmann Research Award,
Virginia Commonwealth University. Newton earned a Lindback Teaching Award, and other honors.
PhD in neurophysiology and a BS in physical therapy John P. Scanlon, DPM, is a graduate of the Temple
from the Medical College of Virginia, Virginia Com- University School of Podiatric Medicine and maintains
monwealth University, and a BS in biology from Mary a podiatric clinical practice in Philadelphia. Dr. Scanlon
Washington College. She is the recipient of the Ameri- is also the Chief Medical Officer at Chestnut Hill
can Physical Therapy’s Catherine Worthingham Fellow Hospital in Philadelphia and directs the Chestnut Hill
Award. Dr. Newton has written, along with Dennis W. Hospital Podiatric Residency Program. Crystal N.
Klima, PT, PhD, GCS, NCS, formerly Dr. Newton’s Gonzalez, DPM, Benjamin R. Denenberg, DPM, and
doctoral student and now assistant professor in the Krupa J. Triveda, DPM, were residents in Podiatry
Department of Physical Therapy at University of under Dr. John Scanlon at Chestnut Hill Hospital and
Maryland Eastern Shore, Princess Anne, Maryland, a are now all in private practice.
wonderful chapter on fall risk identification, preven- Joseph I. Boullata, PharmD, RPh, BCNSP, is a
tion, and management. Dennis Klima joined the faculty clinician-educator on the standing faculty of the Uni-
at University of Maryland, Eastern Shore, in the fall of versity of Pennsylvania School of Nursing in Phila-
2002. Prior to his UMES appointment, Dennis served delphia. He received his Doctorate in Pharmacy from
as Program Director of the Physical Therapist Assis- the University of Maryland in Baltimore after com-
tant Program at the Baltimore City Community pleting undergraduate degrees in Nutrition Science
College for thirteen years. He received his Bachelor of (Pennsylvania State University), State College, Penn-
Science degree in Physical Therapy from the Medical sylvania, and in Pharmacy (Philadelphia College of
College of Virginia. He completed a PhD in Physical Pharmacy & Science, Philadelphia). He completed a
Therapy from Temple University where his dissertation residency at the Johns Hopkins Hospital in Balfimore
focused on physical performance and fear of falling in and a nutrition support fellowship at the University
older men. Dr. Klima received his geriatric and neuro- of Maryland Medical System. His teaching experi-
logic clinical specializations from the American Board ences have spanned well over a dozen years mostly in
of Physical Therapy Specialties. His APTA experience pharmacy education through didactic, small group, and
also includes serving as an on-site reviewer for both bedside teaching. Outside the classroom, Dr. Boul-
PT and PTA programs with the Department of lata is involved with student mentoring and profes-
Accreditation since 1990. He has presented geriatric sional organizations as well as his clinical practice and
and neurological continuing education courses both scholarship. Dr. Boullata’s research agenda generated
nationally and internationally. Areas of research include from questions that arise during clinical practice and
both management of adults with TBI and fall preven- then developed further through interdisciplinary col-
tion in older adults. laboration. His research areas have included phar-
Robert B. Raffa, PhD, is Professor of Pharmacology macotherapeutic issues within the intensive care unit
and Chair of the Department of Pharmaceutical Sci- setting, pharmacotherapeutic implications of nutrition
ences at Temple University School of Pharmacy and regimens, and drug-nutrient interactions. The phar-
Research Professor at Temple University School of macology and therapeutics of individual nutrients and
Medicine. Dr. Raffa holds bachelor’s degrees in Chem- natural health products in disease management as well
ical Engineering and in Physiological Psychology, mas- as their interaction with medication require further
ter’s degrees in Biomedical Engineering and in exploration. Dr. Boullata has achieved and maintained
Toxicology, and a doctorate in Pharmacology. Dr. Raffa board certification in nutrition support. He has also
was a Research Fellow and Team Leader for an received recognition for his active membership in
2560_FM_i-xii.indd vi 3/17/2015 4:21:07 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Preface vii
several multidisciplinary, national professional organi- teaching responsibilities, he maintains an active clini-
zations including the American Society for Parenteral cal schedule including research and patient care. His
and Enteral Nutrition. He has also served on the edito- main research interests revolve around clinical decision
rial boards for Nutrition in Clinical Practice and Current making, clinical education strategies/models, patient
Topics in Nutraceutical Research. outcomes, chronic pain management and manual phys-
David M. Kietrys, PT, PhD, OCS, received his ical therapy interventions for various musculoskeletal
entry-level physical therapy degree from Hahnemann conditions. His work, entitled “Short-term response
University in Philadelphia and his doctorate from of hip mobilizations and exercise in individuals with
Temple University. Dr. Kietrys is currently Associate chronic low back pain: a case series” was awarded the
Professor of Rehabilitation and Movement Sciences at Dick Erhard Award for Best Platform Presentation at
the Rutgers School of Health Related Professions (for- AAOMPT Conference in 2010. In 2014, Dr. Burns
merly known as UMDNJ–School of Health Related was selected as the recipient for the College of Public
Professions) in Stratford, New Jersey. Dr. Kietrys has Health Excellence in Teaching Award.
published extensively in the field of HIV and exercise Amy Heath, PT, PhD, OCS, is Chair and Assistant
and repetitive strain injury. Mary Lou Galantino, PT, Professor of Physical Therapy at Simmons College. She
PhD, MS, MSCE, has a dual appointment: Adjunct received her BS in Health Studies and DPT from
Associate Professor of Family Medicine and Commu- Simmons College, and her PhD in Educational Psy-
nity Health at the Perelman School of Medicine, Uni- chology from Temple University. Dr. Heath is creden-
versity of Pennsylvania, and Professor of Physical tialed by the American Physical Therapy Association
Therapy at Richard Stockton College. An accom- as a Clinical Instructor.
plished funded researcher, Dr. Galantino has published Teri O’Hearn, DPT, CHT received a bachelor’s
extensively in the areas of HIV-related neuropathy, degree in Health Science from the University of North
holistic medicine, and women’s health. Florida, Jacksonville, Florida, a master’s of science
Bill Egan, DPT, OCS, FAAOMPT, received a BA degree in Physical Therapy from the University of
in psychology from Rutgers University, New Bruns- North Florida, and a Doctor of Physical Therapy
wick, New Jersey, in 1997, and an MPT from the degree from Boston University, Boston. She became a
US Army–Baylor University in San Antonio, Texas, Certified Hand Therapist in 2007. She is currently
in 1999. He served as an active duty Army physical employed at Ministry Door County Medical Center in
therapist for 6 years. Dr. Egan completed the tDPT Sturgeon Bay, Wisconsin.
and Manual Therapy Fellowship program through Megan Mulderig McAndrew, DPT, MS, is employed
Regis University in Denver, Colorado, in 2006, and in the Drucker Brain Injury Center at Moss Rehabili-
he now serves as affiliate faculty for these programs. tation Hospital in Elkins Park, Pennsylvania. Ms.
Currently, Dr. Egan is an associate professor in the McAndrew has presented and written extensively in
Doctor of Physical Therapy program at Temple Uni- the field of neurotrauma and neurorehabilitation. She
versity. He is a board-certified Orthopedic Clinical is a graduate of the Moss Rehabilitation Neurological
Specialist and a Fellow of the American Academy of Physical Therapy Residency.
Orthopedic Manual Therapists. Dr. Egan serves as an Elizabeth Spencer Steffa, OTR/L, CHT, is an occu-
adjunct instructor for various local physical therapy pational therapist, certified hand therapist, partner of
programs teaching manual therapy and thrust manipu- Highline Hand Therapy, and a clinical faculty member
lation. He is also an instructor for Evidence In Motion. at the University of Washington, Seattle, Washing-
Dr. Egan maintains a part-time clinical practice at the ton, her alma mater. Ms. Steffa treats hand and upper
Sports Physical Therapy Institute in Princeton, New extremity injuries, performs physical capacity evalua-
Jersey. Scott Burns, PT, DPT, OCS, FAAOMPT, tions, and participates in splinting/orthosis fabrication.
received his Master of Physical Therapy and transi- Each chapter begins with a title, germane quotation,
tional Doctor of Physical Therapy from the University objectives, key terms, and an introduction. The text is
of Colorado-Denver. He is currently Associate Pro- supplemented liberally with photographs, tables, and
fessor and Assistant Chair in the Doctor of Physical diagrams. Each chapter includes a case study and
Therapy Program at Temple University. Dr. Burns’s sample questions. A comprehensive list of references
teaching responsibilities include the Musculoskeletal also is included with each chapter. At the end of the
Management course series, Orthopaedic Residency text is a comprehensive glossary of definitions of all key
Coursework and Advanced Musculoskeletal Elec- terms in the chapters. An index is also provided for
tive, and Clinical Decision Making. In addition to his ease of locating subject matter.
2560_FM_i-xii.indd vii 3/17/2015 4:21:07 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
REVIEWERS
Kevin Ball, PhD Jennifer A. Mai, PT, DPT, MHS, NCS

Assistant Professor Assistant Professor
Physical Therapy Physical Therapy
Director Clarke University
Human Performance Laboratory Dubuque, Iowa
University of Hartford
Karen McCulloch, PT, PhD, NCS
West Hartford, Connecticut
Professor
James W. Bellew, PT, EdD Division of Physical Therapy–Allied Health
Associate Professor Sciences
Physical Therapy University of North Carolina–Chapel Hill
Krannert School of Physical Therapy Chapel Hill, North Carolina
University of Indianapolis
Stefanie D. Palma, DPT, PT, NCS, CBIS
Indianapolis, Indiana
Chair
Shaun G. Boe, BPhEd (Hon), MPT, PhD Physical Therapy
Assistant Professor North Georgia College & State University
School of Physiotherapy Dahlonega, Georgia
Dalhousie University
E. Anne Reicherter, PT, DPT, PhD, OCS, CHES
Halifax, Nova Scotia, Canada
Associate Professor
Rafael Escamilla, PhD, PT Physical Therapy and Rehabilitation Sciences
Professor University of Maryland School of Medicine
Physical Therapy Baltimore, Maryland
Sacramento State University
Linda J. Tsoumas, PT, MS, EdD
Sacramento, California
Professor
Claudia B. Fenderson, PT, EdD, PCS Physical Therapy
Professor Springfield College
Physical Therapy Belchertown, Massachusetts
Mercy College
David Walton, BScPT, MSc, PhD
Dobbs Ferry, New York
Assistant Professor
Cynthia K. Flom-Meland, PT, PhD, NCS Faculty of Health Sciences
Assistant Professor The University of Western Ontario
Physical Therapy London, Ontario, Canada
University of North Dakota
Kevin C. Weaver, PT, DPT, MA, OCS, CEA, CIE
Grand Forks, North Dakota
Clinical Assistant Professor
Erin Hussey, DPT, MS, NCS Physical Therapy
Clinical Associate Professor New York University
Health Professions–Physical Therapy New York, New York
University of Wisconsin–La Crosse
Mark R. Wiegand, PT, PhD
La Crosse, Wisconsin
Professor and Program Director
Physical Therapy
Bellarmine University
Louisville, Kentucky
viii
2560_FM_i-xii.indd viii 3/17/2015 7:02:52 PM

Process CyanProcess
YellowProcess Black
CONTENTS
Section One: Anatomy, Physiology, Section Two: Etiology of Peripheral Nerve

Biomechanics, and Pathophysiology of Injury, 35
Peripheral Nerve Injury, 1 Chapter 4: Peripheral Neuropathy and Vasculitic,
Chapter 1: The Anatomy and Physiology of the Connective Tissue, and Seronegative
Peripheral Nerve, 1 Spondyloarthropathic Disorders, 35
Introduction, 2 Introduction, 36
Functional Anatomy of the Peripheral Nervous Vasculitic Diseases, 36
System, 2 Connective Tissue Disorders, 38
The Cell Body, 3 Rheumatoid Arthritis, 38
Dendrites, 3 Juvenile Idiopathic Arthritis, 39
Axon, 4 Systemic Lupus Erythematosus, 40
Endoneurium, 5 Primary Sjögren’s Syndrome, 41
Perineurium, 6 Adamantiades-Behçet Disease, 43
Epineurium, 6 Seronegative Spondyloarthropathies, 43
Mesoneurium, 6 Ankylosing Spondylitis, 44
Vascular Components, 6 Reactive Arthritis, 44
Neuron Type: Directional Transport, 7 Psoriatic Arthritis, 46
Biomechanics of Peripheral Nerves, 7 Enteropathic Arthritis, 47
Classification and Pathophysiology of Peripheral Nerve Celiac Disease, 48
Injury, 9 Chapter 5: Environmental Toxic Neuropathies, 53
Seddon Classification, 9 Introduction, 53
Sunderland Classification, 11 Anesthetic Agent, 54
Wallerian Degeneration, 11 Nitrous Oxide, 54
Chapter 2: The Biomechanics of Peripheral Nerve Heavy Metal Toxicities, 55
Injury, 15 Lead, 55
Introduction, 15 Thallium, 59
Efferent, Afferent, and Autonomic Pathways, 15 Arsenic, 60
Structure of the Peripheral Nerve, 16 Mercury, 61
Peripheral Nerve Response to Injury, 18 Chemical Toxicities, 62
Physiological Basis for Biomechanical and Chemotoxic Ethylene Glycol, 62
Nerve Injury, 19 Alcohol-Related Neuropathy, 63
Chapter 3: Pathophysiology of Peripheral Nerve Chapter 6: Critical Illness Polyneuropathy, 69
Injury, 25 Introduction, 69
Introduction, 25 Clinical Signs and Symptoms, 70
Peripheral Nerve Damage and Inflammation With Pathophysiology, 70
Overuse, 25 Prevention and Intervention, 71
Effects of Overuse on Nerves in Human Chapter 7: Diabetes Mellitus and Peripheral
Subjects, 26 Neuropathy, 75
Rat Model of Overuse Injury, 26 Introduction, 75
Nerve Injury, Inflammation, and Fibrosis Induced by Pathophysiology of Diabetes Mellitus, 75
Overuse, 27 Complications of Diabetes, 76
Spinal Cord Neuroplastic Changes Induced by Demographics, 79
Peripheral Nerve Inflammation, 28 Pathophysiology of Diabetic Neuropathy, 80
Cortical Brain Neuroplastic Changes Induced by Polyol Pathway, 80
Repetitive Strain Injury, 29 Microvascular Theory, 80
Links Between Pain Behaviors and Peripheral or Nonenzymatic Glycosylation Theory, 80
Central Neural Changes, 30 Classification and Clinical Characteristics of Diabetic
Peripheral Nerve Sensitization, 30 Neuropathies, 81
Spinal Cord Central Sensitization, 31 Symmetrical Neuropathies, 81
Does Sensitization Result From Both Peripheral and Asymmetrical Neuropathies, 81
Central Changes? 31 Intervention, 82
ix
2560_FM_i-xii.indd ix 3/17/2015 4:21:07 PM

Process CyanProcess
YellowProcess Black
x Contents
Chapter 8: Peripheral Neuropathy and Infection, 89 Chapter 13: Laboratory Investigation of Suspected
Introduction, 89 Peripheral Neuropathy, 143
Lyme Disease, 90 Introduction, 143
Poliomyelitis, 91 Laboratory Screening Tests, 145
HIV Infection, 92 Complete Blood Count, 145
Hepatitis C Virus, 94 Basic Metabolic Panel, 146
Tuberculosis, 94 Laboratory Diagnostic Testing, 147
Varicella-Zoster Virus Infections, 95 Hemostasis, 147
Parasitic Infections, 97 Inflammation, 147
Chronic Fatigue Syndrome, 99 Cardiac Enzymes, 148
Parsonage-Turner Syndrome, 100 Liver Enzymes, 148
Leprosy, 100 Immunological Tests, 148
Chapter 9: Peripheral Neuropathy Associated With Urinalysis, 149
Nutritional Deficiency, 105 Culture, 150
Introduction, 105 Rapid Plasma Reagin, 150
Nutrients, Nutritional Status, and the Nervous Hemoglobin A1c, 150
System, 106 Chapter 14: The Examination: Evaluation of the
Nutrients and Nutritional Status, 106 Patient with Suspected Peripheral
Nutrition and the Nervous System, 106 Neuropathy, 153
Neuropathy by Presentation, 107 Introduction, 153
Neuropathy by Specific Nutrient, 108 The Chief Complaint, 153
Macronutrients, 108 History of the Present Illness, 154
Vitamins, 108 Past Medical and Surgical Histories, 154
Electrolytes, 111 Social and Occupational Histories, 154
Magnesium, 111 Review of Systems, 156
Trace Elements, 111 Physical Examination, 156
Copper, 111 Vital Signs, 157
Chapter 10: Peripheral Neuropathy and Chronic Postural Examination and Corporal
Kidney Disease, 115 Presentation, 157
Introduction, 115 Integument Examination, 158
Functions of the Kidney, 115 Musculoskeletal Examination, 160
Kidney Physiology, 116 Neurological Examination, 160
Chronic Kidney Disease, 117 Sensory System Examination, 160
Chronic Kidney Disease–Induced Neuropathy, 119 Deep Tendon Stretch Examination, 163
Cranial Nerve Examination, 163
Chapter 11: Medication-Induced Neuropathy, 125 Balance Assessment, 163
Introduction, 125
Cognitive Examination, 164
Mechanisms of Medication-Induced Neuropathy, 125
Functional Examination, 165
Chemotherapeutic Agents, 126
Platinum Drugs, 126 Section Four: Rehabilitative Procedural
Taxanes, 126
Vinca Alkaloids, 127 Intervention for Peripheral Nerve
Thalidomide, 127 Injury, 171
Bortezomib, 127 Chapter 15: Overview of Rehabilitation Intervention
Suramin, 127 for Peripheral Nerve Injury, 171
Leflunomide, 127 Introduction, 172
Statins, 128 International Classification of Functioning, Disability
Highly Active Antiretroviral Therapy, 128 and Health, 172
Anti–Tumor Necrosis Factor Alpha Drugs, 128 Hypothesis-Oriented Algorithm for Clinicians, 173
Amiodarone, 128 Overview of Intervention, 174
Additive and Synergistic Considerations, 129 Coordination, Communication, and
Documentation, 174
Section Three: Evaluation and Assessment of Direct Intervention: Behavioral Concerns, 176
Peripheral Nerve Injury, 135 Direct Intervention: Clinical Concerns, 177
Chapter 12: Electroneurodiagnostic Assessment and Chapter 16: Manual Therapy Techniques for
Interpretation, 135 Peripheral Nerve Injuries, 181
Introduction, 135 Introduction, 181
Electroneurodiagnostic Process, 136 Common Disorders, 182
Motor Nerve Conduction Studies, 136 Cervical Radiculopathy, 182
Sensory Nerve Conduction Studies, 137 Thoracic Outlet Syndrome, 184
F Waves, 138 Lateral Epicondylalgia, 184
Repetitive Nerve Stimulation, 138 Cubital Tunnel Syndrome, 185
Electromyography, 139 Carpal Tunnel Syndrome, 185
2560_FM_i-xii.indd x 3/17/2015 4:21:07 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Contents xi
Lumbar Radiculopathy, 186 Examples of Physical Therapy Goals for
Piriformis Syndrome, 189 Rehabilitation, 235
Hamstring Strains, 190 Short-Term Goals, 235
Meralgia Paresthetica, 190 Long-Term Goals, 235
Neuropathies of the Foot and Ankle Region, 190 Assessment and Outcome Measures, 235
Chapter 17: The Role of Physical Agents in Prognosis, Recovery of Function, and Quality of
Peripheral Nerve Injury, 195 Life, 235
Introduction, 195 Chapter 21: Peripheral Nerve Injury in the
Physical Agents, 195 Athlete, 239
Role of Physical Agents, 195 Introduction, 239
What Are Physical Agents?, 196 Background, 239
Physical Agents for Peripheral Nerve Injury, 196 Football, 241
Electrical Stimulation, 196 Trampoline, 244
Regeneration of Nerve, 196 Cheerleading, 245
Modulation of Pain, 197 Baseball, 246
Frequency Rhythmic Electrical Modulation Volleyball, 248
System, 198 Tennis, 248
Preservation of Denervated Muscle, 199 Golf, 249
Ultrasound, 199 Ice Hockey, 250
Laser, 201
Pulsed Electromagnetic Field, 202 Chapter 22: Effects of Peripheral Neuropathy on
Monochromatic Infrared Energy, 203 Posture and Balance, 253
Introduction, 253
Chapter 18: Orthotic Intervention for Peripheral Peripheral Nerve Contributions to Posture
Neuropathy, 209 Control, 254
Introduction, 209 Somatosensory Signals, 254
Splinting Mechanics and Terminology, 210 Vestibular Signals, 254
Brachial Plexus Splinting, 211 Visual Signals, 255
Radial Nerve Splinting, 212 Postural Adaptation to Loss of a Sensory
Median Nerve Splinting, 215 Pathway, 255
Ulnar Nerve Splinting, 216 Sensory Reweighting, 255
Combined Peripheral Nerve Injures and Loss of Individual Inputs, 257
Complications, 217 Intramodal Dependencies, 257
Chapter 19: Counseling and Behavior Modification Neuropathic Effects on Balance, 258
Techniques for Functional Loss and Chronic Automatic Postural Reactions, 258
Pain, 219 Anticipatory Postural Compensation, 259
Introduction, 219 Assessing the Risk of Falls With Peripheral
Behavior Therapy, 220 Neuropathy, 259
Cognitive Behavior Therapy, 222 New Treatments and Interventions for Instability
Alternative Approaches, 222 Caused by Neuropathy, 261
Behavior Modification Strategies, 223 Vibrating Insoles and Whole Body Vibration, 261
Research, 224 Rocker Shoes, 261
Limiting Lateral Motion, 262
Section Five: Special Considerations, 227 Chapter 23: Brachial Plexopathies, 269
Chapter 20: Guillain-Barré Syndrome, 227 Introduction, 269
Introduction, 227 Historical Background, 270
Epidemiology, 228 Vascular Syndromes, 271
Clinical Presentation and Diagnosis, 229 Arterial Thoracic Outlet Syndrome, 271
Medical Management and Treatment, 230 Venous Thoracic Outlet Syndrome, 272
Clinical Implications, 231 Treatment of Vascular Thoracic Outlet Syndrome, 272
Cardiovascular and Respiratory Compromise, 231 Neurological Thoracic Outlet Syndromes, 272
Autonomic Dysfunction, 231 “True Neurogenic” Thoracic Outlet Syndrome, 272
Muscle Weakness, 231 Classic Thoracic Outlet Syndrome, 273
Pain and Sensory Dysfunction (Dysesthesia), 232 Lower Brachial Plexus Syndromes (Lower Thoracic
Fatigue, 232 Outlet Syndrome), 273
Gait, 233 Upper Brachial Plexus Syndromes (Upper Thoracic
Integument, 233 Outlet Syndrome), 274
Swallowing and Speech, 233 Mixed Plexus Syndromes, 274
Deep Vein Thrombosis, 233 Parsonage-Turner Syndrome, 275
Heterotopic Ossification, 233 Associated Musculoskeletal Problems, 275
Psychosocial Implications, 234 Impingement Syndrome (Rotator Cuff Tear), 275
Rehabilitative Care, 234 Trapezius Spasm, 275
Classification of Signs and Symptoms, 234 Biceps Tendonitis, 275
2560_FM_i-xii.indd xi 3/17/2015 4:21:07 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
xii Contents
Trigger Points, 276 Deep Peroneal Nerve, 315
Lateral Epicondylitis, 276 Posterior Tibial Nerve, 316
Pathophysiology, 276 Medial Plantar Nerve, 317
Embryology, 276 Lateral Plantar Nerve, 317
Anterior Scalene Anomalies, 277 Saphenous Nerve, 317
Middle Scalene Anomalies, 277 Neuroma, 318
Congenital Fibromuscular Bands, 277 Chapter 26: Fall Risk and Fall Prevention Strategies
Scalenus Minimus and Pleuralis, 278 for Individuals With Peripheral Neuropathy, 321
Axillary Arch Muscles, 278 Introduction, 321
Radiation Fibrosis, 279 Mechanisms Contributing to Falls, 322
Other Fibrous Anomalies, 279 Peripheral Sensory Declines, 323
Clavicle Abnormalities, 279 Neuromotor Dysfunction in the Lower
Cervical Rib Anomalies, 279 Extremities, 323
Elongated C7 Transverse Process, 280 Lifestyle and Activity Level, 324
First Rib Anomalies, 280 Medications, 324
Postural Abnormalities, 280 Elements of a Fall Prevention Program, 324
Traction Plexopathy, 281 Guidelines for Assessing Individuals at Risk for
Complex Regional Pain Syndrome, 281 Falls, 324
Surgery, 282 Fall History and Fear of Falling, 325
Transaxillary First Rib Resection, 283 Medical and Medication History, 325
Scalenotomy and Scalenectomy, 283 Sensory Integrity, 325
Total Brachial Plexus Decompression, 283 Integumentary and Foot Posture, 325
Combined Anterior and Transaxillary Procedure, 285 Deep Tendon Reflexes and Electromyographic
Robotic Surgery, 285 Examination, 325
Complications, 285 Range of Motion and Muscle Strength, 325
Results, 286 Health Status and Measure of Physical Performance
Chapter 24: Entrapment Neuropathy in the Forearm, and Ability to Accomplish Activities of Daily
Wrist, and Hand, 289 Living, 325
Introduction, 289 Functional Mobility and Gait, 325
Pathogenesis of Tunnel Injuries, 290 Balance Assessments, 326
Clinical Symptoms and Signs, 291 Social, Occupational, Leisure, and Functional
Radial Nerve, 292 Status, 326
Radial Tunnel Syndrome, 292 Fall Prevention Strategies, 326
Posterior Interosseous Nerve Syndrome, 293 Education and Activity, 326
Wartenberg’s Syndrome, 294 Chapter 27: Peripheral Neuropathies in Individuals
Median Nerve, 294 With HIV Disease, 331
Pronator Syndrome, 294 Introduction, 331
Anterior Interosseous Nerve Syndrome, 296 Overview of HIV/AIDS–Associated
Carpal Tunnel Syndrome, 297 Neuropathies, 332
Ulnar Nerve, 299 Pathophysiology and Risk Factors, 333
Cubital Tunnel Syndrome, 299 Diagnosis, 335
Guyon’s Canal Syndrome (Ulnar Tunnel Medical Management and Pharmacological
Syndrome), 301 Interventions, 336
Treatment of Entrapment Neuropathies, 303 Physical Therapy Interventions, 338
Manual Therapy, 303 Pain Management Integrative Modalities: Acupuncture,
Neural Mobilization, 304 Mind-Body Therapy, and Supplements, 340
Therapeutic Taping, 305 Other Types of Neuropathy Associated With HIV
Therapeutic Modalities, 305 Disease, 341
Ultrasound, 305 Autonomic Neuropathy, 341
Laser Therapy, 306 Inflammatory Demyelinating Neuropathies, 341
Electrical Stimulation, 306 Mononeuropathies, 342
Neuropathy Associated With Infiltrative
Chapter 25: Entrapment Neuropathies in the Foot Lymphomatosis Syndrome, 342
and Ankle, 311 Progressive Polyradiculopathy, 342
Introduction, 311 Neuropathies Related to Opportunistic
Anatomy, 311 Infections, 342
Pathology, 312
Examination, 313
Intervention Overview, 314
Glossary, 347
Entrapment Neuropathy of Specific Lower Extremity
Nerves, 314 Appendix: Case Study Answers, 361
Sural Nerve, 314
Superficial Peroneal Nerve, 315 Index, 365
2560_FM_i-xii.indd xii 3/17/2015 4:21:08 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
SECTION ONE
Anatomy, Physiology, Biomechanics,

and Pathophysiology of Peripheral
Nerve Injury
Chapter 1
The Anatomy and Physiology of
the Peripheral Nerve
STEPHEN J. CARP, PT, PHD, GCS
“Facts are the air of scientists. Without them you can never fly.”
—LINUS PAULING (1901–1994)
Objectives
On completion of this chapter, the student/practitioner will be able to:
• Describe the basic anatomical structure of a peripheral nerve.
• Relate the structural and functional anatomy of a peripheral nerve.
• Define the process of wallerian degeneration.
• Compare and contrast the various common nerve classifications.
• Discuss the structural and functional impact of aberrant tensile and compressive forces on peripheral nerves.
Key Terms
• Classification of peripheral nerve injury
• Compression
• Endoneurium
• Epineurium
• Perineurium
• Tension
• Wallerian degeneration
2560_Chapter 1_0001-0014.indd 1 3/16/2015 4:13:12 PM

Process CyanProcess
YellowProcess Black
2 Section One | Anatomy, Physiology, Biomechanics, and Pathophysiology of Peripheral Nerve Injury
Introduction The PNS is often simplistically likened to an electri-

cal source such as a generator, a conduction system
(wiring), synapse (outlet), or effector organ (appliance
Homeostasis (Greek: homoios, similar; histēmi, to cause such as a vacuum cleaner or electric light). In many
to stand still) is the property of an open or closed ways, this analogy is effective, but our neurological
system that allows regulation of its internal environ- system must accommodate one variable that household
ment.1 In other words, homeostasis is the physiological wiring does not: mobility. With skilled movements, the
and anatomical capacity of an organism to regulate PNS is asked to function in a stretched, stationary,
itself by rapidly analyzing and, if aberrant, restoring mobile, or compressed environment. A skilled observa-
environmental conditions following a sudden pertur- tion of a gymnast performing a complicated routine
bation in the internal or external environment. Such provides ample evidence for this statement. Millesi
internal or external environmental conditions or et al.2 calculated that the median nerve as measured
“stimuli” initiate electrical impulses in peripheral and from axilla to hand is 20% longer in an elbow-extended,
central sensory receptors. The impulses travel afferently wrist-extended compared with an elbow-flexed, wrist-
from the receptors via nerves to the spinal cord and flexed posture. The spinal cord is 5 to 9 cm longer with
brain where they are analyzed, compared, learned, and trunk flexion compared with trunk extension. In addi-
coordinated by a process called “integration.” Once the tion, nerve trunks must be able to deflect compressive
afferent information is received and deciphered, the forces directed from extrinsic sources such as an inflated
spinal cord and brain convey efferent impulses through blood pressure cuff and intrinsic sources such as com-
nerves to muscles and glands. In an effort to maintain pression from a bony prominence (e.g., the ulnar nerve
homeostasis, muscles either contract or relax, and within the olecranon fossa during elbow flexion).
glands either secrete or stop secreting their products. PNS tissues can be divided into conduction and
The nervous and endocrine systems are the two support structures. The conduction structures—nerve
major regulatory systems of the body, and both are fibers and synaptic components such as the dendrites
specialized (and defined) by making appropriate and and synaptic cleft—and the support structures—axon
timely responses to internal or external stimuli. The sheath, myelin, Schwann cells, and epineurium among
nervous system, using a combination of electrical others—combine to form a quite vigorous and adapt-
potentials and neurotransmitters to communicate mes- able functional nexus. However, each conduction and
sages and tasks, is the faster of the two; the endocrine support structure is prey to a host of diseases and inju-
system depends on a slower transmission system, a ries leading to potentially severe functional impairment.
chemical system using hormones. Typically, long-term The nervous system is unique among corporal
organism growth, metabolic activity, and the reproduc- systems because of its vast complexity and its control,
tion system are controlled by the endocrine system. regulation, decoding, transmitting, and action func-
Faster and immediate tasks such as movement and tions. There are 100 billion nerve cells, or neurons,
autonomic regulation are controlled by the neurologi- functionally and anatomically specialized to maintain
cal system. Although considered two distinct corporal homeostasis. The purpose of this chapter is to present
systems, the endocrine and neurological systems are an overall anatomical framework of the PNS, an analy-
considered a singular regulatory system. sis of the functions of the various entities and subenti-
Albeit a unified system peripherally and centrally, ties of the PNS, and, lastly, a review of the biomechanics
the nervous system is typically anatomically defined as of the PNS.
having central and peripheral components—the central
nervous system (CNS) and the peripheral nervous
system (PNS). The CNS consists of the brain and
spinal cord. The PNS consists of all neurological tissue
Functional Anatomy of the
outside of the spinal cord and brain. Peripheral Nervous System
Failure of the PNS to transmit afferent, efferent, or
autonomic data completely or in a timely manner The PNS includes 12 pairs of cranial nerves and 31
because of illness or trauma is called peripheral neu- pairs of spinal nerves and their terminal branches (Fig.
ropathy. Peripheral neuropathy results in possible loss 1-1). The cranial nerves, spinal nerves, and terminal
of homeostasis in all corporal systems. Specific neuro- branches are called peripheral nerves. Each spinal
logical illness or trauma leads to impairment of par- nerve is connected to the spinal cord through a poste-
ticular functional units of the PNS, defining the scope rior root and an anterior root. The two roots combine
of impairment and the prognosis for recovery. Along within the bony intervertebral foramen to form the
with the broad picture of loss of homeostasis, periph- spinal nerve. The posterior roots contain fibers of
eral neuropathy may lead to functional impairments sensory neurons, and the anterior roots contain mainly
associated with mobility, balance, and activities of daily fibers of motor neurons. Immediately after the spinal
living. nerve exits the intervertebral foramen, it divides into
2560_Chapter 1_0001-0014.indd 2 3/16/2015 4:13:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 1 | The Anatomy and Physiology of the Peripheral Nerve 3
conductivity, the ability to conduct an electrical signal,
Cervical
plexus and excitability, the ability to generate and respond to
Cervical
nerves
stimuli. Most neurons consist of three principal parts:
Brachial
C1–C8 plexus
the cell body, the cell dendrites, and the axon. Each of
these is associated with specific neural functions.
Cervical
enlargement The Cell Body
The cell body, also known as the soma (Greek: soma,
Intercostal body) or perikaryon (Greek: peri, near, and karyon, nut
Thoracic nerves or kernel), may appear microscopically stellate, round,
nerves
T1–T12 oval, or pyramid-shaped, depending on the function of
the particular neuron (Fig. 1-3). The most striking
Lumbar feature of the cell body is the large number of projec-
enlargement tions or processes that either transmit or receive signals
from other cells. Each cell body has a large nucleus that
contains a nucleolus as well as additional organelles
Lumbar responsible for growth, production, and reproduction;
nerves
L1–L5
Lumbar these include, but are not limited to, the endoplasmic
plexus
reticulum, neurotubules, neurofilaments, Nissl bodies,
lysosomes, mitochondria, neurotubules, and Golgi
Sacral apparatuses. The neurotubules and neurofilaments are
nerves threadlike lipoprotein structures that extend through-
S1–S5 Sacral
plexus out the cell body and process of the neuron and run
parallel to the long axis of each process. Neurotubules
Coccygeal assist with intracellular transport of chemicals and
nerve
C0 proteins responsible for cell growth, repair, and con-
Cauda equina ductivity. Neurofilaments provide the scaffolding or
endoskeleton of the neuron. Alzheimer disease and
senile dementia of Alzheimer type (SDAT) are histo-
Figure 1-1 The peripheral nervous system (PNS) consists
logically defined by “tangles” of the neurofilaments and
of 12 pairs of cranial nerves and 31 pairs of spinal nerves,
neurotubules in the neurons of the cerebral cortex.3
which are each denoted by their respective exit from the
spinal cord, through the intervertebral foramen, and to Dendrites
their designated destinations (C1–C8, T1–T12, L1–L5,
Dendrites and the axon are the two processes extend-
S1–S5). Although there are only seven cerebral vertebrae,
ing from the cell body. Dendrites (Greek: dendron, tree)
there are eight spinal nerves within the cervical region of
are short, threadlike branches that conduct nerve
the spine because the first cervical nerve exits superiorly
impulses toward the cell body. Typical peripheral nerve
to C1.
cell bodies have up to 300 dendrites.4
The structure and branching of a neuron’s dendrites
as well as the availability and variation in voltage gate
two branches: the dorsal ramus and the ventral ramus. ion channels allow neurons to conduct nerve impulses.5
The dorsal rami typically innervate muscles, skin, and Voltage-gated ion channels are a class of transmem-
sensory receptors of the head, neck, and back. The brane ion channels that are activated by changes in
ventral rami often unite to form plexus (Greek: plexi, electrical potential differences near the ion channels.
to plait or intertwine) before innervating the ventral These channels strongly influence how the nerve cell
structures. Proximal peripheral nerves, also known as responds to the input from other neurons, particularly
nerve trunks, consist of blood vessels, connective tissue, neurons that input weakly. This integration is both
and fascicles. The fascicles contain the functional neural “temporal”—involving the summation of stimuli that
element, the neuron. Each of these elements is struc- arrive in rapid succession—and “spatial”—entailing the
turally and strategically required for nerve function, aggregation of excitatory and inhibitory inputs from
and each element is susceptible to chemotoxic, com- separate branches.6
pressive, and tensile injuries of particular type, force, Dendrites were previously believed to convey stimu-
and duration (Fig. 1-2). lation passively. The passive cable theory describes how
Nerve cells, or neurons (Greek: neuron, nerve), are voltage changes at a particular location on a dendrite
cells that are specially adapted in size and shape to transmit this electrical signal through a system of con-
transmit electrical impulses over relatively long dis- verging dendrite segments of different diameters,
tances. Neurons have two unique characteristics: lengths, and electrical properties. Based on passive
2560_Chapter 1_0001-0014.indd 3 3/16/2015 4:13:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
C1
C2
C3
Cervical
C4
nerves
C5 Dorsal Dorsal horn
C6 Grey matter
C7 Central
White matter canal
C8
T1
T2 Ventral Mixed
T3 horn peripheral
nerve
T4 Ventral
T5
T6
Thoratic T7
nerves
T8
T9
T10
T11
T12
L1
L2
Lumbar
L3
nerves
L4
L5 Figure 1-2 Spinal nerves of the peripheral nervous

system are connected to the spinal cord by anterior
roots (sensory neurons) and posterior roots (motor
neurons) within the intervertebral foramen. On
S1
Sacral exiting the spinal column, the spinal nerve splits
S2 into dorsal and ventral rami. Dorsal rami typically
nerves
S3
innervate muscles, skin, and sensory receptors of
S4 the head, neck, and back. Ventral rami often unite
S5 to form plexus, such as the brachial plexus before
innervating ventral structures.
cable theory, one can track how changes in dendritic tree. This retrograde conduction, known as back propa-
morphology of a neuron change the membrane voltage gating action potentials, depolarizes the dendritic tree
at the soma and thus how variation in dendrite struc- and provides a crucial component toward synapse
ture impacts the overall output characteristics as well modulation, long-term propagation, and postsynaptic
as function of the neuron.7,8 potentiation. In addition, a train of back propagating
Although passive cable theory offers clues regarding action potentials artificially generated at the soma can
input propagation and specificity along dendrite seg- induce a calcium action potential at the dendritic ini-
ments, dendrite membranes are host to a variety of tiation zone in certain types of neurons. Whether or
proteins that, along with the cable theory, assist with not this mechanism is of physiological or structural
amplification or attenuation of synaptic input. In importance remains an open question.10
addition, various calcium, potassium, and sodium ion
channels all assist with synaptic modulation. It is Axon
hypothesized that each of these channel types has its Most PNS cell bodies have one axon. The axon is a
own biological characteristics relevant to synaptic narrow process that extends from the cell body and
modulation.9 varies in length depending on the cell from 1 mm to
An important feature of dendrites that is allowed by greater than 1 m. Axons, as they travel centrally or
their active voltage-gated conductances is their ability peripherally, are often grouped together into bundles,
to send action potentials retrograde into the dendritic called fascicles. Axons run an undulating course within
2560_Chapter 1_0001-0014.indd 4 3/16/2015 4:13:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
the fascicles to allow for elongation with articular hillock. The axon may have side branches, called col-
movements. Functionally, the axon carries the action lateral branches, that exit the main axon. The axon and
potential between the cell body and a nerve, gland, collateral branches end in a spray of tiny branches
receptor, or motor unit. The axon originates from a called telodendria. The branches of the telodendria
cone-shaped projection on the cell body called the axon have small bulbs called synaptic boutons. A synapse
(Greek: synapsis, connection) is where the synaptic
Neuron boutons interact with the plasma membrane of another
neuron (Table 1-1).
Dendrites The cytoplasm of an axon is called axoplasm, and
(receivers) the plasma membrane is known as the axolemma. The
axon may be covered with a laminated shell of myelin
(Greek: myelos, marrow), which forms an external
Cell body sheathing called the myelin sheath. A nerve fiber with
a myelin sheath is called a myelinated nerve; a nerve
fiber without a myelinated sheath is called an unmy-
Nucleus elinated nerve. The peripheral nerve myelin sheath is
called a neurolemmocyte or Schwann cell. The outer-
most layer of the Schwann cell is the neurolemma
(Greek: neuri, nerve; lemma, husk). The myelin sheath
is classically interrupted at regular intervals by depres-
sions or gaps called neurofibral nodes or, more famil-
Node of
Ranvier
iarly, nodes of Ranvier. The distance between nodes is
Myelin sheath
the internodal distance. The myelin is absent at each
(insulating fatty layer internode. Myelin appears to increase conduction
that speeds transmission) velocity. Myelinated nerves conduct at velocities
Axon between 3 m/sec and 120 m/sec; unmyelinated fibers
(the conducting conduct at velocities of 0.7 to 2.3 m/sec (Fig. 1-4).
fiber)
Schwann’s cells
(they make Endoneurium
the myelin) The innermost layer of connective tissue in a peripheral
nerve, forming an interstitial layer around each indi-
Axon terminals vidual fiber outside the neurolemma, is the endoneu-
(transmitters)
rium. The matrix of tightly bound connective tissue
Figure 1-3 The primary structures that make up also contains capillaries, mast cells, Schwann cells, and
neurological tissue consist of the cell bodies, dendrites, and fibroblasts. There is no evidence of lymphatic tissue
axon fibers. Via saltatory conduction, cell bodies transmit being present. The endoneurium appears to have two
electrical signals down axon fibers to neighboring neurons primary functions: to maintain the endoneurial space
to communicate sensory or motor information. and fluid pressure and to sustain a homeostatic nerve
Table 1-1 Mammalian Nerve Fiber Type With Functional and Velocity Characteristics
Fiber Type Function Fiber Diameter Conduction Velocity Spike Duration Absolute Refractory
(μm) (m/sec) (m/sec) Period
Aα Somatic motor, proprioception 12–20 70–120
Aβ Rapidly adapting touch, pressure 5–12 30–70 0.4–0.5 0.4–1
Aλ Motor to muscle spindle 3–6 5–30
Aδ Nociception, cold, touch 2–5.0 12–30
B Preganglionic autonomic <3 3–15 1.2 1.2
C dorsal root Nociception, temperature 5–12 0.5–2 2 2
C sympathetic Postganglionic sympathetic 0.3–1.3 0.7–2.3 2 2
Data from Millesi H, Zöch G, Reihsner R. Mechanical properties of peripheral nerves. Clin Orthop. 1995;314:76–83; Sunderland S. Nerve Injuries
and Their Repair. A Critical Appraisal. Melbourne: Churchill Livingstone; 1991; Kaye AH. Classification of nerve injuries. In: Essential Neurosurgery.
London: Churchill Livingstone; 1991:333–334; Seddon H. Nerve injuries. Med Bull (Ann Arbor). 1965;31:4–10; and Sunderland S. The anatomy
and physiology of nerve injury. Muscle Nerve. 1990;13:771–784.
2560_Chapter 1_0001-0014.indd 5 3/16/2015 4:13:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Dendrites endoneurial environment via the blood-nerve
barrier and the perineurial diffusion barrier
(discussed later in this chapter).11–14
Nucleus Along with the aforementioned longitudinal colla-
gen fibers, and in contrast to the endoneurium, there
is a rich circular and angled matrix of collagen fibers
that protects nerves from “kinking” as they bend in
Cell body
response to articular joint flexion, extension, and rota-
tory maneuvers.14
Epineurium
Myelinated
region of The epineurium, a loose connective tissue, is subdi-
axon vided into internal and external components. The inter-
Unmyelinated
Axon nal epineurium is the base collagenous tissue that
region of axon
physically separates the fascicles. It provides two basic
Schwann
Schwann cell nucleus cell functions: assisting the external epineurium in provid-
Neurilemmal sheath nucleus ing truncal protection from compressive forces and,
more importantly, facilitating gliding between the fas-
Node of cicles. As nerves stretch and rebound, fascicles glide
Axon Ranvier
within the base collagen matrix of the nerve trunk. As
Myelinated an anisotropic structure, the peripheral nerve’s content
axon of internal epineurium, as a percentage of nerve diam-
Myelin
eter, varies along the course of the nerve. There is a
Neurofibrils Myelin direct relationship between diameter of the nerve and
the volume of epineurium.15 There is also greater epi-
Figure 1-4 Produced by Schwann cells throughout the neurium content in peripheral nerves as they cross
nervous system, myelin serves as insulation for electrical joints and as they pass under or near fibrous bands such
signals that pass along axonal fibers. Increased myelination as the flexor retinaculum at the wrist.14 The external
of axons increases the nerve fiber diameter and the epineurium surrounds the nerve trunk and provides
conduction velocity of the information. Many different protection from compressive and tensile forces. The
types of myelinated or unmyelinated nerves exist that serve spinal nerves are devoid of epineurium and perineu-
multiple purposes within the nervous system. rium, and they may be more susceptible to chronic and
acute compressive trauma compared with their termi-
nal branches.11
fiber environment. A slightly positive pressure is main- Mesoneurium
tained within the endoneurial tube. Researchers report
an association between endoneurial tube disruption The mesoneurium is the outermost tissue around
and neural disorganization including neuronal forma- peripheral nerve trunks. It is classified as loose and
tion and aberrant synapses.11,12 The collagen within the areolar and is the entry portal for many of the arteries
endoneurial tube is primarily longitudinal, evidence that supply the vasa nervorum, the highly anastomos-
that supports the fact that the endoneurium assists ing venous and arterial network within the nerve
with protecting the neuron from tensile challenges.11 trunk.13 The function of the mesoneurium is not fully
understood; however, the “slippery” surface of the
Perineurium mesoneurium limits frictional forces with longitudinal
Each fascicle is surrounded by a layered sheath known and side-to-side movement of the nerve trunk against
as the perineurium. The perineurium has three primary local structures. There may also be substantial “sliding”
functions: motion between the mesoneurium and the external
epineurium facilitating the extensibility characteristics
● To protect the endoneurial tubes from normal of nerve. The mesoneurium may also provide limited
articular movement patterns through the tensile protection from compressive and tensile forces impact-
and compressive resisted characteristics of the ing the nerve trunk.13–16
basement collagen fibers and elastin.
● To protect the endoneurial tube from external Vascular Components
trauma. Although possessing only 2% of the body’s mass, the
● To serve as a molecular diffusion barrier, CNS and PNS at any given time use 20% of the oxygen
keeping certain potentially neurotoxic carried by the bloodstream.17 In contrast to some of the
compounds away from the perineurial and less metabolically active tissues such as bone or skin,
2560_Chapter 1_0001-0014.indd 6 3/16/2015 4:13:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
nerve tissue is especially sensitive to changes to the epineurial blood vessels to the endoneurial vessels. For
partial pressure of oxygen (PO2).18 The circulatory example, radioactive isotopes and dyes do not cross the
system within peripheral nerves is known as the vasa barrier. Glucose molecules may cross the barrier,
nervorum. The blood supply to individual nerves and whereas specific nonsteroidal medications do not cross
nerve trunks is well understood. A combination of the barrier. Despite the efficient selectivity of the
extrinsic and intrinsic arteries and capillaries provides barrier, it is easily broken with acute or chronic nerve
a redundant supply of oxygenated blood via a rich trauma. The perineurial diffusion barrier is facilitated
system of anastomoses. Large external vessels approach by junctions in the perineurial lamellae called “tight
a peripheral nerve and run parallel along a section of cells.” With increased intrafascicular pressure, the
the course. At intervals, small vessels divide off the “tight cells” function to limit bidirectional vascular
main artery and enter the epineurial layer. They imme- transport to and from the fascicle. The limitation of
diately divide into ascending and descending branches bidirectional blood flow is hypothesized to occur to
and anastomose with vessels in the perineurium and limit the passage of potential local toxins and proin-
endoneurium. Small-vessel injury rarely results in nerve flammatory mediators to the neuron.22
ischemia.19 Typically, large-vessel injury, such as from
atherosclerosis, precipitates nerve ischemia and loss of Neuron Type: Directional Transport
conduction. In addition, the extrinsic supply of blood PNS neurons may be defined by the direction of trans-
to the nerves is designed to allow vessel laxity, which port of the action potentials. Neurons transporting
allows uninterrupted blood flow to the nerve in action potentials from cortical centers to the periphery
extremes of articular posture.17 Feeder vessels tend to or away from the CNS to effector end organs (typically
enter the nerve at locations where there is intrinsically glands, muscles, and blood vessels) are called efferent
little tension with movement, again ensuring uninter- or motor neurons. Neurons transporting action poten-
rupted blood flow.19 The intrinsic or intraneural blood tial from the periphery to central locations are called
supply is extremely redundant (Fig. 1-5). afferent or sensory neurons. The afferent neuron cell
A slightly positive tissue pressure exists within the bodies are located in ganglia that are situated close the
fascicle compared with outside the fascicle (+1.5; ± CNS. The distal ends of these neurons are typically
0.7 mm Hg).20,21 Research has shown a “mushrooming” sensory receptors that are responsive to light touch,
of fascicular contents if the perineurium is cut.21 The pain, sharp, dull, hot, and cold sensations; joint position
relatively positive fascicular pressure is needed to main- and movement; and muscle length and state of con-
tain a homeostatic endoneurial environment, facilitat- traction. Most interneurons rest in the CNS, but a few
ing blood flow, nerve conduction, and axoplasmic are distributed between the CNS and the PNS. They
flow. The blood-nerve barrier and the perineurial dif- carry impulses from sensory neurons to motor neurons,
fusion barrier maintain the endoneurial environment. process incoming neural information, and disseminate
The selective barrier limits toxins crossing from the afferent information to more than one higher center.
Epineurium Biomechanics of Peripheral Nerves

Vasa Nerve fiber Perineurial
Nerve partition/
Adipose nervorum fasicle Peripheral nerves are remarkably complex tissues that
septum
tissue not only conduct electrical impulses and communicate
chemically and electrically with neighboring nerves,
muscles, glands, and receptors but also must bend and
stretch to accommodate the movement and potential
passive insufficiency that may occur as a result of move-
ments of limb and muscle. To achieve this extensibility,
nerves have a complex structure consisting of bundles
of neurons packed into fascicles and surrounded by
Endoneurium Perineurim
multiple connective tissue layers. Both neural and con-
nective tissue elements of nerve trunks are tethered
Multiple Single proximally at the spinal cord and have numerous
fascicles fascicle
branch points allowing neurons from a single nerve
Figure 1-5 The vasa nervorum is the circulatory system trunk to synapse with various target organs. Despite
within peripheral nerves that, along with intrinsic and some physiological connections—primarily vascular—
extrinsic arteries and capillaries, forms an anastomosis to surrounding tissue, nerve trunks are largely free to
around the nerve. Anastomoses form redundant blood glide along their length within their tissue bed. Fre-
supply pathways that perfuse nervous tissue and help quent intraneural and extraneural anastomoses with
prevent tissue ischemia. blood vessels and a highly redundant vasa nervorum
2560_Chapter 1_0001-0014.indd 7 3/16/2015 4:13:14 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
of maximal elongation of a typical peripheral nerve
before reaching the elastic limit are 20% or greater over
resting length.12 Elongation greater than 20% over
resting length may lead to decreased perfusion, vascular
congestion, and macrophage/monocyte migration
leading to intraneural and extraneural fibrosis.24,25 The
development of fibrosis eventually leads to a reduction
in nerve stretch capability. With severe tensile-induced
trauma, the nerve fibers in the nerve under tension
appear to rupture before their endoneurial tubes and
perineurium.26 From a regeneration sense, this is an
important finding. In relatively minor injuries, regen-
erating axons may have intact pathways to follow
during their regrowth toward the periphery.
Figure 1-6 Normal functioning of peripheral nerves allows Identifying the maximum tension that nerves can
fibers to stretch and slide freely on surrounding tissue. withstand and maintain appropriate conduction prop-
However, after surgical repair or secondary to intraneural erties and understanding the origin of their mechanical
fibrosis, limb movement can result in localized increases in resilience are of great functional importance to improv-
tension—leading to a loss of range of motion and ing the outcome of surgical nerve gap repairs. As a
function, increased pain and fibrotic tissue, or potential sutured nerve is stretched, the perineurium tightens. As
neuropathy. To test the status of the median nerve, the a result, the endoneurial fluid pressure is increased, and
patient is placed in a position such that the median nerve the intraneural capillary bed may become compressed.
is at its longest length. Severe pain or loss of sensation At a certain stage of tensile force, the microcirculation
along the course of the nerve may indicate a possible system fails to function. In studies involving a rat
lesion to the median nerve. model, an elongation of just 8% over resting length
leads to impaired venule flow.14 As elongation increases
above 8%, arteriole flow begins to diminish, stopping
help prevent nerve ischemia with moderated move- entirely at 15% over resting length.27 The slow growth
ment patterns and minimal compressive forces. of space-occupying compressive and tensile lesions of
However, the nerve routes through the limbs tend to nerves, such as caused by a schwannoma, allows for the
lie outside the plane of movement of the joints making development of sufficient vascular collateralization
some degree of length change inevitable during normal often to prohibit ischemic nerve injury.
function. When this ability of nerves to stretch and Action potential quality under loading is influenced
glide freely is compromised by adhesion to surrounding by viscoelasticity. It is dependent on many factors,
tissues, for example, after surgical repair or via intra- including the anatomical construction (ratio of each
neural fibrosis secondary to repeated trauma and resul- type of connective tissue to each other and the ratio of
tant inflammation, limb movement can result in connective versus neural tissue) of the nerve at the
localized increases in tension leading to loss of range point of tension or compression and the internal and
of motion and function, increases in pain and fibrosis, external nerve environment, such as the presence of
and potentially symptomatic neuropathy (Fig. 1-6).20,23 potentially neurotoxic chemicals or medication con-
Nerves are strong structures with considerable centrations (e.g., lead, chemotherapeutic drugs, or an
tensile strength. Numerous studies have been under- elevated blood glucose concentration). Additional
taken to define the limits to which nerves can be environmental concerns that are potentially impacted
stretched before their function, structure, and vascular by environmental forces are the internal neuron fluid
system are compromised. The obvious difficulty in pressure maintained by the impermeable perineurial
attempting to make generic rules about stretch and the membrane28; the outer-inner nerve trunk layer integ-
resultant impact on nerve strain and blood flow is the rity29; the number, location within the nerve trunk, and
fact that nerve is an anisotropic structure. As a nerve arrangement of fascicles30; and the molecular structural
progresses along its length, the ratio of neural to con- elements of the extracellular matrix such as collagen
nective tissue and the individual percentage composi- and elastin.25,27,31
tion of each connective tissue type constantly change. Although understanding the upper limit to which
However, it is known that straining nerves beyond the nerves can be safely stretched is such an important
physiological tension range can alter their conduction clinical variable, the investigation of stretch properties
properties20,21 and intraneural blood flow14 with com- within normal physiological conditions and articular
pressive and tensile forces resulting in permanent loss movements has been limited because of the anisotropic
of function. This process is currently understood as a property of nerve. In particular, scant information is
breakdown in integrity of the nerve fiber.22 Estimates available on whether increased nerve tension and
2560_Chapter 1_0001-0014.indd 8 3/16/2015 4:13:14 PM

Process CyanProcess
YellowProcess Black
compression generated by limb flexion, extension, rota- the peripheral nerve, the more severe the motor, sensory,
tion, and distraction is focused around the joint or is and autonomic signs and symptoms become. Many
dissipated along the full length of the nerve. The aniso- classification systems have been developed to aid in
tropic property of the nerve trunk is often discussed in diagnosis, prognosis, and intervention strategy.33–37
terms of the contribution of different concentric struc- Most systems attempt to correlate the degree of injury
tural and neural layers to overall mechanical behavior; with symptoms, pathology, and prognosis. In 1943,
however, little is known about the presence and impact Seddon35,36 introduced a classification of nerve injuries
of the longitudinal variation in these structures. For based on three main types of nerve fiber injury and
example, variations in the number of fascicles have whether there is continuity of the nerve (Table 1-2).
been observed along the length of human nerves,24,30 The three types of nerve injuries are neurapraxia, ax-
and increased fasciculation has been suggested to be a onotmesis, and neurotmesis. In 1951, Sunderland37
protective feature of nerves crossing joints.32 Such expanded Seddon’s classification by two and developed
structural variation could possibly result in localized an ordinal rather than categorical scale (Table 1-3).
areas of damage and localized areas of sparing with
tensile forces. Seddon Classification
Neurapraxia is the mildest form of peripheral nerve
injury and results from a temporary interruption in the
Classification and Pathophysiology conduction of the impulse distally along the nerve fiber,
without a loss of axonal continuity. The endoneurium,
of Peripheral Nerve Injury perineurium, and epineurium remain intact. The inter-
ruption is physiological and not structural. Recovery
A peripheral nerve contains sensory fibers, motor takes place from seconds to weeks without wallerian
fibers, autonomic fibers, and mixed (sensorimotor) degeneration occurring. This is probably a biochemical
fibers. Typically, the more severe the trauma impacting lesion caused by concussive or shocklike injuries to the
Table 1-2 Seddon Classification of Peripheral Neuropathy

Neurapraxia Axonotmesis Neurotmesis
Pathology
Anatomical continuity Preserved Preserved May be lost
encapsulating structures
Primary damage None Nerve fiber Complete interruption of nerve
interruption fiber and encapsulating structures
Clinical
Motor paralysis None, partial, or complete Complete Complete
Muscle atrophy None Progressive Progressive
Sensory loss None, partial, or complete Complete Complete
Autonomic loss Usually spared Complete Complete
Visual fasciculations No Yes Yes
Electroneuromyography Findings
Reaction to degeneration Present Present Present
Nerve conduction distal to lesion Preserved Absent Absent
Motor unit action potentials Absent Absent Absent
Fibrillation Rare Present Present
Recovery
Surgical repair required Never Occasionally Essential
Rate of recovery Minute to weeks 1–3 mm/day 1–3 mm/day after repair
Quality of recovery Perfect Occasionally perfect Rarely perfect
Data from Sunderland S. Nerve Injuries and Their Repair. A Critical Appraisal. Melbourne: Churchill Livingstone; 1991; Seddon H. Advances in
nerve repair. Triangle. 1968;8:252–259; and Seddon H. Nerve injuries. Med Bull (Ann Arbor). 1965;31:4–10.
2560_Chapter 1_0001-0014.indd 9 3/16/2015 4:13:14 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Table 1-3 Sunderland Classification System of Peripheral Neuropathy

Sunderland Terminology Equivalent Seddon Terminology Descriptors
First-degree Neurapraxia • Nerve in continuity
• Compression or ischemic etiology
• Local conduction block
• Spontaneous recovery in minutes to weeks
Second-degree Axonotmesis • Injury to axon
• Encapsulating structures intact
• Wallerian degeneration occurs
• Recovery 1–3 mm/day
• Spontaneous recovery length dependent
Third-degree Neurotmesis • Injury to axon
• Endoneurium disrupted; epineurium and perineurium intact
• Surgical neurolysis may benefit healing
• Spontaneous recovery length dependent
Fourth-degree Neurotmesis • Injury to axon
• Disruption in all encapsulating elements but with intact epineurium
• Requires surgical intervention for recovery
Fifth-degree Neurotmesis • Injury to axon
• Disruption in all encapsulating elements
• Requires surgical intervention for recovery
Data from Sunderland S, Lavarack JO, Ray LJ. The caliber of nerve fibers in human cutaneous nerves. J Comp Neurol. 1949;91:87–101;
Sunderland S. Anatomical features of nerve trunks in relation to nerve injury and nerve repair. Clin Neurosurg. 1970;17:38–62; Sunderland S.
Nerve Injuries and Their Repair. A Critical Appraisal. Melbourne: Churchill Livingstone; 1991; Seddon H. Advances in nerve repair. Triangle.
1968;8:252–259; and Seddon H. Nerve injuries. Med Bull (Ann Arbor). 1965;31:4–10.
fiber as a result of compressive, tensile, or chemotoxic regeneration to occur, this loss must first be overcome.
insult. There is frequently greater involvement of motor The regeneration fibers must cross the injury site and
than sensory function with autonomic function typi- regenerate through the proximal or retrograde area of
cally being retained. Symptoms typically occur distal degeneration. This may require several weeks. The
to the lesion. Nerve conduction examination is normal regenerating neuron progresses down the distal site,
in the proximal segment and the distal segment but not such as the wrist or hand. Proximal lesions may grow
across the area of injury. Electroneuromyography (using distally 2 to 3 mm per day; distal lesions may grow only
an electromyography [EMG] needle) examination is 1.5 mm per day.36 Various factors, including local rest
typically benign with no fibrillation potential or posi- versus activity, neural tension, and the presence or
tive sharp waves noted (Fig. 1-7).35 absence of neurotoxic chemicals such as chemotherapy
Axonotmesis involves a loss of the relative continu- medications or elevated blood glucose concentrations,
ity of the axon and its covering of myelin but preserva- may impact regeneration times.36–38 Surgical interven-
tion of the connective tissue framework of the nerve tion sometimes is required to assist healing secondary
(the encapsulating Schwann cells, epineurium, and to extraneural and intraneural scarring.
perineurium are preserved). Because axonal continuity Neurotmesis, as described by Seddon,35 is the most
is lost, wallerian degeneration occurs. EMG examina- severe lesion involving peripheral nerves based on the
tion performed 2 to 3 weeks after injury shows fibril- quality and quantity of trauma to the nerve and the
lations and denervation potentials in musculature distal impact of the damage on regeneration and recovery.
to the injury site. Loss in myotomal and dermatomal Etiologies include laceration, a severe compression, or
distributions is more complete and pervasive with ax- tension injury affecting the nerve. Similar to axono-
onotmesis than with neurapraxia, and recovery occurs tmesis, the axon is injured. In addition, the encapsulat-
only through regeneration of the axons, which requires ing connective tissues lose their continuity. Denervation
substantial time. Axonotmesis is usually the result of changes recorded by EMG are the same as changes
a more severe crush, traction, or contusion injury seen with axonometric injury. There is usually a com-
than neurapraxia. There is usually an element of retro- plete loss of motor, sensory, and autonomic function.
grade proximal degeneration of the axon, and for However, partial function may be retained if there is
2560_Chapter 1_0001-0014.indd 10 3/16/2015 4:13:14 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Temporary interuption conduction
Neuropraxia
• Injury – Mild
• Recovery: Myelin
spontaneous Axon Endoneurium
in minutes to weeks
Spontaneous degeneration/regeneration
Axonotmesis
• Injury – Severe
• Regeneration
(immediately)
• Recovery:
spontaneous
in months to years
Transection of nerve
Neurotmesis
• Injury
• Degeneration
• Neuroma
formation
• Recovery: only with surgical
interaction. Recovery may take
months to years.
Figure 1-7 The presence and extent of peripheral neuropathy can be classified using Seddon’s
terminology. Recognizing pathological, clinical, recovery-based, and electromyogram-observed
characteristics of neurapraxia, axonotmesis, and neurotmesis helps in the proper diagnosis of
peripheral neuropathy.
dual myotomal or dermatomal innervation through an Wallerian Degeneration

undamaged nerve. Neurotmesis always requires surgi- Wallerian degeneration is a process that follows ax-
cal intervention if there is to be hope of regeneration. onotmetic and neurotmetic (Sunderland classification
Sunderland’s classification divides Seddon’s neurot- second- to fifth-degree) peripheral nerve injuries.33
metic lesion into degrees.33 When a nerve fiber is cut, crushed, severely tensioned,
or chemotoxically damaged resulting in axonotmesis or
Sunderland Classification neurotmesis, the axon, separated from the neuron’s cell
In 1951, Sunderland expanded Seddon’s classification nucleus, degenerates. Wallerian degeneration occurs
to five degrees of peripheral nerve injury.33,34,37 A first- after axonal injury in both the PNS and the CNS. It
degree, or, as per the later nomenclature, class 1, nerve occurs in the axon stump distal to a site of injury and
lesion is analogous to Seddon’s definition of neura- usually begins within 24 to 36 hours of a lesion.38,39
praxia. Second-degree, or class 2, corresponds to Sed- Before degeneration, distal axon stumps tend to remain
don’s definition of axonotmesis. Sunderland’s third-, electrically excitable. After injury, the axonal skeleton
fourth-, and fifth-degree lesions, all termed class 3, disintegrates, and the axonal membrane breaks apart.
correspond to Seddon’s neurotmetic nerve injury. The axonal degeneration is followed by degradation of
Third-degree describes a nerve fiber interruption. There the myelin sheath and infiltration by macrophages. The
is a disruption of the endoneurium, but the epineurium macrophages, accompanied by Schwann cells, serve to
and perineurium remain intact. Recovery from a third- clear the debris from the degeneration.39–42
degree injury is possible but rare without surgical inter- Although most injury responses include a calcium
vention. Sunderland’s fourth-degree lesion results in influx signaling to promote resealing of severed parts,
only the epineurium remaining intact; all encapsulated axonal injuries initially lead to acute axonal degen-
structures are disrupted. A fifth-degree lesion is a com- eration (AAD), which is rapid separation of the
plete transection of the peripheral nerve. Fourth- and proximal part and distal ends within 30 minutes of
fifth-degree injuries require surgical intervention. injury.42 Degeneration follows with swelling of the
2560_Chapter 1_0001-0014.indd 11 3/16/2015 4:13:14 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
axolemma eventually leading to a beadlike formation. sufficient quantities of the essential axonal protein
The process takes roughly 24 hours in the PNS and NmnAT2 is a key initiating event.49,50
longer in the CNS. The signaling pathways leading
to axolemma degeneration are currently unknown.
However, research has shown that this AAD process
is calcium-independent.43,44
Granular disintegration of the axonal cytoskeleton
and inner organelles occurs after axolemma degrada-
CASE STUDY
tion. Early changes include accumulation of mitochon- Jack is an 18-year-old high school football player. He
dria in the paranodal regions at the site of injury. The plays the position of running back. On a play late in
endoplasmic reticulum degrades, and mitochondria the first half, the quarterback handed the ball off to
swell up and eventually disintegrate. The depolymer- Jack who sprinted toward the sidelines, attempting to
ization of microtubules occurs and is soon followed by turn up field for a large gain. As he was making his
degradation of the neurofilaments and other cytoskel- turn, the defender launched himself at Jack attempting
eton components. The rate of degradation depends on to tackle him. The defender’s helmet hit Jack square in
the type of injury and is also slower in the CNS than the left upper arm. Jack felt an immediate stabbing
in the PNS. Another factor that affects degradation pain in his upper arm as he tumbled out of bounds.
rate is the diameter of the axon—larger axons require He could not lift his left arm above 90°.
a longer time for the cytoskeleton to degrade and take Jack was taken to the emergency department, and
a longer time to degenerate.45 x-rays were taken. The x-rays revealed no fractures or
The neurolemma of the nerve fiber does not degen- dislocations of left humerus, scapula, clavicle, or
erate and remains as a hollow tube. Within 96 hours cervical spine. On physical examination at the
of the injury, the proximal end of the nerve fiber sends hospital, Jack still could not lift the arm greater than
out sprouts toward those tubes, and these sprouts are 90°, and a small patch, approximately 4 cm × 4 cm
attracted by growth factors produced by Schwann cells of skin over the left middle deltoid, was unable to
within the tubes. If a sprout reaches the tube, it grows perceive tactile sensation.
into it and advances about 1 mm per day, eventually Jack’s left arm was placed in a sling, and he was
reaching and reinnervating the target tissue. If the referred to an orthopedist. The next day when Jack
sprouts cannot reach the tube—for instance, because saw the orthopedist, the clinical signs were unchanged.
the gap is too wide or scar tissue has formed—surgery The orthopedist referred Jack for an
can help to guide the sprouts into the tubes.45,46 electroneuromyogram to be performed in 2 weeks and
Schwann cells have been observed to recruit macro- for physical therapy.
phages via the release of proinflammatory cytokines
and chemokines after sensing of axonal injury. The
Case Study Questions
recruitment of macrophages helps improve the clearing
rate of myelin debris. The resident macrophages present 1. Based on the history given, the most likely etiology
in the nerves release further chemokines and cytokines for Jack’s clinical signs is which tissue?
to attract further macrophages. The degenerating nerve a. Bone
also produces macrophage chemotactic molecules. b. Muscle
Another source of macrophage recruitment factors is c. Tendon
serum.46 d. Nerve
Murinson et al.47 observed that nonmyelinated or
2. Based on the history given, which of the following
myelinated Schwann cells in contact with an injured
nerves is most likely involved?
axon enter the cell cycle, leading to proliferation.
a. Axillary
Observed time duration for Schwann cell divisions
b. Radial
were approximately 3 days after injury.48 Schwann cells
c. Median
emit growth factors that attract new axonal sprouts
d. Ulnar
growing from the proximal stump after complete
degeneration of the injured distal stump. This leads to 3. If the electroneuromyography study found positive
possible reinnervation of the target cell or organ. sharp waves and denervation potentials in the
However, the reinnervation is not perfect because mis- deltoid, and considering the mechanism of injury, the
leading can occur during reinnervation of the proximal most likely Seddon classification for this injury would
axons to target cells.47,48 be which of the following?
A related process known as “wallerian-like degen- a. Neurapraxia
eration” occurs in many neurodegenerative diseases, b. Neurotmesis
especially diseases where axonal transport is impaired. c. Axonotmesis
Primary culture studies suggest that a failure to deliver d. Bruising
2560_Chapter 1_0001-0014.indd 12 3/16/2015 4:13:14 PM

Process CyanProcess
YellowProcess Black
4. The electroneuromyography examination will most 16. Sarikcioglu L, Demirel BM, Demir N, Yildirim FB,
likely reveal similar findings with which muscle in Demirtop A, Oguz N. Morphological and ultrastructural
analysis of the watershed zones after stripping of the vasa
addition to the deltoid? nervorum. Int J Neurosci. 2008;118:1145–1155.
a. Biceps 17. Myers RR, Powell HC, Heckman HM, Costello ML, Katz J.
b. Teres minor Biophysical and pathological effects of cryogenic nerve lesion.
c. Extensor carpi ulnaris Ann Neurol. 1981;10:478–485.
d. Subscapularis 18. Powell HC, Costello ML, Myers RR. Endoneurial fluid
pressure in experimental models of diabetic neuropathy.
5. If the diagnosis is an axonotmetic lesion of the left J Neuropathol Exp Neurol. 1981;40:613–624.
axillary nerve, what would be the expected 19. Dunn JS, Wyburn GM. The anatomy of the blood brain
barrier: A review. Scott Med J. 1972;17:21–36.
approximate length of time for healing? 20. Hunter JM. Recurrent carpal tunnel syndrome, epineurial
a. 2 days fibrous fixation, and traction neuropathy. Hand Clin.
b. 1 week 1991;7:491–504.
c. 2 months 21. Kwan MK, Wall EJ, Massie J, Garfin SR. Strain, stress and
d. 2 years stretch of peripheral nerve. Rabbit experiments in vitro and
in vivo. Acta Orthop Scand. 1992;63:267–272.
22. Haftek J. Stretch injury of peripheral nerve. Acute effects of
stretching on rabbit nerve. J Bone Joint Surg Br.
1970;52:354–365.
References 23. Millesi H, Zöch G, Reihsner R. Mechanical properties of
1. Sunderland S. A classification of peripheral nerve injuries peripheral nerves. Clin Orthop. 1995;314:76–83.
producing loss of function. Brain. 1951;74:491–516. 24. Sunderland S, Lavarack JO, Ray LJ. The caliber of nerve
2. Millesi H, Zöch G, Rath T. The gliding apparatus of fibers in human cutaneous nerves. J Comp Neurol.
peripheral nerve and its clinical significance. Ann Hand Surg. 1949;91:87–101.
1990;9:87–97. 25. Rydevik BL, Kwan MK, Myers RR, Brown RA, Triggs KJ,
3. Yamamoto T, Hirano A. Nucleus raphe dorsalis in Woo SL, Garfin SR. An in vitro mechanical and histological
Alzheimer’s disease: Neurofibrillary tangles and loss of large study of acute stretching on rabbit tibial nerve. J Orthop Res.
neurons Ann Neurol. 1985;17:573–577. 1990;8:694–701.
4. Glees P. Observations on the connective tissue sheaths of 26. Sunderland S. Anatomical features of nerve trunks in relation
peripheral nerves. J Anat. 1942;77:153–159. to nerve injury and nerve repair. Clin Neurosurg. 1970;
5. Jordan PC. Semimicroscopic modeling of permeation 17:38–62.
energetics in ion channels. IEEE Trans Nanobioscience. 27. Miyamoto Y. Experimental studies on repair for peripheral
2005;4:94–101. nerves—relationship between circulatory disturbances at
6. Ahern CA, Horn R. Specificity of charge carrying residues in nerve stumps caused by tension at the suture line and axon
the voltage sensor of potassium channels. J Gen Physiol. regeneration. Hiroshima J Med Sci. 1979;28:87–93.
2004;123:204–216. 28. Low P, Marchand G, Knox F, Dyck PJ. Measurement of
7. Rall W, Agmon-Snir H. Cable theory for dendritic neurons. endoneurial fluid pressure with polyethylene matrix capsules.
In: Koch C, Segev I, eds. Methods in Neuronal Modeling. Brain Res. 1977;122:373–377.
2nd ed. Cambridge, MA: MIT Press; 1998:27–92. 29. Walbeehm ET, Afoke A, de Wit T, Holman F, Hovius SE,
8. Jack JJB, Noble D, Tsien RW. Electric Current Flow in Brown RA. Mechanical functioning of peripheral nerves:
Excitable Cells. Oxford: Calderon Press; 1975. Linkage with the mushrooming effect. Cell Tissue Res.
9. Rall W. Cable theory for neurons. In: Kandel ER, Brookhardt 2004;316:115–121.
JM, Mountcastle VB, eds. Handbook of Physiology: The Nervous 30. Sunderland S, Bradley KC. Stress-strain phenomena in
System. Vol 1. Baltimore: Williams & Wilkins; 1977:39–98. human peripheral nerve trunks. Brain. 1961;84:102–119.
10. Hartzell HC, Kuffler SW, Yoshikami D. Post-synaptic 31. Wall EJ, Massie JB, Kwan MK, Rydevik BL, Myers RR,
potentiation: Interaction between quanta of acetylcholine at Garfin SR. Experimental stretch neuropathy. Changes in
the skeletal neuromuscular synapse. J Physiol. nerve conduction under tension. J Bone Joint Surg Br.
1975;251:427–463. 1992;74:126–129.
11. Tassler PL, Dellon AL, Canoun C. Identification of elastic 32. Sunderland S. Nerve Injuries and Their Repair. A Critical
fibers in the peripheral nerve. J Hand Surg (Br Eur). Appraisal. Melbourne: Churchill Livingstone; 1991.
1994;19B:48–54. 33. Kaye AH. Classification of nerve injuries. In: Essential
12. Sunderland S, Bradley KC. The cross-sectional area of Neurosurgery. London: Churchill Livingstone; 1991:333–334.
peripheral nerve trunks devoted to nerve fibres. Brain. 34. Greenberg MS. Injury classification system. In: Handbook of
1949;72:428–449. Neurosurgery. 3rd ed. Lakeland, FL: Greenberg Graphics;
13. Driscoll PJ, Glasby MA, Lawson GM. An in vivo study of 1994:411–412.
peripheral nerves in continuity: Biomechanical and 35. Seddon H. Advances in nerve repair. Triangle. 1968;
physiological responses to elongation. J Orthop Res. 8:252–259.
2002;20:370–375. 36. Seddon H. Nerve injuries. Med Bull (Ann Arbor). 1965;
14. Lundborg G, Rydevik B. Effects of stretching the tibial nerve 31:4–10.
of the rabbit. A preliminary study of the intraneural 37. Sunderland S. The anatomy and physiology of nerve injury.
circulation and the barrier function of the perineurium. J Bone Muscle Nerve. 1990;13:771–784.
Joint Surg Br. 1973;55:390–401. 38. Wall EJ, Kwan MK, Rydevik BL, Woo SL, Garfin SR. Stress
15. Salvador-Sanz JF, Torres AN, Calpena FT, Sanz-Gimenez- relaxation of a peripheral nerve. J Hand Surg (Am).
Rico JR, Lopez SC, Barraquer EL. Anatomical study of the 1991;16:859–863.
cutaneous perforator arteries and vascularisation of the biceps 39. Coleman MP, Freeman MF. Wallerian degeneration WldS
femoris muscle. Br J Plast Surg. 2005;58(8):1079-1085. and Nmnat. Ann Rev Neurosci. 2010; 33:245–267.
2560_Chapter 1_0001-0014.indd 13 3/16/2015 4:13:14 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
40. Liu HM, Yang LH, Yang YJ. Schwann cell properties: 3. 46. Vargas ME, Singh SJ, Barres BA. Why is Wallerian
C-fos expression, bFGF production, phagocytosis and degeneration so slow in the CNS? Soc Neurosci. 2005;Program
proliferation during Wallerian degeneration. J Neuropathol No. 439.2
Exp Neurol. 1995;54:487–496. 47. Murinson BB, Archer DR, Li Y, Griffin JW. Degeneration of
41. Coleman MP, Conforti M, Buckmaster AE, Tarlton A, myelinated efferent fibers prompts mitosis in Remak
Ewing RM, Brown MC, et al. An 85-kb tandem triplication Schwann cells of uninjured C-fiber afferents. J Neurosc.
in the slow wallerian degeneration (Wlds) mouse. Proc Natl 2005;25:1179–1187.
Acad Sci U S A. 1998;95:9985–9990. 48. Liu HM, Yang LH, Yang YJ. Schwann cell properties: 3.
42. Kerschensteiner M, Schwab ME, Lichtman JW, Misgeld T. C-fos expression, bFGF production, phagocytosis and
In vivo imaging of axonal degeneration and regeneration in proliferation during Wallerian degeneration. J Neuropathol
the injured spinal cord. Nat Med. 2005;11:572–577. Exp Neurol. 1995;54:487–496.
43. Vargas ME, Barres BA. Why is wallerian degeneration in the 49. Coleman MP, Freeman MF. Wallerian degeneration, WldS
CNS so slow. Annu Rev Neurosci. 2007;30:153–179. and Nmnat. Annu Rev Neurosci. 2010;33:245–267.
44. Zimmerman UP, Schlaepfer WW. Multiple forms of 50. Gilley J, Coleman MP. Endogenous Nmnat2 is an essential
Ca-activated protease from rat brain and muscle. J Biol Chem. survival factor for maintenance of healthy axons. PLOS Biol.
1984;259:3210–3218. 2010;8:27–47.
45. Guertin AD, Zhang DP, Mak KS, Alberta JA, Kim HA.
Microanatomy of axon/glial signaling during Wallerian
degeneration. J Neurosci. 2005;25:3478–3487.
2560_Chapter 1_0001-0014.indd 14 3/16/2015 4:13:14 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 2
The Biomechanics of
“Seize the moment of excited curiosity on any subject to solve your doubts;
for if you let it pass, the desire may never return and you may remain
forever in ignorance.”
—WILLIAM WIRT (1772–1834)
Objectives
• Develop an evidenced-based evaluative algorithm for the assessment of suspected peripheral neuropathy.
• Develop sufficient knowledge of the cognitive components of the peripheral neuropathy evaluation to enable
the development of the psychomotor components of the evaluation.
• Identify important signs and symptoms that may relate to peripheral neuropathy.
Key Terms
• Epineurium
• Lower motor neuron
• Mesoneurium
• Perineurium
• Vasa nervorum
Introduction Efferent, Afferent, and

The peripheral nerve is a functional component of an Autonomic Pathways
intricate intrinsic conduction system that serves as a
mediator for bidirectional transport between the central The bidirectional movement of action potentials along
nervous system (CNS) and the peripheral nervous the peripheral nerve serves as afferent pathways, effer-
system (PNS). Peripheral nerves extend to distal tissues ent pathways, and autonomic pathways. The afferent
to aid in system regulation, homeostasis, repair, func- pathways are primarily sensory. A wide spectrum of
tion, learning, posture, reproduction, mobility, and pro- sensory modalities exist: vision, hearing, smell, taste,
tection. For descriptive purposes, the peripheral nerves rotational acceleration, linear acceleration, verticality,
may be classified via segmental and peripheral nomen- touch, pressure, warmth, cold, pain, proprioception,
clature according to their function and site of CNS kinesthesia, muscle length, muscle tension, arterial
origin: The cranial nerves emerge from the base of the blood pressure, central venous pressure, inflation of
brain, the spinal nerves originate in the spinal cord, and lung, temperature of blood in the head, osmotic pres-
the autonomic system is intimately associated with the sure of plasma, and arteriovenous blood glucose differ-
cranial and spinal nerves but differs in function and in ence. A loss or diminished function in any of these
the details of structure and distribution. modalities may have devastating homeostatic and
15
2560_Chapter 2_0015-0024.indd 15 3/16/2015 4:13:56 PM

Process CyanProcess
YellowProcess Black
functional consequences. The signs and symptoms of The second type of motor (efferent) system that may
loss are directly related to the specific sensory modality be affected by injury to the peripheral nerve is the
that is compromised. Positive signs of sensory nerve autonomic nervous system (ANS). The ANS is a divi-
injury are typically described as sensations additive to sion of the PNS that is distributed to glands and
normal perception, such as burning, formication, tin- smooth muscle. Most functions of the ANS are carried
gling, hyperalgesia, pain, or a feeling of temperature out below the level of conscious input. The cell body of
change. Negative signs are a reduction in sensory per- the preganglionic or presynaptic neuron, located within
ception, such as numbness, ataxia, orthostasis, loss of the CNS, sends out its axon to one of the outlying
visual acuity and tracking, deafness, movement degra- ganglia from where the postganglionic axon extends to
dation, and dyskinesia. In higher level animals, there is its terminal distribution. Cell bodies of presynaptic
a redundancy of sensory modalities that allows for con- sympathetic nerve fibers lie in the ventral horn from
tinued, albeit diminished, function with the loss of cord segments T1–L3. Postganglionic fibers arise from
specific sensory modalities. An example of redundancy the sympathetic trunk. The ANS is divided into the
in humans is balance. The visual, vestibular, and senso- sympathetic and parasympathetic systems. With injury
rimotor systems all contribute to balance control. to a peripheral nerve, signs and symptoms related to
Functional performance with loss of one or more of an autonomic dysfunction may appear. These include,
these systems has been extensively studied.1–6 but are not limited to, aberrations in vascular flow, skin
The efferent pathways are primarily motoric. Motion moisture, and hair growth; trophic changes; nail loss;
is a fundamental property required for most organisms and delayed wound healing.
to maintain life. Unicellular organisms achieve motion
through accessory organs such as cilia and flagella.
High-level, multicellular organisms have a much more Structure of the Peripheral Nerve
complicated motoric system requiring a complex
variety and interaction of afferent and efferent neural The nerve fiber represents the greatly elongated process
tissues, in addition to both contractile and noncontrac- of a nerve cell whose body lies within the CNS or one
tile connective tissues. These elements work in harmony of the outlying ganglia. The nerve cell, or neuron, con-
to provide coordinated movement patterns and sists of a cell body and all of its processes. The nucleus-
locomotion. containing cell body is the vital center controlling the
The lower motor neuron, also called the final metabolic activity of the cell. Injury to the nerve cell
common pathway, consists of a cell body located in the or fiber results in degeneration of the distal segment
anterior gray column of the spinal cord or the brain- (Fig. 2-1).
stem and an axon passing via the peripheral nerve to A typical spinal motor neuron has many processes,
the motor end plates within the muscles. It is called called dendrites, which extend out from the cell body
the final common pathway because it is acted on by the and arborize. The spinal neuron has a long axon that
rubrospinal, olivospinal, vestibulospinal, corticospinal, originates from an area of the cell body called the axon
and tectospinal tracts and their associated interseg- hillock. Near its origin, the typical motor neuron devel-
mental and intrasegmental reflex neurons and is the ops a sheath of myelin composed of a multilayered,
ultimate pathway through which neural impulses lipoprotein complex. The myelin sheath envelops the
reach the muscle. Motor disturbances associated with axon except at its ending and at periodic constrictions,
peripheral nerve injury may consist of weakness, dys-
kinesia, obligatory posturing, and tonal change. Such
disturbances may be the result of lesions within the
Epineurium
muscle, at the myoneural junction, within the periph- Perineurium
eral nerve, or within the CNS. The specific nature Fascicle
of the patient’s presenting signs and symptoms may Endoneurium
lead an astute clinician to the specific etiology of
the observed weakness and serve to guide future
Axon
intervention.
The predominant clinical sign of a lower motor
neuron injury is weakness. The spectrum of involve- Myelin
sheath Blood
ment ranges from subclinical weakness to complete vessels
paralysis. Movement disorders such as dyskinesia may
also occur. Depending on the site of injury, one muscle
or a patterned group of muscles may be involved. Typi-
cally, there is a concurrent decrease in or absent deep Figure 2-1 Cross-sectional representation of a peripheral
tendon reflex. Myalgias, or muscle-specific pain and nerve. Note the complexity of the protective elements
cramping, may also accompany the weakness. surrounding the functional components.
2560_Chapter 2_0015-0024.indd 16 3/16/2015 4:13:57 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 2 | The Biomechanics of Peripheral Nerve Injury 17
Nucleus
Myelin sheath Dendrites
Nucleus Dendrites
Axon
Cell Nissl
body bodies Golgi
Endoplasmic apparatus
reticulum
Axon
Myelin
Axon
Mitochondria
Figure 2-2 Representation of a myelinated peripheral Microtubules Cell body
neuron. The myelin sheath protects the neuron and and neurofibrils
increases the velocity of conduction.
Figure 2-3 Schematic representation of a cell body.
which are approximately 1 mm apart. This arrangement Connective tissue components
of the myelin sheath is known as the nodes of Ranvier.
The discontinuity in the myelin sheath allows rapid Mesoneurium External
impulse conduction as the action potential leaps from epineurium
Nerve Axon
one node to the next. In nonmyelinated fibers, one Internal
fiber Myelin
Schwann cell is associated with many axons, whereas epineurium
in the myelinated fibers, the ratio is one Schwann cell
per axon. Unmyelinated axons are enveloped by Fascicle
Schwann cell cytoplasm and plasma membrane but
do not have the multiple wrappings of Schwann Perineurium
Endoneurium
cell plasma membranes similar to myelinated axons
(Fig. 2-2).
The dendritic zone is the term used to refer to the
receptor membrane of a neuron. The axon is a single
elongated protoplasmic neuronal process with the spe-
cialized function of moving impulses away from the
dendritic zone and ends in numerous terminal buttons
or axon telodendra. Typically, the cell body is located
at the dendritic zone, but it may occasionally be located
Figure 2-4 Cross-sectional representation of a peripheral
within the axon or attached to the side of the axon
nerve focusing on the connective tissue components.
(Fig. 2-3).
The nerve fiber, which is the functional component
of the peripheral nerve, is surrounded by connective
tissues similar to those found in muscle or ligament. likely provides friction relief between the nerve and
Together, these connective tissues provide protection adjacent structures such as bone, ligament, or muscle.9–11
to the nerve fibers through their combined abilities to There may also be some sliding of the fascicles inside
resist compressive and tensile forces and, in some cases, the mesoneurium.10,11
chemotoxic elements. Axons and the bundled nerve The epineurium is the outermost connective tissue
fibers, called fascicles, run an undulated course through of the fascicles.12 Collagen bundles in the epineurium
the peripheral nerve that serves to resist tensile forces are arranged longitudinally. External epineurium pro-
(Fig. 2-4). In the peripheral nerve, fascicle number is vides a definitive sheath among the fascicles.13 Internal
greater proximally than distally.7,8 epineurium helps keep the fascicles apart and assists
The mesoneurium is a loose areolar tissue that sur- gliding between fascicles, a necessary adjunct to move-
rounds peripheral nerve trunks. The function of the ment, especially when the nerve is asked to move about
mesoneurium is unclear; however, the mesoneurium a joint.14 The epineurium also supports a well-developed
2560_Chapter 2_0015-0024.indd 17 3/16/2015 4:13:57 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
intrinsic circulation. A lymphatic capillary network Interoceptors are sensitive to changes within visceral
exists in the epineurium, drained by channels accom- tissues and blood vessels.
panying the arteries of the nerve trunk.15 The epineu-
rial layer includes bundles of type I and type III
collagen fibrils and elastic fibers as well as fibroblasts,
mast cells, and fat cells.14,15
Peripheral Nerve Response
A thin sheath, called the perineurium, surrounds to Injury
bundles of nerve fibers; microscopically, the perineu-
rium is lamellar in design with up to 15 layers present The inflammatory acute phase response to peripheral
in the larger nerve trunks.16 Lundborg17–21 described nerve tissue injury is thoroughly explained in Chapter
the role of the perineurium as protecting the contents 3. From a clinical point of view, there are three basic
of the endoneural tubes, acting as mechanical barriers ways nerve fibers may respond to injury. These catego-
to external forces, and serving as a diffusion barrier by ries of nerve injury were initially described by
keeping certain substances out of the intrafascicular Seddon26,27 and expanded on by Sunderland.28–39
environment. With a high ratio of elastin to collagen, Nerves are not homogeneous structures, but rather are
the perineurium is thought to prevent neural damage considered to be anisotropic with varying diameter,
from tensile forces more so than protecting the nerve length, level of myelination, blood supply, percentages
from compressive forces.22 Lundborg et al.20,21 described of surrounding protective tissue types, and distance
the perineurium as having elastin fibers running paral- from the cell body.40–42 Most nerve injuries result in a
lel to the nerve and, to a lesser extent, oblique fibers combination of the three primary categories of nerve
running at an angle to the longitudinal fibers. It is injury: neurapraxia, neurotmesis, and axonotmesis.30–32
hypothesized that the oblique fibers may assist in the Neurapraxia is defined as a segmental block of
prevention of kinking of the nerve as it flexes at the axonal conduction. The nerve can conduct an action
interior surfaces of joints. potential above and below the blockage but not across
The endoneurium, with its longitudinally arranged the blockage. The nerve is in continuity but does not
collagen fibers, is the membrane associated with the function. This phenomenon is due to a focal region of
neural tube and serves to establish a constant nerve demyelination of the nerve. The conduction block is
fiber environment by maintaining a slightly positive due to a physiological process without histological
pressure around the neuron.20 The endoneurium con- change. No wallerian degeneration is present in neura-
sists of fibroblasts, capillaries, mast cells, and Schwann praxia.33 Etiologies include mild blunt trauma, pro-
cells.15 Cutaneous nerves have a greater percentage of longed mild compression, repetitive strain, and stretch.
endoneurium than motor nerves; this is due to the Stimulation proximal to the injury often fails to produce
extra protection a cutaneous nerve requires because of a muscle contraction; however, stimulation distal to the
its more superficial location.16,17 injury provokes a muscle contraction. Neurapraxia
The blood supply of the PNS is called the vasa typically affects larger, myelinated fibers, and fine fibers
nervorum. Vessels extrinsic to the nerve supply feed innervating pain and autonomic function are often
arteries to the multiple neural layers. Once inside the spared. Recovery is usually uncomplicated and can
nerve, there is a rich anastomotic intrinsic blood supply. occur minutes to months after injury.30–32
The redundant blood supply to the nerve, necessary Axonotmesis is defined as a loss of continuity of the
because of the high metabolic demands of neural nerve axon with maintenance of the continuity of the
tissue23 and the mobility of the PNS,24,25 provides for connective sheathes. Axonotmesis leads to wallerian
excellent perfusion even with significant intrinsic arte- degeneration of the distal part of the nerve. Electro-
riole or extrinsic artery injury. The intrinsic arteriole myography (EMG) performed 2 to 3 weeks after injury
system is quite extensive, linking the mesoneurium, shows fibrillations and denervation potentials in the
endoneurium, and perineurium. Intraneural blood musculature distal to the injury site32 with a concomi-
vessels have autonomic innervation25 that most likely tant normal response in muscles proximal to the injury
allows for an adjustable blood supply required for the site. Loss of motor and sensory function is typically
functional demands of the nerve. more advanced than that observed with neurapraxia.
Various mammalian receptor and effector neurons Recovery occurs only through regeneration of the axon.
are associated with the PNS, which allow for the The etiology of axonotmesis is similar to the etiology
appreciation of sensation. Specialized cells for detect- of neurapraxia with the difference being the intensity
ing particular changes in the environment are called of the injury. There is usually an element of additional
receptors. Exteroceptors include receptors affected by retrograde nerve injury that must be overcome for
changes in the external environment. Teleceptors are complete recovery to occur.34 The rate of axonal regen-
receptors sensitive to distant stimuli. Proprioceptors eration varies according to the presence of comorbidi-
receive impulses directly from muscle spindles, Golgi ties (especially conditions implicated in the cause of
tendon organs, tendons, and periarticular tissues. the neuropathy), physical activity impacting the site
2560_Chapter 2_0015-0024.indd 18 3/16/2015 4:13:57 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
of the injury, and the distance between the injury site neural and nonneural connective tissue with composi-
and the CNS.36 Uncomplicated recovery rates range tion percentages varying with location along the nerve.
from 1.5 to 3 mm/day.30–32 In other words, forces that may result in severe injury
Neurotmesis, similar to axonotmesis, involves at one location along a peripheral nerve as measured
destruction of the axons. The connective supporting by functional examination, electroneuromyography
tissues of the axon are injured as well. Neurotmesis is examination, and biomarker examination may result in
caused by a severe contusion, stretch, avulsion, lacera- no measurable injury at a different location along the
tion, or chemotaxis. There are three basic types of same nerve. In addition, the location of extrinsic ancil-
neurotmesis36–38: The first type is a loss of the continu- lary structures such as bone, ligament, or retinaculum
ity of the axons and endoneurium with an intact peri- may predispose a particular nerve location to injury in
neurium; the second type is loss of the continuity of the the presence of mechanical insult.
axons, endoneurium, and perineurium with an intact Nerves are elastic structures with substantial ability
epineurium; and the third type is a complete transec- to resist tensile forces. However, the tensile demands
tion of the nerve. EMG examination of neurotmesis on peripheral nerve tissue often produce symptoms
typically reveals the same findings that are seen with before histological or gross changes within the nerve
axonotmetic injury.42 Stimulation above and below the and nerve sheaths.45 With the application of a small
injury site does not produce a muscle contraction. tensile force, the intact nerve reacts with characteristics
Spontaneous repair and recovery of function is much of an elastic material. As the linear limit is reached, the
less likely to occur compared with axonotmetic injury nerve fibers begin to rupture within the endoneurial
because the regeneration axons become entangled in a tube. The epineurium and perineurium begin to rupture
swirl of collagen and fibroblasts. This phenomenon with the ever-increasing load of force and there is
creates a disorganized, impenetrable repair site.34–36 disintegration of the elastic properties of the nerve, and
Regenerating axons may not function even after the nerve begins to react more like a plastic mate-
reaching distal end organs, unless they arrive close to rial.46,47 Sunderland31 estimated that the elastic limit of
their original sites.20 Cutaneous fibers do not cross a nerve is resting length plus 20% of resting length and
certain boundaries even for sensory reinnervation. In that maximum elongation before rupture is resting
addition, ulnar and median motor fibers that have length plus 30% resting length.
undergone regeneration have seldom been found to Sunderland31 reported that the median nerve at the
return to normal function.43 A similar inability to level of the wrist can withstand 70 to 220 N of traction
return to normal function is seen with the synkinesis before complete transection occurs. Ochs et al.48
of the muscles of facial expression after facial nerve reported an in vivo complete action potential block
injury.44,45 after 30 minutes of mild stretch with no apparent his-
Histological changes typically occur in the dener- tological changes. These authors postulated that the
vated muscles by the 3rd week. The muscle fibers kink, nerve block was due to vascular ischemia. Sunderland31
and their cross striations decrease. With continued believed that most of the tensile resistance of the nerve
denervation and lack of movement or extrinsic muscle is due to the perineurium. As long as the perineurium
stimulation, the entire muscle may be replaced by fat remains intact, the tensile resisting function of the
or fibrous tissue within 2 to 3 years.29,30 nerve remains sufficient.
Thomas and Olson49 assessed structural changes of
nerves during compression of peroneal nerves in rats.
The nerves were compressed at different pressures for
Physiological Basis for various amounts of time. The initial event of injury is
Biomechanical and Chemotoxic the expression of endoneurial fluid, followed by com-
pression of the outflow of axoplasm, and cleavage and
Nerve Injury displacement of myelin. Clinically, the fact that nerve
fiber rupture occurs before epineurial and perineurial
The three primary etiologies of neuropathy include rupture indicates that after a moderate stretch injury,
mechanical, ischemic, and metabolic factors. The forces the axons may have intact pathways to follow to their
that contribute to mechanical nerve injury typically respective end organ; this bodes well for the recovery
include any combination of compression, traction, fric- of normal functioning. As seen with chronic nerve
tion, shear, contusion, or laceration. Although consen- compression and tension, epineurial and perineurial
sus exists regarding the mechanical factors that result scarring may result in loss of nerve elasticity, resulting
in peripheral nerve injury, confusion remains regarding in early rupture. One must also question the effect of
the magnitude of the injurious force and the signifi- epineurial and perineurial scarring on blood flow. Such
cance of the injury. Much of this confusion relates scarring may limit oxygen and nutrient uptake by the
directly to the fact that peripheral nerve tissue is an neural components, leading to a worsening of the
anisotropic structure, consisting of a combination of injury and slower healing.
2560_Chapter 2_0015-0024.indd 19 3/16/2015 4:13:57 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Cornefjord et al.50 used a porcine model to investi- arteriole flow, and all arteriole flow stopped completely
gate the effects of chronic nerve compression. They at 15% greater than resting nerve length. Studies of the
identified inflammatory cells, nerve fiber damage, rat sciatic nerve demonstrated that blood flow is
endoneurial hyperemia, and bleeding at the site of reduced by 50% with a strain of 11% and 100% with a
compression. Barr et al.51 reported similar findings sustained strain of 15.7%.55 This strain may impact the
using a rat model of work relating nerve compression quality of repair after epineurial repair, especially if the
to musculoskeletal disorder. Typically, the relationship trauma resulted in a gap between the two ends. From
between force of compression and time of compression a therapist standpoint, care must be taken during
is significant in defining the extent of the nerve injury. passive stretching maneuvers that result in neurological
In a rat model, pressures of 30 mm Hg have been symptoms so as not to interfere with normal healing.
shown to cause functional loss and intraneural edema Long-term usage of handheld vibratory tools such
with epineurial scarring. It was found that 80 mm Hg as sanders, jackhammers, and dental tools can induce
of pressure immediately caused local ischemia. Pres- changes in peripheral circulation and tissue oxygen
sures of 80 mm Hg resulted in a fourfold increase of levels as well as sensory disturbances, motor weakness,
edema compared with 30 mm Hg of pressure, indicat- and injury.56,57 Loss of tactile and position sense may
ing a force/trauma relationship to injury. In addition, a be associated with long-term inflammatory changes
threefold increase in edema was found at both 80 mm within the median and ulnar nerves at the level of the
Hg and 30 mm Hg at 8 hours compared with 4 hours, wrist and hand.58,59 In addition, injuries to nearby
indicating a time/trauma relationship to injury. Such structures such as skin receptors and nerve cell bodies
an increase in endoneurial fluid pressure may interfere have been implicated as a potential cause for the
with intrafascicular capillary flow, constituting an sensory loss.60
important pathological mechanism for the develop- Space-occupying lesions may also result in signifi-
ment of compressive neuropathies. In a related study, cant biomechanical changes causing peripheral nerve
indirect compression at very high pressures caused less injury. Bony exostoses caused by trauma have been
of a functional loss than direct compression at much associated with neuropathy.61 Tumors may also impinge
lower pressures.50 This finding suggests that direct on peripheral nerves leading to injury.62 For instance,
compressive trauma to a nerve, as seen with bony Pancoast tumors of the lung may affect the lower
abnormalities from arthritis, compression from the trunks of the brachial plexus with initial symptoms of
transverse carpal tunnel ligament, or compressive forces tumor development being hand weakness and pares-
in response to local tumor infiltration, may have a thesias. Degenerative arthropathies caused by connec-
significant functional impact on nerve function. tive tissue disorders may result in elongation or
Compared with other tissues, peripheral nerves are compression neuropathies.
relatively resistant to direct or indirect ischemic injury In addition to biomechanical factors, a host of infec-
because of their abundant circulation. In addition to a tious and chemotoxic etiologies may result in direct or
rich intraneural network of vasa nervorum, there are indirect peripheral nerve injury. Diabetes mellitus is
extensive anastomotic connections with the nutrient the most common cause of peripheral neuropathy.
arterial supply to the nerve. Impulse propagation is Objective evidence of a sensory or motor neuropathy
directly related to local oxygen supply.52–54 For that is present in 59% of patients with type 2 diabetes and
reason, the vasa nervorum has a large reserve capacity. 66% of patients with type 1 diabetes.63 Although inter-
Large vessels approach the peripheral nerve along the vention is available for diabetic neuropathy, prevention
course of the nerve. These large vessels divide into of complications from diabetes through tight glycemic
ascending and descending branches. The ascending and control from the onset of diagnosis is the most effective
descending branches run longitudinally and frequently therapy.
join with vessels in the perineurium and endoneurium. Diabetes mellitus may result in focal and multifocal
Each fascicle has a longitudinally oriented capillary neuropathies. Nerves in patients with diabetes are more
plexus with loop formations at various levels. This rich susceptible to tensile and compressive forces than
anastomosis provides a wide safety margin in the pres- nerves in individuals without diabetes.63 Common
ence of a nerve transection. Lundborg et al.21 dissected nerve injuries include injuries to the third and sixth
the regional nutrient vessels from a 15-cm section of cranial nerves, the median nerve at the wrist, the ulnar
rabbit sciatic nerve and found no reduction in the nerve at the elbow, the lateral femoral cutaneous nerve,
intrafascicular blood flow. and the common peroneal nerve at the head of the
From a clinical standpoint, several scenarios of vas- fibula as well as truncal sensory neuropathy.
cular compromise may result in neuropathic signs and Diabetic polyneuropathy is a systemic complication
symptoms secondary to ischemia. Lundborg et al.19 usually beginning at the feet and moving proximally.
showed that elongation of just 8% of resting length The hands are often involved as well. Initially, there
results in impaired venular flow. At elongations greater may be complaints of severe paresthesias and pain,
than 8% of resting nerve length, there was impaired which eventually change to complaints of numbness.
2560_Chapter 2_0015-0024.indd 20 3/16/2015 4:13:57 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Often there are complaints of residual pain, which is the clinical examination of a patient with suspected
frequently paroxysmal in nature. Atrophy and intrinsic peripheral neuropathy cannot be overemphasized. An
motor weakness eventually develop. Autonomic symp- accurate clinical examination, correlated with relevant
toms and signs may appear as well, including cardio- radiographic, electrophysiological, and laboratory diag-
vascular manifestations such as postural hypotension nostic studies, allows the therapist to develop an accu-
or altered heart rate. Neurological impotence may also rate functional and clinical diagnosis. Only with the
occur, which consists of an atonic bladder, hyperhydro- correct clinical diagnosis can an effective intervention
sis or hypohydrosis of the skin, diarrhea, and gastric program be developed.
paresis. Richardson63 discussed three important clinical
signs as a prediction model for diagnosing diabetic References
peripheral neuropathy: an absent Achilles reflex even 1. Bucci MP, Le TT, Wiener-Vacher S, Bremond-Gignac D,
with Jendrassik maneuver, diminished vibratory sense, Bouet A, Kapoula Z. Poor postural stability in children with
and diminished proprioception. The etiology of focal vertigo and vergence abnormalities. Invest Ophthalmol Vis Sci.
and patterned neuropathy related to diabetes mellitus 2009;50(10):4678–4684.
2. Glasauer S, Schneider E, Jahn K, Strupp M, Brandt T. How
is unclear. The two major theories of nerve injury the eyes move the body. Neurology. 2005;65(8):1291–1293.
related to diabetes include metabolic and vascular 3. Guo X, Chau WW, Hui-Chan CW, Cheung CS, Tsang
abnormalities. The variability of glycemic control also WW, Cheng JC. Balance control in adolescents with
affects the development of neuropathy. idiopathic scoliosis and disturbed somatosensory function.
Guillain-Barré syndrome (GBS) typically consists Spine (Phila Pa 1976). 2006;31(14):E437–440.
4. Horak FB. Postural compensation for vestibular loss. Ann N Y
of a variety of disorders—all are acute PNS disorders Acad Sci. 2009;1164:76–81.
that are monophasic, with peak neurological deficit 5. Horlings CG, Kung UM, Honegger F, et al. Vestibular and
reached in most cases within 2 weeks—and is fre- proprioceptive influences on trunk movements during quiet
quently preceded by an antecedent event. Antecedent standing. Neuroscience. 2009;161(3):904–914.
events include acute infections such as with Epstein- 6. Swanenburg J, de Bruin ED, Favero K, Uebelhart D, Mulder
T. The reliability of postural balance measures in single and
Barr or influenza virus, systemic illnesses such as sar- dual tasking in elderly fallers and non-fallers. BMC
coidosis and Hodgkin disease, and other medically Musculoskelet Disord. 2008;9:162.
invasive conditions such as surgical procedures and 7. Grinberg Y, Schiefer MA, Tyler DJ, Gustafson KJ. Fascicular
immunizations. The diseases are presumed to be perineurium thickness, size, and position affect model
immune-mediated, have albuminocytological dissocia- predictions of neural excitation. IEEE Trans Neural Syst
Rehabil Eng. 2008;16(6):572–581.
tion in the spinal fluid, and are generally associated 8. Sekiya S, Suzuki R, Miyawaki M, Chiba S, Kumaki K.
with spontaneous recovery in most cases.64 In almost Formation and distribution of the sural nerve based on nerve
85% of patents, symptom presentation follows a pattern fascicle and nerve fiber analyses. Anat Sci Int. 2006;81(2):
of “classical” GBS.64,65 Initial symptoms are typically 84–91.
sensory dysfunction in the extremities with associated 9. Burge PD, Shewring DJ. Vascularized pedicle graft of the
lower trunk for reconstruction of the branchial plexus. J Hand
arthralgias and myalgias. The pain typically begins in Surg Br. 1995;20(2):215–217.
the low back and extends down the thighs to the calves. 10. Starkweather RJ, Neviaser RJ, Adams JP, Parsons DB. The
Weakness follows the sensory manifestations, begin- effect of devascularization on the regeneration of lacerated
ning in the legs and extending proximally to the trunk peripheral nerves: an experimental study. J Hand Surg Am.
and arms. Electrodiagnostic guidelines for the identi- 1978;3(2):163–167.
11. Tazaki K. Experimental study on the repair of peripheral
fication of peripheral nerve demyelination in patients nerve lesions—subacute compression neuropathy and
with GBS have been established.64 neurolysis. Nihon Seikeigeka Gakkai Zasshi. 1983;57(12):
Peripheral neuropathies may also be associated with 1821–1833.
connective tissue diseases, such as systemic lupus ery- 12. Biers SM, Brading AF. Nerve regeneration: might this be the
thematosus, scleroderma, rheumatoid arthritis and only solution for functional problems of the urinary tract?
Curr Opin Urol. 2003;13(6):495–500.
Sjögren syndrome. These connective tissue diseases 13. Dagum AB. Peripheral nerve regeneration, repair, and
represent a diverse group of disorders.66,67 A hallmark grafting. J Hand Ther. 1998;11(2):111–117.
is the related presentation of trigeminal sensory neu- 14. Johnson EO, Charchanti A, Soucacos PN. Nerve repair:
ropathy. This entity appears to be associated with a experimental and clinical evaluation of neurotrophic factors
lesion of the sensory ganglion of the fifth cranial nerve. in peripheral nerve regeneration. Injury. 2008;39(suppl 3):
S37–42.
Almost all of the connective tissue disorders are associ- 15. Kuntzer T, Antoine JC, Steck AJ. Clinical features and
ated with a length-dependent sensorimotor neuropa- pathophysiological basis of sensory neuronopathies
thy. Other, less common illnesses that may result in (ganglionopathies). Muscle Nerve. 2004;30(3):255–268.
peripheral neuropathy include HIV infection, familial 16. Elsohemy A, Butler R, Bain JR, Fahnestock M. Sensory
amyloid polyneuropathy, leprosy, organ transplanta- protection of rat muscle spindles following peripheral nerve
injury and reinnervation. Plast Reconstr Surg. 2009;124(6):
tion, cancer, and radiation-induced plexopathies. 1860–1868.
Because of the incredible spectrum of possible eti- 17. Kanda T. Peripheral neuropathy and blood-nerve barrier.
ologies and functional impairments, the importance of Rinsho Shinkeigaku. 2009;49(11):959–962.
2560_Chapter 2_0015-0024.indd 21 3/16/2015 4:13:57 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
18. Lundborg G. Regeneration after peripheral nerve injury—a 43. Charness ME, Ross MH, Shefner JM. Ulnar neuropathy and
biological and clinical problem. Lakartidningen. 1982; dystonic flexion of the fourth and fifth digits: clinical
79(20):2013–2017. correlation in musicians. Muscle Nerve. 1996;19(4):431–437.
19. Lundborg G, Dahlin LB, Danielsen N, et al. Nerve 44. Furlong R. Peripheral pain in the arm. Lond Clin Med J.
regeneration in silicone chambers: influence of gap length 1970;11(2):17–21.
and of distal stump components. Exp Neurol. 1982; 45. Davis DS, Anderson JB, Carson MG, Elkins CL, Stuckey
76(2):361–375. LB. Upper limb neural tension and seated slump tests: the
20. Lundborg G, Dahlin LB, Danielsen N, Nachemson AK. false positive rate among healthy young adults without
Tissue specificity in nerve regeneration. Scand J Plast Reconstr cervical or lumbar symptoms. J Man Manip Ther.
Surg. 1986;20(3):279–283. 2008;16(3):136–141.
21. Lundborg G, Gelberman RH, Minteer-Convery M, Lee YF, 46. Lundborg G, Rydevik B. Effects of stretching the tibial nerve
Hargens AR. Median nerve compression in the carpal of the rabbit. A preliminary study of the intraneural
tunnel—functional response to experimentally induced circulation and barrier function of the perineurium. J Bone
controlled pressure. J Hand Surg Am. 1982;7(3):252–259. Joint Surg Br. 1973;55:3390–3401.
22. Rigoard P, Lapierre F. Review of the peripheral nerve. 47. Haftek J. Stretch injury to peripheral nerves. Acute effects of
Neurochirurgie. 2009;55(4-5):360–374. stretching rabbit nerve. J Bone Joint Surg Br. 1970;52:354.
23. Salvador-Sanz JF, Torres AN, Calpena FT, Sanz-Gimenez- 48. Ochs S Pourmand R, Si K, Friedman RN. Stretch of
Rico JR, Lopez SC, Barraquer EL. Anatomical study of the mammalian nerve in vitro: effect on compound action
cutaneous perforator arteries and vascularisation of the biceps potential. J Peripher Nerv Syst. 2000;5:227–235.
femoris muscle. Br J Plast Surg. 2005;58(8):1079–1085. 49. Thomas PK, Olson Y. Microscopic anatomy and the function
24. Sarikcioglu L, Demirel BM, Demir N, Yildirim FB, of the connective tissue components of the peripheral nerve.
Demirtop A, Oguz N. Morphological and ultrastructural In: Dyck PJ, Thomas PK, Lambert EH, Bunge R, eds.
analysis of the watershed zones after stripping of the vasa Peripheral Neuropathy. 2nd ed. Philadelphia: Saunders;
nervorum. Int J Neurosci. 2008;118(8):1145–1155. 2001:128–143.
25. Yang HJ, Gil YC, Lee HY. Topographical anatomy of the 50. Cornefjord M, Sato K, Olmarker K, Rydevik B, Nordborg
transverse facial artery. Clin Anat. 2010;23(2):168–178. CA. Model for chronic nerve root compression studies.
26. Seddon H. Advances in nerve repair. Triangle. Presentation of a porcine model for controlled, slow-onset
1968;8(7):252–259. compression with analyses of anatomic aspects, compression
27. Lee SK, Wolfe SW. Peripheral nerve injury and repair. J Am onset rate, and morphological and neurophysiologic effects.
Acad Orthop Surg. 2000;8(4):243–252. Spine. 1997;22:946–957.
28. Leffert RD, Seddon H. Infraclavicular plexus injuries. J Bone 51. Barr AE, Amin M, Barbe MF. Dose response relationship
Joint Surg Br. 1965;31:9–22. between reach repetition and indicators of inflammation and
29. Seddon H. Nerve injuries. Med Bull (Ann Arbor). 1965; movement dysfunction in a rat model of work-related
31:4–10. musculoskeletal disorder. Proceedings of the Human Factors
30. Sunderland S. Anatomical features of nerve trunks in relation and Ergonomics Society 46th Annual Meeting; Baltimore,
to nerve injury and nerve repair. Clin Neurosurg. 1970; MD. September 30–October 4, 2002.
17:38–62. 52. Barbe MF, Safadi FF, Rivera-Nieves EI, Montara TE, Popoff
31. Sunderland S. A classification of peripheral nerve injuries SN, Barr AE. Expression of ED1, ED2, IL-1 and COX2 in
producing loss of function. Brain. 1951;74(4):491–516. bone and in the rat model of cumulative trauma disorder
32. Sunderland S. Rate of regeneration of sensory nerve fibers. (CTD). Journal of Bone and Mineral Research. 1999;14
Arch Neurol Psychiatry. 1947;58(1):1–6. (suppl.1): 1099–1115.
33. Sunderland S. Observations on the treatment of traumatic 53. Barr AE, Barbe MF. Inflammation reduces physiological
injuries of peripheral nerves. Br J Surg. 1947;35(137):36–42. tissue tolerance in the development of work-related
34. Sunderland S. Rate of regeneration in human peripheral musculoskeletal disorders. J Electromyogr Kinesiol.
nerves: analysis of the interval between injury and onset of 2004;14:77–85.
recovery. Arch Neurol Psychiatry. 1947;58(3):251–295. 54. Appenzeller O, Dithal KK, Dowan T, Burnstock G. The nerves
35. Sunderland S. The effect of rupture of the perineurium on the to blood vessels supplying blood nerves: the innervation of the
contained nerve-fibres. Brain. 1946;69:149–152. vasa nervorum. Brain Res 1984;304:383–386.
36. Mackinnon, SE, Jost S. FK506 promotes functional recovery 55. Ogata K, Naito M. Blood flow of the peripheral nerve effects
in crushed rat sciatic nerve. Muscle Nerve. 2000;4:633–640. of dissection, stretching and compression. J Hand Surg Br.
37. Sunderland S, Bradley KC. The cross-sectional area of 1986;18:149–155.
peripheral nerve trunks devoted to nerve fibers. Brain. 56. Lundborg G, Sollerman C, Stromberg T, Pyykko I, Rosen B.
1949;72(3):428–449. A new principle for assessment of vibrotactile sense in
38. Sunderland S, Lavarick J, Ray LJ. The caliber of nerve fibers vibration induced neuropathy. Scand J Work Environ Health.
in human cutaneous nerves. J Comp Neurol. 1987;13:375–379.
1949;91(1):87–101. 57. Farkkilii M. Grip force in vibration disease. Scand J Work
39. Sunderland S, Ray LJ. The intraneural topography of the Environ Health. 1978;4:159–166.
sciatic nerve and its popliteal divisions in man. Brain. 58. Rosen I, Stromberg T, Lundborg G. Neurophysiological
1948;71(pt 3):242–273. investigation of hands damaged by vibration: comparison
40. de Campos Vidal B, Mello ML, Caseiro-Filho AC, Godo C. with idiopathic carpal tunnel syndrome. Scand J Plast Reconstr
Anisotropic properties of the myelin sheath. Acta Histochem. Surg Hand Surg. 1993;27:209–216.
1980;66(1):32–39. 59. Hjortsberg U, Rosen I, Orback P, Lundborg G, Balough I.
41. Kuroiwa T, Ueki M, Chen Q, Ichinose S, Okeda R. Is the Finger receptor dysfunction in dental technicians exposed to
swelling in brain edema isotropic or anisotropic? Acta high frequency vibration. Scand J Work Environ Health.
Neurochir Suppl (Wien). 1994;60:155–157. 1989;15:339–344.
42. Shinar H, Seo Y, Navon G. Discrimination between the 60. McLain RF, Weinstein JN. Nuclear cleft in dorsal ganglion
different compartments in sciatic nerve by 2H double- neurons: a response to whole body vibration. J Comp Neurol.
quantum-filtered NMR. J Magn Reson. 1997;129(1):98–104. 1992;322:538–547.
2560_Chapter 2_0015-0024.indd 22 3/16/2015 4:13:57 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
61. Maquirriain J. Posterior ankle impingement syndrome. J Am Exchange/Sandoglobulin Guillain-Barré Syndrome Trial
Acad Orthop Surg. 2005;6:365–371. Group. Ann Neurol. 1998;44:780–788.
62. Carp S, Eddy L, Whitenack S. Complete excision of the 65. Zhang Q, Gu Z, Jiang J, et al. Orthostatic hypotension as a
lower trunk and C8 and T1 nerve roots in a patient with presenting symptom of the Guillain-Barre syndrome. Clin
Pancoast tumor with a resulting fully functional hand. Auton Res. 2010;20:209–210.
Physiother Res Int. 1997;1:51–55. 66. Cortes S, Chambers S, Jeronimo A, Isenberg D. Diabetes
63. Richardson JK. The clinical identification of peripheral mellitus complicating systemic lupus erythematosus—analysis
neuropathy among older persons. Arch Phys Med. of the UCL lupus cohort and review of the literature. Lupus.
2002;83:1553–1558. 2008;17(11):977–980.
64. Hadden RD, Cornblath DR, Hughes RA, et al. 67. Mellgren SI, Goransson LG, Omdal R. Primary Sjogren’s
Electrophysiological classification of Guillain-Barré syndrome associated neuropathy. Can J Neurol Sci.
syndrome: clinical associations and outcomes. Plasma 2007;34(3):280–287.
2560_Chapter 2_0015-0024.indd 23 3/16/2015 4:13:57 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
2560_Glossary_0347-0360.indd 360 3/17/2015 12:11:29 PM
Chapter 3
Pathophysiology of Peripheral
Nerve Injury
MARY F. BARBE, PHD, AND ANN E. BARR, DPT, PHD
“To kill an error is as good a service as, and sometimes even better than, the
establishing of a new truth or fact.”
—CHARLES DARWIN (1809–1882)
Objectives
• Relate the structural anatomy of the peripheral nerve to the etiologies of injury.
• Outline the role of cytokines in the inflammatory cascade of peripheral nerve injury.
• Define spinal cord sensitization as it relates to peripheral nerve injury.
• Define the local and systemic impact of peripheral nerve inflammation.
• Define “fibrosis” as it relates to peripheral nerve injury.
Key Terms
• Fibrosis
• Inflammation
• Neuropathy
• Overuse
Introduction Peripheral Nerve Damage and

Inflammation With Overuse
Neuropathies can result from mechanical trauma, such
as shear or compressive forces on the nerve, particularly Risk factors for the development of neuropathies
if repeated, and have been linked to the following risk include the performance of jobs characterized by repet-
factors: gender (female), advanced age, and reduced itiveness, forcefulness, or awkward postures.1,3,6,7 A rela-
fitness.1–4 Patients with median nerve neuropathy tionship between advancing age and susceptibility to
report symptoms such as pain in the hands and wrists other risk factors for neuropathies has also been
or fingers that may travel into the forearm, elbow, and reported,3,5,6,8 albeit one longitudinal study suggested
shoulder; paresthesias; numbness; and weakness.5 An that slowing of conduction in the median nerve occurs
objective diagnosis of median nerve dysfunction is naturally with increasing age.4 CTS has the highest
typically based on electrophysiological evidence of incidence rate of all occupation-related peripheral neu-
slowed median nerve conduction localized to the ropathies, with 10,780 combined cases reported to the
wrist, although the combination of electrodiagnostic U.S. Occupational Safety and Health Administration
findings and symptom characteristics is reported to in 2009 by private industry and state and local govern-
provide the most accurate diagnosis of carpal tunnel ment, resulting in a median of 21 lost workdays per case.
syndrome (CTS).2 The overall CTS incidence rate affects 1 in 10,000
25
2560_Chapter 3_0025-0034.indd 25 3/16/2015 4:14:34 PM

Process CyanProcess
YellowProcess Black
workers. Among female workers, CTS affects 1.5 in Table 3-1 Repetitive Task Group Parameters of the Barbe
10,000 workers, whereas among men, CTS affects 0.7
and Barr Rat Model of Overuse
in 10,000 workers. The incidence rate for CTS was
highest among workers 45 to 64 years old (1.5 in Group Target Reach Rate Actual Reach Rate Reach Force (% of
10,000) compared with rates of 0.3 in 10,000 for (Reaches/min) (Reaches/min) Maximum Pull Force)
workers 20 to 24 years old and 0.7 in 10,000 for workers
25 to 34 years old.6 In a 3-year prospective study of HRHF 8 12 60 ± 5
incidence in newly hired workers in computer-intensive MRHF 4 9.4 60 ± 5
jobs, computer operators older than age 30 showed an HRLF 8 12 15 ± 5
increased risk of developing neck, shoulder, arm, and
HRNF = 4 8 <5a
hand symptoms, such as pain, aching, burning, numb- MRNF
ness, or tingling.8 The most common disorder identified
by the study relative to this population was somatic pain LRNF 2 3.3 <5a
syndrome. Our laboratory has reported that patients HRHF = high repetition high force; MRHF = moderate repetition high
with upper extremity overuse injuries have increased force; HRLF = high repetition low force; HRNF = high repetition
frequency of local signs of pain and tenderness, periph- negligible force, redefined as MRNF based on the repetition rate;
LRNF = low repetition negligible force.
eral nerve irritation and weakness, and increased fre- a
The negligible force rats retrieved a 45-mg food pellet, which was
quency of these symptoms at multiple anatomical sites estimated to be less than 5% maximum pulling force.
(mean age = 45 years; age range, 19 to 74 years; 23 of
31 subjects older than 30). These findings correlated
with increased serum inflammatory cytokines.9,10 upper extremity. Also, Viikari-Juntura20,21 stated that
laboratory studies of animals examining the effects of
repetitive loading on tissue function may be extrapo-
Effects of Overuse on Nerves lated to human exposures and responses. We developed
in Human Subjects a unique rat model of voluntary repetitive reaching in
which rats can be trained to perform an upper limb
Human studies examining tissue biopsy specimens in repetitive hand and wrist–intensive task. Reach rate
patients with long-term chronic overuse syndromes and force levels used in our model, which are shown in
found evidence of nerve compression and injury, Table 3-1, were derived from investigations of indus-
inflammation, fibrosis, and degeneration. Freeland et trial workers by Silverstein et al.22,23 They defined risk
al.11 detected increased tenosynovium interleukin levels for repetitiveness to be high when reaching and
(IL)-6, an inflammatory cytokine, and increased serum grasping motions are performed faster than 30 sec/
malondialdehyde, a cell injury biomarker and a reactive cycle. Force is considered negligible to low if less than
oxygen species that initiates arachidonic acid metabo- 15% of maximum voluntary contraction (MVC) is
lism into products (e.g., prostaglandin E2), in patients required and high if it is greater than 50% of MVC.
with CTS. As mentioned earlier, increased inflamma- Our rat model of a paced reaching and grasping task
tory cytokines have also been detected in serum of may be generalized to humans in terms of both behav-
patients with early onset of moderate to severe symp- ioral and tissue responses for some types of physically
toms of upper limb overuse injury,9 presumably as a constrained and paced occupational tasks, as explained
result of increased cytokines in injured or inflamed further elsewhere.24,25 An example of such a paced task
tissues. However, despite numerous epidemiological would be packing, in which a worker repeatedly places
studies demonstrating a positive relationship between small objects presented on a conveyor belt into a
exposure to repetitive or forceful motion and the preva- package crate.
lence of overuse injuries,1 the mechanisms of patho- In our model, rats are placed into operant test cham-
physiology are incompletely understood. Animal bers for rodents with a portal located in one wall, as
models provide an opportunity to examine such tissue described previously.26–29 They are trained to perform a
effects at a much earlier time point and under experi- repetitive reaching task in which they reach through
mental conditions in which exposure can be controlled. the portal to grasp and retrieve a food pellet or to grasp
In an effort to understand the underlying mechanisms and isometrically pull a force handle that is attached
of these disorders, we and numerous other authors have to a force transducer, until a predetermined force
developed animal models of overuse injuries.2,12–17 threshold is reached and held for at least 50 msec. On
successful achievement of reach force and time criteria,
the rat releases the handle and retrieves a food pellet
Rat Model of Overuse Injury reward by mouth from a food trough. Using this appa-
ratus, the short-term effects (3 to 12 weeks) of a vol-
Whishaw18,19 quantified the similarities between rats untary low force task performed at low, moderate, or
and humans in targeted reach submovements of the high reach rates, with force requirements of low or high
2560_Chapter 3_0025-0034.indd 26 3/16/2015 4:14:35 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 3 | Pathophysiology of Peripheral Nerve Injury 27
(see details in Table 3-1), on sensorimotor behavior, demyelination and focal axonal swelling in the median
forelimb musculoskeletal and nerve tissues, spinal cord, nerve at the level of the wrist, suggestive of focal nerve
and brain have been determined.26–41 With regard to injury, in combination with increased extraneural con-
the peripheral nerve, the short-term effects of repeti- nective tissue and fibroblasts, suggestive of nerve fibro-
tive or forceful tasks on nerve pathophysiology have sis (Fig. 3-1A–D).27,28,35,36 These tissue changes were
been characterized, focusing on injury, inflammation, accompanied by a decrease in nerve conduction veloc-
inflammation-induced catabolic changes, and fibrotic ity (Fig. 3-1E) as well as changes in forepaw sensation
changes that might contribute to peripheral nerve and a decrease in grip strength, both significantly cor-
injury and degeneration. Inflammation-induced central relating with the declines in nerve conduction velocity
nervous system changes that might contribute to sen- (Fig. 3-2). This correlation strongly indicates that nerve
sorimotor behavior changes, such as the development compression injury is contributing to these behavioral
of pain behaviors as a result of spinal cord sensitization declines. The declines in median nerve conduction
or the development of reduced fine motor control as a were exposure-dependent with reductions ranging
result of sensory and motor cortex reorganization, have from 9% to 23% depending on the level of task inten-
also been investigated in our model. sity and the age of the rat, with greater losses with high
repetition high force tasks and in aged rats. Chronic
Nerve Injury, Inflammation, and Fibrosis inflammatory responses were also induced by task
Induced by Overuse performance, such as persistently increased macro-
A peripheral nerve injury mechanism has been identi- phages and proinflammatory cytokines in nerves and
fied in our overuse model. We have observed serum (Fig. 3-1F).26–28,30,31,40,42–44 Increased fibrotic
A B
Figure 3-1 Development of pathology in median nerve in a rat model of repetitive reaching and grasping. Rats
performed a high repetition low force (HRLF) task for 12 weeks. A, Median nerve of a normal control rat.
B, Median nerve from 12-week HRLF rat showing an increase in connective tissue (CT), indicative of nerve fibrosis.
C, Median nerve from 12-week HRLF rat showing increased inflammatory cells (arrows) within the median nerve.
D, Median nerve from 12-week HRLF rat showing presence of axonal swelling (arrow), indicative of nerve injury. Scale
bars = 5 μm. E, Bar graph showing decreased nerve conduction velocity (NCV) in median nerve of 12 week HRLF rats
compared with normal control rats (NC) and rats that underwent the initial training only (TR). *P < 0.05 compared
with NC. ***P < 0.001 compared with NC. F, Median nerve of 12-week HRLF rat showing presence of tumor necrosis
factor (TNF)-α, a key proinflammatory cytokine. (Used by permission from Elliott MB, Barr AE, Clark BD, Wade CK,
Barbe MF. Performance of a repetitive task by aged rats leads to median neuropathy and spinal cord inflammation with
associated sensorimotor declines. Neuroscience. 2010;170:929–941.)
2560_Chapter 3_0025-0034.indd 27 3/16/2015 4:14:35 PM

Process CyanProcess
YellowProcess Black
Reach Limb Grip Strength Reach Limb Cutaneous Sensitivity
500 6.5
6.0
Maximum grip strength (g)
Withdrawal threshold (g)

5.5
400 5.0
4.5
300 4.0
3.5
3.0
200 2.5
2.0
100 1.5
1.0
0.5
0 0.0
Naive 0 3 6 9 12 Naive 0 3 6 9 12
A HRLF task rats B HRLF
65 65
60 60
55 55
NCV (m/s)
NCV (m/s)
50 50
45 45
40 40
r ⫽ 0.70 r ⫽ 0.81
35 p ⬍ 0.0001 35 p ⬍ 0.0001
30 30
0 100 200 300 400 500 600 700 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5
C Grip strength (g) D Withdrawal threshold (g)
Figure 3-2 Development of grip strength declines and cutaneous hypersensitivity in the reach forelimbs of
rats performing a high repetition low force (HRLF) task for 12 weeks. A, Grip strength declines from naïve
levels with continued task performance. B, Cutaneous hypersensitivity develops, shown as a reduction in
Von Frey hair size (threshold) needed to induce a forelimb withdrawal response with continued task
performance. C, Scatterplot showing positive correlation between median nerve conduction velocity (NCV)
and grip strength by Spearman’s r test. D, Scatterplot showing positive correlation between median nerve
conduction velocity (NCV) and withdrawal threshold by Spearman’s r test. *P < 0.05 compared with NC.
**P < 0.01 compared with NC. (Used by permission from Elliott MB, Barr AE, Clark BD, Wade CK, Barbe
MF. Performance of a repetitive task by aged rats leads to median neuropathy and spinal cord inflammation with
associated sensorimotor declines. Neuroscience. 2010;170:929–941.)
tissue changes were observed in the synovial sheaths of phenotype alterations that favor substance P expres-
adjacent flexor digitorum tendons,38 which likely also sion.48,49 Schaible et al.50 described this type of afferent
contributed to compression of the median nerve. influx of excitatory transmitters into the spinal cord
dorsal horn after injury as the presynaptic component
Spinal Cord Neuroplastic Changes Induced of central sensitization. An increase in neurokinin 1, a
by Peripheral Nerve Inflammation key receptor for substance P, occurs in the postsynaptic
Several studies have found phenotypic changes in spinal cord neurons and most likely occurs as a response
dorsal root ganglion neurons in which the expression to the increased release of substance P from nociceptive
of proteins, receptors, neurotransmitters, and neuro- afferent terminals.49
trophic factors was altered.45,46 For example, substance It was not a surprise to see increased substance P
P increases in spinal cord dorsal horns following and neurokinin 1 in dorsal horns in cervical spinal cord
chronic constriction injury from partial nerve ligation, regions with performance of low and moderate repeti-
peripheral nerve injury, or inflammation.46,47 This tive tasks with or without high force (Fig. 3-3).34–37
increase may be due to inflammation-induced increases This neurochemical response was associated temporally
in afferent synaptic input to the spinal cord through with a peripheral tissue macrophage or inflammatory
an increased rate of discharge, increased peptide pro- cytokine response. This association supports the
duction by the dorsal root ganglion, or afferent fiber hypothesis that task-induced peripheral tissue injury
2560_Chapter 3_0025-0034.indd 28 3/16/2015 4:14:35 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
A B
Figure 3-3 Increased substance P, a nociceptor-related neurotransmitter, in the upper laminae of the dorsal
horn of cervical spinal cord segments in a rat model of repetitive reaching and grasping. Rats performed
a high repetition low force (HRLF) task for 12 weeks. A, The dorsal horn of the untrained side (i.e.,
the support limb side), showing only a small amount of substance P immunoreactivity (dark staining;
HRP-DAB reaction product) in the bracketed area. B, The dorsal horn of the trained side (i.e., the reach
limb side), showing an increase of substance P immunoreactivity in the bracketed area.
and inflammation drives a spinal cord neurochemical moderate repetition and negligible force demands for
response from nociceptive afferent terminals. Such 2 hours per day, 3 days per week for 8 weeks. We found
increases in substance P and neurokinin 1 are tempo- repetitive task-induced degradation of S1 neuronal
rally associated with mechanical hypersensitivity47,51 properties, such as increased cortical receptive fields
and behavioral changes (see Fig. 3-2). These studies that represented several forepaw subdivisions (i.e.,
combined provide evidence that spinal cord sensitiza- several digits or palmar pads rather than a single digit
tion associated with injury and inflammatory condi- or pad), increased receptive fields that represented both
tions may contribute to chronic pain conditions in glabrous and hairy surfaces, and increased cortical
patients with overuse injury. responsiveness to light tactile stimulation. In addition,
Numerous studies show spinal cord inflammatory the receptive fields located on the glabrous forepaw
responses after unilateral peripheral nerve injury as were significantly larger in rats performing repetitive
well. For example, peripheral nerve crush or ligation tasks than in control rats. Also, the forepaw representa-
leads to an increase in activated microglia and increased tion in the S1 cortical map was patchy and disrupted
production of proinflammatory cytokines in neurons in rats performing repetitive tasks relative to control
and glial cells in spinal cord segments innervating that rats. In the aforementioned study, the enlargement of
nerve.51–55 We observed increased interleukin (IL)-1β S1 receptive fields and the emergence of large receptive
and tumor necrosis factor (TNF)-α immunoexpression fields that encompassed the whole forepaw (digits and
in neurons within the dorsal horn superficial lamina in palmar pads) or dorsal hand and wrist or forearm cor-
aged rats that had performed a moderate demand task related statistically with a reduction in successful
(HRLF) for 12 weeks compared with normal control reaches, an increase in the inefficient raking food
rats (Fig. 3-4A).36 retrieval pattern, and an increase in reach time. These
findings support our hypothesis that ambiguous inter-
pretation of tactile cues results in reduced motor per-
formance, particularly with fine motor skills. These data
Cortical Brain Neuroplastic confirm and extend data found in primates in which
Changes Induced by Repetitive repetitive, rewarded hand grasp led to a dedifferentia-
tion of the finger maps in the S1 cortex, characterized
Strain Injury by enlarged, overlapping receptive fields; the emer-
gence of multidigit and hairy-glabrous receptive fields;
The possibility that both peripheral inflammatory and and abnormal somatosensory maps in the thalamus.56–58
central cortical neuroplastic change mechanisms coexist In the motor (M1) cortex, performance of a moder-
with altered motor performance has been studied only ate repetitive task in our model drastically increased the
more recently.32 We examined primary somatosensory size of the M1 forepaw maps, especially the movement
cortical (S1) and primary motor cortical (M1) changes representation of the digits, digits-arm, and elbow-
in rats performing a reaching and grasping task with wrist specifically involved in the behavioral task.32 The
2560_Chapter 3_0025-0034.indd 29 3/16/2015 4:14:35 PM

Process CyanProcess
YellowProcess Black
150
IL-1Beta-immunoreactive
neurons in spinal cord
100
50
r ⫽ *0.47
p ⫽ 0.01
0
0 5 10 15 20 25 30
B Withdrawal threshold (g)
100
TNF-Alpha-immunoreactive
neurons in spinal cord
A 75
50
25
r ⫽ *0.52
p ⫽ 0.009
30
0 5 10 15 20 25 30
C Withdrawal threshold (g)
Figure 3-4 Increased proinflammatory cytokines in neurons scattered throughout the cervical spinal cord
segments in a rat model of repetitive reaching and grasping. Rats performed a high repetition low force
(HRLF) task for 12 weeks. A, Low-power micrograph showing increased tumor necrosis factor (TNF)-α
(white staining), a key proinflammatory cytokine, in neurons throughout the spinal cord gray matter. B,
Scatterplot showing negative correlation between interleukin (IL)-1β immunoreactivity in neurons and
withdrawal threshold by Pearson’s r test. C, Scatterplot showing negative correlation between TNF-α
immunoreactivity n neurons and withdrawal threshold by Pearson’s r test. (From data generated for Elliott MB,
Barr AE, Clark BD, Wade CK, Barbe MF. Performance of a repetitive task by aged rats leads to median neuropathy
and spinal cord inflammation with associated sensorimotor declines. Neuroscience. 2010;170:929–941.)
movement representation area of the elbow-wrist mul-

tijoint responses tripled, and the arm-digits multijoint
Links Between Pain Behaviors
areal extent was 17 times larger than in untrained rats. and Peripheral or Central
The cortical increase in the multijoint movement rep-
resentation for elbow-wrist, arm, and arm-digits cor- Neural Changes
related strongly with the increased prevalence of a
degraded reaching and grasping strategy. Unexpect- Peripheral Nerve Sensitization
edly, but interesting to consider here as well, task- Heightened pain sensitivity is a known consequence of
induced peripheral increases in inflammatory cytokines increased inflammatory mediators, particularly TNF-
in muscles and nerves of rats performing repetitive α. Proinflammatory cytokines activate and sensitize
tasks had a strong negative correlation with not only peripheral terminals of nociceptors both directly (e.g.,
grip strength but also with the amount of current within the nerve) and indirectly (e.g., in surrounding
required to evoke movements of the wrist, elbow-wrist, tissues), leading to hypersensitivity.59,60 We reported a
and arm-digits multijoints in the primary motor cortex. correlation between increased inflammatory cytokines
The higher the inflammation in flexor muscles and in the median nerve and forepaw mechanical hyper-
nerves specifically involved in the task, the lower the sensitivity.36 Alternatively, a task-induced systemic
threshold required to elicit arm-digits movements, cytokine response may also be associated with the
which was decreased in trained rats relative to controls. widespread mechanical hypersensitivity found in our
This latter finding suggests that the peripheral inflam- rat model. We previously observed a significant cor-
matory responses are altering the cortical maps nega- relation between reduced grip strength and task-
tively and altering, in this indirect manner, the ability induced increases in serum inflammatory cytokines30,36
to perform fine motor tasks. as well as a significant correlation between cutaneous
2560_Chapter 3_0025-0034.indd 30 3/16/2015 4:14:35 PM

Process CyanProcess
YellowProcess Black
hypersensitivity and task-induced increases in spinal response prevent us from separating peripheral versus
cord inflammatory cytokines (Fig. 3-4B and C).36 central mechanisms contributing to observed cutane-
These findings combined suggest that inflammation- ous sensation changes in forepaws. Proinflammatory
driven peripheral sensitization contributes to senso- cytokines have been shown to sensitize peripheral
rimotor changes with performance of repetitive tasks. terminals of nociceptors both directly and indirectly,
leading to hypersensitivity.59,60 We reported the pres-
Spinal Cord Central Sensitization ence of inflammatory cytokines in peripheral nerves,
The phenomenon of central sensitization is character- in musculoskeletal tissues, and widely circulating in
ized by adaptations in neurons and glial cells, such as serum in our model (see Fig. 3-1F).25,26,30,33,38,40,44 We
changes in neuronal structure, protein production, also reported statistical correlation between these cyto-
function, and survival within the central nervous kine increases, hypersensitivity, and declines in grip
system, which contribute to abnormal pain behaviors.61 strength in several studies, suggesting a link between
For example, it has been proposed that spinal cytokines increased peripheral cytokines and pain-related behav-
released in the dorsal horn nerve terminal region ipsi- iors with overuse injuries.
lateral to the affected peripheral nerve spread to nearby Nerve compression can be initially irritating to
spinal nerve terminals and affect uninvolved peripheral nerves, resulting in cutaneous hypersensitivity. Our
nerves and central sensory processing.62 These changes findings of mechanical hypersensitivity in the presence
may elicit remote and contralateral sensitization effects. of decreased nerve conduction velocity and histological
We have observed forepaw hypersensitivity bilaterally findings of increased extraneuronal connective tissue
in our model.25,36 However, we also showed that the and axonal swelling in the median nerve are suggestive
nonreach limb is used as a support limb in our model.38 of nerve compression with long-term repetitive task
The bilateral hypersensitivity responses in our study are performance, particularly HRHF tasks. Hand and arm
not a type of “mirror allodynia” sometimes seen after pain in the distribution of the median nerve is a
unilateral nerve ligation, in which there is a contralat- common symptom in patients with electrophysiologi-
eral spread of symptoms via spinal cord mecha- cally diagnosed CTS, particularly in patients who
nisms,52,62,63 but rather are due to bilateral use of the engage in full-time intensive manual work.64
forelimbs in performing the task and then bilateral With regard to central sensitivity, we can only point
changes in the median nerves. to numerous other studies showing spinal cord inflam-
We have also reported the presence of hind paw matory responses after unilateral peripheral nerve
mechanical hypersensitivity in our model25,36 in limbs injury (e.g., increased spinal cord cytokines produced
not involved with performing an upper extremity by neurons and glia, increases that are temporally asso-
repetitive task. We observed hind paw mechanical ciated with mechanical hypersensitivity).52,53,65–69 The
hypersensitivity in aged rats performing a HRLF task contribution of central sensitization to repetition-
for 12 weeks36 and an early increase in hind paw sensi- induced hypersensitivity is also suggested by studies
tivity at 3 weeks in young rats performing a high rep- from our laboratory showing increased substance P and
etition high force (HRHF) task (before the development neurokinin-1 receptors in spinal cord dorsal horns.34–37
of hyposensation in these latter rats). These findings are These increases in substance P correlated statistically
suggestive of an extraterritorial spread of symptoms via with declines in forelimb grip strength34 and coincided
central sensitization mechanisms that may contribute with degraded forelimb movement patterns.37 We have
to pain behaviors with overuse injuries. Studies showing also observed increased substance P in forelimb tendons
mirror allodynia (mechanical hypersensitivity) or extra- with HRHF task performance—changes that correlate
territorial hyperalgesia in cases of unilateral nerve strongly with declines in grip strength38 and bring us
injury provide evidence of nerve injury–induced mech- back to a potential peripheral sensitization mechanism.
anisms of central sensitization.62 We suggest that the We hypothesize that both mechanisms are at work in
hypersensitivity in the uninvolved hind paws in our our model as well as in cases of overuse injury in which
model may be due to increased proinflammatory cyto- chronic pain is present.
kines in cervical spinal cord affecting cells or process- Our data from a rat model of overuse injury show
ing in distal spinal cord segments (see Fig. 3-4). that peripheral nerve injury, peripheral inflammatory
responses, spinal cord sensitization, and central neuro-
plastic mechanisms coexist. Each of these factors
Does Sensitization Result appears to contribute to motor behavior declines and
From Both Peripheral and the development of pain-related behaviors. What was
previously unknown was whether peripheral inflam-
Central Changes? mation was primarily responsible for the movement
performance deficits that emerge in these rats over
Signs of injury and inflammation occurring in the time or whether cortical degradation was responsible
median nerve in addition to the spinal cord inflammatory for the movement defects.56 It is clear from our studies
2560_Chapter 3_0025-0034.indd 31 3/16/2015 4:14:35 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
that both sensorimotor cortical reorganization and median mononeuropathy in Macaca fascicularis. J Orthop Res.
peripheral inflammation and injury mechanisms con- 2007;25:713–724.
18. Sacrey LA, Alaverdashvili M, Whishaw IQ. Similar hand
tribute to declines in movement performance and shaping in reaching-for-food (skilled reaching) in rats and
changes in movement patterns in the progression of humans provides evidence of homology in release, collection,
the overuse injury. and manipulation movements. Behav Brain Res. 2009;
204:153–161.
19. Whishaw IQ, Pellis SM, Gorny BP. Skilled reaching in rats
References and humans: evidence for parallel development or homology.
1. Bernard B. Musculoskeletal Disorders and Workplace Factors. Behav Brain Res. 1992;47:59–70.
NIOSH Report 97-141. Cincinatti: National Institute for 20. Viikari-Juntura ER. The scientific basis for making guidelines
Occupational Safety and Health; 1997. and standards to prevent work-related musculoskeletal
2. Rempel DM, Diao E. Entrapment neuropathies: disorders. Ergonomics. 1997;40:1097–1117.
pathophysiology and pathogenesis. J Electromyogr Kinesiol. 21. Viikari-Juntura E, Silverstein B. Role of physical load factors
2004;14:71–75. in carpal tunnel syndrome. Scand J Work Environ Health.
3. Zambelis T, Tsivgoulis G, Karandreas N. Carpal tunnel 1999;25:163–185.
syndrome: associations between risk factors and laterality. Eur 22. Silverstein BA, Fine LJ, Armstrong TJ. Hand wrist
Neurol. 2010;63:43–47. cumulative trauma disorders in industry. Br J Ind Med.
4. Nathan PA, Keniston RC, Myers LD, Meadows KD, 1986;43:779–784.
Lockwood RS. Natural history of median nerve sensory 23. Silverstein BA, Fine LJ, Armstrong TJ. Occupational factors
conduction in industry: relationship to symptoms and carpal and carpal tunnel syndrome. Am J Ind Med. 1987;11:343–358.
tunnel syndrome in 558 hands over 11 years. Muscle Nerve. 24. Barr AE, Barbe MF. Pathophysiological tissue changes
1998;21:711–721. associated with repetitive movement: a review of the evidence.
5. Gerr F, Marcus M, Monteilh C. Aerobic exercise, median Phys Ther. 2002;82:173–187.
nerve conduction, and the reporting of study results. J Occup 25. Barr AE, Barbe MF, Clark BD. Systemic inflammatory
Environ Med. 2002;44:303. mediators contribute to widespread effects in work-related
6. Bureau of Labor Statistics. Nonfatal Occupational Injuries and musculoskeletal disorders. Exerc Sport Sci Rev.
Illnesses Requiring Days Away From Work. Washington, D.C.: 2004;32:135–142.
U.S. Department of Labor; 2010. 26. Barbe MF, Barr AE, Gorzelany I, Amin M, Gaughan JP,
7. Szabo RM. Carpal tunnel syndrome as a repetitive motion Safadi FF. Chronic repetitive reaching and grasping results in
disorder. Clin Orthop Relat Res. 1998;(351):78–89. decreased motor performance and widespread tissue responses
8. Gerr F, Marcus M, Ensor C, et al. A prospective study of in a rat model of MSD. J Orthop Res. 2003;21:167–176.
computer users: I. study design and incidence of 27. Clark BD, Al-Shatti TA, Barr AE, Amin M, Barbe MF.
musculoskeletal symptoms and disorders. Am J Ind Med. Performance of a high-repetition, high-force task induces
2002;41:221–235. carpal tunnel syndrome in rats. J Orthop Sports Phys Ther.
9. Carp SJ, Barbe MF, Winter KA, Amin M, Barr AE. 2004;34:244–253.
Inflammatory biomarkers increase with severity of 28. Clark BD, Barr AE, Safadi FF, et al. Median nerve trauma in
upper-extremity overuse disorders. Clin Sci (Lond). a rat model of work-related musculoskeletal disorder.
2007;112:305–314. J Neurotrauma. 2003;20:681–695.
10. Carp SJ, Barr AE, Barbe MF. Serum biomarkers as signals 29. Rani S, Barbe MF, Barr AE, Litivn J. Role of TNF alpha and
for risk and severity of work-related musculoskeletal injury. PLF in bone remodeling in a rat model of repetitive reaching
Biomark Med. 2008;2:67–79. and grasping. J Cell Physiol. 2010;225:152–167.
11. Freeland AE, Tucci MA, Barbieri RA, Angel MF, Nick TG. 30. Barbe MF, Elliott MB, Abdelmagid SM, et al. Serum and
Biochemical evaluation of serum and flexor tenosynovium in tissue cytokines and chemokines increase with repetitive
carpal tunnel syndrome. Microsurgery. 2002;22:378–385. upper extremity tasks. J Orthop Res. 2008;26:1320–1326.
12. Topp KS, Byl NN. Movement dysfunction following 31. Barr AE, Safadi FF, Gorzelany I, Amin M, Popoff SN, Barbe
repetitive hand opening and closing: anatomical analysis in MF. Repetitive, negligible force reaching in rats induces
Owl monkeys. Mov Disord. 1999;14:295–306. pathological overloading of upper extremity bones. J Bone
13. Hollander MS, et al. Effects of age and glutathione levels on Miner Res. 2003;18:2023–2032.
oxidative stress in rats after chronic exposure to stretch- 32. Coq JO, Barr AE, Strata F, et al. Peripheral and central
shortening contractions. Eur J Appl Physiol. changes combine to induce motor behavioral deficits in a
2010;108:589–597. moderate repetition task. Exp Neurol. 2009;220:234–245.
14. Baker BA, Hollander MS, Mercer RR, Kashon ML, Cutlip 33. Driban JB, Barr AE, Amin M, Sitler MR, Barbe MF. Joint
RG. Adaptive stretch-shortening contractions: diminished inflammation and early degeneration induced by high-force
regenerative capacity with aging. Appl Physiol Nutr Metab. reaching are attenuated by ibuprofen in an animal model of
2008;33:1181–1191. work-related musculoskeletal disorder. J Biomed Biotechnol.
15. Stauber WT, Willems ME. Prevention of histopathologic 2011;2011:691412.
changes from 30 repeated stretches of active rat skeletal 34. Elliott MB, Barr AE, Barbe MF. Spinal substance P and
muscles by long inter-stretch rest times. Eur J Appl Physiol. neurokinin-1 increase with high repetition reaching. Neurosci
2002;88:94–99. Lett. 2009;454:33–37.
16. Willems ME, Miller GR, Stauber FD, Stauber WT. 35. Elliott MB, Barr AE, Clark BD, Amin M, Amin S, Barbe
Effects of repeated lengthening contractions on skeletal MF. High force reaching task induces widespread
muscle adaptations in female rats. J Physiol Sci. inflammation, increased spinal cord neurochemicals and
2010;60:143–150. neuropathic pain. Neuroscience. 2009;158:922–931.
17. Sommerich CM, Lavender SA, Buford JA, J Banks J, 36. Elliott MB, Barr AE, Clark BD, Wade CK, Barbe MF.
Korkmaz SV, Pease WS. Towards development of a Performance of a repetitive task by aged rats leads to median
nonhuman primate model of carpal tunnel syndrome: neuropathy and spinal cord inflammation with associated
performance of a voluntary, repetitive pinching task induces sensorimotor declines. Neuroscience. 2010;170:929–941.
2560_Chapter 3_0025-0034.indd 32 3/16/2015 4:14:35 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
37. Elliott MB, Barr AE, Kietrys DM, Al-Shatti T, Amin M, 53. Hunt JL, Winkelstein BA, Rutkowski MD, Weinstein JN,
Barbe MF. Peripheral neuritis and increased spinal cord DeLeo JA. Repeated injury to the lumbar nerve roots
neurochemicals are induced in a model of repetitive motion produces enhanced mechanical allodynia and persistent spinal
injury with low force and repetition exposure. Brain Res. neuroinflammation. Spine (Phila Pa 1976).
2008;1218:103–113. 2001;26:2073–2079.
38. Fedorczyk JM, Barr AE, Rani S, et al. Exposure-dependent 54. Rutkowski MD, Winkelstein BA, Hickey WF, Pahl JL,
increases in IL-1beta, substance P, CTGF, and tendinosis in DeLeo JA. Lumbar nerve root injury induces central nervous
flexor digitorum tendons with upper extremity repetitive system neuroimmune activation and neuroinflammation in
strain injury. J Orthop Res. 2010;28:298–307. the rat: relationship to painful radiculopathy. Spine (Phila Pa
39. Rani S, Barbe MF, Barr AE, Litvin J. Induction of periostin- 1976). 2002;27:1604–1613.
like factor and periostin in forearm muscle, tendon, and nerve 55. Winkelstein BA, Rutkowski MD, Weinstein JN, DeLeo JA.
in an animal model of work-related musculoskeletal disorder. Quantification of neural tissue injury in a rat radiculopathy
J Histochem Cytochem. 2009;57:1061–1073. model: comparison of local deformation, behavioral outcomes,
40. Xin DL, Harris MY, Wade CK, Amin M, Barr AE, Barbe and spinal cytokine mRNA for two surgeons. J Neurosci
MF. Aging enhances serum cytokine response but not Methods. 2001;111:49–57.
task-induced grip strength declines in a rat model of 56. Byl NN, Melnick M. The neural consequences of repetition:
work-related musculoskeletal disorders. BMC Musculoskelet clinical implications of a learning hypothesis. J Hand Ther.
Disord. 2011;12:63. 1997;10:160–174.
41. Rani S, Barbe MF, Barr AE, Litvin J. Periostin-like-factor 57. Byl NN, Merzenich MM, Cheung S, Bedenbaugh P,
and Periostin in an animal model of work-related Nagarajan SS, Jenkins WM. A primate model for studying
musculoskeletal disorder. Bone. 2009;44:502–512. focal dystonia and repetitive strain injury: effects on the
42. Elliott MB, Barr AE, Clark BD, Amin M, Amin S, Barbe primary somatosensory cortex. Phys Ther. 1997;77:269–284.
MF. High force reaching task induces widespread 58. Byl NN, Merzenich MM, Jenkins WM. A primate genesis
inflammation, increased spinal cord neurochemicals and model of focal dystonia and repetitive strain injury: I.
neuropathic pain. Neuroscience. 2009;158:922–931. learning-induced dedifferentiation of the representation of
43. Fedorczyk JM, Barr AE, Rani S, et al. Exposure-dependent the hand in the primary somatosensory cortex in adult
increases in IL-1beta, substance P, CTGF, and tendinosis in monkeys. Neurology. 1996;47:508–520.
flexor digitorum tendons with upper extremity repetitive 59. Moalem G, Tracey DJ. Immune and inflammatory mechanisms
strain injury. J Orthop Res. 2010;28:298–307. in neuropathic pain. Brain Res Rev. 2006;51:240–264.
44. Al-Shatti T, Barr AE, Safadi FF, Amin M, Barbe MF. 60. Schafers M, Sorkin L. Effect of cytokines on neuronal
Increase in inflammatory cytokines in median nerves in a rat excitability. Neurosci Lett. 2008;437:188–193.
model of repetitive motion injury. J Neuroimmunol. 61. Woolf CJ, Salter MW. Neuronal plasticity: increasing the
2005;167:13–22. gain in pain. Science. 2000; 288:1765–1769.
45. Hammond DL, Ackerman L, Holdsworth R, Elzey B. 62. Chacur M, Milligan ED, Gazda LS, et al. A new model of
Effects of spinal nerve ligation on immunohistochemically sciatic inflammatory neuritis (SIN): induction of unilateral
identified neurons in the L4 and L5 dorsal root ganglia of and bilateral mechanical allodynia following acute unilateral
the rat. J Comp Neurol. 2004;475:575–589. peri-sciatic immune activation in rats. Pain. 2001;94:231–244.
46. Chao T, Pham K, Steward O, Gupta R. Chronic nerve 63. Kelly S, Dunham JP, Donaldson LF. Sensory nerves have
compression injury induces a phenotypic switch of neurons altered function contralateral to a monoarthritis and may
within the dorsal root ganglia. J Comp Neurol. 2008;506: contribute to the symmetrical spread of inflammation. Eur J
180–193. Neurosci. 2007;26:935–942.
47. Rothman SM, Winkelstein BA. Chemical and mechanical 64. Bonfiglioli R, Mattioli S, Violante FS. Relationship between
nerve root insults induce differential behavioral sensitivity symptoms and instrumental findings in the diagnosis of
and glial activation that are enhanced in combination. Brain upper limb work-related musculoskeletal disorders. Med Lav.
Res. 2007;1181:30–43. 2007;98:118–126.
48. Neumann S, Doubell TP, Leslie T, Woolf CJ. Inflammatory 65. Hatashita S, Sekiguchi M, Kobayashi H, Konno S, Kikuchi S.
pain hypersensitivity mediated by phenotypic switch in Contralateral neuropathic pain and neuropathology in dorsal
myelinated primary sensory neurons. Nature. 1996;384: root ganglion and spinal cord following hemilateral nerve
360–364. injury in rats. Spine (Phila Pa 1976). 2008;33:1344–1351.
49. Pitcher GM, Henry JL. Nociceptive response to innocuous 66. Hubbard RD, Winkelstein BA. Transient cervical nerve root
mechanical stimulation is mediated via myelinated afferents compression in the rat induces bilateral forepaw allodynia and
and NK-1 receptor activation in a rat model of neuropathic spinal glial activation: mechanical factors in painful neck
pain. Exp Neurol. 2004;186:173–197. injuries. Spine (Phila Pa 1976). 2005;30:1924–1932.
50. Schaible HG, Ebersberger A, Von Banchet GS. 67. Schafers M, Svensson CI, Sommer C, Sorkin LS. Tumor
Mechanisms of pain in arthritis. Ann N Y Acad Sci. necrosis factor-alpha induces mechanical allodynia after
2002;966:343–354. spinal nerve ligation by activation of p38 MAPK in primary
51. Winkelstein BA, Rutkowski MD, Sweitzer SM, Pahl JL, sensory neurons. J Neurosci. 2003;23:2517–2521.
DeLeo JA. Nerve injury proximal or distal to the DRG 68. Ohtori S, Takahashi K, Moriya H, Myers RR. TNF-alpha
induces similar spinal glial activation and selective cytokine and TNF-alpha receptor type 1 upregulation in glia and
expression but differential behavioral responses to neurons after peripheral nerve injury: studies in murine DRG
pharmacologic treatment. J Comp Neurol. 2001;439:127–139. and spinal cord. Spine (Phila Pa 1976). 2004;29:1082–1088.
52. DeLeo JA, Colburn RW, Rickman AJ. Cytokine and growth 69. Shubayev VI, Myers RR. Anterograde TNF alpha transport
factor immunohistochemical spinal profiles in two animal from rat dorsal root ganglion to spinal cord and injured
models of mononeuropathy. Brain Res. 1997;759:50–57. sciatic nerve. Neurosci Lett. 2002;320:99–101.
2560_Chapter 3_0025-0034.indd 33 3/16/2015 4:14:35 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
2560_Glossary_0347-0360.indd 360 3/17/2015 12:11:29 PM
SECTION TWO
Etiology of Peripheral Nerve Injury
Chapter 4
Peripheral Neuropathy and
Vasculitic, Connective Tissue,
and Seronegative
Spondyloarthropathic Disorders
“A merry heart doeth good like medicine.”

—SOCRATES (469 B.C.–399 B.C.)
Objectives
• Develop an evidenced-based understanding of vasculitic, connective tissue, and spondyloarthropathic
disorders as they relate to neuropathic signs and symptoms.
• Identify on the physical examination potential neuropathic impairments related to vasculitic, connective
tissue, and seronegative spondyloarthropathic disorders.
• Develop a goal-oriented treatment plan for vasculitic, connective tissue, and seronegative
spondyloarthropathic disorders.
Key Terms
• Connective tissue disorders
• Seronegative spondyloarthropathies
• Vasculitic disorders
35
2560_Chapter 4_0035-0052.indd 35 3/16/2015 4:14:38 PM

Process CyanProcess
YellowProcess Black
36 Section Two | Etiology of Peripheral Nerve Injury
Vasculitides can also be secondary to other condi-
Introduction tions (secondary vasculitis), such as infections, malig-
nancy, reactions to certain medications, complications
The group of disorders comprising the vasculitides,
after organ transplant, connective tissue disease, or
connective tissue disorders, and seronegative spon-
others. Vasculitis can also be a primary disease that is
dyloarthropathies produces impairments related to
not associated with another disease process. The differ-
most corporal systems, including respiratory, muscu-
ent types of vasculitis are usually first categorized by
loskeletal, renal, cardiac, gastrointestinal, integument,
size of blood vessels involved. Large vessels are involved
and neurological. Vasculitic disorders affect primar-
in temporal arteritis (also called giant cell arteritis) and
ily the vasculature resulting in “downstream” impair-
Takayasu arteritis. Medium-sized vessels are affected
ments related to perfusion issues and inflammation.
in polyarteritis nodosa and Kawasaki disease. Diseases
On a system-wide scale, connective tissue disorders
such as Wegener’s granulomatosis, Churg-Strauss syn-
and seronegative spondyloarthropathies (SpAs) affect
drome, and Henoch-Schönlein purpura affect small
multiple tissue types. In many of these disorders,
vessels.8,9
peripheral neuropathy is a common, although often
In some diseases, vasculitis is the most overt disease
secondary, manifestation. In addition, many of the
manifestation (e.g., in temporal arteritis), but it may
interventions currently indicated for these disorders—
manifest in varying intensities in other diseases (e.g.,
immunomodulating drugs, biologicals, steroids, and
systemic lupus erythematosis).8 In general, most types
nonsteroidal anti-inflammatory drugs (NSAIDs)—
of primary vasculitis are uncommon. For example,
may produce signs and symptoms that may require
Wegener’s granulomatosis affects 1 to 5 people per
rehabilitation services interventions.
100,000.10 Henoch-Schönlein purpura affects up to 10
people per 100,000.11 Temporal arteritis affects around
50 people per 100,000.11 Some diseases affect certain
Vasculitic Diseases populations more than others. Temporal arteritis is
usually a disease of older individuals, whereas Henoch-
Knowledge of vasculitic neuropathy is important for Schönlein purpura usually affects children 5 to 15 years
clinicians for three reasons: (1) Once diagnosed, vas- old. Some ethnic groups have much higher incidences
culitic diseases are often treatable with immunosup- of certain diseases; for example, Kawasaki disease
pressive medications and therapies, especially when the affects up to 1 in 1000 children in Japan.
disease is identified in its early stages. (2) Neuropathy The symptoms of vasculitis stem from the general
is often the presenting sign of vasculitic disease. (3) The inflammatory process as well as from complications of
neuropathic signs are often present in the well- ischemia to the specific organ system affected. There
recognized pattern of multifocal motor, sensory, and are usually some nonspecific systemic complaints such
autonomic neuropathy. as fever, weakness, or body aches as well as specific
Vasculitis is a local or systemic inflammation of the symptoms depending on the end-organ system com-
vasculature, including the arteries, capillaries, and veins. promised. The nonspecific symptoms are most likely
Typically, lymph vessels are spared. Inflammation of related to the systemic impact of the proinflammatory
the blood vessels is characterized by leukocyte and mediators such as tumor necrosis factor (TNF)-α and
macrophage infiltration of the vessel walls resulting in interleukin (IL)-1β produced by the macrophages.
edema, angiogenesis, scarring and potential vascular Patients with Henoch-Schönlein purpura typically
necrosis, clot, and hemorrhage.1–3 Local inflammation, present with the triad of abdominal pain; palpable
if of sufficient magnitude, may produce systemic signs purpura; and periarticular inflammation, swelling, and
of inflammation, such as cachexia, anemia of chronic tenderness.11 Wegener’s granulomatosis can affect the
disease, depression, and sickness behavior.4–6 lungs and the kidneys, so patients may complain of
Although there are many theories regarding the eti- symptoms related to these organ systems, such as respi-
ology of vasculitic disorders, the exact pathogenesis is ratory issues related to lung involvement and metabolic
not fully understood. Some vasculitides are thought to impairments secondary to renal failure.10
be an allergic-type reaction, and others are thought to The fact that there are many different kinds of vas-
be autoimmune-mediated. This inflammation and the culitides that affect different organs and cause different
body’s subsequent inflammatory cascade reactions may symptoms in different patients often makes the diag-
cause the vessels to become weakened and may impair nosis of vasculitis difficult. Vasculitis is usually sus-
the integrity of the vessel walls, which can prevent pected in patients with some systemic symptoms as
adequate flow of blood through the affected vessels. well as a specific organ involved (e.g., the skin, lungs,
Ischemia of the organ and body tissues perfused by the kidneys). Screening blood tests to assess the function
blood supply may result. The resultant ischemia is the of organ systems are needed. Other blood tests, such
cause for many of the problems that the different types as a test for antineutrophil cytoplasmic antibodies
of vasculitis can cause.7–9 (ANCA), are abnormal in certain types of vasculitis
2560_Chapter 4_0035-0052.indd 36 3/16/2015 4:14:39 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 4 | Peripheral Neuropathy and Vasculitic, Connective Tissue, and Seronegative Spondyloarthropathic Disorders 37
and can aid in the diagnosis. However, a biopsy of the 300 μm, which leads to focal nerve necrosis: neur-
most affected organ is usually needed to identify vessel apraxia, neurotmesis, and potentially axonotmesis. The
inflammation and to verify the diagnosis.2 signs and symptoms related to vasculitic neuropathy are
Although making a definitive diagnosis of vascu- directly related to which portion of the nerve is injured.
litis is difficult, early diagnosis is important because Motor, sensory, and autonomic nerve injuries—alone
these diseases do respond to appropriate treatments. or in combination with varying levels of severity—have
For example, untreated Wegener’s granulomatosis has been reported.17–20 Table 4-1 lists common vasculopa-
100% mortality with an average survival of only 5 thies with the relative frequency of associated periph-
months. However, aggressive treatment of this disease eral neuropathy.
achieves remission in 80% to 90% of patients, and the
5-year survival is approximately 75% with treatment.
This example illustrates the importance of being per-
sistent in obtaining a definitive diagnosis in patients Table 4-1 Classification of Vasculitic Syndromes and Relative
with possible vasculitis.12,13 Frequency of Neuropathy
The American College of Rheumatology has devel-
oped a classification rubric based on symptoms to help Syndrome Relative Frequency
identify the type of vasculitis a patient has, and this of Neuropathya
rubric is useful in determining which treatments may
Polyarteritis Group
be most appropriate and in aiding with prognosis.
However, this classification system is more of a screen- Classic polyarteritis nodosa +++
ing tool; a biopsy of the most involved organ is con- Allergic granulomatosis of Churg-Strauss +++
sidered necessary for a definitive diagnosis, prognosis, syndrome
and intervention.14–16 Polyangiitis +++
Because the vasculitides are primarily immune-
Microscopic polyangiitis +++
related inflammatory diseases, the treatments are often
steroid-type medications to combat the inflammation Hypersensitivity vasculitis
as well as other immune system–modifying medica- Serum sickness
tions. Long-term use of these medications is typically Drug-induced vasculitis
required for many types of vasculitis, but their use is
not without a downside. People who die of the disease Infectious disease–associated +
usually die as a result of direct complications (e.g., Henoch-Schönlein purpura
failure of the affected organ), but they often exhibit Essential mixed cryoglobulinemia ++
severe complications related to the immune suppres-
Malignancy-associated vasculitis +
sion and other complications of the medications used
to treat the disease. Because discontinuing the medica- Vasculitis associated with connective tissue +++
tions may result in acute disease flare, the balance disease
between the complications from the disease and the Vasculitis associated with congenital
potential complications from the treatments can be deficiencies of complement
difficult. Wegener’s granulomatosis +++
In vasculitic neuropathy, a relatively common disease Giant cell arteritis
complication, the target anatomy of the disease is the
vasa nervorum, the intraneuronal vasculature system. Temporal arteritis +
The vasa nervorum and the nerve tissues downstream Takayasu’s arteritis
are supplied with nutrient blood via numerous small Other Vasculitic Syndromes
artery anastomoses with larger trunk vessels entering
Kawasaki disease
the nerve periodically along its course to and from
the central nervous system (CNS) to its target organ. Isolated CNS vasculitis
When inside the epineurium and perineurium of the Isolated PNS vasculitis +++
peripheral nerve, the vascular branches anastomose Adamantiades-Behçet disease
frequently, establishing a complex and rich collater-
alization of blood flow within the nerve. The frequent Buerger’s disease
anastomoses with larger, extraneural blood vessels and Polymyalgia rheumatica +
the collateralization within the nerve often prevent Rheumatoid vasculitis ++
focal neuropathic ischemic injury secondary to trauma
or atherosclerotic processes involving the larger trunk CNS = central nervous system; PNS = peripheral nervous system.
a
+ indicates neuropathy complication infrequent; ++ indicates
vessels. However, processes such as vasculitis damage neuropathy complication moderately frequent; +++ indicates
smaller blood vessels ranging in diameter from 50 to neuropathy complication very frequent.
2560_Chapter 4_0035-0052.indd 37 3/16/2015 4:14:39 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
may result in tensile or compressive neuropathies.
Connective Tissue Disorders Lastly, medications directed at modifying the rheuma-
tological disease may result in injury to the peripheral
Many diseases in rheumatological classifications are
nerve.
associated with peripheral motor, sensory, and auto-
Rheumatoid vasculitis (RV), a relatively rare com-
nomic neuropathies. For the diagnosing rheumatolo-
plication of RA, results in inflammatory disease in
gist or neurologist, there is often confusion if the
small and medium-sized blood vessels. RV most com-
presenting symptoms are those of a connective tissue
monly occurs in the skin as venulitis or capillaritis, but
disease or multiple sclerosis (MS). Clinically, in the
it may occur in other organ systems. RV occurs in
early stages of the disease, differentiation of autoim-
approximately 3% to 5% of patients who have RA.24 It
mune disease and MS is difficult. Autoantibodies, such
is unclear why RV develops in some patients with RA
as antinuclear antibody (ANA), are typically present in
and not others. Genetic factors may be involved. Viral
these diseases but may also be present in MS, increas-
infections and drug reactions have been suggested as
ing the confusion. An acute isolated peripheral nervous
causes of RV, but there is little research to support this.
system (PNS) or CNS sign identified on magnetic
Some research suggests that the prolonged use of med-
resonance imaging (MRI) manifesting with a func-
ications such as corticosteroids, gold compounds, peni-
tional impairment or musculoskeletal or neurological
cillamine, and azathioprine that are currently prescribed
symptom presents the biggest diagnostic problem: dif-
or were prescribed in the past to treat RA can cause
ferentiating between the etiology of MS and connec-
the development of RV. However, this cause may be
tive tissue disease.21 Later in the course of the disease,
difficult to determine because the accelerated use of
the clinical presentation and MRI are much more sen-
these drugs is probably due to severe or long-standing
sitive in disease identification compared with tests per-
RA, and either severe or long-standing RA may be
formed at the time of disease presentation.
associated with the development of RV.24,25
Central and peripheral neuropathies are strongly
RV typically occurs in patients who have had RA
associated with rheumatological diseases. The etiology
for longer than a decade.25 In one study, the average
of the peripheral neuropathies may be compressive or
time between the diagnosis of RA and the onset of RV
tensile secondary to space-occupying lesions or abnor-
symptoms was 13.6 years. Patients with RA seem more
mal biomechanics, direct vasculitic injury resulting in
likely to develop RV when high rheumatoid factor
nerve injury related to the disease process, and compli-
(RF) levels are present. Men with RA are two to
cations related to therapies.
four times more likely than women with RA to
develop RV.26
Rheumatoid Arthritis The clinical manifestations of RV can involve many
Rheumatoid arthritis (RA) is an inflammatory polyar- organs of the body, including the skin, nerves to the
thritis often leading to pain, stiffness, joint destruction, hands and feet, blood vessels of the fingers and toes,
deformity, and eventually loss of function. Additive, and the eyes. The most common clinical manifestations
progressive, and symmetrical swelling of peripheral of vasculitis are small digital infarcts along the nail
joints, often worse in the morning, is the hallmark of beds. These can occur in 90% of patients with the
the disease. Extra-articular features and systemic symp- complication of RV. The abrupt onset of an ischemic
toms such as malaise, myalgia, and fever can commonly sensory or motor mononeuropathy (mononeuritis mul-
occur and may antedate the onset of joint symptoms. tiplex) or progressive scleritis is typical of RV. Ischemia
Chronic pain, disability, and excess morbidity and mor- induced by a vasculitis may also lead to skin necrosis.27–31
tality are sequelae. Limited data are available concerning the functional
RA has a worldwide distribution with an estimated outcome of patients with RV and specific therapies,
prevalence of 1% to 2%. Prevalence increases with age although this cohort of patients with RA usually has
and is almost 5% in women older than age 55. The worse and more ongoing symptoms than patients with
average annual incidence in the United States is about RA who do not have RV.26
70 per 100,000 annually. Both incidence and preva- Rheumatoid nodules are firm, flesh-colored cutane-
lence of RA are two to three times greater in women ous lumps that grow close to the affected joints. Typical
than in men. Although RA may manifest at any age, locations include the hands, fingers, knuckles, elbows,
patients most commonly are first affected in the third and heels. Rheumatoid nodules can range in size from
to sixth decades.22,23 as large as a walnut to as small as a pea. The nodules
There are three broad classifications of peripheral may be fixed or movable. Fixed nodules are typically
neuropathy associated with rheumatological condi- connected to tendons or fascia.32,33 Nodules are found
tions. These include the relatively uncommon vasculitic in 25% to 35% of adults with RA.32 Other factors may
component of specific rheumatological diseases. Space- increase the risk of RA nodules. One study positively
occupying lesions related to subcutaneous nodules, correlated cigarette smoking and the presence of
joint deformity, synovitis, edema, and bony changes nodules in patients with RA.32 Methotrexate, a
2560_Chapter 4_0035-0052.indd 38 3/16/2015 4:14:39 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Common sites for

rheumatoid nodules
Figure 4-2 Aseptic synovitis in a child with juvenile

idiopathic arthritis. With synovitis, the knee tends to rest in
the open-packed position resulting in periarticular scarring
and eventually a 20° knee flexion contracture. Functionally,
the contracture results in an apparent leg-length
discrepancy leading to a shortened leg gait pattern.
Figure 4-1 Rheumatoid nodules, a common complication
of rheumatoid arthritis, not only may result in pain and
disfigurement but also may lead to compressive neuropathy
secondary to pressure on superficial peripheral nerves. shown via electroneuromyographic evidence to result
The nodules vary in size from a pea to a walnut and are in neuropathy.30–33
commonly found in the metacarpophalangeal region of
the hand, the wrist, and the elbow. Nodules may be Juvenile Idiopathic Arthritis
functionally benign or may cause pain (especially over The term juvenile idiopathic arthritis ( JIA) is used to
weight-bearing areas), become infected, or lead to tensile describe arthritis with onset before 16 years of age.
or compressive neuropathies if located along the path of a Previously called juvenile RA, the name was changed
peripheral nerve. to reflect the difference between the juvenile (child-
hood) forms of arthritis and adult forms of arthritis.
Although JIA is idiopathic, it is likely the result of a
commonly used RA therapy, has also been linked combination of genetic, infectious, and environmental
to increased development of rheumatoid nodules factors. Because arthritis in children may resemble the
(Fig. 4-1).33 joint pain associated with infections, cancer, bone dis-
Rheumatoid nodules can also form on the vocal orders, and other inflammatory disorders, these poten-
cords, causing hoarseness. Nodules may appear in the tial causes must be excluded before the diagnosis of JIA
lungs, heart, and other internal organs. Most nodules can be made.34,35
do not produce pain or symptoms. However, some Symptoms of JIA include morning stiffness; pain,
patients find the nodules to be painful, especially if the swelling, and tenderness of joints; and gait dysfunction—
nodules are located on weight-bearing surfaces of the typically antalgic gait or shortened leg gait as a result
buttocks, feet, elbows, or hands. The size and location of hip or knee flexion contracture (Fig. 4-2). Nonspe-
of nodules may have a direct impact on activities of cific complaints of fever, rash, malaise, weight loss,
daily living by interfering with grasp, limiting joint fatigue, and irritability often manifest as the first symp-
range of motion, or limiting weight bearing. There is toms. Aseptic conjunctivitis and complaints of blurred
evidence in the literature of compressive and tensile vision often are present.
neuropathies directly attributable to the location of the JIA is the most common type of arthritis in children.
nodule near a peripheral nerve.31–33 It affects about 1 in 1000 children, or about 300,000
Nodules may be treated by disease-modifying anti- children in the United States.34 The American College
rheumatic drugs (DMARDs). DMARDs can reduce of Rheumatology classifies juvenile RA into three dis-
the size of the nodules. If nodules are thought to tinct subtypes: pauciarticular juvenile RA, polyarticular
be a result of methotrexate treatment, a change in juvenile RA, and systemic juvenile RA. Other child-
medication regimen may help; however, this deci- hood arthritides, such as juvenile ankylosing spondyli-
sion must be made carefully on an individual basis. tis (AS) and psoriatic arthritis (PsA), are classified
Injections of glucocorticoids may help shrink nodules. under SpAs (Box 4-1).34,35
Surgery sometimes is necessary if rheumatoid nodules The etiology and progression of JIA are not com-
become infected, result in progressive symptoms, or are pletely understood. An external factor (e.g., bacterial
2560_Chapter 4_0035-0052.indd 39 3/16/2015 4:14:39 PM

Process CyanProcess
YellowProcess Black
Box 4-1
The pathogenesis of JIA involves humoral and cell-
mediated immunity. T lymphocytes and macrophages/
Classification System of Juvenile Idiopathic Arthritis monocytes have a central role, releasing local and sys-
temic proinflammatory cytokines (e.g., TNF-α, IL-6,
Systemic arthritis: Also called Still’s disease, this type IL-1) and favoring a type 1 helper T-lymphocyte
occurs in about 10%–20% of children with JIA. A response. A complex interaction between type 1 and
systemic illness is one that can affect the entire person type 2 T-helper cells has been postulated. Studies of
or many body systems. Systemic JIA usually causes a T-cell receptor expression confirm recruitment of T
high fever and a rash, which most often appears on lymphocytes specific for synovial nonself antigens. Evi-
the trunk, arms, and legs. Multiple organ systems are
dence for abnormalities in the humoral immune system
involved. The heart, liver, spleen, and lymph nodes
may be symptomatic. Systemic arthritis typically affects
includes the increased presence of autoantibodies
boys and girls equally and rarely affects the ocular (especially ANAs), increased serum immunoglobulins,
system. presence of circulating immune complexes, and com-
Oligoarthritis: This type of JIA affects fewer than five plement activation.36
joints in the first 6 months of disease, most often the Chronic inflammation of synovium is characterized
knee, ankle, and wrist joints. Ocular symptoms are by B-lymphocyte infiltration and expansion. Macro-
common including uveitis, iridocyclitis, or iritis. About phages and T-cell invasion are associated with the
half of all children with JIA have this type, and it is release of cytokines, which evoke synoviocyte prolifera-
more common in girls than in boys. Symptoms diminish tion, angiogenesis, and interarticular and periarticular
by adulthood. scarring. A study by Scola et al.37 found synovium
Polyarthritis: This type of JIA affects five or more joints in to contain messenger RNA for vascular endothelial
the first 6 months, often the same joints on each side
of the body. Polyarthritis can also affect the neck and
growth factor, angiopoietin 1, and their respective
jaw joints and small joints such as those in the hands receptors, suggesting that induction of angiogenesis by
and feet. It is more common in girls than in boys. products of lymphocytic infiltration may be involved
Psoriatic arthritis: This type of arthritis affects children in persistence of disease.38
who have arthritis associated with psoriasis. Nail Systemic-onset JIA may be more accurately classi-
changes are common. The arthritis can precede the fied as an autoinflammatory disorder, such as familial
rash by many years or vice versa. Mediterranean fever (FMF) or cryopyrin-associated
Enthesitis-related arthritis: This type of arthritis often periodic fever syndromes, than other subtypes of JIA.
affects the spine, hips, and enthesis and occurs mainly This theory is supported by work demonstrating similar
in boys older than 8 years. The eyes are often affected expression patterns of a phagocytic protein (S100A12)
in this type of arthritis. There is often a family history of in systemic-onset JIA and FMF as well as the same
arthritis of the back (spondylitis) in male relatives.
marked responsiveness to IL-1 receptor antagonists.
Data compiled from Carbajal-Rodriguez L, Perea-Martinez A, FMF is associated with mutations in the MEFV gene.
Loredo-Abdala A, Rodriguez-Herrera R, del Angel-Aguilar A, Reynes- These mutations are associated with activation of the
Manzur JN. Neurologic involvement in juvenile rheumatoid arthritis. Bol
Med Hosp Infant Mex. 1991;48:502–508; El-Sayed ZA, Mostafa IL-1β pathway, resulting in inflammation.38 A study by
GA, Aly GS, El-Shahed GS, El-Aziz MM, El-Emam SM. Ayaz et al.39 of Turkish children with a diagnosis of
Cardiovascular autonomic function assessed by autonomic function systemic JIA found an increased frequency of MEFV
tests and serum autonomic neuropeptides in Egyptian children and
adolescents with rheumatic diseases. Rheumatology (Oxford). mutations; this study has not been replicated in other
2009;48:843–848; Lindehammar H, Lindvall B: Muscle involvement populations.
in juvenile idiopathic arthritis. Rheumatology (Oxford). Peripheral neurological complications associated
2004;43:1546–1554; Pineda Marfa M. Neurological involvement in
rheumatic disorders and vasculitis in childhood. Rev Neurol. with JIA are relatively rare. The complication of visual
2002;35:290–296; Quartier P, Taupin P, Bourdeaut F, et al. Efficacy loss or decreased vision is associated with iridocyclitis
of etanercept for the treatment of juvenile idiopathic arthritis according or uveitis rather than direct involvement with the
to the onset type. Arthritis Rheum. 2003;48:1093–1101; and Ayaz
NA, Ozen S, Bilginer Y, et al. MEFV mutations in systemic onset optic nerve. Peripheral neurological manifestations are
juvenile idiopathic arthritis. Rheumatology (Oxford). 2009;48:23–25. typically secondary to tension or compressive neuropa-
thies associated with synovitis, joint instability or
contracture, reduction via arthroplasty of long-joint
or viral infection, trauma) triggering an autoimmune contractures with concomitant adaptive shortening of
cascade and leading to synovial hypertrophy and the peripheral nerve, or abnormal biomechanics.34–38
chronic joint inflammation along with the potential
for extra-articular manifestations is theorized to occur Systemic Lupus Erythematosus
in genetically susceptible individuals. JIA is a geneti- Systemic lupus erythematosus (SLE) is a multisystem
cally complex trait in which multiple genes are impor- autoimmune disease with protean manifestations char-
tant for disease onset and manifestations. The IL2RA/ acterized by acute and chronic inflammation of various
CD25 gene has been implicated as a JIA susceptibility tissues of the body. SLE may result in disease of the
locus, as has the VTCN1 gene.35–37 skin, heart, lungs, kidneys, joints, or nervous system.
2560_Chapter 4_0035-0052.indd 40 3/16/2015 4:14:39 PM

Process CyanProcess
YellowProcess Black
When only the skin is involved, the condition is called Involvement of the CNS, PNS, and autonomic
lupus dermatitis or cutaneous lupus erythematosus. nervous system (ANS) in SLE is common. CNS lupus
Discoid lupus is a form of lupus dermatitis that can be may manifest with a spectrum of signs and symptoms
isolated to the skin, without internal disease. When including headache, cognitive loss, fatigue, depression,
internal organs are involved, the condition is referred anxiety, seizure, stroke, central vision loss, and variabil-
to as SLE. Both discoid lupus and SLE are more ity in mood. Adding confusion is the fact that medi-
common in women than men (about eight times more cations used to treat SLE—NSAIDs, corticosteroids,
common).40 The disease can affect individuals of all immune-modulating drugs, and antihypertensives—
ages but most commonly manifests in individuals 20 may have similar side effects.45 CNS vasculitis, a rare but
to 45 years old. Statistics demonstrate that lupus is potentially lethal complication, is characterized by high
more frequent in African Americans and people of fevers, seizures, psychosis, and meningitis-like stiffness
Chinese and Japanese descent.40 of the neck. CNS vasculitis is the most dangerous
Genetic factors increase the likelihood of developing form of lupus involving the nervous system and usually
autoimmune diseases, and autoimmune diseases such requires recurrent hospitalizations and high doses of
as lupus, RA, and autoimmune thyroid disease are more corticosteroids to suppress the inflammation.46–48
common among relatives of people with lupus than the PNS lupus may be caused by direct trauma to
general population. Some researchers hypothesize that peripheral nerves related to expansive articular or
the immune system in lupus is more easily stimulated muscle edema or due to generalized systemic inflam-
by external factors such as viruses or ultraviolet light.40,41 mation. Compressive and tensile neuropathies such as
Symptoms of lupus sometimes can be precipitated or tarsal tunnel syndrome, carpal tunnel syndrome, and
aggravated by only a brief period of sun exposure or the cervical or lumbosacral radiculopathy are common.
onset of the menstrual period. More recently, research Cranial nerve symptoms may include loss of visual
has demonstrated evidence that failure of a key enzyme acuity, diplopia, trigeminal neuralgia, tinnitus, vertigo,
to dispose of dying cells may contribute the develop- and ptosis.47
ment of SLE. The enzyme, DNase1, normally elimi- ANS lupus is typically the result of nonspecific
nates what is called “garbage DNA” and other cellular nerve inflammation. Aberrant resting and exercise
debris by chopping them into tiny fragments for easier heart rate, blood pressure, and positional responses
disposal. In DNase1 knockout mice, the mice appeared such as orthostatic hypotension are common. Percep-
healthy at birth, but after 6 to 8 months, most mice tions of abnormal corporal coldness or warmth have
without DNase1 showed signs of SLE.42 been reported. Gastric motility issues are common
Neurological impairments, symptoms, and signs are including constipation, vomiting, and diarrhea. Incon-
quite common in SLE. Neuropsychiatric signs are tinence or inability to void is often reported. The
present in 60% of persons with SLE.40 Demyelinating “fishnet” appearance on the arms and legs are a common
syndrome and myelopathy are 2 of the 19 defined sign of livedo reticularis and palmar erythema com-
syndromes associated with neuropsychiatric SLE.40–42 monly seen with ANS lupus.48 Raynaud’s phenomenon
The term lupoid sclerosis is used to describe the mani- is a common complaint of patients with ANS lupus
festation of neurological signs and symptoms of SLE (Fig. 4-3).
similar to those of multiple sclerosis (MS). Presenting Symptoms of cognitive dysfunction, often referred
complaints of lupoid sclerosis are often indistinguish- to in the lay literature as “lupus fog,” are described by
able from presenting complaints of early MS. Signs 50% of patients with SLE. Symptoms include confu-
and symptoms of lupoid sclerosis include neuropsychi- sion, fatigue, memory loss, and difficulty expressing
atric disorders such as bipolar disorder, generalized thoughts and needs. Cognitive dysfunction most often
anxiety disorder, and depression; headache; gait dys- affects patients with mild to moderately active lupus.
function; paresthesia; and seizure. MRI offers the best Cognitive symptoms are variable.45,46,49 Compared with
combination of sensitivity and specificity to confirm or the general population, patients with lupus are twice as
rule out MS. ANA, previously considered a strong dif- likely to experience migraine headaches, commonly
ferentiator between lupoid sclerosis and MS, has been known as “lupus headaches.” The features of lupus
found not to be sufficiently specific; ANAs were found headaches are similar to migraines and may be seen
in patients with MS at a frequency of 2.5% to 81%, more often in patients who also have Raynaud’s phe-
although no correlation between the presence of ANA nomenon. However, headaches can also be caused by
and symptoms of SLE was established in many vasculitis.46
studies.43 Despite these results, clinically, when ANA
titers are high and persistent and appear in the context Primary Sjögren’s Syndrome
of other autoimmune diagnostic signs, a diagnosis of Sjögren’s syndrome (SS), also known as sicca syndrome
SLE should be strongly considered. Visual evoked and Mikulicz disease, is a chronic autoimmune exocri-
potentials are rarely typically normal in patients with nopathy, which, in addition to the two most common
MS and act as a differentiator between MS and SLE.44 characteristics of xerostomia (dry mouth) and dry eyes,
2560_Chapter 4_0035-0052.indd 41 3/16/2015 4:14:40 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
the lower lip are often used to obtain a biopsy sample
of the salivary gland tissue.50,51
Patients with SS typically produce various autoan-
tibodies, including ANAs, which are present in nearly
all patients. Typical antibodies that are found in most,
but not all, patients are SS-A and SS-B antibodies (SS
A and B antibodies), RF thyroid antibodies, and others.
Anemia and an elevated erythrocyte sedimentation
rate are typical findings in patients with SS. The absence
of antibodies (ANA, anti-La, RF) does not automati-
cally exclude a diagnosis of SS, although most patients
with SS do have the antibodies.50,51
Neurological signs and symptoms have been reported
in 20% to 35% of patients with SS.51 However, some
studies report a strongly negative association. Neuropa-
Figure 4-3 Raynaud’s phenomenon is a vasospastic disorder thies are characterized by paresthesias, which can com-
of the hands and feet. When exposed to cold, the arteries prise numbness and tingling or painful dysesthesias
in the fingers, toes, earlobes, and occasionally other parts such as burning and aching. The neurological examina-
of the body constrict, severely limiting blood flow. Often tion may be normal despite clinical complaints because
a complication of rheumatological disease, Raynaud’s of involvement of small fibers. The lower extremities
phenomenon is an autonomic nervous system impairment are more involved than the upper extremities.52
resulting in a permanent or intermittent diminished blood Types of possible neuropathies include sensory neu-
flow primarily to the distal hands and feet resulting in loss ropathy or dorsal root ganglioneuropathy. Patients may
of tactile sensation and a feeling of “coldness.” Blood flow present with a history of a fall, ataxia, loss of vibration
may be so impaired as to lead to ischemic skin lesions. and position sense, or hyperalgesia. There also may be
alterations in appreciation of pain and temperature
with hypoesthesia. Reflexes may be absent, especially
in the lower extremities.53
may have extraglandular manifestations in various Motor involvement can occur along with sensory
organ systems. Approximately 4 million Americans involvement. Weakness, if present, is typically subacute
have SS. Women account for 9 out of 10 patients.50 and symmetrical. There can also be a rapidly progres-
SS may occur alone or in the presence of another sive course of weakness to include a mononeuritis
autoimmune connective tissue disease such as RA, multiplex. Asymmetrical findings as well as stocking-
lupus, or scleroderma. When SS occurs alone, it is glove distribution of motor weakness have also been
referred to as primary SS. When it occurs with reported.53
another connective tissue disease, it is referred to as Polyradiculoneuropathy may be present. Polyradicu-
secondary SS. loneuropathy associated with SS is characterized by
Because symptoms of SS mimic other conditions findings mimicking disc abnormalities with nerve root
and diseases, it can often be overlooked or misdiag- pain and weakness in a radicular distribution.
nosed. On average, it takes nearly 7 years to make a Trigeminal sensory neuropathy can occur and may be
diagnosis of SS.50 SS often goes unrecognized because characterized by progressive sensory complaints involv-
of the spectrum and varying intensity of signs and ing the face. These sensations are generally spontaneous
symptoms. and nonlancinating. They typically begin unilaterally
The diagnosis of SS involves detecting the features and subsequently become bilateral. They may be pro-
of dryness of the eyes and mouth. The dryness of the gressive over months to years. Motor involvement of
eyes can be determined by testing the ability of the eye the fifth cranial nerve with associated impairment of
to wet a small testing paper strip placed under the chewing and jaw movements is uncommon. There can
eyelid (Schirmer’s test using Schirmer tear test strips). be tissue destruction around the nostrils because of
More sophisticated testing can be performed by an picking and scratching secondary to abnormal sensa-
ophthalmologist. tions, corneal ulcerations, lingual ulcerations, and alter-
Salivary glands can become larger and harden or ation of taste and smell.53 Other cranial nerves can be
become tender. Salivary gland inflammation can be involved, such as the second cranial nerve, resulting in
detected by nuclear medicine salivary scans. Also, the signs associated with optic neuritis.54 In some patients,
diminished ability of the salivary glands to produce the optic signs occurred before the diagnosis of SS. SS
saliva can be measured with salivary flow testing. The should be considered in any patient with unexplained
diagnosis of SS is strongly supported by abnormal find- optic neuropathy and serological abnormalities sugges-
ings of a biopsy of salivary gland tissue. The glands of tive of a connective tissue disorder.54
2560_Chapter 4_0035-0052.indd 42 3/16/2015 4:14:40 PM

Process CyanProcess
YellowProcess Black
Multiple mononeuropathies, such as carpal tunnel matter lesions seen on MRI resemble lesions found
syndrome, ulnar neuropathy, or tarsal tunnel syndrome, in MS. In end-stage ABD, atrophy of the brainstem
can occur. There can be autonomic neuropathy with rather than cortical atrophy is a classic finding, which
anhydrosis, postural hypotension, and bradycardia differs from MS. Patients with ABD also have different
leading to light-headedness and dizziness with change serum and cerebrospinal fluid cytokine and chemokine
of body position.54 profiles and concentrations than typically seen with
MS. Progression of impairment in MS tends to be
Adamantiades-Behçet Disease polyphasic, whereas impairments with ABD tend to
Adamantiades-Behçet disease (ABD), often referred be slow-progressive.57
to as Behçet disease, is an inflammatory, multisystem Clinical manifestations of ABD include optic
disorder affecting primarily arteries and veins and pathology primarily secondary to necrosis and perivas-
characterized by erythema nodosum—skin lesions cular demyelination with macrophage/monocyte infil-
involving the dermis, oral mucosa, and genitalia—and tration of the optic nerves and cognitive and focal
uveitis.55 The incidence is highest in people living motor signs. Motor signs, especially tonal changes, are
around the Mediterranean basin and in Japan.56 The typically present whether the involvement is central or
mean age at onset is the third decade of life.57 Children peripheral. Sensory impairment is rarely seen even with
are rarely affected, and few neonatal cases have been fairly dense motor neuropathy.58,59 Memory tends to be
reported. In large series of patients, the incidence is affected in most cases, particularly affecting recall and
greater in men than in women.56 Infectious agents, learning. Orientation (time, place, person) and calcula-
immune mechanisms, and genetic factors are impli- tive math skills appear unaffected. Behavioral changes,
cated in the etiopathogenesis of the disease, which primarily apathy, depression, or disinhibition, occur in
remains to be determined. The pathology of the lesions 54% of cases.59
consists of widespread vasculitis; eyes, skin, joints, the
oral cavity, blood vessels, and CNS are usually involved, Seronegative Spondyloarthropathies
although less frequently the heart, lung, kidney, genital Seronegative SpAs include AS, reactive arthritis (ReA),
system, gastrointestinal tract, and PNS may be affected. PsA, arthritis associated with ulcerative colitis, and
The prognosis of the disease is improved with early Crohn’s disease, plus other forms that do not meet the
diagnosis and suitable treatment. Treatment comprises criteria for definite categories and are labeled as undif-
local therapies and systemic administration of colchi- ferentiated seronegative SpAs. Two sets of classifica-
cine, corticosteroids, immunosuppressives, and other tion criteria have been proposed more recently for
agents (Fig. 4-4).57,58 the entire group including undifferentiated forms: the
Neurological manifestations are present in 10% European Spondyloarthropathies Study Group and
to 50% of patients.56 Most are late manifestations of the Amor criteria.60
the disease; manifestations occur 1 to 8 years after SpAs, or spondyloarthritides as proposed more
diagnosis. As is the case with many connective tissue recently, represent a group of distinct diseases with
diseases and vasculopathies, there is often early diag- similar clinical features and a common genetic predis-
nostic confusion with MS. Multiple hemispheric white position. The five major subtypes are AS, PsA, ReA,
inflammatory bowel disease–associated SpA (IBD-
SpA), and undifferentiated SpA. The main recognized
genetic association is with HLA-B27, but it is clear
that there are other genes involved.
According to the European Spondyloarthropathy
Study Group (ESSG) criteria, IBD is a criterion of
SpA; psoriasis or enteric infections are two other mani-
festations included in the ESSG criteria for identifying
patients with PsA and ReA. Patients with IBD pre-
senting with inflammatory back pain or synovitis (pre-
dominantly of the lower limbs) are given a diagnosis
of SpA. The ESSG criteria, designed to be applicable
without radiological examination and laboratory
testing, have good sensitivity (75%) and specificity
(87%), at least in established disease. An alternative
classification scheme was suggested by Amor et al.,
Figure 4-4 Adamantiades-Behçet disease is an inflammatory, which is more complicated but has improved sensitiv-
multisystem disorder primarily affecting the vasculature and ity (85%) and specificity (90%) owing to the incor-
often characterized by erythema nodosum—skin lesions poration of common extra-articular manifestations of
involving the dermis, oral mucosa, and genitalia. disease, including enthesopathy, dactylitis, eye disease,
2560_Chapter 4_0035-0052.indd 43 3/16/2015 4:14:40 PM

Process CyanProcess
YellowProcess Black
and HLA-B27 positivity. The basic concepts underly-
ing each classification set are similar.60
The prevalence of SpAs is directly correlated with
the prevalence of the HLA-B27 antigen in the popula-
tion. The highest prevalence of AS (4.5%) has been
found in Canadian Haida Indians61; 50% of this popu-
lation is HLA-B27–positive. Among Europeans, the
frequency of the HLA-B27 antigen in the general
population ranges from 3% to 13%, and the prevalence
of AS is estimated to be 0.1% to 0.23%.
Seronegative SpAs have common clinical and radio-
logical manifestations, including inflammatory spinal
pain, sacroiliitis, chest wall pain, peripheral arthritis,
peripheral enthesitis, dactylitis, lesions of the lung
apices, conjunctivitis, uveitis, and aortic incompetence
together with cardiac conduction disturbances. These
symptoms may occur in tandem or groups or in
isolation.62
Ankylosing Spondylitis
The term ankylosing spondylitis derives from the
Greek roots ankylos (crooked or bent) and spondylos
(facet joint of the back). The name of the disease is
evocative of the severely kyphotic, forward head posture
exhibited by patients with advanced cases of AS. This
disease is also known as rheumatoid spondylitis,
Figure 4-5 Ankylosing spondylitis is a progressive
Bechterew syndrome, and Marie-Strümpell spondyli-
inflammatory disorder of the facet joints that may also
tis. AS is a progressive inflammatory disorder of the
affect extra-articular connective tissues. Initial complaints
facet joints that may also affect extra-articular con-
are early morning stiffness that is relieved by activity.
nective tissues and is the principal example of the
Eventually, intra-articular scarring leads to an immobile
seronegative SpAs. The hallmark initial symptoms of
spine.
inflammatory low back and joint stiffness usually first
appear insidiously in late adolescence or early
adulthood—80% of the time before age 30—and affect
men about twice as often as women (Fig. 4-5).63 Osteoporosis is another widespread extra-articular
The most common initial symptoms are low back feature of the disease.63–65 Patients commonly expe-
pain and joint stiffness occurring primarily in the early rience fatigue, which is often the product of muscle
morning.63–65 The low back pain and joint stiffness are imbalance and the need to expend energy to maintain
worsened by rest and relieved by activity. Articular pain an upright posture, and may be prone to other consti-
may spread to the chest and buttocks or may first tutional symptoms such as weight loss and low-grade
appear appendicularly (especially in the hips or shoul- fevers. Risk of falling is common. AS may affect the
ders), rather than axially, in one fifth of patients. Ini- eyes, digestive tract, heart, kidney, lungs, or nervous
tially, radiating pain to one buttock may be mistaken system (Box 4-2).
as a symptom of thoracic, lumbar, or sacral radiculopa-
thy; however, the buttock pain eventually becomes Reactive Arthritis
bilateral and is not accompanied by motor or sensory Previously known as Reiter’s syndrome, reactive,
symptoms or signs. Reflexes are typically preserved. RF-seronegative, HLA-B27–linked SpA arthritis, is
Over years to decades, the axial and appendicular artic- an autoimmune disorder that develops in response to
ular symptoms become more pronounced. In a few an infection—hence the adjective “reactive” in its
patients, the axial articular manifestations may eventu- name.67,68 ReA is also known as arthritis urethritica,
ally reach the point where the entire spine is effectively venereal arthritis, and polyarteritis enterica. The former
fused into a single, markedly kyphotic unit, resulting name Reiter’s syndrome, after German physician Hans
in spinal immobility.66 Conrad Reiter, was discredited when Reiter’s history
Extra-articular symptoms of AS manifest as the of eugenics, Nazi party membership, human experi-
disease evolves. Enthesitis frequently ensues, espe- ments in the Buchenwald concentration camp, and
cially at sites of greater physical stress, and results prosecution in Nuremburg as a war criminal came to
in considerable extra-articular tenderness and pain. light.69
2560_Chapter 4_0035-0052.indd 44 3/16/2015 4:14:40 PM

Process CyanProcess
YellowProcess Black
Box 4-2 Table 4-2 Percent Sensitivity and Specificity of Criteria

for Typical Reactive Arthritis
Organ-Specific Extraskeletal Manifestations or Associations of
Ankylosing Spondylitis Method of Diagnosis Sensitivity (%) Specificity (%)
1. Episode of arthritis of more 84.3 98.2
Eyes
than 1 month with urethritis
Acute anterior uveitis or cervicitis or both
Gastrointestinal
2. Episode of arthritis of more 85.5 96.4
Crohn’s disease than 1 month and either
Heart/vascular urethritis or cervicitis or
Aortic inflammation bilateral conjunctivitis
Aortic valve incompetence 3. Episode of arthritis, 50.6 98.8
Arrhythmia conjunctivitis, and urethritis
Cardiomegaly 4. Episode of arthritis of more 48.2 98.8
Pericarditis than 1 month, conjunctivitis,
Vertebrobasilar artery insufficiency and urethritis
Kidneys
IgA nephropathy
Amyloidosis
Lungs is more common in white men than in black men. The
Apical lobe fibrosis last-mentioned is due to the fact that white individuals
Reduced tidal volume
are more likely to have tissue type HLA-B27 than
black individuals. Persons who are HIV-positive have
Reduced maximum oxygen
an increased risk of developing ReA.73
Restrictive lung disease The manifestations of ReA include a combination
Nervous system of three seemingly unlinked disorders: an inflamma-
Radiculopathy tory polyarthritis of large joints, often including the
Cauda equina syndrome spine; conjunctivitis or uveitis of the eyes; and urethri-
Myelopathy tis in men or cervicitis in women. A useful mnemonic
Vertebrobasilar insufficiency is “the patient can’t see, can’t pee, can’t bend the knee”
Peripheral neuropathy or “can’t see, can’t pee, can’t climb a tree.”73 A fourth,
relatively common manifestation is a complex of
Data compiled from Nanke Y, Kotake S, Goto M, Matsubara M,
Ujihara H. A Japanese case of Behcet’s disease complicated by psoriasis-like skin lesions, including the rashes circi-
recurrent optic neuropathy involving both eyes: a third case in the nate balanitis and keratoderma blennorrhagicum
English literature. Mod Rheumatol. 2009;19:334–337; Rudwaleit M, (Fig. 4-6). The pathogenesis and broad spectrum of
van der Heijde D, Landewé R, et al. The development of assessment
of Spondyloarthritis International Society classification criteria for axial symptoms and signs of ReA may result from the
spondyloarthritis (part II): validation and final selection. Ann Rheum Dis. complex interplay of genetic factors (HLA-B27) and
2009;68:777–783; Olivieri I, Barozzi L, Padula A, De Matteis M, environmental factors—molecular mimicry between
Pavlica P. Clinical manifestations of seronegative spondylarthropathies.
Eur J Radiol. 1998;27(Suppl 1):S3–6; Barozzi L, Olivieri I, De Matteis bacterial fragments in synovial fluid and the HLA-B27
M, Padula A, Pavlica P. Seronegative spondylarthropathies: imaging of molecule. Most patients (75% to 85%) with ReA
spondylitis, enthesitis and dactylitis. Eur J Radiol. 1998;27(Suppl 1): are positive for HLA-B27 compared with 7% in the
S12–17; and Rehart S, Kerschbaumer F, Braun J, Sieper J. Modern
treatment of ankylosing spondylitis. Orthopade. general population. The arthritis may be induced by
2007;36:1067–1078. the manifestation of cytotoxic T lymphocytes by
microbial fragments in the joints, but these cytotoxic
lymphocytes have specificity for the HLA-B27 cells.
The “trigger” infection is often healed or is in remis- The presence of HLA-B27 may allow for more persis-
sion making determination of the etiological microbe tent and destructive axial and appendicular skeletal
difficult. The most common triggers are sexually infections.74,75
transmitted chlamydial infection and, perhaps less Nervous system involvement in ReA is extremely
commonly, gonorrhea. Salmonella, Shigella, and Cam- rare. The literature documents a few cases of patients
pylobacter intestinal infections have also been impli- who initially presented with progressive cervical
cated. ReA has also been reported to occur after tetanus myelopathy and were diagnosed as having ReA 2 years
and rabies vaccinations. ReA usually manifests about 1 later. The myelopathy was stable after treatment with
to 3 weeks after a known infection (Table 4-2).70–72 methotrexate and sulfasalazine. These cases suggest
ReA most commonly affects individuals 20 to 40 that ReA can manifest as progressive myelopathy and
years old, is more common in men than in women, and should be considered in the differential diagnosis of
2560_Chapter 4_0035-0052.indd 45 3/16/2015 4:14:40 PM

Process CyanProcess
YellowProcess Black
Box 4-3
Presentations of Psoriatic Arthritis

Arthritis mutilans: This extremely severe form of chronic
psoriatic arthritis and rheumatoid arthritis is
characterized by resorption of bones and the
consequent collapse of soft tissue; when this affects the
hands, it can cause a phenomenon sometimes referred
to as “telescoping fingers.” Similar changes can occur
in the feet.
Asymmetric psoriatic arthritis: The mildest form of
psoriatic arthritis typically affects joints on only one side
of the body or different joints on each side hip, knee,
ankle, or wrist joints. Fewer than five joints are
generally involved. When asymmetric arthritis occurs in
the hands and feet, swelling and inflammation in the
tendons can cause fingers and toes to resemble small
sausages (dactylitis).
Distal interphalangeal joint–predominant arthritis: Distal
interphalangeal joint–predominant psoriatic arthritis
occurs in only about 5%–10% of patients with psoriatic
arthritis. The primary features are involvement of the
distal joints of the fingers and toes (the joint closest to
the nail) and evidence of nail changes.
Spondylitis: Spondylitis can cause inflammation in the
facet joints of the vertebral spine and the sacroiliac
joints. Inflammatory changes can also occur at the
Figure 4-6 This patient presented with what was diagnosed
insertion of ligaments and tendons on the spine. As the
as reactive arthritis with accompanying circinate balanitis disease progresses, movement tends to become
of the glans penis. In reactive arthritis, a useful mnemonic increasingly painful, and range of motion becomes
is “the patient can’t see, can’t pee, can’t bend the knee” or limited.
“can’t see, can’t pee, can’t climb a tree” (73). A fourth, Symmetric psoriatic arthritis: Symmetric psoriatic arthritis
relatively common manifestation is a complex of psoriasis- usually affects five or more of the same joints on both
like skin lesions, including rashes termed circinate balanitis sides of the body. More women than men have
and keratoderma blennorrhagicum. symmetric psoriatic arthritis, and psoriasis associated
with this condition tends to be severe.
Data compiled from Narayanaswami P, Chapman KM, Yang ML,
Rutkove SB. Psoriatic arthritis-associated polyneuropathy: a report of
treatable myelopathies. There have also been fragmen- three cases. J Clin Neuromuscul Dis. 2007;9:248–251; Rothenberg
tary reports of polyneuropathy—primarily small-fiber RJ, Sufit RL. Drug-induced peripheral neuropathy in a patient with
sensory, cranial nerve palsy and myelopathy.75 psoriatic arthritis. Arthritis Rheum. 1987;30:221–224; and Kane D,
Stafford L, Brenihan B, Fitzgerlad O. A prospective, clinical and
radiological study of early psoriatic arthritis: an early synovitis clinic
Psoriatic Arthritis experience. Rheumatology. 2003;42:1460–1468.
PsA is a multigenic autoimmune disease that involves
synovial tissue, entheseal sites, and skin, and often
results in significant appendicular joint damage. in which the CD8+ T cell plays a central role. Finally,
Although there are no diagnostic tests for PsA, research in contrast to RA, imaging and cytokine studies have
has identified consistent features that help to distin- demonstrated entheseal involvement in PsA, and it is
guish the condition from other common rheumatic possible that entheseal-derived antigens may trigger an
and connective diseases. Comparison of HLA-B immune response that is critically involved in the
and HLA-C regions in patients with PsA with these disease pathogenesis and progression (Box 4-3).77
regions in patients with psoriasis without joint involve- In contrast to most other rheumatic diseases, hered-
ment demonstrates significant differences, and PsA ity influence plays a strong role in the development
cannot be viewed simply as a subset of genetically of PsA. About 15% of the relatives of a patient with
homogeneous psoriasis.76 T-cell receptor phenotypic PsA also have PsA, and an additional 30% to 45%
studies have failed to identify antigen-driven clones, have psoriasis. The presence of either psoriasis or
and an alternative hypothesis for CD8 stimulation PsA in a family member of a patient with signs and
involving innate immune signals is proposed. There is symptoms suggestive of PsA provides support for the
increasing evidence that PsA is an autoimmune disease diagnosis.78
2560_Chapter 4_0035-0052.indd 46 3/16/2015 4:14:40 PM

Process CyanProcess
YellowProcess Black
Enteropathic Arthritis
Inflammation of axial or peripheral joints is one of the
most frequent extraintestinal manifestations compli-
cating the clinical course and therapeutic approach in
Normal Pencil-in-cup
IBD. Musculoskeletal manifestations occur in 20% to
50% of patients with IBD.81–83 The frequency of these
complications seems to be similar for both Crohn’s
disease and ulcerative colitis. Arthritis associated with
IBD belongs to the category of SpAs. Axial involve-
ment ranges from isolated inflammatory back pain to
AS, whereas peripheral arthritis is noted in periarticu-
lar and polyarticular disease. Asymptomatic radiologi-
cal involvement of the sacroiliac joints is reported to
occur in 50% of patients.83 Other musculoskeletal
manifestations, such as buttock pain, dactylitis, calca-
neal enthesitis, and thoracic pain, are frequently under-
Figure 4-7 Schematic representation of the “pencil-in-cup” diagnosed and consequently are not treated appropriately.
interdigital deformity associated with psoriatic arthritis. Several diagnostic approaches and criteria have been
proposed over the past 40 years in an attempt to classify
and diagnose such manifestations correctly. The correct
recognition of SpAs requires an integrated multidisci-
The classic radiological features of PsA include new plinary approach to identify common therapeutic strat-
bone formation at entheseal sites; bone resorption or egies, especially in the era of the new biological
osteolysis; sacroiliitis, which is often asymmetrical; and therapies.84
the hallmark “pencil-in-cup” deformity of the inter- The recognition of this entity is based on clinical
phalangeal and metacarpophalangeal or tarsophalan- diagnosis (e.g., joint swelling and tenderness) but
geal joints (Fig. 4-7), which results from a combination may be confirmed by ultrasound examination83 or
of new bone formation and osteolysis. These features MRI,84,85 whereas conventional radiographs usually are
sometimes have diagnostic utility, but none are specific, not helpful. Enthesitis is inflammation at the site of
and more often the radiological features in PsA are the tendon, ligament, and joint capsule insertion to
either minimal or nonspecific. For example, erosions bone. The most frequent clinical expressions are Achil-
occur in PsA but less frequently than in RA, and the les tendinitis, plantar fasciitis, and pain and swelling of
rate of development of new erosions is much slower. In the tibial tubercle.86
one study of patients with early PsA, 47% of patients Two subtypes of peripheral arthritis are recognized.86
had developed erosive disease at 2 years, but the number Type 1 involves fewer than five joints and is clinically
of erosions increased from a mean of 1.2 (±2.9) to a characterized by acute self-limiting attacks of less than
mean of only 3 (±5.2). Although this increase was 10 weeks’ duration often paralleling intestinal inflam-
significant (P = 0.002), the number of new erosions matory activity. It is also strongly associated with other
over a similar time frame is fewer than described in extraintestinal manifestations of IBD such as erythema
RA.79 In contrast, new bone formation is not a feature nodosum. Type 2 peripheral arthritis is polyarticular,
of RA. The use of MRI in PsA has emphasized the involving five or more joints with symptoms that persist
importance of enthesitis with bone marrow edema for months and years running independently from IBD
occurring at entheseal sites.80 As a result of these flares. This type is associated with uveitis but not with
observations, it has been proposed that involvement of other extraintestinal manifestations. Both types are
the enthesis is the primary event in PsA, with synovial seronegative, usually nonerosive and nondeforming,
involvement occurring later and in a nonspecific but may become chronic and erosive in 10% of patients.
manner.80 In addition, no significant association has been shown
Neurological symptoms associated with PsA are between peripheral arthropathies and HLA-B27 in
relatively rare compared with RA and are associ- IBD. A type 3 peripheral arthritis has been proposed,
ated with the more severe and progressive forms of which includes patients with both axial involvement
PsA: spondylitis and arthritis mutilans. Symptoms and peripheral arthritis.87
are typically related to compression or tension of a Dactylitis is characterized by inflammatory swelling
peripheral nerve—related to articular and osteogenic of one or more fingers (“sausage” fingers) or toes caused
changes affecting the local nerve and nerve trunk. by tenosynovitis of the flexor tendons and sheaths.
Motor, sensory, and autonomic nerve involvement is Metacarpophalangeal or proximal interphalangeal
possible.77,78 joint arthritis may also be present (Fig. 4-8). Thoracic
2560_Chapter 4_0035-0052.indd 47 3/16/2015 4:14:40 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
supplements are typically used to correct deficiencies.
Short-term or long-term corticosteroids may be pre-
scribed for refractory disease.
The exact cause of celiac disease is unknown. The
intestines contain projections (called villi) that absorb
nutrients. In undiagnosed or untreated celiac disease,
these villi become flattened, which affects the ability to
absorb nutrients properly. The disease can develop at
any point in life, from infancy to late adulthood. People
with a family member with celiac disease are at greater
risk for developing the disease. The disorder is most
common in Caucasians and those of European ances-
try. Women are affected more commonly than men.89
Symptoms of peripheral neuropathy associated
with celiac disease are often related to osteoporosis.
In one study, anemia was the most common manifesta-
tion accounting for 66% of patients.89 Less than half
of the patients had any of the classic symptoms of
celiac disease, and 25% had none of the classic symp-
toms at presentation.90 Anti-gliadin antibodies, anti-
Figure 4-8 Dactylitis (“sausage” fingers) is characterized by endomysial antibody, and anti–tissue transglutaminase
inflammatory swelling of one or more fingers or toes showed 75%, 68%, and 90% sensitivity. In combina-
secondary to tenosynovitis of the flexor tendons and tion, serology results were 100% sensitive as screen-
sheaths. One of the many causes of dactylitis is ing tests for adult celiac disease. Either osteoporosis
enteropathic arthritis. or osteopenia was present in 59% of patients. There
were no malignant complications observed during the
follow-up of our patients.91
pain results from enthesitis of costovertebral, costoster-

nal, or manubriocostal articulations; is exacerbated by
cough and deep inspirations; limits respiratory expan-
sion; and has episodes of variable duration. Buttock
pain is part of the IBD, irradiates to the sacrum, and
CASE STUDY
may be alternating; it is related to inflammation of Chris is a 67-year-old corporate executive in whom
sacroiliac joints. rheumatoid arthritis was diagnosed 20 years ago.
Extra-articular features include uveitis (25%), aortic Surgeries related to the rheumatoid arthritis include a
insufficiency (4% to 10%), and cardiac conduction dis- left total knee arthroplasty and a right hip arthroplasty.
turbances (3% to 9%).88 These latter cardiac complica- The disease is relatively stable with methotrexate and
tions seem to be related to disease duration and are occasional nonsteroidal medications. Recently, Chris
associated with HLA-B27. has been complaining of progressive numbness in his
right hand and weakness of his thumb. He was
Celiac Disease referred to a physical therapist for evaluation and
The symptoms of celiac disease can vary significantly treatment.
from patient to patient. The spectrum of symptoms On examination, the physical therapist noted
may vary from constipation to diarrhea, to abdominal moderate right wrist edema and tenosynovitis. Finger
pain to bloating, to cramps to no pain, and this is and thumb range of motion was functional and
part of the reason the diagnosis is frequently delayed. painless, but the wrist tended to rest in 45° of ulnar
Additional symptoms may include unexpected weight deviation with −10° of passive radial deviation. Wrist
loss, lactose intolerance, nausea and vomiting, and flexion and extension range of motion were full and
decreased appetite. Nonintestinal symptoms include painless. Elbow range of motion was normal. The
anemia, bone and joint pain, osteoporosis, ecchymoses, therapist noted a large rheumatoid nodule 10 cm
dental enamel defects, alopecia, mouth ulcers, vitamin proximal to the radial styloid. Sensory examination
deficiency impairments, and fatigue.89–92 revealed loss of tactile sense of the palmar side of the
Celiac disease is treated primarily by following thumb, fore, middle, and ring fingers. Pinch
a gluten-free diet. This diet allows the diseased intes- assessments revealed a 40% decrease in strength
tinal villi to heal. In addition, vitamin and mineral compared with the uninvolved side.
2560_Chapter 4_0035-0052.indd 48 3/16/2015 4:14:40 PM

Process CyanProcess
YellowProcess Black
Case Study Questions 5. Dantzer R. Cytokine induced sickness behavior: mechanisms
and implications. Ann N Y Acad Sci. 2001;933:222–234.
1. Possible etiologies of the neuropathy include which 6. Dantzer R. Innate immunity at the forefront of
of the following? psychoneuroimmunology. Brain Behav Immun. 2001;15:7–24.
a. A traction-induced median neuropathy caused by 7. Jacobi C, Lenhard T, Meyding-Lamade U. Vasculitis of the
nervous system in infectious diseases. Nervenarzt. 2010;81:
the static ulnar deviated posture of the wrist 172–180.
b. A compressive neuropathy of the median nerve 8. Leelavathi M, Aziz SA, Gangaram HB, Hussein SH.
secondary to pressure from the rheumatoid nodule Cutaneous vasculitis: a review of aetiology and clinical
c. A compressive neuropathy of the median nerve manifestations in 85 patients in Malaysia. Med J Malaysia.
secondary to the tenosynovitis at the wrist 2009;64:210–212.
9. Rowley AH, Shulman ST. Pathogenesis and management of
d. All of the above Kawasaki disease. Expert Rev Anti Infect Ther. 2010;8:197–203.
2. Which of the following tests is the most effective test 10. Holle JU, Laudien M, Gross WL. Clinical manifestations and
treatment of Wegener’s granulomatosis. Rheum Dis Clin North
for determining location and severity of the Am. 2010;36:507–526.
neuropathy? 11. Agras PI, Guveloglu M, Aydin Y, Yakut A, Kabakus N.
a. Tinel Lower brachial plexopathy in a child with Henoch-Schonlein
b. Filament sensory testing purpura. Pediatr Neurol. 2010;42:355–358.
c. Electroneuromyogram 12. Pettersson T, Karjalainen A. Diagnosis and management of
small vessel vasculitides. Duodecim. 2010;126:1496–1507.
d. X-ray 13. Pierrot-Deseilligny Despujol C, Pouchot J, Pagnoux C, Coste
3. Which orthosis may be most indicated for this J, Guillevin L. Predictors at diagnosis of a first Wegener’s
granulomatosis relapse after obtaining complete remission.
patient? Rheumatology (Oxford). 2010;49:2181–2190.
a. A functional wrist splint placing the wrist in a 14. Hanly JG. ACR classification criteria for systemic lupus
neutral radial/ulnar deviation posture erythematosus: limitations and revisions to neuropsychiatric
b. An elbow pad variables. Lupus. 2004;13:861–864.
c. A shoulder sling 15. Rao JK, Allen NB, Pincus T. Limitations of the 1990
American College of Rheumatology classification criteria in
d. A cervical collar the diagnosis of vasculitis. Ann Intern Med. 1998;129:
4. Along with orthoses, other interventions for this 345–352.
16. Saleh A, Stone JH. Classification and diagnostic criteria in
patient, before a definitive diagnosis, would include systemic vasculitis. Best Pract Res Clin Rheumatol. 2005;19:
which of the following? 209–221.
a. Energy conservation 17. Bussone G, La Mantia L, Frediani F, Tredici G, Petruccioli
b. Joint conservation Pizzini MG. Vasculitic neuropathy in panarteritis nodosa:
c. Review of total hip arthroplasty precautions clinical and ultrastructural findings. Ital J Neurol Sci. 1986;7:
265–269.
d. All of the above 18. Fathers E, Fuller GN. Vasculitic neuropathy. Br J Hosp Med.
1996;55:643–647.
5. _______________ is a rare complication of
19. Griffin JW. Vasculitic neuropathies. Rheum Dis Clin North
rheumatoid arthritis resulting in inflammatory disease Am. 2001;27:751–760.
in small to medium-sized blood vessels and may 20. Pagnoux C, Guillevin L. Peripheral neuropathy in systemic
lead to an ischemic motor or sensory vasculitides. Curr Opin Rheumatol. 2005;17:41–48.
mononeuropathy. 21. Pender MP, Chalk JB. Connective tissue disease mimicking
multiple sclerosis. Aust N Z J Med. 1989;19:469–472
a. Rheumatoid vasculitis
22. Agarwal V, Singh R, Wiclaf, et al. A clinical,
b. Rheumatoid nodule electrophysiological, and pathological study of neuropathy in
c. Fibromyalgia rheumatoid arthritis. Clin Rheumatol. 2008;27:841–844.
d. Scleritis 23. Albani G, Ravaglia S, Cavagna L, Caporali R, Montecucco
C, Mauro A. Clinical and electrophysiological evaluation of
peripheral neuropathy in rheumatoid arthritis. J Peripher Nerv
Syst. 2006;11:174–175.
24. Gemignani F, Giovanelli M, Vitetta F, et al. Non-length
dependent small fiber neuropathy: a prospective case series.
References J Peripher Nerv Syst. 2010;15:57–62.
1. Chung MP, Yi CA, Lee HY, Han J, Lee KS. Imaging of 25. Genc H, Balaban O, Karagoz A, Erdem HR. Femoral
pulmonary vasculitis. Radiology. 2010;255:322–341. neuropathy in a patient with rheumatoid arthritis. Yonsei
2. Hellmich B. Update on the management of systemic Med J. 2007;48:891–893.
vasculitis: what did we learn in 2009? Clin Exp Rheumatol. 26. Bartels C, Bell C, Rosenthal A, Shinki K, Bridges A. Decline
2010;28(1 Suppl 57):98–103. in rheumatoid vasculitis, prevalence among US veterans:
3. Herlyn K, Moosig F, Gross WL. The significance of health- a retrospective cross-sectional study. Arthritis Rheum. 2009;60:
related quality of life in systemic vasculitides. Z Rheumatol. 2553–2557.
2010;69:220–226. 27. Kerschbaumer F, Kerschbaumer GY. Peripheral nerve
4. Dantzer R. Cytokine-induced sickness behaviour: a entrapment syndrome of the upper extremities in cases of
neuroimmune response to activation of innate immunity. Eur inflammatory, rheumatic joint diseases. Z Rheumatol. 2007;66:
J Pharmacol. 2004;500:399–411. 9–12, 14.
2560_Chapter 4_0035-0052.indd 49 3/16/2015 4:14:40 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
28. Sahatciu-Meka V, Rexhepi S, Manxhuka-Kerliu S, Rexhepi 46. Brooks WH. Systemic lupus erythematosus and related
M. Extra-articular manifestations of seronegative and autoimmune diseases are antigen-driven, epigenetic diseases.
seropositive rheumatoid arthritis. Bosn J Basic Med Sci. 2010; Med Hypotheses. 2002;59:736–741.
10:26–31. 47. Santos MS, de Carvalho JF, Brotto M, Bonfa E, Rocha FA.
29. Sugiura F, Kojima T, Oguchi T, et al. A case of peripheral Peripheral neuropathy in patients with primary
neuropathy and skin ulcer in a patient with rheumatoid antiphospholipid (Hughes’) syndrome. Lupus. 2010;19:
arthritis after a single infusion of tocilizumab. Mod 583–590.
Rheumatol. 2009;19:199–203. 48. Yu KH, Yang CH, Chu CC. Swallowing disturbance due to
30. Tatsumura M, Mishima H, Shiina I, et al. Femoral nerve isolated vagus nerve involvement in systemic lupus
palsy caused by a huge iliopectineal synovitis extending to the erythematosus. Lupus. 2007;16:746–749.
iliac fossa in a rheumatoid arthritis case. Mod Rheumatol. 49. Maisonobe T, Denys V, Amoura Z. Sensory neuropathy and
2008;18:81–85. autoimmune diseases. Rev Neurol (Paris). 2009;165(Suppl 3):
31. Tektonidou MG, Serelis J, Skopouli FN. Peripheral S70–76.
neuropathy in two patients with rheumatoid arthritis 50. Voulgarelis M, Tzioufas AG. Pathogenetic mechanisms in the
receiving infliximab treatment. Clin Rheumatol. 2007;26: initiation and perpetuation of Sjogren’s syndrome. Nat Rev
258–260. Rheumatol. 2010;6:529–537.
32. Mikuls TR, Hughes LB, Westfall AO, et al. Cigarette 51. Gemignani F, Giovanelli M, Vitetta F, et al. Non-length
smoking, disease severity and autoantibody expression in dependent small fiber neuropathy: a prospective case series.
African Americans with recent-onset rheumatoid arthritis. J Peripher Nerv Syst. 2010;15:57–62.
Ann Rheum Dis. 2008;67:1529–1534. 52. Gono T, Kawaguchi Y, Katsumata Y, et al. Clinical
33. Harel-Meir M, Sherer Y, Shoenfeld Y. Tobacco smoking and manifestations of neurological involvement in primary
autoimmune diseases. Nat Clin Pract Rheumatol. 2007;3: Sjogren’s syndrome. Clin Rheumatol. 2011;30:485–490.
707–715. 53. Chai J, Logigian EL. Neurological manifestations of primary
34. Carbajal-Rodriguez L, Perea-Martinez A, Loredo-Abdala A, Sjogren’s syndrome. Curr Opin Neurol. 2010;23:509–513.
Rodriguez-Herrera R, del Angel-Aguilar A, Reynes-Manzur 54. Sakai K, Hamaguchi T, Yamada M. Multiple cranial nerve
JN. Neurologic involvement in juvenile rheumatoid arthritis. enhancement on MRI in primary Sjogren’s syndrome. Intern
Bol Med Hosp Infant Mex. 1991;48:502–508. Med. 2010;49:857–859.
35. El-Sayed ZA, Mostafa GA, Aly GS, El-Shahed GS, 55. Akbulut L, Gur G, Bodur H, Alli N, Borman P. Peripheral
El-Aziz MM, El-Emam SM. Cardiovascular autonomic neuropathy in Behcet disease: an electroneurophysiological
function assessed by autonomic function tests and serum study. Clin Rheumatol. 2007;26:1240–1244.
autonomic neuropeptides in Egyptian children and 56. Cho BS, Kim HS, Oh SJ, et al. Comparison of the clinical
adolescents with rheumatic diseases. Rheumatology (Oxford). manifestations, brain MRI and prognosis between
2009;48:843–848. neuroBechet’s disease and neuropsychiatric lupus. Korean J
36. Lindehammar H, Lindvall B. Muscle involvement in juvenile Intern Med. 2007;22:77–86.
idiopathic arthritis. Rheumatology (Oxford). 2004;43: 57. Siva A, Saip S. The spectrum of nervous system involvement
1546–1554. in Behcet’s syndrome and its differential diagnosis. J Neurol.
37. Scola MP, Imagawa T, Boivin GP, Giannini EH, Glass DN, 2009;256:513–529.
Hirsch R, Grom AA. Expression of angiogenic factors 58. Finsterer J. Systemic and non-systemic vasculitis affecting the
in juvenile rheumatoid arthritis: Correlation with peripheral nerves. Acta Neurol Belg. 2009;109:100–113.
revacularization of human synovium engrafted into SCID 59. Nanke Y, Kotake S, Goto M, Matsubara M, Ujihara H. A
mice. Arthritis and Rheumatism. 2001;44:794–801. Japanese case of Behcet’s disease complicated by recurrent
38. Quartier P, Taupin P, Bourdeaut F, et al. Efficacy of optic neuropathy involving both eyes: a third case in the
etanercept for the treatment of juvenile idiopathic arthritis English literature. Mod Rheumatol. 2009;19:334–337.
according to the onset type. Arthritis Rheum. 2003;48: 60. Rudwaleit M, van der Heijde D, Landewé R, et al. The
1093–1101. development of assessment of Spondyloarthritis International
39. Ayaz NA, Ozen S, Bilginer Y, et al. MEFV mutations in Society classification criteria for axial spondyloarthritis
systemic onset juvenile idiopathic arthritis. Rheumatology (part II): validation and final selection. Ann Rheum Dis.
(Oxford). 2009;48:23–25. 2009;68:777–783.
40. Honczarenko K, Budzianowska A, Ostanek L. Neurological 61. Olivieri I, Barozzi L, Padula A, De Matteis M, Pavlica P.
syndromes in systemic lupus erythematosus and their Clinical manifestations of seronegative spondylarthropathies.
association with antiphospholipid syndrome. Neurol Neurochir Eur J Radiol. 1998;27(Suppl 1):S3–6.
Pol. 2008;42:513–517. 62. Barozzi L, Olivieri I, De Matteis M, Padula A, Pavlica P.
41. Brown AC. Lupus erythematosus and nutrition: a review of Seronegative spondylarthropathies: imaging of spondylitis,
the literature. J Ren Nutr. 2000;10:170–183. enthesitis and dactylitis. Eur J Radiol. 1998;27(Suppl 1):
42. Ilniczky S, Kamondi A, Aranyi Z, et al. Simultaneous central S12–17.
and peripheral nervous system involvement in systemic lupus 63. Rehart S, Kerschbaumer F, Braun J, Sieper J. Modern
erythematosus. Ideggyogy Sz. 2007;60:398–402. treatment of ankylosing spondylitis. Orthopade. 2007;36:
43. Bultink IE, Lems WF, Kostense PJ, Dijkmans BA, Voskuyl 1067–1078.
AE. Prevalence of and risk factors for low bone mineral 64. Chan JW, Castellanos A. Infliximab and anterior optic
density and vertebral fractures in patients with systemic lupus neuropathy: case report and review of the literature. Graefes
erythematosus. Arthritis Rheum. 2005;52:2044–2050. Arch Clin Exp Ophthalmol. 2010;248:283–287.
44. Santos MS, de Carvalho JF, Brotto M, Bonfa E, Rocha FA. 65. Gunduz OH, Kiralp MZ, Ozcakar L, Cakar E, Yildirim P,
Peripheral neuropathy in patients with primary Akyuz G. Nerve conduction studies in patients with
antiphospholipid (Hughes’) syndrome. Lupus. 2010;19: ankylosing spondylitis. J Natl Med Assoc. 2010;102:243–246.
583–590. 66. Tham VM, Cunningham E Jr. Anterior ischaemic optic
45. Yu KH, Yang CH, Chu CC. Swallowing disturbance due to neuropathy in a patient with HLA-B27 associated anterior
isolated vagus nerve involvement in systemic lupus uveitis and ankylosing spondylitis. Br J Ophthalmol. 2001;
erythematosus. Lupus. 2007;16:746–749. 85:756.
2560_Chapter 4_0035-0052.indd 50 3/16/2015 4:14:40 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
67. Rudwaleit M, Braun J, Sieper J. Treatment of reactive 80. McGonagle D, Gibbon W, O’Connor P, Green M, Pease C,
arthritis: a practical guide. BioDrugs. 2000;13:21–28. Emery P. Characteristic magnetic resonance imaging
68. Carter JD, Hudson AP. The evolving story of Chlamydia- entheseal changes of knee synovitis in spondylarthropathy.
induced reactive arthritis. Curr Opin Rheumatol. 2010;22: Arthritis Rheum. 1998;41:694–700.
424–430. 81. Riise OR, Handeland KS, Cvancarova M, et al. Incidence
69. Ackerman AB. Reiter syndrome and Hans Reiter: neither and characteristics of arthritis in Norwegian children: a
legitimate! J Am Acad Dermatol. 2009;60:517–518. population-based study. Pediatrics. 2008;121:e299–306.
70. Aksu K, Gokhan K, Eker D. Reactive arthritis following 82. Karimi O, Pena AS. Indications and challenges of
tetanus and rabies vaccinations. Rheumatol Int. 2006;27: probiotics, prebiotics, and synbiotics in the management
209–210. of arthralgias and spondyloarthropathies in inflammatory
71. Chou YS, Horng CT, Huang HS, Hu SC, Chen JT, Tsai bowel disease. J Clin Gastroenterol. 2008;42(Suppl 3 Pt 1):
ML. Reactive arthritis following Streptococcus viridans urinary S136–141.
tract infection. Ocul Immunol Inflamm. 2010;18:52–53. 83. Colombo E, Latiano A, Palmieri O, Bossa F, Andriulli A,
72. van der Helm-van Mil AH. Acute rheumatic fever and Annese V. Enteropathic spondyloarthropathy: a common
poststreptococcal reactive arthritis reconsidered. Curr Opin genetic background with inflammatory bowel disease? World J
Rheumatol. 2010;22:437–442. Gastroenterol. 2009;15:2456–2462.
73. Li CW, Ma JJ, Yin J, Liu L, Hu J. Reiter’s syndrome in 84. Kono M, Oshitani N, Sawa Y, et al. Crohn’s disease
children: a clinical analysis of 22 cases. Zhonghua Er Ke Za complicated by adult-onset Still’s disease. J Gastroenterol.
Zhi. 2010;48:212–215. 2003;38:891–895.
74. Miranda S, Vernet M, Heron F, Vittecoq O, Levesque H, 85. Zhang JL, Jin JY, Li HX, Zhu J, Huang F. The clinical
Marie I. Acute reactive arthritis after intravesical instillation characters of 30 patients with enteropathic arthritis and
of bacillus Calmette-Guerin. Two case reports and literature literature review. Zhonghua Nei Ke Za Zhi. 2010;49:
review [in French]. Rev Med Interne. 2010;31:558–561. 223–225.
75. Kim SK, An JY, Park MS, Kim BJ. A case report of Reiter’s 86. Orchard TR, Wordworth BP, Jewell DP. Peripheral
syndrome with progressive myelopathy. J Clin Neurol. 2007;3: arthropathies in inflammatory bowel disease: their articular
215–218. distribution and natural history. Gut. 1998;42:387–391.
76. Candia L, Cuellar ML, Marlowe SM, Marquez J, Iglesias A, 87. Smale S, Natt RS, Orchard TR, Russell AS, Bjarnason I.
Espinoza LR. Charcot-like arthropathy: a newly-recognized Inflammatory bowel disease and spondylarthropathy. Arthritis
subset of psoriatic arthritis. Clin Exp Rheumatol. 2006;24: Rheum. 2001;44:2728–2736.
172–175. 88. Bergfeldt L. HLA-B27-associated cardiac disease. Ann Intern
77. Narayanaswami P, Chapman KM, Yang ML, Rutkove SB. Med. 1997;127(8 Pt 1):621–629.
Psoriatic arthritis-associated polyneuropathy: a report of three 89. Jones S, D’Souza C, Haboubi NY. Patterns of clinical
cases. J Clin Neuromuscul Dis. 2007;9:248–251. presentation of adult coeliac disease in a rural setting. Nutr J.
78. Rothenberg RJ, Sufit RL. Drug-induced peripheral 2006;5:24.
neuropathy in a patient with psoriatic arthritis. Arthritis 90. Maki M, Collin P. Coeliac disease. Lancet. 1997;349:
Rheum. 1987;30:221–224. 1755–1759.
79. Kane D, Stafford L, Brenihan B, Fitzgerlad O. A prospective, 91. Feighery C. Coeliac disease. BMJ. 1999;319:236–239.
clinical and radiological study of early psoriatic arthritis: an 92. Collin P, Reunala T, Pukkala E, Laippala P, Keyrilainen O,
early synovitis clinic experience. Rheumatology. 2003;42: Pasternack A. Coeliac disease—associated disorders and
1460–1468. survival. Gut. 1994;35:1215–1218.
2560_Chapter 4_0035-0052.indd 51 3/16/2015 4:14:40 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
2560_Glossary_0347-0360.indd 360 3/17/2015 12:11:29 PM
chapter 5
Environmental Toxic
Neuropathies
“Poison is in everything, and nothing is without poison. The dosage makes it

either a poison or a remedy.”
—PARACELSUS (1493–1541)
Objectives
• Identify common environmental toxins and exposure vectors that may lead to peripheral neuropathy.
• Discuss the type of neuropathy associated with each toxin and the common clinical picture including signs
and symptoms that may be encountered by rehabilitation therapists.
• Construct treatment intervention schema for each of the common environmental toxic neuropathies presented.
Key Terms
• Alcohol
• Arsenic
• Lead
• Mercury
• Nitrous oxide
• Thallium
Introduction agent through careful history-taking, follow-up ques-

tioning, laboratory data analysis, and a valid and reli-
Knowledge of the neurotoxicity of environmental com- able physical examination.
pounds and elements has a very practical application For example, nitrous oxide, a potent etiological
in the evaluation of patients with signs and symptoms agent for peripheral neuropathy, is commonly found in
of peripheral neuropathy. Consultation on patients the aerospace, automobile, and food preparation indus-
with numerous neurotoxic exposures including envi- tries. It is also used as a dental anesthetic. Additionally,
ronmental compounds and elements; prescribed, over- nitrous oxide is a popular recreational drug. Ethylene
the-counter, and recreational drugs; and dietary and glycol is a very common toxin because of its use
absorption compromises is common. as a coolant in automobiles. Metal toxicity (thallium,
Exposure often is occupational or related to a hobby, arsenic, and lead) receives much commentary in neu-
but occasionally there is exposure by happenstance or, rological and pathophysiology textbooks and is of
especially in cases of nitrous oxide, thallium, and eth- interest to medical practitioners when investigating the
ylene glycol, purposeful exposure. These compounds etiology of peripheral neuropathy. The etiology of
and elements produce signs and symptoms common to alcohol neuropathy is most likely twofold: (1) a nutri-
neuropathies associated with medication, primary or tionally based neuropathy primarily owing to thiamine
secondary disease processes, and biomechanical forces. deficiency and (2) the direct toxic effects of alcohol on
An astute clinician is able to identify the etiological the peripheral nerve.
53
2560_Chapter 5_0053-0068.indd 53 3/16/2015 4:14:43 PM

Process CyanProcess
YellowProcess Black
In this chapter, we discuss the relationship of the expo- dental procedures via a relative analgesia machine with
sure of specific common environmental compounds a demand valve inhaler over the nose. Because the N2O
and elements and the onset and pathogenesis of periph- is minimally metabolized by humans, it retains its
eral neuropathy. Toxins are discussed under specific potency when exhaled into the room by the patient.
headings as follows: anesthetic agent, heavy metal tox- When used as an anesthetic, a continuous fresh air
icities, and chemical toxicities including alcohol-related ventilation system or N2O “scavenger system” must be
neuropathy. There are hundreds of environmentally and used to protect medical personnel from waste-gas
clinically available toxins that, with exposure, may lead buildup.2
to symptoms of peripheral neuropathy. It is beyond the Along with the medical benefits as a mild to moder-
scope of this book to include all of these toxins. Chapter ate anesthetic, N2O may also cause analgesia, deper-
11 discusses medication-associated neuropathy. sonalization, hallucinations, dizziness, euphoria, sight
and sound distortion, suggestibility, and increased
imagination.4 In 1799, the first documented “laughing
Anesthetic Agent gas parties” were held by upper class Englishmen.3 This
recreational usage of N2O has continued to the present
Nitrous Oxide day. The gas is typically obtained illegally via contacts
Nitrous oxide (N2O) is more commonly known to the in the medical and food industries. The gas is initially
lay population as “laughing gas.” It is a nonflammable, sold by the cylinder to an individual and then individu-
inorganic gas used in medicine, in industry, and as a ally to recreational users via “nitrous oxide balloons.”
recreational drug. It is a major source of air pollution The N2O used in rockets and automobiles is typically
as well as a major source of greenhouse emissions.1 spiked with sulfur dioxide to prevent recreational drug
In industry, N2O is used as an oxidizer and mono- use and is not used for recreational purposes.
propellant in rocket engines. In the presence of a heated The pharmacological mechanism of action of N2O
catalyst, N2O decomposes exothermically into hydro- in recreational and medical usage is not fully known.
gen and oxygen. Because of the large heat release and However, N2O has been shown to modulate directly a
its relative lack of toxicity, it is an effective propellant broad range of ligand-gated ion channels,5 and this
and thruster fuel source. In the automobile industry, likely plays a major role in many of its therapeutic
nitrous oxide, often referred to simply as “nitrous,” effects. N2O moderately blocks N-methyl-D-aspartate
allows the engine to burn more fuel and air resulting (NMDA) receptor and slightly potentiates gamma-
in a more powerful combustion and a greater horse- aminobutyric acid and glycine receptors.6 Although
power surge. In automobiles, N2O is stored as a com- N2O affects numerous ion channels, its anesthetic,
pressed liquid and injected into the intake manifold. In euphoric, and hallucinogenic effects are likely caused
the food industry, N2O has been approved as a food predominantly via inhibition of NMDA receptor–
additive and spray propellant. The stable nature of N2O mediated currents.5,6 In addition to its effects on ion
makes it an effective aerator for whipped cream canis- channels, ingested N2O may act on the central nervous
ters (Fig. 5-1). As a food additive, N2O is known as system (CNS) as well, and this may relate to its anx-
E942 and has two primary functions: as a propellant iolytic and distortion function.7 N2O also oxidizes the
for cooking sprays and to displace oxygen in snack food monovalent core of cobalamin (vitamin B12), affecting
packing that functions to limit bacterial growth on the mitochondrial enzyme dependent on the cobalamin-
the food.1 derived cofactors. The net result is a vitamin B12–
N2O has been used as an anesthetic in dentistry for deficient state exacerbating the N2O effects.8
more than 150 years.2,3 It is now administered during N2O is also a strong anxiolytic. Animal studies show
that benzodiazepine-tolerant animals are also partially
tolerant to N2O administration.9 In a human model,
persons10 given N2O and benzodiazepine receptor
antagonists did not have an alteration of motor control
skills, whereas persons given N2O alone did.
The analgesic effects of N2O are linked to the inter-
action between the endogenous opioid pathway and
the descending noradrenergic pathway. When animals
are given morphine, they develop tolerance to the drug
after a period of time.11 Morphine-tolerant animals
given N2O exhibit similar tolerance behaviors. Drugs
Figure 5-1 Canister of nitrous oxide used as a whipping that inhibit the breakdown of endogenous opioids also
cream agent. Canisters of nitric oxide used to aerosolize potentiate the antinociceptive effects of N2O.11
cream into whipped cream are a common source of nitrous Similar to other NMDA antagonists such as ket-
oxide used for recreational purposes. amine, N2O has been demonstrated to produce central
2560_Chapter 5_0053-0068.indd 54 3/16/2015 4:14:44 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 5 | Environmental Toxic Neuropathies 55
neurotoxicity in the form of Olney’s lesions (damage range from 3 months to 5 years, but the onset of
to the posterior cingulate and retrosplenial cortices of symptoms is most likely associated with frequency of
the cerebral cortex) in a rodent model.7 However, it exposure and gas concentration along with duration
also simultaneously exerts widespread neuroprotec- of exposure.15
tive effects via inhibiting glutamate-inducing toxicity, Classically, peripheral neuropathy manifests with
and it has been argued that on account of its very mild, transient numbness in a stocking-glove dis-
short duration under normal circumstances, N2O may tribution.16 As exposure persists, the large 1a afferent
not share the neurotoxicity of other NMDA antago- neurons become involved with loss of dynamic ambu-
nists.6,12 In rodents, short-term exposure results in only latory balance, difficulty walking or standing with eyes
mild injury that is rapidly reversible, and permanent closed (Romberg examination), and progression to a
neuronal death occurs only after constant and sus- motor neuropathy with involvement of the intrinsic
tained exposure.10 Exposure to N2O causes short-term and extrinsic muscles of the hands and feet. The neu-
decreases in mental performance, audiovisual ability, rological examination reveals impaired vibratory, light
and manual dexterity.10 touch, proprioception, and kinesthetic appreciation;
Chronic N2O exposure may also lead to periph- positive Romberg test; impaired Timed Up and Go
eral myeloneuropathy, which was first reported in test; positive upper extremity pronator drift test; and
1978.13 Clinically, myeloneuropathy associated with gait dysfunction (wide-based, shortened stride length)
N2O is similar and potentially related to cobalamin similar to ataxia.17 Deep tendon reflexes are symmetri-
deficiency.14 Patients with cobalamin deficiency can cally decreased distally and normal proximally. Manual
develop a myeloneuropathy with only one exposure muscle testing and dynamometry reveal weakness of
to N2O (Table 5-1). Researchers have attempted to the intrinsic and extrinsic muscles of the feet and
determine the length of exposure to N2O required to hands. The onset of upper motor neuron signs includ-
produce peripheral neurological symptoms. Estimates ing hyperreflexia, positive Babinski sign, and clonus has
been reported.18
Electroneuromyography studies reveal an axonal
neuropathy with reduced amplitude of sensory nerve
Table 5-1 Clinical Features of Nitrous Oxide and motor action potentials. Motor and sensory con-
Peripheral Myeloneuropathy duction velocities are typically normal but may be
slightly decreased. Needle examination shows denerva-
Clinical indication Anesthetic agent for selective
invasive procedures, especially
tion potentials in distal leg and arm muscles.19
dental Treatment is symptomatic and directed toward the
removal of the exposure toxin. Improvement is typi-
Recreational Euphoria, pain control,
cally seen clinically, subjectively, and electrophysiologi-
indication disassociation
cally in weeks to months after complete removal of the
Method of Inhalation offending toxin.20–22
administration
Impairments with Stocking-glove distribution of
chronic use positive sensory signs; large-fiber Heavy Metal Toxicities
(proprioception and kinesthetic)
sensory loss; symmetrically Lead
diminished deep tendon reflexes, Lead intoxication (also known as saturnism, plumbism,
positive Babinski sign
colica pictonum, Devon’s colic, and painter’s colic) is
Electroneuromyogram Reduced sensory and motor caused by increased plasma and tissue levels of lead.
studies potentials distal > proximal; normal Lead interferes with various body processes and is toxic
or mildly reduced nerve conduction to tissues in the cardiac, gastrointestinal, neurological,
velocities, distal denervation
renal, and reproductive systems. Lead interferes with
potentials via electromyography
the development of the nervous system and is particu-
Nerve biopsy studies Axonal degeneration and axonal larly toxic to fetuses and children, causing potentially
atrophy permanent cognitive, learning, reasoning, and behavior
Data from Maze M, Fujinaga M. Recent advances in understanding disorders.23 Lead has no known physiologically rele-
the actions and toxicity of nitrous oxide. Anaesthesia. 2000;55:311– vant role in the body.23
314; Dohrn CS, Lichtor JL, Coalson DW, Uitvlugt A, de Wit H, Zacny Since first identified by French physician L. Tan-
JP. Reinforcing effects of extended inhalation of nitrous oxide in
humans. Drug Alcohol Depend. 1993;31:265–280; Wu LT, queral des Plances in 1839, the frequency of lead-
Schlenger WE, Ringwalt CL. Use of nitrite inhalants (“poppers”) among induced peripheral neuropathy has waxed and waned
American youth. J Adolesc Health. 2005;37:52–60; and Wu LT, throughout the years.24 Humans have been mining and
Pilowsky DJ, Schlenger WE. Inhalant abuse and dependence among
adolescents in the United States. J Am Acad Child Adolesc Psychiatry. using lead for thousands of years—including its use in
2004;43:1206–1214. goblets, dinner plates, cutlery, and cookware, poisoning
2560_Chapter 5_0053-0068.indd 55 3/16/2015 4:14:44 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
themselves in the process. Although lead poisoning is threats to children is lead in paint, used as a fungicide
one of the oldest known work and environmental additive to paint. This tainted paint still exists in many
hazards, the modern understanding of the small amount older homes and businesses. The U.S. federal govern-
of lead necessary to cause harm did not come about ment banned lead as an additive to interior and exterior
until the latter half of the 20th century. No safe thresh- paint in 1978, but homes built before 1978 may have
old for lead exposure has been discovered—that is, lead paint underlying newer painted areas. Lead paint
there is no known amount of lead that is too small to can become exposed as the later paint weathers and
cause the body harm.23 cracks and with the scraping and sanding of painted
The waxing and waning of lead intoxication fre- surfaces in preparation for repainting. Children who
quency over the past 300 years is due partially to the demonstrate pica behavior—the eating of substances
use of lead in industry during a particular era and the that are not food—should be monitored for potential
level of exposure as allowed by industry, government, paint chip eating (Fig. 5-2).27 Authorities such as the
and health regulations.25 The present time is a period American Academy of Pediatrics define lead poisoning
of rare lead intoxication—a large difference from pub- requiring medical intervention as blood lead levels
lished epidemiological studies from the early and (BLLs) greater than 10 mcg/dL.27,28
middle industrial age. After exposure, lead is stored in blood, soft tissues,
Routes of exposure (Box 5-1) to lead include con- and bone. The half-life of lead in these tissues is mea-
taminated water, air, soil, and food and the purposeful sured in weeks for blood, months for soft tissues, and
additives used in consumer products such as crystal and years for bone.29 The estimated half-life of lead in bone
earthenware.26 Occupational exposure is a common is 20 to 30 years, and bone, with ongoing remodeling,
cause of lead poisoning in adults. One of the largest can introduce lead into the bloodstream long after the
initial exposure is gone.30 Lead in the teeth, hair, and
nails is bound tightly and unavailable to other tissues
BOX 5-1 and is generally thought to be harmless.31 In adults,
94% of absorbed lead is deposited in the bones and
Potential Occupational Sources of Lead Exposure
Battery manufacturing
Battery recycling
Bridge painting
Commercial and institutional refinishing
Demolition
House refinishing
Lead glaze pottery finishing
Lead, copper, or zinc mining
Lead, copper, or zinc smelting
Munitions industry
Plastics industry
Plumbing
Roofing
Rubber industry
Soldering with the use of lead
Stained glass manufacturing
Welding
Data compiled from Guidotti T, Ragain L. Protecting children from toxic
exposure: three strategies. Pediatr Clin North Am. 2007;54:227–
235; Ekong E, Jaar B, Weaver V. Lead-related nephrotoxicity: a
review of the epidemiologic evidence. Kidney Int. 2006;70:2074–
2084; Cleveland LM, Minter ML, Cobb KA, Scott AA, German VF.
Lead hazards for pregnant women and children: part 1: immigrants
and the poor shoulder most of the burden of lead exposure in this
country. Part 1 of a two-part article details how exposure happens,
whom it affects, and the harm it can do. Am J Nurs. 2008;108:40–
49; Payne M. Lead in drinking water. Can Med Assoc J. 2008;179:
253–254; Rossi E. Low level environmental lead exposure—a Figure 5-2 Lead was a common additive to house paint
continuing challenge. Clin Biochem Rev. 2006;29:63–70; and Hu H, before 1978. Lead was added to paint to increase the
Shih R, Rothenberg S, Schwartz S. The epidemiology of lead toxicity
in adults: measuring and consideration for other methodological issues. drying rate, increase durability, maintain a fresh
Environ Health Persp. 2007;115:455–462. appearance, and resist moisture that causes corrosion.
2560_Chapter 5_0053-0068.indd 56 3/16/2015 4:14:44 PM

Process CyanProcess
YellowProcess Black
teeth, but children store only 70% in this manner, a fact Table 5-2 U.S. Centers for Disease Control and Prevention
that may partially account for the more serious health
Management Guidelines for Children with Elevated
effects of lead exposure in children.27 The half-life of
Blood Lead Levels
lead in the blood in men is about 40 days, but it may
be longer in children and pregnant women, whose Blood Lead Level (mcg/dL) Treatment
bones are undergoing accelerated osteoclastic and
10–14 Education, serial screening
osteoblastic activity, which allows the lead to be con-
tinuously reintroduced into the bloodstream.27 Many 15–19 Repeat screening, multidisciplinary
other tissues store lead, and tissues with the highest focus to abate sources
concentrations (other than blood, bone, and teeth) are 20–44 Medical evaluation, case
the brain, spleen, kidneys, liver, and lungs. Lead is management, multidisciplinary focus
removed from the body very slowly, primarily through to abate sources
renal filtration.28 Smaller amounts of lead are also 45–69 Medical evaluation, chelation, case
eliminated through the feces, and very small amounts management
are eliminated in hair, nails, and sweat.28 >69 Hospitalization, immediate chelation,
Elevated BLLs can cause a variety of signs and case chelation, case management
symptoms depending on the individual and the dura-
tion of lead exposure.29 Symptoms are nonspecific and Data from Jones L, Homa M, Meyer A, et al. Trends in blood lead
levels and blood lead testing among US children aged 1 to 5 years,
may be subtle, and someone with elevated BLLs may 1988–2004. Pediatrics. 2009;123:e376–e385; and Murata K,
have no symptoms.30 Symptoms usually develop over Iwata T, Dakeishi M, Karita K. Lead toxicity: does the critical level of
weeks to months as BLL concentration increases with lead resulting in adverse effects differ between adults and children?
J Occup Health. 2009;51:1–12.
chronic exposure, but acute symptoms from brief,
intense exposures also occur.31 Symptoms from expo-
sure to organic lead, which is probably more toxic than
inorganic lead because of its lipid solubility, occur changes in the sperm motility and morphology.33 An
rapidly.32 Poisoning by organic lead compounds has elevated BLL in a pregnant woman can lead to miscar-
symptoms predominantly in the CNS, such as insom- riage, premature birth, and low birth weight and later
nia, delirium, cognitive deficits, hallucinations, and problems with motor and cognitive development in the
seizures. child.25,33 Lead is able to pass through the placenta
Symptoms may be different in adults and children. impacting the fetus and into breast milk impacting the
In adults, symptoms may begin with a BLL of approxi- newborn. BLLs of mothers with lead toxicity and their
mately 40 mcg/dL but are more likely to occur at newborns are usually similar.33 Even with withdrawal
BLLs greater than 50 to 60 mcg/dL.32 These symp- of the acute and chronic causes of lead poisoning, the
toms include headache; abdominal pain; back pain; fetus may still be poisoned in utero if lead from
lethargy; impotence; and weakness, pain, or tingling in the mother’s bones is subsequently mobilized by the
the extremities.30 The classic signs and symptoms in changes in metabolism secondary to pregnancy.
children, which typically begin to appear at BLLs of Increased calcium intake in pregnancy may help miti-
60 mcg/dL, are loss of appetite; pain; vomiting; weight gate this phenomenon (Table 5-2).25,34
loss; constipation; anemia; kidney failure; irritability; Chronic poisoning usually manifests with symp-
and the behavioral/cognitive grouping of erratic behav- toms affecting multiple systems but is associated with
ior, cognitive impairment, and loss of attention.30 three main types of impairments: gastrointestinal, neu-
Children may also experience hearing loss; delayed romuscular, and neurological. CNS signs typically
growth; drowsiness; clumsiness; and loss or delay of result from acute poisoning, whereas gastrointestinal
developmental milestones such as speech, creeping, and symptoms usually result from exposure over longer
bipedal gait.33 In adults, abdominal colic, involving periods.31 Signs of chronic exposure include loss of
episodes of pain, may appear at BLLs greater than short-term memory and concentration, depression,
80 mcg/dL.32 Signs that occur in adults at BLLs nausea, abdominal pain, loss of coordination, and
exceeding 100 mcg/dL include distal motor paralysis paresthesias in the extremities.35 Additional manifesta-
such as wrist drop and footdrop and signs of toxic tions of chronic lead poisoning include fatigue, prob-
encephalopathy.28 In children, signs of encephalopathy lems with sleep, headaches, stupor, inattention, slurred
such as bizarre behavior, dyscoordination, and apathy speech, and anemia.31 A gray “lead hue” of the skin
occur at BLLs exceeding 70 mcg/dL.23 For both adults with generalized pallor is another common feature of
and children, it is rare to be asymptomatic if BLLs chronic poisoning.36 A blue line along the gum with
exceed 100 mcg/dL.32 bluish black edging to the teeth may also be an indica-
Lead affects both the male and female reproductive tion of chronic lead poisoning.36
systems. In men, when BLLs exceed 40 mcg/dL, Elevated lead in the body can be detected by the
sperm count is reduced, and there are associated presence of changes in blood cells visible with a
2560_Chapter 5_0053-0068.indd 57 3/16/2015 4:14:44 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
microscope and dense lines in the bones of children exposure, such as children who live near lead-related
seen on x-ray.37 Anemia accompanied by basophilic industries and children living in older homes located
stippling is a common characteristic of lead intoxica- in lower income neighborhoods.
tion. BLL is typically measured as micrograms of lead Recommended steps by individuals to reduce the
per deciliter of blood (mcg/dL). risk of elevated BLLs in children include increasing
Enzymes used in hemoglobin synthesis, δ- their frequency of hand washing and their intake of
aminolevulinic acid dehydratase and coproporphyrino- calcium and iron; discouraging them from putting their
gen, are particularly susceptible to elevated lead hands to their mouths; vacuuming frequently; and
concentrations.38 The urinary metabolites of abnormal eliminating the child’s access to lead-containing objects
hemoglobin synthesis can be identified in the urine such as old paint, stained glass, plumbing supplies,
of toxic individuals. Inhibition of ferrochelatase, the nails, ammunition, and lead crystal.23,27 Lead pipes or
enzyme responsible for incorporating ferritin into the lead-based plumbing solder in houses can be replaced.41
porphyrin core, results in an elevated blood level of A less permanent but less expensive method of dealing
erythrocyte protoporphyrin28,35; this is a very sensitive with lead plumbing is running water in the morning
test to determine lead exposure. Serum creatinine (Cr), to flush out the most contaminated water. Lead testing
blood urea nitrogen (BUN), and uric acid levels begin kits are commercially available for detecting the pres-
to increase at blood levels of 40 mcg/dL indicating ence of lead in the household water supply.32
impaired renal function. Chronically elevated Cr and Prevention measures also exist on national and
BUN levels by themselves may lead to signs of periph- municipal levels. Recommendations by health care pro-
eral neuropathy. Lead poisoning inhibits excretion of fessionals for decreasing childhood exposures include
the waste product urate and causes a predisposition for banning the use of lead where it is not essential and
gout, in which urate concentration increases and even- strengthening regulations that limit the amount of lead
tually precipitates.39,40 This condition is known as sat- in soil, water, air, household dust, and products. Regu-
urnine gout. lations exist to limit the amount of lead in paint; for
Electroneuromyography studies typically reveal example, a 1978 law in the United States restricted
an axonal neuropathy with mildly generally reduced the lead in paint for residences, furniture, and toys to
motor nerve conduction studies accompanied by 0.06% or less.42 In October 2008, the U.S. Environ-
increased amplitude of waveform. Needle examination mental Protection Agency (EPA) reduced the allow-
reveals denervation potentials supporting a diagnosis able lead level by a factor of 10 to 0.15 mcg per cubic
of an axonal process. Typically, lead concentrations meter of air, giving states 5 years to comply with the
greater than 40 mcg/dL result in electroneuromyog- standards. The Restriction of Hazardous Substances
raphy changes with severe abnormalities occurring Directive from the European Union limits the use of
with BLLs greater than 60 mcg/dL. Autopsy studies toxic substances in electronics and electrical equip-
support the theory of axonal involvement. Much ment. In some places, remediation programs exist to
research interest over the past 3 decades has focused reduce the presence of lead when it is found to be high,
on the correlation between elevated BLL and the onset for example, in public drinking water.42,43 As a more
of motor neuron disease such as amyotrophic lateral radical solution, entire towns located near former lead
sclerosis. To date, the evidence has been insufficient to mines have been “closed” by the government and the
prompt a correlation between lead and motor neuron population resettled elsewhere, as was the case with
disease.27,34,35 Picher, Oklahoma, in 2009.42
Along with axonal abnormalities, elevated lead con- The mainstays of treatment are removal from the
centrations also affect the renal system. In the kidneys, source of lead and, for people who have significantly
lead interferes with vitamin D metabolism resulting in high BLLs or symptoms of poisoning, chelation
renal tubulopathy (Fanconi syndrome) characterized therapy.35 Correction of potential iron, calcium, and
by proteinuria and eventually interstitial fibrosis and zinc deficiencies, which are associated with increased
tubular atrophy.35 lead absorption, is mandatory.35 When lead-containing
Prevention can be divided into individual (measures materials are present in the gastrointestinal tract (as
taken by a family), preventive medicine (identifying evidenced by abdominal x-rays), bowel irrigation,
and intervening with high-risk individuals), and public endoscopic procedures, or surgical removal may be
health (reducing risk on a population level) strategies.23 used to eliminate the lead from the gut and prevent
Testing kits are commercially available for detecting further exposure.43 Lead-containing bullets and shrap-
lead in consumer items and paint. Swabs, when wiped nel may also present a threat of further exposure and
on a surface, turn pink in the presence of lead27; this is may need to be surgically removed if they are in or near
an excellent method for identifying lead-based paint in fluid-filled spaces.43,44 If lead encephalopathy is present,
homes. Screening is an important method in preven- anticonvulsants can be given to control seizures. Treat-
tive medicine strategies.23,27 Screening programs exist ment of organic lead poisoning involves removing the
to test the blood of children at high risk for lead lead compound from the skin, preventing further
2560_Chapter 5_0053-0068.indd 58 3/16/2015 4:14:44 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
exposure, treating seizures, and possibly chelation Table 5-3 Clinical Signs and Symptoms of Acute and Chronic
therapy for people with high BLL concentrations.30
Thallium Poisoning
Thallium Acute Poisoning Chronic Poisoning
Thallium (Greek: thallos, a green twig or stick) is a
Gastrointestinal Gastrointestinal
chemical element with the symbol TI and atomic
number 81. This soft gray metal was accidentally dis- Retrosternal and abdominal pain Weight loss
covered by Sir William Crookes in 1861 by burning Anorexia Anorexia
the dust from a sulfuric acid industrial plant in Vomiting Vomiting
England.45 Approximately 60% to 70% of thallium
production is used in the electronics industry, and the Constipation Constipation
remainder is used in the pharmaceutical and pesticide Neurological Neurological
industries and in the production of the green color used Motor and sensory neuropathy Motor and sensory
in fireworks and glass manufacturing.46 In the last 20 neuropathy
years, thallium has been used in medical imaging Insomnia with agitation Insomnia with agitation
studies (thallium-201 is widely used in myocardial
imaging). Thallium is also present in the environment Delirium Visual loss
in its natural state. Its use has been decreased or elimi- Hallucination Integument
nated in many countries because of its nonselective Seizure Darkening of hair roots
toxicity. Use of thallium as a rodent poison was banned
Integument Alopecia
in the United States in 1972.
Thallium is extremely soft and malleable and can be Darkening of hair roots Cardiopulmonary
cut with a knife at room temperature. It has a metallic Alopecia ST-T ECG changes
luster, but when exposed to air, it quickly tarnishes with Mees’ lines Hypotension
a bluish gray tinge that resembles lead. It may be pre-
served by keeping it under oil. A heavy layer of oxide Peripheral cyanosis Arrhythmia
builds up on thallium if left in air. Cardiopulmonary Genitourinary
Thallium and its compounds are extremely toxic and ST-T ECG changes Hematuria
should be handled with great care. Contact with skin Hypotension Albuminuria
is dangerous, and adequate ventilation should be pro-
vided when melting this metal. Thallium compounds Arrhythmia
have a high aqueous solubility and are readily absorbed Data from Gettler A, Weiss L. Thallium poisoning. III. Clinical
through the skin. Exposure to them should not exceed toxicology of thallium. Am J Clin Pathol. 1943;13:422–429; Prick
0.1 mg per m2 of skin in an 8-hour time-weighted JJG. Thallium poisoning. In: Vinken PJ, Bruyn GW, eds. Intoxications of
the Nervous System. Handbook of Clinical Neurology. vol 36. New
average (40-hour work week). Thallium is a suspected York: Elsevier Science; 1978:239–278; Chamberlain PH, Stavinoha
human carcinogen.47 For a long time, thallium com- WB, Davis H, Kniker WT, Panos TC. Thallium poisoning. Pediatrics.
pounds were easily available commercially as rodent 1958;22:1170–1182; Herrero F, Fernández E, Gómez J, et al.
Thallium poisoning presenting with abdominal colic, paresthesia, and
poison. This fact and the fact that it is water soluble irritability. Clin Toxicol. 1995;33:261–264; Luckit J, Mir N,
and nearly tasteless led to frequent intoxications by Hargreaves M, Costello C, Gazzard B. Thrombocytopenia associated
accident or by criminal intent.48 Because of its use for with thallium poisoning. Hum Exp Toxicol. 1990;9:47–48; Malbrain
ML, Lambrecht GL, Zandijk E, et al. Treatment of severe thallium
murder, thallium has gained the nicknames “the poi- intoxication. J Toxicol Clin Toxicol. 1997;35:97–100; McMillan TM,
soner’s poison” and “inheritance powder.”47 Part of the Jacobson RR, Gross M. Neuropsychology of thallium poisoning.
reason for the high toxicity of thallium is that when J Neurol Neurosurg Psychiatry. 1997; 63:247–250; and Moeschlin
S. Thallium poisoning. Clin Toxicol. 1980;17:133–146.
present in aqueous solution as the univalent thallium
ion (Tl+), it exhibits some similarities with essential
alkali metal cations, particularly potassium (because
the atomic radius is almost identical). It can enter the a period of time). Exposure routes include oral, dermal,
body via potassium uptake pathways. Among the dis- and inhalation. Signs and symptoms of acute intoxica-
tinctive effects of thallium poisoning are loss of hair tion include gastrointestinal symptoms of anorexia,
(which led to its initial use as a depilatory before its constipation, vomiting, and abdominal pain.50 Neuro-
toxicity was properly appreciated) and painful periph- logical symptoms are generally a mild length-dependent
eral neuropathy.49 motor and sensory neuropathy—typically initiating
Severe symptoms have been reported with purpose- with painful paresthesias.51 Integument changes are
ful or accidental ingestion of a single dose of 100 mg darkening of hair, alopecia, and horizontal white lines
or more in adults (Table 5-3).5 Symptoms are specific on nail beds (Mees lines).52 With lethal dosages, causes
as to whether the intoxication of thallium is acute of death include gastrointestinal hemorrhage, cardiac
(large single dose) or chronic (small multiple doses over arrest, and respiratory failure.52,53 Signs and symptoms
2560_Chapter 5_0053-0068.indd 59 3/16/2015 4:14:44 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
of chronic exposure differ from signs of acute exposure. Typically, a simple urine screen for thallium is sufficient
Signs of chronic exposure include visual loss, weight to make the diagnosis. The classic triad of clinical signs
loss, progressive delirium or psychoses, arrhythmia, of thallium intoxication is gastroenteritis, alopecia, and
hematuria, and albuminuria.54,55. Nerve biopsy typically neuropathy.47
shows both axonal degeneration and segmental demy- Treatment is intravenous potassium chloride, which
elination.56,57 To assess the effects of thallium on the effectively drives the thallium from body tissues into
conduction velocities of faster and slower nerve fibers, the plasma where it is excreted through urine and stool.
the distribution of conduction velocities in sensory Symptoms and signs often immediately worsen with
fibers of the median nerve was examined in a patient the onset of treatment, owing to the increase in plasma
with acute thallium poisoning 2 months and 11 months thallium concentrations.59 One of the main methods
after the onset of symptoms. In the first examination, of removing thallium (both radioactive and normal)
the patient showed evidence of a distal sensorimotor from humans is the use of Prussian blue, which is a
neuropathy and had an elevated urinary thallium con- material that absorbs thallium.60 Up to 20 g per day
centration (3.5 mg/L); the conduction velocities of of Prussian blue is fed by mouth to the person, and it
faster fibers were below the normal lower limit, whereas passes through the digestive system and comes out in
the conduction velocities of slower fibers were within the stool. Hemodialysis is also used to remove thallium
normal limits. At the second examination, with the from the blood serum.60
return of normal thallium concentrations, the conduc-
tion velocities of all faster and slower fibers were Arsenic
increased and were within normal limits; clinical signs Arsenic is primarily known by its use as a homicidal
and symptoms of neuropathy almost disappeared. It agent from the times of ancient Greece and Rome to
was concluded that the conduction velocities of faster the present time.61 In Frank Capra’s film Arsenic and
fibers significantly decrease in an early stage of acute Old Lace, two elderly spinsters used arsenic in elder-
thallium poisoning and recover after recuperation from berry wine to murder their male suitors. Most current
the poisoning; the conduction velocities of slower fibers exposure is through occupational or environmental
are minimally affected and then improve.58 exposures. Arsenic trioxide (As2O3), the inorganic form
Diagnosis is based on the clinical presentation, the of arsenic, is used primarily in pesticides and as a wood
history, and the presence of thallium in body fluids. preservative. Inorganic arsenic is not found naturally;
it is the by-product of the copper and lead ore smelting
industry. People at risk for exposure to arsenic are indi-
viduals who work in the smelting industry (chronic
arsenic intoxication that occurs as a result of smelting
is called Ronnskar disease—a name derived from the
Ronnskar smelting plant in Sweden), individuals who
imbibe water from contaminated wells and aquifers
near smelting plants and mines, painters, tree sprayers,
farmers, leatherworkers, taxidermists, and jewelers.61
The two areas of the world affected the worst by arsenic
aquifer contamination are in Bangladesh and West
Bengal, India. In those two areas alone, almost 120
million people are exposed to groundwater arsenic con-
centrations that are above the maximum permissible
limit of 50 mcg/L set by the World Health Organiza-
tion.62,63 In the late 19th century and early 20th century,
inorganic arsenic was employed in the treatment of
trypanosomiasis and syphilis61; there are now much
more effective agents available. The only current phar-
maceutical use of arsenic trioxide is in the treatment of
promyelocytic leukemia, based on its mechanism as an
inducer of apoptosis (programmed cell death).64 Arsenic
is a key nutritional item in the diet of some animals
Figure 5-3 The fingers of a young person with a diagnosis and is an additive to their food (Box 5-2).65
of heavy metal intoxication. Note the Mees fingernail Absorption occurs predominantly from ingestion
lines—dense lines of demarcation. Mees lines, also called from the small intestine, although minute absorption
Aldrich-Mees lines, are lines of discoloration across the occurs from skin contact and inhalation. Peripheral
fingernails and toenails often associated with heavy metal neuropathy is the primary presenting sign with chronic
poisoning and renal failure. arsenic exposure or after survival from exposure to a
2560_Chapter 5_0053-0068.indd 60 3/16/2015 4:14:44 PM

Process CyanProcess
YellowProcess Black
BOX 5-2 BOX 5-3
Signs and Symptoms of Acute Arsenic Poisoning Signs and Symptoms of Chronic Arsenic Poisoning
• Clinical features manifest in most body systems • Clinical features manifest in most body systems
• Prominent features are nausea, vomiting, profuse • Absorbed arsenic accumulates in kidneys, heart,
watery diarrhea, abdominal pain, and excessive lungs, and liver with smaller concentrations in muscles,
saliva production tendons, gastrointestinal tract, and spleen
• Acute psychoses and neuroses • High concentrations of arsenic are deposited in
• Cardiomyopathy with congestive heart failure and keratin-rich tissues such as nails, hair, and skin
hypotension • Mees lines develop in fingernails and toenails
• Pulmonary edema • Dermatological changes include hyperpigmentation,
• Peripheral motor and sensory neuropathy hyperkeratosis, and sloughing of skin of the palms of
• Metabolic encephalopathy the hands and soles of the feet
• Elevated urine arsenic concentration • There is increased risk of cardiovascular disease,
diabetes, peripheral vascular disease, cerebrovascular
Data compiled from Balakumar P, Kaur J. Arsenic exposure and
cardiovascular disease. Cardiovasc Toxicol. 2009;9(4):169; disease, and neutropenia
Steinmaus C, Moore L, Hopenhayn-Rich C, Biggs ML, Smith A. Data compiled from Balakumar P, Kaur J. Arsenic exposure and
Arsenic in drinking water and bladder cancer. Cancer Invest. cardiovascular disease. Cardiovasc Toxicol. 2009;9(4):169;
2000;18:174–182; Buchet JP, Lison D. Clues and uncertainties in the Steinmaus C, Moore L, Hopenhayn-Rich C, Biggs ML, Smith A.
risk assessment of arsenic in drinking water. Food Chem Toxicol. Arsenic in drinking water and bladder cancer. Cancer Invest.
2000;38:S81–85; Campbell JP, Alvarez JA. Acute arsenic 2000;18:174–182; Buchet JP, Lison D. Clues and uncertainties in the
intoxication. Am Fam Physician. 1989;40:93–97; Schoolmeester WL, risk assessment of arsenic in drinking water. Food Chem Toxicol.
White DR. Arsenic poisoning. South Med J. 1980;73:198–208; and 2000;38:S81–85; Campbell JP, Alvarez JA. Acute arsenic
Goddard MJ, Tanhehco JL, Dau PC. Chronic arsenic poisoning intoxication. Am Fam Physician. 1989;40:93–97; Schoolmeester WL,
masquerading as Landry-Guillain-Barre syndrome. Electromyogr Clin White DR. Arsenic poisoning. South Med J. 1980;73:198–208; and
Neurophysiol. 1992;32:419–423. Goddard MJ, Tanhehco JL, Dau PC. Chronic arsenic poisoning
masquerading as Landry-Guillain-Barre syndrome. Electromyogr Clin
Neurophysiol. 1992;32:419–423.
large dose. Large doses, used to commit homicide,

cause a quick death as a result of vomiting, diarrhea, From a diagnostic standpoint, because arsenic is
and vasomotor collapse. A length-dependent senso- easily filtered by the kidneys, blood arsenic levels are
rimotor neuropathy results from acute and chronic helpful for only a few days after acute exposure. Urine
exposure. Although the large myelinated afferents are clearance can often be measured. Low-level chronic
primarily affected, sensory testing typically reveals loss exposure is difficult to identify by blood test. Anemia
in all the tactile modalities. Ascending distal motor and pancytopenia are typically present. Arsenic binds
weakness begins after the sensory component. On to the keratin of the nails and hair, and the measured
examination, along with ascending motor weakness tissue content can be a valid and reliable measure
(similar to Guillain-Barré syndrome), deep tendon of toxicity. Electroneuromyography studies reveal an
reflexes are hypoactive or absent. Cranial nerves are axonal neuropathy. Sensory nerve action potential
rarely involved.66 amplitudes are reduced. Needle examination shows
CNS changes are also common and include changes denervation with increased insertional activity with
in behavior and mood escalating to psychoses and neu- fibrillations. In individuals with chronic intoxication,
roses. In a study of 8,102 men with chronic arsenic enlarged motor units with polyphasic potentials are
exposure, cognitive changes and an elevated risk for seen. Nerve biopsy reveals axonal degeneration.68
cerebrovascular disease, primarily small vessel vascular Treatment with penicillamine or British antilewisite
disease, were found (Box 5-3).67 (BAL) has been used in the past with some success.
A primary feature of chronic exposure is the classic BAL (also known as dimercaprol) displaces the arsenic
integument signs, which include hyperpigmentation, from the sulfhydryl groups of enzyme proteins to
hyperkeratosis, sloughing of skin from the palms and produce an excretable compound. Penicillamine facili-
soles of the feet, and Mees lines on the fingernails. tates excretion of arsenic from the kidneys. A regimen
Although watery stools are a classic sign of acute of vitamins, mineral supplements, and antioxidant
arsenic exposure, in chronic toxicity, diarrhea occurs in therapy has been advocated more recently. Fully
recurrent bouts and may be associated with vomiting. developed neuropathy as a result of arsenic is not
Exposure should be suspected with complaints of diar- affected by arsenic remediation treatment and is often
rhea in the presence of skin changes and peripheral permanent.69,70
motor and sensory neuropathy.67 Recovery after mild
chronic exposure is rapid and complete; however, there Mercury
are often residual neuropathic impairments after sig- Mercury poisoning, also known as hydrargyria or mer-
nificant toxicity.61 curialism, is a disease caused by exposure to mercury
2560_Chapter 5_0053-0068.indd 61 3/16/2015 4:14:44 PM

Process CyanProcess
YellowProcess Black
or one of its organic or inorganic compounds.71 Mercury lavage. Many of the toxic effects of mercury are
exists in elemental, inorganic, and organic forms. The partially or wholly reversible, either through specific
population is primarily exposed to organic mercury therapy or through natural elimination of the metal
from fish consumption and mercury vapor from the after exposure has been discontinued.79 However, large
processing of dental amalgam.72 The concentration of acute or chronic long-term exposure may result in irre-
mercury bioaccumulates up the food chain; large pred- versible damage, particularly in fetuses, infants, and
ator species such as tuna, shark, swordfish, whale, and young children. Young syndrome, also known as azo-
marlin may have very high concentrations of mercury ospermia sinopulmonary infections, sinusitis-infertility
in their tissues. Mercury vapor exposure occurs primar- syndrome, and Barry-Perkins-Young syndrome, is a
ily in dentistry, mining, and the manufacture of electri- rare condition that encompasses a combination of syn-
cal equipment and medical instruments.72,73 Thimerosal, dromes such as bronchiectasis, rhinitis, sinusitis, and
a mercury-containing preservative, has been essentially reduced fertility, and may be a long-term consequence
phased out of the vaccine industry.74 Elemental mercury of early childhood mercury poisoning.82 Common use
exposure can occur through spilling of mercury or of mercuric chloride, a chemical previously used in the
improper disposal of fluorescent lamps.75,76 photography industry and used as an injectable, oral,
The efficiency of absorption of mercury depends on and topical medication for the treatment of syphilis,
the form of mercury and the route of absorption. Ele- has been all but discontinued because of the many
mental mercury absorption is minimal through an oral potentially dangerous side effects.83 Methyl mercury
route.75 Mercury vapor is well absorbed through inha- (also known as methylmercuy) an environmental toxin,
lation.77 Oral absorption of mercury compounds is has entered the human food chain resulting in mercury
poor depending on the precise form. Oral absorption exposure and illness.84 The EPA has classified mercuric
of organic mercury is nearly 100%.75 Once absorbed, chloride and methyl mercury as possible human
mercury is distributed through the vascular system to carcinogens. Peripheral neuropathy associated with
the kidneys, CNS, and peripheral nervous system.71 mercury is typically reversible, but this may take con-
The half-life of organic mercury in the body is about siderable time if the neuropathy is axonotmetic.82–84
70 days, and the half-life of inorganic mercury in the
body is about 40 days.78
The signs and symptoms of mercury poisoning Chemical Toxicities
include oral symptoms of gingivitis, stomatitis, exces-
sive salivation, and a strong metallic taste. Neurologi- Ethylene Glycol
cal manifestations include paresthesias secondary to Ethylene glycol (ethane-1,2-diol) is an organic com-
peripheral sensory neuropathy and central effects such pound widely used as an automotive antifreeze, coolant,
as personality changes, irritability, intention tremor, solvent, and airplane deicer. In its pure form, it is an
fatigue, memory loss, difficulty with concentration odorless, colorless, syrupy, sweet-tasting liquid. Ethyl-
and learning, and sleep disturbances. Integument signs ene glycol is toxic, and ingestion can result in death.
include desquamation of the hands and feet and pink Approximately 60% of ethylene glycol produced is
cheeks, fingers, and toes. Mercury poisoning in a preg- used for antifreeze manufacturing, and the remainder
nant woman may result in the occurrence of potential is mainly used as a precursor to polymers. Because this
neuropsychiatric diagnoses in the child.79–81 material is cheaply available, there are many niche
Diagnosis of mercury poisoning can be made applications. The primary source of ethylene glycol in
through the measure of mercury concentrations in the the environment is from runoff at airports where it is
blood or urine.71 With potential organic mercury poi- used in deicing agents for runways and airplanes. Eth-
soning, the blood value is the preferred method of ylene glycol can also enter the environment through
assessment. Studies suggest that developing fetuses the disposal of products that contain it, such as radia-
may be affected by mercury blood levels of 40 mcg/L; tor antifreeze. In air, ethylene glycol degrades in about
in adults, symptoms appear at 100 mcg/L.81 10 days; in soil and water, the process takes about 2
Identifying the source of mercury poisoning and weeks (85).
removal of the source are imperative. Contaminated Exposure is typically oral and includes accidental
clothing must be removed and bagged. For acute oral ingestions, suicide attempts, and ingestions by alcohol-
intoxication, treatment is gastric lavage, charcoal, and ics. Toxicity levels are greater than 25 mg/dL, and the
chelation therapy including penicillamine.71,78 Sup- lethal level is greater than 200 mg/dL. Ethylene glycol
portive measures may include items such as correcting is rapidly absorbed from the gastrointestinal tract.
electrolyte imbalance, hemodialysis for renal failure, Clinical features are usually described in relation to
and possible surgical intervention for gastrointestinal hours after ingestion (Table 5-4).86
perforation.79 Contaminated skin must be scrubbed One of the leading factors for the frequency of acci-
with soap and water. Eye contact is treated with saline dental ingestion of ethylene glycol is its sweet taste.
2560_Chapter 5_0053-0068.indd 62 3/16/2015 4:14:44 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
85
the neuropathic symptoms. Cranial nerve involve-
Table 5-4 Clinical Phases of Ethylene Glycol Poisoning
ment, especially the facial nerve; distal motor weak-
30 Minutes to CNS depression ness; and painful distal paresthesias are typically seen.
12 Hours Sleepiness Electroneuromyography studies typically reveal a sen-
sorimotor radiculopathy similar to Guillain-Barré syn-
12–24 Hours Nausea, vomiting
Abdominal pain
drome but with an atypical distribution. If the patient
Noncardiac chest pain survives the ingestion, there is typically a good recovery
Myalgia from the neuropathic involvement.90
Confusion
Discoordination Alcohol-Related Neuropathy
Renal toxicity Debate has occurred over the past few decades
5–20 days Cranial nerve VII distribution weakness about the etiology of alcohol-related neuropathy. Is
bilaterally the peripheral neuropathy associated with alcoholism
Optic neuritis with edema and atrophy a true toxic neuropathy that is due to the direct or
Loss of hearing indirect impact of alcohol on peripheral nerves, or is it
Dysphagia directly related to nutritional—particularly thiamine—
Hoarseness deficiency, or is it a combination of the two?91
Dysarthria Alcoholism is a disorder characterized by addiction
Coma to alcohol that is prevalent worldwide. Individuals with
Seizure
Diffuse, asymmetric weakness
this addiction crave alcoholic beverages and eventually
Distal sensory loss of vibration, tactile, develop tolerance to the intoxicating effects. Alcohol-
and temperature ism is defined as recurrent episodes of excessive drink-
Diminished deep tendon reflexes ing despite serious economic, social, familial, or medical
consequences with symptoms of withdrawal when
Data from Hess R, Bartels MJ, Pottenger LH. Ethylene glycol: an drinking is stopped.91 Alcoholism has a large societal
estimate of tolerable levels of exposure based on a review of animal
and human data. Arch Toxicol. 2004;78:671–680; Tobe TJM, Braam cost. Of U.S. hospital admissions, 20% involve medical
GB, Meulenbelt J, van Dijk GW. Ethylene glycol poisoning mimicking complications of excessive acute or chronic alcohol
Snow White. Lancet. 2002;359:444; Spillane L, Roberts JR, Meyer ingestion; the socioeconomic cost is greater than $100
AE. Multiple cranial nerve deficits after ethylene glycol poisoning. Ann
Emerg Med. 1991;20:208–210; Hasbani MJ, Sansing LH, Perrone J, billion annually.91
Asbury AK, Bird SJ. Encephalopathy and peripheral neuropathy Ethanol, the active ingredient in alcoholic beverages,
following diethylene glycol ingestion. Neurology. 2005;64:1273– enters the bloodstream within minutes of ingestion
1375; Zhou L, Zabad R, Lewis RA. Ethylene glycol intoxication:
electrophysiological studies suggest a polyradiculopathy. Neurology. and quickly diffuses throughout the vascular system.
2002;59:1809–1810; and Lewis LD, Smith BW, Mamourian AC. Virtually all alcohol is detoxified in the liver where
Delayed sequelae after acute overdoses or poisonings: cranial alcohol dehydrogenase converts ethanol to acetalde-
neuropathy related to ethylene glycol ingestion. Clin Pharmacol Ther.
1997;61:692–699. hyde, which is metabolized by aldehyde dehydrogenase
to acetate. Excessive accumulation of acetaldehyde
results in the typically seen “alcoholic flush” as a result
of the vasodilatory response and the associated tachy-
Because of the taste, children and animals are more cardia and hypotension.92
inclined to consume large quantities of it than they Ethanol rapidly crosses the blood-brain barrier, and
are other poisons. On ingestion, ethylene glycol is oxi- the ethanol concentration in the brain matches that of
dized to glycolic acid, which is oxidized to oxalic acid, the peripheral circulation soon after ingestion.93 Emo-
which is toxic. Oxalic acid and its toxic by-products tionally, alcohol ingestion usually results in euphoria, a
affect the CNS first, then the heart, and finally the loss of social inhibitions, garrulousness, and outgoing
kidneys. Ingestion of sufficient amounts can be fatal if behavior. However, some persons react with belliger-
untreated.87,88 ence, gloominess, tiredness, or depression.94 Blood
According to the annual report of the American alcohol content (BAC) is most commonly used as a
Association of Poison Control Centers’ National metric of intoxication for legal or medical purposes.
Poison Data System in 2007, there were about 1,000 BAC is usually expressed as a fractional percentage in
total cases of ethylene glycol ingestions resulting in 16 terms of volume of alcohol per volume of blood in the
deaths. The 2008 annual report of the American Asso- body. It is a ratio without units that is commonly
ciation of Poison Control Centers’ National Poison expressed as a decimal with two to three significant
Data System listed seven deaths.89 digits followed by a percentage sign (Table 5-5).95
The neuropathy associated with ethylene glycol Alcoholic tolerance may be acute or chronic. The
ingestion typically occurs after diagnosis; the CNS, acute tolerance phenomenon is typically seen with
cardiac, and renal symptoms outweigh the severity of someone who initially appears inebriated, continues to
2560_Chapter 5_0053-0068.indd 63 3/16/2015 4:14:45 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
drink, and appears to become sober even though the
Table 5-5 Behavioral Changes and Impairments Associated BAC is markedly elevated. Chronic tolerance is a char-
with Progressive Blood Alcohol Concentrations acteristic feature of alcoholism. Eventually, the emo-
0.01% to Greater than 4.00% by Volume tional and physical reactions to a given volume of
Blood Alcohol Behavior Changes Impairment
alcohol diminish; however, the BAC continues to
Concentration
increase as ingestion increases.94
(% by vol.)
Peripheral polyneuropathy is the most common
neurological complication seen with alcoholism.94
0.010–0.029 Average individual Subtle effects that Presenting symptoms include paresthesias, pain, and
appears normal can be detected intrinsic and extrinsic muscle weakness of the feet. The
with special tests paresthesias and dysesthesias may be so painful that
0.030–0.059 Mild euphoria Concentration walking and standing are affected. Physical examina-
Sense of well-being Recall tion typically reveals a nerve length–dependent rela-
Friendliness Cognitive/learning tionship of reduced pain, tactile, and proprioceptive
Relaxation ability and kinesthetic perception. The corporal appearance
Joyousness often mimics a malnourished state. It is frequently
Talkativeness
difficult to separate muscle atrophy from cachexia.
Decreased inhibition
Increased libido There is often a nerve length–dependent relationship
of motor weakness and atrophy; this is more commonly
0.06–0.10 Blunted feelings Reasoning seen in the lower extremities than in the upper extrem-
Disinhibition Depth perception
ities. Deep tendon reflexes are often diminished or
Extroversion Peripheral vision
Glare recovery
absent distally compared with proximally. Gait dys-
Fine motor control function is common secondary to either large fiber
afferent neuropathy resulting in ataxia or primary cer-
0.11–0.20 Overexpression Reflexes ebellar degeneration or Wernicke syndrome. Distal
Emotional swings Reaction time
Angriness or sadness Gross motor
trophic changes such as hair loss and hypohydrosis
Boisterousness control suggest a concomitant autonomic neuropathy. Although
Superhuman feeling Staggering most of the presenting signs and symptoms are slowly
Decreased libido Slurred speech progressive, there have been reported cases of acute
presentation similar to that seen with Guillain-Barré
0.21–0.29 Stupor Severe motor
Loss of understanding impairment syndrome. Patients with alcoholism frequently have
Impaired sensations Loss of compressive or tensile neuropathies associated with
consciousness abnormal static posturing when inebriated.94–96
Memory Prevalence of neuropathy is difficult to determine.95–97
0.30–0.39 Severe CNS Loss of bladder
Studies suggest that 10% to 15% of persons with
depression function chronic alcoholism develop signs and symptoms of
Unconsciousness Breathing peripheral neuropathy.95 If electroneuromyography evi-
Death possible Heart rate dence is used as the criteria of diagnosis, 33% of persons
0.40 or General lack of Breathing
with chronic alcoholism may have peripheral neuropa-
greater behavior Heart rate thy.97 The quantity and frequency of alcoholic ingestion
Unconsciousness required to develop neuropathy are difficult to deter-
Death mine because of the many individual and extrinsic
factors involved.
Data from Lewis LD, Smith BW, Mamourian AC. Delayed sequelae Laboratory testing generally reveals mild to moder-
after acute overdoses or poisonings: cranial neuropathy related to
ethylene glycol ingestion. Clin Pharmacol Ther. 1997;61:692–699; ate liver enzyme abnormalities with evidence of mal-
Lieber CS. Interaction of alcohol with other drugs and nutrients: nutrition (diminished serum protein and albumin).
implication for the therapy of alcoholic liver disease. Drugs. Cerebrospinal fluid assessment is typically normal.95
1990;40:23–44; Wetterling T, Veltrup C, Driessen M, John U.
Drinking pattern and alcohol-related medical disorders. Alcohol Electroneuromyography typically reveals reduced sen-
Alcohol. 1990;34:330–336; Manzo L, Costa LG. Manifestations of sory nerve action potentials, mildly reduced distal com-
neurotoxicity in occupational diseases. In: Costa, LG, Manzo L, eds. pound motor potentials, and relative preservation of
Occupational Neurotoxicology. Vol 2. Boca Raton, FL: CRC Press;
1998:1–20; Claus D, Egger R, Engelhardt A, Neundorfer B, sensory and motor nerve conduction velocities. Needle
Warecka K. Ethanol and polyneuropathy. Acta Neurol Scand. examination often shows distal denervation.96–98
1985;72:312–316; Burrit MF, Anderson CF. Laboratory assessment of As previously mentioned, even with the extensive
nutritional status. Hum Pathol. 1984;15:130–133; Dyck PJ. Detection,
characterization and staging of polyneuropathy assessed in diabetics. body of literature related to alcoholic neuropathy, there
Muscle Nerve. 1998;11:21–32; and Behese F, Buchtal F. Alcoholic is no clear evidence to support a single theory of patho-
neuropathy: clinical, electrophysiological and biopsy findings. Ann genesis. The most compelling evidence for a nutritional
Neurol. 1997;2:95.
etiology is the correlation of malnutrition, including
2560_Chapter 5_0053-0068.indd 64 3/16/2015 4:14:45 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
low serum thiamine, albumin, and total protein con- 3. Amy’s physician, noting the results of Amy’s serum
centrations, with a neuropathy that is very similar in lead level, recommended that Amy’s mother also
appearance to known nutritional-induced neuropa- undergo serum lead level testing. What is the reason
thies. Evidence also suggests that alcohol interferes for this recommendation?
with the intestinal absorption of thiamine and may a. Amy’s mother may also have lead intoxication and
increase the metabolic corporal demands for thiamine, may have passed the high level of lead to Amy
further implicating a nutritional etiology. while Amy was in utero.
Other studies appear to support a direct toxic impact b. Lead intoxication is contagious.
of alcohol on the peripheral nervous system. Most c. Amy’s mother eats a diet rich in fruit and
persons with alcoholism and neuropathy have no direct vegetables.
laboratory rationale to implicate a nutritional etiol- d. Amy’s mother has a medical history of
ogy.95 One large study showed little correlation between hypertension.
thiamine levels in persons with alcoholism with and 4. If Amy is not treated for the lead intoxication, her
without neuropathy as diagnosed with electroneuro- symptoms may progress to which of the following?
myography. Behse and Buchthal reported differences a. Encephalopathy
in electroneuromyography and biopsy analysis of nerves b. Bizarre behavior
of persons with alcoholic neuropathy and persons with c. Abdominal colic
gastric bypass–induced nutritional neuropathy sug- d. All of the above
gesting a nonnutritional etiology.99
The only effective treatment of alcohol-related neu- 5. Additional signs of lead intoxication in children
ropathy is the complete avoidance of alcohol and nutri- include which of the following?
tional supplementation of thiamine, vitamins, protein, a. Changes in the shape of blood cells
and carbohydrates. Improvement is often indolent with b. Dense lines seen in the bones seen on x-ray
noticeable functional improvement occurring 6 months c. A blue line along the gum line
after risk factor remediation.91,95,100 d. All of the above
References
1. Maze M, Fujinaga M. Recent advances in understanding
the actions and toxicity of nitrous oxide. Anaesthesia.
CASE STUDY 2000;55:311–314.
2. Yamakura T, Harris RA. Effects of gaseous anesthetics
Amy is a 3-year-old girl who lives in a house that was nitrous oxide and xenon on ligand-gated ion channels.
built in the late 1800s. Amy was diagnosed as having J Anesth. 2000;93(4):1095–1101.
pica behavior—the eating of nonfood items such as 3. Keys TE. The development of anesthesia. Anesth J. 1977;2:
soil, cotton, and paint chips. Because of developmental 552–574.
delay (height, weight, motor milestones), recent weight 4. Jevtovic-Todorovic V, Beals J, Benshoff N, Olney JW.
Prolonged exposure to inhalational anesthetic nitrous oxide
loss, loss of appetite, poorly healing wounds, and kills neurons in adult rat brain. Neuroscience. 1997;122:
evidence of mild chronic kidney disease, Amy’s family 609–616.
physician tested Amy for lead intoxication. The serum 5. Yamakura T, Harris RA. Effects of gaseous anesthetics
lead level was reported as 70 mcg/dL. nitrous oxide and xenon on ligand-gated ion channels.
J Anesth. 2000;93(4):1095–1101.
6. Sawamura S, Kingery WS, Davies MF, et al. Antinociceptive
Case Study Questions action of nitrous oxide is mediated by stimulation of
noradrenergic neurons in the brainstem and activation of
1. Noting Amy’s history, the high levels of lead in her adrenoceptors. J. Neurosci. 2000;20:9242–9251.
blood most likely are the result of which of the 7. Branda EM, Ramza JT, Cahill FJ, Tseng LF, Quock, RM.
following? Role of brain dynorphin in nitrous oxide antinociception in
mice. Pharmacol Biochem Behav. 1999;65:217–221.
a. Ingesting lead-based paint 8. Dohrn CS, Lichtor JL, Coalson DW, Uitvlugt A, de Wit H,
b. Poor quantity of food intake Zacny JP. Reinforcing effects of extended inhalation of
c. Lack of social integration nitrous oxide in humans. Drug Alcohol Depend. 1993;31:
d. A medication side effect 265–280.
9. David HN, Ansseau M, Lemaire M, Abraini JH. Nitrous
2. Which symptom experienced by Amy is not typically oxide and xenon prevent amphetamine-induced carrier-
associated with lead intoxication in children? mediated dopamine release in a memantine-like fashion and
a. Developmental delay protect against behavioral sensitization. Biol Psychiatry. 2009;
60:49–57.
b. Weight loss 10. Berkoitz BA, Finck AD, Hynes MD, Ngai SH. Tolerance to
c. Kidney failure nitrous oxide analgesia in rats and mice. J Anesth. 1979;51:
d. Poorly healing wounds 309–312.
2560_Chapter 5_0053-0068.indd 65 3/16/2015 4:14:45 PM

Process CyanProcess
YellowProcess Black
11. Benturquia N, Le Guen S, Canestrelli C. Specific blockade effects: 3. lead exposure. Can Med Assoc J. 2002;166:
of morphine- and cocaine-induced reinforcing effects in 1287–1292.
conditioned place preference by nitrous oxide in mice. 31. Needleman H. Lead poisoning. Ann Rev Med. 2004;55:
Neuroscience. 2009;149:477–486. 209–222.
12. Jevtovic-Todorovic V, Benshoff N, Olney JW. Ketamine 32. Brodkin E, Copes R, Mattman A, Kenned J, Kling R, Yassi
potentiates cerebrocortical damage induced by the common A. Lead and mercury exposures: interpretation and action.
anesthetic nitrous oxide in rats. Br J Pharm. 2000;130: Can Med Assoc J. 2006;176:59–63.
1692–1698. 33. Bellinger DC. Lead. Pediatrics. 2004;113:1016–1022.
13. Wu LT, Schlenger WE, Ringwalt CL. Use of nitrite 34. Goyer RA. Transplacental transport of lead. Environ Health
inhalants (“poppers”) among American youth. J Adolesc Perspect. 2006; 89:101–105.
Health. 2005;37:52–60. 35. Rossi E. Low level environmental lead exposure—a
14. Turner CF, Lessler JT, Gfroerer JC, eds. Survey measurement continuing challenge. Clin Biochem Rev. 2006;29:63–70.
of drug use: methodological studies. DHHS Publication No. 36. James W, Berger T, Elston D. Andrews’ Diseases of the Skin:
ADM 92-1929. Rockville, MD: National Institute on Drug Clinical Dermatology. 10th ed. Philadelphia: Saunders; 2005.
Abuse; 1992. 37. Woolf A, Goldman R, Bellinger D. Update on the clinical
15. Wu LT, Pilowsky DJ, Schlenger WE. Inhalant abuse and management of childhood lead poisoning. Pediatr Clin North
dependence among adolescents in the United States. J Am Am. 2007;54:271–294.
Acad Child Adolesc Psychiatry. 2004;43:1206–1214. 38. Hu H, Shih R, Rothenberg S, Schwartz S. The
16. Woody GE, Donnell D, Seage GR, et al. Non-injection epidemiology of lead toxicity in adults: measuring and
substance use correlates with risky sex among men having consideration for other methodological issues. Environ
sex with men: data from HIVNET. Drug Alcohol Depend. Health Persp. 2007;115:455–462.
1999;53:197–205. 39. Jones L, Homa M, Meyer A, et al. Trends in blood lead
17. Schütz CG, Chilcoat HD, Anthony JC. The association levels and blood lead testing among US children aged 1 to 5
between sniffing inhalants and injecting drugs. Compr years, 1988–2004. Pediatrics. 2009;123:e376–e385.
Psychiatry. 1994;35:99–105. 40. Murata K, Iwata T, Dakeishi M, Karita K. Lead toxicity: does
18. Storr CL, Westergaard R, Anthony JC. Early onset inhalant the critical level of lead resulting in adverse effects differ
use and risk for opiate initiation by young adulthood. Drug between adults and children? J Occup Health. 2009;51:1–12.
Alcohol Depend. 2005;78:253–261. 41. Mañay N, Cousillas AZ, Alvarez C, Heller T. Lead
19. Seage GR 3rd, Mayer KH, Horsburgh CR Jr, Holmberg contamination in Uruguay: the “La Teja” neighborhood case.
SD, Moon MW, Lamb GA. The relation between nitrite Rev Environ Contam Toxicol. 2009;195:93–115.
inhalants, unprotected receptive anal intercourse, and the 42. Pokras M, Kneeland M. Lead poisoning: using
risk of human immunodeficiency virus infection. Am J transdisciplinary approaches to solve an ancient problem.
Epidemiol. 1992;135:1–11. Ecohealth. 2008;5:379–385.
20. Soderberg LS. Immunomodulation by nitrite inhalants 43. Schep J, Fountain S, Cox, M, Pesola R. Lead shot in the
may predispose abusers to AIDS and Kaposi’s sarcoma. appendix. N Engl J Med. 2006;354:1757.
J Neuroimmunol. 1998;83:157–161. 44. Madsen HH, Skjødt T, Jørgensen PJ, Grandjean P. Blood
21. Tapia-Conyer R, Cravioto P, De La Rosa B, Velez C. Risk lead levels in patients with lead shot retained in the
factors for inhalant abuse in juvenile offenders: the case of appendix. Acta Radiol. 1987;29:745–746.
Mexico. Addiction. 1995;90:43–49. 45. Chandler HA, Scott M. A review of thallium toxicology.
22. Wu LT, Pilowsky DJ, Schlenger WE. High prevalence of J R Nav Med Serv. 1996;72:75–79.
substance use disorders among adolescents who use 46. Barroso-Moguel R, Méndez-Armenta M, Villeda-Hernández
marijuana and inhalants. Drug Alcohol Depend. 2005;78: J, Ríos C, Galván-Arzate S. Experimental neuromyopathy
23–32. induced by thallium in rats. J Appl Toxicol. 1996;16:385–389.
23. Guidotti T, Ragain L. Protecting children from toxic 47. Gettler A, Weiss L. Thallium poisoning. III. Clinical
exposure: three strategies. Pediatr Clin North Am. 2007;54: toxicology of thallium. Am J Clin Pathol. 1943;13:422–429.
227–235. 48. Prick JJG. Thallium poisoning. In: Vinken PJ, Bruyn GW,
24. Ekong E, Jaar B, Weaver V. Lead-related nephrotoxicity: a eds. Intoxications of the Nervous System. Handbook of Clinical
review of the epidemiologic evidence. Kidney Int. 2006;70: Neurology. vol 36. New York: Elsevier Science; 1978:239–278.
2074–2084. 49. Chamberlain PH, Stavinoha WB, Davis H, Kniker WT, Panos
25. Cleveland LM, Minter ML, Cobb KA, Scott AA, German TC. Thallium poisoning. Pediatrics. 1958;22:1170–1182.
VF. Lead hazards for pregnant women and children: part 1: 50. Herrero F, Fernández E, Gómez J, et al. Thallium poisoning
immigrants and the poor shoulder most of the burden of presenting with abdominal colic, paresthesia, and irritability.
lead exposure in this country. Part 1 of a two-part article Clin Toxicol. 1995;33:261–264.
details how exposure happens, whom it affects, and the 51. Luckit J, Mir N, Hargreaves M, Costello C, Gazzard B.
harm it can do. Am J Nurs. 2008;108:40–49. Thrombocytopenia associated with thallium poisoning. Hum
26. Payne M. Lead in drinking water. Can Med Assoc J. 2008; Exp Toxicol. 1990;9:47–48.
179:253–254. 52. Malbrain ML, Lambrecht GL, Zandijk E, et al. Treatment
27. Ragan P, Turner T. Working to prevent lead poisoning in of severe thallium intoxication. J Toxicol Clin Toxicol.
children: getting the lead out. J Am Acad Physician Assist. 1997;35:97–100.
2008;22:40–45. 53. McMillan TM, Jacobson RR, Gross M. Neuropsychology of
28. Timbrel JA. Biochemical mechanisms of toxicity: specific thallium poisoning. J Neurol Neurosurg Psychiatry. 1997;63:
examples. In: Timbrell JA, ed. Principles of Biochemical 247–250.
Toxicology. 4th ed. London: Informa Healthcare; 2008. 54. Moeschlin S. Thallium poisoning. Clin Toxicol. 1980;17:
29. Baselt RC. Therapeutic drug monitoring and chemical 133–146.
aspects of toxicology. In: Marshall WJ, Bangert SK, eds. 55. Mulkey JP, Oehme FW. A review of thallium toxicity.
Clinical Chemistry. 6th ed. St Louis: Mosby; 2008:366. Vet Hum Toxicol. 1993;35:445–453.
30. Sanborn MD, Abelsohn A, Campbell M, Weir E. 56. Dumitru D, Kalantri A. Electrophysiological investigation
Identifying and managing adverse environmental health of thallium poisoning. Muscle Nerve. 1990;13:433–437.
2560_Chapter 5_0053-0068.indd 66 3/16/2015 4:14:45 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
57. Limos CL, Ohnishi A, Suzuki N, et al. Axonal degeneration human subjects after inhalation of mercury vapor. Arch
and focal muscle fiber necrosis in human thallotoxicosis: Environ Health. 1978;33:190–214.
histopathological studies of nerve and muscle. Muscle Nerve. 80. Risher JF, Amler SN. Mercury exposure: evaluation and
1982;5:598–706. intervention in the inappropriate use of chelating agents in
58. de Groot G, van Heijst ANP, van Kesteren RG, Maes RAA. the diagnosis and treatment of putative mercury poisoning.
An evaluation of the efficacy of charcoal haemoperfusion in Neurotoxicology. 2005;26:691–699.
the treatment of three cases of acute thallium poisoning. 81. Ngim CH, Foo SC, Boey KW, Keyaratnam J. Chronic
Arch Toxicol. 1985;57:61–66. neurobehavioral effects of elemental mercury in dentists.
59. Kamerbeek HH, Rauws AG, Ten Ham M, van Heijst ANP. Br J Ind Med. 1992;49:782–790.
Prussian blue in therapy of thallotoxicosis: an experimental 82. Hendry WF, A’Hern FPA, Cole PJ. Was Young’s syndrome
and clinical investigation. Acta Med Scand. 1971;189:321–324. caused by mercury exposure in childhood? BMJ. 1993;307:
60. Kravzov J, Ríos C, Altagracia M, Monroy-Noyola A, López 1579–1582.
F. Relationship between physicochemical properties of 83. Mutter J, Naumann J, Schneider R, Walach H, Haley B.
Prussian blue and its efficacy as antidote against thallium Mercury and autism: accelerating evidence? Neuro Endocrinol
poisoning. J Appl Toxicol. 1993;13(3):213–216. Lett. 2005;26:439–446.
61. Balakumar P, Kaur J. Arsenic exposure and cardiovascular 84. Ibrahim D, Froberg B, Wolf A, Rusyniak DE. Heavy metal
disease. Cardiovasc Toxicol. 2009;9(4):169. poisoning: clinical presentations and pathophysiology. Clin
62. Steinmaus C, Moore L, Hopenhayn-Rich C, Biggs ML, Lab Med. 2006;26:67–97.
Smith A. Arsenic in drinking water and bladder cancer. 85. Hess R, Bartels MJ, Pottenger LH. Ethylene glycol: an
Cancer Invest. 2000;18:174–182. estimate of tolerable levels of exposure based on a review of
63. Buchet JP, Lison D. Clues and uncertainties in the risk animal and human data. Arch Toxicol. 2004;78:671–680.
assessment of arsenic in drinking water. Food Chem Toxicol. 86. Tobe TJM, Braam GB, Meulenbelt J, van Dijk GW.
2000;38:S81–85. Ethylene glycol poisoning mimicking Snow White. Lancet.
64. Campbell JP, Alvarez JA. Acute arsenic intoxication. 2002;359:444.
Am Fam Physician. 1989;40:93–97. 87. Spillane L, Roberts JR, Meyer AE. Multiple cranial nerve
65. Schoolmeester WL, White DR. Arsenic poisoning. South deficits after ethylene glycol poisoning. Ann Emerg Med.
Med J. 1980;73:198–208. 1991;20:208–210.
66. Goddard MJ, Tanhehco JL, Dau PC. Chronic arsenic 88. Hasbani MJ, Sansing LH, Perrone J, Asbury AK, Bird SJ.
poisoning masquerading as Landry-Guillain-Barre Encephalopathy and peripheral neuropathy following
syndrome. Electromyogr Clin Neurophysiol. 1992;32:419–423. diethylene glycol ingestion. Neurology. 2005;64:1273–1275.
67. Quatrehomme G, Ricq O, Lapolus P. Acute arsenic 89. Zhou L, Zabad R, Lewis RA. Ethylene glycol intoxication:
intoxication: forensic and toxicologic aspects. J Forensic Sci. electrophysiological studies suggest a polyradiculopathy.
1992;37:1163–1171. Neurology. 2002;59:1809–1810.
68. Mazumder DN, Das-Gupta J, Santra A, Pal A, Ghose A, 90. Lewis LD, Smith BW, Mamourian AC. Delayed sequelae
Sarkar S. Chronic arsenic toxicity in West Bengal—the after acute overdoses or poisonings: cranial neuropathy
worst calamity in the world. J Indian Med Assoc. 1998;96: related to ethylene glycol ingestion. Clin Pharmacol Ther.
4–7, 18. 1997;61:692–699.
69. Axelson O, Dahlgren E, Jansson CD, et al. Arsenic exposure 91. Lieber CS. Interaction of alcohol with other drugs and
and mortality: a case-referent study from a Swedish copper nutrients: implication for the therapy of alcoholic liver
smelter. Br J Ind Med. 1978;35:8–15. disease. Drugs. 1990;40:23–44.
70. Fincher RM, Koerker RM. Long term survival in acute 92. Wetterling T, Veltrup C, Driessen M, John U. Drinking
arsenic encephalopathy: follow up using newer measures of pattern and alcohol-related medical disorders. Alcohol Alcohol.
electrophysiologic parameters. Am J Med. 1987;82:549–552. 1990;34:330–336.
71. Clarkson TW, Magos L. The toxicology of mercury and its 93. Manzo L, Costa LG. Manifestations of neurotoxicity in
chemical compounds. Crit Rev Toxicol. 2006;36:609–662. occupational diseases. In: Costa, LG, Manzo L, eds.
72. Cursh JB, Clarkson TW, Miles E, Goldsmith LA. Occupational Neurotoxicology. Vol 2. Boca Raton, FL: CRC
Percutaneous absorption of mercury vapour by man. Arch Press; 1998:1–20.
Environ Health. 1989;44:120–127. 94. Claus D, Egger R, Engelhardt A, Neundorfer B, Warecka K.
73. Mozaffarian D, Rimm EB. Fish intake, contaminants, and Ethanol and polyneuropathy. Acta Neurol Scand. 1985;72:
human health: evaluating risks and benefits. JAMA. 312–316.
2006;296:1885–1899. 95. Burrit MF, Anderson CF. Laboratory assessment of
74. Thompson WW, Price C, Goodson B. Early thimersol nutritional status. Hum Pathol. 1984;15:130–133.
exposure and neuropsychological outcomes at 7 to 10 years. 96. Dyck PJ. Detection, characterization and staging of
N Engl J Med. 2007; 357:1281–1292. polyneuropathy assessed in diabetics. Muscle Nerve. 1998;
75. Aucott M, McLinden M, Winka M. Release of mercury 11:21–32.
from broken fluorescent bulbs. J Air Waste Manag Assoc. 97. Behese F, Buchtal F. Alcoholic neuropathy: clinical,
2003;53:143–151. electrophysiological and biopsy findings. Ann Neurol. 1997;
76. Tunnessen WW Jr, McMahon KJ, Baser M. Acrodynia: 2:95.
exposure to mercury from fluorescent light bulbs. Pediatrics. 98. Bosch EP, Pelham RW, Rasool CG, Chattorjee A, Lasch
1987;79:786–789. RW, Brown L. Animal models of alcoholic neuropathy:
77. Liang YX, Sun RK, Chen ZQ, Li LH. Psychological effects morphological, electrophysiological and biochemical
of low exposure to mercury vapor: application of computer- findings. Muscle Nerve. 1979;2:133–144.
administered neurobehavioral evaluation system. Environ 99. Behse F, Buchthal F. Alcoholic neuropathy: Clinical,
Res. 1993;60:320–327. electrophysiological, and biopsy finds. Ann of Neurology.
78. Langford NJ, Ferner RE. Toxicity of mercury. J Hum 1977;2:95–110.
Hypertens. 1999;13:651–656. 100. Palliyath S, Schwartz BD. Peripheral nerve functions
79. Cherian MG, Hursh JG, Clarkson TW. Radioactive improve in chronic alcoholic patients on abstinence. J Stud
mercury distribution in biological fluids and excretion in Alcohol. 1993;54:684–686.
2560_Chapter 5_0053-0068.indd 67 3/16/2015 4:14:45 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
2560_Glossary_0347-0360.indd 360 3/17/2015 12:11:29 PM
Chapter 6
Critical Illness Polyneuropathy
“It is in moments of illness that we are compelled to recognize that we live not
alone but chained to a creature of a different kingdom, whole worlds apart,
who has no knowledge of us and by whom it is impossible to make ourselves
understood: our body.”
—MARCEL PROUST
Objectives
• Define critical illness and its two subsets: critical illness polyneuropathy and critical illness myopathy.
• Demonstrate an understanding of the relationship between critical illness and critical illness polyneuropathy
and critical illness myopathy.
• Apply knowledge of critical illness polyneuropathy and critical illness myopathy to the development of a
valid rehabilitation assessment and goal-oriented intervention schema.
Key Terms
• Critical illness
• Critical illness myopathy (CIM)
• Critical illness polyneuropathy (CIP)
Introduction CIP and CIM were first described by Bolton et al.

in 19841 and further elucidated by Bolton et al. in
Critical illness polyneuropathy (CIP) and critical 1986.2 Five patients admitted to an acute care hospital
illness myopathy (CIM) are two major complications in London, Ontario, Canada, with multiple primary
of critical illness. CIP and CIM affect many aspects diagnoses all complicated by multisystem organ failure
of the therapeutic intervention spectra of critical illness. and sepsis were described as having difficulties in
These include the progression and success of ventilator weaning from the ventilator when the primary illness
weaning; the initiation and progression of physical, had subsided and development of flaccid and areflexic
emotional, and vocational rehabilitation; and the limbs. Early electroneurodiagnostic studies, especially
risk of idiopathic and iatrogenic complications of the needle examination, provided definitive evidence of
long-term bedrest. Etiological factors for CIP and an acute, systemic motor neuropathy. Bolton et al.1
CIM include sepsis, acute respiratory failure, systemic described the symptoms as “a primary axonal polyneu-
inflammatory response syndrome (SIRS), and multiple ropathy with sparing of the central nervous system.”
organ failure. This chapter focuses on the epidemiology, These investigators believed that nutritional issues may
diagnostics, pathophysiology, risk factors, clinical con- have provided the etiology of the motor loss because,
sequences, and potential therapeutic interventions to as they noted, symptoms appeared to have improved
reduce the incidence and severity of CIP and CIM. with the addition of total parenteral nutrition. Wil-
This chapter is written for the rehabilitative clinician liams et al.3 reported similar findings in children.
but may also benefit residents, interns, primary care CIM and CIP have similar symptoms, signs are
physicians, nurse practitioners, hospital-based nurses, often difficult to differentiate, and they frequently
and critical care physicians. co-occur. Combined electroneurophysiological testing
69
2560_Chapter 6_0069-0074.indd 69 3/16/2015 4:14:47 PM

Process CyanProcess
YellowProcess Black
and histological studies often show the overlap.4 From that change of baseline nerve conduction response
an interventional standpoint, these illnesses are often amplitude at 1 week was predictive of the development
treated together—hence the often used diagnostic of acquired lower motor neuron impairment.7 At 2 to
interpretation of CIM/CIP. Because the relationship 3 weeks after onset of critical illness, fibrillation poten-
of CIP and CIM is so intertwined in the literature tials and positive sharp waves appeared on the needle
dealing with etiology, pathogenesis, and treatment of examination.8 One study reported that electrophysio-
critical illness and many researchers believe the two logical screening using peroneal compound muscle
components are part of the same disease process, the action potential reduction greater than 2 standard devi-
collective term CIP/CIM is used in the remainder of ations below the normal value is reliable in determin-
this chapter. ing a diagnosis of CIM/CIP.9
Serum creatine kinase (CK) concentrations are
diagnostically helpful if they are normal, but often
Clinical Signs and Symptoms elevated CK concentrations may be secondary to
trauma, long-term bedrest, or surgical intervention.
CIP/CIM is a manifestation of a critical illness in the CK may be more beneficial as related to the specificity
peripheral nervous and skeletal muscle systems. For rather than the sensitivity for this particular diagnosis.
this reason, the signs and symptoms of CIP/CIM Muscle biopsy is also an effective diagnostic tool. Three
are of lower motor neuron origin or muscle origin. subtypes of acute myopathy found in intensive care
Elevated tone and tendon reflexes, the presence of units (ICUs) have been reported and are often noted
clonus and Babinski sign, and encephalopathy-induced as “acute quadriplegic myopathy.”10 These subtypes
changes in mental status are possible symptoms of the are diffuse nonnecrotizing cachectic myopathy, thick-
impact of severe illness on the central nervous system— filament myopathy or myopathy with selective loss
symptoms associated with involvement of upper motor of thick myosin filaments, and acute necrotizing
neurons and higher centers—but are not part of CIP/ myopathy. Nonnecrotizing myopathy is accompanied
CIM complications. Patients with CIP/CIM exhibit by abnormal variation of muscle fiber size, atrophy
the major clinical signs of flaccid symmetrical paralysis of predominantly type II fibers, angulated fibers, inter-
or symmetrical weakness; absent or diminished deep nalized nuclei, rimmed vacuoles, fatty degeneration
tendon reflexes; myopathic pain; and a distal loss of of muscle fibers, and fibrosis. In thick filament myop-
sensitivity to pain, temperature, and vibration. Facial athy, there is a selective loss of myosin filaments.
muscles tend to be spared but may be involved in rare Acute necrotizing myopathy of critical illness is
instances. Ventilator weaning issues are typically due characterized by prominent myonecrosis with vascu-
to diaphragm paralysis or weakness secondary to lization and phagocytosis of the muscle fibers. In a
phrenic and intercostal nerve involvement resulting few of these patients, the myopathy may progress to
from the CIP/CIM.5 rhabdomyolysis.5
The Medical Research Council (MRC) sum score is Incidence is related to the particular ICU case
a screening tool for CIP/CIM.6 In individuals with mix being studied. Of patients with sepsis or SIRS,
critical illness, manual muscle tests of six muscle groups 70% may develop CIM/CIP.5 With the addition of a
bilaterally are assessed on a scale of 0 to 5. The maximum diagnosis of multiple organ failure, the incidence may
score is 60. CIP/CIM is arbitrarily diagnosed if the increase to 100%.11 Patients with a diagnosis of acute
MRC sum score is less than 48. Two conditions affect respiratory distress syndrome have a 60% chance of
the reliability of the MRC sum score: (1) there can be developing CIM/CIP.11 Among all patients with diag-
no confounding cause of muscle weakness (e.g., iso- noses requiring mechanical ventilation for at least 4
lated nerve compression or Guillain-Barré syndrome) days, the incidence is 25%12 on clinical evaluation, and
affecting the manual muscle tests of the tested muscles, this number increases to 58% on electroneurodiagnos-
and (2) the patient must be sufficiently awake, coopera- tic evaluation.13
tive, and alert to be tested.
Laboratory and electroneuromyography testing can
assist with pinpointing the diagnosis of CIM/CIP. Pathophysiology
Electroneuromyography evidence is often the first
indication of CIM/CIP before manifestation of clini- Similar to the etiology, the pathophysiology of CIM/
cal symptoms. At 2 to 5 days after the onset of a critical CIP is unclear. The appearance of CIM/CIP in patients
illness, there is a reduction in amplitude of nerve con- with multiple organ system failure may raise the pos-
duction potentials or sensory nerve action potentials, sibility that the presenting signs and symptoms are
or both, with preserved conduction velocities. One evidence of failure of additional systems such as
study cited data showing most patients admitted to one musculoskeletal and peripheral neurological.14 Bolton
hospital for sepsis demonstrated reduced nerve con- et al.1 hypothesized that the failure of the microcircula-
duction amplitudes within 3 days of admission and tion secondary to cardiopulmonary collapse resulted in
2560_Chapter 6_0069-0074.indd 70 3/16/2015 4:14:48 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 6 | Critical Illness Polyneuropathy 71
impaired circulation to muscles, tendons, and periph- More recently, studies have been published examin-
eral nerves, which may result in CIM/CIP.1 Fenzi ing the relationship between intensive insulin therapy
et al.15 added to this argument by hypothesizing in mechanically ventilated patients and the prevention
that the microvascular collapse may be secondary to of CIM/CIP. These studies were prompted by a finding
the systemic effects of the proinflammatory cytokines by Witt et al. in 199121 noting a relationship between
expressed by macrophages/monocytes at the site of the hyperglycemia and CIM/CIP. The authors concluded
inflammation. The impact of the proinflammatory that avoidance of prolonged hyperglycemic concen-
cytokine messengers may be increased vascular perme- trations during the critical illness periods intuitively
ability resulting in endoneural edema inducing hypox- may affect the development of CIM/CIP. Insulin,
emia and energy depletion. This “bioenergetic failure” along with the blood sugar concentration control
as discussed by Bolton16 may also be exacerbated by function, also provides endothelial protection22 and
rapid swings in blood sugar concentration and the anti-inflammatory effects23 and has been shown to
passage of neurotoxic factors into the endoneurium in have neuroprotective effects in animals.24 Two trials
the critically ill patient leading to neuropathy. compared the use of intensive therapy (proactively
The pathophysiology of the myopathy component prescribing insulin to maintain blood sugar concen-
of CIM/CIP is equally complex. Muscle biopsies in trations of 80 to 110 mg/dL and conventional insulin
these patients reveal a decrease in total amino acid therapy—prescribing insulin only when blood sugar
concentration and glutamine levels. Glutamine is values exceeded 220 mg/dL) in patients with ventilator-
known to stimulate protein synthesis and inhibit dependent critical illnesses.25,26 In the subanalyses,27,28
protein breakdown.17 There appears to be a relative intensive insulin therapy aiming to maintain blood
deficiency of glutamine secondary to the increased sugar concentrate of 80 to 110 mg/dL offered to
physiological demands in critical illness. ventilator-dependent patients with critical illnesses in
Diaphragmatic studies using animal models18,19 elu- medical and surgical ICUs decreased the incidence
cidated how even a relatively short immobilization of CIM/CIP from 49% to 25% in the surgical ICU
period may lead to diminished diaphragm function. and from 51% to 39% in the medical ICU as mea-
Diaphragm immobilization under mechanical ventila- sured via electroneurodiagnostic studies. In addition,
tion for only 18 hours induced a significant decrease in the requirement for mechanical ventilation of 2 weeks
diaphragmatic force coupled with muscle atrophy and or longer decreased from 42% to 32% in the surgical
an increase in muscle markers of oxidative stress and ICU and from 47% to 35% in the medical ICU. A rela-
calpain and ubiquitin-proteasome activity. Preliminary tionship was noted between the tightness of glucose
data in humans suggest that the combination of short- control and lower incidence of CIM/CIP and ventila-
term diaphragmatic inactivity and mechanical ventilator dependency of greater than 2 weeks.
tion results in marked atrophy of human diaphragm The effectiveness of corticosteroids in the prevention
myofibers and loss of sarcomeres.20 or treatment of CIM/CIP remains speculative. Corti-
costeroids are an effective intervention in certain classes
of patients with septic shock, acute respiratory distress
Prevention and Intervention syndrome, acute asthma, and multiple organ failure—
all of which have been linked to CIM/CIP. In
The primary functional problem associated with a two studies, corticosteroids showed a beneficial impact
diagnosis of CIM/CIP in a patient who is dependent on the prevention of CIM/CIP.27,28 However, three
on a ventilator is ventilator weaning. In addition, the additional studies concluded that prescriptive use of
diagnosis of CIM/CIP increases the risk of complica- corticosteroids in ventilator-dependent patients with
tions of long-term bedrest, including hospital-acquired critical illness is a risk factor for the development of
pneumonia, deep vein thrombosis and pulmonary em- CIM/CIP.13,29
bolism, the development of pressure neuropathies, and The impact to persons performing rehabilitation
skin breakdown. In addition, length of stay is increased, services is related to prevention and intervention.
inpatient rehabilitation is often delayed, and patient Knowledge of specific predictor criteria for the devel-
costs are increased. opment of CIM/CIP allows the therapist to act
A review of preventive and interventional therapies proactively to prevent complications related to neu-
reveals numerous attempts to affect the development ropathy, myopathy, prolonged ventilator dependence,
and pathogenesis of CIM/CIP. These include nutri- and longer lengths of stays in the acute and rehabilita-
tional schemas and interventions; supplemental thera- tion settings.
pies; antioxidant therapy; and the use of testosterone Early identification of patients with diagnoses of
derivatives, human growth hormone, and immuno- acute respiratory distress syndrome, multiple organ
globulins.5 None of these interventions has shown a failure, or sepsis in combination with ventilator depen-
beneficial result in preventing or improving functional dency is important because these patients should be
outcome associated with CIM/CIP. strictly monitored with serial assessments of skin
2560_Chapter 6_0069-0074.indd 71 3/16/2015 4:14:48 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
BOX 6-1
High-Risk Locations for Pressure-Related Skin Ulcers

Occiput
Acromion
Lateral epicondyle of the elbow
Sacrum
Greater trochanter
Fibular head
Lateral malleolus
Calcaneus
Figure 6-1 Proper bed positioning for patients on long-
term bedrest assists with preventing integumentary and
musculoskeletal complications. Examples of proper bedrest
positioning techniques include frequent positional changes, BOX 6-2
avoidance of long-term flexion at all joints, pressure relief
over superficial bony prominences such as the calcaneus Locations for Possible Tensile and Compressive Neuropathies
and sacrum, and positioning to prevent loss of range of in Patients on Long-Term Bedrest
motion of two-joint muscle.
Brachial plexus
Axillary nerve at the humerus
Radial nerve at the elbow
integrity, muscle weakness, sensory neuropathy, myal- Ulnar nerve at the elbow
gias, and neuropathic pain along with the common Median nerve at the wrist
complications of long-term bedrest, including pneu- Lumbar nerve roots in the low back
Common peroneal nerve at the level of the fibular head
monia, atelectasis, and deep vein thrombosis. Pre-
ventive integument measures include every-2-hour
changes in bed positioning—supine, left side lying,
right side lying—to assist with unweighting bony maintenance of articular, axial, muscular, and neuro-
prominences for the prevention of pressure-induced logical ranges of motion and the prevention of adap-
peripheral neuropathies. The use of an outcome tion shortening of tissues; normalizing muscle strength;
measure such as the Braden Scale30 is often helpful in and early mobilization including weight-bearing activ-
identifying patients at risk for skin breakdown. The ities. The two-joint muscles that are typically adaptively
judicious use of pillows, towel rolls, specialty beds and shortened with prolonged bedrest are the biceps, rectus
coverlets, and over-the-counter braces and supports femoris, gastrocnemius, and hamstrings. The mainte-
may assist with pressure ulcer prevention (Fig. 6-1). nance of range of motion is accomplished through
Common areas of breakdown include the skin over the daily passive, active-assistive, and active range-of-
calcaneus, lateral malleolus, fibular head, greater tro- motion exercises supervised by the therapist.
chanter, sacrum, acromion, elbow, scapula, and occiput. Deep vein thrombosis prophylaxis should also be
Common nerves associated with pressure-related and instituted early in the hospitalization course. Effective
tensile-related neuropathies include the common pero- intervention along with pharmaceuticals includes anti-
neal nerve at the level of the fibular head, the ulnar embolism stockings, pneumatic antithrombotic stock-
nerve posterior to the elbow, the axillary nerve at the ings, ankle exercises, and frequent shifting of position
shoulder, the brachial plexus, and the median nerve at in bed (Fig. 6-2). To assist with the prevention of
the wrist (Boxes 6-1 and Box 6-2). hospital-acquired pneumonia, patients should be
Musculoskeletal complications are very common instructed in coughing and deep breathing, frequent
and reflect the prolonged abnormal positional stresses positional changes, and the use of incentive spirometry.
and lack of muscular activity associated with enforced An early mobilization functional plan should be insti-
bedrest. Abnormalities include fixed flexion deformi- tuted progressing the patient from bed mobility activi-
ties, especially at the shoulders, hips, knees, cervical ties to sitting upright to sitting upright over the edge
spine, and ankles; progressive instability of joints, most of the bed to out of bed to chair, and so forth.
notably at the glenohumeral joint; osteoporosis; and Martin et al.,31 Aldrich and Karpel,32 Sprague and
fractures. Cervical and lumbar radiculopathy is common Hopkins,33 and Martin et al.34 have published well-
and may manifest as neck and back pain often with constructed research studies on the effectiveness
variable radicular sensory symptoms and rarely motor of inspiratory muscle strength training (IMST) on
signs. Radiculopathy is typically related to bed posi- weaning of failure-to-wean patients. In most of the
tioning. Goals of intervention should include the studies, IMST was performed 5 days per week with a
2560_Chapter 6_0069-0074.indd 72 3/16/2015 4:14:48 PM

Process CyanProcess
YellowProcess Black
Chapter 6 | Critical Illness Polyneuropathy 73
2. Clinical signs of CIM/CIP include which of the
following?
a. Distal loss of vibration and pain
b. Symmetrical paralysis
c. Myalgias
d. All of the above
3. Often _______________ is/are the first diagnostic
sign of CIM/CIP.
a. Electrodiagnostic studies
Figure 6-2 Pneumatic antiembolism stockings along with b. Elevated blood urea nitrogen
other forms of deep vein thrombosis prophylaxis may c. Weakness
lessen the risk of leg clots that can delay mobilization. d. Elevated muscle enzymes
4. Extended time on a ventilator may lead to which of
threshold inspiratory muscle trainer that provided a the following complications?
threshold inspiratory pressure load between −4 cm H2O a. Deep vein thrombosis
and −20 cm H2O. The IMST device was attached to the b. Skin breakdown
tracheotomy tube, and the cuff remained inflated. Sub- c. Longer length of stay
jects used room air during the intervention and were d. All of the above
asked to perform multiple sets of 4 to 10 breaths per day 5. The Braden Scale is a useful assessment tool to assist
with 2 minutes of rest and ventilator support between the therapist with identifying ventilator-dependent
each set. Subjects were asked to inhale and exhale as patients at risk for which of the following
forcibly as possible during the training. Evidence sug- complications?
gests that IMST intervention provided improved a. Deep vein thrombosis
maximum inspiratory pressure and weaning outcome b. Pneumonia
compared with conventional and sham treatment.32–34 c. Skin breakdown
d. Fall risk
CASE STUDY
John is a 70-year-old man admitted to the ICU with References
acute respiratory distress secondary to a very aggressive 1. Bolton CF, Gilbert JJ, Hahn AF, Sibbald WJ. Polyneuropathy
bacterial pneumonia. He was placed on the ventilator in critically ill patients. J Neurol Neurosurg Psychiatry. 1984;
and prescribed antibiotics. John’s medical history is 47(11):1223–1231.
2. Bolton CF, Laverty DA, Brown JD, Witt NJ, Hahn AF,
significant for a 40 pack-year history of cigarette Sibbald WJ. Critically ill polyneuropathy: electrophysiological
smoking, moderate chronic obstructive pulmonary studies and differential from Guillain Barre syndrome.
disease, and hypertension. After 3 days in the ICU, his J Neurol Neurosurg Psychiatry. 1986;49(5):563–573.
white blood cell count and temperature are trending 3. Williams S, Horrocks IA, Ouvrier RA, Gillis J, Ryan MM.
downward, and his lungs are clearing as per the chest Critical illness polyneuropathy and myopathy in pediatric
intensive care: a review. Pediatr Crit Care Med. 2007;8:18–22.
x-ray. However, weaning has become problematic. 4. Latronico N, Fenzi F, Recupero D, et al. Critical illness
The therapist treating John has been performing myopathy and neuropathy. Lancet. 1996;347:1579–1582.
daily active-assistive range of motion to prevent loss of 5. Hermans G, De Jonghe B, Bruyninckx F, Van den Berghe G.
articular range of motion, daily strengthening exercises, Critical illness polyneuropathy and myopathy. Crit Care.
and a functional progression including bed mobility 2008;12:238–253.
6. De Jonghe B, Sharshar T, Lefaucheur JP, et al; Groupe de
and supine-to-sit transfers. John has been in a chair for Réflexion et d’Etude des Neuromyopathies en Réanimation.
up to 2 hours per day. Paresis acquired in the intensive care unit: a prospective
multicenter study. JAMA. 2002;288:2859–2867.
7. Khan J, Harrison TB, Rich MM, Moss M. Early
Case Study Questions development of critical illness myopathy and neuropathy in
patients with severe sepsis. Neurology. 2006;67:1421–1425.
1. On day 3 of the hospital stay, the physical therapist 8. Tennila A, Salmi T, Pettila V, Roine RO, Varpula T,
notes a progression in muscle weakness and loss of Takkunen O. Early signs of critical illness polyneuropathy in
deep tendon reflexes. Differential diagnoses include ICU patients with systemic inflammatory response syndrome
all of the following except: or sepsis. Intensive Care Med. 2000;26:1360–1363.
a. CIM/CIP 9. Coakley JH, Nagendran K, Yarwood GD, Honavar M, Hinds
CJ. Patterns of neurophysiological abnormality in prolonged
b. Guillain-Barré syndrome critical illness. Intensive Care Med. 1998;24:801–807.
c. Metabolic encephalopathy 10. Hund E. Myopathy in critically ill patients. Crit Care Med.
d. Urinary tract infection 1999;27:2544–2547.
2560_Chapter 6_0069-0074.indd 73 3/16/2015 4:14:48 PM

Process CyanProcess
YellowProcess Black
11. Tennila A, Salmi T, Pettila V, Roine RO, Varpula T, 23. Hansen TK, Thiel S, Wouters PJ, Christiansen JS, Van den
Takkunen O. Early signs of critical illness polyneuropathy in Berghe G. Intensive insulin therapy exerts anti-inflammatory
ICU patients with systemic inflammatory response syndrome effects in critically ill patients and counteracts the adverse
or sepsis. Intensive Care Med. 2000;26:1360–1363. effect of low mannose-binding lectin levels. J Clin Endocrinol
12. Bercker S, Weber-Carstens S, Deja M, et al. Critical illness Metab. 2003;88:1082–1088.
polyneuropathy and myopathy in patients with acute 24. Ishii DN, Lupien SB. Insulin-like growth factors protect
respiratory distress syndrome. Crit Care Med. 2005;33: against diabetic neuropathy: effects on sensory nerve
711–715. regeneration in rats. J Neurosci Res. 1995;40:138–144.
13. Douglass JA, Tuxen DV, Horne M, et al. Myopathy in severe 25. Van den Berghe G, Wouters P, Weekers F, et al. Intensive
asthma. Am Rev Respir Dis. 1992;146:517–519. insulin therapy in the critically ill patients. N Engl J Med.
14. Leijten FS, de Weerd AW, Poortvliet DC, De Ridder VA, 2001;345:1359–1367.
Ulrich C, Harink-De Weerd JE. Critical illness 26. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive
polyneuropathy in multiple organ dysfunction syndrome and insulin therapy in the medical ICU. N Engl J Med. 2006;354:
weaning from the ventilator. Intensive Care Med. 1996;22: 449–461.
856–861. 27. Van den Berghe G, Schoonheydt K, Becx P, Bruyninckx F,
15. Fenzi F, Latronico N, Refatti N, Rizzuto N. Enhanced Wouters PJ. Insulin therapy protects the central and
expression of E-selectin on the vascular endothelium of peripheral nervous system of intensive care patients.
peripheral nerve in critically ill patients with neuromuscular Neurology. 2005;64:1348–1353.
disorders. Acta Neuropathol. 2003;106:75–82. 28. Hermans G, Wilmer A, Meersseman W, et al. Impact of
16. Bolton CF. Neuromuscular manifestations of critical illness. intensive insulin therapy on neuromuscular complications and
Muscle Nerve. 2005;32:140–163. ventilator-dependency in MICU. Am J Respir Crit Care Med.
17. Gamrin L, Andersson K, Hultman E, Nilsson E, Essen P, 2007;175:480–489.
Wernerman J. Longitudinal changes of biochemical 29. Vespa P. Deep venous thrombosis prophylaxis. Neurocrit Care.
parameters in muscle during critical illness. Metabolism. 2011;15(2):295–297.
1997;46:756–762. 30. Kozier B, Erb G, Snyder S, Berman B. Fundamentals of
18. Shanely RA, Zergeroglu MA, Lennon SL, et al. Mechanical Nursing: Concepts, Process, and Practice. 8th ed. Upper Saddle
ventilation-induced diaphragmatic atrophy is associated with River, NJ: Pearson Education; 2008:905–907.
oxidative injury and increased proteolytic activity. Am J Respir 31. Martin AD, Davenport PD, Franceschi AC, Harman E. Use
Crit Care Med. 2002;166:1369–1374. of inspiratory muscle strength training to facilitate ventilator
19. Testelmans D, Maes K, Wouters P, Powers SK, Decramer M, weaning: a series of 10 consecutive patients. Chest. 2002;122:
Gayan-Ramirez G. Infusions of rocuronium and 192–196.
cisatracurium exert different effects on rat diaphragm 32. Aldrich TK, Karpel JP. Inspiratory muscle resistive training in
function. Intensive Care Med. 2007;33:872–879. respiratory failure. Am Rev Respir Dis. 1985;131:461–462.
20. Levine S, Nguyen T, Taylor N, et al. Rapid disuse atrophy of 33. Sprague SS, Hopkins PD. Use of inspiratory strength training
diaphragm fibers in mechanically ventilated humans. N Engl J to wean six patients who were ventilator-dependent. Phys
Med. 2008;358:1327–1335. Ther. 2003;83:171–181.
21. Witt NJ, Zochodne DW, Bolton CF, et al. Peripheral nerve 34. Martin AD, Smith BK, Davenport PD, et al. Inspiratory
function in sepsis and multiple organ failure. Chest. 1991;99: muscle strength training improves weaning outcome in failure
176–184. to wean patients: a randomized trial. Crit Care. 2011;15:
22. Langouche L, Vanhorebeek I, Vlasselaers D, et al. Intensive 96–108.
insulin therapy protects the endothelium of critically ill
patients. J Clin Invest. 2005;115:2277–2286.
2560_Chapter 6_0069-0074.indd 74 3/16/2015 4:14:48 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 7
Diabetes Mellitus and
Peripheral Neuropathy
“Someone once told me that God figured that I was a pretty good juggler. I
could keep a lot of balls in the air at one time. So He said, ‘Let ’s see if you can
juggle another one.’ ”
—ARTHUR ASHE (1943–1993)
Objectives
• Discuss the signs and symptoms of diabetes and diabetic neuropathy.
• Discuss the possible etiologies of diabetic neuropathy.
• Explain the difference between the three classic subgroups of diabetic neuropathy.
• Discuss, compare, and contrast the common presentations of diabetic neuropathy.
• Discuss physical therapy intervention for diabetic neuropathy.
Key Terms
• Diabetes
• Gestational diabetes
• Insulin
signs, symptoms, and complications. The etiology may

Introduction be primary or secondary as the result of tumor, trauma,
obesity, or medication.
Diabetes mellitus (DM), or simply diabetes, is a
chronic health condition in which the body either fails
to produce a sufficient amount of insulin or responds
abnormally to insulin production.1 DM as a disease
Pathophysiology of
entity has been known for centuries. DM takes its Diabetes Mellitus
name from the Greek for “passing through” because of
one of its main symptoms—excessive urine production. The pathophysiology of the different types of DM is
During the 15th century, the word “mellitus” was added related to the hormone insulin, which is secreted by the
from the Latin for “honey” when it was noted that beta cells of the pancreas. This hormone is responsible
many patients with diabetes had high levels of sugar in for maintaining a homeostatic glucose level in the
their blood and urine.2,3 Classically, diabetes is divided blood. Insulin allows cells to use glucose as a main
into three broad subcategories: type 1 diabetes, type energy source. However, in a person with DM, because
2 diabetes, and gestational diabetes. The primary of abnormal insulin metabolism, the body cells and
impairment of all three types of diabetes is a high tissues do not make use of glucose from the blood. This
blood glucose level, or hyperglycemia. The pathophysi- situation results in an elevated level of glucose outside
ology of DM is very complex because the disease is the cell and a high blood glucose concentration. Over
characterized by different etiologies that share similar time, a high glucose level in the bloodstream may lead
75
2560_Chapter 7_0075-0088.indd 75 3/16/2015 4:14:51 PM

Process CyanProcess
YellowProcess Black
to severe complications, such as ocular disorders,
cardiovascular diseases, renal insufficiency, cerebral
blood insufficiency, peripheral vascular disease, and
neuropathy.4
In type 1 DM, the pancreas cannot synthesize a
sufficient amount of insulin hormone as required by
the metabolic demands of the body. The pathophysiol-
ogy of type 1 DM suggests that it is an autoimmune
disease affecting the beta cells of the pancreas. Conse-
quently, the pancreas secretes little or no insulin. Type Figure 7-1 Newborn with macrosomia secondary to
1 diabetes is more common in children and young gestational diabetes. Elevated blood glucose levels in a
adults than in older adults. Because it is common pregnant woman with gestational diabetes also occur in
among young individuals and insulin hormone is used the growing fetus resulting in higher-than-expected body
for treatment, type 1 diabetes is also referred to by its weight at birth. Excessive weight may result in injury to
older nomenclature: insulin-dependent diabetes mel- the infant at birth and potential long-term health
litus or, when affecting children, juvenile diabetes.5 concerns.
In type 2 DM, there is normal production of insulin
hormone, but cells are resistant to insulin resulting in
an elevated blood concentration of glucose. Type 2 DM
commonly manifests in middle-aged adults (older than children who are at risk for obesity and adults who are
40 years). Because insulin is often not necessary for at risk for type 2 diabetes (Fig. 7-1).2,6
treatment of type 2 diabetes and adults are mostly In “borderline” or “prediabetes,” fasting blood glucose
affected, it is also known as non–insulin-dependent concentration is impaired. In this condition, the fasting
diabetes mellitus or adult-onset diabetes.5 blood glucose concentration is elevated above what is
Pregnant women who have never been diagnosed considered to be normal. However, these levels are
with diabetes before pregnancy but who have high not sufficiently elevated to be diagnostic of DM. The
blood glucose levels during pregnancy have gestational “prediabetic state,” for want of a better term, is associ-
diabetes. Gestational diabetes affects about 4% of all ated with insulin resistance and an increased risk of
pregnant women. There are approximately 135,000 cardiovascular pathologies. According to the World
new cases of gestational diabetes in the United States Health Organization,7 fasting plasma glucose levels
each year. The placenta provides nutritional and protec- between 110 mg/dL and 125 mg/dL are diagnostic for
tive support to the fetus as it grows. Gestational dia- prediabetes.
betes develops when the mother’s body is unable to
make and use all the insulin it needs for pregnancy.
Without enough insulin, glucose cannot exit the blood Complications of Diabetes
and pass through the cell walls. Glucose concentration
increases in the blood. Gestational diabetes affects the The quantity and severity of the complications of dia-
mother during the later stages of pregnancy. Because betes are directly related to the duration of the disease
of this, gestational diabetes does not cause the kinds of and the quality of short-term and long-term blood
complications sometimes seen in babies whose mothers sugar control. Short-term blood sugar control is best
had diabetes before pregnancy. However, untreated or measured by frequent finger-stick assessments, and
poorly controlled gestational diabetes can injure the long-term control is best measured via the hemoglobin
fetus. High blood glucose passes through the placenta, A1c blood test. Complications typically affect the visual,
resulting in the fetus having high blood glucose levels. integument, cardiovascular, neurological, renal, immune,
The relative hyperglycemia stimulates the fetus’s pan- and reproductive systems.
creas to produce extra insulin to normalize the blood The most common visual complication of diabetes
glucose levels. Because the fetus is often receiving is diabetic retinopathy. Diabetic retinopathy affects
more glucose than it needs to grow and develop, the 80% of all patients who have diabetes for 10 years or
extra glucose is stored as fat; this can lead to macroso- more.6 However, research indicates that at least 90% of
mia, or “fat baby syndrome.” Babies with macrosomia these new cases could be eliminated if there were
who are delivered vaginally face potential complica- proper and vigilant treatment and monitoring of the
tions, including structural damage to the shoulders and eye and improved glycemic control.8
brachial plexus lesions. Because of the extra insulin Diabetic retinopathy often has no early warning
made by the fetal pancreas during gestation, newborns signs. Even macular edema, which may enhance the
may have very low blood glucose levels at birth and rate of visual loss, may not have any warning signs for
are at higher risk for respiratory issues during the neo- some time. In general, a person with macular edema is
natal period. Babies with excess insulin grow up to be likely to have blurred vision prompting complaints of
2560_Chapter 7_0075-0088.indd 76 3/16/2015 4:14:51 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 7 | Diabetes Mellitus and Peripheral Neuropathy 77
difficulty with driving, reading, and performing fine
motor tasks. In some cases, the quality of vision may
change throughout the day, often relative to the blood
glucose concentration.
As new blood vessels form at the back of the eye as
a part of proliferative diabetic retinopathy, bleeding
may occur with resultant loss of visual acuity. Symp-
toms following the initial bleed may be minor or not
noticeable to the patient. In many cases, funduscopic
examination identifies blood specks floating in the
visual field, although the spots often disappear after a
few hours or days. These specks are often followed
within a few days or weeks by a much greater leakage
of blood, which blurs vision. In extreme cases, with
recurrent bleeds or a major bleed, the patient is able to Figure 7-2 Ulcerations associated with diabetes mellitus
determine only light from dark in that eye. Clearance may be due to many factors, including microvascular and
of blood may take a few days to months or years to macrovascular disease, afferent neuropathy, autonomic
clear from the inside of the eye, and in some cases the neuropathy, and abnormal foot mechanics. Ulcerations may
blood does not completely clear. These types of large become infected potentially leading to limb loss.
hemorrhages tend to occur more than once, often
during sleep.8
Elevation of blood glucose levels can also cause
edema (swelling) of the crystalline lens (hyperphaco-
sorbitomyopicosis) as a result of osmotic changes asso-
ciated with sorbitol accumulating in the lens. This Normal Artery Narrowing of Artery
edema often causes transient myopia, whereas near Plaque
vision remains constant. The lens edema, as a result of Artery wall Narrowed
the hyperglycemia, is often symptomatic via decreased artery
visual acuity.
Individuals with diabetes are more likely to have
length-dependent integument concerns because of
the length-dependent nerve-related and blood vessel–
related damage. The further from the heart, the greater
the risk of neural and vessel damage and the greater
the associated risk of skin complications. Large-fiber Plaque
and small-fiber neuropathy may lead to insensate skin
areas increasing the risk for pressure and traumatic
ulcerations (Fig. 7-2). Motor neuropathy may lead to
focal or patterned muscle weakness, which leads to gait
dysfunction and a heightened risk for ulceration
because of improper weight-bearing vectors through
the lower extremity. Vascular complications include a
length-dependent stenosis of the vasculature leading to
intermittent claudication and possibly ischemia (Fig.
7-3). Both neuropathy and vasculopathy may result in
slow healing of or an inability to heal skin wounds and
a greater than expected risk of infection. Small sores or Normal blood Abnormal blood
flow flow
breaks in the skin may turn into deep skin ulcers if not
treated properly. If these skin ulcers do not improve or Figure 7-3 Progressive stenosis of an artery subject to
progress in size and depth, amputation of the affected prolonged hyperglycemia. Elevated hemoglobin A1c has
limb may be needed. been correlated with worsening microvascular and
Skin care is an effective preventive measure of the macrovascular disease, often the result of atherosclerotic
loss of skin integrity in patients with diabetes. Patients plaque formation. Many of the impairments associated
with diabetes should be encouraged to learn proper with diabetes—retinopathy, renal disease, cerebrovascular
skin care and precautions. Although tedious and time- disease, peripheral vascular disease, and heart disease—are
consuming, frequent skin checks are of utmost impor- associated with diminished blood flow or blood vessel
tance in preventing limb injury or loss. Examples of pathology.
2560_Chapter 7_0075-0088.indd 77 3/16/2015 4:14:52 PM

Process CyanProcess
YellowProcess Black
BOX 7-1
Diabetic Skin Care

• Monitor and work toward a healthy blood glucose
level. Perform frequent blood glucose monitoring. Ask
your physician about a home testing kit. Ask your
physician about routine hemoglobin A1c testing. Work
with your health care team to keep your blood
glucose in your target range. Maintain your
prescribed diet. Exercise. Take your medication.
• Monitor the skin on your legs and feet daily. Check
your bare feet and legs for red spots, cuts, swelling,
and blisters. If you cannot see the bottoms of your
feet, use a mirror or ask someone for help.
• Exercise daily. Ask your physician for a referral to a
physical therapist for an exercise prescription. Figure 7-4 Use of Semmes Weinstein monofilaments to
• Wash your feet every day with a mild soap and assess tactile and protective sensation. Ongoing filament
warm water. Dry them carefully, especially between analysis of tactile perception related to dermatomal
the toes. geography is an excellent method of predicting the risk
• Keep your skin soft and smooth. Rub a thin coat of of developing insensate foot ulcers related to trauma.
skin lotion over the tops and bottoms of your feet but Filaments of various sizes are pressed to the dermal areas,
not between your toes. and the patient is asked to vocalize when he or she feels
• If you can see and reach your toenails, trim them the filament touch the skin. The greater the diameter of
when needed. Trim your toenails straight across and the filament, the greater the pressure needed to excite the
file the edges with an emery board or nail file. Have dermal pressure receptors—and a greater risk of
your nails trimmed by a podiatrist if you cannot see
developing foot ulcers because of insensate skin.
your toenails clearly, if you have trouble reaching
them, or if you have ever had a wound related to
your diabetes on your feet.
• Wear shoes and socks at all times. Never walk Cardiovascular and cerebrovascular complications
barefoot. Wear comfortable shoes that fit well and are common and include vascular cardiomyopathy,
protect your feet. Check inside your shoes before
myocardial infarction, arrhythmia, stroke, and renal
wearing them. Make sure the lining is smooth and
there are no objects inside.
disease. Untreated hypertension, hyperlipidemia, and
• Protect your feet from hot and cold. Wear shoes at hypercholesterolemia may increase the risk of an
the beach or on hot pavement. Do not put your feet adverse event. Other complications of diabetes include
into hot water. Test water before putting your feet in it a greater than expected risk of infections of the female
just as you would before bathing a baby. genitourinary tract, chronic kidney disease, polyuria,
• Keep the blood flowing to your feet. Put your feet up polydipsia, polyphagia, weight loss, confusion, and
when sitting. Wiggle your toes and move your ankles impotence in men (Fig. 7-5).
up and down for 5 minutes two or three times a day. Early and correct detection of the specific type of
Do not cross your legs for long periods of time. diabetes affecting the patient is necessary to prevent
• Do not smoke. Smoking is detrimental to circulation. severe downstream health effects. After diagnosis, a
• Visit your eye doctor regularly. Diabetes may result in
physician may prescribe appropriate medications and
severe eye complications.
• Visit your dentist regularly. Diabetes can hasten gum
lifestyle changes to assist with glycemic control. Exam-
and tooth diseases. ples of lifestyle modifications include dietary restric-
• Get started now. Begin taking good care of your feet tions and an exercise prescription for regular aerobic
today. Set a time every day to check your feet. exercise.9,10 Glycemic control is directly related to
three variables: caloric intake of food, activity, and
medication.
diabetic skin care include skin checks such as daily Diabetic neuropathies—neuropathies associated
examination of the feet and legs with a mirror for signs with prediabetes, type 1 diabetes, type 2 diabetes, and
of ulceration, redness, edema, or infection; clipping of gestational diabetes—are heterogeneous; affect differ-
toenails by a podiatrist; and avoidance of walking in ent parts of the nervous system; and result in the pre-
socks or barefoot (Box 7-1). Monofilament examina- sentation of diverse clinical symptoms and impairments
tions should be performed routinely every 3 months to secondary to involvement of the sensory, motor, and
assess for insensate skin areas (Fig. 7-4). An individual autonomic nervous systems. Diabetic neuropathies are
with a suspected skin lesion should be referred to a characterized by a progressive loss of nerve fibers,
health care practitioner for evaluation. which can be assessed noninvasively by several tests of
2560_Chapter 7_0075-0088.indd 78 3/16/2015 4:14:52 PM

Process CyanProcess
YellowProcess Black
9
Trial (DCCT). An association between impaired
glucose tolerance and peripheral neuropathy has been
construed as further evidence of a dose-dependent
effect of hyperglycemia on nerves, although this rela-
tionship remains controversial for type 2 diabetes and
prediabetes.12–14 Pathologically, numerous changes have
been demonstrated in both myelinated and unmyelin-
ated fibers.15
The etiology of diabetic neuropathy is unclear; many
conflicting hypotheses exist. The diabetic neuropathies
may be focal or diffuse. Most common among the
neuropathies are chronic sensorimotor distal symmet-
rical polyneuropathy and autonomic neuropathies.16
The early recognition and appropriate management of
neuropathy in a patient with diabetes is important for
the following reasons: (1) Of diabetic neuropathies,
50% may be subclinical or asymptomatic and early,
medically supervised risk factor modification may elicit
downstream benefits17; (2) nondiabetic neuropathies
Figure 7-5 Poorly controlled diabetes may lead to lacunar may be present in patients with diabetes18; (3) an
(small, deep) brain infarcts as a result of cerebrovascular increasing number of treatment options exist for symp-
disease. As the number of infarcts increases, functional and tomatic diabetic neuropathy; (4) patients with diabetic
cognitive impairments similarly increase. neuropathy are at risk for insensate injury to their feet,
and provision of education and appropriate foot care
may result in a reduced incidence of ulceration and
consequently amputation19; and (5) autonomic neu-
Table 7-1 Classification of Diabetic Neuropathy ropathy, if unrecognized and untreated, may cause sub-
Symmetrical Distal symmetrical sensorimotor stantial morbidity and increased mortality, particularly
Polyneuropathies polyneuropathy if cardiovascular autonomic neuropathy is present.20
Small-fiber neuropathy
Diabetic autonomic neuropathy
Diabetic neuropathic cachexia Demographics
Asymmetrical Cranial mononeuropathy
Neuropathies Somatic mononeuropathies Among all persons with a diagnosis of diabetes, regard-
Diabetic thoracic radiculoneuropathy less of the duration of the disease, the incidence of
Diabetic radiculoplexus neuropathy neuropathy was noted to be 5% to 100%18 depending
Charcot neuropathy on the diagnostic criteria, and 7.5% of persons with a
new diagnosis of diabetes have objective evidence of
neuropathy.20 These results are similar for studies
outside the United States. More than half of patients
nerve function, including nerve conduction studies and with a new diagnosis of diabetes have distal sym-
electromyography, quantitative sensory testing, and metrical polyneuropathy. Focal syndromes such as
autonomic function tests.11 carpal tunnel syndrome (14% to 30%),20 radiculopathies/
A widely accepted definition of diabetic periph- plexopathies, and cranial neuropathies account for
eral neuropathy is “the presence of symptoms and/or the rest of neuropathies. Solid prevalence data for
signs of peripheral nerve dysfunction in people with the common syndromes are lacking. A Belgian study
diabetes after exclusion of other causes.”12 Diabetic reported that after 25 years of having diabetes, the
neuropathy is classified into several syndromes, each incidence of neuropathy increased to 45%.21
with a distinct pattern of involvement of peripheral Patients with poorly controlled diabetes as measured
nerves. Patients often have multiple or overlapping by daily blood glucose levels and hemoglobin A1c
syndromes (Table 7-1). titers have significantly higher rates of neuropathy and
Peripheral neuropathies have been described in higher rates of neuropathic complications.21 There does
patients with primary (types 1 and 2) and secondary not appear to be varying incidences of neuropathy
diabetes of diverse causes suggesting a common etio- associated with race.22 Men with type 2 diabetes often
logic mechanism based on chronic hyperglycemia. The develop neuropathy earlier than women when duration
contribution of hyperglycemia has received strong and severity of disease are controlled.22 Diabetic neu-
support from the Diabetes Control and Complications ropathy accounts for more hospitalizations than all
2560_Chapter 7_0075-0088.indd 79 3/16/2015 4:14:52 PM

Process CyanProcess
YellowProcess Black
other diabetic complications combined and are respon- without changing the level of hyperglycemia or the
sible for 50% to 75% of nontraumatic amputations. sorbitol or fructose levels, suggesting that myo-inositol
Older adults with diabetic neuropathy, owing to gen- itself may be an important polyol.34 The mechanism
eralized system decline with age, are especially at risk for decreased intracellular myo-inositol concentrations
for falls because of neuropathic effects on stability, causing decreased nerve conduction velocity is unclear.
gait, balance, muscle strength, pain, and sensorimotor Evidence suggests that decreased myo-inositol concen-
function.23,24 trations may lead to decreased phosphoinositides.34
Phosphoinositides are labile phospholipids, impor-
tant structural components of the nerve membrane.
Pathophysiology of Aberrant membrane structure may affect the sodium-
potassium pump resulting in increased intracellular
Diabetic Neuropathy sodium, as evidenced by osmotic-induced paranodal
nerve swelling in rats with diabetes.33
Seminal discussions regarding the etiology of diabetic
neuropathy continue to evolve; there is not yet a con- Microvascular Theory
sensus. Possible etiologies can be classified into one of The microvascular theory, also known as the microvas-
three groups: the polyol pathway theory, the microvascular ischemic theory of diabetic neuropathy, is well
cular theory, and the glycosylation end-product theory. known and well represented in the literature.35–45 Dia-
betes of long duration has been correlated with micro-
Polyol Pathway vascular changes in the kidney, retina, and nerve.37
The polyol pathway is a two-step metabolic pathway These changes include capillary basement membrane
in which glucose is reduced to sorbitol, which is con- thickening and endothelial cell hypertrophy.38 Evi-
verted to fructose.25 It is one of the most attractive dence suggests that these alterations could result in
candidate mechanisms to explain, at least in part, the changes in oxygen and nutrient distribution and uptake
cellular toxicity of diabetic hyperglycemia because by the peripheral nerve.38,39 In addition to the capillary
wall changes, findings of erythrocyte and platelet
● the pathway becomes active when intracellular
abnormalities have been found.39 These abnormalities
glucose concentrations are elevated above
are characterized by decreased red cell deformability
normal26;
and an increase in red cell and platelet aggregation.
● the two enzymes required for pathway
These findings may result in decreased oxygen delivery
completion are present in human tissues and
to perineural tissues. These protein aggregates perma-
organs that are sites of common diabetic
nently bind to the blood vessel walls via attachments
complications, such as eye, kidney, and
to collagen and may be the locus of attachment for
nerve27; and
monocyte/macrophage complexes.40–42 The monocytes/
● the products of the pathway and the altered
macrophages produce proinflammatory cytokines such
balance of cofactors generate the types of
as tumor necrosis factor-α and interleukin-1β leading
cellular stress that occur at the sites of diabetic
to the local inflammatory changes of angiogenesis,
complications.28
scarring, and alterations in vascular permeability com-
The polyol pathway is so named because polyol is bining to result in accelerated atherosclerosis and pro-
the general term for sugar alcohols, of which glucose gressive tissue ischemia.42–45
is one.29 Glucose uptake in the peripheral nerve,
in contrast to most corporal tissues, is not insulin- Nonenzymatic Glycosylation Theory
dependent.30 Elevated blood glucose levels always lead The nonenzymatic glycosylation theory expands on the
to elevated intracellular nerve glucose concentrations. notion that glucose attaches to proteins at a rate pro-
High intracellular concentrations of nerve glucose lead portional to glucose concentration.46 The resultant
to conversion of glucose to sorbitol via the polyol protein:glucose structures are called “nonenzymatic
pathway using the enzyme aldose reductase.31 This glycosylation products” and can bind to proteins of the
conversion also occurs in the renal glomerulus, lens, erythrocyte membrane, basement membrane, intraneu-
and retina.32 In a rat model, high sorbitol concentration ral tubulin, or other exposed proteins. The glycosylation
leads to cataract formation.33 products accumulate over time hastening in correlation
There is also evidence that increased sorbitol con- with above-average blood glucose levels.47
centration in peripheral nerve leads to decreased myo- Inhibition or ablation of aldose reductase, the first
inositol levels in the peripheral nerve.33 Myo-inositol and rate-limiting enzyme in the pathway, prevents dia-
is a sugar that is very similar molecularly to glucose. betic retinopathy in diabetic rodent models, but the
Intracellular myo-inositol levels are decreased in the dia- results of a major clinical trial have been disappoint-
betic rat model.34 Myo-inositol supplementation pre- ing.48 It has become evident that truly informative
vents nerve conduction abnormalities in the rat model indicators of polyol pathway activity or inhibition are
2560_Chapter 7_0075-0088.indd 80 3/16/2015 4:14:52 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
elusive but are likely to be other than sorbitol levels if and ascend proximally in a stockinglike distribution.52
meant to predict tissue consequences accurately. The Similar symptoms in the upper extremity (glovelike
spectrum of abnormalities known to occur in human distribution) may occur.53 Clinicians often combine the
diabetic retinopathy has enlarged to include glial and two terms and refer to distal symmetrical sensory poly-
neuronal abnormalities, which in experimental animals neuropathy as being a “stocking-glove sensorimotor
are mediated by the polyol pathway. The endothelial neuropathy.”53 Mild intrinsic muscle foot weakness
cells of human retinal vessels have been noted to have may be present bilaterally, and there may be a loss of
aldose reductase. Specific polymorphisms in the pro- or diminishment of the Achilles reflex bilaterally.
moter region of the aldose reductase gene have been Vibratory sense is typically diminished in the feet and
found associated with susceptibility or progression of hands. Foot ulcerations or slow-healing wounds may
diabetic retinopathy.49 This new knowledge has rekin- be present. There may be evidence of loss of proprio-
dled interest in a possible role of the polyol pathway ception in the lower extremities as noted by a dimin-
in diabetic retinopathy and in methodological investi- ished Romberg, Berg, and other balance examination
gation that may prepare new clinical trials. Only new tools.54
drugs that inhibit aldose reductase with higher efficacy Small-Fiber Neuropathy
and safety will make it possible to learn if the resilience Small-fiber neuropathy involves primarily the small-
of the polyol pathway means that it has a role in human diameter, unmyelinated sensory fibers such as the A
diabetic retinopathy.50 delta and C fibers.52 Symptoms include painful pares-
thesias that patients characterize as “burning,” “fiery,”
“achy,” and “cramping.”54 Similar to distal symmetrical
Classification and Clinical sensorimotor polyneuropathy, symptoms of small-fiber
neuropathy tend to be length-dependent and begin in
Characteristics of a stocking-glove distribution with the feet and legs
Diabetic Neuropathies often experiencing the worst symptoms. Symptoms are
often improved during the day and worsened at night.
Diabetic neuropathy is not a homogeneous disorder. Typically, there is no motor weakness, and reflexes are
Rather, diabetic neuropathy comprises a group of syn- preserved. Tactile sensation is also typically intact.
dromes with various clinical presentations and impair- There are no balance issues unrelated to pain.
ments often associated with different types of diabetes Diabetic Autonomic Neuropathy
and with varying prognoses. A generally accepted Pure autonomic diabetic neuropathy is extremely rare.55
classification of diabetic neuropathies divides them Some degree of autonomic involvement is present in
broadly into symmetrical and asymmetrical neuropa- most patients with distal symmetrical diabetic poly-
thies. Development of symptoms depends on many neuropathy, but patients may not notice or appreciate
risk factors, such as total hyperglycemic exposure; ele- the presence of the autonomic symptoms.55 Common
vated lipids; blood pressure; smoking; increased height; autonomic signs include labile blood pressure and heart
and high exposure to other potentially neurotoxic rate (especially with postural change and severe effort),
agents such as ethanol, lead, and neurotoxic medica- an absent ability to sweat, orthostatic hypotension,
tions. Genetic factors may also play a role. Establishing resting tachycardia, anhydrosis of the extremities, bowel
the diagnosis requires careful evaluation because or bladder dysfunction, pupils sluggishly reacting to
patients with diabetes may have neuropathy from light and accommodation, and impotence.20,55–57 Often
another cause. autonomic symptoms are the predominant complaint
early on in the course of type 1 diabetes.57
Symmetrical Neuropathies Diabetic Neuropathic Cachexia
Distal Symmetrical Sensorimotor Polyneuropathy The hallmark of diabetic neuropathic cachexia is a pre-
Distal symmetrical sensorimotor polyneuropathy is the cipitous and profound weight loss followed by severe
most common presentation of diabetic neuropathy.51 and unremitting cutaneous pain, small-fiber neuropa-
For proper diagnosis, the patient must have DM as thy, and autonomic dysfunction. Diabetic neuropathic
determined by the definitions outlined by the Ameri- cachexia appears most commonly in older men.51,55
can Diabetes Association or World Health Organiza- Concomitant impotence is common, although muscle
tion.51 Additionally, the severity of the polyneuropathy weakness is uncommon. Weight loss symptoms
should parallel the duration and severity of the disease, improve with improved glycemic control; however, the
and other differential diagnoses should have been cutaneous pain symptoms do not.2
excluded. Sensory, motor, and autonomic impairments
are present in varying degrees with the sensory impair- Asymmetrical Neuropathies
ments most apparent. There is a length-dependent, Cranial Mononeuropathy
symmetrical pattern of nerve involvement.6 Symptoms Cranial mononeuropathies typically affect cranial
begin as painful paresthesias and numbness in the toes nerves (cranial nerve [CN] II, CN III, CN IV, CN VI,
2560_Chapter 7_0075-0088.indd 81 3/16/2015 4:14:52 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
and CN VII). Involvement of CN III, CN IV, and CN course is typically self-limiting with some degree of
VI is typically manifested as acute or subacute perior- improvement over many months.11 Residual weakness
bital pain or headache with diplopia.56 Muscle weak- or sensory losses often remain. When occurring in the
ness is not generalized; it is limited to the myotome of hip, this syndrome is often confused with an acute
the involved nerve.57 Pupillary light reflexes are spared. femoral neuropathy. However, careful examination
Complete spontaneous recovery occurs within 3 to 6 reveals weakness in the obturator nerve distribution
months.58 Facial neuropathy, simulating idiopathic along with the femoral nerve distribution muscles, and
Bell’s palsy, can be recurrent and bilateral. Most facial electromyography needle examination reveals wide-
neuropathies recover spontaneously in 3 to 6 months. spread spontaneous activity in all muscle groups.15
Anterior ischemic optic neuropathy manifests as acute Charcot Neuropathy
visual loss or visual field cuts. The optic disc often Charcot neuropathy is a progressive malady associated
appears pale and edematous. Hemorrhages may be with diabetes and neuropathy of long duration and
present.59 characterized by joint pain, dislocation/subluxation,
Somatic Mononeuropathies pathological fracture, and functional impairment.63 The
Somatic mononeuropathies are focal sensory and most common location of Charcot neuropathy is in the
motor neuropathies occurring in the extremities that ankle, subtalar, or midtarsal joints.9 The current theory
are caused by entrapment, compression, ischemia, or regarding the articular changes is that diabetes-induced
epineural or endoneural fibrosis.20 Entrapments typi- autonomic neuropathy increases blood flow to the
cally occur at common entrapment sites similar to sites affected joint resulting in bone resorption and osteo-
found in persons without diabetes.60 Treatment, along penia. Concomitant motor neuropathy results in muscle
with risk factor modification, includes interventions imbalance leading to abnormal biomechanics and
such as release and neurolysis—similar procedures used eventually joint dislocation and fracture. Tendon short-
for nondiabetic neuropathies. Neuropathy secondary to ening may be caused by the abnormal precipitation of
nerve infarction, a rare occurrence resulting from the glycation end products.63 Sensory abnormalities lead to
frequent extraneural and intraneural blood vessel anas- a decreased perception of pain resulting in further joint
tomoses, manifests acutely, usually with focal pain, degradation and abnormal biomechanics secondary to
associated with weakness and variable sensory loss in large-fiber (proprioceptive) feedback (Fig. 7-6).
the distribution of the affected nerve. Multiple nerves
may be affected (mononeuritis multiplex).60
Diabetic Thoracic Radiculoneuropathy Intervention
The hallmark of diabetic thoracic radiculoneuropathy
is burning, stabbing, and aching pain at, just below, or The most effective treatment to prevent and to slow the
just above the beltline.61 Allodynia and dermatomal progression of diabetic neuropathy is optimal glycemic
numbness may occur in the distribution of the inter- control as reported by the Diabetes Control and Com-
costal nerves or thoracic spinal nerves. Multiple nerves plications Trial (DCCT) (Box 7-2).9 With the benefits
may be involved.62 Truncal weakness from either the
anterior or the posterior divisions of the thoracic nerve
root may occur. Anterior division weakness may lead
to trunk instability and bulging abdomen. Posterior
division weakness may lead to overuse backache, sco-
liosis, and truncal weakness. Except for the pain, inter-
costal weakness rarely results in a functional impairment.
Men older than age 50 are most affected.61 This syn-
drome often coexists with distal symmetrical polyneu-
ropathy. Recovery is often spontaneous over a period
of months.
Diabetic Radiculoplexus Neuropathy
Synonyms for diabetic radiculoplexus neuropathy often
found in the literature include diabetic amyotrophy,
Bruns-Garland syndrome, and diabetic plexopathy.62
The initial complaint is a sudden onset of unilateral Figure 7-6 Charcot arthropathy: collapse of midfoot arch
neck, low back, or hip pain quickly followed by allo- secondary to diabetic neuropathy. Charcot arthropathy,
dynia, paresthesias, and sensory loss. Weakness typi- also called diabetic neuropathic arthropathy, leads to
cally follows within a few weeks or months. Symmetrical biomechanical changes in the feet. The combination of
attacks may occur. Reflexes in the affected limbs Charcot arthropathy, abnormal perception of tactile and
become diminished or absent. The syndrome is associ- pain sense, and microvascular and macrovascular pathology
ated with significant weight loss, elevated hemoglobin puts the patient at great risk for developing pressure ulcers
A1c, and labile finger-stick blood sugar values.62 The on the feet that may be slow to heal and prone to infection.
2560_Chapter 7_0075-0088.indd 82 3/16/2015 4:14:52 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
BOX 7-2
Benefits of Improved Glycemic Control from the Diabetes

Control and Complications Trial (DCCT) and Epidemiology of
Diabetes Interventions and Complications (EDIC)
DCCT Study Findings
Intensive blood glucose control reduces risk of:
Eye disease: 76% reduced risk
Kidney disease: 50% reduced risk
Nerve disease: 60% reduced risk
EDIC Study Findings
Intensive blood glucose control reduces risk of:
Any cardiovascular disease event: 42% reduced risk
Nonfatal heart attack, stroke, or death from
cardiovascular causes: 57% reduced risk
Data from The effect of intensive treatment of diabetes on the
development and progression of long-term complications in insulin-
dependent diabetes mellitus. The Diabetes Control and Complications
Trial Research Group. N Engl J Med. 1993;329(14):977–986; and
Nathan DM, Cleary PA, Backlund JY, et al; Diabetes Control and Figure 7-7 Plastic footplate on posterior leaf spring to
Complications Trial/Epidemiology of Diabetes Interventions and assist with ankle dorsiflexion in a patient with diabetes
Complications (DCCT/EDIC) Study Research Group. Intensive diabetes mellitus with secondary common peroneal neuropathy.
treatment and cardiovascular disease in patients with type 1 diabetes.
N Engl J Med 353(25):2643–2653, 2005. Focal motor neuropathy is a common complication of
diabetes. To prevent knee collapse during heel strike and
stance, a brace with a locked knee has been prescribed.
of improved glycemic control from DCCT and Epide-
miology of Diabetes Interventions and Complications reductase inhibitors, aspirin, nerve growth factors,
(EDIC) as methods of blood sugar monitoring and the and insulin-like growth factors will produce positive
development and administration venues of insulin and results.68–71
noninsulin medications improve, there is real hope that For symptomatic relief of diabetic neuropathic
the incidence and severity of diabetic neuropathy will pain, tricyclic antidepressants such as amitriptyline are
be reduced. Eventually, therapies will move from con- sometimes successful.72 Gabapentin (Neurontin), phe-
trolling to curing this complicated disease. The initial nytoin, and carbamazepine appear to be less success-
reports of halting the progression of diabetic neuropa- ful.73 Capsaicin-containing creams and topical lidocaine
thy in patients with type 1 diabetes with pancreatic have reported moderate success.74 Physical therapy
transplantation are highly encouraging.64 modalities including transcutaneous electrical nerve
Most aspects of current treatment for diabetic neu- stimulation, ultrasound, and thermal modalities have
ropathy involve the use of patient education, modalities shown little effectiveness.75,76 Bed cradles can be used
to control nerve pain, and physical therapy for thera- to lift sheets and blankets off sensitive legs.77
peutic exercise and bracing related to weakened Ongoing daily exercise, along with diet and medica-
muscles.65 Many insurance companies now provide tion, is one of the hallmarks of improved glycemic
coverage for diabetes education programs for persons control.78 Because of the common comorbidities of
with a new diagnosis of diabetes.66 Along with discus- diabetes that may have a potential impact on exercise
sions related to the types of diabetes, medications, tolerance, physical therapists are often asked to develop
pathophysiology, terminology, and diabetic technology, exercise programs for patients with diabetes.79 Other
certified diabetic educators also teach patients skin potential physical therapy and medicine interventions
monitoring and checks to assist with early detection are determined by whether large-fiber or small-fiber
of ulcerations.66 Serial Semmes Weinstein filament neuropathy is present. Interventions related to large-
testing can identify the existence or progression of fiber neuropathies include strength, gait, and balance
dermatomal areas with diminished or absent percep- training; fall prevention initiatives; pain management;
tion of pain.67 orthoses fitted with specialty shoes; tendon stretching
The science of pharmacology as related to the treat- to prevent deformity; bisphosphonates for the treat-
ment of nerve pain is evolving. To date, all medications ment of osteopenia; and total contact casting for the
appear to be symptom related; there is of yet no proven treatment of insensate ulcerations (Fig. 7-7).80,81 Inter-
pharmaceutical agents that halt or diminish diabetic ventions related to small-fiber neuropathies include
neuropathy. It is hoped that ongoing studies of aldose foot protection such as orthoses, specialty shoes, and
2560_Chapter 7_0075-0088.indd 83 3/16/2015 4:14:52 PM

Process CyanProcess
YellowProcess Black
white padded socks; twice-daily self-foot inspection Problems identified by the physical therapist included
with a mirror (many patients are too obese to see the loss of protective sensation in both feet; loss of tactile
bottoms of their feet); monthly visits with a podiatrist sensation; decreased proprioceptive and kinesthetic
for nail and skin care; serial Semmes Weinstein fila- sensation; a heightened fall risk; weakness of the right
ment examination by a health professional; and educa- anterior tibialis, peroneal, and extensor hallucis longus
tion regarding the prevention of thermal injury (e.g., muscles; and lack of patient knowledge about diabetes
from hot bathwater or winter weather) and the use of and the complications of diabetes.
emollient creams to maintain skin moisture.81 The therapist’s treatment plan included ongoing
diabetes-related education using multimedia, including
oral discussion, Internet sites, handouts, and referral to
a diabetes educator. Fall prevention guidelines were
provided including a home-safety checklist, education,
CASE STUDY and the use of a cane. To assist the therapist with
Harold is a 44-year-old man who presents to his clinical decision making regarding whether or not to
primary care practitioner with a 4-week history of an order an ankle brace to compensate for the extrinsic
unexplained 20-pound weight loss, polyuria, weakness, the therapist referred the patient for an
polydipsia, increased appetite, gait dysfunction, and electroneurodiagnostic examination. The needle
impotence. Routine blood testing was normal except for examination revealed an axonal injury consistent with
a fasting blood glucose of 242 mg/dL (normal, 70 to diabetic neuropathy. With that information, the therapist
110 mg/dL) and a hemoglobin A1c of 8.2% (normal, recommended and ordered a custom-molded ankle-foot
4% to 5.9%). Type 2 diabetes was diagnosed, orthosis. With the addition of the orthosis, balance
and Harold was immediately begun on oral testing scores improved to the point where the therapist
antihyperglycemic agents. He was referred to a advised the patient he no longer needed the cane.
urologist for the impotence and to a physical therapist Lastly, the therapist prescribed a long-term exercise
for gait dysfunction. program comprising aerobic, anaerobic, flexibility, and
After taking the history of the present illness, medical balance exercises for Harold to assist with maintaining
history, and social/vocational history, the therapist good glycemic control.
began her physical evaluation. The results were as
follows: Case Study Questions
Cardiovascular: 118/66, 76, 24, 98% oxygen
1. Which of the following testing methods is the best
saturation, 0/10 pain scale at rest and with activity.
method to use for identifying whether a patient with
The lungs were clear to auscultation.
diabetes has protective sensation over a particular
Musculoskeletal: Tone was normal. Upper extremity
dermatomal area?
and lower extremity strength testing revealed
a. Electroneurodiagnostic testing
symmetrical strength at 5/5 with focal weakness of
b. Monofilament testing
right anterior tibialis, extensor hallucis longus, and
c. Berg Balance Scale
peroneal muscle group of 2/5. Range of motion was
d. Vibrometer
functional throughout except for a 10-degree plantar
flexion contracture at the right ankle. 2. Which blood test is best for determining long-term (3
Integument: Distal lower extremity and upper months) blood glucose control?
extremity pulses were +2. No skin openings, rashes, or a. Blood urea nitrogen
contusions were noted. Calves were without edema, b. Hemoglobin
nontender, and without palpable cords. c. Finger-stick blood sugar
Neurological: Cranial nerves II through XII were d. Hemoglobin A1c
intact. Vision was 20/20 in each eye with adaptive
3. Which of the following is a symptom of diabetic
eyewear. Sensory examination revealed loss of tactile
autonomic neuropathy?
(light touch, pin), vibration, proprioception, and
a. Elevated fall risk
kinesthesia in both lower extremities from the knees to
b. Weakness of the gastrocnemius muscle
the toes. Monofilament testing revealed large areas on
c. Inability to sweat
the plantar surface of both feet that exhibited loss of
d. Renal failure
protective sensation. Bowel and bladder were intact.
Mini-mental state examination revealed no cognitive 4. Small-fiber neuropathy is typically associated with
disability. Bowel and bladder were intact. Berg which symptom of diabetes?
Balance Scale was 49; Romberg test eyes open was a. Painful paresthesias
15 seconds, eyes closed 8 seconds; and unilateral leg b. Motor weakness
stance was 9 seconds on the left and 7 seconds on c. Kidney failure
the right—all indicative of a potential fall risk. d. Stroke
2560_Chapter 7_0075-0088.indd 84 3/16/2015 4:14:52 PM

Process CyanProcess
YellowProcess Black
5. Charcot neuropathy is associated with which 16. Lozeron P, Nahum L, Lacroix C, Ropert A, Guglielmi JM,
body part? Said G. Symptomatic diabetic and non-diabetic neuropathies
in a series of 100 diabetic patients. J Neurol. 2002;249(5):
a. Head and neck 569–575.
b. Shoulder 17. Ziegler D. Treatment of diabetic neuropathy and neuropathic
c. Knee pain: how far have we come? Diabetes Care. 2008;31(Suppl 2):
d. Ankle S255–261.
18. Apfel SC. Neurotrophic factors in the therapy of diabetic
neuropathy. Am J Med. 1999;107(2B):34S–42S.
19. Bromberg MB. Peripheral neurotoxic disorders. Neurol Clin.
2000;18(3):681–694.
References 20. Vinik A, Mehrabyan A. Diagnosis and management of
1. Zochodne DW. Diabetic polyneuropathy: an update. Curr diabetic autonomic neuropathy. Compr Ther. 2003;29(23):
Opin Neurol. 2008;21(5):527–533. 130–145.
2. Knuiman M, Welborn T, McCann V, Stanton K, Constable I. 21. Vinik AI, Holland MT, LeBeau JM, Liuzzi FJ, Stansberry
Prevalence of diabetic complications in relation to risk factors. KB, Colen LB. Diabetic neuropathies. Diabetes Care. 1992;15:
Diabetes. 1986;35:1332–1339. 1926–1975.
3. Vinik AI, Mitchell BD, Leichter SB, Wagner AL, O’Brian 22. Llewelyn JG, Tomlinson DR, Thomas PK. Diabetic
JT, Georges LP. Epidemiology of the complications of neuropathies. In: Dyck PJ, Thomas PK, eds. Peripheral
diabetes. In: Leslie RDG, Robbins DC, eds. Diabetes: Clinical Neuropathies. 4th ed. Philadelphia: Saunders; 2005:
Science in Practice. Cambridge: Cambridge University Press; 1951–1991.
1995:221–287. 23. Inzitari M, Carlo A, Baldereschi M, et al. Risk and predictors
4. Vinik AI, Pittenger GL, Milicevic Z, Cuca J. Autoimmune of motor-performance decline in a normally functioning
mechanisms in the pathogenesis of diabetic neuropathy. In: population-based sample of elderly subjects: the Italian
Eisenbarth RG, ed. Molecular Mechanisms of Endocrine and Longitudinal Study on Aging. J Am Geriatr Soc. 2006;54:
Organ Specific Autoimmunity. Georgetown, TX: Landes 318–324.
Company; 1998:217–251. 24. Schwartz AV, Hillier TA, Sellmeyer DE, et al. Older women
5. Pirart J. Diabetes mellitus and its degenerative complications: with diabetes have a higher risk of falls: a prospective study.
a prospective study of 4,400 patients observed between 1947 Diabetes Care. 2002;25:1749–1754.
and 1973. Diabetes Care. 1978;1:252–263. 25. Lorenzi M. The polyol pathway as mechanism for diabetic
6. Caputo GM, Cavanagh PR, Ulbrecht JS, Gibbons GW, retinopathy; attractive, elusive and resilient. Exp Diab Res.
Karchmer AW. Assessment and management of foot disease 2007:22(15):32–42.
in patients with diabetes. N Engl J Med. 1994;331:854–860. 26. Szwergold BS, Kappler F, Brown TR. Identification of
7. World Health Organization. Definition, Diagnosis and fructose 3-phosphate in the lens of diabetic rats. Science.
Classification of Diabetes Mellitus and its Complications. 1990;247(4941):451–454.
http://whqlibdoc.who.int/hq/1999/who_ncd_ncs_99.2.pdf. 27. González RG, Miglior S, Von Saltza I, Buckley L, Neuringer
1999. Accessed October 30, 2014. LJ, Cheng H-M. 31P NMR studies of the diabetic lens. Magn
8. Costa LA, Canani LH, Lisboa HR, Tres GS, Gross JL. Reson Med. 1988;6(4):435–444.
Aggregation of features of the metabolic syndrome is 28. Barnett PA, González RG, Chylack LT Jr, Cheng H-M. The
associated with increased prevalence of chronic complications effect of oxidation on sorbitol pathway kinetics. Diabetes.
in type 2 diabetes. Diabet Med. 2004;21:252–255. 1986;35(4):426–432.
9. The effect of intensive treatment of diabetes on the 29. Williamson JR, Chang K, Frangos M, et al. Hyperglycemic
development and progression of long-term complications in pseudohypoxia and diabetic complications. Diabetes. 1993;
insulin-dependent diabetes mellitus. The Diabetes Control 42(6):801–813.
and Complication Trial Research Group. N Engl J Med. 30. Lassègue B, Clempus RE. Vascular NAD(P)H oxidases:
1993;329:977–986. specific features, expression, and regulation. Am J Physiol
10. Nathan DM, Cleary PA, Backlund JY, et al. Diabetes Control Regul Integr Comp Physiol. 2003;285(2):R277–R297.
and Complications Trial/Epidemiology of Diabetes 31. Dagher Z, Park YS, Asnaghi V, Hoehn T, Gerhardinger C,
Interventions and Complications (DCCT/EDIC) Study Lorenzi M. Studies of rat and human retinas predict a role
Research Group. Intensive diabetes treatment and for the polyol pathway in human diabetic retinopathy.
cardiovascular disease in patients with type 1 diabetes. Diabetes. 2004;53(9):2404–2411.
N Engl J Med. 2005;353(25):2643–2653. 32. Lorenzi M, Gerhardinger C. Early cellular and molecular
11. Boulton AJ, Malik RA. Diabetic neuropathy. Med Clin North changes induced by diabetes in the retina. Diabetologia. 2001;
Am. 1998;82(4):909–929. 44(7):791–804.
12. Harati Y. Diabetes and the nervous system. Endocrinol Metab 33. Obrosova IG, Minchenko AG, Vasupuram R, et al. Aldose
Clin North Am. 1996;25(2):325–359. reductase inhibitor fidarestat prevents retinal oxidative
13. Young MJ, Boulton AJ, MacLeod AF, Williams DR, Sonksen stress and vascular endothelial growth factor overexpression
PH. A multicentre study of the prevalence of diabetic in streptozotocin-diabetic rats. Diabetes. 2003;52(3):
peripheral neuropathy in the United Kingdom hospital clinic 864–871.
population. Diabetologia. 1993;36(2):150–154. 34. Obrosova IG, Pacher P, Szabó C, et al. Aldose reductase
14. Pirart J. Diabetes mellitus and its degenerative complication: inhibition counteracts oxidative-nitrosative stress and
a prospective study of 4,400 patient observed between 1947 poly(ADP-ribose) polymerase activation in tissue sites for
and 1973. Diabetes Care. 1978;1:168–188. diabetes complications. Diabetes. 2005;54(1):234–242.
15. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach 35. Kassab E, McFarlane SI, Sowers JR. Vascular complications
JM, et al. The prevalence by staged severity of various types of in diabetes and their prevention. Vasc Med. 2001;6:
diabetic neuropathy, retinopathy, and nephropathy in a 249–255.
population-based cohort: the Rochester Diabetic Neuropathy 36. American Diabetes Association. Economic costs of diabetes
Study. Neurology. 1993;43(4):817–824. in the U.S. in 2002. Diabetes Care. 2003;26:917–932.
2560_Chapter 7_0075-0088.indd 85 3/16/2015 4:14:52 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
37. Skyler JS. Microvascular complications—retinopathy and 59. Vinik AI, Park TS, Stansberry KB, Pittenger GL. Diabetic
nephropathy. Endocrinol Metab Clin North Am. 2001;30: neuropathies. Diabetologia. 2000;43(8):957–973.
833–855. 60. Wilbourn AJ. Diabetic entrapment and compression
38. Nathan DM. Long-term complications of diabetes mellitus. neuropathies. In: Dyck PJ, Thomas PK, eds. Diabetic
N Engl J Med. 1993;328:1676–1685. Neuropathy. Philadelphia: Saunders; 1999:481–508.
39. Hanefeld M, Fischer S, Julius U, et al. Risk factors for 61. Skyler JS. Diabetic complications. The importance of glucose
myocardial infarction and death in newly detected NIDDM: control. Endocrinol Metab Clin North Am. 1996;25(2):
The Diabetes Intervention Study, 11-year follow-up. 243–254.
Diabetologia. 1996;39:1577–1583. 62. Krendel DA, Costigan DA, Hopkins LC. Successful
40. Cummings M, Browne D. Endothelial dysfunction—from treatment of neuropathies in patients with diabetes mellitus.
research to clinical practice. Practical Diabetes International. Arch Neurol. 1995;52:1053–1061.
2001;18(6):184–185. 63. Young MJ, Marshall M, Adams JE, Selby P, Boulton AJM.
41. Ishii H, Koya D, King GL. Protein kinase C activation and Osteopenia, neurological dysfunction, and the development of
its role in the development of vascular complications in Charcot neuroarthropathy. Diabetes Care. 1995;18:34–38.
diabetes mellitus. J Mol Med. 1998;76:21–31. 64. Ruhnau KJ, Meissner HP, Finn R, et al. Effects of 3-week
42. American Diabetes Association. Standards of medical care oral treatment with the antioxidant thioctic acid (alpha-lipoic
for patients with diabetes mellitus. Diabetes Care. 2000; acid) in symptomatic diabetic polyneuropathy. Diabet Med.
23(Suppl 1):S32–S42. 1999;16(12):1040–1043.
43. UK Prospective Diabetes Study Group. Tight blood pressure 65. Valensi P, Le DC, Richard JL, Farez C, et al. A multicenter,
control and risk of macrovascular and microvascular double-blind, safety study of QR-333 for the treatment of
complications in type 2 diabetes (UKPDS 38). BMJ. 1998; symptomatic diabetic peripheral neuropathy. A preliminary
317:703–713. report. J Diabetes Complications. 2005;19:247–253.
44. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin 66. Gruessner AC, Sutherland DE. Pancreas transplant outcomes
therapy prevents the progression of diabetic microvascular for United States (US) and non-US cases as reported to the
complications in Japanese patients with non–insulin- United Network for Organ Sharing (UNOS) and the
dependent diabetes mellitus: a randomized prospective 6-year International Pancreas Transplant Registry (IPTR) as of June
study. Diabetes Res Clin Pract. 1995;28:103–117. 2004. Clin Transplant. 2005;19(4):433–455.
45. Swidan SZ, Montgomery PA. Effect of blood glucose 67. Feng Y, Schlosser FJ, Sumpio BE. The Semmes Weinstein
concentrations on the development of chronic complications monofilament examination as a screening tool for diabetic
of diabetes mellitus. Pharmacotherapy. 1998;18:961–972. peripheral neuropathy. J Vasc Surg. 2009;50(3):675–682.
46. Koenig RJ, Cerami A. Synthesis of hemoglobin A1c in normal 68. Forst T, Nguyen M, Forst S, Disselhoff B, Pohlmann T,
and diabetic mice: potential model of basement membrane Pfutzner A. Impact of low frequency transcutaneous electrical
thickening. Proc Natl Acad Sci U S A. 1975;72:3687–3691. nerve stimulation on symptomatic diabetic neuropathy using
47. Bunn HF, Haney DN, Kamin S, et al. The biosynthesis of the new Salutaris device. Diabetes Nutr Metab. 2004;17(3):
human hemoglobin A1c: slow glycosylation of hemoglobin in 163–168.
vivo. J Clin Invest. 1976;57:1652–1659. 69. Jin DM, Xu Y, Geng DF, Yan TB. Effect of transcutaneous
48. Koenig, Peterson, Jones, et al. The correlation of glucose electrical nerve stimulation on symptomatic diabetic
regulation and hemoglobin A1c in diabetes mellitus. N Engl J peripheral neuropathy: a meta-analysis of randomized
Med. 1976;295:417–420. controlled trials. Diabetes Res Clin Pract. 2010;89(1):10–15.
49. Fluckiger R, Winterhalter KH. In vitro synthesis of 70. Pieber K, Herceg M, Paternostro-Sluga T. Electrotherapy for
hemoglobin A1c. FEBS Lett. 1976;71:356–360. the treatment of painful diabetic peripheral neuropathy: a
50. Cole RA, Bunn HF, Soeldner JS. New rapid assay method review. J Rehabil Med. 2010;42(4):289–295.
for hemoglobin (hemoglobin A1c) and total fast Hb. Diabetes. 71. Veves A, Backonja M, Malik RA. Painful diabetic
1977;26(Suppl 1):392. neuropathy: epidemiology, natural history, early diagnosis, and
51. O’Brien SP, Schwedler M, Kerstein MD. Peripheral treatment options. Pain Med. 2008;9(6):660–674.
neuropathies in diabetes. Surg Clin North Am. 1998;78(3): 72. Morello CM, Leckband SG, Stoner CP, Moorhouse DF,
393–408. Sahagian GA. Randomized double-blind study comparing
52. Galer BS, Gianas A, Jensen MP. Painful diabetic the efficacy of gabapentin with amitriptyline on diabetic
polyneuropathy: epidemiology, pain description, and quality peripheral neuropathy pain. Arch Intern Med. 1999;159:
of life. Diabetes Res Clin Pract. 2000;47(2):123–128. 1931–1937.
53. Boulton AJ, Malik RA. Neuropathy of impaired glucose 73. Dworkin RH, Backonja M, Rowbotham MC, et al. Advances
tolerance and its measurement. Diabetes Care. 2010;33(1): in neuropathic pain: diagnosis, mechanisms, and treatment
207–209. recommendations. Arch Neurol. 2003;60:1524–1534.
54. Vinik AI, Erbas T. Recognizing and treating diabetic 74. LaRoche SM, Helmers SL. The new antiepileptic drugs:
autonomic neuropathy. Cleve Clin J Med. 2001;68(11): scientific review. JAMA. 2004;291:605–614.
928–944. 75. Rosenstock J, Tuchman M, LaMoreaux L, Sharma U.
55. Baumgartner RN. Body composition in healthy aging. Ann N Pregabalin for the treatment of painful diabetic peripheral
Y Acad Sci. 2000;904:437–448. neuropathy: a double-blind, placebo-controlled trial. Pain.
56. Young MJ, Boulton AJM, MacLeod AF, Williams DRR, 2004;110:628–638.
Sonksen PH. A multicenter study of the prevalence of 76. Andersen H, Gjerstad MD, Jakobsen J. Atrophy of foot
diabetic peripheral neuropathy in the United Kingdom muscles: a measure of diabetic neuropathy. Diabetes Care.
hospital clinic population. Diabetologia. 1993;36:1–5. 2004;27:2382–2385.
57. Goetz CG, Pappert EJ. Textbook of Clinical Neurology. 77. Bus SA, Yang QX, Wang JH, Smith MB, Wunderling R,
Philadelphia: Saunders; 1999. Cavanag PR. Intrinsic muscle atrophy and toe deformity in
58. Martin CL, Albers J, Herman WH, et al. Neuropathy the diabetic neuropathic foot. Diabetes Care. 2002;V25:
among the diabetes control and complications trial cohort 1444–1450.
8 years after trial completion. Diabetes Care. 2006;29(2): 78. Cavanagh PR, Derr JA, Ulbrecht JS, Maser RE, Orchard TJ.
340–344. Problems with gait and posture in neuropathic patients with
2560_Chapter 7_0075-0088.indd 86 3/16/2015 4:14:52 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
insulin-dependent diabetes mellitus. Diabet Med. 1992;9: women aged 75 to 85 with low bone mass: a 6-month
469–474. randomized, controlled trial. J Am Geriatr Soc. 2004;52:
79. Nelson ME, Fiatarone MA, Morganti CM, Trice I, 657–665.
Greenberg RA, Evans WJ. Effects of high-intensity strength 81. Murray H, Veves A, Young M, Richie D, Boulton A. Role of
training on multiple risk factors for osteoporotic fractures. A experimental socks in the care of the high risk diabetic foot.
randomized controlled trial. JAMA. 1994;272:1909–1914. A multi-center patient evaluation study. American Group for
80. Liu-Ambrose T, Khan KM, Eng JJ, Janssen PA, Lord SR, the Study of Experimental Hosiery in the Diabetic Foot.
McKay HA. Resistance and agility training reduce fall risk in Diabetes Care. 1993;16:1190–1192.
2560_Chapter 7_0075-0088.indd 87 3/16/2015 4:14:52 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
2560_Glossary_0347-0360.indd 360 3/17/2015 12:11:29 PM
Chapter 8
and Infection
“Tut, man, one fire burns out while another’s burning. One pain is lessen’d by
another’s anguish; turn giddy and behold by backward turning; one’s desperate
grief is cured by another’s languish: take thou to some new infection of thine
eye and the rank of poison of.”
—WILLIAM SHAKESPEARE (1564–1616)
Objectives
• Define the common infection diagnoses that may lead to peripheral neuropathy.
• Develop a clinical understanding of the typical neurological signs and symptoms associated with specific
infections that may lead to peripheral neuropathy.
• Apply knowledge of the common infection diagnoses into “clinical scripts” used in the development of the
differential diagnoses list.
• Choose the appropriate assessment tools that will “map back” to the potential diagnosis.
Key Terms
• Hepatitis
• Infection
• Lyme disease
• Parasite
or, at worst, increase in prevalence. HIV-related neu-

Introduction ropathy is discussed in detail in Chapter 27.
The clinician attempting to identify the etiology of
When comparing the prevalence of etiologies of sus- suspected peripheral nerve injury must be aware of the
pected peripheral nerve disease, infectious causes are potential of infection to cause neuropathy. This state-
much less frequent than traumatic, overuse, metabolic, ment is true for several reasons. Correct diagnosis is a
environmental, and degenerative etiologies. However, requirement for correct intervention. With many infec-
many of the infectious etiologies described in this tious etiologies, time from onset to treatment may have
chapter, such as tuberculosis (TB), hepatitis, HIV, a great impact on potential recovery. Lastly, many of
Lyme disease, and leprosy, have prevalence rates in the the diseases described in this chapter are contagious.
United States and worldwide that are either staying Early diagnosis may prevent further dissemination of
consistent or increasing. One would expect peripheral the offending agent. As with all peripheral nerve injury
nerve injuries resulting from the aforementioned infec- etiologies, exhaustive history taking, review of the clin-
tious diseases to, at best, remain at their current levels ical data set, and performance of valid and reliable tests
89
2560_Chapter 8_0089-0104.indd 89 3/16/2015 4:14:55 PM

Process CyanProcess
YellowProcess Black
and measures are required for the diagnostician to
reach the correct diagnosis.
Lyme Disease
A large amount of knowledge has been acquired since
the original descriptions of Lyme borreliosis (LB) and
of its causative agent, Borrelia burgdorferi. The com-
plexity of the organism, the variations in the clinical
manifestations of LB caused by the different B. burg-
dorferi species, and the difficulty in obtaining an
evidence-based treatment regimen were not originally
anticipated. Considerable improvement in reliability
and validity of the detection of B. burgdorferi by labora-
tory and physical assessment as well as in the effective-
ness of therapy has occurred since the early stage of
disease presentation.1–3
The etiologic agent, B. burgdorferi, was recovered in
1982 from the vector tick Ixodes dammini (now Ixodes
scapularis) and subsequently, from skin biopsy, cerebro- Figure 8-1 Erythema migrans is often the first objective
spinal fluid (CSF), and blood specimens of patients sign of B. burgdorferi infection. Note the central macule
with LB in the United States4 and Europe.5 In the with the expanding circular patch of erythema with central
United States, the Centers for Disease Control and clearing. Erythema migrans occurs in approximately 70%
Prevention (CDC) initiated surveillance for LB in to 80% of infected persons and begins at the site of the
1982,2 and the Council of State and Territorial Epide- tick bite after a delay of 3 to 30 days (mean, 7 days).
miologists adopted a resolution making LB a nation-
ally notifiable disease in 1990.3 LB is the most common
vector-borne disease in North America and represents LB. In approximately 80% of patients, the first clinical
a major public health challenge.1 Since 1982, more sign of early infection is a localized erythema migrans
than 200,000 LB cases in the United States have been (EM) at the site of the tick bite, which may be followed
reported to the CDC, with about 17,000 cases reported within days or weeks by clinical evidence of dissemi-
yearly between 1998 and 2001. In 2002, the number of nated infection that may affect the skin, nervous system,
cases of LB in the United States increased to 23,763, heart, or joints (Fig. 8-1).8 Arthritis appears to be more
with a national incidence of 8.2 cases per 100,000 frequent in patients in North America, whereas lym-
persons. Approximately 95% of the cases occurred in phocytoma, chronic atrophic acrodermatitis (also
12 states located in the northeastern, mid-Atlantic, and known as acrodermatitis chronica atrophicans), and
north-central regions: Connecticut, Delaware, Maine, encephalomyelitis have been seen primarily in patients
Maryland, Massachusetts, Minnesota, New Hamp- in Europe.5–7
shire, New Jersey, New York, Pennsylvania, Rhode The EM rash begins as a red macule or papule at
Island, and Wisconsin. LB is widely distributed in the site of the tick bite, rapidly enlarges, and sometimes
European countries and occurs in Far Eastern Russia develops central clearing.8 The clinical diagnosis of
and in some Asian countries.6 early LB with EM relies on recognition of the charac-
Infection with B. burgdorferi can result in dermato- teristic appearance of a skin lesion at least 5 cm in
logical, neurological, cardiac, and musculoskeletal diameter.9 At this stage, patients may be asymptomatic
impairments. The basic clinical spectra of the disease or, more commonly in the United States, experience
are similar worldwide, although differences in clinical flu-like symptoms such as headache, myalgias, arthral-
manifestations between LB occurring in Europe and gias, or fever.8–10 The presence of constitutional signs
North America are well documented. Such differences and symptoms in a patient with EM has been consid-
are attributed to differences in B. burgdorferi species ered evidence of dissemination by some investigators,
causing LB on the two continents.5–7 In addition, dif- but this declaration is not evidence-based.9
ferences in clinical presentations exist among geo- Hematogenous dissemination of B. burgdorferi to
graphic regions of Europe, presumably secondary to the nervous system, joints, heart, or other skin areas
differences in the rates of occurrence of infection as well as occasionally to other organs may give rise to
caused by distinct B. burgdorferi subspecies.5 a wide spectrum of clinical manifestations in early
Patients with B. burgdorferi infection may experi- LB.11,12 Usually, patients with objective evidence of dis-
ence one or more clinical syndromes of early or late semination experience one or more of the following
2560_Chapter 8_0089-0104.indd 90 3/16/2015 4:14:56 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 8 | Peripheral Neuropathy and Infection 91
17
syndromes: multiple EM lesions, atrioventricular mouth route. The virus has been identified only in
conduction defects (primarily heart block), myopericar- humans and a few subhuman primate species; there is
ditis, arthritis, facial palsy, meningitis, and meningora- no known nonhuman reservoir for the virus.17 After
diculoneuritis (Bannwarth syndrome).12 Lyme arthritis infection, the virus replicates in the gastrointestinal
begins as intermittent attacks of joint pain, loss of tract and may cause a viremia with symptoms of
range of motion, inflammation, and effusion involv- malaise, fever, loss of appetite, and gastrointestinal
ing primarily the appendicular skeleton. In 10% of symptoms. Occasionally (about 1 in 150 cases), the
patients, the typically seen monarticular or pauciarticu- virus invades the anterior horn cells of the spinal cord
lar arthritis, especially of large joints, may persist for producing a clinically distinctive motor loss with only
months or years despite treatment with antimicrobials. rare sensory involvement.18
Treatment-resistant arthritis is seen more frequently in In the anterior horn cell, the poliovirus spreads
patients with the certain HLA DRB alleles. Autoim- along nerve fiber pathways, preferentially replicating in
munity has been suggested to play a role in this clinical and destroying motor neurons within the spinal cord
entity.6,7 or peripheral nerve leading to a lower motor neuron
Late LB may develop in some untreated patients paralysis. The various forms of paralytic poliomyelitis
months to a few years after tick-transmitted infection. (spinal, bulbar, and bulbospinal) vary only with the
The major manifestations of late LB include worsening amount of neuronal damage and inflammation that
arthritis, progressive heart block, and neuroborreliosis occurs and the regions of the central nervous system
(peripheral neuropathy or encephalomyelitis).7,8,10,11,13,14 (CNS) or peripheral nervous system (PNS) that are
The peripheral neuropathy seen with late LB is typi- affected.17
cally large and small fiber afferent, primarily in a The destruction of neuronal cells produces lesions
stocking-glove distribution neuropathy, but motor within the spinal ganglia; these may also occur in the
symptoms have also been reported.7,8 reticular formation, vestibular nuclei, and cerebellar
vermis, and deep cerebellar nuclei.18 Macroscopically,
inflammation associated with nerve cell destruction
Poliomyelitis often alters the color and appearance of the gray matter
in the spinal column, causing it to appear reddish and
Poliomyelitis originally appeared in epidemic form, swollen. Early symptoms of paralytic polio include
became endemic on a global scale, and has been reduced high fever, headache, stiffness in the back, nuchal rigid-
to near-elimination, all within the span of medical ity, asymmetrical weakness of various muscles, sensitiv-
history. The earliest references to the disease include an ity to touch, dysphagia, myalgia, loss of superficial and
ancient Egyptian frieze from 1580 B.C.E. showing an deep reflexes, paresthesia, irritability, constipation, and
adult with a crutch and an atrophied leg quite similar difficulty with initiation of urinating.19 Paralysis gener-
to more modern photographic images of patients with ally develops 1 to 10 days after early symptoms begin,
monoplegic poliomyelitis. Sir Walter Scott wrote about progresses for 2 to 3 days, and is usually complete
an attack of “infantile paralysis” in 1773 that left him within 7 to 10 days, coinciding with the return to being
with a permanent limp and withered leg.15 By 1880, afebrile.17–19
there were numerous reports of paralysis epidemics. The likelihood of developing paralytic polio increases
The epidemic phase eventually was replaced by annual with age, as does the extent of paralysis.19 In children,
seasonal outbreaks during the first half of the 20th nonparalytic meningitis is the most likely consequence
century, and by the latter second half of the 20th of CNS involvement, and paralysis occurs in only 1 in
century, there was a near elimination of the disease.16 1,000 cases. In adults, paralysis occurs in 1 in 75 cases.20
A striking aspect of poliomyelitis infection is the sea- In children younger than 5 years old, paralysis of one
sonality of infections in temperate zones. This season- leg is most common; in adults, extensive paralysis of
ality was most marked in the colder climates and is the chest and abdomen and paraplegia and quadriple-
gradually decreased toward the equator. The disease gia are more common than a monoplegia. Paralysis
was almost totally absent in the tropics. The wild polio- rates also vary depending on the serotype of the infect-
virus was eliminated in the United States by 2000. The ing poliovirus; the highest rates of paralysis (1 in 200)
annual prevalence of 600,000 new cases per year in the are associated with poliovirus type 1, the lowest rates
United States alone in 1940 dwindled to less than (1 in 2,000) are associated with type 2.19,20
1,000 new cases worldwide in 2000. Localized circula- The extent of spinal paralysis depends on the region
tion of poliovirus types 1 and 3 in Asia and Africa of the cord affected, which may result in any combina-
continue to be intermittently problematic preventing tion of cranial, cervical, thoracic, or lumbar dorsal and
total disease eradication.17 ventral root myotomal weakness. Weakness may be
Polioviruses are enteroviruses that are transmitted unilateral or bilateral but is often in an asymmetrical
from person to person following improper handling of distribution. Proximal motor nerves are often more
feces and pharyngeal virus excretion via a hand-to- affected than distal motor nerves.20,21
2560_Chapter 8_0089-0104.indd 91 3/16/2015 4:14:56 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Bulbar polio, which accounts for about 2% of cases deaths occur daily as a result of AIDS.26 In the United
of paralytic polio, occurs when poliovirus invades and States alone, reports indicate that there are more
destroys nerves within the bulbar region of the spinal than 1 million infections; almost 1 in 300 persons
cord—the white matter pathway connecting the cortex harbors HIV.25 In some African countries, the infec-
to the brainstem.16 The destruction of these nerves tion rate approaches 30% of the population.25 Since
weakens the muscles supplied by the cranial nerves, the introduction of highly active antiretroviral therapy
inducing symptoms of encephalitis, and causes respira- (HAART) in communities where this treatment is
tory difficulties, dysarthria, and dysphagia. Critical available and affordable, AIDS is becoming a chronic
nerves affected are the glossopharyngeal, vagus, acces- illness with dramatic reductions in morbidity and mor-
sory, and trigeminal nerves.16,17 tality. However, in most of the world, where HAART
Approximately 19% of patients with paralytic polio therapy is either not available or not affordable, AIDS
have both bulbar and spinal symptoms; this subtype of remains an acute illness with a high morbidity rate.
polio is called respiratory polio or bulbospinal polio.16 HIV is a neuroinvasive and neurovirulent (resulting
The virus, along with the extremity and truncal impact, in myopathy, myelopathy, radiculopathy, and dementia)
also affects the midcervical roots (C3 through C5), and disease with neurological signs, along with fever, often
paralysis of the diaphragm occurs. The critical nerves being among the earliest signs and symptoms of the
affected are the two phrenic nerves that drive the dia- disease (Table 8-1).26 Classification, incidence, preva-
phragm to inflate the lungs and the nerves that drive lence, and etiological agent of peripheral neuropathy
the muscles needed for swallowing. By injuring these associated with HIV infection is quite complex. The
nerves, this form of polio affects breathing, making it immunosuppression associated with HIV may lead to
difficult or impossible for the patient to breathe without secondary infections such as TB, herpes zoster, and
the support of an assistive device and to swallow. Along Guillain-Barré syndrome (GBS) that may themselves,
with the appendicular and axial weakness, this form of
polio is especially devastating.
The polio vaccine was introduced into the United
States in 195516 with the oral version arriving in 1961.17 Table 8-1 HIV-Related Peripheral Neuropathies
Both versions were designed to protect immunized Occurring During Inflammatory demyelinating
recipients. The annual incidence of polio declined Early-Stage HIV polyradiculoneuropathy
exponentially beginning in 1955 as more and more Infections Cranial nerve VII palsy
Americans were immunized. The last U.S. outbreak Large-fiber–induced sensory gait
occurred in 1979 in an underimmunized Amish popu- ataxia
lation and was caused by a wild poliovirus traced back Occurring During Multiple mononeuropathy (sensory
to a visitor from Turkey via The Netherlands and Intermediate-Stage and motor)
Canada.22,23 HIV Infections
Occurring During Distal symmetrical polyneuropathy
HIV Infection Late-Stage HIV
Infections
Lumbosacral polyradiculopathy/
cauda equina syndrome
Brachial plexopathy
The story of the AIDS virus began with numerous Autonomic neuropathy
clinical articles published in the early 1980s describing Diffuse infiltrative lymphocytosis
an increased incidence of heretofore uncommon syndrome
medical illnesses such as Kaposi’s sarcoma and Pneu-
Occurring at Any Herpes zoster radiculitis (sensory)
mocystis carinii pneumonia in certain populations, most Mononeuropathy (motor and sensory)
Time of Infection
noticeably homosexual men, intravenous drug users,
and patients receiving blood transfusions.24 Subsequent Data from CDC. HIV AIDS resources: prevention in the United States at
reports found that the causative agent was a micro- a critical crossroads. http://cdc.gov/hiv/resources/reports/
hiv_prev_us.htm; Time from HIV-1 seroconversion to AIDS and death
scopic agent transmitted from person to person via before widespread use of highly active antiretroviral therapy: a
blood or body fluid contact, primarily through sexual collaborative re-analysis. Collaborative Group on AIDS Incubation and
contact, intravenous drug use, or the receiving of blood HIV Survival including the CASCADE EU Concerted Action. Concerted
Action on SeroConversion to AIDS and Death in Europe. Lancet.
and blood products. This agent was found to impact 2000;355(9210):1131–1137; Schneider MF, Gange SJ, Williams
T-cell immunity resulting in a global immunodefi- CM, et al. Patterns of the hazard of death after AIDS through the
ciency syndrome.25 evolution of antiretroviral therapy: 1984–2004. AIDS.
2005;19(17):2009–2018; Reeves JD, Doms RW. Human
Since the onset of the AIDS pandemic in 1981, immunodeficiency virus type 2. J Gen Virol. 2002;83(Pt 6):1253–
infection with HIV has spread exponentially through- 1265; Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus
out the world; at the present time, 60 million children infection in type II cryoglobulinemia. N Engl J Med.
1992;327:1490–1495; and Agnello V, Abel G. Localization of
and adults are affected.24 There are approximately hepatitis C virus in cutaneous vasculitic lesions in patients with type II
16,000 new infections per day.25 More than 8,000 cryoglobulinemia. Arthritis Rheum. 1997;40:2007–2015.
2560_Chapter 8_0089-0104.indd 92 3/16/2015 4:14:56 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
along with the AIDS virus, elicit neuropathic symp- Table 8-2 HIV-Related Distal Sensory Peripheral Neuropathy
toms. Noninfection comorbidities possibly associated
with HIV, such as diabetes mellitus, vitamin B12 defi- Clinical • Length-dependent lower > upper limb
ciency, malnutrition, anorexia, cachectic syndrome, Findings paresthesias and dysesthesias
alcohol abuse, and recreational drug use, all may pre- • Distal weakness
dispose HIV-infected persons to peripheral neuropa- • Stocking-glove distribution large- and
thy. Lastly, many antiretroviral medications used to small-fiber sensory loss
treat HIV may themselves cause neuropathy.27,28 • Distal areflexia
Peripheral neuropathy rates in patients with symp- • Gait ataxia
tomatic HIV infection range from 0% to 95%.24,27 The • Decreased performance on balance
testing
variance is most likely due to the manner of diagnos-
tics; researchers who used solely a physical examination Laboratory Electroneuromyography studies show:
to document neuropathy had lower incidences, whereas Examination • Reduced amplitudes of sensory nerve
researchers who used electroneurodiagnostics had action potential and compound muscle
middle percentages, and researchers who used post- action potentials
• Prolongation of distal latencies and
mortem sural biopsies had the highest percentages. In possible slowing of conduction velocities
all instances, the duration of HIV infection in symp- • Needle examination shows distal
tomatic individuals was directly correlated with CD4+ denervation
T-cell count and with the prevalence of symptoms of
Symptom Early- to intermediate-stage infection
peripheral neuropathy. In asymptomatic patients with
Staging
HIV infection, the incidence of neuropathy was gener-
ally less than in individuals with symptomatic HIV. As Treatment Risk factor modification:
with the studies of patients with symptomatic HIV • Check vitamin B12 levels
infection, the assessment technique influenced preva- • Regulate blood sugar levels of patients
with diabetes
lence. Independent of the technique, the prevalence
• Investigate possible medication etiology
rates ranged from 5% to 25%.24
The most frequently encountered peripheral nerve Prognosis If risk factor modification is ineffective,
disorder induced by HIV is length-dependent distal poor, with no spontaneous remission
sensory peripheral neuropathy (DSPN), also referred Data from Time from HIV-1 seroconversion to AIDS and death before
to in the literature as distal symmetrical polyneuropa- widespread use of highly active antiretroviral therapy: a collaborative
thy and distal symmetrical sensory polyneuropathy re-analysis. Collaborative Group on AIDS Incubation and HIV Survival
including the CASCADE EU Concerted Action. Concerted Action on
(Table 8-2). The prevalence rate without HAART has SeroConversion to AIDS and Death in Europe. Lancet.
been estimated to be about 35% as diagnosed using 2000;355(9210):1131–1137; Schneider MF, Gange SJ, Williams
physical examination and 95% at autopsy using sural CM, et al. Patterns of the hazard of death after AIDS through the
evolution of antiretroviral therapy: 1984–2004. AIDS.
nerve biopsy.24 Risk factors for the development of 2005;19(17):2009–2018; Reeves JD, Doms RW. Human
DSPN include high HIV viral load; low CD4+ T-cell immunodeficiency virus type 2. J Gen Virol. 2002;83(Pt 6):1253–
count; length of duration of having HIV; and comor- 1265; Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus
infection in type II cryoglobulinemia. N Engl J Med.
bidities such as diabetes mellitus, alcohol intake, and 1992;327:1490–1495; and Agnello V, Abel G. Localization of
recreational drug use.29 Presenting symptoms are the hepatitis C virus in cutaneous vasculitic lesions in patients with type II
classic “painful and numb feet and ankles,” worse with cryoglobulinemia. Arthritis Rheum. 1997;40:2007–2015.
ambulation and better with rest and elevation. The
impairment is typically a large- and small-fiber sensory
neuropathy with little, if any, motor or autonomic use. Although the clinical presentations of neuropa-
involvement.27 Physical examination is noted for thies associated with antiretroviral medications and
depressed or absent Achilles deep tendon reflex, a DSPN are similar, the drug-related neuropathies are
decreased appreciation of tactile and joint position sen- more likely to be painful and to have an abrupt onset.
sation, mild gait ataxia, and lower than expected fall Medication combinations such isoniazid or hydroxy-
risk assessment (Romberg test, Timed Up and Go test, urea with antiretrovirals may exacerbate the onset and
Berg Balance Scale).28 Intervention therapy is primar- severity of DSPN.30
ily designed to control risk factors, such as maintaining Inflammatory demyelinating neuropathy is a
adequate blood sugar control if the patient has diabe- common complication of HIV. GBS and chronic
tes, correcting vitamin B12 levels if required, and elimi- inflammatory demyelinating polyradiculoneuropathy
nating alcohol and recreational drug use. (CIDP) are the two most common variations noted in
The nucleoside reverse transcriptase inhibitors used persons with HIV infection. Most cases of GBS and
to treat HIV infection such as stavudine and zalcitabine CIDP arise in HIV-infected patients at or near the
have also been shown to create a dose-dependent, time of seroconversion or in HIV-positive patients
length-dependent peripheral neuropathy with ongoing without evidence of immune compromise or evidence
2560_Chapter 8_0089-0104.indd 93 3/16/2015 4:14:56 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
of opportunistic infections such as P. carinii pneumo- triggered immune-mediated mechanisms rather than
nia.28 The early timing of the inflammatory demyelin- direct nerve infection and in situ replication.32 Neu-
ating neuropathy during the HIV infection course ropathy typically associated with HCV infections is a
coupled with the evidence of spontaneous improve- subacute, distal sensorimotor polyneuropathy but
ment tends to suggest that the HIV infection does not mononeuropathy and multiple mononeuritis have also
directly cause the complication, but rather the etiology been reported.33
may be autoimmune mediated as seen in individuals Santoro and Manganelli34 published the first large
without HIV infection. However, there are case reports prospective survey of randomly selected consecutive
indicating the onset of GBS and CIDP in patients series of unrelated patients with HCV infection who
with late-stage HIV infection.28 underwent systematic clinical and electrophysiological
HIV-associated GBS and CIDP have similar clini- studies to assess the prevalence and characteristics of
cal pictures as GBS and CIDP occurring in individuals peripheral neuropathy in the HCV population. In their
without HIV infection. Areflexia with often ascending sample, using a clinical examination assessment model,
proximal and distal limb weakness and variable sensory peripheral neuropathy was found in 10.6% of the sub-
loss are the typical presenting signs. Myalgias, arthral- jects. The electrophysiological examination revealed
gias, and neuropathic pain are rare. Facial weakness is subclinical neuropathy in an additional 4.7% of sub-
more common in GBS than CIDP. Respiratory failure jects indicating that a purely clinical assessment tends
may develop in some individuals. In GBS, the evolu- to underestimate PNS involvement in patients with
tion of the ascending weakness develops over days to HCV. A strong correlation was found between the
weeks; a diagnosis of CIDP requires that weakness patient’s age and the existence of peripheral neuropa-
progress over a period of at least 2 months.26–29 thy, and a much weaker correlation was found between
Laboratory and electroneuromyography results are the duration from first positive diagnostic laboratory
similar to the results found in individuals without HIV test for HCV and neuropathy. This weaker correlation
infection.30 CSF protein is typically elevated. One may be partially explained by the timing of the diag-
distinguishing feature of CSF seen in HIV-positive nostic workup and the time of the infection by the
patients with GBS or CIDP compared with patients hepatitis virus.
with GBS or CIDP without HIV infection is the pres-
ence of CSF pleocytosis.25 The presence of pleocytosis
in patients with GBS or CIDP who do not have a Tuberculosis
diagnosis of HIV should indicate the need for HIV
testing. Electroneuromyography assessment typically The current TB epidemic is sustained by three impor-
reveals slowed nerve conduction velocities, delayed tant factors: (1) HIV and its association with new
F-wave responses, prolonged distal latencies, and con- active TB cases, (2) recidivism of patients with TB in
duction block. Needle examination reveals reduced completing the prescribed course of antibiotics, and
motor unit potential recruitment with denervation (3) increasing resistance of the tubercular strains to
potentials.28 most effective first-line anti-TB drugs.36 Other con-
Treatment of HIV-associated GBS or CIDP is tributing factors include population expansion, emigra-
intravenous immune globulin and physical therapy to tion from rural areas to crowded cities, poor case
regain functional status. Corticosteroids and plasma detection and cure rates in impoverished countries,
exchange should be used carefully because of the wars, famines, increased prevalence of diabetes melli-
greater risks of this therapy in immunocompromised tus, social decay, and homelessness.37 Although expo-
patients.26 sure to Mycobacterium tuberculosis leads to active disease
in approximately 10% of people exposed, there were a
reported 9 million new active disease cases and 2
Hepatitis C Virus million deaths reported worldwide in 2008.37 Nearly
one third of the world’s population is latently infected
Hepatitis C virus (HCV) is a parenterally transmitted, with M. tuberculosis, and 5% to 10% of infected indi-
hepatotropic and lymphotropic RNA virus. Approxi- viduals develop active disease during their lifetime.
mately 170 million people are infected worldwide, and Coinfection with HIV exacerbates the risk of transi-
HCV is a primary cause of chronic hepatitis, cirrhosis, tioning from latent to active infection by 5% to 15%
and hepatocellular carcinoma. Along with peripheral per year and by approximately 50% over a lifetime38;
neuropathy, HCV may be associated with cryoglobuli- this is illustrated by the incidence rates of TB and HIV
nemia; lymphoproliferation; and various extrahepatic being the highest in sub-Saharan Africa. Although
manifestations including sicca syndrome, inflamma- active transmission of the bacterium is the primary
tion of the thyroid, and porphyria cutanea tarda.31 route to active infection worldwide, researchers are
In contrast to HIV-related peripheral neuropathy, seeing an increased number of active cases precipitated
neuropathy associated with HCV is related to virus- by coinfection with HIV).39
2560_Chapter 8_0089-0104.indd 94 3/16/2015 4:14:56 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
TB is a communicable infection and disease spread diabetes range from 2.44% to 8.33%. Several large-
by inhalation of droplet nuclei (1- to 5-μm particles) scale longitudinal cohort studies have shown similar
containing M. tuberculosis expectorated by patients findings.40
with active pulmonary or laryngeal TB, typically Infections, including TB, often worsen glycemic
with a cough or sneeze.37 Transmission is facilitated in control in patients with diabetes mellitus, and poorly
small households, crowded places, and repetitive close controlled diabetes mellitus may augment the severity
contact. The chance of acquisition is higher in immu- of infections. Some studies suggest that TB can pre-
nocompromised and older patients compared with cipitate diabetes in persons not previously known to be
younger and healthier individuals. diabetic.39 Many studies have used oral glucose toler-
Immediately after entry of the M. tuberculosis, alveo- ance testing to show that patients with TB have
lar macrophages and monocytes produce proinflamma- higher rates of glucose intolerance than community
tory cytokines and chemokines that serve to signal controls.39
infection. Monocytes, macrophages, neutrophils, and Nutritional status is significantly lower in patients
lymphocytes migrate to the infection site but often are with active pulmonary TB compared with healthy
unable to kill the invading bacteria efficiently because control subjects in different studies in Indonesia,
M. tuberculosis resists the phagosome-lysosome fusion. England, India, and Japan.41 The TB abscess usually
The bacteria multiply in the phagosome and eventually resolves with antituberculous drug therapy. However,
escape. The released bacteria multiply extracellularly failure of improvement or deterioration in neurological
developing a new inflammatory cascade reaction. Bac- status on antituberculous drug therapy is an indication
teria continue to escape developing distant metastasis. of surgical decompression.42 Cauda equina syndrome
The accumulation of macrophages, T cells, and other has been reported to be caused by TB. Cauda equina
host cells (dendritic cells, fibroblasts, endothelial cells, syndrome is a surgical emergency, and in cases related
and stromal cells) leads to the formation of granuloma to TB, early drainage is important for early recovery of
at the site of infection.38 bladder and bowel control. Kallmann and Resiner
Diabetes mellitus and TB have a strong clinical rela- studied several factors responsible for a successful
tionship. Besides resulting in multiple complications outcome in cauda equina syndrome and believed that
including vascular disease, neuropathy, and increased early diagnosis and early decompression are the most
susceptibility to infection, poorly controlled diabetes important predictors of a successful outcome.43
mellitus may also lead to increased susceptibility to The standard treatment for TB in the United States
disease caused by M. tuberculosis via multiple mecha- and Canada is daily self-administered therapy with
nisms. These mechanisms include those directly related isoniazid (INH) for 9 months, but this regimen can
to hyperglycemia and cellular insulinopenia as well often be reduced to 6 months in patients with serone-
as indirect effects on macrophage and lymphocyte gative HIV testing. The overall efficacy of INH therapy
function leading to diminished ability to contain the is greater than 90% in individuals who successfully
tubercular organism. The most important effector complete the course of prescribed therapy. However,
cells for containment of TB are phagocytes (alveolar completion rates with ongoing clinical monitoring are
macrophages and their precursor monocytes) and lym- only 30% to 64% and in nonclinical settings only 10%.
phocytes. Diabetes is known to affect chemotaxis, Although INH is tolerated relatively well, there is a
phagocytosis, activation, and antigen presentation by risk of hepatotoxicity in selected patients, especially
phagocytes in response to M. tuberculosis. In patients patients with high levels of alcohol ingestion. INH can
with diabetes, chemotaxis of monocytes is impaired, result in peripheral neuropathy, primarily a length-
and this defect does not improve with insulin. In mice dependent, large-fiber and small-fiber afferent sensory
with streptozotocin-induced persistent diabetes mel- impairment. The risk of INH-induced peripheral neu-
litus (streptozotocin is an islet-cell toxin), macrophages ropathy can be decreased with adjuvant vitamin B6.42
had one tenth of the phagocytic activity of control mice
but similar intracellular killing. In these experiments,
90% of mice died after challenge with TB compared Varicella-Zoster Virus Infections
with 10% of normal mice.39
Studies of diabetes mellitus and TB generally focus The varicella-zoster virus (VZV) is a human neuro-
on active TB disease. However, in one study in a general tropic alpha-herpesvirus. Primary infection causes
medicine clinic in Spain, 69 (42%) of 163 patients with varicella (chickenpox), after which the virus becomes
diabetes mellitus had a positive tuberculin skin test, latent in cranial nerve ganglia, dorsal root ganglia, and
suggesting a high rate of latent TB in patients with autonomic ganglia. Years later, most likely as a result of
diabetes mellitus, although this could have been con- diminished cell-mediated immunity in elderly and
founded by age, geographic location, and lack of a immunocompromised individuals, VZV reactivates
control group. Several case-control studies have shown initiating a wide spectrum of neurological diagnoses,
that the relative odds of developing TB in patients with including herpes zoster, postherpetic neuralgia (PHN),
2560_Chapter 8_0089-0104.indd 95 3/16/2015 4:14:56 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
vasculopathy, myelopathy, retinopathy, cerebellitis, and or sneeze. The diagnosis is made by the atypical vesicu-
zoster sine herpete (ZSH).44 lar rash. Treatment is symptomatic. Antiviral medica-
Initial VZV infection results in varicella, which is tions may be given to immunocompromised individuals
typically seen in children 1 to 9 years old but may also and newborns exposed to VZV during the perinatal
occur in adults.45 Adult infections tend to be more period.
severe than infections in children with accompanying VZV reactivation may lead to numerous peripheral
high fever and interstitial pneumonia.46 Infection in neuropathic diagnoses.49,50 Herpes zoster (zoster),
immunocompromised individuals causes widespread the most common of the reactivation manifestations,
disseminated disease.47 Varicella infection is character- affects 1 million individuals per year in the United
ized by fever and a self-limiting rash on the skin and States.49 Most patients are older than age 60 or have a
mucosa. Headache, malaise, loss of appetite, and fever diagnosis leading to concomitant immune compro-
are often seen. The rash begins as macules, rapidly mise.47 The annual incidence of zoster is approximately
progressing to papules, vascularization, and eventually 5 to 6.5 per 1,000 individuals at age 60 and increasing
slough. Slough occurs 1 to 3 weeks after infection to 8 to 11 per 1,000 individuals at age 70.49 Zoster
(Figs. 8-2 and 8-3).48 Spread is via direct contact with begins with a prodromal phase characterized by pain,
the skin lesions or by respiratory aerosols from cough itching, paresthesias, dysesthesias, and allodynia in one
to three dermatomes. All dermatomal segments may
be affected by zoster, but most infections are found in
the dorsal roots of the cervical, thoracic, and lumbar
nerve roots followed by the face, typically in the oph-
thalmic distribution of the trigeminal nerve.
Herpes zoster ophthalmicus is often accompanied
by keratitis, which can lead to blindness if unrecog-
nized and untreated.57 Involvement of the optic nerves
with subsequent optic neuritis has occurred rarely in
association with zoster ophthalmicus and other zoster
eruptions.52 Ophthalmoplegia after zoster most fre-
Figure 8-2 Varicella macules. Varicella is an extremely quently involves cranial nerve (CN) III, CN VI, and
contagious disease and appears most commonly in children CN VII and less frequently CN VI.53 Zoster involving
younger than 8 years old. The typical skin rash appears 1 the CN VII ganglion may cause weakness or paralysis
or 2 days after the onset of flu-like symptoms. Skin lesions of the ipsilateral muscles of facial expression with rash
pass through four distinct stages: (1) A small area of in the ear canal (zoster oticus) or on the ipsilateral
redness appears, (2) the area of redness evolves into a anterior two thirds of the tongue and hard palate.54
papule, (3) the papule becomes a serum-filled blister, and Ramsay Hunt syndrome is traditionally defined as a
(4) the papules dry and crust. lower motor neuron facial palsy with zoster oticus.
Many patients also have hearing loss, vomiting, nausea,
vertigo, and nystagmus.55
Cervical, thoracic, and lumbar distribution zoster
may be followed by lower motor neuron weakness or
paralysis in the muscles of the segmental nerve distri-
bution. Rare cases of thoracic zoster may cause abdom-
inal weakness leading to hernia, and there have been
case reports of diaphragm weakness secondary to zoster
involving CN III through CN V.56
Approximately 40% of patients older than age 60
with zoster develop PHN.57 PHN is characterized by
constant, severe, stabbing or burning dysesthetic pain
in the segmental distribution of the involved nerve or
nerves that persists months to years after infection. The
etiology of PHN is unknown. Management is a chal-
lenge. Treatments including tricyclic antidepressants,
neuroleptic drugs, analgesics, antivirals, and opiates
Figure 8-3 Crusted varicella-zoster lesions. Blisters have been attempted.48
associated with zoster infections typically form in one and ZSH (pain without rash) is caused by reactivation
occasionally two or three adjacent dermatomes. As with of VZV, a concept supported by patient descriptions
chickenpox, the blisters begin as red spots, become raised, of dermatomal distribution radicular pain in areas
fill with fluid, and eventually crust. distinct from pain with rash in patients with zoster.
2560_Chapter 8_0089-0104.indd 96 3/16/2015 4:14:56 PM

Process CyanProcess
YellowProcess Black
Historically, most clinicians regard ZSH as a rare
occurrence of chronic radicular pain without rash
with virologic confirmation. However, in recent years,
the detection of VZV DNA and anti-VZV antibody
in patients with meningoencephalitis, vasculopathy,
myelitis, cerebral ataxia, and cranial polyneuritis, all
without rash, has expanded the spectrum of ZSH.
Prevalence estimates of VZV-induced pathology with-
out rash require additional studies. ZSH should be
considered in the differential diagnosis for patients
with unexplained radicular pain or the above-listed
diagnoses who are immunocompromised.48
Figure 8-4 Taeniasis in humans is a parasitic infection
caused by the tapeworm species T. saginata (beef
Parasitic Infections tapeworm), T. solium (pork tapeworm), and T. asiatica
(Asian tapeworm). Humans can become infected with
Parasitic infections of the nervous system can produce
these tapeworms by eating raw and undercooked beef
various signs and symptoms. Because many of the neu-
(T. saginata) or pork (T. solium and T. asiatica). People with
rological symptoms produced by parasites are minimal
taeniasis may not know they have a tapeworm infection
or nonspecific, diagnosis can be difficult. Familiarity
because symptoms are usually mild or nonexistent.
with the basic epidemiological characteristics, labora-
Parasitic flatworms (tapeworms) tend to occur in areas that
tory findings, and imaging studies can increase the
lack adequate sanitation. Eggs are generally ingested
likelihood of detection and proper treatment of para-
through food, water, or soil contaminated with host feces.
sitic infections affecting the PNS and CNS.
Cestodes, trematodes, and protozoans can infect the
CNS or PNS, producing various clinical signs and
symptoms.58–61 Cestodes and trematodes are members of increasing intracranial pressure. Cyst removal is the
of Platyhelminthes, a phylum characterized by an most effective treatment.61
inability to live outside the host. Cestodes are often Sparganosis is an infection caused by the larval form
referred to as “tapeworms” and may exist in either adult of tapeworms from the genus Spirometra. Spirometra
or larva forms. Anatomically, cestodes are ribbon- are parasites of cats, dogs, birds, and humans that eat
shaped, segmentally differentiated worms with a scolex raw and undercooked fish. Sparganosis is common in
in the anterior portion used to attach to the host. In the Gulf states of the United States. Clinically, infected
general, larval forms are more pathogenic to the human patients develop a discrete subcutaneous nodule that
nervous system because adult forms rarely spread migrates locally. Metastasis to the brain is common
outside the gastrointestinal tract. Neurocysticercosis, with seizures, slowly progressing motor and sensory
caused by the cestode Taenia solium, is perhaps the hemiparesis, and headache. Diagnosis is made based on
most common cause of epilepsy in the world (Fig. eosinophilia and biopsy.62
8-4).59 The most common cestode is Echinococcus, also Trematodes, also referred to as “flukes,” can invade
known as hydatid disease, and is endemic in the Medi- the nervous system secondarily after a primary infec-
terranean, the Middle East, Latin America, and the tion occurring in the blood, liver, intestinal mucosa, or
Arctic.60 Epidemiological data support transmission lung. Most species are hermaphroditic and are capable
from dogs, cats, foxes, and rodents to humans. Echino- of reproduction within the host. Trematodes have two
coccus resides in the intestinal tract of dogs and other anterior suckers used to attach to the host (Fig. 8-5).
canids. It quickly transits to the liver, blood, lymph, Paragonimus is the only mammalian lung fluke capable
lung, pericardium, and brain. Humans and sheep are of infecting humans. An estimated 20 million people
intermediate hosts and acquire infection by ingesting are infected worldwide. Human infection is almost
eggs eliminated by infected animals. Human infection always acquired through incorrectly cooked freshwater
results in the formation of hydatid cysts that contain crab or crayfish. Domesticated cats, dogs, and pigs can
serous fluid. Most of the cysts occur in the liver. Hydatid harbor the fluke and transmit it to humans. Initial
infections often remain undetected until the cyst infections produce intestinal symptoms. There are often
becomes problematic, which usually occurs when the migratory subcutaneous masses typically located in the
cyst bursts spreading infection and resulting in the abdominal region. With time, migration to the lung
development of space-occupying lesions primarily in parenchyma occurs. Adult worms may live 20 or more
the CNS. Clinical signs and symptoms include motor years. Long-standing infection typically results in
and sensory neuropathy; upper motor signs such as worm transmission to brain tissue. CNS infection
spasticity, clonus, and Babinski sign; and clinical signs can produce meningoencephalitis, headache, weakness
2560_Chapter 8_0089-0104.indd 97 3/16/2015 4:14:57 PM

Process CyanProcess
YellowProcess Black
Figure 8-7 Numerous species of parasitic protozoa using

various vectors can infect the human body. Often the
intestine is the site of initial infection, but infection may
Figure 8-5 Long-standing fluke parasites are a type of also begin in capillaries, skin, stomach, and blood.
parasitic flatworm or trematode that can migrate from host Neurological symptoms often depend on the site of
tissue (primarily digestive) to the central nervous system migration.
resulting in upper motor neuron and sensory impairment.
drinking, bathing, washing clothes, washing dishes, and

walking barefoot. Initial infection occurs when the
forked tail penetrates the skin. The tail is then shed,
and the larva migrates into the venous system. Clinical
symptoms depend on which species infects; each
species has a different corporal locus. S. mansoni infects
the inferior mesenteric vein, S. haematobium infects the
peri-bladder veins, and S. japonicum infects the superior
mesenteric veins. Eggs from S. japonicum tend to
metastasize to the brain, whereas the larger eggs of
S. mansoni and S. haematobium typically metastasize to
the spinal cord. The metastasized eggs do not develop
into worms; rather, their presence initiates an inflam-
matory cascade reaction culminating in a granuloma-
tous response as tissues attempt to wall off the invading
parasite.65 After a period of time, the granulomas
become exudative, invasive, and necrotic, damaging
local upper motor neuron and lower motor neuron
Figure 8-6 S. mansoni is a human trematode parasite that tissue beginning weeks after the acute infection. Lower
is the major disease agent for schistosomiasis. Early motor neuron involvement often mimics cauda equina
symptoms may mimic scabies. Diagnosis is confirmed via syndrome or conus medullaris syndrome.66 Diagnosis
eggs in the stool. is made by biopsy or detection of eggs in stool or urine.
For patients with spinal cord infection, CSF enzyme-
linked immunosorbent assay for immunoglobulin G
(general or focal), nausea, and seizures. Diagnosis is against egg antigens is recommended. Praziquantel is
based on serum and CSF eosinophilia, biopsy speci- effective against all Schistosoma species and is curative
men showing egg material, and serum antibody detec- in 90% of patients.67
tion testing.63 Protozoans are classified by mode of locomotion
Schistosomiasis, also known as bilharziasis, is an and can be either free-living or obligate parasites. The
extremely common parasite, infecting more than 300 spectrum of clinical symptoms and signs of protozoa
million people worldwide per year. CNS and PNS infections is diverse, and nervous system infection may
involvement has been reported in three of the species: occur secondary to distant infection. Because of their
Schistosoma mansoni, Schistosoma haematobium, and large size, protozoan infections are easily identified
Schistosoma japonicum. Humans and at least 30 other via light microscopy (Fig. 8-7). American trypanoso-
mammals are possible hosts (Fig. 8-6).63 Infection is miasis, also known as Chagas disease, is endemic to
spread through contaminated water sources including South and Central American countries. With increased
2560_Chapter 8_0089-0104.indd 98 3/16/2015 4:14:57 PM

Process CyanProcess
YellowProcess Black
emigration and urbanization, infection is becoming
more common in the United States. Infection is spread
Chronic Fatigue Syndrome
by the reduviid bug (Triatoma infestans) or by ingesting
meat of the guinea pig.68 Infection may also be spread Chronic fatigue syndrome (CFS) is the most common
via blood transfusion or organ transplantation. The name given to a variably debilitating disorder or disor-
protozoa may pass through the placenta to the fetus. ders generally defined by persistent fatigue unrelated
Primary infection occurs when the reduviid bug takes to exertion, not substantially relieved by rest, and
a blood meal from the host and leaves fecal material accompanied by the presence of other specific symp-
behind containing Trypanosoma cruzi eggs. The eggs toms for a minimum of 6 months.72 The disorder
remain on the skin until embedded through itching of may also be referred to as postviral fatigue syndrome
the bug bite. The cells migrate quickly via binary fusion (when the condition arises after a flu-like illness)
and metastasize to distant sites through venous and or myalgic encephalomyelitis.73 The disease process
arterial blood circulation.69 Protozoa reproduce within in CFS displays a range of neurological, immunologi-
host cells, and when the host cell ruptures, additional cal, and endocrine system abnormalities. Although
vectors are created. classified by the World Health Organization under
Acute infections result in malaise, myalgia, head- diseases of the nervous system, the etiology of CFS is
ache, asthenia, and anorexia. Romaña’s sign (unilateral unknown, and there is no diagnostic laboratory test or
or bilateral palpebral edema) is pathognomonic for biomarker to confirm the presence or absence of the
Chagas disease. Cardiac failure and intestinal symp- disorder.74
toms are the major cause of morbidity and mortality. Intermittent fatigue is a common symptom in many
In Brazil, the primary cause of acute congestive heart illnesses, but CFS is a multisystemic disease and is rare
failure is Chagas disease. Only 5% of infected persons by comparison. Symptoms of CFS include postexer-
develop severe complications. Neurological symptoms tional malaise; unrefreshing sleep; widespread myalgia
are limited to meningitis with headache, malaise, and and arthralgia affecting the axial and appendicular
photophobia. Only acute Chagas disease can be eradi- skeletons; cognitive deficits; chronic, often severe
cated by treatment. Chronic infections can be treated mental and physical exhaustion; and other characteris-
symptomatically only. Benznidazole is the treatment of tic symptoms in a previously healthy and active person.
choice.70 Patients with CFS may report additional symptoms,
African trypanosomiasis, also known as human including patterned or unpatterned muscle weakness,
African trypanosomiasis and sleeping sickness, is hypersensitivity to sensory stimuli, and orthostatic
endemic to sub-Saharan Africa-—primarily in the hypotension with positional changes. Vague symptoms
Democratic Republic of the Congo and Uganda. of depression, cardiopulmonary symptoms, a depressed
Widespread political unrest and poor reporting proce- immune system, and respiratory problems have been
dures most likely diminish the actual number of cases. reported. It is unclear if these additional symptoms
Officially, the World Health Organization reports represent comorbid or reactive symptoms to CFS or
approximately 300,000 new cases in Africa each year.71 the medication used to treat the disorder or conditions
The tsetse fly is the vector for infection. The prevalence produced by an underlying etiology of CFS.75
of infection is directly related to the concentration of The prevalence of CFS varies widely, ranging from
tsetse flies in a particular region. Only a few dozen 7 to 3,000 cases of CFS for every 100,000 adults, but
cases have been reported in the United States over the national health organizations have estimated more
past few years with most of these occurring in persons than 1 million Americans and approximately a quarter
with recent travel to the African subcontinent. Follow- of a million people in the United Kingdom have CFS.
ing the fly bite, a superficial chancre develops at the CFS occurs most often in people in their 40s and 50s,
site of the bite. Larvae within the chancre migrate more often in women than men, and is less prevalent
through blood and lymphatic vessels to the CNS, among children and adolescents. A prognosis study
maturing and reproducing during the migratory review calculated a median full recovery rate of 5%
process. When the infection reaches the CNS, an among untreated patients and median improvement
immune response is created with a severe inflammatory rate of approximately 40% compared with premorbid
response. Peri-infection edema causes the clinical find- status.76
ings of behavioral abnormalities, a reversal in sleep There is agreement on the genuine threat to health,
patterns (sleep during the day and insomnia at night), happiness, and productivity posed by CFS, but various
hypothermia or hyperthermia, ataxia, hypertonus, and physicians’ groups, researchers, and patient advocates
akinesia. Fatal arrhythmia secondary to parasitic inva- promote different nomenclature, diagnostic criteria,
sion of the heart is the most common cause of death. etiologic hypotheses, and treatments, resulting in
Definitive diagnosis is made through blood, CSF, or marked controversy of the disorder.76 The name CFS
chancre sampling. Drug regimens are fairly effective, itself is controversial; many patients and advocacy
although drug resistance is emerging.71 groups as well as some experts want the name changed
2560_Chapter 8_0089-0104.indd 99 3/16/2015 4:14:57 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
because they believe that it stigmatizes by not convey- is a peripheral neuropathy that is not mediated by the
ing the seriousness of the illness.77 infectious agent, but rather by the immune response.
There are no characteristic laboratory, clinical, or Leprosy, common throughout all of written history,
imaging abnormalities to diagnose CFS, and testing is remains a problematic disease in many parts of the
used to rule out other potential causes for symptoms. world. The number of new cases reported each year
When symptoms are attributable to certain other con- (500,000 to 700,000 worldwide) has remained con-
ditions, the diagnosis of CFS is excluded.78 Rehabilita- stant for the past decade.87
tion therapists should be aware of the existence of this The precise mechanism of transmission of Mycobac-
diagnosis and the possibility that symptoms may be terium leprae is unknown.88 No highly effective vaccine
related to PNS impairment. has yet been developed.89 No clinical tests for early
diagnosis have been found for a clinically unapparent
disease.87 Leprosy manifests with a wide range of clini-
Parsonage-Turner Syndrome cal, histopathological, and functional manifestations.
This great diversity puzzled and frustrated clinicians
Parsonage-Turner syndrome is a term used to describe and researchers until it was found that this diversity
a neuritis involving the brachial plexus. It was first was based on the ability of the host to develop an
described by Feiburg in 1897, who reported a case of individualized cellular immune response to M. leprae.
unilateral brachial plexopathy associated with an influ- The five-part Ridley-Jopling classification of patients
enza infection. In 1948, Parsonage and Turner described with leprosy identifies patients based on the degree of
136 cases of plexopathy and gave it the name “shoulder cell-mediated immunity. At one extreme are patients
girdle syndrome.” They described a typical presentation with a high degree of cell-mediated immunity and
of sudden onset of shoulder pain without trauma fol- delayed hypersensitivity presenting with a single, well-
lowed by flaccid paralysis of the shoulder girdle, arm, demarcated lesion with central hypopigmentation and
forearm, and hand at which time the pain subsided. hypoesthesia. At the other extreme are patients who
Associated sensory symptoms may or may not be appear to have no resistance at all to M. leprae. These
present. Complete recovery of strength occurred in patients present with numerous, poorly demarcated
90% of patients within 3 years. The remaining cohort raised or nodular lesions on all parts of the body. Biopsy
had residual weakness. More recent research indicates specimens of the lesions reveal a large number of mac-
the incidence as 1.64 cases per 100,000 population rophages and dermis containing numerous individual
with men being affected more than women. Peak inci- bacilli and grouped microcolonies of bacilli called globi.
dence occurs in the third and seventh decades of life. This highly nonresistant form of leprosy is called polar
There is no relationship between hand dominance. The lepromatous leprosy.87
condition occurs bilaterally in 3% of the cases.80 In contrast to TB and other acquired infections,
Treatment is supportive. In their review of 99 leprosy has not been observed to have an increased
patients, Tsairis et al.81 found no significant benefit of prevalence in individuals with a diagnosis of HIV in
oral corticosteroids. There was no substantial support areas where both diseases are endemic. Suggestions for
of physical therapy modalities such as ultrasound or this phenomenon include the relatively low virulence
electrical stimulation. Surgery is indicated only for of M. leprae or that patients with HIV often die before
the small cohort of patients showing no improve- leprosy—with its long incubation period—becomes
ment. Surgical intervention includes tendon transfers apparent (Fig. 8-8).88
and shoulder stabilization procedures. A few patients The diagnosis of leprosy is made by a full-thickness
may experience relapse of symptoms, but these tend skin biopsy specimen obtained from the advancing
to be less severe than the original symptoms and of margin of active lesion, fixed in neutral buffered for-
much shorter duration.85,86 Rehabilitative treatment malin, embedded in paraffin, and examined microscop-
is directed at maintaining articular passive range of ically. The primary characteristics of a positive biopsy
motion, strengthening of the existing and reinner- specimen include the classic histological patterns of the
vated musculature, and prevention of glenohumeral host response in hematoxylin and eosin–stained sec-
subluxation. tions, the involvement of the cutaneous afferent nerves,
and the identification of non–acid-fast bacilli within
the nerves using the Fite stain. No serological tests are
Leprosy available for the routine laboratory diagnosis of leprosy.
An enzyme-linked immunosorbent assay and related
The best way to understand the clinical and functional immunoassay has been developed to detect antibodies
impact of leprosy (Hansen’s disease) is to consider it as to M. leprae, and these have been used in epidemiologi-
two conjoined diseases. The first is a chronic mycobac- cal studies, but the sensitivity and specificity of the test
terial infection that may elicit an extraordinary range are below satisfactory levels to enable the test to be
of cellular immunity responses in humans. The second used as a diagnostic tool (Table 8-3).89
2560_Chapter 8_0089-0104.indd 100 3/16/2015 4:14:57 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Type 1 leprosy reactions occur in patients in the neuropathy, these patients often experience iridocycli-
borderline (less severe) portion of the Ridley-Jopling tis, episcleritis, orchitis, myalgias, arthralgias, and
scale. These are often called “reversible reactions” myositis.91
because early observations suggested that after the The neuropathic process of leprosy is directly related
reaction has subsided, clinical and histopathological to the M. leprae infection, and this effect is unique
evidence indicated that the immunity in the lesions among bacterial pathogens.87 With infection, there is
had increased. Type 1 reactions manifest as indurated a strong predilection of the M. leprae bacillus to migrate
and erythematous lesions with edema and progressive to peripheral nerves.91 The infection aggregates in the
sensory greater than motor peripheral neuropathy. epineural lymphatics and blood vessels and enters the
These reactions develop gradually and may last for endoneural compartment via the vasa nervorum. If
weeks. Patients with type 2 lesions experience an there is no or limited effective immune response, the
abrupt onset of crops of tender, erythematous nodules bacilli proliferate within macrophages and Schwann
that develop throughout the body.90 Along with the cells. The resultant perineural and endoneural inflam-
mation and thickening, angiogenesis, and laying down
of aberrant connective tissue over time lead to a decrease
in nerve conduction velocity and eventually neur-
apraxic, axontometic, and neurotometic lesions. Infec-
tion tends to begin distally and move proximally with
the fingers and toes most often infected. There also
seems to be a predilection for the facial nerve.87 Typical
pathogenesis in untreated or antibiotic-resistant disease
is a progression of lesions with concomitant ascending
sensory loss and motor loss.
Treatment is antibiotics. Dapsone, introduced in the
1950s, quickly became the standard treatment, but
poor compliance in many areas quickly led to dapsone-
resistant leprosy. Rifampin and clofazimine were later
introduced, but antibiotic-resistant strains again began
to appear. More recently, multidrug cocktails have
Figure 8-8 Leprous hands. Contrary to folklore, leprosy proved to be an effective intervention, but even with
(Hansen’s disease) does not result in body parts “falling the newer therapies, the number of new cases reported
off.” Rather, secondary infections may result in per year has remained relatively constant. Relapse, with
interventional amputations. Fingers and toes may become a rate of 20 per 1,000 persons, has been reported in
shortened and deformed secondary to absorption of patients treated with a 2-year course of multidrug
cartilage, bone, and connective tissue. therapy.92,93
Table 8-3 Comparison of Clinical Features of Types 1 and 2 Immunological Leprosy Reactions
Parameter Type 1 Type 2
Onset of reaction Gradual, over weeks to months Abrupt
Cutaneous lesions Increased erythema and induration Widespread and numerous erythematous, tender nodules
of previously existing lesions on face, extremities, or trunk, without relationship to prior
lesions
Neuritis Primarily sensory, frequent, often Primarily sensory, frequent, often severe
severe
Systemic symptoms Malaise Fever, malaise, chills, loss of appetite
Histopathological features No specific findings Polymorphonuclear cell infiltrates in lesions <24 hours old
Course (untreated) Weeks or months Days to weeks
Treatment Corticosteroids Thalidomide, corticosteroids
Data from Ridley DS, Jopling WH. Classification of leprosy according to immunity. A five-group system. Int J Lepr Other Mycobact Dis
1996;34(3):255–273; Modlin RL. Th1-Th2 paradigm: insights from leprosy. J Invest Dermatol. 1994;102(6):828–832; James WD, Berger TG.
Andrews’ Diseases of the Skin: Clinical Dermatology. Philadelphia: Saunders; 2006; Jardim MR, Antunes SL, Santos AR. Criteria for diagnosis of
pure neural leprosy. J Neurol. 2003;250(7):806–809; and Mendiratta V, Khan A, Jain A. Primary neuritic leprosy: a reappraisal at a tertiary care
hospital. Indian J Lepr. 2006;78(3):261–267.
2560_Chapter 8_0089-0104.indd 101 3/16/2015 4:14:57 PM

Process CyanProcess
YellowProcess Black
2. Wormser GP. Clinical practice. Early Lyme disease. N Engl J
CASE STUDY Med. 2006;354:2794–2801.
3. Tibbles CD, Edlow JA. Does this patient have erythema
JB, a 46-year-old man, arrived in the physical therapy migrans? JAMA. 2007;297:2617–2627.
clinic with a chief complaint of bilateral knee swelling 4. Centers for Disease Control and Prevention. Lyme disease—
United States, 2003–2005. MMWR Morb Mortal Wkly Rep.
and pain that he believed was due to a long weekend 2007;56:573–576.
of walking through the woods while hunting. On 5. Nowakowski J, McKenna D, Nadelman RB. Failure of
physical examination, the therapist noted synovitis and treatment with cephalexin for Lyme disease. Arch Fam Med.
tenderness at both knees with a corresponding antalgic 2000;9:563–567.
gait pattern. The pain was most severe with sit-to-stand 6. Sigal LH. Toward a more complete appreciation of the
clinical spectrum of Borrelia burgdorferi infection: early Lyme
transfers and stair climbing. Past medical history was disease without erythema migrans. Am J Med. 2003;114:
unremarkable. The therapist found no other joint 74–75.
involvement. Neurological examination was 7. Sigal LH. Summary of the first 100 patients seen at a Lyme
unremarkable. Integument examination revealed a red disease referral center. Am J Med. 1990;88:577–581.
macule that enlarged into a large round circular patch 8. Centers for Disease Control and Prevention.
Recommendations for test performance and interpretation
with some central clearing on the patient’s right shoulder. from the Second National Conference on Serologic Diagnosis
of Lyme Disease. MMWR Morb Mortal Wkly Rep. 1995;44:
Case Study Questions 590–591.
9. Aguero-Rosenfeld ME, Wang G, Schwartz I, Wormser GP.
1. Considering the history of walking in the woods and Diagnosis of Lyme borreliosis. Clin Microbiol Rev. 2005;18:
the red macule, the therapist should consider which 484–509.
10. Shapiro ED, Dattwyler R, Nadelman RB, Wormser GP.
of the following diagnoses? Response to meta-analysis of Lyme borreliosis symptoms.
a. Poliomyositis Int J Epidemiol. 2005;34:1437–1439.
b. Lyme disease 11. Cairns V, Godwin J. Post-Lyme borreliosis syndrome: a
c. HIV meta-analysis of reported symptoms. Int J Epidemiol. 2005;34:
d. Protozoan infection 1340–1345.
12. Shadick NA, Phillips CB, Sangha O. Musculoskeletal and
2. The description of the integument may be labeled as neurologic outcomes in patients with previously treated Lyme
which of the following? disease. Ann Intern Med. 1999;131:919–926.
13. Kalish RA, Kaplan RF, Taylor E, Jones-Woodward L,
a. Erythema migrans Workman K, Steere AC. Evaluation of study patients with
b. Kaposi sarcoma Lyme disease, 10–20-year follow-up. J Infect Dis. 2001;183:
c. Varicella 453–460.
d. Varicella slough 14. Klempner MS. Controlled trials of antibiotic treatment in
patients with post-treatment chronic Lyme disease. Vector
3. Which of the following is the bacterium that causes Borne Zoonotic Dis. 2002;2:255–263.
Lyme disease? 15. Heymann DL, Aylward RB. Eradicating polio. N Engl J Med.
a. Proteus mirabilis 2004;351:1275–1277.
16. Kidd D, Williams A, Howard RS. Classical diseases
b. Borrelia burgdorferi revisited—poliomyelitis. Postgrad Med J. 1996;72:641–647.
c. Escherichia coli 17. Fine PE. Poliomyelitis: very small risks and very large risks.
d. Salmonella Lancet Neurol. 2004;3:703–710.
18. Dalakas MC, Elder G, Hallett M, et al. A long-term
4. Lyme disease may result in impairments to which of follow-up study of patients with post-poliomyelitis
the following systems? neuromuscular symptoms. N Engl J Med. 1986;314:
a. Integument 959–963.
b. Neurological 19. Kidd D, Howard RS, Williams AJ, Heatley FW,
Panayiotopoulos CP, Spencer GT. Late functional
c. Cardiopulmonary deterioration following paralytic poliomyelitis. QJM. 1997;90:
d. All of the above 189–196.
20. Sejvar JJ. West Nile virus and poliomyelitis. Neurology. 2004;
5. Treatment for Lyme disease includes which of the
63:206–207.
following? 21. Howard RS. Late post-polio functional deterioration. Pract
a. Antimicrobials Neurol. 2003;3:66–77.
b. Radiation 22. Kilpatrick DR, Nottay B, Yang CF, Yang SJ, Mulders MN,
c. Chemotherapy Holloway BP. Group specific identification of poliovirus by
PCR using primers containing mixed-base or deoxyinosine
d. Cauterization
residues at positions of codon degeneracy. J Clin Microbiol.
1996;34:2990–2996.
23. Alexander LN, Seward JF, Santibanez TA, et al. Vaccine
References policy changes and epidemiology of poliomyelitis in the
1. Coyle BS, Strickland GT, Liang YY, Pena C, McCarter R, United States. JAMA. 2004;292:1696–1701.
Israel E. The public health impact of Lyme disease in 24. Weiss RA. How does HIV cause AIDS? Science. 1993;
Maryland. J Infect Dis. 1996;173:1260–1262. 260(5112):1273–1279.
2560_Chapter 8_0089-0104.indd 102 3/16/2015 4:14:57 PM

Process CyanProcess
YellowProcess Black
25. Douek DC, Roederer M, Koup RA. Emerging concepts in 46. Ibanga H, Brookes R, Hill P, et al. Early clinical trials with a
the immunopathogenesis of AIDS. Annu Rev Med. 2009;60: new tuberculosis vaccine, MVA85A, in tuberculosis-endemic
471–484. countries: issues in study design. Lancet Infect Dis. 2006;6(8):
26. CDC. HIV AIDS resources: prevention in the United States 522–528.
at a critical crossroads. http://cdc.gov/hiv/resources/reports/ 47. Steiner I, Kennedy PG, Pachner AR. The neurotropic herpes
hiv_prev_us.htm. viruses: herpes simplex and varicella-zoster. Lancet Neurol.
27. Time from HIV-1 seroconversion to AIDS and death before 2007;6(11):1015–1028.
widespread use of highly active antiretroviral therapy: a 48. Johnson RW, Dworkin RH. Treatment of herpes zoster and
collaborative re-analysis. Collaborative Group on AIDS postherpetic neuralgia. BMJ. 2003;326(7392):748–750.
Incubation and HIV Survival including the CASCADE EU 49. Kennedy PG. Varicella-zoster virus latency in human ganglia.
Concerted Action. Concerted Action on SeroConversion Rev Med Virol. 2002;12(5):327–334.
to AIDS and Death in Europe. Lancet. 2000;355(9210): 50. Peterslund NA. Herpesvirus infection: an overview of the
1131–1137. clinical manifestations. Scand J Infect Dis Suppl. 1991;80:
28. Schneider MF, Gange SJ, Williams CM, et al. Patterns of 15–20.
the hazard of death after AIDS through the evolution of 51. Jones AD. Infection. Viral Immunol. 2003;16(3):243–258.
antiretroviral therapy: 1984–2004. AIDS. 2005;19(17): 52. Dworkin RH, Johnson RW, Breuer J. Recommendations for
2009–2018. the management of herpes zoster. Clin Infect Dis. 2006;
29. Reeves JD, Doms RW. Human immunodeficiency virus type 44(Suppl 1):S1–26.
2. J Gen Virol. 2002;83(Pt 6):1253–1265. 53. Donahue JG, Choo PW, Manson JE, Platt R. The incidence
30. Agnello V, Chung RT, Kaplan LM. A role for hepatitis C of herpes zoster. Arch Intern Med. 2005;155(15):1605–1609.
virus infection in type II cryoglobulinemia. N Engl J Med. 54. Araújo LQ, Macintyre CR, Vujacich C. Epidemiology and
1992;327:1490–1495. burden of herpes zoster and post-herpetic neuralgia in
31. Agnello V, Abel G. Localization of hepatitis C virus in Australia, Asia and South America. Herpes. 1997;14(Suppl 2):
cutaneous vasculitic lesions in patients with type II 40A–44A.
cryoglobulinemia. Arthritis Rheum. 1997;40:2007–2015. 55. Cunningham AL, Breuer J, Dwyer DE, et al. The prevention
32. Bonetti B, Scardoni M, Monaco S. Hepatitis C virus and management of herpes zoster. Med J Aust. 2008;188(3):
infection of peripheral nerves in type II cryoglobulinaemia. 171–176.
Virchows Arch. 1999;434:533–535. 56. Holmes G, Kaplan J, Gantz N, et al. Chronic fatigue
33. Smith DK, Grohskopf LA, Black RJ, et al; U.S. Department syndrome: a working case definition. Ann Intern Med.
of Health and Human Services. Antiretroviral postexposure 1998;108(3):387–389.
prophylaxis after sexual, injection-drug use or other non- 57. Helgason S, Sigurdsson JA, Gudmundsson S. The clinical
occupational exposure to HIV. MMWR Recomm Rep. 2005; course of herpes zoster: a prospective study in primary care.
54(RR-2):1–20. Eur J Gen Pract. 1996;2(1):12–16.
34. Santoro L, Manganelli C. Prevalence and characteristics of 58. World Health Organization (WHO). Prevention and control
peripheral neuropathy in hepatitis C virus population. of schistosomiasis and soil transmitted helminthiasis: report
J Neurol Neurosurg Psychiatry. 2006;77(5):626–629. of WHO Expert Committee. WHO Technical Report Series,
35. Caruntu FA, Benea L. Acute hepatitis C virus infection. No. 912. Geneva: WHO; 2002.
J Gastrointest Liver Dis. 2006;15(3):249–256. 59. UNAIDS/WHO. AIDS epidemic update 2006. http://
36. Kamal SM. Acute hepatitis C: a systematic review. Am J www.un-ngls.org/spip.php?page=article_s&id_article=186.
Gastroenterol. 2008;103(5):1283–1297. 60. Grossman Z, Meier-Schellersheim M, Sousa AE, Victorino
37. Villano SA, Vlahov D, Nelson KE, Cohn S, Thomas DL. RM, Paul WE. CD4+ T-cell depletion in HIV infection: are
Persistence of viremia and the importance of long-term we closer to understanding the cause. Nat Med. 2002;8:
follow-up after acute hepatitis C infection. Hepatology. 1999; 319–323.
29(3):908–914. 61. Borkow G, Bentwich Z. Chronic immune activation
38. Parish T, Stoker N. Mycobacteria: bugs and bugbears (two associated with chronic helminthic and human
steps forward and one step back). Mol Biotechnol. 1999;13(3): immunodeficiency virus infections: role of hypo-
191–200. responsiveness and energy. Clin Microbiol Rev. 2004;17(4):
39. van Soolingen D, Hoogenboezem T, de Haas PE. A novel 1012–1030.
pathogenic taxon of the Mycobacterium tuberculosis complex. 62. MacDonald AS, Araujo MI, Pearce EJ. Immunology of
Int J Syst Bacteriol. 1997;47(4):1236–1245. parasite helminth infections. Infect Immun. 2002;70:
40. Restrepo BI. Convergence of the tuberculosis and diabetes 427–433.
epidemics: renewal of old acquaintances. Clin Infect Dis. 63. Secor WE, Shah A, Mwinzi PM, Ndenga BA, Watta CO,
1997;45(4):436–438. Karanja DM. Increased density of human immunodeficiency
41. Nijland HM, Ruslami R, Stalenhoef JE, et al. Exposure virus type 1 co-receptors CCR5 and CXCR4 on the
to rifampicin is strongly reduced in patients with surfaces of CD4+ T cells and monocytes of patients with
tuberculosis and type 2 diabetes. Clin Infect Dis. 2006; Schistosoma mansoni infection. Infect Immun. 2003;71:
43(7):848–854. 6668–6671.
42. Nnoaham KE, Clarke A. Low serum vitamin D levels and 64. Kalinkovich A, Borkow G, Weisman Z, Tsimanis A, Stein M,
tuberculosis: a systematic review and meta-analysis. Int J Bentwich Z. Increased CCR5 and CXCR4 expression in
Epidemiol. 2008;37(1):113–119. Ethiopians living in Israel: environmental and constitutive
43. Kallmann FJ, Reisner D. Twin studies on the significance of factors. Clin Immunol. 2001;100(1):107–117.
genetic factors in tuberculosis. Am Rev Tuberc. 1942;16: 65. Shapira-Nahor O, Kalinkovich A, Weisman Z, et al.
593–617. Increased susceptibility to HIV-1 infection of peripheral
44. Kaufmann S. Protection against tuberculosis: cytokines, blood mononuclear cells from chronically immune activated
T cells and macrophages. Ann Rheum Dis. 1996;61(Suppl 2): individuals. AIDS. 1998;12:1731–1733.
ii54–58. 66. Fincham JE, Markus MB, Adams VJ. Could control of
45. Skeiky YA, Sadoff JC. Advances in tuberculosis vaccine soil-transmitted helminthic infection influence the HIV/
strategies. Nat Rev Microbiol. 2006;4(6):469–476. AIDS pandemic? Acta Trop. 2003;86(2–3):315–333.
2560_Chapter 8_0089-0104.indd 103 3/16/2015 4:14:57 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
67. Gupta S, Narang S, Nunavath V, Singh S. Chronic diarrhea management of chronic fatigue syndrome: a systematic
in HIV patients: prevalence of coccidian parasites. Indian J review. JAMA. 2006;286(11):1360–1368.
Med Microbiol. 2008;26:172–175. 79. Parsonage MJ, Turner JW. Neuralgic amyotrophy; the
68. Kelly P, Todd J, Sianongo S, et al. Susceptibility to intestinal shoulder-girdle syndrome. Lancet 1948;1(6513):973–978.
infection and diarrhea in Zambian adults in relation to HIV 80. Magee KR, DeJong RN. Paralytic brachial neuritis. JAMA.
status and CD4 count. BMC Gastroenterol. 2009;9:7. 1960;174:1258–1262.
69. Habtamu B, Kloos H. Intestinal parasitism. In: Berhane Y, 81. Tsairis P, Dyck PJ, Mulder DW. Natural history of brachial
Hailemariam D, Kloos H, eds. Epidemiology and Ecology of plexus neuropathy. Report of 99 patients. Arch Neurol. 1972;
Health and Diseases in Ethiopia. Addis Ababa: Shama Books; 27:109–117.
2006:519–538. 82. McCarty EC, Tsairis P, Warren RF. Brachial neuritis. Clin
70. Cheesbrough M. District Laboratory Practice in Tropical Orthop. 1999;368:37–43.
Countries, Part 1. Cambridge: Cambridge University Press; 83. Misamore GW, Lehman DE. Parsonage-Turner syndrome
2000. (acute brachial neuritis). J Bone Joint Surg Am. 1996;78:
71. Awole M, Gebre-Selassie S, Kassa T, Kibru G. Prevalence of 1405–1408.
intestinal parasites in HIV-infected adult patients in 84. Sarikaya S, Sumer M, Ozdolap S, Erdem CZ. Magnetic
southwestern Ethiopia. Ethiop J Health Dev. 2003;17:71–78. resonance neurography diagnosed brachial neuritis: a case
72. Sharpe M, Archard L, Banatvala J, et al. A report—chronic report. Arch Phys Med Rehabil. 2005;86:1058–1059.
fatigue syndrome: guidelines for research. J R Soc Med. 2006; 85. Sasaki S, Takeshita F, Okuda K, Ishii N. Mycobacterium
84(2):118–121. leprae and leprosy: a compendium. Microbiol Immunol. 2006;
73. Carruthers BM, Jain AK, De Meirleir KL, et al. Myalgic 45(11):729–736.
encephalomyelitis/chronic fatigue syndrome: clinical working 86. Leprosy disabilities: magnitude of the problem. Wkly
definition, diagnostic and treatment protocols. Journal of Epidemiol Rec. 1995;70(38):269–275.
Chronic Fatigue Syndrome. 2006;11(1):7–97. 87. Smith DS. Leprosy overview. eMedicine Infectious Diseases.
74. Reeves WC, Lloyd A, Vernon SD, et al. Identification of http://emedicine.medscape.com/article/220455-overview.
ambiguities in the 1994 chronic fatigue syndrome research 88. Singh N, Manucha V, Bhattacharya SN, Arora VK, Bhatia A.
case definition and recommendations for resolution. BMC Pitfalls in the cytological classification of borderline leprosy
Health Serv Res. 2006;3(1):25. in the Ridley-Jopling scale. Diagn Cytopathol. 2004;30(6):
75. Jason LA, Corradi K, Torres-Harding S, Taylor RR, King C. 386–388.
Chronic fatigue syndrome: the need for subtypes. Neuropsychol 89. Ridley DS, Jopling WH. Classification of leprosy according
Rev. 2005;15(1):29–58. to immunity. A five-group system. Int J Lepr Other Mycobact
76. Whistler T, Unger ER, Nisenbaum R, Vernon SD. Dis 1996;34(3):255–273.
Integration of gene expression, clinical, and epidemiological 90. Modlin RL. Th1-Th2 paradigm: insights from leprosy. J Invest
data to characterize chronic fatigue syndrome. J Transl Med. Dermatol. 1994;102(6):828–832.
2006;1(1):10. 91. James WD, Berger TG. Andrews’ Diseases of the Skin: Clinical
77. Kennedy G, Abbot NC, Spence V, Underwood C, Belch JJ. Dermatology. Philadelphia: Saunders; 2006.
The specificity of the CDC-1994 criteria for chronic fatigue 92. Jardim MR, Antunes SL, Santos AR. Criteria for
syndrome: comparison of health status in three groups of diagnosis of pure neural leprosy. J Neurol. 2003;250(7):
patients who fulfill the criteria. Ann Epidemiol. 2004;14(2): 806–809.
95–100. 93. Mendiratta V, Khan A, Jain A. Primary neuritic leprosy: a
78. Whiting P, Bagnall AM, Sowden AJ, Cornell JE, Mulrow reappraisal at a tertiary care hospital. Indian J Lepr. 2006;
CD, Ramirez G. Interventions for the treatment and 78(3):261–267.
2560_Chapter 8_0089-0104.indd 104 3/16/2015 4:14:57 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 9
Associated With Nutritional
Deficiency
JOSEPH I. BOULLATA, PHARMD, RPH, BCNSP
“He that takes medicine and neglects diet wastes the skills of the physician.”
—ANCIENT CHINESE PROVERB
Objectives
• List the common presenting signs and symptoms of nutrition-related peripheral nerve injury.
• Describe the etiologies of alcohol-related neuropathy.
• Discuss the role of “balanced” nutrients in homeostasis.
• List and describe diagnostic neuropathic patterns related to common nutritional deficiencies.
• Explain the complex roles of vitamins and nutrients in peripheral nerve health.
Key Terms
• Macronutrient
• Mineral
• Neuropathies
• Nutrient
• Nutritional deficiency
• Vitamin
influence of nutritional deficiency always needs to be

Introduction considered.
The cells of the peripheral nervous system (PNS)
Localization of lesions in neurology is paramount to and central nervous system (CNS) require a steady
identification and management of disease. In clinical supply of nutrients to maintain optimal function. Sim-
practice, the primary site and cause of a peripheral ilarly, other tissues within the body require an assort-
neuropathy may not be easy to determine. Peripheral ment of nutrients for maintaining metabolic processes
nerve disorders may reflect damage to a neuronal at the cellular and molecular levels. Manifestations of
cell body, its axon, the myelin sheath, supporting tissue, nutrient deficits throughout the body continue to be
and the vascular supply. Nerve conduction studies characterized; the focus in this chapter is on currently
and specific neurological physical examinations can be recognized signs and symptoms associated with the
useful. Otherwise, the clinical presentation and past nervous system, their clinical cause, and their patho-
medical history provide the etiological clues. The logical description.
105
2560_Chapter 9_0105-0114.indd 105 3/16/2015 4:14:59 PM

Process CyanProcess
YellowProcess Black
common than appreciated and includes conditions of
Nutrients, Nutritional Status, and underweight, overweight, and obesity as well as specific
the Nervous System nutrient imbalances and altered states of metabolism.1
Patient-related factors, as elicited from clinical history,
Nutrients and Nutritional Status can indicate patients at risk for malnutrition. An
Human metabolism requires substrate materials that appreciation of the complex absorption and subsequent
cannot be synthesized by the body or are detected in disposition of each nutrient—requiring transporters
quantities insufficient to meet the body’s needs. These and enzymes that are each susceptible to the influence
essential substrates are the nutrients that are consumed of gene polymorphism and environmental exposures—
daily through a healthy diet. The nutrients have been provides an explanation for the many ways that deficits
reasonably well classified as either macronutrients or may occur short of a classic nutrient deficiency. Such
micronutrients. nutrient deficits can adversely influence clinical presen-
Macronutrients are required in gram quantities tations and patient outcomes (Table 9-1).
daily, whereas micronutrients are generally required
in milligram or microgram quantities. Macronutrients Nutrition and the Nervous System
include proteins, carbohydrates, fats, and water. The Central Nervous System
three carbon-based nutrients flow through common The brain depends on the delivery of glucose for energy
routes of intermediary metabolism and contribute to needs. A steady supply of amino acids is also necessary
the energy needs of the body, with most reactions
occurring in environments containing water. Besides
roles in energy metabolism, macronutrients play impor-
tant structural and transport roles within the body. The
Table 9-1 Patient-Related Factors Indicative
fundamental units of any protein are amino acids, of Malnutrition Risk
which are obtained daily via nutrient consumption. Mechanism for Risk Examples of Patient-Related Factors
Proteins serve a structural role in all cells of the body
and function as enzymes, hormones, and membrane Reduced food Impaired appetite, gastrointestinal
transporters. Individual amino acids and fatty acids consumption disease, traumatic neurological
disorders interfering with self-feeding,
have specific physiological roles at cellular targets.1
neuropsychiatric disorders, disease of
Although micronutrients do not provide calories soft or hard oral tissue, alcoholism,
toward energy needs, this group of nutrients, which pregnancy, anorexia and vomiting,
includes vitamins and minerals, is physiologically food hypersensitivity, adverse drug
important in regulating metabolism through roles as effects, and disease requiring a
coenzymes and cofactors, in free radical scavenging, in restricted diet
intracellular signaling, and in gene expression. If any Altered nutrient Absence of normal digestive secretions,
one of these compounds is lacking in the diet, bio- absorption intestinal hypermotility, reduction of
chemical alterations lead to changes in tissue or organ effective absorbing surface, impairment
structure or function that subsequently result in clinical of intrinsic mechanism of absorption,
manifestations known as deficiency diseases. Minerals and drugs preventing absorption
are further differentiated as macrominerals (i.e., elec- Altered utilization Impaired liver function, hypothyroidism,
trolytes) and microminerals (i.e., trace elements). It or storage neoplasm of the gastrointestinal tract,
is important to consider not only the amount of a and drug therapy or radiation
single micronutrient but also the balance among all Increased tissue Severe trauma, achlorhydria in the
required vitamins and minerals because of the signifi- destruction gastrointestinal tract, heavy metals, and
cant nutrient-nutrient interactions among them. Given other metabolic antagonists
the role of agricultural and industrial technology in the
Increased nutrient Lactation, burns, glycosuria and
food supply that provides dietary sources of the micro- excretion albuminuria, acute or chronic blood
nutrients, environmental science and environmental loss, and drug interaction/side effect
toxicology are becoming more tied in with nutritional
and clinical status.1 Increased nutrient Increased physical activity, periods of
requirements rapid growth, pregnancy and lactation,
An individual’s nutritional status is considered fever, hyperthyroidism, drug therapy,
optimal when nutrient requirements are balanced by poor status, homeless status, substance
nutrient intake, while maintaining a healthy body com- addiction, and unconventional dietary
position and function. Nutritional status is regularly habits
evaluated by health care providers to identify risk
factors for deficits and toxicities. Malnutrition (“poor From Boullata JI. Nutrients and associated substances. In: Loyd A, ed.
Remington: The Science and Practice of Pharmacy. 22nd ed.
nutritional status”) refers generally to nutrient intake Philadelphia: Pharmaceutical Press & Philadelphia College of
out of balance with nutrient requirements. It is more Pharmacy; 2012.
2560_Chapter 9_0105-0114.indd 106 3/16/2015 4:15:00 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 9 | Peripheral Neuropathy Associated With Nutritional Deficiency 107
for protein and neurotransmitter synthesis. Addition- numbness, paresthesia, pain, and dysesthesia. As a
ally, numerous fatty acids are required by myelin and result, tactile discrimination, vibration, and position
nonmyelin cell membranes to maintain neuronal and sense are diminished. Residual impact on pain and
supporting cell structure and associated function.2 temperature sensation may also occur. With a periph-
Notwithstanding influences on brain maturation eral neuropathy, patients complain of burning feet,
(e.g., neurogenesis) that may continue beyond early dysesthesia of the soles and palms, numbness, and
development, deficits of these nutrients may influence paresthesia. Patients may also report decreased distal
cognitive performance. Micronutrient deficits can also sensation to light touch, pinprick, and vibration. Cell
influence the CNS. In particular, cognitive function body lesions on the motor side can manifest as muscle
is known to be influenced by deficits in iodine, iron, weakness with wasting and possible diminution of
selenium, and possibly zinc.2 For example, zinc colocal- deep tendon reflexes. Dorsolateral myelopathy can
izes with the neurotransmitter glutamate in some manifest as difficulty walking with leg weakness and
glutamatergic neurons and may possibly act as a brisk knee reflexes in the presence of slow ankle reflexes.
neuromodulator.3 Except for absent ankle reflexes, patients rarely present
Peripheral Nervous System asymptomatically. Complaints with a myeloneuropathy
Peripheral nerves also require ongoing sources of include distal sensory neuropathy in combination with
energy and substrate for structural support and func- ataxia, brisk knee and slow ankle reflexes, and sphincter
tion. Much more is known about the influence of instability.
nutrient status on the PNS. Numerous nutritional Distal sensory and motor deficits are usually sym-
neuropathies and myeloneuropathies are recognized. metrical, which is often a result of axonal degeneration.
Appreciating a patient’s complete medical history can Neuronal damage implicates deficits of essential nutri-
be informative. For example, many familiar neuropa- ents and nutrients (e.g., antioxidants) that otherwise
thies attributed to chronic alcoholism are nutritional in protect neurons from injury. Initial effects on the
origin, especially as energy from ethanol displaces neuron affect the most distal aspect of the axon as
nutrient-dense food. An individual with a history of metabolic needs are interrupted. The process of “dying
malabsorption—whether functional (e.g., inflamma- back” (degeneration) toward the cell body can occur if
tory bowel disease) or anatomical (e.g., after bariatric the damage is not addressed in a timely fashion. This
surgery)—is likely to exhibit many nutrient deficits phenomenon may also explain why lower extremities
over time. Many of these manifest as neurological with their longer afferent fibers are the site of initial
complications.4–6 Although neurological manifesta- presentation compared with the upper extremities. A
tions of gastrointestinal disease often have a nutritional demyelinating lesion may be present secondary to
explanation, they sometimes may be independent.7,8 In axonal degeneration but could also be primary as the
less common situations, individuals with many inborn nutritive functions of the highly metabolic Schwann
errors of metabolism (e.g., abetalipoproteinemia) may cells are interrupted. The initial damage can occur to
present with neurological manifestations that can be the most metabolically active neurons (i.e., cochlea,
managed with nutritional treatment as well. It can be retina, dorsal root, distal axons). For example, the large
difficult to disentangle PNS from CNS effects because myelinated distal axons depend on active transport
they may manifest together in a patient with nutrient systems to maintain their functional and structural
deficits. integrity whereby deficits of substrate, including needs
for adenosine triphosphate (ATP) production, initiate
disruptions that manifest as neuropathy—“glove-and-
Neuropathy by Presentation stocking” symptoms.
Burning mouth syndrome is a neurosensory disorder
Clinical presentation depends on both the primary site that may include nutrient deficits (e.g., vitamin B12,
of the disorder and the most likely cause and can iron) in the differential diagnosis.8 Most complaints
include encephalopathy, myelopathy, optic neuropathy, involve the anterior tongue, hard palate, and lower
myopathy, and polyneuropathy. Patient presentations lip and may be accompanied by dysgeusia. The effect
may include cognitive dysfunction and gait abnormali- may be attributed to medications (e.g., angiotensin-
ties related to the CNS and deafness, blindness, and converting enzyme inhibitors) that cause a nutrient
sensory and motor deficits related to the PNS.2 deficit (e.g., zinc) leading to the oral symptoms.
Although the axon fiber type affected may vary, Visual impairment following optic neuropathy
nutritionally related peripheral neuropathy generally may have a nutritional etiology.10,11 Patients with optic
affects all cell bodies to a similar extent, resulting in a neuropathy complain of blurred vision, photophobia,
symmetrical presentation. Sensory or motor deficits decreased visual acuity, and possible changes in color
can be observed on clinical examination; however, most vision. Hearing impairment, although correlated with
known lesions secondary to nutrient deficiency affect peripheral neuropathy (e.g., in diabetes), has not yet
the sensory side. Sensory complaints include heaviness, been linked with any nutrient imbalance.12
2560_Chapter 9_0105-0114.indd 107 3/16/2015 4:15:00 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Neuropathies and myeloneuropathies in tropical proximal muscle weakness also accompanies protein-
settings described in numerous historical reports may calorie malnutrition.20 Aside from classic dermatologi-
have nutritional roots. Many individuals with weight cal manifestations, deficits of essential fatty acids may
loss and chronic fatigue from a poor diet associated result in peripheral neuropathy and abnormal visual
with economic sanctions in Cuba subsequently devel- function.21 Dietary deficiencies of specific amino acids
oped neurological symptoms that were at least partly have also been implicated in optic neuropathy.11 Any
attributable to nutrient deficits.13 Originating as an additive or synergistic role played by micronutrients in
optic neuropathy with progressive bilateral loss of these presentations remains unclear.
visual acuity, sensorineural deafness and myeloneu-
ropathy were eventually observed as well.14 This neu- Vitamins
ropathy is also reported in other tropical regions15 Retinol (Vitamin A)
Deficits of several of the so-called B vitamins, particu- A patient may develop vitamin A deficiency as a result
larly cyanocobalamin (vitamin B12), along with deficits of reduced intake, malabsorption, or a metabolic defect
of sulfur-containing amino acids (e.g., methionine), such as abetalipoproteinemia. Because this nutrient
minerals (e.g., selenium), and carotenoids (e.g., lyco- is required for the synthesis of glycoproteins in the
pene) seemed to be the major factors in this epidemic cornea and conjunctiva and the aldehyde form is
neuropathy.14,16,17 needed to produce rhodopsin for phototransduction,
There is complexity in the etiology of malnutrition- patients present with corneal and conjunctival xerosis,
related epidemics.16 For example, an interaction be- retinopathy, and night blindness.22 A functional reti-
tween a host’s nutrient deficiency and a symbiotic viral noid cycle is required at the rod and cone cells in the
genome causes conversion to greater virulence and retina, which serve as the peripheral receptors for
associated neuropathy.17 Peripheral neuropathy attrib- vision. Night blindness occurs early and responds well
uted to chronic alcoholism is due partly to direct neu- to repletion in the presence of adequate protein and
rotoxicity of ethanol, but some features are also due to zinc status.
the associated nutrient (e.g., thiamine) deficits in Given multiple sources of vitamin A, such as dietary
patients with poor nutritional status.18 It can be diffi- supplements, total intake may exceed the recommended
cult to attribute a clinical finding to the deficiency of dietary allowance (i.e., 700 mcg for women, 900 mcg
a single nutrient because multiple nutrient deficits may daily for men). It is important to note total intake of
be concurrent. Clinical heterogeneity in presentation vitamin A because vitamin A toxicity can also manifest
may also be the result of genetic variability in nutrient- neurologically. Signs and symptoms include insomnia,
associated pathways or accompanying etiologies. irritability, headache with increased intracranial pres-
The following sections describe reports of specific sure, papilledema without focal neurological signs, and
nutrient deficits causing neuropathy and their patho- myalgias.
physiological mechanisms and potential for reversibil- Thiamine (Vitamin B1)
ity when known. Manifestations of most nutrient Thiamine has a coenzyme role in energy production
deficiencies affect multiple systems, and it is not the of all cells, including neurons, which is necessary for
intent of this chapter to provide a broad description of fuel oxidation and ATP production. Aside from energy
all signs and symptoms. production, thiamine is important to neuronal mem-
brane ion gating, axonal membrane transport, and
neurotransmitter synthesis.23 Given limited capacity
for body stores of thiamine, deficiency may develop
Neuropathy by Specific Nutrient within 2 weeks of poor dietary intake, reduced absorp-
tion, or increased needs. Clinically, thiamine deficiency
Macronutrients can affect the cardiovascular system, the CNS, and
When protein-calorie malnutrition is recognized in the PNS. Neurotoxicity associated with thiamine defi-
adults who are underweight or in children with stunted cits can begin to occur within days.23 Manifestations
growth, micronutrient deficiencies may be observed include a symmetrical, distal sensorimotor peripheral
as well. Altogether an individual is placed at risk for neuropathy, referred to as dry beriberi, which may or
morbidity and mortality. The influence on the nervous may not be accompanied by edema and congestive
system, which in some cases may take time to develop, heart failure (i.e., wet beriberi). Dry beriberi is more
is less often appreciated. Chronic malnutrition, as in often associated with a chronic marginal deficiency.
the setting of anorexia nervosa, has been associated Patients initially may complain of anorexia, headache,
with the development of peripheral neuropathy.19 lethargy, fatigue, and irritability. The neuropathy may
This condition appears to be a distal sensorimotor start with tingling and numbness at the toes before
disorder. Decreased amplitudes on sensory evoked progressing to burning/stabbing pain of the feet. This
potentials with less reduction in conduction veloci- neuropathy may cause an unsteady gait and can inter-
ties would suggest axonal degeneration. Nonspecific fere with sleep. Beriberi neuropathy is motor dominant,
2560_Chapter 9_0105-0114.indd 108 3/16/2015 4:15:00 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
18
influencing superficial and deep sensation. Patients and clinical presentations, it is difficult to discern the
complain of a burning sensation in the soles of the feet, specific effect of riboflavin deficits. Based on animal
calf muscle tenderness, muscle cramps, and general models, riboflavin deficiency manifests with demyelin-
muscular weakness with possible areflexia; loss of sen- ation and Schwann cell hypertrophy with initial sparing
sation, muscle weakness, and paralysis may occur in of the axons.30
upper extremities as well over time. Leg weakness and Niacin (Vitamin B3)
numbness are followed by the loss of the ankle jerk Niacin (nicotinic acid and nicotinamide) is essential for
reflex and footdrop. Glove-stocking hyperesthesia, and the proper functioning of several coenzymes. Defi-
surface anesthesia with deep skeletal muscle pain can ciency may develop in people who use corn as their
occur. main dietary carbohydrate and people with alcoholism
When manifesting as acute denervation (i.e., rapidly and malabsorption. Niacin deficiency may be second-
progressive weakness), beriberi can imitate Guillain- ary to other nutrient deficits (e.g., pyridoxine) and
Barré syndrome.24,25 Normal sensory-nerve (and motor- other disorders (e.g., Hartnup syndrome).2 Deficiency
nerve) conduction velocities coexist with reduced of niacin is characterized by dermatitis, diarrhea, and
compound sensory action potentials. Segmental demy- dementia. CNS deficits and lesions are well described,
elination can occur along with axonal degeneration, but but a peripheral neuropathy is also recognized, although
small myelinated and unmyelinated axons are pre- it is difficult to distinguish clearly from thiamine defi-
served.26 Axonal degeneration has been identified par- ciency.23 Patients may complain of burning sensations
ticularly with large myelinated fibers.27 This degeneration of the tongue and oral cavity. On neuropathological
includes disruption of neurotubules, neurofilaments, examination, chromatinolysis can be identified in
and myelin sheaths. Glutamate-mediated excitotoxic- niacin deficiency. It has been suggested that nicotin-
ity, decreased synaptic transmission, mitochondrial amide riboside may be a more specific substrate for
dysfunction, and apoptosis are possible mechanisms of peripheral neuron function.31
damage.23 The administration of nicotinamide initially at
Thiamine deficiency may also be present in the CNS 100 mg every 6 hours and then 25 to 50 mg once or
as Wernicke-Korsakoff syndrome, most commonly in twice daily encourages the reversal of diarrhea and
the setting of alcoholism. Numerous factors are likely dermatitis. Higher doses may be necessary for neuro-
to predispose to the development of this syndrome.23 logical impairment, and other B vitamins are often
Patients with Wernicke encephalopathy present acutely indicated as well.
with nystagmus, gaze palsies, gait ataxia, apathy, Pyridoxine (Vitamin B6)
disorientation, and confusion. Chronic manifestations Deficiency of pyridoxine has numerous manifestations,
include Korsakoff psychosis, amnesia, confusion, and including seizures and peripheral neuropathy. Sym-
dementia. Most of these patients also experience metrical distal neuropathy may progress to a sensory
peripheral neuropathy, which is a consequence of ataxia and limb weakness.2 Degeneration and regen-
ongoing thiamine deficiency. Generally, alcoholism eration of axons on both myelinated and unmyelinated
causes a chronic symmetrical sensory peripheral neu- fibers has been observed. Although biochemical abnor-
ropathy, whereas beriberi is associated with an acute malities are corrected with 25 mg of pyridoxine, the
form of neuropathy with weakness (distal greater than neuropathy is also reversible with oral replacement of
proximal), paresthesias, and neuropathic pain (burning the vitamin at doses of 50 to 100 mg daily.
discomfort with ache, occasional sharp pains). There may be an etiological role of pyridoxine
The administration of 100 mg of thiamine intrave- overuse in chronic idiopathic axonal polyneuropathy.
nously, followed by daily oral supplementation, corrects Pyridoxine is considered to have a narrow therapeutic
the neuropathy and confusion, whereas ataxia and index in that larger doses (greater than 200 mg daily)
memory impairment may remain. Neuropathic recov- may precipitate a sensory neuropathy and ataxia in the
ery is better for motor than sensory findings.24 The absence of weakness.32 In a group of patients depen-
distal sensory (burning feet) neuropathy may also dent on parenteral nutrition, peripheral neuropathy
respond to several other B vitamins (e.g., niacin, folic was associated with elevated pyridoxine concentrations
acid, pantothenic acid), highlighting the interplay but not with any B-vitamin deficits.33 The mechanism
among many of the B vitamins and supporting the for neuronal degeneration as a result of excess pyridox-
caution to avoid large repletion doses of one B vitamin ine is unclear.
without the others. Biotin (Vitamin B7)
Riboflavin (Vitamin B2) Paresthesias of the extremities may accompany depres-
Riboflavin deficits have been associated with neuropa- sion and lethargy in individuals with biotin deficits.
thy, and repletion of this vitamin has been effective Biotin deficiency may decrease pyruvate carboxylase
in its treatment (28, 29). Deficiencies of B vitamins activity, allowing for lactic acid accumulation as a con-
generally result in an axonal polyneuropathy. Despite tributing factor. This condition is expected to be revers-
some commonalities between B-vitamin deficiency ible within 2 weeks of supplementation.
2560_Chapter 9_0105-0114.indd 109 3/16/2015 4:15:00 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Folic Acid (Vitamin B9) evoked potentials. Vitamin B12 deficits have been asso-
Deficiency of folic acid may occur within months of ciated with optic neuropathy and loss of visual acuity.10,39
the onset of malnutrition. This deficiency may be The myelopathy is referred to as “subacute combined
observed in patients with gastrointestinal disease or be degeneration.”
a result of drug effects such as ethanol. This nutrient is Subacute combined degeneration manifests as
important in one-carbon metabolism, as is vitamin B12, sensory ataxia, spasticity, and lower extremity weakness.
but less commonly causes neurological manifestations. It is due to posterior and lateral column degeneration
When present, deficits may be manifest as an affective in the spinal cord.37 As these manifestations become
disorder and mental status changes.23 However, periph- chronic, they can be quite disabling leading to an
eral neuropathy including subacute combined degen- unsteady gait from the loss of proprioception and pos-
eration and myelopathy is rarely observed.34 Optic tural sense. Leg weakness and stiffness become pro-
neuropathies leading to bilateral visual loss also have gressive as brisk knee reflexes and a positive Babinski
been attributed to folic acid deficiency in the absence sign are present. Without intervention, patients may
of alcohol abuse or other deficits of B vitamins.35 A develop ataxic paraplegia with spasticity and contrac-
hypothesized mechanism involves the accumulation of tures. Abnormal production of the neurotrophic factors
formic acid, normally cleared in the presence of ade- (e.g., epidermal growth factor) in vitamin B12 defi-
quate tetrahydrofolate, with subsequent mitochondrial ciency also contributes to neural damage.
impairment and neuronal damage. Pathology initially reveals separation of myelin
Cyanocobalamin (Vitamin B12) lamellae, vacuolization, and axonal damage in the
Deficits of vitamin B12 are often seen in elderly indi- dorsal columns of the upper spinal cord. Later, the
viduals, individuals with natural or iatrogenic gastric lesions are more scattered in a characteristic “honey-
achlorhydria, and individuals with malabsorption syn- comb” pattern. Spongy degeneration of the optic nerve
dromes. Given significant body stores of this nutrient, leads to the visual loss. Neuronal demyelination appears
the deficits may take at least 1 to 2 years to develop. in both the PNS and the CNS.
The metabolic conversion of methylmalonyl CoA to Although oral repletion with crystalline vitamin B12
succinyl CoA is impaired with deficiency, resulting in is considered appropriate in patients with adequate
reduced availability of activated methyl groups neces- absorptive area, parenteral dosing may be considered
sary for synthesis of myelin and neurotransmitters.2 initially for patients with severe symptoms or for
The brain, spinal cord, optic nerves, and peripheral patients with insufficient gastrointestinal surface area.
nerves all are affected by vitamin B12 deficiency. Vitamin The degree of reversibility with vitamin B12 repletion
B12 deficiency with neuropsychiatric findings may exist depends largely on the duration of deficits, and deficits
in the absence of anemia, macrocytosis, or markedly are less responsive after 1 year. Myeloneuropathy,
low serum cobalamin concentrations.36 Deficiency of exhibited as muscle weakness of less than 3 months’
this vitamin should be included in the differential diag- duration, is reversible a few weeks from the onset of
nosis of any patient with peripheral nerve and neuro- repletion. Paresthesias are more likely to respond to
psychiatric manifestations.37 cobalamin repletion than ataxia.37 Sensory deficits may
Neurological manifestations of vitamin B12 defi- take much longer. Repletion is more likely to improve
ciency include a myelopathy that may be accompanied impaired sense of touch, pain, and position than
by a neuropathy, paresthesias, optic neuropathy, and impaired vibration sense. Most patients have a residual
cognitive impairment.23 The neuropathy is character- abnormality of tibial somatosensory evoked potentials
ized by a spastic paraparesis, extensor plantar response, after treatment.37
and impaired perception of both vibration and posi- Pantothenic Acid (Vitamin B15)
tion. Patients complain of tingling, paresthesias, and Vitamin B15 is important in carbohydrate and fatty
pins-and-needles sensations in the feet, but it can also acid metabolism throughout the body—particularly
occur in the hands.38 Although some patients have within the nervous system. Deficits can result in numb-
axonal neuropathy and demyelination, this glove- ness and burning sensations of the feet that can be
stocking distribution may reflect dorsal column lesions reversed only by pantothenic acid regardless of other
more than alterations in peripheral nerves. Symptoms concurrent deficits.40 Peripheral nerve lesions can be
occur secondary to a decrease in the universal methyl accompanied by cramping of the legs and impaired
donor (S-adenosylmethionine). Particularly vulnerable motor coordination.
are the long tracts of white matter in the posterior and α-Tocopherol (Vitamin E)
lateral spinal columns that are responsible for conduct- Vitamin E represents a number of compounds: α-, β-,
ing vibration and position sense. Posterior spinal γ-, and δ-tocopherol (each of which can exist in various
columns are more adversely affected than lateral stereoisomers) and α-, β-, γ-, and δ-tocotrienol. Clini-
columns; anterior column involvement is rare. Nerve cally, the term vitamin E refers to the tocopherols with
conduction studies suggest a somatosensory and motor the biological activity of α-tocopherol. One function
axonopathy, with abnormalities also present on visual of vitamin E is to serve as an antioxidant to prevent
2560_Chapter 9_0105-0114.indd 110 3/16/2015 4:15:00 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
peroxidative damage to cell membranes. With a deficit require 6 months to 4 years of therapy. The most dra-
of vitamin E, membrane lipid peroxidation is more matic recovery occurs if the condition is diagnosed
likely, which may interfere with neuronal function.41 and treated early. Best results occur in patients with
Although the peripheral nerves contain more vitamin AVED, but larger daily doses may be necessary for
E than the brain, they still degenerate in the face of patients with abetaliporoteinemia.44,47 There may be
deficits.41 The neurological role of vitamin E was first only partial recovery of efferent nerve conduction after
recognized in deficient animals in the early years after vitamin E supplementation despite recovery of sensory
its discovery in the 1920s. More recently, neurological conduction.45
findings in humans have been attributed to deficiency Calciferol (Vitamin D)
of the vitamin, although it rarely manifests as an iso- Deficits of vitamin D are common because of reduced
lated neuropathy.23 These are most often secondary to sun exposure, minimal dietary intake, or malabsorp-
malabsorption or to genetic abnormalities in vitamin tion. Aside from bone-related consequences, vitamin D
E disposition rather than dietary insufficiency. deficits may cause a proximal myopathy of lower and
Vitamin E deficits may occur in patients with upper extremities and hyperesthesia unresponsive to
chronic malabsorption (e.g., cystic fibrosis, short opioid analgesics.48,49 The association between vitamin
bowel syndrome) or defects in vitamin E disposi- D deficits and multiple sclerosis requires further study.2
tion (e.g., hypolipoproteinemia or abetalipoprotein-
emia, α-tocopherol transport protein mutation). With
chronic malabsorption, vitamin E deficiency may take Electrolytes
years to emerge. A rare, autosomal recessive syndrome
produces vitamin E deficiency with neurological mani- Magnesium
festations (e.g., hyporeflexia, tremor, gait ataxia, loss Magnesium is an abundant intracellular mineral essen-
of proprioception and vibratory sensation) and has tial for regulation of numerous cellular functions. Neu-
been referred to as “ataxia with vitamin E deficiency” ronal injury is enhanced by magnesium deficiency.50
(AVED).42 AVED is characterized in young adults by This enhanced injury may occur partly as the result of
a progressive peripheral neuropathy of the large-caliber substance P release from C fibers after N-methyl-D-
myelinated axons of sensory neurons.43 Patients may aspartate receptor activation.51
present with areflexia, gait and limb ataxia, sensory
impairment, muscle weakness, amyotrophy, decreased
vibration sense, and bilateral Babinski sign.44 With Trace Elements
ongoing vitamin E deficiency, besides a loss of deep
tendon reflexes, truncal and limb ataxia, and reduced Copper
vibrational and positional sense, ophthalmoplegia and As a critical cofactor for many enzymes, copper defi-
muscle weakness can occur.41 On pathological exami- ciency affects physiological function in numerous
nation, damage is to large-fiber axons and dorsal root systems. A deficiency of copper is uncommon except
ganglia. Lipofuscin may accumulate in the Schwann in cases of malabsorption after gastric surgery (i.e.,
cell cytoplasm and in dorsal root sensory neurons.41 gastrectomy, bypass) or inadequate copper intake in the
Peripheral sensory nerves exhibit neuroaxonal dystro- presence of excess zinc intake with which it competes
phy (dystrophic degeneration with secondary demy- for absorption. Adverse neurological consequences of
elination).41 Motor neuron demyelination has been copper deficits influence both the CNS and the PNS.
reported in patients complaining of impaired sensa- The neuropathy attributed to copper deficiency in par-
tion in the feet and feeling unsteady when walking,45 ticular may reflect a relative deficiency compared with
but the usual presentation is of significantly reduced zinc excess and the combined effect on the stability of
sensory nerve action potentials without abnormali- the neuronal cell membrane.52 Peripheral neuropathy
ties in motor conduction. Sensory nerve conduction may precede anemia or pancytopenia often associated
studies reveal low-amplitude action potentials and with copper deficiency.52 Patients can present with a
limited delays in conduction velocities.43 Although myelopathy or a neuropathy that can mimic those
basophilic deposits throughout the muscle fiber may seen with vitamin B12 deficiency.53,54 Reduced mobility
play a role, muscle weakness may also be the result of and an unsteady spastic gait may be combined with
a denervation-reinnervation process with a variation sensory loss at the soles of the feet and vibration sensa-
of muscle fiber size.41 In vitamin E–deficient patients tion to the knees.53 A positive Romberg test may be
with peripheral neuropathy, α-tocopherol content in present indicating a proprioceptive lesion. Sensory
the sural nerve is significantly lower.46 The low levels symptoms may also occur in the hands.53 The sensory
and accompanying biochemical alterations appear to ataxia is caused by dysfunction in the dorsal column.23
precede histological degeneration. Footdrop may be present, and optic neuritis with
Reversibility of these lesions with oral or parenteral peripheral neuropathy has also been reported. Optic
vitamin E supplementation is not guaranteed and may neuropathy with diminished peripheral vision and
2560_Chapter 9_0105-0114.indd 111 3/16/2015 4:15:01 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
posterolateral myelopathy is a rare presentation in 4. Rapidly evolving thiamine deficiency characterized
patients with copper deficiency.54 A cessation of neu- by acute motor neuropathy may mimic which of the
rological deterioration is more likely to accompany following diseases?
copper repletion than an outright improvement in neu- a. Multiple sclerosis
rological symptoms.23 b. Guillain-Barré syndrome
In patients presenting with a peripheral nerve dis- c. Muscular dystrophy
order, the influence of nutrient deficits should be con- d. Parkinson’s disease
sidered. A thorough history and physical examination
5. WM’s memory loss, confabulation, and auditory
and appropriate diagnostic tests are valuable in identi-
hallucinations may be related to which of the
fying peripheral neuropathy associated with nutritional
following complications of alcoholism?
deficiency and in optimizing patient outcome.
a. Wernicke-Korsakoff syndrome
b. Elevated liver enzymes
c. Weight loss
CASE STUDY d. Osteoporosis
WM has chronic alcoholism. He resides alone in a
small apartment that does not have a kitchen. He
estimates his alcohol intake per day at 12 to 18 cans References
of beer. He is employed part-time as a dishwasher in
1. Boullata JI. Nutrients and associated substances. In: Loyd A,
an Asian restaurant. The owner of the restaurant allows ed. Remington: The Science and Practice of Pharmacy. 22nd ed.
her employees to take home leftover food; this is Philadelphia: Pharmaceutical Press & Philadelphia College of
primarily rice of some sort. WM often skips breakfast Pharmacy; 2012.
and lunch and eats the leftover rice as his dinner. 2. Román GC. Nutritional disorders of the nervous system. In:
Over a period of 1 month, WM’s supervisor at the Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds.
Modern Nutrition in Health and Disease. 10th ed. Philadelphia:
restaurant has become concerned about WM’s loss of Lippincott Williams & Wilkins; 2006:1362–1380.
memory, confabulation, and, on one occasion, an 3. Tóth K. Zinc in neurotransmission. Annu Rev Nutr. 2011;31:
auditory hallucination. She also noted that WM has 139–153.
been dragging his foot when walking. After many 4. Freeman HJ. Neurologic disorders in adult celiac disease. Can
unsuccessful attempts to have WM see his family J Gastroenterol. 2008;22:909–911.
5. Chang CG, Adams-Huet B, Provost DA. Acute post-gastric
physician, she eventually drove him to the hospital. reduction surgery (APGARS) neuropathy. Obes Surg. 2004;
On examination, the physician suspected thiamine 14:182–189.
deficiency, which was corroborated with a blood test. 6. Juhasz-Pocsine K, Rudnicki SA, Archer RL, Harik SI.
Intravenous thiamine was ordered followed by daily Neurologic complications of gastric bypass surgery for morbid
oral dosages. obesity. Neurology. 2007;68:1843–1850.
7. Ghezzi A, Zaffaroni M. Neurologic manifestations of
gastrointestinal disorders, with particular reference to the
Case Study Questions differential diagnosis of multiple sclerosis. Neurol Sci. 2001;22:
S117–122.
1. Thiamine deficiency is also known as which of the 8. Vaknin A, Eliakim R, Ackerman Z, Steiner I. Neurological
following? abnormalities associated with celiac disease. J Neurol. 2004;
251:1393–1397.
a. Beriberi 9. Brown RS, Farquharson AA, Sam FE, Reid E. A
b. Scurvy retrospective evaluation of 56 patients with oral burning and
c. Rhabdomyolysis limited clinical findings. Gen Dentist. 2006;Jul-Aug:267–271.
d. Dysphagia 10. Stambolian D, Behrens M. Optic neuropathy associated with
vitamin B12 deficiency. Am J Ophthalmol. 1977;83:465–468.
2. Common symptoms of thiamine deficiency include all 11. Sadun AA. Metabolic optic neuropathies. Semin Ophthalmol.
of the following except: 2002;17:29–32.
a. Insomnia owing to foot pain 12. Bainbridge KE, Hoffman HJ, Cowie CC. Risk factors for
hearing impairment among U.S. adults with diabetes. Diabetes
b. Gait dysfunction Care. 2011;34:1540–1545.
c. Fatigue 13. Menéndez AR-O, Matos CM, Acosta SJ, et al. Evaluación
d. Skin rash del estado nutricional de enfermos con neuropatía epidémica
al año de evolución: indicadores bioquímicos. Rev Cuban Med
3. “Dry” thiamine deficiency involves primarily the Trop. 1998;50:254–258.
peripheral nerves. Symptoms of “wet” thiamine 14. Román GC. An epidemic in Cuba of optic neuropathy,
deficiency include which of the following? sensorineural deafness, peripheral sensory neuropathy and
a. Hair loss (alopecia) dorsolateral myeloneuropathy. J Neurol Sci. 1994;127:11–28.
15. Madhusudanan M, Menon MK, Ummer K, Radhakrishnanan
b. Loss of central vision K. Clinical and etiological profile of tropical ataxic
c. Peripheral edema and congestive heart failure neuropathy in Kerala, South India. Eur Neurol. 2008;60:
d. Constipation 21–26.
2560_Chapter 9_0105-0114.indd 112 3/16/2015 4:15:01 PM

Process CyanProcess
YellowProcess Black
16. Bowman BA, Bern C, Philen RM. Nothing’s simple about 36. Stabler SP, Allen RH, Savage DG, Lindenbaum J. Clinical
malnutrition: complexities raised by epidemic neuropathy in spectrum and diagnosis of cobalamin deficiency. Blood. 1990;
Cuba. Am J Clin Nutr. 1996;64:383–384. 76:871–881.
17. Beck MA, Levander OA, Handy J. Selenium deficiency and 37. Hemmer B, Glocker FX, Schumacher M, Deuschl G,
viral infection. J Nutr. 2003;133:1463S–1467S. Lücking CH. Subacute combined degeneration: clinical,
18. Koike H, Sobue G. Alcoholic neuropathy. Curr Opin Neurol. electrophysiological, and magnetic resonance imaging
2006;19:481–486. findings. J Neurol Neurosurg Psychiatry. 1998;65:822–827.
19. MacKenzie JR, LaBan MM, Sackeyfio AH. The prevalence 38. Healton EB, Savage DG, Brust JCM, et al. Neurologic
of peripheral neuropathy in patients with anorexia nervosa. aspects of cobalamin deficiency. Medicine. 1991;70:229–245.
Arch Phys Med Rehabil. 1989;70:827–830. 39. Moschos M. Optic neuropathy in vitamin B12 deficiency
20. Wade AN, Dolan JM, Cambor CL, Boullata JI, Rickels MR. (correspondence). Lancet. 1998; 352:146–147.
Fatal malnutrition 6 years after gastric bypass surgery. Arch 40. Glusman M. The syndrome of “burning feet” as a
Intern Med. 2010;170:993–995. manifestation of nutritional deficiency. Am J Med. 1947;3(2):
21. Uauy R, Dangour AD. Nutrition in brain development and 211–223.
aging: role of essential fatty acids. Nutr Rev. 2006;64: 41. Sokol RJ. Vitamin E and neurologic function in man. Free
S24–S33. Rad Biol Med. 1989;6:189–207.
22. Smith J, Steinemann TL. Vitamin A deficiency and the eye. 42. Traber MG. Vitamin E. In: Zempleni J, Rucker RB,
Int Ophthalmol Clin. 2000;40(4):83–91. McCormick DB, Suttie JW (eds). Handbook of Vitamins.
23. Kumar N. Neurologic presentations of nutritional deficiencies. 4th ed. Boca Raton, FL:CRC Press; 2007:153–174.
Neurol Clin. 2010;28:107–170. 43. Sokol RJ, Kayden HJ, Bettis DB, et al. Isolated vitamin E
24. Koike H, Misu K, Hattori N, et al. Postgastrectomy deficiency in the absence of fat malabsorption—familial and
polyneuropathy with thiamine deficiency. J Neurol Neurosurg sporadic cases: characterization and investigation of causes.
Psychiatry. 2001;71:357–362. J Lab Clin Med. 1988;111:548–559.
25. Murphy C, Bangash IH, Varma A. Dry beriberi mimicking 44. Benomar A, Yahyaoui M, Marzouki N, et al. Vitamin E
the Guillain-Barré syndrome. Pract Neurol. 2009;9:221–224. deficiency ataxia associated with adenoma. J Neurol Sci. 1999;
26. Kril JJ. Neuropathology of thiamine deficiency disorders. 162:97–101.
Metab Brain Dis. 1996;11:9–17. 45. Puri V, Chaudhry N, Tatke M, Prakash V. Isolated vitamin E
27. Koike H, Iijima M, Mori K, et al. Postgastrectomy deficiency with demyelinating neuropathy. Muscle Nerve.
polyneuropathy with thiamine deficiency is identical to 2005;32:230–235.
beriberi neuropathy. Nutrition. 2004;20:961–966. 46. Traber MG, Sokol RJ, Ringel SP, et al. Lack of tocopherol on
28. Osuntakun B, Aladetoyinbo A, Bademosi O. Vitamin B peripheral nerves of vitamin E-deficient patients with
nutrition in the Nigerian tropical ataxic neuropathy. J Neurol peripheral neuropathy. N Engl J Med. 1987;317:262–265.
Neurosurg Psychiatry. 1985;48:154–156. 47. Kayden HJ. The neurologic syndrome of vitamin E deficiency:
29. Mashima Y, Kigasawa K, Wakakura M, Oguchi Y. Do a significant cause of ataxia. Neurology. 1993;43:2167–2169.
idebenone and vitamin therapy shorten the time to achieve 48. Russell JA. Osteomalacic myopathy. Muscle Nerve. 1994;17:
visual recovery in Leber hereditary optic neuropathy? 578–580.
J Neuroophthal. 2000;20:166–170. 49. Gloth FM, Lindsay JM, Zelesnick LB, et al. Can vitamin D
30. Cai Z, Blumbergs PC, Finnie JW, Manavis J, Thompson PD. deficiency produce an unusual pain syndrome? Arch Intern
Selective vulnerability of peripheral nerves in avian riboflavin Med. 1991;151:1662–1664.
deficiency demyelinating polyneuropathy. Vet Pathol. 2009;46: 50. Oyanagi K, Kawakami E, Kikuchi-Horie K, et al. Magnesium
88–96. deficiency over generations in rats with special references to
31. Bogan KL, Brenner C. Nicotinic acid, nicotinamide, and the pathogenesis of the parkinsonism-dementia complex and
nicotinamide riboside: a molecular evaluation of NAD+ amyotrophic lateral sclerosis of Guam. Neuropathology. 2006;
precursor vitamins in human nutrition. Annu Rev Nutr. 2008; 26:115–128.
28:115–130. 51. Weglicki WB. Hypomagnesemia and inflammation: clinical
32. Parry GJ, Bredesen DE. Sensory neuropathy with low-dose and basic aspects. Annu Rev Nutr. 2012;32:4.1–4.17.
pyridoxine. Neurology. 1985;35:1466–1468. 52. Imataki O, Ohnishi H, Kitanaka A, et al. Pancytopenia
33. Mikalunas V, Fitzgerald K, Rubin H, McCarthy R, Craig complicated with peripheral neuropathy due to copper
RM. Abnormal vitamin levels in patients receiving home deficiency: clinical diagnostic review. Intern Med. 2008;47:
total parenteral nutrition. J Clin Gastroenterol. 2001;33: 2063–2065.
393–396. 53. Bertfield DL, Jumma O, Pitceathly RDS, Sussman JD.
34. Parry TE. Folate-responsive neuropathy. Presse Med. 1994;23: Copper deficiency: an unusual case of myelopathy with
131–137. neuropathy. Ann Clin Biochem. 2008;45:434–435.
35. Hsu CT, Miller NR, Wray ML. Optic neuropathy from folic 54. Pineles SL, Wilson CA, Balcer LJ, Slater R, Galetta SL.
acid deficiency without alcohol use. Ophthalmology. 2002;216: Combined optic neuropathy and myelopathy secondary to
65–67. copper deficiency. Surv Ophthalmol. 2010;55:386–392.
2560_Chapter 9_0105-0114.indd 113 3/16/2015 4:15:01 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
2560_Glossary_0347-0360.indd 360 3/17/2015 12:11:29 PM
Chapter 10
Peripheral Neuropathy and
Chronic Kidney Disease
SUSAN BRAY, MD
“Happiness is nothing more than good health and a bad memory.”

—ALBERT SCHWEITZER
Objectives
• Discuss renal physiology and the function of the kidneys.
• Define the possible etiologies and clinical characteristics of chronic kidney disease.
• Compare the various methods of dialysis.
• Describe the various peripheral neuropathies associated with chronic kidney disease.
Key Terms
• Capillary filtration coefficient
• Chronic kidney disease
• Glomerular filtration rate
• Hemodialysis
• Renal blood flow
erythematosus and scleroderma, glomerulonephritis,

Introduction renal calculi, and reflux nephropathy.2–4 Culturally,
African Americans, Hispanics, Pacific Islanders, Amer-
Following a brief overview of renal physiology and
ican Indians, and adults older than age 60 are at greater
chronic kidney disease (CKD), this chapter discusses
risk for the development of CKD compared with Cau-
the interaction between kidney disease and peripheral
casians and northern Asian groups.2,3
neuropathy. With increasing life expectancy and the
Presenting symptoms include anorexia, malaise,
increased prevalence of diabetes mellitus and hyperten-
pruritus, dry skin, and weight loss. Later symptoms
sion, CKD, also known as chronic renal failure, chronic
include drowsiness and confusion, changes in skin
renal insufficiency, and chronic kidney failure, now
pigmentation, excessive thirst, insomnia, edema, and
affects 26 million Americans.1
peripheral neuropathy.2,3 A wide variety of neuropa-
The primary function of the kidney is to remove
thies are associated with CKD because of the strong
metabolic waste products and excess water from the
correlation of diabetes and CKD and the large amount
body. In early stages of CKD, symptoms rarely occur.
of downstream corporal system impairment associated
Symptoms may not appear until kidney function is
with CKD.
less than one tenth of normal. The final stage of CKD
is called end-stage renal disease (ESRD). The two
most common causes of CKD are diabetes and uncon-
trolled high blood pressure. Less common etiologies Functions of the Kidney
include renal artery atherosclerotic disease, genetic dis-
eases such as polycystic kidney disease, drug interac- The kidneys serve multiple functions. The first is to rid
tion, autoimmune disorders such as systemic lupus the body of waste materials and products that are either
115
2560_Chapter 10_0115-0124.indd 115 3/16/2015 4:13:16 PM

Process CyanProcess
YellowProcess Black
Box 10-1
kidneys are the only means for eliminating from the
body certain types of acids generated by metabolic
Functions of the Kidney processes such as sulfuric and phosphoric acid.
The quantity of red blood cells is an important
Excretion of metabolic waste products and foreign homeostatic element for cellular function. The kidneys
chemicals secrete erythropoietin, which stimulates the production
Gluconeogenesis of red blood cells. The stimulus for secretion is the
Regulation of acid-base balance relative oxygen content in the circulating blood. In
Regulation of water and electrolyte balances a healthy person, the kidneys have the sole responsibil-
Regulation of arterial blood pressure ity for erythropoietin secretion and regulation. In
Secretion, metabolism, and excretion of hormones
Regulation of body fluid osmolality and electrolyte
patients with severe CKD, anemia develops secondary
concentration to decreased erythropoietin production and secretion.
Vitamin D is an important adjunct to many chemi-
cal processes within the body. The kidneys produce the
active form of vitamin D, 1,25-dihydroxyvitamin D3
(calcitriol) by hydroxylating this vitamin at the number
ingested or produced by metabolism. A second func- “1” position. Calcitriol is essential for normal calcium
tion is to control the volume and composition of deposition in osteogenesis and for reabsorption by the
the body fluids. For water and virtually all electrolytes gastrointestinal tract.
in the body, balance between intake (secondary to The kidneys also assist with glucose synthesis from
oral or parenteral ingestion or metabolic production) amino acids and other precursors during prolonged
and output (secondary to excretion or metabolic con- fasting. This process is called gluconeogenesis. The
sumption) is maintained largely by the kidneys. The ability of the kidneys to add glucose to the bloodstream
regulatory function of the kidney allows cells to func- during fasting rivals that of the liver.
tion in an optimally stable metabolic environment CKD or acute kidney failure disrupts all these
(Box 10-1). homeostatic functions resulting in severe abnormalities
The kidneys are the primary means for the body to of fluid volume, electrolyte concentration, red blood
excrete metabolic wastes. These products include urea concentration, acid-base balance, calcitonin concentra-
(from the metabolism of amino acids), creatinine (from tion, and aberrant glucose levels during fasting. Inter-
muscle creatine), uric acid (from nucleic acids), the vention, such as hemodialysis, is an attempt to restore
end products of hemoglobin breakdown (bilirubin), these balances.
and metabolites of various hormones. The kidneys also
work to eliminate toxins that are either produced by
the body or ingested, such as pesticides, recreational Kidney Physiology
and prescribed drugs, and food additives.
For cells to function efficiently, water and electrolyte Urine formation begins with filtration of large amounts
homeostasis must be maintained. The kidneys match of fluid through the glomerular capillaries into Bow-
excretion to intake. If excretion is greater than intake, man’s capsule. Similar to most capillaries, the glomeru-
electrolyte concentrations decrease; if excretion is less lar capillaries are relatively impermeable to proteins, so
than intake, electrolyte concentrations increase. Elec- that the filtered fluid is essentially protein-free and
trolyte concentrations controlled by the kidney include devoid of cellular elements including blood products.
sodium, potassium, hydrogen, chloride, calcium, mag- Concentrations of the other constituents of the glo-
nesium, and phosphate. Failure to control electrolyte merular filtrate are similar to those of plasma.
concentrations affects many corporal systems. The glomerular filtration rate (GFR) is determined
The kidneys also play a dominant role in the long- by the balance of colloid osmotic forces and hydrostatic
term and short-term maintenance of arterial blood pressure acting across the capillary membrane. A key
pressure. Long-term control is accomplished by excret- determinant is also the capillary filtration coefficient
ing variable quantities of sodium and water. Short- (Kf ), the product of the permeability and filtering
term control is performed by the secretion of vasoactive surface areas of the capillaries.5 The high glomerular
factors or substances, such as renin, which either hydrostatic pressure and large Kf allow for a much
directly or indirectly assist with the excretion of vasoac- higher rate of filtration within the glomerular capillar-
tive products such as angiotensin II. Many blood ies than with other capillaries throughout the body.6 In
pressure–controlling medications exert their actions a typical adult, the GFR is about 125 mL/min or
directly on the kidney. 180 L/day.5 The fraction of the renal plasma flow that
Along with the lungs and various body fluid buffers, is filtered, known as the filtration fraction, averages
the kidneys contribute to regulation of acid-base about 20%5 indicating that on average about 20% of
balance by regulating the body fluid buffer stores. The plasma flowing through the kidney at a given time is
2560_Chapter 10_0115-0124.indd 116 3/16/2015 4:13:17 PM

Process CyanProcess
YellowProcess Black
Chapter 10 | Peripheral Neuropathy and Chronic Kidney Disease 117
filtered through the glomerular capillaries. The formula Table 10-1 Etiology of Chronic Kidney Disease
for filtration fraction is as follows:7
Filtration fraction = GFR/Renal plasma flow Etiology Number in the United States
Determinants of GFR that are most variable and Diabetes 197,037

subject to physiological control include the glomerular Hypertension 127,935
hydrostatic pressure and the glomerular capillary Glomerulonephritis 81,599
colloid osmotic pressure. Factors that may influence
Cystic kidney 24,828
these particular variables include activity of the sym-
pathetic nervous system, hormones and autacoids Urological disease 13,139
(vasoactive substances that are released by the kidneys All other 82,745
and act locally), and other feedback controls that are
Data from U.S. Department of Health and Human Services. National
particular to kidney function. Essentially all blood Kidney and Urologic Diseases Information Clearinghouse (NKUDIC).
vessels within the kidney have rich sympathetic and http://kidney.niddk.nih.gov/kudiseases/pubs/kustats/#2. Accessed
parasympathetic innervation. Sympathetic stimulation November 12, 2012.
may constrict the renal arterioles and decrease renal
blood flow, decreasing GFR. Hormones that constrict
afferent and efferent arterioles, such as norepinephrine percentile loss in GFR. The progressive inability of
and epinephrine released from the adrenal medulla, the kidney to filter plasma affects all corporal systems.
may also cause a reduction in GFR.3 Many disease processes may result in a comorbid-
The effectiveness of renal blood flow volume may ity of CKD: uncontrolled hypertension, urinary tract
also affect GFR. In an average 70-kg man, the com- obstruction, urinary tract infection, hereditary defects
bined blood flow through both kidneys averages of the kidneys, glomerular disorders, renal neoplasm,
1,100 mL/min, or about 20% of the cardiac output. diabetes mellitus, and systemic lupus erythematosus.
Because both kidneys combined constitute only about Chronic and persistent use or overuse of certain medi-
0.4% of total body weight, one can easily see that the cations such as nonsteroidal anti-inflammatory drugs
kidneys receive a disproportionate amount of blood and acetaminophen may result in CKD. There is also
flow compared with other organs or tissues. A small a relationship between aging and CKD. Age-related
percentage of this volume is used to nourish the kidney reduced GFR and the increased frequency of concur-
with oxygen, sugars, proteins, and fats, but the large rent diseases among elderly adults may lead to progres-
percentage of the volume is used for filtration.4 Renal sive diminished GFR. Age-related reduced GFR may
blood flow is determined by the pressure gradient lead to greater susceptibility to nephrotoxic side effects
across the renal vasculature (the calculated difference of certain medications.2–7
between renal vein and renal artery hydrostatic pres- As a result of the chronic and cumulative loss of
sure) divided by the total renal vascular resistance:5 nephrons, CKD is marked by the inability of the kidney
to remove metabolic waste products from the blood
Renal blood flow = (renal artery pressure − renal
adequately, to regulate fluid and electrolyte homeosta-
vein pressure)/total renal vascular resistance
sis, and to balance the pH of the extracellular fluids.
Normal kidney function is defined as a GFR of
100 mL/min.3 A diagnostic criterion for CKD is a
Chronic Kidney Disease chronically low GFR for at least 3 months’ duration.4
CKD, as indicated in Table 10-2, is classified
CKD is a huge health problem in the United States into five stages. The normal GFR is 100 mL/min
affecting 26 million people. In 2007 in the United (mL/min/1.73 m2).3 The GFR is determined by the
States, there were about 527,000 individuals with patient’s serum creatinine value and a prediction equa-
ESRD requiring dialysis or transplantation (Table tion.3 Many patients move through the early stages of
10-1). Americans receiving hemodialysis or peritoneal CKD unaware of the decline in renal function. In early
dialysis numbered 368,265 in 2007. The cost to treat CKD, functioning nephrons may compensate for the
Americans with CKD in 2007 was $35.32 billion. As damaged or nonfunctional nephrons. Loss of 80% of
the prevalence of diabetes and hypertension continue nephrons may occur without the patient becoming
to increase, the prevalence of CKD will also increase.1 symptomatic. With loss of greater than 90% of the
Any pathology that results in permanent loss of nephrons, the patient experiences multisystem signs
nephrons will result in CKD. The nephron is the and symptoms and requires dialysis or renal transplan-
functional unit of the kidney that filters water, waste, tation to sustain body viability (Table 10-3).7
electrolytes, acids, and bases and is also responsible A patient with ESRD is at risk for developing a
for selective reabsorption and excretion of ions. The wide spectrum of systemic impairments. Although
permanent loss of nephrons results in a correlative interventions such as dialysis may improve many of
2560_Chapter 10_0115-0124.indd 117 3/16/2015 4:13:17 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
these impairments, not all conditions are reversible.
Table 10-2 Stages of Chronic Kidney Disease
Patients with ESRD require lifelong medical interven-
Description GFR (mL/min/1.73 m2) tion to manage the accompanying symptoms.
CKD is associated with a high risk of cardiovascu-
Normal kidney function 125 lar disease (CVD), and the management of patients
At risk for development of CKD 91–124 with with CKD includes management of CVD as well,
CKD risk factors including active treatment of existing disease and risk
Stage 1: Kidney damage with normal ≥90 factor modification preventing hypertension, hyperlip-
or increase in kidney function idemia, congestive heart failure, and coronary artery
Stage 2: Kidney damage with mild 60–89 disease.6 Some of the medications used in this popula-
loss of kidney function tion include angiotensin-converting enzyme inhibitors,
angiotensin receptor blockers, statins, beta blockers,
Stage 3: Moderate loss of kidney 30–59
function
aspirin, nitrates, and niacin. The risk of death from
CVD is much higher than the risk of mandatory
Stage 4: Severe loss of kidney function 15–29 dialysis therapy. Traditional CVD risk factors, includ-
Stage 5: Kidney failure <15 ing hypertension, smoking history, diabetes, dyslipid-
emia, and older age, are very prevalent in patients with
CKD, Chronic kidney disease; GFR, glomerular filtration rate.
Data compiled from National Kidney Foundation. K/DOQI clinical CKD.7 These patients are more likely to have metabolic
practice guidelines for chronic kidney disease: evaluation, syndrome, defined as insulin resistance, dyslipidemia,
classification, and stratification. Am J Kidney Dis. 2002;39(2 Suppl elevated serum glucose, abdominal obesity, and hyper-
1):S1–266; Levey AS, Eckardt KU, Tsukamoto Y, et al. Definition and
classification of chronic kidney disease: a position statement from tension. Metabolic syndrome is an obvious contributor
Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. to CVD risk.5
2005;67:2089; Fraser CL, Arieff AI. Nervous system complications in Hemodialysis is the process by which plasma water
uremia. Ann Intern Med. 1988;109:143; and Foley RN, Murray AM,
Li S, et al. Chronic kidney disease and the risk for cardiovascular and chemical solutes are filtered from the patient’s
disease, renal replacement, and death in the United States Medicare blood as the blood passes through a semipermeable
population, 1998 to 1999. J Am Soc Nephrol. 2005;16:489. membrane. Blood is directed from the patient’s vascu-
lar access through tubing and a semipermeable mem-
brane. The semipermeable membrane is often referred
as an “artificial kidney” or dialyzer. Types of vascular
access to the patient’s blood are via an arteriovenous
fistula, arteriovenous graft, and temporary catheters
(Fig. 10-1). An arteriovenous fistula is created by anas-
Table 10-3 Systemic Signs and Symptoms of End-Stage tomosing an artery to a vein. An arteriovenous fistula
Renal Disease is the preferred method of access because of a much
lower risk of infection and clotting than the other
Corporal System Clinical Signs and Symptoms methods. An arteriovenous graft is created by “bridg-
ing” a peripheral artery and vein with a synthetic mate-
Gastrointestinal Nausea, vomiting, anorexia, diarrhea, rial. Synthetic material grafts have an increased risk of
constipation, abdominal pain, stomatitis
infection and clotting compared with fistulas. Large-
Cardiovascular Hypertension, arrhythmias, uremic bore catheters, placed in the femoral, subclavian, or
pericarditis, congestive heart failure, jugular veins, may be used for temporary or emergent
peripheral edema, shortness of breath access. Hemodialysis can be performed in outpatient,
Hematological Anemia of chronic disease, increased inpatient, or home settings.
bleeding tendencies, impaired leukocyte Common side effects of hemodialysis include hypo-
function tension, muscle cramping, bleeding from the access
Musculoskeletal Soft tissue calcifications, myositis site, and risk of local and systemic infection. Hypoten-
ossificans, bone pain, pathological sion and muscle cramping often occur as a result of
fractures, osteoporosis, joint pain, joint rapid changes in osmolality of the blood. Maintaining
effusion graft or fistula competency is another concern. Fre-
Respiratory Pulmonary edema, pneumonia, pleural quent assessment for a bruit and thrill in the dialysis
effusions, Kussmaul’s respiration access is mandatory, and prompt action must be under-
Integumentary Pruritus, dry skin, altered pigmentation, taken if the graft or fistula becomes occluded.8
pallor Peritoneal dialysis (PD) is a safe and effective alter-
native to hemodialysis therapy. Approximately 8% of
Neurological Peripheral neuropathy, headaches,
insomnia, altered level of consciousness, patients undergoing dialysis use PD as their method
weakness, asterixis, coma of choice. PD involves inserting approximately 2 L of
dialysis solution into the patient’s peritoneal cavity. The
2560_Chapter 10_0115-0124.indd 118 3/16/2015 4:13:17 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chronic Kidney Disease–

Induced Neuropathy
Arteriovenous Among the many goals of treatment of CKD is man-
fistula agement of one of the most severe complications,
neuropathy, which occurs in 65% of patients with
Vein
CKD.10 Uremic neuropathy has several forms, includ-
ing peripheral mononeuropathy, peripheral polyneu-
Artery ropathy, motor neuropathy, and encephalopathy.11
Encephalopathy is a change in mental status secondary
to the toxic state of uremia, found in untreated stage 5
CKD. Patients with early uremic encephalopathy may
present with fatigue or impaired memory or concen-
tration. As the severity of encephalopathy progresses,
hallucinations, disorientation, and coma may develop,
followed, if untreated, by death.12
With metabolic encephalopathy, electroencephalog-
raphy (EEG) often reveals generalized slowing and
bilateral spike and wave complexes even in the absence
of clinically obvious seizure activity. EEG measures of
Figure 10-1 An arteriovenous shunt, also known as an
sleep are also abnormal in patients with stage 5 CKD.
arteriovenous fistula, is a connection between an artery
Computed tomography scan or magnetic resonance
and a vein that permits blood to flow between the two
imaging (MRI) may show cerebral atrophy but do not
bypassing the capillary system. Fistulas can occur
reveal findings indicative of CKD specifically.12
congenitally, traumatically, or surgically. Surgical fistulas
Peripheral neuropathy secondary to CKD may
are often created to facilitate hemodialysis procedures. A
manifest as peripheral polyneuropathy, autonomic dys-
surgeon creates an arteriovenous fistula by connecting an
function, restless legs syndrome (RLS), and peripheral
artery directly to a vein, frequently in the forearm.
mononeuropathy.12–14 Neuropathic symptoms do not
Connecting the artery to the vein causes more blood to
typically occur unless the GFR is consistently less than
flow into the vein. As a result, the vein grows larger and
20 mL/min.13 Generally, the occurrence of neuropathy
stronger. The stronger walled vein facilitates the repeated
correlates with the severity of the kidney disease and
needle insertions required by ongoing hemodialysis.
not so much with the actual type or etiology of under-
lying kidney disease. However, there are diseases that
produce kidney damage and cause neuropathy, includ-
ing amyloidosis, diabetes mellitus, systemic lupus ery-
unique constituents of the dialysis solution coupled thematosus, polyarteritis nodosa, and end-stage liver
with the principles of osmosis and diffusion allow fluid failure.15 For this reason, the spectrum of neuropathies
and solute to pass from the patient’s blood into the occurring with CKD is quite extensive.
dialysis solution. Access to the peritoneum is via a Normally, kidneys, along with removal of the
catheter through the abdominal wall. Repeated inser- by-products of metabolism and respiration, filter and
tion and withdrawal of dialysis fluid allows for proper remove excess small proteins from the blood. With
metabolic exchange. Automated PD systems called advanced CKD, especially in patients receiving dialysis,
“cyclers” allow patients to perform PD at their conve- the concentration of one type of small protein called
nience. The most common complication of PD is peri- beta-2-microglobulin, increases in the blood. When
tonitis, or infection of the peritoneum. Peritonitis this increase occurs, beta-2-microglobulin molecules
results from contamination of the dialysis fluid or may join together, similar to the links of a chain,
access catheter. Rarer complications include hypergly- forming a few very large molecules from many smaller
cemia, abdominal pain, protein store losses, and hernia.9 ones. These large molecules can deposit onto and even-
Continuous renal replacement therapy (CRRT) is tually damage the surrounding tissues and cause great
the filtration of blood through a hollow semipermeable discomfort. This condition is called dialysis-related
membrane located outside the body. CRRT is used in amyloidosis (DRA).16
patients who are hemodynamically unstable. CRRT is DRA is common in patients, especially older adults,
a slow, continuous process. Patients with hemodynamic who have been on hemodialysis for more than 5
instability are patients with hypervolemia, hypovole- years.16 Older hemodialysis membranes do not effec-
mia, severe uremia, electrolyte imbalance, and acid- tively remove the large, complex beta-2-microglobulin
base imbalance.3 proteins from the bloodstream. Newer hemodialysis
2560_Chapter 10_0115-0124.indd 119 3/16/2015 4:13:17 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
membranes as well as PD remove beta-2-microglobu- may include transient nystagmus, miosis, impaired
lin more effectively but not enough to keep blood con- extraocular movement, and facial asymmetry.
centrations normal. As a result, blood levels remain Autonomic neuropathy (dysautonomia or auto-
elevated, and deposits form in bone, joints, and nomic dysfunction) is a common problem in patients
tendons.14 DRA may result in pain, stiffness, and with CKD.18 In patients with autonomic neuropathy,
chronic appendicular joint synovitis. Patients with clinical findings include abnormal tilt test, ortho-
DRA may also develop cysts in some of their bones, static hypotension, and abnormal heart and respira-
and these cysts may lead to pathological bone fractures. tory rates at rest and when challenged by exercise and
Amyloid deposits may cause tears in ligaments and are present in about 50% of patients with stage 5 CKD.19
tendons.14 Most patients with these problems can be Autonomic neuropathy may be a causal factor in the
helped by surgical intervention. From a neuropathy frequent hypotensive episodes seen during dialysis.19
viewpoint, the amyloid deposits on peripheral nerves Some tests that evaluate different aspects of this neu-
result in epineural fibrosis resulting in passive insuffi- ropathy include the Valsalva maneuver, which probes
ciency of the peripheral nerve. Peripheral nerves stretch the integrity of the low-pressure and high-pressure
to accommodate various axial and appendicular posi- baroreceptors in the cardiopulmonary circulation, the
tioning, and the fibrosis limits this extensibility. If afferent and efferent limbs of these pathways, and both
patients with CKD and amyloid neural deposits stretch sympathetic and parasympathetic function.18 It is a
beyond the capability of the peripheral nerve, the sup- useful test to detect the existence of autonomic neurop-
porting structures of the nerve are injured, an inflam- athy but not to identify the site of the abnormality. The
matory cascade develops, and more scarring is laid amyl nitrate inhalation test evaluates the low-pressure
down. Eventually, the fibrosis becomes so thickened baroreceptors and the resultant efferent sympathetic
the action potential cannot propagate resulting in outflow, which is the expected result when blood pres-
denervation. sure decreases.18 The cold pressor test reflects efferent
Approximately 50% of patients with DRA also sympathetic function in response to cold-induced vaso-
develop carpal tunnel syndrome, which results from the constriction.19 The most common autonomic defect in
unusual buildup of amyloid at the level of the wrists.13 patients undergoing dialysis is in the baroreceptor/
If detected before significant motor neuron loss, the afferent side of the autonomic loop.18,19 This particular
condition may be reversible with surgical release. No dysfunction minimizes the reflex increase in circulating
effective treatment exists for DRA, although a success- catecholamines that should increase when hypotension
ful kidney transplant may stop the disease from pro- occurs during hemodialysis.
gressing. However, DRA has caught the attention of Autonomic dysfunction can impair the ability to
dialysis engineers, who are attempting to develop new maintain systolic blood pressure after significant ultra-
dialysis membranes that can remove larger amounts of filtration because of an inability to increase systemic
beta-2-microglobulin from the blood.15 vascular resistance. The decrease in blood pressure
In addition to the compressive and traction neu- occurring secondary to a decrease in intravascular
ropathies caused by deposits of amyloid, distal mono- volume cannot be remediated, leading to orthostatic
neuropathies may occur in an extremity during and symptoms. There is as yet no effective therapy for auto-
after the construction of arteriovenous fistulas. The sur- nomic dysfunction in patients undergoing dialysis.
gical procedure itself or later trauma to the perifistular There are two possibly helpful drugs that improve
tissue may lead to a diminished loss of distal blood flow symptomatic orthostatic hypotension: midodrine, a
and ultimately tissue and nerve ischemia. Local weak- selective alpha-1-adrenergic agonist, and sertraline, a
ness, sensory loss, and positive Tinel sign at the site of central nervous system serotonin reuptake inhibitor.
ischemia are often present. The benefit may be due to an attenuation of sympa-
Common risk factors, along with CKD, for develop- thetic withdrawal.20
ment of distal sensory or motor neuropathy include Primary sensory dysfunction, along with the classic
diabetes, alcoholism, nonalcoholic liver disease, malig- symptoms of hypothesia and hyperthesia, may also
nancy, and HIV. The neuropathy is distal, symmetrical, manifest in a patient with CKD as RLS, burning foot
and mixed sensorimotor and is seen more commonly syndrome, or paradoxical heat sensation.21 RLS is a
in male patients. The symptoms, because of the long persistent, uncomfortable sensation in the lower
axons being more severely damaged, are worse in the extremities that is relieved only by movement of the
lower extremities. Sensory symptoms, such as paresthe- legs. The symptoms are much more bothersome at
sias, burning sensations, and pain, occur before the night and are quite common in end-stage renal failure
motor symptoms. Findings on physical examination (patients on long-term dialysis).22 Studies of patients
commonly include impaired vibratory perception and with RLS describe a decreased quality of life, and
absent deep tendon reflexes. Paradoxical heat sensation strong correlations exist with concomitant iron defi-
in the feet can be found in 40% of patients with CKD.17 ciency, smoking history, and duration of ESRD.23 RLS
Cranial nerve involvement is rare and when present can often be treated by correcting iron deficiency
2560_Chapter 10_0115-0124.indd 120 3/16/2015 4:13:18 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
22
or administering levodopa or dopamine agonists. been a widely held theory explaining the development
Burning foot syndrome involves severe pain and a of uremic polyneuropathy.3 The nature of the toxic sub-
burning sensation distally in the lower extremities. Its stances in uremia is not clearly defined. Myo-inositol,
presence may be associated with thiamine deficiency a precursor of phosphoinositide, is metabolized rapidly
(formerly common in dialysis patients).22 Paradoxical in neural membranes. It is elevated abnormally in
heat sensation, in which low-temperature stimuli above CKD, poorly eliminated by hemodialysis, but excreted
or below the noxious threshold trigger perceived sensa- by the renal cortex of successfully transplanted kidneys.
tions typically seen with high-temperature stimuli, is Substances of moderate molecular weight (i.e., 500
found in approximately 10% of patients with stage 5 to 2,000 daltons) can be toxic agents in uremia.
CKD. The perceived sensations may range from warmth Advanced glycosylated end products and parathyroid
to intense burning.23 hormone generally are recognized as major uremic
The pathophysiology of uremic neuropathy is not well toxins (Box 10-2).3–5
understood.12,13 The most sensitive test for detection of The clinical presentation of uremic polyneuropathy
neuropathy is the nerve conduction velocity test, which usually begins with lower extremity symptoms because
shows slowed sensory nerve conduction velocity. There
is also evidence of axonal degeneration and secondary
demyelination of peripheral nerves. These conditions
may be due to neurotoxic compounds of uremia, which
deplete energy supplies via inhibition of nerve fiber Box 10-2
enzymes necessary for maintenance of energy produc-
tion. The long axons degenerate earliest because they Uremic Toxins Possibly Associated With Uremic Neuropathy
have a greater metabolic load for the perikaryon to bear. 3-Carboxy-4-methyl-5-propyl-2-furanpropionic acid
The “dying back” of axons is more severe in the distal Advanced glycosylated end products
aspect of the neuron, possibly owing to metabolic failure Asymmetrical dimethylarginine
of the perikaryon. The axonal degeneration may initiate Beta-2-microglobulin
the process, and this then leads to secondary segmental Complement factor D
demyelination. CKD-associated polyneuropathy is a Creatinine
specific term referring to a generalized homogeneous Guanidines
process affecting many peripheral nerves, with the distal Hippuric acid
nerves usually being affected most prominently.11 Homocysteine
Interference with the axon membrane function Indoles
and inhibition of Na+/K+-activated ATPase by uremic Indoxyl sulfate
Medium-size to large molecules (500–2,000 daltons)
toxins has been theorized as a possible etiology for
Oxalate
CKD-induced neuropathy.12 Potassium (K+), often Oxidation products
elevated in uremia, may contribute to the development Parathyroid hormone
of neuropathy. Peripheral nerve dysfunction may be P-cresol polyamines
related to an interference with the nerve axon mem- Peptides (beta-endorphin, methionine-enkephalin,
brane function and inhibition of Na+/K+-activated beta-lipotropin, granulocyte inhibiting proteins I and II,
ATPase by toxic factors in uremic serum.13 Bolton and degranulation-inhibiting protein, adrenomedullin)
Young12 postulated that membrane dysfunction was Phosphorus
occurring at the perineurium, which functioned as a Protein-bound compounds
diffusion barrier between interstitial fluid and nerve, or Purines
within the endoneurium, which acted as a barrier Small water-soluble compounds
Urea
between blood and nerve. As a result, uremic toxins
may enter the endoneural space at either site and cause Data compiled from National Kidney Foundation. K/DOQI clinical
direct nerve damage and water and electrolyte shifts practice guidelines for chronic kidney disease: evaluation,
classification, and stratification. Am J Kidney Dis. 2002;39(2 Suppl
with expansion or retraction of the space. 1):S1–266; Levey AS, Eckardt KU, Tsukamoto Y, et al. Definition and
Other theories for the development of uremic neu- classification of chronic kidney disease: a position statement from
ropathy include thiamine deficiency; decreased trans- Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int.
2005;67:2089; Fraser CL, Arieff AI. Nervous system complications in
ketolase activity; and reduced concentrations of other uremia. Ann Intern Med. 1988;109:143; Foley RN, Murray AM, Li
compounds or enzymes necessary for proper nerve S, et al. Chronic kidney disease and the risk for cardiovascular
function, including decreased levels of biotin and zinc disease, renal replacement, and death in the United States Medicare
population, 1998 to 1999. J Am Soc Nephrol. 2005;16:489; Foley
and increased concentrations of phenols and myo- RN, Wang C, Collins AJ. Cardiovascular risk factor profiles and
inositol. Secondary hyperparathyroidism is also associ- kidney function stage in the US general population: the NHANES III
ated with the presence of polyneuropathy.13 study. Mayo Clin Proc. 2005;80:1270; and Shishehbor MH, Oliveira
LP, Lauer MS, et al. Emerging cardiovascular risk factors that account
In addition, the accumulation of uremic toxins of for a significant portion of attributable mortality risk in chronic kidney
medium molecular weight (“middle molecules”) has disease. Am J Cardiol. 2008;101:1741.
2560_Chapter 10_0115-0124.indd 121 3/16/2015 4:13:18 PM

Process CyanProcess
YellowProcess Black
the longer axons are affected earliest. Motor symptoms uremic neuropathy, is performed. After transplantation,
follow the onset of sensory symptoms. Patients typi- clinical recovery occurs over 3 to 6 months and may
cally present with slowly progressive sensory loss and continue over the next 2 years. Thorough adequate
dysesthesias such as numbness, burning sensation in thrice-weekly hemodialysis or daily peritoneal dialysis
feet, and mild gait abnormalities; this is followed by may halt the progression of neuropathy. Dialysis rarely
weakness in the legs and then in the hands. Typical results in significant and substantial clinical improve-
symptoms are insidious in onset and consist of a tin- ment. If neuropathy worsens despite dialysis, this may
gling and prickling sensation in the lower extremities. be an important indicator of insufficient dialysis. Some
Paresthesia is the most common and earliest symptom. studies indicate an improved prognosis in neuropathy
Additionally, increase in pain sensation is a prominent with daily or nightly hemodialysis compared with
symptom. Many patients experience RLS and muscle thrice-weekly sessions.25
cramping even if they are not yet experiencing neuro- Patients with painful neuropathy can benefit from
pathic symptoms. If patients remain untreated, sensory treatment with tricyclic antidepressants such as ami-
symptoms are followed by motor symptoms (weakness triptyline or with anticonvulsant medications such as
in lower extremities and muscle atrophy.) Later, the sodium valproate or gabapentin. These medications
symptoms progress to involve the upper extremities.12 may provide symptomatic or palliative relief from
Obtaining “clinical scripts” from the history fol- painful symptoms. Vitamin supplements including
lowed by a hypothesis-oriented physical evaluation is water-soluble B vitamins, pyridoxine, and methylco-
very important in helping to discern the type of neu- balamin have been shown to help improve neuropathic
ropathy with which the patient is presenting. Abnor- pain in CKD.26 Dietary restriction of potassium intake
malities in the physical examination are determined by may also be helpful in preventing progression of
the type of neuropathy. In patients with uremic axonal neuropathy.27
polyneuropathy, there may be wasting of the intrinsic
muscles of the feet and hands. Distal loss of sensation
to pinprick, light touch, vibration, cold, and proprio-
ception may occur as well. Reflexes become hypoactive
distally.
The most sensitive ways to detect neuropathy in
CASE STUDY
renal disease are electrophysiological studies (even in JG is a 24-year-old woman with a 5-year history of
clinically asymptomatic patients). Of these, the more chronic kidney disease secondary to chronic overuse of
commonly used is motor nerve conduction velocity, over-the-counter nonsteroidal anti-inflammatory drugs.
usually measured in the peroneal nerve. Slowing of the Past medical history is significant for chronic alcohol
motor nerve conduction velocity worsens with further abuse and breast cancer. For the past 2 years, she has
decline in renal function. Greater than 50% of patients received hemodialysis three times weekly at a local
have abnormal studies when the creatinine clearance dialysis center via a fistula located in her right forearm.
decreases to 10 mL/min.24 At this advanced stage of She presents to physical therapy with numbness in the
CKD, patients may also experience paradoxical heat palmar surface of both hands and complaints of
sensation.7 dropping objects. She has noted atrophy of the
Polyneuropathy of kidney disease needs to be dis- muscles at the bases of her thumbs. Complaints include
tinguished from other diseases of the peripheral nervous difficulty turning doorknobs and holding utensils when
system, including mononeuropathies and mononeu- she is cutting food. Sensory examination reveals a loss
ropathy multiplex. Mononeuropathy refers to focal of tactile sense over the palmar surface of her thumbs
involvement of a single nerve usually secondary to and first three fingers bilaterally. There is no overt
a local cause, including trauma, compression, or weakness via manual muscle testing. JG does not
entrapment. An example is carpal tunnel syndrome. complain of any lower extremity symptoms. JG has
Mononeuropathy multiplex refers to simultaneous or recently received a diagnosis of type 2 diabetes
sequential involvement of noncontiguous nerve trunks; mellitus.
this usually includes multiple nerve infarcts resulting
from a systemic vasculitis process affecting the vasa
nervorum.
The later development of motor symptoms can lead 1. Important laboratory values for the outpatient
to muscle atrophy, myoclonus, and, rarely, paralysis. therapist to review before initiating therapy include
Complete recovery of this stage of peripheral polyneu- which of the following?
ropathy is unlikely even with the initiation of dialysis a. Thiamine
therapy. Untreated, uremic polyneuropathy progresses b. Hemoglobin A1c
and becomes less likely to reverse even when kidney c. Parathyroid hormone
transplantation, the only treatment for later stage d. All of the above
2560_Chapter 10_0115-0124.indd 122 3/16/2015 4:13:18 PM

Process CyanProcess
YellowProcess Black
2. For this case study, what is the most important portion of attributable mortality risk in chronic kidney
adjunct diagnostic test to determine the severity of disease. Am J Cardiol. 2008;101:1741.
8. Murphy E, Byrne G. The role of the nurse in the
the neuropathy? management of acute kidney injury. Br J Nurs. 2010;36:
a. MRI of the brain 146–152.
b. MRI of the cervical spine 9. Prowant B. Peritoneal dialysis nursing. Nephr Nurs J. 2009:36;
c. Electroneuromyography of both upper extremities 197–227.
d. Tinel sign at the level of the median nerve 10. Krishnan AV, Kiernan MC. Uremic neuropathy: clinical
features and new pathophysiological insights. Muscle Nerve.
3. A key clinical script that may lead the therapist to 2007;35:273.
believe the symptoms are not the result of uremic 11. Makkar RK, Kochar DK. Somatosensory evoked potentials
(SSEPs): sensory nerve conduction velocity (SNCV) and
polyneuropathy is which of the following? motor nerve conduction velocity (MNCV) in chronic renal
a. Lack of lower extremity symptoms failure. Electromyogr Clin Neurophysiol. 1994;34:295.
b. No focal motor weakness via manual muscle test 12. Bolton CF, Young GB. Uremic neuropathy. In: Neurological
c. Symmetrical presentation of symptoms Complications of Renal Disease. Boston: Butterworth; 1990:
d. Loss of tactile sensation 76–107.
13. Bazzi C, Pagani C, Sorgato G, et al. Uremic polyneuropathy:
4. Common risk factors, along with the chronic kidney a clinical and electrophysiological study in 135 short- and
disease, for development of distal sensory/motor long-term hemodialyzed patients. Clin Nephrol. 1991;35:176.
14. Benson MD, Kincaid JC. The molecular biology and
neuropathy in this patient include which of the clinical features of amyloid neuropathy. Muscle Nerve. 2007;
following? 36:411.
a. Diabetes 15. Hafer-Macko C, Hsieh ST, Li CY, et al. Acute motor axonal
b. Alcoholism neuropathy: An antibody-mediated attack on axolemma. Ann
c. Malignancy Neurol. 1996;40:635.
16. Dyck PJ, Dyck JB, Grant IA, Fealey RD. Ten steps in
d. All of the above characterizing and diagnosing patients with peripheral
5. During the integument examination, the therapist neuropathy. Neurology. 1996;47:10.
17. England JD, Gronseth GS, Franklin G, et al. Practice
should inspect the fistula. “Red flags” include which parameter: evaluation of distal symmetric polyneuropathy:
of the following? role of autonomic testing, nerve biopsy, and skin biopsy
a. Tenderness (an evidence-based review). Report of the American
b. Lack of audible bruit Academy of Neurology, American Association of
c. Rubor Neuromuscular and Electrodiagnostic Medicine, and
American Academy of Physical Medicine and Rehabilitation.
d. All of the above Neurology. 2009; 72:177.
18. Ewing DJ, Winney R. Autonomic function in patients with
chronic renal failure on intermittent hemodialysis. Nephron.
1975;15:424.
References 19. Henrich WL. Autonomic insufficiency. Arch Intern Med.
1. U.S. Department of Health and Human Services. National 1982;142:339.
Kidney and Urologic Diseases Information Clearinghouse 20. Converse RL Jr, Jacobsen TN, Jost CM, et al. Paradoxical
(NKUDIC). http://kidney.niddk.nih.gov/kudiseases/pubs/ withdrawal of reflex vasoconstriction as a cause of
kustats/#2. Accessed November 12, 2012. hemodialysis-induced hypotension. J Clin Invest. 1992;
2. National Kidney Foundation. K/DOQI clinical practice 90:1657.
guidelines for chronic kidney disease: evaluation, 21. Kavanagh D, Siddiqui S, Geddes CC. Restless legs syndrome
classification, and stratification. Am J Kidney Dis. 2002; in patients on dialysis. Am J Kidney Dis. 2004;43:763.
39(2 Suppl 1):S1–266. 22. Unruh ML, Levey AS, D’Ambrosio C, et al. Restless legs
3. Levey AS, Eckardt KU, Tsukamoto Y, et al. Definition and symptoms among incident dialysis patients: association with
classification of chronic kidney disease: a position statement lower quality of life and shorter survival. Am J Kidney Dis.
from Kidney Disease: Improving Global Outcomes 2004;43:900.
(KDIGO). Kidney Int. 2005;67:2089. 23. Thorp ML. Restless legs syndrome. Int J Artif Organs. 2001;
4. Fraser CL, Arieff AI. Nervous system complications in 24:755.
uremia. Ann Intern Med. 1988;109:143. 24. Nardin R, Chapman KM, Raynor EM. Prevalence of ulnar
5. Foley RN, Murray AM, Li S, et al. Chronic kidney disease neuropathy in patients receiving hemodialysis. Arch Neurol.
and the risk for cardiovascular disease, renal replacement, and 2005;62:271.
death in the United States Medicare population, 1998 to 25. Rocco M, Lockridge R, Beck G, et al. The effects of frequent
1999. J Am Soc Nephrol. 2005;16:489. nocturnal home hemodialysis: the Frequent Hemodialysis
6. Foley RN, Wang C, Collins AJ. Cardiovascular risk factor Network Trial. Kidney Int. 2011;80:1080–1091.
profiles and kidney function stage in the US general 26. Guay DR. Update on gabapentin therapy of neuropathic
population: the NHANES III study. Mayo Clin Proc. 2005; pain. Consult Pharm. 2003;18:158–170.
80:1270. 27. Dheenan S, Venkatesan J, Grubb BP, Henrich WL. Effect of
7. Shishehbor MH, Oliveira LP, Lauer MS, et al. Emerging sertraline hydrochloride on dialysis hypotension. Am J Kidney
cardiovascular risk factors that account for a significant Dis. 1998;31:624.
2560_Chapter 10_0115-0124.indd 123 3/16/2015 4:13:18 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
2560_Glossary_0347-0360.indd 360 3/17/2015 12:11:29 PM
Chapter 11
Medication-Induced
Neuropathy
ROBERT B. RAFFA, PHD
“Awareness of the potential of medications to cause peripheral neuropathy is

key to preventing significant nerve damage in treated patients.”
—PELTIER AND RUSSELL
Objectives
• Understand the common classes of medications that can induce neuropathy and the major
pathophysiological mechanisms that are likely involved.
Key Terms
• Apoptosis
• Demyelination
• Paresthesia
• Peripheral neuropathy
Introduction neuropathy coincides with the onset of medication

use, stabilization or improvement of neuropathy when
There are about 100 known causes of neuropathy.1 the drug is temporarily discontinued, and neuropa-
Medication-induced neuropathy accounts for about thy resumes when medication is resumed), biological
4% of outpatient neurology cases.2 A representative list plausibility, absence of likely alternative explanations,
of drugs that can have neurotoxic effects is provided in and analogy (similar adverse effects occur with similar
Table 11-1.3 This chapter concentrates on chemother- medications).56
apeutic agents (platinum drugs, taxanes, vinca alka- The underlying neuropathology typically involves
loids, thalidomide, bortezomib, suramin), leflunomide, three main processes that damage or destroy nerves:
statins, highly active antiretroviral therapy (HAART), axonal degeneration, segmental demyelination, and
antitumor necrosis factor alpha (anti-TNFα) drugs, neuronopathy.1 Medication-induced neuropathies often
and amiodarone. involve axonal degeneration, but any or all processes can
occur concurrently.57 Symptoms can give insight into
the type of nerve damage causing the neuropathy.58
Mechanisms of Medication- Spinal cord neurons are generally protected by the
blood-brain barrier, whereas sensory, autonomic, and
Induced Neuropathy peripheral neurons are more vulnerable.3 The latter
are supplied by capillaries with fenestrated walls,
Neuropathy may be considered medication induced allowing relatively free exchange of small molecules
if it meets generally established criteria for associa- with the circulatory system and extracellular fluid
tions, such as a temporal association (the onset of within ganglia.22 Medications can interfere with axonal
125
2560_Chapter 11_0125-0134.indd 125 3/16/2015 4:13:20 PM

Process CyanProcess
YellowProcess Black
Table 11-1 Selected Drugs Associated With Medication-Induced Neuropathy

Drug Rate of Occurrence Comments
Amiodarone 3%–30%4–6 Duration of treatment affects neurotoxicity7
8 9–17
Bortezomib 12% or 31%–45% Dose dependent13,18
Carboplatin 4%–6%19 >400 mg/m2 dose20
Cisplatin 12%–60% at conventional doses3,19,21,22 90% of patients who receive cumulative
and 70%–100% at higher doses doses of >300 mg/m2 experience
(>540 mg/m2)3 peripheral neuropathy23,24
Docetaxol 17.9%25 >600 mg/m2 dose26,27
Highly active antiretroviral 36%–48%28 overall, 9% severe29 HIV can cause neuropathy so rates are
therapy (HAART) unclear; advanced age is associated with
higher rates of neuropathy28
Leflunomide 1%–10%,30–32 but one study showed 54%33 Unclear if dose dependent
Oxaliplatin—acute neuropathy 60%–98%22,34–37 Occurs at onset of therapy; no cumulative
effect
Oxaliplatin—chronic ~50%19 ≥540–800 mg/m2 dose20,38,39
neuropathy
Paclitaxel 4%–20%22,40,41 >175–200 mg/m2 dose20,42; >175 mg/m2
any single dose43
Suramin 30%–55%44,45 Dose dependent46
Thalidomide 20%–50%22,47 >20 g dose48; appears to be cumulative
and dose dependent49,50
Vincristine 10.5%51 >4 mg/m2 dose20
Vinflunine <10%–12% 52,53
Dose dependent, reversible53
Zalcitabine 30%–60%55
transport (disrupting cell processes) or can damage the The antineoplastic effect of platinum drugs includes
axon and the myelin sheath (Schwann cells). Antican- their effect on tumor vasculature.61 Platinum com-
cer agents that interfere with the increased mitochon- pounds also bind avidly to plasma proteins20 and neu-
drial activity that is typical of cancer cells likewise can ronal DNA.62,63 The number of DNA cross-links in the
interfere with mitochondrial activity of neurons and neurons of the dorsal root ganglia (DRG) has been
may lead to neuronopathy or death of the nerve cell.22 associated with the drug’s degree of neurotoxicity.64
Ganglionopathy occurs when ganglia are damaged or The resulting DNA repair arrests cell division.65 The
die and results in sensory or autonomic symptoms.59 platinum concentration in peripheral nervous tissue is
similar to that in tumor tissue in patients treated with
Chemotherapeutic Agents platinum agents.66
Although chemotherapy-induced peripheral neurop-
athy can give rise to several commonly used antineo- Taxanes
plastic agents, the pathophysiology of nerve damage is Taxane drugs, including paclitaxel and docetaxel, are
related to drug class. The resulting symptoms may associated with dose-dependent drug-induced neu-
be sensory, motor, or autonomic and may be dose ropathy.20 Taxanes disrupt microtubular dynamics and
limiting.60 polymerization within cells, and interrupted axonal
transport may be involved in taxane-induced neuropa-
Platinum Drugs thy.3 Taxanes appear to have a direct effect on Schwann
Three major platinum chemotherapeutic agents are cells, cause axonal loss, and disturb the cytoplasmic
cisplatin, carboplatin, and oxaliplatin.19 Platinum- flow in the affected neurons.67,68
induced neuropathies are common, are cumulative, In a randomized clinical trial comparing pacli-
and may involve “coasting” (neuropathic symptoms taxel with a control group (single-agent gemcitabine
persist in the initial weeks and months after drug or vinorelbine) in chemotherapy-naïve patients, neu-
discontinuation).19 ropathy occurred significantly more often in patients
2560_Chapter 11_0125-0134.indd 126 3/16/2015 4:13:21 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 11 | Medication-Induced Neuropathy 127
receiving paclitaxel than control subjects (30% vs. 5%, ropathy remain unclear, but an accumulation of the
P < 0.001).40 Although paclitaxel is associated with agent in DRG cells has been observed.12 Metabolic
more severe forms of medication-induced neuropathy changes caused by bortezomib accumulation in the
than docetaxel,69 severe docetaxel-induced neuropathy DRG and mitochondrial-mediated dysregulation of
has also been reported.70 Ca2+ homeostasis and disruption of neurotrophins
Risk factors for taxane-induced neuropathy include have been implicated as mechanisms of bortezomib-
cumulative dose, high single doses, rapid infusion induced neuropathy.11 It may also cause demyelin-
times, previous or simultaneous administration of other ation.11 Because certain neuropathies persist or develop
chemotherapeutic agents,20 and a large number of che- after bortezomib is discontinued, it has been suggested
motherapy cycles.71 that immune-mediated mechanisms may also play
a role.84
Vinca Alkaloids Preexisting neuropathy has been reported to be a
Vinca alkaloids inhibit the assembly of microtu- risk factor for the development of a more severe
bules and promote their disassembly, which interferes bortezomib-induced neuropathy.85 Other risk factors
with cytoskeletal axonal transport within the cell.22,72 for bortezomib-induced neuropathy are cumulative
By inhibiting tubulin polymerization into microtu- dose,16 no concurrent dexamethasone administration,
bules, vinca alkaloids destabilize the mitotic spindle.18 male sex,71 lack of neurological monitoring,86 and
Microscopy of sensory neurons reveals cytoskeletal prior use of thalidomide12,87 or vincristine.86 Advancing
structural changes in the large sensory neurons and age is likely a risk factor with a suggested 6% increase
myelinated axons as well as an accumulation of neuro- in risk for every year of age.88 Diabetes has been
filaments in sensory DRG.73 Vinflunine, a newer vinca explored as a potential risk factor with conflicting
alkaloid drug, has less affinity for tubulin-binding sites results.13,87
and appears to be less neurotoxic than vincristine.74
Suramin
Thalidomide Suramin is an experimental antineoplastic agent89 and
Despite its association with birth defects, thalidomide reverse transcriptase inhibitor90 used in chemothera-
has reemerged as an approved drug for certain cancers.47 peutic applications.91 Suramin-induced neuropathy has
Thalidomide is thought to modulate cytokines, par- been described as an axonal neuropathy with acute
ticularly by decreasing the production of TNFα in Guillain-Barré–type symptoms, elevated cerebrospinal
monocytes and macrophages and by increasing the fluid protein levels, and variable response to plasma
elimination of TNFα messenger RNA, which leads exchange.44,45,92 Rats administered suramin develop
to a decrease in the signaling that induces TNFα axonal degeneration and lysosomal inclusion bodies
production.75,76 Thalidomide also possesses antiangio- in the DRG and Schwann cells, but demyelination
genic properties, which appear to function indepen- is rare.46
dently of its TNFα-inhibiting effects.47 Suramin has numerous cellular effects. It inhibits
Thalidomide-induced neuropathy is possibly related enzyme function, blocks mitogenic growth factors,93
to neurotrophin dysregulation, leading to inhibition blocks nerve growth factor (NGF) binding,94 and acti-
of nuclear factor-κβ, which sensory neurons need vates and induces phosphorylation and downstream
to survive.77,78 Multiple mechanisms may be involved signaling of the NGF receptor.95–97 Based on results
because of the observed “glove-and-stocking” effect using animal tissue cultures, the mechanism underlying
(sensory neuropathy in the hands and feet, distributed suramin-induced neuropathy may involve glycolipid
in a pattern similar to gloves and stockings), suggesting imbalance, which would lead to neuronal degradation
axonal degeneration79 and poor recovery rates (suggest- and subsequent cell death.46
ing permanent damage to the DRG).80
Thalidomide neurotoxicity appears to be dose Leflunomide
dependent and cumulative,48,50,80 and it has been Leflunomide is a disease-modifying drug used
recommended that therapy be restricted to courses in the treatment of rheumatoid arthritis. Leflu-
less than 6 months81 under careful neurological nomide is the prodrug of the active metabolite
monitoring.82 A77 1726 [N-(4-Trifluoromethylphenyl)-2-cyano-3-
hydroxycrotonamide], which has immunosuppressive
Bortezomib effects. New and exacerbated peripheral neuropathy,
Bortezomib, a proteasome inhibitor and boronic acid including paresthesia, has been reported with leflu-
dipeptide, is a newer agent used in the treatment of nomide use31,98–101 but is relatively rare30,31,33 and may
multiple myeloma.9 Bortezomib is thought to treat be reversible.102
cancer by inducing apoptosis, arresting tumor growth, It has been suggested that the mechanism underly-
and reversing chemoresistance in myeloma cells.83 ing leflunomide-induced neuropathy involves a neu-
The mechanisms underlying bortezomib-induced neurological vasculitis affecting the peripheral nervous
2560_Chapter 11_0125-0134.indd 127 3/16/2015 4:13:21 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
system.99 Vasculitis may be triggered by a leflunomide- caused by HIV.114 These drugs appear to be toxic to
induced immune system response. Nerve biopsy speci- mitochondria.115
mens from three patients receiving leflunomide revealed The mechanisms underlying HAART-induced
epineurial perivascular inflammation around the large neuropathy are unclear, but viral infections may
and small myelinated nerve fibers, suggesting a type of alter peripheral nerve antigens, which may result in
axonopathy with features of vasculitis.31 Electrophysi- a form of autoimmune response.116 The presence of
ological study results from 37 patients with leflunomide- antiviral and autoantibodies could promote immuno-
induced neuropathy were consistent with distal axonal, logical cross reaction. NRTIs are phosphorylated by
sensory, or sensorimotor polyneuropathies.102 thymidine kinase isoforms, allowing them to compete
Risk factors for the development of leflunomide- with the substrates for HIV reverse transcriptase,
induced neuropathy include advanced age, diabetes, which terminates DNA chains.114,117 NRTIs also selec-
and the concurrent use of other neurotoxic agents.32 tively affect γ-DNA polymerase, decreasing mitochon-
drial DNA replication. Zalcitabine, didanosine, and
Statins stavudine preferentially affect axons and Schwann cells,
whereas zidovudine affects the mitochondria of skel-
Statins are taken by millions of people around the
etal muscles.118
world to reduce serum cholesterol.103 Statins interfere
Increased longevity conferred by HAART119,120
with cholesterol synthesis by inhibiting two distinct
makes neurological adverse events increasingly impor-
processes: HMG CoA (3-hydroxy-3-methylglutaryl
tant to address, particularly those that might occur
coenzyme A) reductase and ubiquinone (a mitochon-
with prolonged use of HAART drugs.121 Risk factors
drial respiratory chain enzyme).104,105 Although stains
for HAART-induced neuropathy include advanced
are generally well tolerated, these inhibitory effects
age.122
have been suggested to disrupt the energy use patterns
of neurons, leading to neuropathic symptoms in some
patients.104 Anti–Tumor Necrosis Factor Alpha Drugs
Statin drugs have been extensively studied in numer- TNFα is an immune-regulatory cytokine with pro-
ous landmark clinical trials, none of which found evi- inflammatory properties. Infliximab, etanercept, and
dence of statin-induced neuropathy.106 However, an adalimumab are TNFα antagonists that are used for
epidemiological 5-year study found the odds ratio treating rheumatoid arthritis and other conditions.
linking idiopathic polyneuropathy with statin use to These agents launch a T-cell and immune system
be 3.7 (95% confidence interval, 1.8 to 7.6) for all cases attack on peripheral nerve myelin, provoke a vasculitis-
and 14.2 (95% confidence interval, 5.3 to 38.0) for induced ischemia, and inhibit axonal signaling sys-
patients with a diagnosis of “definite” rather than “prob- tems.123 Anti-TNFα therapy may be associated with
able” or “possible” polyneuropathy.104 Other reports in an immune-modulated form of neuropathy, although
the literature link long-term statin use to neuropathic the mechanism is unclear.18 Anti-TNFα drugs may not
symptoms.107–112 In contrast, in a cross-sectional arm have a class effect in terms of neuropathy, in that adali-
of the Fremantle Diabetes Study (n = 531), patients mumab has no clear association with neuropathy.58
treated with statins had a significantly decreased risk Infliximab-induced neuropathy appears to be either
of diabetic neuropathy.113 The possible neuroprotective an axonal sensory polyneuropathy or a multifocal motor
mechanisms behind this finding remain to be eluci- neuropathy.124 Discontinuation of the TNFα blocker is
dated. Although statins may confer neuroprotective not necessarily required for symptom resolution.125
benefits to diabetic patients, this does not rule out
the simultaneous existence of a statin-induced form Amiodarone
of neuropathy.58 The controversy over the existence or
Amiodarone is a class III antiarrhythmic agent and
extent of statin-induced neuropathy is unresolved.
benzofuran derivative with known dermatological,
hepatic, ocular, pulmonary, and thyroid adverse events.
Highly Active Antiretroviral Therapy Amiodarone neurotoxicity is possibly underreported.126
HAART combines at least one nucleoside analog Mixed sensory and motor neuropathies have been
reverse transcriptase inhibitor (NRTI) with at least one observed within 6 to 36 months of onset of amiodarone
protease inhibitor and may include one or more non- therapy.5 Nerve biopsy specimens in patients with
nucleoside analog reverse transcriptase inhibitors. Only amiodarone-induced neuropathy may show lamellar
NRTIs have been associated with neuropathy.114 When inclusions in Schwann cells, possibly a consequence of
phosphorylated, NRTIs, such as zidovudine, stavudine, inactivation of lysosomal enzymes.72
fialuridine, didanosine, zalcitabine, and lamivudine, Case reports suggest that amiodarone-induced neu-
compete with nucleotides for reverse transcriptase ropathic symptoms become markedly reduced within
binding, which helps prevent the DNA elongation days or weeks of discontinuation of the drug.4,126,127 The
2560_Chapter 11_0125-0134.indd 128 3/16/2015 4:13:21 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
primary risk factor for amiodarone-induced neuropa- neuropathy 1 month later, primarily in his lower limbs in
thy may be duration of treatment.63 a “stocking” distribution. His hand symptoms remained
mild and unchanged. The predominant feature was
severe burning, which gave rise to sleep disturbance,
Additive and Synergistic high levels of distress, and reduced general function.
Symptoms progressed to the point that he was virtually
Considerations bed-bound. The bortezomib was discontinued.
The literature contains few reports of the additive or
synergistic neurotoxicities of specific drug combina- Case Study Questions
tions. Combination therapy is typical in chemotherapy,
1. Which of the following statements about medication-
but the combinations have not been reported to be
induced peripheral neuropathy is true?
associated with notably higher rates of neurotoxicity
a. Medication-induced neuropathy is extremely rare
than monotherapeutic use of the same drugs.22,128 The
and is typically associated with medications for
combination of paclitaxel and cisplatin is an exception,
cancer treatment.
in that it may provoke a rapidly progressing medication-
b. Medication-induced neuropathy is relatively
induced neuropathy at rates exceeding that of pacli-
common, but the symptoms tend to be mild and
taxel or cisplatin alone.68,129 Thalidomide and bortezomib
do not affect quality of life.
may have additive neurotoxicity.8,15,87,130–132
c. Medication-induced neuropathy is extremely
Medication-induced neuropathy can be both treat-
common but is easily treated with medication.
ment limiting and treatable. The mechanisms behind
d. Medication-induced neuropathy is a common side
medication-induced neuropathies are not thoroughly
effect of pharmaceutical intervention, the symptoms
understood and may be specific to drug class. Although
may have a great impact on the quality of life of
axonal degeneration, disruption of axonal transport,
the patient, and effective treatment may be difficult
and demyelination have been described, apoptosis
to attain.
increasingly emerges as an important pathway.3 Con-
duction block can mimic immune-mediated neuropa- 2. The pathology underlying medication-induced
thy, whereas genuine immune-mediated neuropathies neuropathy typically involves which of the following?
are thought to occur with anti-TNFα agents. a. Axonal degeneration
The risk factors for medication-induced neuropathy b. Neuronopathy
include the specific drug, acute dose, cumulative c. Segmented demyelination
dose, frequency of administration, duration of therapy, d. All of the above
patient age, and presence of preexisting neuropathy.
3. Which of the following is the most susceptible to
In many cases, medication-induced neuropathies can
medication-induced neuropathy?
be effectively treated by discontinuing the drug, but
a. Central (brain and spinal cord) neurons
the damage is permanent in some instances. Many
b. Peripheral neurons
treatment modalities have been proposed apart from
c. Interneurons associated with the basal ganglia
drug discontinuation, including the use of neuropro-
d. Cutaneous receptors
tective agents.133 Further study is warranted on the
additive and synergistic neurotoxic effects of medica- 4. Risk factors for medication-induced neuropathy
tion combinations. include which of the following?
a. Specific drug
b. Dose
CASE STUDY c. Patient’s age
Severe bortezomib-induced neuropathy developed in a d. All of the above
69-year-old man with a 39-month history of multiple 5. The primary neuropathic complication of thalidomide
myeloma. His previous medications included melphalan, is a “stocking-glove” neuropathy. Which of the
cyclophosphamide, dexamethasone, and thalidomide following best defines “stocking-glove” neuropathy?
(which had been discontinued because a stable partial a. A tactile sensory neuropathy involving the hands
response had been attained, with no neuropathic and feet
symptoms). Bortezomib was added as third-line b. A motor neuropathy involving the hands and feet
treatment. After two cycles of bortezomib, the man c. Loss of proprioception and kinesthesia in the
began to complain of paresthesia, numbness, and hands and feet but preservation of tactile sense
“lightning-like” pains in both hands, which did not d. A tactile sensory and motor neuropathy involving
resolve despite reduction of the dose by half for the third the hands and feet
cycle. He developed an extremely painful peripheral
2560_Chapter 11_0125-0134.indd 129 3/16/2015 4:13:21 PM

Process CyanProcess
YellowProcess Black
chemotherapy for non-seminomatous testicular cancer. Ann
References Oncol. 2002;13(2):229–236.
1. McLeod J. Investigation of peripheral neuropathy. J Neurol 22. Windebank A, Grisold W. Chemotherapy-induced
Neurosurg Psychiatry. 1995;58:274–283. neuropathy. J Peripher Nerv Syst. 2008;13:27–46.
2. Jain KK. Drug-induced peripheral neuropathies. In: Jain 23. Hamers F, Gispen W, Neijt J. Neurotoxic side effects of
KK, ed. Drug-Induced Neurological Disorders. 2nd ed. Seattle, cisplatin. Eur J Cancer. 1991;27:372–376.
WA: Hogrefe & Huber; 2001:237–261. 24. Pace A, Giannarelli D, Galiè E, et al. Vitamin E
3. Weimer L. Medication-induced peripheral neuropathy. neuroprotection for cisplatin neuropathy: a randomized,
Curr Neurol Neurosci Rep. 2003;3:86–92. placebo-controlled trial. Neurology. 2010;74(9):762–766.
4. Kang H, Kang Y, Kim S, et al. Amiodarone-induced 25. Kaya A, Coskun U, Buyukberber S, et al. Efficacy and
hepatits and polyneuropathy. Korean J Intern Med. 2007;22: toxicity of preoperative chemotherapy with docetaxel and
225–229. epirubicin in locally advanced invasive breast cancer.
5. Martinez-Arizala A, Sobol S, McCarty G, Nichols B, J BUON. 2010;15(2):248–252.
Rakita L. Amiodarone neuropathy. Neurology. 1983;33(5): 26. Hilkens P, Verweij J, Stoter G, Vecht C, van Putten WL,
643–645. van den Bent MJ. Peripheral neurotoxicity induced by
6. Zimetbaum P. Amiodarone for atrial fibrillation. N Engl J docetaxel. Neurology. 1996;46(1):104–108.
Med. 2007;356:935–941. 27. Pronk L, Stoter G, Verweij J. Docetaxol (Taxotere): single
7. Orr C, Ahlskog E. Frequency, characteristics, and risk agent activity, development of combination treatment and
factors for amiodarone neurotoxicity. Arch Neurol. 2009; reducing side-effects. Cancer Treat Rev. 1995;21(5):463–478.
66(7):865–869. 28. Shurie J, Deribew A. Assessment of the prevalence of distal
8. Richardson P, Barlogie B, Berenson J, et al. A phase 2 study symmetrical polyneuropathy and its risk factors among
of bortezomib in relapsed, refractory myeloma. N Engl J HAART-treated and untreated HIV infected individuals.
Med. 2003;348(26):2609–2617. Ethiop Med J. 2010;48(2):85–93.
9. Jagannath S, Durie B, Wolf J, et al. Bortezomib therapy 29. Forna F, Liechty C, Solberg P, et al. Clinical toxicity of
alone and in combination with dexamethasone for highly active antiretroviral therapy in a home-based AIDS
previously untreated symptomatic multiple myeloma. Br J care program in rural Uganda. J Acquir Immune Defic Syndr.
Haematol. 2005;129(6):776–783. 2007;44:456–462.
10. Richardson P, Briemberg H, Jagannath S, et al. Frequency, 30. Metzler C, Arlt A, Gross W, Brandt J. Peripheral
characteristics, and reversibility of peripheral neuropathy neuropathy in patients with systemic rheumatic disease
during treatment of advanced multiple myeloma with treated with leflunomide. Ann Rheum Dis. 2005;64:
bortezomib. J Clin Oncol. 2006;25(19):3113–3120. 1798–1800.
11. Argyriou A, Iconomou G, Kalofonos H. Bortezomib- 31. Bharadwaj A, Haroon N. Peripheral neuropathy in patients
induced peripheral neuropathy in multiple myeloma: a on leflunomide. Rheumatology. 2004;43:934.
comprehensive review of the literature. Blood. 2008;112: 32. Martin K, Bentaberry F, Dumoulin C, et al. Peripheral
1593–1599. neuropathy associated with leflunomide: is there a risk
12. El-Cheikh J, Stoppa A, Bouabdallah R, et al. Features and patient profile? Pharmcoepidemiol Drug Saf. 2007;16(1):
risk factors of peripheral neuropathy during treatment with 74–78.
bortezomib for advanced multiple myeloma. Clin Lymphoma 33. Richards BL, Spies J, McGill N, et al. Effect of leflunomide
Myeloma. 2008;8(3):146–152. on the peripheral nerves in rheumatoid arthritis. Intern Med
13. Richardson P, Sonneveld P, Schuster M, et al. Reversibility J. 2007;37:101–107.
of symptomatic peripheral neuropathy with bortezomib in 34. Becouarn Y, Ychou M, Ducreux M, et al. Phase II trial of
the phase III APEX trial in relapsed multiple myeloma: oxaliplatin as first-line chemotherapy in metastatic colorectal
impact of a dose-modification guideline. Br J Haematol. cancer patients. Digestive Group of French Federation of
2009;144:895–903. Cancer Centers. J Clin Oncol. 1998;16(8):2739–2744.
14. Chen SL, Jiang B, Qiu LG, Yu L, Zhong YP, Gao W. 35. Diaz-Rubio E, Sastre J, Zaniboni A, et al. Oxaliplatin as
Bortezomib plus thalidomide for newly diagnosed multiple single agent in previously untreated colorectal carcinoma
myeloma in China. Anat Rec (Hoboken). 2010;293: patients: a phase II multicentric study. Ann Oncol. 1998;
1679–1684. 9(1):105–108.
15. Bang S, Lee J, Yoon S, et al. A multicenter retrospective 36. Machover D, Diaz-Rubio E, DeGramont A, et al. Two
analysis of adverse events in Korean patients using consecutive phase II studies of oxaliplatin (L-OHP) for
bortezomib for multiple myeloma. Int J Hematol. 2006;83(4): treatment of patients with advanced colorectal carcinoma
309–313. who were resistant to previous treatment with
16. Cavaletti G, Jakubowiak A. Peripheral neuropathy during fluoropyrimidines. Ann Oncol. 1996;7(1):95–98.
bortezomib treatment of multiple myeloma: a review of 37. Ta L, Low P, Windebank A. Mice with cisplatin and
recent studies. Leuk Lymphoma. 2010;51(7):1178–1187. oxaliplatin-induced painful neuropathy develop distinct early
17. Kaufman J, Nooka A, Vrana M, Gleason C, Heffner L, responses to thermal stimuli. Mol Pain. 2009;5:9–20.
Lonial S. Bortezomib, thalidomide, and dexamethasone as 38. Cersosimo C. Oxaliplatin-associated neuropathy: a review.
induction therapy for patients with symptomatic multiple Ann Pharmacother. 2005;39:128–135.
myeloma. Cancer. 2010;116:3143–3151. 39. Peltier A, Russell J. Advances in understanding drug-
18. Toyooka K, Fujimura H. Iatrogenic neuropathies. Curr Opin induced neuropathies. Drug Saf. 2006;29(1):23–30.
Neurol. 2009;22:475–479. 40. O’Brien M, Socinski M, Popovich A, et al. Randomized
19. McWhinney S, Goldberg R, McLeod H. Platinum phase III trial comparing single-agent paclitaxel polglumex
neurotoxicity pharmacogenetics. Mol Cancer Ther. 2009;8(1): (CT-2103, PPX) with single-agent gemcitabine or
10–16. vinorelbine for the treatment of PS 2 patients with
20. Quasthoff S, Hartung H. Chemotherapy-induced peripheral chemotherapy-naive advanced non-small cell lung cancer.
neuropathy. J Neurol 2002;249:9–17. J Thorac Oncol. 2009;3:728–734.
21. Strumberg D, Brügge S, Korn M, et al. Evaluation of 41. Chon H, Rha S, Im C, et al. Docetaxel versus paclitaxel
long-term toxicity in patients after cisplatin-based combined with 5-FU and leucovorin in advanced gastric
2560_Chapter 11_0125-0134.indd 130 3/16/2015 4:13:21 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
cancer: combined analysis of two phase II trials. Cancer Res 63. Ta L, Espeset L, Podratz J, Windebank A. Neurotoxicity of
Treat. 2009;41(4):196–204. oxaliplatin and cisplatin for dorsal root ganglion neurons
42. Makino H. Treatment and care of neurotoxicity from taxane correlates with platinum-DNA binding. Neurotoxicology.
anticancer agents. Breast Cancer. 2004;11(1):100–104. 2006;27:992–1002.
43. Kannarkat G, Lasher E, Schiff D. Neurologic complications 64. Dzagnidze A, Katsarava Z, Makhalova J, et al. Repair
of chemotherapy agents. Curr Opin Neurol. 2007;20: capacity for platinum-DNA adducts determines the severity
719–725. of cisplatin-induced peripheral neuropathy. J Neurosci.
44. Soliven B, Dhand U, Kobayashi K, et al. Evaluation of 2007;27(35):9451–9457.
neuropathy in patients on suramin treatment. Muscle Nerve. 65. Gill J, Windebank A. Cisplatin-induced apoptosis in rat
1997;20(1):83–91. dorsal root ganglia neurons is associated with attempted
45. Chaudhry V, Eisenberger M, Sinibaldi V, Sheikh K, Griffin entry in the cell cycle. J Clin Invest. 1998;101:2842–2850.
J, Cornblath D. A prospective study of suramin-induced 66. Screnci D, McKeage M, Galettis P, Hambley T, Palmer B,
peripheral neuropathy. Brain. 1996;119(Pt 6):2039–2052. Baguley B. Relationships between hydrophobicity, reactivity,
46. Russell J, Gill J, Sorenson E, Schultz D, Windebank A. accumulation and peripheral nerve toxicity of a series of
Suramin-induced neuropathy in an animal model. J Neurol platinum drugs. Br J Cancer. 2000;82:966–972.
Sci. 2001;192(1–2):71–80. 67. Cavaletti G, Tredici G, Braga M, Tazzari S. Experimental
47. Matthews S, McCoy C. Thalidomide: a review of approved peripheral neuropathy induced in adult rats by repeated
and investigational uses. Clin Ther. 2003;25:342–395. intraperitoneal administration of taxol. Exp Neurol. 1995;
48. Cavaletti G, Beronio A, Reni L, et al. Thalidomide sensory 133:64–72.
neurotoxicity: a clinical and neurophysiologic study. 68. Sahenk Z, Barohn R, New P, Mendell J. Taxol neuropathy.
Neurology. 2004;62(12):2291–2293. Electrodiagnostic and sural nerve biopsy findings. Arch
49. Cavaletti G, Marmiroli P. Chemotherapy-induced peripheral Neurol. 1994;51(7):726–729.
neurotoxicity. Expert Opin Drug Saf. 2004;3(6):535–546. 69. Bhagra A, Rao R. Chemotherapy-induced neuropathy.
50. Lagueny A, Rommel A, Vignolly B, et al. Thalidomide Curr Oncol Rep. 2007;9:290–299.
neuropathy: an electrophysiologic study. Muscle Nerve. 70. Hilkens PH, Verweij J, Vecht CJ, Stoter G, van den Bent
1986;9(9):837–844. MJ. Clinical characteristics of severe peripheral neuropathy
51. Othieno-Abinya N, Nyabola L. Experience with vincristine- induced by docetaxel (Taxotere). Ann Oncol. 1997;8:
associated neurotoxicity. East Afr Med J. 2001;78(7): 187–190.
376–378. 71. Kanbayashi Y, Hosokawa T, Okamoto K, et al. Statistical
52. Yun-San Yip A, Yuen-Yuen Ong E, Chow LW. Vinflunine: identification of predictors for peripheral neuropathy
clinical perspectives of an emerging anticancer agent. Expert associated with administration of bortezomib, taxanes,
Opin Investig Drugs. 2008;17(4):583–591. oxaliplatin or vincristine while using ordered logistic
53. Ng J. Vinflunine: review of a new vinca alkaloid and its regression analysis. Anticancer Drugs. 2010;21(9):877–881.
potential role in oncology. J Oncol Pharm Pract. 2011;17(3): 72. Saleh F, Seidman R. Drug-induced myopathy and
209–224. neuropathy. J Clin Neuromuscul Dis. 2003;5(2):81–92.
54. Dalakas M, Semino-Mora C, Leon-Monzon M. 73. Topp K, Tanner K, Levine J. Damage to the cytoskeleton of
Mitochrondrial alterations with mitochondrial DNA large diameter sensory neurons and myelinated axons in
depletion in the nerves of AIDS patients with peripheral vincristine-induced painful peripheral neuropathy in the rat.
neuropathy induced by 2′,3′-dideoxycytidine (ddC). J Comp Neurol. 2000;424:563–576.
Lab Invest. 2001;81:1537–1544. 74. Bennouna J, Delord J, Campone M, Nguyen L. Vinflunine:
55. Maschke M, Kastrup O, Esser S, Ross B, Hengge U, a new microtubule inhibitor agent. Clin Cancer Res. 2008;
Hufnagel A. Incidence and prevalence of neurological 14(6):1625–1632.
disorders associated with HIV since the introduction of 75. Sampaio E, Sarno E, Galilly R, Cohn Z, Kaplan G.
highly active antiretroviral therapy (HAART). J Neurol Thalidomide selectively inhibits tumor necrosis factor alpha
Neurosurg Psychiatry. 2000;69(3):376–380. production by stimulated human monocytes. J Exp Med.
56. Miller F, Hess E, Clauw D, et al. Approaches for identifying 1991;173(3):699–703.
and defining environmentally associated rheumatic disorders. 76. Moreira A, Sampaio E, Zmuidzinas Z, Frindt P, Smith K,
Arthritis Rheum. 2000;43(2):243–249. Kaplan G. Thalidomide exerts its inhibitory action on tumor
57. Pratt R, Weimer L. Medication- and toxin-induced necrosis factor alpha by enhancing mRNA degradation.
peripheral neuropathy. Semin Neurol. 2005;25(2):204–216. J Exp Med. 1993;177(6):1675–1680.
58. Weimer L, Schdev N. Update on medication-induced 77. Briani C, Zara G, Rondinone R, et al. Thalidomide
peripheral neuropathy. Curr Neurol Neurosci Rep. 2009;9: neurotoxicity: prospective study in patients with lupus
69–75. erythematosus. Neurology. 2004;62(12):2288–2290.
59. Giannini F, Volpi N, Rossi S, Passero S, Fimiani M, Cerase 78. Hamanoue M, Middleton G, Wyatt S, Jaffray E, Hay R,
A. Thalidomide-induced neuropathy: a ganglionopathy? Davies A. p75-mediated NF-kappaB activation enhances
Neurology. 2003;60(5):877–878. the survival response of developing sensory neurons to nerve
60. Rosson G. Chemotherapy-induced neuropathy. Clin Podiatr growth factor. Mol Cell Neurosci. 1999;14(1):28–40.
Med Surg. 2006;23:637–649. 79. Isoardo G, Bergui M, Durelli L, et al. Thalidomide
61. Kirchmair R, Walter D, Ii M, et al. Antiangiogenesis neuropathy: clinical, electrophysiological and
mediates cisplatin-induced peripheral neuropathy: neuroradiological features. Acta Neurol Scand. 2004;
attenuation or reversal by local vascular endothelial growth 109(3):188–193.
factor gene therapy without augmenting tumor growth. 80. Molloy F, Floeter M, Syed N, et al. Thalidomide neuropathy
Circulation. 2005;111(20):2662–2670. in patients treated for metastatic prostate cancer. Muscle
62. McDonald E, Randon K, Knight A, Windebank A. Nerve. 2001;24(8):1050–1057.
Cisplatin preferentially binds to DNA in dorsal root 81. Reddy G, Mughal T, Lonial S. Optimizing the
ganglion neurons in vitro and in vivo: a potential management of treatment-related peripheral neuropathy
mechanism for neurotoxicity. Neurobiol Dis. 2005;18: in patients with multiple myeloma. Support Cancer Ther.
305–313. 2006;4:19–22.
2560_Chapter 11_0125-0134.indd 131 3/16/2015 4:13:21 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
82. Mateos MV. Management of treatment-related adverse 103. Herper M. How many people take cholesterol drugs? Forbes
events in patients with multiple myeloma. Cancer Treat Rev. 2008. http://www.forbes.com/2008/10/29/cholesterol-
2010;36(Suppl 2):S24–S32. pharmacuticals-statins-biz-cx_mh_1030cholesterol.html.
83. Orlowski R. Bortezomib and its role in the management of Accessed October 3, 2010.
patients with multiple myeloma. Exp Rev Anticancer Ther. 104. Gaist D, Jeppesen U, Andersen M, Garcia-Rodriguez L,
2004;4:171–179. Hallas J, Sindrup S. Statins and risk of polyneuropathy: a
84. Ravaglia S, Corso A, Piccolo G, et al. Immune-mediated case-control study. Neurology. 2002;58(9):1333–1337.
neuropathies in myeloma patients treated with bortezomib. 105. Walravens P, Greene C, Seerman E. Lovastatin, isoprenes,
Clin Neurophys. 2008;119:2507–2512. and myopathy. Lancet. 1989;2:1097–1098.
85. Lanzani F, Mattavelli L, Frigeni B, et al. Role of a pre-existing 106. Chong P, Boskovich A, Stevkovic N, Bartt R. Statin-
neuropathy on the course of bortezomib-induced peripheral associated peripheral neuropathy: review of the literature.
neurotoxicity. J Peripher Nerv Syst. 2008;13:267–274. Pharmacotherapy. 2004;24:1194–1203.
86. Velasco R, Petit J, Clapes V, Verdu E, Navarro X, Bruna J. 107. Gaist D, Rodriguez LG, Huerta C, Hallas J, Sindrup S. Are
Neurological monitoring replaces the incidence of users of lipid-lowering drugs at increased risk of peripheral
bortezomib-induced peripheral neuropathy in multiple neuropathy? Eur J Clin Pharmacol. 2001;56:931–933.
myeloma patients. J Peripher Nerv Syst. 2010;15:17–25. 108. Lovastatin 5-year safety and efficacy study. Lovastatin
87. Badros A, Goloubeva O, Dalal J, et al. Neurotoxicity of Study Groups I through IV. Arch Intern Med. 1993;153:
bortezomib therapy in multiple myeloma: a single-center 1079–1087.
experience and review of the literature. Cancer. 2007;110(5): 109. Jeppesen U, Gaist D, Smith T, Sindrup S. Statins and
1042–1049. peripheral neuropathy. Eur J Clin Pharmacol. 1999;54:
88. Corso A, Mangiacavalli S, Varettoni M, Pascutto C, 835–838.
Zappasodi P, Lazzarino M. Bortezomib-induced peripheral 110. Ahmad S. Lovastatin and peripheral neuropathy. Am Heart
neuropathy in multiple myeloma: a comparison between J. 1995;130:1321.
previously treated and untreated patients. Leuk Res. 2010;34: 111. Ziajka P, Wehmeier T. Peripheral neuropathy and lipid-
471–474. lowering therapy. South Med J. 1998;91(7):667–668.
89. Eisenberger M, Reyno L, Jodrell D, et al. Suramin, an active 112. Phan T, McLeod J, Pollard J, Peiris O, Rohan A, Halpern J.
drug for prostate cancer: interim observations in a phase I Peripheral neuropathy associated with simvastin. J Neurol
trial. J Natl Cancer Inst. 1993;85(8):611–621. Neurosurg Psychiatry. 1995;58:625–628.
90. DeClerq E. Suramin: a potent inhibitor of the reverse 113. Davis T, Yeap B, Davis W, Bruce D. Lipid-lowering therapy
transcriptase of RNA tumor viruses. Cancer Lett. 1979;8: and peripheral sensory neuropathy in type 2 diabetes: the
9–22. Fremantle Diabetes Study. Diabetologia. 2008;51(4):562–566.
91. Broder S, Yarchoan R, Collins J, et al. Effects of suramin on 114. Dalakas M. Peripheral neuropathy and antiretroviral drugs.
HTLV-III/LAV infection presenting as Kaposi’s sarcoma J Peripher Nerv Syst. 2001;6(1):14–20.
or AIDS-related complex: clinical pharmacology and 115. Lewis W, Dalakas M. Mitochondrial toxicity of antiviral
suppression of virus replication in vivo. Lancet. 1985; drugs. Nat Med. 1995;1:417–422.
2(8456):627–630. 116. Miller R. Neuromuscular complications of human
92. LaRocca R, Meer J, Gilliatt R, et al. Suramin-induced immunodeficiency virus infection and antiretroviral therapy.
polyneuropathy. Neurology. 1990;40(6):954–960. West J Med. 1994;160:447–452.
93. Coffey R, Leof E, Shipley G, Moses H. Suramin inhibition 117. White A. Mitochondrial toxicity and HIV therapy. Sex
of growth factor receptor binding and mitogenicity in Transm Infect. 2001;77:158–173.
AKR-2B cells. J Cell Physiol. 1987;132:143–148. 118. Peltier A, Russel J. Recent advances in drug-induced
94. Russell J, Windebank A, Podratz J. Role of nerve growth neuropathies. Curr Opin Neurol. 2002;15:633–638.
factor in suramin neurotoxicity studied in vitro. Ann Neurol. 119. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining
1994;36:221–228. morbidity and mortality among patients with advanced
95. Gill J, Connolly D, McManus M, Maihle N, Windebank A. human immunodeficiency virus infection. HIV Outpatient
Suramin induces phosphorylation of the high-affinity nerve Study Investigators. N Engl J Med. 1998;338(13):853–860.
growth factor receptor in PC12 cells and dorsal root 120. Hogg R, Yip B, Kully C, et al. Improved survival among
ganglion neurons. J Neurochem. 1996;66:963–972. HIV-infected patients after initiation of triple-drug
96. Gill J, Windebank A. Direct activation of the high-affinity antiretroviral regimens. Can Med Assoc J. 1999;160(5):
nerve growth factor receptor by a non-peptide symmetrical 659–665.
polyanion. Neuroscience. 1998;87:855–860. 121. Kaul M. HIV-1 associated dementia: update on pathological
97. Cardinali M, Sartor O, Robbins K. Suramin, an mechanisms and therapeutic approaches. Curr Opin Neurol.
experimental chemotherapeutic drug, activates the receptor 2009;22(3):315–320.
for epidermal growth factor and promotes growth of certain 122. Lichtenstein KA, Armon C, Baron A, Moorman AC, Wood
malignant cells. J Clin Invest. 1992;89:1242–1247. KC, Holmberg SD; HIV Outpatient Study Investigators.
98. Martin K, Bentaberry F, Dumoulin C, et al. Neuropathy Modification of the incidence of drug-associated
associated with leflunomide: a case series. Ann Rheum Dis. symmetrical peripheral neuropathy by host and disease
2005;64(4):649–650. factors in the HIV outpatient study cohort. Clin Infect Dis.
99. Carulli M, Davies U. Peripheral neuropathy: an unwanted 2005;40(1):148–157.
effect of leflunomide? Rheumatology. 2002;41:952–953. 123. Stübgen J. Tumor necrosis factor-alpha antagonists and
100. Hill C. Leflunomide-induced peripheral neuropathy: rapid neuropathy. Muscle Nerve. 2008;37(3):281–292.
resolution with cholestyramine wash-out. Rheumatology. 124. Tektonidou M, Serelis J, Skopouli F. Peripheral neuropathy
2004;43:809. in two patients with rheumatoid arthritis receiving
101. Kho L, Kermode A. Leflunomide-induced peripheral infliximab treatment. Clin Rheumatol. 2007;26:258–260.
neuropathy. J Clin Neurosci. 2007;14:179–181. 125. Lozeron P, Denier C, Lacroix C, Adams D. Long-term
102. Bonnel R, Graham D. Peripheral neuropathy in patients course of demyelinating neuropathies occurring during
reated with leflunomide. Clin Pharmacol Ther. 2004;75: tumor necrosis factor-alpha-blocker therapy. Arch Neurol.
580–585. 2009;66(4):490–497.
2560_Chapter 11_0125-0134.indd 132 3/16/2015 4:13:21 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
126. Krauser D, Sega A, Kligfield P. Severe ataxia caused by multiple myeloma: results of an IFM phase II study.
amiodarone. Am J Cardiol. 2005;96:1463–1464. Heamatologica. 2006;91(11):1498–1505.
127. Hindle J, Ibrahim A, Ramaraj R. Ataxia caused by 131. Mateos M, Hernandez J, Hernandez M, et al. Bortezomib
amiodarone in older people. Age Ageing. 2008;37: plus melphalan and prednisone in elderly untreated patients
347–348. with multiple myeloma: results of a multicenter phase 1/2
128. Caruba T, Cottu PH, Madelaine-Chambring I, Espie M, study. Blood. 2006;108(7):2165–2172.
Misset JL, Gross-Goupil M. Gemcitabine-oxaliplatin 132. Mateos M, Oriol A, Martinez-Lopez J, et al. Bortezomib,
combination in heavily pretreated metastatic breast cancer: melphalan, and prednisone versus bortezomib, thalidomide,
a pilot study on 43 patients. Breast J. 2007;13(2):165–171. and prednisone as induction therapy followed by
129. Postma TJ, van Groeningen CJ, Witjes RJ, Weerts JG, maintenance treatment with bortezomib and thalidomide
Kralendonk JH, Heimans JJ. Neurotoxicity of combination versus bortezomib and prednisone in elderly patients with
chemotherapy with procarbazine, CCNU and vincristine untreated multiple myeloma: a randomised trial. Lancet.
(PCV) for recurrent glioma. J Neurooncol. 1998;38(1): 2010;11(10):934–941.
69–75. 133. Meyer L, Patte-Mensah C, Taleb O, Mensah-Nyagan A.
130. Harousseau J, Attal M, Leleu X, et al. Bortezomib plus Cellular and functional evidence for a protective action of
dexamethasone as induction treatment prior to autologous neurosteroids against vincristine chemotherapy-induced
stem cell transplantation in patients with newly diagnosed painful neuropathy. Cell Mol Life Sci. 2010;67:3017–3034.
2560_Chapter 11_0125-0134.indd 133 3/16/2015 4:13:21 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
2560_Glossary_0347-0360.indd 360 3/17/2015 12:11:29 PM
SECTION THREE
Evaluation and Assessment of Peripheral

Nerve Injury
Chapter 12
Electroneurodiagnostic
Assessment and Interpretation
“Sometimes the correct questions are more important than the correct answers.”
—NANCY WILLARD (1936– )
Objectives
• Understand why the electroneurodiagnostic examination is an important diagnostic tool for rehabilitation
professionals.
• Define the components of the electroneurodiagnostic examination.
• Discuss the purpose of the electroneurodiagnostic examination.
• Interpret the results of the electroneurodiagnostic examination and translate the results into clinical practice.
Key Terms
• Electromyography
• F wave
• Motor nerve conduction
• Sensory nerve conduction
Introduction a “how to” primer for the performance of the spectrum

of electroneurodiagnostic testing; many other well-
Electroneurodiagnostic studies are the natural physi- written texts are available. Rather, the author presents
ological extension of the neurological physical exami- the subject of electroneurodiagnostic testing in a con-
nation. They are used to confirm, add to, or remove ceptualized state to allow the reader to develop an
differential diagnoses suggested by clinical scripts understanding of the various types of testing available
taken from the history, prior diagnostic workup, and and the clinical and diagnostic implications of normal
physical examination. This chapter is not meant to be and aberrant testing results and, for the rehabilitation
135
2560_Chapter 12_0135-0142.indd 135 3/16/2015 4:13:23 PM

Process CyanProcess
YellowProcess Black
136 Section Three | Evaluation and Assessment of Peripheral Nerve Injury
clinician, to develop an appreciation of the ability of motor nerve conduction studies and ends with
this powerful tool to facilitate diagnostics, goal setting, the needle examination. The agenda may be
and interventional planning for patients with periph- amended “midstream” based on evidence
eral nerve injury. obtained during the examination. Additional
In the performance of clinical testing, the electro- testing such as quantitative sensory testing,
neurodiagnostic clinician works to prove, disprove, or autonomic testing, and somatosensory evoked
add to the differential diagnosis list via the scientific potential testing may be employed.
method. Clinical scripts provide differential diagnoses, 3. Synthesis and correlation: Following the history
and the clinician, through the use of various electro- taking and electroneurodiagnostic assessment,
neurodiagnostic tests, collects data, develops the diag- the clinician begins to define the site of the
nostic hypotheses, collects more data, reworks the lesion; the pathological (neurapraxic, axonal, or
diagnostic hypothesis, and confirms or disproves the demyelination) process; possible etiologies of
differential diagnosis. During the testing, the patient is the nerve lesion; and, if possible, the prognosis
awake and alert and can provide additional historical of healing.
data if needed to the clinician. In contrast to many
diagnostic studies, the electroneuromyogram does not
have a strict procedural component; the clinician may Motor Nerve Conduction Studies
perform as many or as few specific tests as needed to
isolate a diagnosis. Electroneurodiagnostic testing is a Nerve conduction studies as part of the examination
unique test in that the patient by supplying the clini- for suspected peripheral nerve injury are an extension
cian with information during the study is an active of the clinical examination and are important in the
partner in the diagnostic process. management of cranial and peripheral neuromuscular
The primary goal of the electroneurodiagnostic eval- disease as well as contributing to diagnosis of spinal
uation is to determine the site of the lesion; the find- cord lesions. The purpose of nerve conduction testing
ings do not identify the process leading to the aberrant in suspected peripheral nerve injury is to assess the
findings. To obtain information about the “localiza- degree and extent of motor axonal nerve injury, to
tion,” the following processes are used: motor nerve determine the presence or lack of nerve connectivity
studies, sensory nerve studies, and needle electromy- (gap), and to identify if the repair process has begun
ography (EMG). Correlation with aspects of the phys- (sprouting, regeneration). Nerve conduction studies
ical examination and other diagnostic tests is needed can be extremely useful both in localizing lesions and
to isolate the diagnosis. in providing adjuvant data as to the etiologies of the
pathological processes responsible. It is vital for the
electromyographer to carry out tests accurately and
reproducibly and to develop an investigation strategy
Electroneurodiagnostic Process based on the patient’s symptoms and signs rather than
a fixed protocol. The investigator should report the
The complete electroneurodiagnostic process is as
results clearly, place them in the context of the clinical
follows:
situation, and correlate the findings with any support-
1. History taking: Following the development of ing diagnostic studies.
the clinician-patient collaborative relationship, Motor conduction studies, also known as motor
the clinician should take a thorough history conduction velocities (MCVs,) are performed by elec-
of the present illness using open-ended trically stimulating a nerve and recording the com-
questions and follow-up queries. Past medical pound muscle action potential (CMAP) from surface
and surgical histories and current and past electrodes overlying a muscle supplied by that nerve
medications should be thoroughly documented. (Table 12-1). The most frequently examined nerves are
Social, nutritional, medication, and vocational the peroneal, tibial, ulnar, and median—not coinciden-
histories should be adequately explored with tally, all superficial nerves affected by external forces.
concentration on possible behavioral and The primary advantage of motor conduction over
chemical influences that may result in sensory conduction studies is that several segments
peripheral nerve injury. along the course of the nerve are available for motor
2. Establishing the agenda of study. Similar to the sensory examination, side-to-side
electroneurodiagnostic evaluation: Based on comparison studies are quite helpful. The active elec-
clinical scripts produced during the history- trode is placed over the muscle belly, and the reference
taking process, the clinician develops an agenda electrode is placed over an electrically inactive site
of procedures to perform to confirm, disprove, (usually the muscle tendon). A ground electrode is also
or add to the differential list. The typical study placed somewhere between the stimulating and record-
begins with sensory conduction studies and ing electrodes providing a zero voltage reference point.
2560_Chapter 12_0135-0142.indd 136 3/16/2015 4:13:24 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 12 | Electroneurodiagnostic Assessment and Interpretation 137
same motor axons innervate the muscle fibers making
Table 12-1 Common Abbreviations Used in
up the response. However, the latency is greater for
Electroneurodiagnostic Studies
elbow stimulation compared with wrist stimulation
Ach Acetylcholine because of the longer distance between the stimulating
and recording electrodes. The difference in latency rep-
AIDP Acute inflammatory demyelinating polyneuropathy
resents the time taken for the fastest nerve fibers to
AMAN Acute motor axonal neuropathy conduct between the two stimulation points because
CMAP Compound muscle action potential all other factors involving neuromuscular transmission
CN Clinical neurophysiologist and muscle activation are common to both stimulation
sites. If one measures the distance between the two
DRG Dorsal root ganglion sites, the fastest motor nerve conduction velocity
EMG Electromyography (FMNCV) can be calculated as follows: FMNCV
LEMS Lambert-Eaton myasthenic syndrome (m/sec) ಟ=ಟ distance between stimulation site 1 and site
2 (mm)/[latency site 2 − latency site 1 (msec).
NAP Nerve action potential
Seddon1,2 described three major types of traumatic
NCS Nerve conduction study nerve injuries. Neurotmesis implies the nerve cannot
NMTD Neuromuscular transmission disorder regenerate spontaneously because it is either severed
PNE Peripheral neurophysiological examination completely or disrupted by an obstruction such as
internal or external scar tissue. In axonotmesis, regen-
RNS Repetitive nerve stimulation
eration can occur because endoneurial coverings main-
SNAP Sensory nerve action potential tain the proper alignment. In neurapraxia, conduction
SSEP Somatosensory evoked potential is locally blocked (possibly secondary to focal demye-
TMS Transcranial magnetic stimulation
lination), and recovery is relatively rapid—minutes to
weeks.
In the first two types nerve injury, wallerian degen-
eration occurs distal to the lesion, whereas in neura-
For example, the median nerve motor study might praxia, no such distal changes take place. In all three
involve stimulation at the wrist, the elbow, the axilla types, no response is obtained from stimulation proxi-
(less frequently), and the brachial plexus. mal to the lesion. However, with distal stimulation,
For each motor nerve conduction study, four values normal conduction is maintained in neurapraxia and
are typically obtained and recorded: CMAP amplitude serves to distinguish it from the other states.
and duration at each stimulation site, latency at each The electrical distinction between neurotmesis and
stimulation site, conduction velocity between stimula- axonotmesis may be difficult. If there is some preserva-
tion sites, and F-wave latencies. The CMAP is a sum- tion of either voluntary activity or response to electrical
mated voltage response from the individual muscle stimulation of a nerve, a complete neurotmesis is ruled
fiber action potentials. The shortest latency of the out. If no such function is preserved, serial studies
CMAP is the time from stimulus artifact to onset of may be necessary to distinguish between these two
the response and is a biphasic response with an initial processes.
upward deflection followed by a smaller downward
deflection. The CMAP amplitude is measured from
baseline to negative peak (the neurophysiological con- Sensory Nerve Conduction Studies
vention is that negative voltage is demonstrated by an
upward deflection) and measured in millivolts (mV). Sensory nerve conduction studies, often referred to as
To record the CMAP, the stimulating current or sensory nerve action potential (SNAP) studies, involve
voltage is gradually increased until a point is reached stimulation of a nerve while recording from the skin
where an increase in stimulus produces no incremental over the nerve. Sensory nerve studies are extremely
increase in CMAP amplitude as observed on the oscil- useful discriminators regarding the site of the pathol-
loscope. Only at this (supramaximal) point can a repro- ogy because the presence of a normal sensory action
ducible value for CMAP amplitude and the latency potential implies that large-diameter dorsal root gan-
between the stimulus and the onset of the CMAP be glion cells and large myelinated axons are appropriately
recorded accurately. connected and are likely to be functioning normally. If
The nerve is stimulated at a more proximal site—in studies indicate that this component of the peripheral
the median nerve examination for carpal tunnel syn- nervous system is normal and if the patient has a large-
drome, this would be the antecubital fossa, close to the fiber type of sensory loss, the pathology must be proxi-
biceps tendon. In the normal state, stimulating the mal to the dorsal root ganglion.3
median nerve at the wrist and the elbow results in two The SNAP is obtained by electrically stimulating
CMAPs of similar shape and amplitude because the sensory fibers and recording the nerve action potential
2560_Chapter 12_0135-0142.indd 137 3/16/2015 4:13:24 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Table 12-2 Summary of Electroneurodiagnostic Findings in Various Pathologies

Anterior Horn Cell Disease Neuropathy Myopathy Neuromuscular Radiculopathy
Junction Disease
Fasciculations at Rest Present Rare Rare Absent Rare
Conduction Studies Normal or slightly Normal, slightly slowed, Normal Normal Normal
slowed or markedly slowed
Repetitive Supramaximal Usually normal Usually normal Usually normal Abnormal Normal
Stimulation
Motor Unit Potentials Markedly increased Increased Decreased Occasionally Increased
Amplitude/Duration decreased
Recruitment Pattern Decreased Decreased Increased Normal Decreased
From Dyck PJ. Quantitative sensory testing: a consensus report from the Peripheral Neuropathy Association. Neurology. 1993;43:1050–1052; and
Fisher MA. AAEM Minimonograph #13: H reflexes and F waves: physiology and indications. Muscle Nerve. 1992;15:1223–1233.
at a point further along that nerve. Again the stimulus different populations of neurons normally backfire
must be supramaximal. Recording the SNAP ortho- with each stimulus. The most reliable measure of the F
dromically refers to distal nerve stimulation and wave is the minimum latency of 10 to 20 firings.5
recording more proximally (the direction in which F waves allow testing of proximal segments of nerves
physiological sensory conduction occurs). Different that would otherwise be inaccessible to routine nerve
electroneurodiagnostic testing laboratories prefer anti- conduction studies. F waves test long lengths of nerves,
dromic or orthodromic methods for testing different whereas motor studies test shorter segments. F wave
nerves. The sensory latency and the peak-to-peak abnormalities can be a sensitive indicator of peripheral
amplitude of the SNAP are measured. The velocity nerve pathology, particularly if sited proximally. The F
correlates directly with the sensory latency, and the wave ratio, which compares the conduction in the
result may be expressed either as latency over a proximal half of the total pathway with the distal half,
standard distance or, more commonly, as a velocity may be used to determine the site of conduction
(Table 12-2). slowing—for example, to distinguish a root lesion from
Only the 20% largest diameter and fastest con- a patient with a distal generalized neuropathy.6
ducting sensory fibers are tested using conventional
sensory studies functionally supplying fine touch, vibra-
tion, and position sense.4 Predominantly small-fiber Repetitive Nerve Stimulation
neuropathies affecting the other 80% of fibers exist
usually with prominent symptoms of pain, and con- Repetitive nerve stimulation (RNS) is used in the
ventional sensory studies may be normal. In such cases, evaluation of patients with suspected neuromuscular
quantitative sensory testing and autonomic testing are transmission disorders (NMTDs) such as myasthe-
required. nia gravis or Lambert-Eaton myasthenic syndrome
(LEMS). RNS is a modified motor nerve conduc-
tion study in which instead of recording CMAPs with
F Waves single supramaximal electrical stimuli, a train of 8 to 10
stimuli is applied, and the sequential response ampli-
F waves (F for foot, where they were first described) tudes or areas are measured. This study may be carried
are a type of late motor response. When a motor nerve out at low-frequency (3 to 4 Hz) or high-frequency (20
axon is electrically stimulated at any point, an action to 50 Hz) stimulation. In the latter case, the train is
potential is propagated in both directions away from prolonged to allow 2 to 10 seconds of continuous data
the initial stimulation site. The distally propagated to be measured. Both distal and proximal muscles and
impulse gives rise to the CMAP. However, an impulse nerves should be studied in every patient suspected to
also conducts proximally to the anterior horn cell, have an NMTD because the sensitivity of the test is
depolarizing the axon hillock and causing the axon to greatly increased by this means.7
backfire; this leads to a small additional muscle depo- With low-frequency stimulation in normal subjects,
larization (F wave) at a longer latency. Only about 2% the CMAP amplitude or area falls over the first four
of axons backfire with each stimulus. In contrast to the to five stimuli by a maximum of 10% to 12%. The
M response, F waves vary in latency and shape because maximum fall should be between potentials 1 and 2.
2560_Chapter 12_0135-0142.indd 138 3/16/2015 4:13:24 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Numerous department-specific protocols have been begins in the muscle and muscle weakness resulting
published to study RNS over time both before and from nerve disorders. EMG can be used to detect true
after a period of maximum voluntary contraction of the weakness as opposed to weakness from reduced use
muscle to detect early or late neuromuscular transmis- because of pain or lack of motivation. EMG can also
sion failure.8 be used to isolate the level of nerve irritation or injury.
EMG can detect disease involving the lower motor
neuron from the anterior horn cell to the neuromus-
Electromyography cular junction, defects in transmission at the neuro-
muscular junction, and primary muscle disease.
The electromyograph is a device that amplifies and A needle is inserted through the skin into the
converts the minute voltages recorded by a needle muscle. Electrical activity—at insertion, at rest, at voli-
electrode—typically a fine wire inserted within a tional contraction, and at maximal contraction—is
24-gauge hollow needle—inserted into muscle and detected by this needle (which serves as an electrode).
expresses these currents by speaker or visually by a The activity is displayed visually on an oscilloscope and
cathode ray oscilloscope. A permanent record of the may be detected audibly with a speaker.
examination can be saved and printed. By this means, Because skeletal muscles are often large, several
the electrical potentials of normal, diseased, or dener- needle electrodes may need to be placed at various
vated muscle can be studied. Normal, healthy muscle locations to obtain an informative electromyogram.
has two significant electromyographic characteristics: The presence, size, and shape of the waveform (the
it emits no detectable impulses at rest, and on insertion action potential) produced on the oscilloscope provide
of the needle electrode, the electrical activity caused by information about the ability of the muscle to respond
the mechanical stimulation of insertion is quickly to nervous stimulation. Each muscle fiber that con-
dissipated. tracts produces an action potential. The size of the
EMG is often performed when patients have unex- muscle fiber affects the rate (how frequently an action
plained motor weakness. EMG helps to distinguish potential occurs) and the size (the amplitude) of the
between muscle conditions in which the problem action potential (Figs. 12-1, 12-2, and 12-3).
Figure 12-1 Fibrillation potentials and positive sharp waves share many of the same
characteristics and have the same clinical importance. Although subtle differences exist, both
represent spontaneous muscle activity in association with neural denervation or irritable
myopathy. An example of a positive sharp wave is pictured. Positive sharp waves represent
spontaneous muscle activity seen on electromyography in association with denervation or irritable
myopathy.
100␮V
PSW
20 msec
Figure 12-2 Fibrillation potentials, similar to positive sharp waves, are often diagnostic of
denervation. In contrast to fasciculations, which may be visibly observed and may be benign,
fibrillations cannot visibly observed and are pathological. Fibrillation potentials occur when
muscle fibers lose contact with their innervating axon producing a spontaneous action potential
that results in muscle contraction of the individual motor unit.
2560_Chapter 12_0135-0142.indd 139 3/16/2015 4:13:24 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
myotonia, which is a prominent feature in the genetic
diseases myotonia congenita, myotonia dystrophica,
and paramyotonia congenita.11
Following complete or partial nerve damage, it is
essential to know the sequence of changes in the inner-
vated muscle. At first, the only change noted is the
absence or decrease of muscle contraction noted on
EMG. Fibrillation potentials begin to appear with the
insertion or “tweaking” of the recording needle about
1 week after injury. Spontaneous fibrillations begin to
appear 2 to 4 weeks after injury. Sequential examina-
Figure 12-3 Similar to fibrillation potentials and positive tions may reveal additional aberrant tracings or, as rein-
sharp waves, giant motor unit potentials are suggestive nervation occurs, the emergence of low-amplitude,
of denervation. With chronic muscle reinnervation, the often polyphasic, action potentials, which gradually
amplitude of the motor unit increases, as does its duration, develop normal patterns.
producing the greater size of the new motor unit. A motor Fasciculation potentials occur in many conditions,12
unit greater than 5 mV is referred to as a giant motor unit including motor neuron disease; cord diseases such as
and is consistent with chronic reinnervation. hematomyelia, syringomyelia, and cervical spondylosis;
irritative disorders of nerve roots; hypomagnesemia;
and pancreatic adenoma with hyperinsulinism. Most
Normally, some electrical activity occurs when the commonly, fasciculations are benign and are observed
needle is inserted, but this quickly dissipates. Increased in many individuals especially after severe exercise and
insertional activity, fibrillation potentials, and positive concomitant fatigue. Coupled discharges can be seen
sharp waves9 can be seen in diseases producing axonal in latent tetany, induced by hyperventilation or by
degeneration, blockade of the neuromuscular junction muscle ischemia.13
such as often seen with botulinum poisoning10 or myo- Activity is also monitored during EMG with voli-
pathic processes. Repetitive discharges may be seen tional contraction of the muscle. When an anterior
in myotonia. A relaxed muscle is electrically silent. horn cell is activated, an action potential travels down
Fibrillation and fasciculations may be detected in the its axon and terminal nerve fibers to produce an almost
relaxed denervated muscle. During voluntary contrac- synchronous depolarization of the muscle fibers that it
tion, muscle action potentials can be visualized on the innervates. The summated potential generated by these
oscilloscope. With minimal contraction, often single specific muscle fibers is called the motor unit potential.
action potentials may be seen and analyzed. With In actuality, the full complement of muscle fibers
maximal contraction, an “interference pattern” is visual- innervated by one anterior horn cell lie in an area that
ized on the oscilloscope. The amplitude, duration, exceeds the effective pick-up zone of a needle. What
number, and configuration of the muscle action poten- is called the motor unit potential is only a fraction of
tials are noted in differentiating neurogenic from the whole.
myogenic involvement. In myogenic weakness, the The number of active motor units and their fre-
amplitude of the action potential is decreased with quency of discharge depend on the volitional effort
little decrease in the number of action potentials. exerted. A small effort recruits a small number of motor
Two types of bizarre high-frequency discharges may units; a large effort recruits much of the muscle. When
also be present. In the first, the frequency and ampli- much of the muscle is recruited, this is called a com-
tude of the action potentials do not wax and wane but plete interference pattern. The number of motor units
are relatively constant. These discharges are usually activated can be inferred by monitoring the oscillo-
composed of complex-appearing potentials that tend scope pattern. The recruitment pattern on maximal
to stop and start spontaneously. They are not generally exertion reflects the degree of denervation. With com-
provoked by voluntary movement but rather by needle plete denervation, no observable motor units are seen.
insertion and manipulation or muscle percussion. These If only a few axons are lost, a complete interference
have been termed “pseudomyotonic” discharges and are pattern may still be seen. In contrast, myopathies tend
now realized to be a nonspecific finding occurring in to show a complete interference pattern on minimal
lower motor neuron lesions. effort.
The other form of bizarre high-frequency discharges The amplitude of the motor unit potential is a func-
wax and wane to provoke the familiar “dive bomber” tion of the number of activated muscle fibers that lie
sound. These are commonly found in myotonic disor- adjacent to the EMG needle. The duration is a variable
ders where needle movement, percussion near the of the relative degree of asynchronicity between the
needle insertion, or voluntary motion provokes their number of active fibers adjacent to the needle. In addi-
appearance. They are the electrical analogy of a clinical tion, because the number of muscle fibers included in
2560_Chapter 12_0135-0142.indd 140 3/16/2015 4:13:24 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
a particular motor unit varies, the amplitude and conduction latency was prolonged at the left median
duration vary among normal subjects. Short-duration wrist/abductor pollicis brevis on the right. Sensory
motor unit potentials are thought to be the result of nerve action potentials revealed no response at the
loss of muscle fibers. The dropout of fibers can account right median wrist/second digit.
for decreased amplitude or an increased number of
phases (polyphasic units). Such motor unit potentials
are common in myopathies where random degenera-
tion of muscle fibers develop. BSAPPs is an acronym 1. Fibrillation potentials in the right abductor pollicis as
for brief small abundant polyphasic potentials, and this a singular finding may be the result of which of the
term has been suggested to describe a recruitment following?
strategy consisting of the aforementioned motor unit a. Median neuropathy
potentials. Although BSAPPs are seen in myopathies, b. Median neuropathy at the elbow
they may occur in other pathologies as well. The c. Median neuropathy in the forearm
increased dispersion in conduction along terminal d. All of the above
nerve fibers accounts for the long-duration polyphasic
2. The positive median nerve Tinel sign at the wrist and
motor unit potentials. The greater the disparity of
Phalen sign point to pathology near which
arrival of the action potentials arriving to various
landmark?
muscle fibers, the longer the duration of the motor unit
a. Wrist
potentials. The long-duration polyphasic potentials as
b. Forearm
seen during nerve degeneration or regeneration by
c. Elbow
themselves are not sufficient to diagnose a worsening,
d. Shoulder
static, or improving illness. Giant motor unit potentials
are defined as peak-to-peak amplitude greater than 3. Which of the following is true of fasciculations?
5 mV. These units most likely indicate that reinnerva- a. Often visible to the eye
tion is occurring or has occurred by the process of b. May be a sign of motor neuron disease
collateral sprouting. The appearance of giant motor c. May be benign
unit action potentials on EMG indicates a chronic d. All of the above
rather than acute process.
4. Which of the following shows the three items in
Electroneurodiagnostic testing is a vital adjunct to
order of severity?
the neurological examination. The qualified examiner,
a. Neurapraxia, neurotmesis, axonotmesis
in partnership with the patient, uses the nerve conduc-
b. Neurotmesis, axonotmesis, neurapraxia
tion velocity and EMG tests to facilitate the diagnostic
c. Axonotmesis, neurapraxia, neurotmesis
process and localize the site or sites of injury and may
d. Axonotmesis, neurotmesis, neurapraxia
be able to develop a prognosis for recovery. The elec-
troneuromyogram provides a unique data picture not 5. Which of the following is an example of a diagnosis
provided by other methods of diagnostic testing and that produces bizarre high-frequency (“dive bomber”)
when correlated with the history and physical exami- discharges?
nation facilitates the diagnostic process. a. Myotonia
b. Amyotrophic lateral sclerosis
c. Polio
d. C5 radiculopathy
CASE STUDY
The patient, DM, developed right wrist and hand pain
a few days after painting a ceiling. About the same References
time, DM noticed that he had begun dropping objects 1. Seddon HJ. A classification of nerve injuries. Br Med J. 1942;
such as pencils and coins. The pain was located in the 2:237.
right lateral four digits and the lateral palm but did not 2. Seddon HJ. Three types of nerve injury. Brain. 1943;86:237.
extend proximal to the wrist. The Tinel sign was 3. Dyck PJ. Quantitative sensory testing: a consensus report
from the Peripheral Neuropathy Association. Neurology. 1993;
positive at the wrist. The Phalen sign was present on 43:1050–1052.
the right. Medical history was unremarkable. 4. Neilson VK. Sensory and motor nerve conduction in the
DM was referred to a neurologist and physical median nerve in normal subjects. Acta Med Scand. 1973;194:
therapist 4 months after the onset of symptoms. 435–443.
Electroneuromyogram results indicated fibrillation 5. Fisher MA. AAEM Minimonograph #13: H reflexes and F
waves: physiology and indications. Muscle Nerve. 1992;15:
potentials in the right abductor pollicis brevis. The 1223–1233.
remainder of the needle examination was “silent at rest 6. Weber GA. Nerve conduction studies and their clinical
with normal motor unit potentials on volition.” Motor applications. Clin Podiatr Med Surg. 1990;7(1):151–178.
2560_Chapter 12_0135-0142.indd 141 3/16/2015 4:13:24 PM

Process CyanProcess
YellowProcess Black
7. Oh SJ, Eslami T, Nishihira T, et al. Electrophysiological and 10. Josefsson JO, Thesleff S. Electromyographic findings in
clinical correlation in myasthenia gravis. Trans Am Neurol experimental botulinum intoxication. Acta Physiol Scand.
Assoc. 1982;12:348–354. 1961;51:63.
8. Pavesi G, Cattaneo L, Tinchelli S, Mancia D. Masseteric 11. Dabby R, Sadeh M, Herman O, et al. Clinical
repetitive nerve stimulation in the diagnosis of myasthenia electrophysiological and pathologic findings in 10 patients
gravis. Clin Neurophysiol. 2001;112:1064–1069 with myotonic dystrophy 2. Isr Med Assoc J. 2011;13(12):
9. Buchthal F, Rosenfalck P. Electrophysiological aspect of 745–747.
myopathy with particular reference to progressive muscular 12. Wettstein A. The origin of fasciculations in motoneuron
dystrophy. In: Bourne GH, Golarz MN, eds. Muscular disease. Ann Neurol. 1979;3:295–300.
Dystrophy in Man and Animals. New York: Hafner; 1963: 13. Lagueny A. Single fiber electromyography. Rev Med Liege.
193–262. 2004;59(Suppl 1):141–149.
2560_Chapter 12_0135-0142.indd 142 3/16/2015 4:13:24 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 13
Laboratory Investigation
of Suspected Peripheral
Neuropathy
“The investigation of nature is an infinite pasture ground where all may

graze, and where the more bite, the longer the grass grows, the sweeter is its
flavor and the more it flourishes.”
—ALDOUS HUXLEY (1894–1963)
Objectives
• To gain appreciation of the hypothesis-oriented algorithm for clinicians as a method of improving efficiency
and timeliness of the evaluation process for patients with suspected peripheral neuropathy.
• To be able to differentiate screening versus diagnostic laboratory testing.
• To use clinical laboratory testing results as an important adjuvant to the diagnostic process.
• To begin to correlate laboratory data with the physical examination to add to, remove, or confirm the
differential diagnoses.
Key Terms
• Laboratory values
• Hypothesis-Oriented Algorithm for Clinicians (HOAC)
• Laboratory testing
• Screening
• Electrodiagnostic testing
Introduction for the clinician. Initial “clinical scripts” provide clues

enabling the clinician to begin to develop a list of dif-
For most presentations of suspected peripheral neu- ferential diagnoses. The clinician can then eliminate
ropathy, the logical starting point for the diagnostician from, add to, or confirm the list of differential diagno-
is the patient interview and review of prior laboratory, ses through the application and analysis of additional
electrodiagnostic, and radiographic data. Visual and evaluative data obtained from performing the physical
audible clues provided by the patient during the taking examination, ordering additional radiological and lab-
of the medical/surgical history and history of the oratory testing, or asking qualifying questions to the
present illness and hard data from the prior diagnostic patient about the history presented. The HOAC frame-
workup allow the clinician to begin to develop a work allows for a systematic and orderly search for the
differential diagnosis list. The Hypothesis-Oriented differential diagnoses rather than the “shotgun” method
Algorithm for Clinicians (HOAC) and the later itera- of ordering batteries of tests and measures and per-
tion, HOAC II1 provide a logical diagnostic framework forming unnecessary physical examination tests and
143
2560_Chapter 13_0143-0152.indd 143 3/16/2015 4:13:27 PM

Process CyanProcess
YellowProcess Black
Diagnostic Algorithm for Suspected Peripheral Neuropathy
Symptomatic patient
History of Medical
present illness history
Current and
Interview
past medications
Surgical Social and
history vocational
history
Laboratory
Electroneuromyogram studies
Review of prior
diagnostic workup
Radiology Biopsy
studies
Figure 13-1 Example of a diagnostic
algorithm for the evaluation of suspected
Ordering and peripheral neuropathy. The algorithm
Differential Physical
interpretation of was developed by the author and reflects
diagnoses examination
additional diagnostic tests the Hypothesis-Oriented Algorithm
developed by Rothstein et al. (From
Rothstein JM, Echternach JL, Riddle DL.
Update Confirm or eliminate The hypothesis-oriented algorithm for
history differential diagnoses clinicians II (HOAC II): a guide for
Final patient management. Phys Ther.
diagnoses
2003;83(5):455–470.)
measures. As research continues to improve the injury—neurapraxia, axonotmesis, or neurotmesis—

sensitivity and specificity of diagnostic utilities, the use and the type of nerve involved—sensory, autonomic,
of frameworks such as the HOAC will improve the or motor or a combination.
cost-effectiveness and timeliness of diagnostic work Radiographic studies have an important but limited
(Fig. 13-1). role in the workup of suspected peripheral neuropa-
Adjuvant to the physical examination, the clinician thies. Magnetic resonance imaging (MRI) has assumed
relies on additional tests and measures to provide the dominant role in radiological diagnostics of spinal
data to help narrow, add to, or confirm the differential stenosis and brachial and lumbosacral plexopathies.
list of neuropathic diagnoses. These include the Flat plate radiographs, computed tomography (CT),
electroneuromyogram, radiographic studies, autonomic and MRI are useful in identifying offending structures
testing, biopsy, and laboratory testing. in entrapment neuropathies. Central lesions associated
Electroneuromyogram studies are a very important with chronic inflammatory demyelinating polyradicu-
part of the diagnostic workup. Abnormal electrodi- loneuropathy may be seen with MRI. Imaging studies
agnostic studies provide unequivocal information to help identify primary tumors related to paraneoplastic
the diagnostician that there is a neuropathic diagno- syndrome and other cancer-induced neuropathies.
sis (normal studies cannot prove or disprove a neuro- However, many diagnoses that result in motor, sensory,
logical diagnosis—small myelinated and unmyelinated and autonomic neuropathies are best evaluated with
fibers cannot be assessed by typical electrodiagnos- tools other than radiography.
tic testing). Electrodiagnostic studies also assist the Autonomic function testing is useful in specific
clinician in determining the neurological extent of circumstances, especially in neuropathies in which
the abnormal process, including uni-, hemi-, para-, or autonomic failure is the predominant manifestation.
quadri-limb involvement; systemic or local; mononeu- Autonomic testing assists the clinician in determin-
ropathy, multiple mononeuropathies, or systemic neu- ing sympathetic and parasympathetic nervous system
ropathy; and involvement of roots, cords, or peripheral involvement, the location as either local or systemic
nerve branches. Lastly, the electroneuromyogram pro- and preganglionic or postganglionic, and the severity
vides the clinician with the neurological extent of the of the manifestation. Examples of autonomic function
2560_Chapter 13_0143-0152.indd 144 3/16/2015 4:13:28 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 13 | Laboratory Investigation of Suspected Peripheral Neuropathy 145
testing are the quantitative sudomotor axon reflex test coronary risk screen laboratory assessments all may
and the simple “tilt test.” be “negative” one day, and the individual may have
Nerve biopsy, an invasive procedure with often per- a myocardial infarction the next day. The positive pre-
sistent (2 to 3 weeks or longer) symptoms after biopsy, dictive value of a test is directly related to the preva-
is used to assist with the confirmation of a host of lence of the disease in the community. The more
neuropathic disorders, including vasculitides, sarcoid- prevalent the disease, the more valid the measure; the
osis, heredity neuropathy, Farber disease, and leprosy. less prevalent the disease, the less valid the measure.
Because of the spectrum of available laboratory A diagnosis can rarely, if ever, be made based on
testing, tests should be ordered on the basis of screen- laboratory testing alone. The reliability, and to a lesser
ing, confirmation, or eliminating a differential diagno- extent the validity, of the diagnostic process depends
sis. Except for basic screening tools, there is no clinical on the clinical decision-making skills, the use of
laboratory order set that fits all patients with suspected evidence-based inquiry, and the clinical expertise of
peripheral neuropathy. In this chapter, we review the the diagnostician.
basic battery of screening laboratory tools and discuss
disease-specific tests to assist with narrowing the dif- Complete Blood Count
ferential diagnosis list. We review basic screening and Screening tests may be ordered individually or ordered
neurological laboratory testing and discuss the diag- in group format such as the complete blood count
nostic, functional, and interventional implications of (CBC) or metabolic panel. These tests typically are not
the test results. diagnostic; rather, they are ordered to provide a cursory
glimpse of the health of all corporal systems. Because
possible etiologies for peripheral nerve injury include
Laboratory Screening Tests dysfunction related to all corporal systems, it is intui-
tive to perform, at a minimum, a screen of each corpo-
Advances in understanding of the pathogenesis and ral system.
progress of disease have led to a spectral systems’ view The CBC is an evaluation of components typically
of illness rather than an isolated system etiology, such found in venous blood. It is not a measure of the
as a disease being of purely neurological, integument, function of these components. For instance, an indi-
or orthopedic origin. For this reason, after the inter- vidual may have a normal red blood cell count but
view and review of previously ordered diagnostic data, may have a disease resulting in abnormal oxygen trans-
master diagnosticians and interventionists advocate port. The components of the CBC include white
one-time screening of all organ systems as a starting blood cell (WBC) count, red blood cell (RBC) count,
point of the diagnostic inquiry. Screening tests, whether hemoglobin (Hgb), hematocrit (Hct), and platelets
part of the physical examination, imaging database, or (Table 13-1).
laboratory workup, are useful adjuncts in evaluating the WBC count volume screens the immune system and
patient’s overall state of health, medical conditions, and assists in identifying the presence of inflammatory pro-
potential contraindications to therapy by adding to, cesses. An increase in WBC count greater than 11 ×
eliminating, or confirming differential diagnoses. 103 is called leukocytosis. Leukocytosis occurs in
As a caveat, there are limitations to laboratory the presence of infection—primarily bacterial. Leuko-
testing. As with all diagnostic tests, each laboratory cytosis is also seen with leukemia, severe trauma,
screening test has a percentage of false-positive and inflammatory disease, significant tissue necrosis, and
false-negative results. Over-the-counter, prescription, pregnancy. WBC counts less than 5 × 103 are known
and illegal medications may affect laboratory values. as leukopenia and are associated with chemotherapy,
Some tests must be ordered for a specific time of day radiation, bone marrow failure, chronic infection, and
and either fasting or nonfasting. Reference ranges and HIV. WBC count differential estimates the percentage
processing of samples may vary by laboratory. Many of different types of WBCs (leukocytes) being pro-
laboratory tests have no predictive value. For instance, duced. Distinctive patterns of WBCs are produced
Table 13-1 Complete Blood Count Normal Values

WBC Count (cells/mL) RBC Count (mL/μL) Hematocrit (%) Hemoglobin (g/dL) Platelet Count (cells/μL)
Men 4,000–10,000 4.7–5.5 43–49 14.4–16.6 15,000–410,000
Women 4,000–10,000 4.1–4.9 38–44 12.2–14.7 15,000–410,000
WBC, White blood cell; RBC, red blood cell.
Pagana K, Pagana T. Mosby’s Rapid Reference to Diagnostic and Laboratory Tests. St. Louis: Mosby; 2000
2560_Chapter 13_0143-0152.indd 145 3/16/2015 4:13:28 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
by different disease states. The differential count is Table 13-2 Basic Metabolic Panel Normal Values
expressed as a percentage of the total number of WBCs.
The absolute number of each type of WBC is obtained Test Normal Value
by multiplying the percentage of one type by the total
WBC count.2 Sodium 136.0–145.0 mEq/L
RBC count measures the quantity of RBCs in a Potassium 3.5–5.0 mEq/L
given volume of blood. RBCs carry the functional unit Carbon dioxide 23.0–33.0 mEq/L
of oxygenation, Hgb. Anemia is the most common
Blood urea nitrogen 10.0–20.0 mg/dL
cause of a low RBC count. The etiologies of anemia are
many and include acute or chronic blood loss, destruc- Creatinine 0.6–1.2 mg/dL
tion of RBCs, decreased production of RBCs, and Glucose 70.0–110.0 mg/dL
molecular defects in the shape of RBCs such as seen Chloride 98.0–106.0 mEq/L
with sickle cell anemia. An elevated RBC count is
known as polycythemia.2
Hct measures the percent, by volume, of packed
RBCs in a centrifuged volume of blood. Hct percent- and diabetes—all with implications of neuropathic
ages often correlate with Hgb values. Hgb is a measure symptoms.
in grams of Hgb found in 1 dL of whole blood and is
often represented in grams. Hgb and Hct are used to Basic Metabolic Panel
assess hydration, anemia, and polycythemia. Low Hct The constituents of the basic metabolic panel (BMP)
and Hgb levels are typically indicative of anemia, are defined by Current Procedure Terminology (CPT)
chronic inflammatory illness, or hemodilution. Ele- codes.5 The BMP replaces the antiquated panels such
vated levels may be indicative of chronic hypoxemia as as the SMA-6, SMA-12, chemistry panel, chemis-
seen with chronic obstructive pulmonary disease and try screen, and SMAC-12. The BMP is a group of
pulmonary fibrosis, polycythemia vera, and residing at eight tests and consists of serum concentrations of
high altitudes.2 sodium, potassium, chloride, calcium, blood urea nitro-
Platelets circulate in the blood and assist with the gen (BUN), creatinine, glucose, and carbon dioxide.
clotting cascade. Platelets form “plugs” in the walls of Venous blood samples obtained after a 10- to 12-hour
ruptured blood vessels to stem the tide of leakage. fast are used for assessment (Table 13-2).2
Normal platelet values are 150,000 to 400,000 per Sodium (Na+) is an electrolyte metal that is impor-
microliter of blood. Thrombocytosis occurs when the tant in the development and propagation of action
platelet count is elevated greater than 1 million per potentials in nerve, in muscle contraction, in con-
microliter of blood. Causes of thrombocytosis include trolling osmotic gradients, and in many aspects of
neoplasm, inflammation, infection, and polycythemia cellular function. Normal values range from 136.0–
vera. Thrombocytosis increases the risk of clot forma- 145.0 mEq/L.3 Sodium blood levels are affected by
tion. Thrombocytopenia occurs when there are less diet, medications, activity, and disease processes.3 Ele-
than 150,000 platelets per microliter of blood.2 Causes vated sodium is referred to as hypernatremia; decreased
of thrombocytopenia include neoplasm, viral infection, sodium is referred to as hyponatremia. Abnormali-
nutritional deficiency, drug interaction, radiation, che- ties in sodium blood concentrations result in many
motherapy, aplastic anemia, HIV, and idiopathic potential impairments. Fluid concentrations within
thrombocytopenia.2,3 Thrombocytopenia may lead to and external to cells are dependent on sodium con-
internal or external hemorrhage of blood vessels, ecchy- centration. Action potential dysfunction may result in
moses, purpura, and petechiae.4 cardiac arrhythmia, muscle weakness, loss of sensation,
Abnormal results of the CBC in conjunction with mental status changes, and potential intracranial hem-
symptoms of peripheral neuropathy may assist with the orrhage with coma and possible death.5 No specific
diagnostic path. For instance, abnormalities in the exercise guidelines are available for individuals with
WBC count may lead the diagnostician to look for a hypernatremia or hyponatremia.
space-occupying abscess that may result in compres- Potassium (K+) is an electrolyte that is strongly asso-
sion of a peripheral nerve or a neoplasm with resultant ciated with optimal neuromuscular function. Even
paraneoplastic syndrome. Elevated platelets may lead minor changes in blood potassium concentrations may
to nerve infarction; diminished platelets may lead to have a severe impact on health. Normal values range
internal hemorrhage resulting in space-occupying from 3.5 to 5.0 mEq/L. Hypokalemia, or decreased
hematoma. Thrombocytopenia may also be indicative potassium concentrations, may produce ventricular
of nutritional deficiencies that may result in systemic arrhythmia including fibrillation, cardiac irritability,
neuropathy. A chronically low Hgb and Hct may be ST-T segment depression, dizziness, low blood pres-
indicative of “anemia of chronic illness,” such as rheu- sure, and a decreased left ventricular ejection fraction.
matoid arthritis, cancer, systemic lupus erythematosus, Hyperkalemia, or elevated potassium concentration,
2560_Chapter 13_0143-0152.indd 146 3/16/2015 4:13:28 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
may produce nausea, vomiting, and electrocardiogram
changes including arrhythmia.5 Because of the small
Laboratory Diagnostic Testing
window of acceptable blood potassium concentrations,
Specialized laboratory tests, alone or in combination
individuals with even minor elevated or decreased
with other tests and measures, are ordered to rule in
potassium levels should not exercise.
or rule out specific pathology or, if a diagnosis is
Carbon dioxide (CO2) content is a measure of the
already confirmed, may be used to assess severity of the
concentration of CO2 in blood. Knowledge of the con-
disease or to measure progression or improvement of
centration assists with evaluating pH and electrolyte
the disease.
status. CO2 also is an indirect measurement of bicar-
bonate (HCO3), which is regulated by the kidneys.
Hemostasis
Because CO2 assists with regulation of pH, abnormali-
ties may produce alkalosis or acidosis.3 Hemostasis, also called clotting studies and bleeding
Blood urea nitrogen (BUN) and creatinine are both time, is used to determine the body’s ability to initiate
regulated by the kidneys. Renal failure causes metabo- the clotting cascade and how rapidly the cascade occurs
lite wastes to accumulate in the blood, which can be and to diagnose specific primary clotting diagnoses
measured to assess renal function. BUN is formed in such as hemophilia. Hemostatic studies may also be
the liver and is the end product of dietary protein used to assess the effectiveness and dosage of antico-
breakdown. It is filtered by the kidney and excreted in agulant therapy used as prophylaxis against clot in
urine. BUN concentration is directly related to kidney various diagnoses such as atrial fibrillation, valvular
function and the metabolic function of the liver. Smaller replacement, arterial thoracic outlet syndrome, and
changes in BUN concentration may be a reflection of deep vein thrombosis.7 Common hemostatic studies
dietary protein intake.3 In individuals with combined include the international normalized ratio (INR), pro-
liver and kidney disease, the BUN concentration may thrombin time (PT), and activated partial thrombo-
be normal secondary to a combined cause of poor plastin time (APTT).2,4 The INR was developed as a
hepatic function creating less BUN and poor renal method to express PT in a standard format, eliminat-
function resulting in poor excretion. Creatinine is the ing laboratory variability.3 The INR is the ratio of the
by-product of normal muscle metabolism and repre- individual’s result to the reference range, correcting for
sents a gradient between production by muscle and variability in the PT testing hardware reagents and
clearance by the kidney. Because muscle mass is rela- materials. The PT evaluates thrombin production. The
tively constant, changes in creatinine concentrations APTT assesses the production and use of clotting
are most likely related to kidney function. Similar to factors. Aberrant clotting times, whether extensive or
BUN, it is regulated by the kidney and is used as a diminished, disease based or intervention based, may
marker for kidney function.4 result in neuropathy secondary to possible internal
Blood glucose (BG) or blood sugar (BS) is a mea- hematoma formation or nerve/cord ischemia owing
surement of the BS level. Evaluation of this concentra- to infarct.
tion must always be based on the time of day the
sample was taken and whether or not it was a fasting Inflammation
sample. Hypoglycemia, a decreased BG level, may be The presence and severity of inflammation can be mea-
secondary to starvation, insulinoma, or insulin (or oral sured in a nonspecific method using erythrocyte sedi-
diabetes medication) overdose. Hyperglycemia, an ele- mentation rate (ESR) and C-reactive protein (CRP).
vated BG concentration, may be due to one of various ESR is the rate that RBCs settle by gravity in a given
diabetes diagnoses or acute stress.6 volume of unclotted plasma in 1 hour. The test is based
Chloride (Cl−) is an electrolyte controlled by the on the premise that inflammation and necrotic pro-
kidneys. Because the concentration varies with fluid cesses lead to an alteration in blood cell proteins,
status, Cl− levels are often used to determine levels of resulting in an aggregation within the RBCs making
hydration. Cl− also assists with acid-base metabolism.5 them denser than RBCs in individuals without inflam-
Abnormalities in the BMP may also affect the diag- mation or necrosis.2 The faster the cells fall, the higher
nostic process when searching for possible etiologies of the ESR and the greater the inflammation. ESR may
neuropathy. Fluid overload may lead to compressive be used as a screening test for systemic inflammatory
neuropathies. Hypokalemia or hyperkalemia may affect diseases such as rheumatoid arthritis, systemic lupus
action potential associated with sensory, autonomic, erythematosus, and infection.8 It is often used as a
and motor nerves resulting in dysfunction. Chronic screening tool to differentiate rheumatic diseases from
kidney disease with associated elevated BUN and complaints organic in nature.5 ESR may also be used
creatinine is strongly associated with peripheral neu- to assess the effectiveness of medications given to
ropathy. Hyperglycemia associated with diabetes is decrease inflammation.7 CRP was originally believed
the leading cause of motor and sensory neuropathy to quantify inflammation specifically associated with
worldwide. coronary artery disease, but subsequent studies have
2560_Chapter 13_0143-0152.indd 147 3/16/2015 4:13:28 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
shown that acute and chronic musculoskeletal condi- organ exposure to bacteria and toxins normally filtered
tions may also lead to an elevated CRP, reducing the by the liver. Because the liver has many functions, there
sensitivity of the test for coronary artery disease.9 is not one test to assess liver function; a battery of tests
Although elevated serum CRP concentration has must be used. Liver tests are typically divided into two
been shown to be associated with even mild neuropa- types: tests diagnostic of liver disease and tests that
thy,9,10 it is not very useful as a diagnostic tool because measure a particular liver function. An example of a
of the lack of specificity of the test. However, the ESR test used to diagnose the cause of liver damage is the
and CBC remain useful as a screening tool for rheu- test for gamma-glutamyltransferase (GGT). This test
matological and infectious diseases that may result in is a very sensitive indicator of hepatobiliary tract
neuropathy.10 disease.3 GGT is elevated after alcohol ingestion and
in hepatitis, primary or metastatic liver malignancy,
Cardiac Enzymes and cirrhosis.3 An example of a liver test measuring
Enzymes are typical organic catalysts that facilitate liver function is alanine aminotransferase (ALT),
chemical reactions within cells but are not destroyed in which is a strong indicator of hepatocellular damage
the process. Normally, these enzymes are found within (Table 13-3).8
cells, but damage to cells, especially to the cell walls, Because of the spectrum of hepatic and biliary func-
may cause leakage into the bloodstream. Some enzymes tions, these organs are affected by many disease pro-
are present in all cells; some are present in specific cesses that may also result in neuropathic symptoms.
organs. Identifying these unique enzymes in the blood- For instance, chronic alcohol abuse eventually leads to
stream can often tell us which organ has been injured. liver disease and quite possibly motor and sensory neu-
Cardiac enzymes are monitored following episodic ropathy. Purposeful, accidental, or environmental expo-
chest pain or suspected myocardial infarction. These sure to toxins such as arsenic and mercury may initially
enzymes change in a predictable waxing and waning manifest as abnormalities in liver function but may also
pattern that allows diagnosticians not only to identify result in neuropathic symptoms. HIV and AIDS may
that a cardiac event has occurred (in correlation with manifest as concomitant liver failure and peripheral
the electrocardiogram, echocardiogram, and angiogra- neuropathy.
phy) but also possibly to pinpoint the actual time the
event occurred.2 Enzyme creatine kinase (CK) is a Immunological Tests
sensitive marker for myocardial infarction but not very Immunological testing results have a broad range of
specific because this particular enzyme is also found in potential implications. These tests are used in the diag-
skeletal muscle and may be elevated after muscle injury nosis of immune disorders and allergic reactions, infec-
or disease.3 The CK-MB is a particular CK enzyme tious disease, rheumatological diagnoses, and neoplastic
found primarily in the heart. The CK-MB and CK are diseases.2,3 Immunoglobulins, antibodies that are pro-
measured in suspected cardiac injury, and if the CK-MB duced in response to antigens, are divided into five
exceeds 5.0% of the CK, there is a strong likelihood classes (IgG, IgA, IgM, IgD, and IgE). In testing, each
that cardiac injury has occurred.3 The volume of of the classes of globulins is divided via electrophoresis
CK-MB in the bloodstream is correlated with the into different fractions.3 The pattern of fractions is
quantity of coronary damage.2,11 Serum CK begins uniquely elevated in response to specific illnesses.
increasing 3 to 8 hours after a cardiac event, peaks in Rheumatoid factor is seen in persons with and without
10 to 30 hours, and returns to normal in 3 to 5 days. rheumatoid arthritis, but most adults with rheumatoid
CK-MB begins increasing 4 to 8 hours after a cardiac arthritis do exhibit it.3 Antinuclear antibodies are non-
event, peaks in 12 to 24 hours, and returns to normal specific antibodies that react with antigens in all organs.
in 2 to 3 days.3 Lactic acid dehydrogenase (LDH) is A positive response is not specific for a particular
an extracellular enzyme distributed to most internal disease, but a negative response rules strongly against
organs. LDH begins increasing 1 to 2 days after a the diagnosis of a rheumatological disease. Antinuclear
cardiac event, peaks in 3 to 5 days, and returns to antibodies are used more as a conformational test
normal in 8 to 14 days.3 rather than for diagnosis.12
A cardiac workup including enzymes, electrocardio- Immunological testing has a large role in confirming
gram, stress testing, and imaging studies is often useful diagnoses associated with signs and symptoms of
in at-risk patients with face, neck, jaw, scapular, arm, peripheral neuropathy. Many rheumatological diseases
and forearm symptoms that may be cardiac in origin including rheumatoid arthritis, systemic lupus erythe-
but may also be due to gastrointestinal or cervical/ matosus, and the spondyloarthropathies have a high
thoracic radicular symptoms. association with neuropathic symptoms. Immunologi-
cal testing is used to confirm the diagnosis of these
Liver Enzymes diseases as well as infectious entities such as Guillain-
Poor liver function places a patient at risk for multior- Barré syndrome (GBS) and the Miller-Fischer varia-
gan dysfunction syndrome because of a higher risk of tion of GBS. Paraneoplastic syndrome, paraneoplastic
2560_Chapter 13_0143-0152.indd 148 3/16/2015 4:13:28 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Table 13-3 Laboratory Tests for Liver and Biliary Disease

Panel Test Normal Range Comment
Bilirubin Direct serum bilirubin 0.1–0.3 mg/dL Increased with biliary obstruction
Indirect serum bilirubin 0.2–0.8 mg/dL Increased with bile duct dysfunction, primary liver disease,
cirrhosis
Total bilirubin 0.1–2.0 mg/dL Increased in cirrhosis, hepatitis, anemia, transfusion
reaction, hepatic malignancy
Urine bilirubin 0.0 mg/dL
Serum proteins Albumin 3.5–5.5 g/dL Decreased in malnutrition states, Crohn’s disease, anorexia,
bulimia, burns, liver disease
Globulin 2.5–3.5 g/dL Increased in hepatitis
Total 6.0–8.0 g/dL See albumin
A:G 1.5:1–2.5:1 Ratio reverses chronic liver disease
Transferrin 250–300 μg/dL Decreases with liver disease; increases with iron deficiency
Alpha-fetoprotein 6–20 ng/mL Cancer-associated antigen
Serum enzymes AST 8–20 U/L Increased in liver damage and primary muscle disease
(i.e., Duchenne)
ALT 5–35 U/L See AST
LDH 45–90 U/L See AST
GGT 5–38 U/L See AST
ALP 30–85 U/L Increased in primary liver cancer, rheumatoid arthritis,
biliary obstruction
Ammonia Blood ammonia <75 μg/dL Increased in liver dysfunction
A:G, Albumin-to-globulin ratio; AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; GGT, gamma-
glutamyltransferase; ALP, alkaline phosphatase.
encephalomyelitis, and subacute sensory neuronopathy Table 13-4 Urinalysis, Microscopic Examination of Sediment,
are associated with antineuronal nuclear antibody type
and Chemical Content
I.3 Immunological testing also has a significant role in
the diagnosis of suspected vasculitic neuropathy. Herpes Urinalysis Examination of Sediment Chemical Content
zoster infections may be detected by varicella-zoster
virus–specific IgM antibody in blood; this antibody Color: Pale Casts: Negative Ketones: Negative
yellow to
appears only during active episodes of chickenpox or
amber-yellow
herpes zoster and not while the virus is dormant.13
Turbidity: Clear Red blood cells: Blood: Negative
Urinalysis to slightly hazy Negative or rare
Urine is best described as the end product of a host of Specific gravity: Crystals: Negative Bilirubin: Negative
metabolic processes in the body, and examination of 1.015–1.025
the urine can provide a host of information about pH: 4.5–8 White blood cells: Nitrate for bacteria:
health and disease. Urine is an extremely complex sub- Negative or rare Negative
stance, 95% liquid and 5% solids, with primary con- Epithelial cells: Leukocyte esterase:
stituents of water, sodium chloride, and urea with Rare Negative
smaller concentrations of protein, glucose, ketones,
blood, and minute concentrations of more than 1000
chemicals (Table 13-4).8 Urine should be pale yellow
in color owing to the presence of urochrome, a chemi- Specific gravity is a measure of urine concentration.
cal found in food and that is also a by-product of bile Diluted urine has a low specific gravity, and concen-
metabolism. Color other than pale yellow is often the trated urine has a high specific gravity. Abnormal spe-
result of food intake (carrots, rhubarb, beats, grape cific gravity with normal hydration status may indicate
juice), medications (antiplatelet drugs, levodopa, lax- renal disease.2 The presence of red blood cells is indica-
itives), or disease (hepatic failure, disseminating intra- tive of occult blood.2 The presence of myoglobinuria is
vascular coagulation).14 Bleeding from the urinary typically related to skeletal muscle injury.3 Glucose
tract may result in urine ranging in color from beet red may be found in the urine if the concentration of blood
to bright red depending on the source of bleeding. glucose exceeds the ability of the renal tubules to
2560_Chapter 13_0143-0152.indd 149 3/16/2015 4:13:28 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
reabsorb it, resulting in “urine spillage.”3 Slight sugar Table 13-5 Relationship of Hemoglobin A1c Percentage and
concentrations found in the urine may not be patho-
Mean Blood Sugar
logical; stress and heavy, sugary meals may lead to
spillage.8 Ketonuria is due to the use of fats as the Hemoglobin A1c (%) Mean Blood Sugar (mg/dL)
primary source of energy and is an early indication of
possible diabetic coma.5 Urine may also be screened for 6 135
prescription, over-the-counter, and illegal drugs.8 7 170
Urinalysis is a useful adjunct in identifying diagno- 8 205
ses related to peripheral neuropathy. Urinalysis can
9 240
be used to assist with the diagnoses of metabolic
abnormalities, diabetes, renal disease, and clotting 10 275
abnormalities. 11 310
12 345
Culture
Normal flora abounds on the skin, in the mouth, and
in the gastrointestinal tract. In some pathological con-
ditions, these bacteria “escape” and enter the blood- falls, and gait dysfunction. These symptoms mimic
stream leading to the potential of life-threatening many systemic peripheral neuropathies.15
metastatic infection. Heart valves, bones, joints, and
internal organs all may be seeded by septicemia. Blood Hemoglobin A1c
culturing is the random sampling of blood and cultur- Finger-stick BS provides only a “snapshot” of BG con-
ing it to determine if bacterial growth occurs. Because centrations. Hgb A1c provides a 3-month view of mean
the chance of obtaining a bacterium from one sampling BG concentrations. Glucose molecules “stick” to the
is small, blood cultures are often drawn three times, proteins within RBCs, and because these cells live for
increasing the chance of encountering a pathogen. For an average of 3 months, laboratory assessment of the
blood culturing to be effective, samples must be drawn number of glucose molecules attached to the proteins
before the initiation of antibiotics.8 in the RBC provides an excellent long-term view of
glucose control. In most laboratories, the normal range
Rapid Plasma Reagin is 4.0% to 5.9%. In patients with diabetes, acceptable
Syphilis is a sexually transmitted disease caused by the Hgb A1c, indicating good control, is less than 7.0%. The
organism Treponema pallidum. The rapid plasma reagin American Association of Clinical Endocrinologists
(RPR) looks for nonspecific antibodies in the blood of recommends a goal of less than 6.5%. Poorly controlled
a patient that may indicate the presence of the bacteria. is defined as greater than 8.0% (Table 13-5).16 Numer-
The RPR level is also a titer and can be used to track ous studies have documented data showing that poorly
the progress of the disease over time and its response controlled diabetes is directly related to the early onset
to antibiotic therapy. The test is most sensitive (90% to of peripheral neuropathy and the severity of the signs
100%) in infections present for at least 1 month and and symptoms.
less sensitive in newly acquired infections or infections
present for months.15
Syphilis, although not directly associated with
peripheral neuropathy, is often on the differential diag-
CASE STUDY
nosis list because of the gummatous and late (tertiary) DB is a 62-year-old man who was referred to a
neurosyphilis complication. Gummatous syphilis, also physical therapist with a diagnosis of falls. His medical
known as late benign syphilis, begins an average of 15 history includes hypertension, type 2 diabetes mellitus,
years after untreated infection acquisition and is char- and hypercholesterolemia. Vital signs at the evaluation
acterized by the formation of chromic gummas, soft included a heart rate of 72, blood pressure 132/88,
tumor-like balls of inflammation that vary in size and respiratory rate of 16, and oxygen saturation of 98%
location. They often affect skin, bone, and liver but may on room air. A fasting finger-stick blood sugar was
appear anywhere. Owing to the potential location adja- 102 mg/dL. Physical examination revealed no focal,
cent to peripheral nerve, gummas may result in com- unilateral, or patterned motor weakness with strength
pressive or tensile neuropathies. Late neurosyphilis 5/5 throughout. Tone was normal. No neurological
occurs 4 to 25 years after acute infection. Tabes dorsa- deficits were noted except for decreased vibration and
lis, a complication of late neurosyphilis, affects the pos- kinesthetic sense in both lower extremities from the
terior white column of the spinal cord resulting in knees to the toes and impaired balance tests: Romberg
decreased proprioception and kinesthetic and vibratory eyes closed 8 seconds and a Timed Up and Go
sense. Functionally, patients with tabes dorsalis have balance assessment of less than expected for the age
loss of gross and fine motor control, ataxia, frequent group. Observational gait examination revealed a
2560_Chapter 13_0143-0152.indd 150 3/16/2015 4:13:28 PM

Process CyanProcess
YellowProcess Black
mildly wide-based gait pattern with shortened stride References
bilaterally and decreased arm swing. DB did not use
1. Rothstein JM, Echternach JL, Riddle DL. The hypothesis-
any assistive devices. oriented algorithm for clinicians II (HOAC II): a guide for
patient management. Phys Ther. 2003;83(5):455–470.
2. Pagana K, Pagana T. Mosby’s Rapid Reference to Diagnostic and
Case Study Questions Laboratory Tests. St. Louis: Mosby; 2000.
3. Fischbach F. Nurses’ Quick Reference to Common Laboratory
1. The therapist can rule out diabetes mellitus as a and Diagnostic Tests. 3rd ed. Philadelphia: Lippincott
possible cause of DB’s falls for which of the Williams & Wilkins; 2002.
following reasons? 4. Tsai H. Advances in the pathogenesis, diagnosis, and
treatment of thrombotic thrombocytopenic purpura. J Am Soc
a. There is no documented focal motor weakness. Nephrol. 2003;14:1072–1081.
b. The finger-stick blood sugar value was in the 5. Goodman CC, Boissonnault WG, Fuller KS. Pathology:
normal range: 102 mg/dL. Implications for the Physical Therapist. 2nd ed. Philadelphia:
c. The blood pressure was mildly elevated. Saunders; 2003.
d. The therapist cannot, with the current information 6. Rother KI. Diabetes treatment—bridging the divide. N Engl J
Med 2007;356(15):1499–1501.
presented, rule out diabetes as a cause of the 7. Poller L, Keown M, Chauhan N, et al. European Concerted
falls. Action on Anticoagulation. Correction of displayed
international normalized ratio on two point-of-care test
2. To assist with “ruling in” diabetes as a cause for the whole-blood prothrombin time monitors (CoaguChek Mini
falls, which laboratory test would be most indicated? and TAS PT-NC) by independent international sensitivity
a. Hemoglobin A1c index calibration. Br J Haematol. 2003;122(6):944–949.
b. Urinalysis 8. Goodman C, Snyder T. Differential Diagnosis in Physical
c. Repeat finger-stick blood sugar Therapy. Philadelphia: Saunders; 1990.
9. Lloyd-Jones DM, Liu K, Tian L, Greenland P. Narrative
d. Complete blood count review: assessment of C-reactive protein in risk prediction for
3. To rule out anemia as a cause for the falls, which cardiovascular disease. Ann Intern Med. 2006;145(1):35–42.
10. Carp SJ, Barbe MF, Barr AE. Serum biomarkers as signals
laboratory test would be most indicated? for risk and severity of work-related musculoskeletal injury.
a. Hemoglobin A1c Biomark Med. 2008;2:67–79.
b. Urinalysis 11. Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger
c. Repeat finger-stick blood sugar HM. Intracellular compartmentation, structure and function
d. Complete blood count of creatine kinase isoenzymes in tissues with high and
fluctuating energy emends: the ‘phosphocreatine circuit’ for
4. To rule out a urinary tract infection as a cause for the cellular energy homeostasis. Biochem J. 1992;281(1):21–40.
falls, which laboratory test would be most indicated? 12. Kavanaugh A, Tomar R, Reveille J, Solomon DH,
Homburger HA. Guidelines for clinical use of the antinuclear
a. Hemoglobin A1c antibody test and tests for specific autoantibodies to nuclear
b. Urinalysis antigens. Arch Pathol Lab Med. 2000;124:71–81.
c. Repeat finger-stick blood sugar 13. Johnson RW, Dworkin RH (2003). Treatment of herpes
d. Complete blood count zoster and postherpetic neuralgia. BMJ
2003;326(7392):748–750.
5. The hemoglobin A1c test looks “back” at the blood 14. Nicolle LE. Uncomplicated urinary tract infection in adults
sugar concentration for a period of how long? including uncomplicated pyelonephritis. Urol Clin North Am.
a. 1 hour 2008;35(1):1–12.
15. Kent ME, Romanelli F. Reexamining syphilis: an update on
b. 1 day epidemiology, clinical manifestations, and management. Ann
c. 1 month Pharmacother. 2003;42(2):226–236.
d. 3 months 16. American Diabetes Association. Standards of medical care in
diabetes—2007. Diabetes Care. 2007;30(Suppl 1):S4–S41.
2560_Chapter 13_0143-0152.indd 151 3/16/2015 4:13:28 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
2560_Glossary_0347-0360.indd 360 3/17/2015 12:11:29 PM
Chapter 14
The Examination: Evaluation of
the Patient With Suspected
“Seize the moment of excited curiosity on any subject to solve your doubts;
for if you let it pass, the desire may never return and you may remain
forever in ignorance.”
—WILLIAM WIRT (1772–1834)
Objectives
• Develop an evidenced-based evaluative algorithm for assessment of suspected peripheral neuropathy.
• Develop sufficient knowledge of the cognitive components of the peripheral neuropathy evaluation to enable
the practicing therapist to develop valid and reliable psychomotor components of the evaluation.
• Identify important signs and symptoms that may relate to peripheral neuropathy.
Key Terms
• Assessment
• Evaluation
• Peripheral neuropathy
by identifying functional problems and developing

Introduction time-based functional goals and a goal-oriented
intervention.
The physical examiner encountering a patient with sus-
pected peripheral neuropathy has four primary chal-
lenges. The first challenge is to obtain a thorough,
comprehensive, and valid oral history of the chief com- The Chief Complaint
plaint, history of the present illness, past medical
history, past surgical history, current and past medica- Following the development of the patient-therapeutic
tions, family history, and review of systems. The second relationship, a good probing question for the part of
challenge is to perform, as directed by the oral history, the interview inquiring about the chief complaint is
a comprehensive physical and functional examination. “So, what brought you here to see me today?” Such an
The third challenge is to review and incorporate key open-ended question encourages the patient to talk.
diagnostic findings such as blood indices, radiological Typically, a patient with neuropathy relates an onset
data, and electroneuromyogram results into the clinical of one or a combination of the following: motor
decision-making algorithm. The fourth challenge is weakness, falls, tonal changes, dyscoordination, sensory
to complete the clinical decision-making algorithm loss, ataxia, or autonomic complaints. The practitioner
153
2560_Chapter 14_0153-0170.indd 153 3/16/2015 4:13:31 PM

Process CyanProcess
YellowProcess Black
should listen closely to the order in which the patient current and past medical issues, including dates of
expresses his or her complaints. Typically, the com- diagnosis. From this list, the examiner identifies any
plaints are presented in the order of the ones that have diagnoses that may directly or secondarily result in a
the most functional impact to ones that have the least complication of peripheral neuropathy. The date of
functional impact. diagnosis of the disease does not always equate with
the onset of the disease, but the date of diagnosis pro-
vides the examiner with a reference especially when
History of the Present Illness searching for time-related neuropathies. Examples
include diabetes mellitus, cancer, and peripheral vascu-
Following the patient’s brief explanation of what lar disease; less obvious examples are malabsorption
brought him or her to the clinic for evaluation, the syndromes and inflammatory bowel disease such as
practitioner should begin to search for the history of Crohn’s disease and irritable bowel syndrome, which
the present illness. Patients often describe their symp- may lead to vitamin deficiencies and resultant periph-
toms with simple but descriptive adjectives and phrases, eral neuropathy.
such as “burning,” “tingling,” “clumsiness,” “loss of Second, the examiner should ask the patient to list
balance,” “dizziness,” “ache,” and “knifelike pain.” Prac- all surgeries and dates of surgeries. The examiner is
titioners should always focus on the time frame of the searching for surgeries that may directly or indirectly
onset of symptoms. Arbitrary but very useful boundar- relate to peripheral neuropathies, such as carpal tunnel
ies have been established to determine if a symptom is syndrome, back fusion or laminectomy, brachial plexus
acute, subacute, or chronic. Categorizing symptoms as neurolysis, and vascular bypass. Gastric bypass surger-
acute (present for days to 4 weeks), subacute (present ies have been linked with essential vitamin deficiencies
for 4 weeks to 2 months), or chronic (present for greater leading to peripheral neuropathy.
than 2 months) is often helpful in establishing differ- Third, the examiner should ask the patient for a
ential diagnoses. For instance, neuropathy related to list of current and recently prescribed and over-the-
Guillain-Barré syndrome1–3 often develops in less than counter medications or herbals including dosages.
4 weeks. Diabetic neuropathy may take years to develop Because this list often requires a bit of work by the
fully and manifests as a chronic condition. Paraneo- patient, the office scheduler can ask the patient to
plastic neuropathies may evolve as subacute or chronic prepare this list before the office visit and examination.
neuropathies.4–6 Many medications have a dose-related complication of
There may be confusion related to the perception of peripheral neuropathy. The examiner also can ask the
the onset of the neuropathy. Often a patient presents patient about recreational drug usage during the dis-
to a practitioner because of an exacerbation or worsen- cussion of medications. Nitrous oxide and cocaine have
ing of symptoms rather than the onset of symptoms. been linked to peripheral neuropathy.10–18
Inherited and some viral neuropathies often begin in Finally, after obtaining the medical, surgical, and
childhood, but the patient presents only when there is medication histories, the examiner should “triangulate”
a functional loss.7,8 Pointed questions often assist with these data to see if any data point was inadvertently
the diagnostic process, such as the following: “Did you excluded. For instance, if the patient is taking an anti-
play sports as a child?”; “Did you walk differently from platelet medication and there is nothing in the medical
the other children when you were a child?”; “Could you or surgical history that explains this medication, further
run as fast as the other children?”; “Did you often have questioning is indicated (Table 14-1).19–38
ankle sprains as a child?”
Location of onset is important. Most neuropathies
have a neural length relationship; the symptoms tend Social and Occupational Histories
to initiate farthest from the body core—that is, the
hands and feet. Sensory symptoms in the trunk, but- The examiner takes a social history to identify potential
tocks, thighs, shoulders, and arms or proximal motor barriers to a successful intervention and to identify
symptoms such as difficulty rising from a chair, climb- hobbies, occupations, habits, and behaviors that may
ing steps, or reaching overhead as presenting symp- have induced the peripheral neuropathy. Table 14-2
toms may suggest an inflammatory demyelinating outlines hobbies and occupations that may involve sus-
polyneuropathy.9 tained exposure to neurotoxic chemical compounds
that may result in signs and symptoms of peripheral
neuropathy.39–54 For example, neurotoxic hexacarbons
Past Medical and Surgical Histories are found in the paint and solvents used by automobile
painters. Similar hexacarbons are found in furniture
Review of the past medical and surgical histories of a stains and paint removers used by furniture makers and
patient with neuropathy should focus on four key areas. refinishers. Welders may exhibit high levels of central
First, the examiner should ask the patient to relate all and peripheral neurotoxic lead. Habits and behaviors
2560_Chapter 14_0153-0170.indd 154 3/16/2015 4:13:31 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 14 | The Examination: Evaluation of the Patient With Suspected Peripheral Neuropathy 155
Table 14-1 Medications That May Result in Table 14-2 Hobbies and Occupations That May Predispose to
Peripheral Neuropathy Peripheral Neuropathy
Procainamide Almitrine Gold salts Occupation/Hobby Neuropathic Toxin
Phenytoin Isoniazid Suramin Oral surgeons, dentists, dental Nitrous oxide
Cisplatin Chloroquine Misonidazole hygienists
Pyridoxine excess Nitrous oxide Amiodarone Cabinet makers, house painters, Hexacarbons
industrial/auto painters
Colchicine Vinca alkaloids Thalidomide
Agricultural workers (farmers, Organophosphates
Dapsone Paclitaxel Metronidazole harvesters, researchers)
Didanosine Nitrofurantoin Perhexiline Dry cleaners, rubber workers, tire Trichloroethylene
Disulfiram Zalcitabine Stavudine manufacturers
Doxorubicin Tacrolimus Sildenafil Manufacturers of batteries, plastics Lead
Ethambutol Welders, firearms instructors, Lead
demolition crews
Data compiled from Ziconotide: new drug. Limited analgesic efficacy,
too many adverse effects. Prescrire Int. 2008;17(97):179–182; Painters, roofers, plumbers, refinishers Lead
Biondi DM. Is migraine a neuropathic pain syndrome? Curr Pain
Headache Rep. 2006;10(3):167–178; Brouwers EE, Huitema AD,
Glassmakers, glassblowers Lead
Boogerd W, Beijnen JH, Schellens JH. Persistent neuropathy after Copper smelters, tree sprayers, Arsenic
treatment with cisplatin and oxaliplatin. Acta Oncol. 2009;48(6):832–
taxidermists, jewelers
841; Castro M. Peripheral sensory neuropathy—fighting cold with
cold. Lancet Oncol. 2008;9(5):415–416; Dees EC, O’Neil BH, Plastic industry workers Acrylamide
Lindley CM, et al. A phase I and pharmacologic study of the
combination of bortezomib and pegylated liposomal doxorubicin in Rayon industry workers Carbon disulfide
patients with refractory solid tumors. Cancer Chemother Pharmacol.
2008;63(1):99–107; Doherty SD, Hsu S. A case series of 48 Data entry clerks, typists, low-force/ Compressive,
patients treated with thalidomide. J Drugs Dermatol. 2008;7(8):769– high-repetition activities inflammatory
773; Eksioglu E, Oztekin F, Unlu E, Cakci A, Keyik B, Karadavut IK.
Sacroiliitis and polyneuropathy during isotretinoin treatment. Clin Exp Data compiled from Occupational Medicine Physician’s Guide to
Dermatol. 2008;33(2):122–124; Gdynia HJ, Muller T, Sperfeld AD, Neuropathy in the Workplace Part 3: Case Presentation. J Occup
et al. Severe sensorimotor neuropathy after intake of highest dosages Environ Med. 2009;51(7):861–862; Gimranova GG, Bakiirov AB,
of vitamin B6. Neuromuscul Disord. 2008;18(2):156–158; Hoque R, Karimova LK. Complex evaluation of work conditions and health
Chesson AL Jr. Pharmacologically induced/exacerbated restless legs state of oil industry workers [in Russian]. Med Tr Prom Ekol. 2009;(8):
syndrome, periodic limb movements of sleep, and REM behavior 1–5; Goffeng LO, Heier MS, Kjuus H, Sjoholm H, Sorensen KA,
disorder/REM sleep without atonia: literature review, qualitative Skaug V. Nerve conduction, visual evoked responses and
scoring, and comparative analysis. J Clin Sleep Med. 2010;6(1):79– electroretinography in tunnel workers previously exposed to acrylamide
83; Kautio AL, Haanpaa M, Leminen A, Kalso E, Kautiainen H, and N-methylolacrylamide containing grouting agents. Neurotoxicol
Saarto T. Amitriptyline in the prevention of chemotherapy-induced Teratol. 2008;30(3):186–194; Huang CC. Polyneuropathy induced
neuropathic symptoms. Anticancer Res. 2009;29(7):2601–2606; by n-hexane intoxication in Taiwan. Acta Neurol Taiwan.
Koh C, Kwong KL, Wong SN. Mercury poisoning: a rare but treatable 2008;17(1):3–10; Krajnak K, Waugh S, Johnson C, Miller R,
cause of failure to thrive and developmental regression in an infant. Kiedrowski M. Vibration disrupts vascular function in a model of
Hong Kong Med J. 2009;15(1):61–64; Kumarasamy N, Venkatesh metabolic syndrome. Ind Health. 2009;47(5):533–542; Kutlu G,
KK, Cecelia AJ, et al. Spectrum of adverse events after generic HAART Gomceli YB, Sonmez T, Inan LE. Peripheral neuropathy and visual
in southern Indian HIV-infected patients. AIDS Patient Care STDS. evoked potential changes in workers exposed to n-hexane. J Clin
2008;22(4):337–344; Moore A, Pinkerton R. Vincristine: can its Neurosci. 2009;16(10):1296–1299; Lagueny A. Drug induced
therapeutic index be enhanced? Pediatr Blood Cancer. 2009;53(7): neuropathies. Rev Prat. 2008;58(17):1910–1916; Lansdown AB.
1180–1187; Nakamura Y, Tajima K, Kawagoe I, Kanai M, Critical observations on the neurotoxicity of silver. Crit Rev Toxicol.
Mitsuhata H. Efficacy of traditional herbal medicine, Yokukansan on 2007;37(3):237–250; Ling SK, Cheng SC, Yen CH. Stonefish
patients with neuropathic pain. Masui. 2009;58(10):1248–1255; envenomation with acute carpal tunnel syndrome. Hong Kong Med J.
O’Connor TL, Kossoff E. Delayed seizure associated with paclitaxel- 2009;15(6):471–473; Majersik JJ, Caravati EM, Steffens JD. Severe
Cremophor el in a patient with early-stage breast cancer. neurotoxicity associated with exposure to the solvent 1-bromopropane
Pharmacotherapy. 2009;29(8):993–996; Pierce DA, Holt SR, (n-propyl bromide). Clin Toxicol (Phila). 2007;45(3):270–276;
Reeves-Daniel A. A probable case of gabapentin-related reversible Matsuoka M. Neurotoxicity of organic solvents—recent findings.
hearing loss in a patient with acute renal failure. Clin Ther. Brain Nerve. 2007;59(6):591–596; Ohnari K, Uozumi T,
2008;30(9):1681–1684; Qi X, Chu Z, Mahller YY, Stringer KF, Tsuji S. Occupation and carpal tunnel syndrome. Brain Nerve.
Witte DP, Cripe TP. Cancer-selective targeting and cytotoxicity by 2007;59(11):1247–1252; Pelclova D, Urban P, Ridzon P, et al.
liposomal-coupled lysosomal saposin C protein. Clin Cancer Res. Two-year follow-up of two patients after severe thallium intoxication.
2009;15(18):5840–5851; Selvarajah D, Gandhi R, Emery CJ, Hum Exp Toxicol. 2009;28(5):263–272; Puriene A, Janulyte V,
Tesfaye S. Randomized placebo-controlled double-blind clinical trial of Musteikyte M, Bendinskaite R. General health of dentists. Literature
cannabis-based medicinal product (Sativex) in painful diabetic review. Stomatologija. 2007;9(1):10–20; Sauni R, Paakkonen R,
neuropathy: depression is a major confounding factor. Diabetes Care. Virtema P, et al. Vibration-induced white finger syndrome and carpal
2010;33(1):128–130; Singh S, Mukherjee KK, Gill KD, Flora SJ. tunnel syndrome among Finnish metal workers. Int Arch Occup Environ
Lead-induced peripheral neuropathy following ayurvedic medication. Health. 2009;82(4):445–453; and Sethi PK, Khandelwal D.
Indian J Med Sci. 2009;63(9):408–410; and Toyooka K, Fujimura H. Cadmium exposure: health hazards of silver cottage industry in
Iatrogenic neuropathies. Curr Opin Neurol. 2009;22(5):475–479. developing countries. J Med Toxicol. 2006;2(1):14–15.
2560_Chapter 14_0153-0170.indd 155 3/16/2015 4:13:31 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
may lead to risk of peripheral neuropathy. Smoking
often leads to neoplasms of the face, neck, jaw, and
Review of Systems
lung possibly resulting in paraneoplastic peripheral
The review of systems is typically performed as a
neuropathy. Excessive alcohol ingestion is linked
question-and-answer session directed by the exam-
to nutritional and vitamin deficiencies, which are
iner. Unless asked, the patient may not connect minor
linked to peripheral neuropathy. Cocaine use may lead
symptoms from distant or seemingly unrelated sites to
to vasculitic neuropathy secondary to hypertension
the neuropathic complaint. In addition, some patients
(Table 14-3).39–54
may be unwilling to offer information about poten-
tially embarrassing symptoms related to reproductive,
genitourinary, or gastrointestinal systems unless asked.
Table 14-3 Habits and Behaviors That May Predispose to
Table 14-4 lists examples of probing system health
inquiries. Affirmative answers should be explored
Habit/Behavior Neuropathic Toxin further to obtain additional data. The review of systems
is important as an adjunct tool to evaluate the possible
Paint eating Lead etiology of the peripheral neuropathy (Table 14-5).55–67
Tobacco ingestion (cigarette, cigar, Carcinogen
pipe, snuff, chew)
Excess alcohol Vitamin deficiency Physical Examination
Sexual preference HIV
Information garnered from the chief complaint, history
Medications and vitamin B6 Toxic of the present illness, past medical and surgical histo-
Intravenous drug use HIV ries, medications, social and occupational histories, and
Cocaine use Hypertension
Nitrous oxide use Cobalamin deficiency
Table 14-4 Examples of Health Systems Probing Questions
Vegan diet Cobalamin deficiency
Excessive keyboarding and video Compressive and System Question
games inflammatory Cardiac Do you have chest pain? Do you have
difficulty walking up steps? Do you
Data compiled from Occupational Medicine Physician’s Guide to
Neuropathy in the Workplace Part 3: Case Presentation. J Occup become short of breath when you lie
Environ Med. 2009;51(7):861–862; Gimranova GG, Bakiirov AB, down?
Karimova LK. Complex evaluation of work conditions and health
state of oil industry workers [in Russian]. Med Tr Prom Ekol. 2009;(8): Cancer Have you ever been diagnosed or
1–5; Goffeng LO, Heier MS, Kjuus H, Sjoholm H, Sorensen KA, treated for cancer? Do you have any
Skaug V. Nerve conduction, visual evoked responses and unusual lumps or moles?
electroretinography in tunnel workers previously exposed to acrylamide
and N-methylolacrylamide containing grouting agents. Neurotoxicol Endocrine Are you often unexpectedly tired? Do
Teratol. 2008;30(3):186–194; Huang CC. Polyneuropathy induced you have excessive thirst? Do you feel
by n-hexane intoxication in Taiwan. Acta Neurol Taiwan. more tired than usual?
2008;17(1):3–10; Krajnak K, Waugh S, Johnson C, Miller R,
Kiedrowski M. Vibration disrupts vascular function in a model of Gastrointestinal How is your appetite? Do you ever
metabolic syndrome. Ind Health. 2009;47(5):533–542; Kutlu G, notice bloody stools? Does your belly
Gomceli YB, Sonmez T, Inan LE. Peripheral neuropathy and visual hurt? Do you have regular bowel
evoked potential changes in workers exposed to n-hexane. J Clin
Neurosci. 2009;16(10):1296–1299; Lagueny A. Drug induced
movements?
neuropathies. Rev Prat. 2008;58(17):1910–1916; Lansdown AB. Genitourinary Do you urinate excessively? Are you
Critical observations on the neurotoxicity of silver. Crit Rev Toxicol.
incontinent? Are there any sexual
2007;37(3):237–250; Ling SK, Cheng SC, Yen CH. Stonefish
envenomation with acute carpal tunnel syndrome. Hong Kong Med J. concerns?
2009;15(6):471–473; Majersik JJ, Caravati EM, Steffens JD. Severe Integument Do you have any skin wounds that are
neurotoxicity associated with exposure to the solvent 1-bromopropane
(n-propyl bromide). Clin Toxicol (Phila). 2007;45(3):270–276; not healing? Do you have any rashes?
Matsuoka M. Neurotoxicity of organic solvents—recent findings. Brain Musculoskeletal Do you have joint or muscle pain? Do
Nerve. 2007;59(6):591–596; Ohnari K, Uozumi T, Tsuji S.
Occupation and carpal tunnel syndrome. Brain Nerve.
you feel stiff? Do you feel weak? Have
2007;59(11):1247–1252; Pelclova D, Urban P, Ridzon P, et al. you fallen recently?
Two-year follow-up of two patients after severe thallium intoxication.
Pulmonary Do you have breathing issues? Do you
Hum Exp Toxicol. 2009;28(5):263–272; Puriene A, Janulyte V,
Musteikyte M, Bendinskaite R. General health of dentists. Literature get short of breath with minimal activity?
review. Stomatologija. 2007;9(1):10–20; Sauni R, Paakkonen R, Do you wheeze when you breathe?
Virtema P, et al. Vibration-induced white finger syndrome and carpal
tunnel syndrome among Finnish metal workers. Int Arch Occup Environ Sensory Have you noticed any recent visual or
Health. 2009;82(4):445–453; and Sethi PK, Khandelwal D. hearing changes? Do you have any
Cadmium exposure: health hazards of silver cottage industry in numb areas on your body?
developing countries. J Med Toxicol. 2006;2(1):14–15.
2560_Chapter 14_0153-0170.indd 156 3/16/2015 4:13:32 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
neuropathy. Heart rate, respiration rate, blood pressure,
Table 14-5 Neuropathies Associated With System Impairment
and oxygen saturation provide a momentary perspec-
System Neuropathy (or Possible Neuropathic-like Symptoms) tive into the patient’s general health and act as a screen-
ing tool for potential issues not yet discovered by the
Cardiac Mitral valve prolapse, arrhythmia, primary care physician. A finger-stick blood sugar test
coronary artery disease
should also be added to the list of vital signs. Although
Endocrine Diabetic, hypothyroid limited in scope, reliability, and validity in diagnosing
Gastrointestinal Amyloid, chronic inflammatory an impairment, the finger-stick blood sugar can act as
demyelinating polyneuropathy a screening tool for potential hyperglycemic impair-
Genitourinary Amyloid ments as well as provide feedback to patients who have
a diagnosis of diabetes regarding their blood control.
Integument Diabetic Lastly, visual analog scales (or happy/sad face or Oucher
Musculoskeletal Compressive, tensile, connective tissue scales for children) have proved reliable in assessing
disease, traumatic pain.68–70 The visual analog scale can be expanded to
Neurological Compressive, tensile, neoplastic, include anterior and posterior corporal figures on
repetitive strain which the patient can mark the location and type of
Pulmonary Sarcoid, paraneoplastic pain symptoms.
Sensory Inherited neuropathies, amyloid, Postural Examination and
chemotoxic, Refsum disease, Fabry Corporal Presentation
disease
Peripheral neuropathy, with possible impact on the
Data from Aboussouan LS, Lewis RA, Shy ME. Disorders of pulmonary efferent and afferent systems, may stress the joints and
function, sleep, and the upper airway in Charcot-Marie-Tooth disease. muscles and induce sufficient pain to alter posture. In
Lung. 2007;185(1):1–7; Coste TC, Gerbi A, Vague P, Maixent JM,
Pieroni G, Raccah D. Peripheral diabetic neuropathy and addition, postural changes resulting from habit, trauma,
polyunsaturated fatty acid supplementations: natural sources or degeneration, or illness may secondarily affect the
biotechnological needs? Cell Mol Biol (Noisy-le-grand). peripheral nervous system leading to sensory, motor,
2004;50(7):845–853; Di Nardo G, Blandizzi C, Volta U, et al.
Review article: molecular, pathological and therapeutic features of and autonomic signs and symptoms. Maintenance of
human enteric neuropathies. Aliment Pharmacol Ther. 2008;28(1):25– correct posture requires motor and somatosensory
42; Freeman R. Autonomic peripheral neuropathy. Neurol Clin. systems that are strong, flexible, and easily adaptable to
2007;25(1):277–301; Lacigova S, Bartunek L, Cechurova D, et al.
Influence of cardiovascular autonomic neuropathy on atherogenesis environmental change.
and heart function in patients with type 1 diabetes. Diabetes Res Clin Postural assessment begins informally with first
Pract. 2009;83(1):26–31; Manzella D, Paolisso G. Cardiac patient contact and expands as an integral and defini-
autonomic activity and Type II diabetes mellitus. Clin Sci (Lond).
2005;108(2):93–99; Maule S, Papotti G, Naso D, Magnino C, tive part of the physical examination. To assess posture
Testa E, Veglio F. Orthostatic hypotension: evaluation Cardiovasc accurately, the patient should be adequately undressed
Hematol Disord Drug Targets. 2007;7(1):63–70; Mehta A, Ricci R, and should not wear shoes or socks. Adaptive equip-
Widmer U, et al. Fabry disease defined: baseline clinical
manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin ment such as orthoses and assistive equipment such as
Invest. 2004;34(3):236–242; Oka N, Sugiyama H, Kawasaki T, walkers, canes, or crutches should be noted. Standing
Mizutani K, Matsui M. Falls in peripheral neuropathy [in Japanese]. and sitting posture should be assessed in the normal or
Rinsho Shinkeigaku. 2005;45(3):207–210; Sacco IC, Bacarin TA,
Canettieri MG, Hennig EM. Plantar pressures during shod gait in relaxed state, which is often difficult for the patient to
diabetic neuropathic patients with and without a history of plantar assume when being watched. A plumb line or plastic
ulceration. J Am Podiatr Med Assoc. 2009;99(4):285–294; Said G. postural assessment screen often aids the postural
Familial amyloid polyneuropathy: mechanisms leading to nerve
degeneration. Amyloid. 2003;10(Suppl 1):7–12; Vial C, Bouhour F. examination (Figs. 14-1 and 14-2).
Vasculitis multiple mononeuropathies [in French]. Rev Prat. Postural assessment begins with a visual screening
2008;58(17):1896–1899; and Yeung H, Krentz HB, Gill MJ, Power of symmetry. In the anteroposterior view, is the head
C. Neuropsychiatric disorders in HIV infection: impact of diagnosis on
economic costs of care. AIDS. 2006;20(16):2005–2009. straight on the shoulders? Is the jaw in midline? Is the
neck line, as defined by the upper trapezius line, sym-
metrical on both sides? Are both acromion processes
review of systems influences the examiner’s algorithm elevated equally? Are the waist angles equal, and are
of the planned physical examination for peripheral the arms hung equidistant from the hips? Are the car-
nerve injury. The physical examination can help confirm rying angles of the elbows equal? Is the internal/
a suspected diagnosis garnered from the interview, or external rotation of the shoulders equal as represented
the physical examination may prompt additional inter- by palm position? Is the spine straight with normal
view questions. cervical, thoracic, and lumbosacral curves? Is there a
scoliosis? Are the anterior superior iliac spines equal in
Vital Signs elevation? Are the patellae of the knees pointing
Standard vital signs should be taken with all new straight ahead? Are the knees straight? Is there genu
patients, not only patients with suspected peripheral valgus or varus? Are the arches present in both feet,
2560_Chapter 14_0153-0170.indd 157 3/16/2015 4:13:32 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Postural Analysis Grid Chart
Figure 14-3 Habitual slouched chair posture may result in

axial and articular dysfunction, which often progresses to
nerve impingement syndromes. Long-standing postural
abnormalities in sitting, standing, or supine/prone may
Figure 14-1 Postural assessment using a postural screen:
result in chronic soft tissue changes leading to nerve injury
posterior view. Postural screen validity is enhanced thorugh
related to aberrant compressive or tensile forces.
the use of static postural graphical screens or through the
use of two-dimensional videography.
and do they appear equal? Are all muscle groups sym-

metrical in size and location? In the mediolateral view,
note the position of the head. Is it forward on the trunk
as measured through an imaginary line passing from
the earlobe to the anterior portion of the acromion
process? Are the scapulae protracted? Is the sternal
angle depressed or exaggerated? Are the thoracic
kyphosis and lumbar lordosis normal, exaggerated, or
depressed? Do the knees exhibit recurvatum?
Posture in the sitting position should also be
assessed anteroposteriorly and mediolaterally. Struc-
tural anatomy impairments noted in standing should
also be noted in sitting. In addition, poor sitting posture
as directed by habit or impairment, such as a flattened
lumbar lordosis, exaggerated thoracic curve, flattened
cervical lordosis, forward head, and protracted scapu-
lae, may lead to axial and articular dysfunction resulting
in nerve impingement (Figs. 14-3 and 14-4).
Integument Examination
Figure 14-2 Asymmetrical position of scapulae as seen Examination of the integument typically follows the
with intrinsic scapular muscle weakness. Visual screening postural assessment. The entire body should be scanned
is a necessary component of the physical examination. as well as the oral mucosa. Skin ulcerations—chronic,
Overt postural abnormalities may result in only small acute, or healing—may be associated with diabetic
changes in articular range of motion and muscle strength. neuropathy or vasculopathy.71 These ulcerations are
typically neural and vascular–length dependent and are
often found on the legs, ankles, feet, and hands.
However, poorly healing traumatic injures may be
2560_Chapter 14_0153-0170.indd 158 3/16/2015 4:13:32 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Figure 14-4 Muscle wasting of calf muscle. Wasting noted Figure 14-5 Mees lines are typical of arsenic or thallium
in the gastrocsoleus complex. intoxication. From Goldsmith, Adult and Pediatric Dermatology,
F.A. Davis, Philadelphia, 1997, page 535.
found anywhere on the body, especially over areas that

are often injured during daily life such as the shins,
elbows, and hips. Cellulitis is associated with diabetic
vasculopathy71 and can be found anywhere on the body.
The cellulitis may be primary—directly related to
trauma—or secondary—that is, “seeded” from a distant
skin opening or infected site. Purpura and livedo retic-
ularis are often associated with vasculitides.72,73 Alope-
cia may be a sign of hypothyroidism, systemic lupus
erythematosis, or thallium intoxication.74–76 Mees lines
are associated with arsenic or thallium intoxication.77–82
Clubbing of the fingertips is associated with inflam-
matory lung disease, lung cancer, liver disease, and
inflammatory bowel disease.83–86 White nails may be
associated with POEMS (polyneuropathy, organo-
megaly, endocrinopathy, monoclonal gammopathy, and
skin changes) (Figs. 14-5).87–90 Figure 14-6 Kaposi’s sarcoma, oral ulcerations, and needle
Integument examination continues with pulse tracks are integument signs of potential HIV infection.
assessment. Upper extremity pulses—radial and From Goldsmith, Adult and Pediatric Dermatology, F.A. Davis,
brachial—and lower extremity pulses—femoral, popli- Philadelphia, 1997, page 414.
teal, dorsalis pedis, and posterior—should be assessed
and graded. Diminished pulse may indicate vascular may be secondary to eclampsia or preeclampsia. The
impingement as seen with arterial thoracic outlet syn- edema may be of sufficient magnitude to have a struc-
drome or peripheral vascular disease. tural impact on a neighboring peripheral nerve.91,92
Peripheral edema has many etiologies, but a few may Edematous articular joints may indicate infection,
have an impact on the diagnosis of peripheral neuropa- joint effusion, trauma, or neuropathic joints. Painful
thy. Venous thoracic outlet syndrome results in acute axial joints may indicate discitis, disc herniation, spinal
or chronic subclavian vein obstruction by a neighbor- stenosis, or compression fracture; all of these etiologies
ing structure and may result in brachial plexus com- are capable of resulting in radicular peripheral nerve
pression. Lower extremity edema may be caused by a symptoms.
lower abdominal space-occupying lesion that may also The presence of needle tracks on the arms or legs,
affect the lumbosacral plexus. Edema in a pregnant oral ulcerations, and Kaposi’s sarcoma may indicate
woman may be related to positional dependency or HIV infection/AIDS (Fig. 14-6).
2560_Chapter 14_0153-0170.indd 159 3/16/2015 4:13:32 PM

Process CyanProcess
YellowProcess Black
Salivary gland swelling may indicate Sjögren syn- examiner should note the end-feel of the blockage.
drome.93,94 Lymphadenopathy may indicate an acute or End-feel may be bony, as with normal full extension of
subacute viral or bacterial infection. the elbow joint; capsular, as with attempts at hyperex-
tension of the metacarpophalangeal joints; springy, as
Musculoskeletal Examination with blockage by a piece of fractured articular cartilage
The musculoskeletal system consists of bones, joints, or loose body; spongy, as with limitations via joint
fascias, ligaments, tendons, and entheses. Documenting effusion; empty, as limited by the patient’s unwilling-
muscle strength, articular range of motion (ROM), ness to allow the joint to be moved further because of
axial ROM, and two-joint muscle lengths is intrinsic pain or fear; spasm secondary to muscle contraction or
to all examinations. Valid measurements of the muscu- tone; and neural, as exemplified by the sensation felt
loskeletal system provide an initial baseline data source by the patient of a neural tethering. In addition to
to serve three purposes: to help with diagnosis and limited movement patterns found with cardinal plane
prognosis, to determine improvement or deterioration goniometry, the examiner should look for evidence of
of function in follow-up assessments, and to assess the joint hypomobility and hypermobility by examining
efficacy of intervention. the structure of the joint capsule and associated col-
Manual muscle testing (MMT) has been validated, lateral and extra-articular and interarticular ligaments.
primarily with larger muscles, in many clinical Joint hypermobility secondary to traumatic lesions,
studies.95–98 To facilitate interrater reliability, the exam- such as lesions often seen in the medial collateral
iner should use a standard method of examination and ligament of overhead baseball pitchers, may also result
standardized semantics of grading. Standardization in compression or tensile neuropathies of local periph-
must include patient position, locus of resistance, and eral nerves (the ulnar nerve in the case of baseball
locus of stabilization. Examiners should develop a pitchers). Limitations in articular or axial ROM may
pattern of MMT that includes at least one muscle from result from peripheral neuropathy secondary to articu-
each central and peripheral myotome. A form-based lar manifestations of neural tethering, space-occupying
assessment is recommended to prompt the examiner as lesions, inflammation, or poorly healed or aligned
to which muscle to assess. When the MMT is com- fracture.
plete, the examiner may look at the data to determine Two-joint muscles, muscles whose proximal and
if the pattern of weakness is unilateral, upper extremity distal attachments cross two joints, should also be
versus lower extremity, central myotome dependent, examined for length. The biceps brachii and the triceps
peripheral myotome dependent, or asymmetrical. brachii in the upper extremity and the rectus femoris,
Intrinsic hand muscles and gross grasp are best assessed hamstring group, and gastrocnemius in the lower
via pinch and grasp dynamometers (Fig. 14-7). extremity may exhibit passive insufficiency with
Axial and articular active range of motion (AROM) attempts to stretch the muscle across two joints. The
and passive range of motion (PROM) are best assessed passive insufficiency may be sufficient to restrict func-
via cardinal plane measurements with a goniometer. tional articular motion and result in tensile stresses to
AROM should be performed first and followed with peripheral nerves at the terminus of range of motion.
PROM measurements if the AROM deviates from
what is expected. With limitations in PROM, the Neurological Examination
The comprehensive neurological examination provides
the examiner with direct evidence of motor, sensory,
and autonomic involvement secondary to nerve injury.
The examiner uses the data provided by the neurologi-
cal examination to determine if the symptoms are
upper motor neuron, lower motor neuron, or mixed; to
define the extent of the impairment; to collect final
data before the functional examination; and to aid in
diagnosis and prognosis. As with muscle strength
testing, an algorithm-based and evidence-driven exam-
ination greatly adds to the reliability of the neurologi-
cal examination.
Sensory System Examination
The sensory system examination is the most difficult
portion of the neurological examination not only
because of the inherent reliability and validity issues
but also because it is driven by the patient’s perception,
Figure 14-7 Manual muscle test of a 5/5 biceps brachii. understanding, and cooperation. In addition, the
2560_Chapter 14_0153-0170.indd 160 3/16/2015 4:13:32 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
presence of a peripheral or central neuropathy may lead are nonspecific screening tests that, if positive, may
to a confused perception and localization of sensory indicate impairment in the sensorimotor, visual, or ves-
symptoms on the part of the patient. Regardless of tibular systems.98–105
these barriers, a meticulously performed sensory system Postural tone, if abnormal, may be indicative of
examination may provide enormous benefits with upper motor neuron, lower motor neuron, basal ganglia,
determination of diagnosis, prognosis, and extent of extrapyramidal, or medication-induced impairments.
the illness. Spasticity, characterized by hyperactive deep tendon
At a minimum, the sensory system examination reflexes, obligatory posturing, a patterned response to
should include an assessment of the following modali- hypertonicity, associated reactions, and a clasp-knife
ties: light touch, sharp, vibration, and proprioception. response to quick stretch by the examiner, is associated
Additional modalities that may be assessed include with upper motor neuron lesions—lesions occurring
temperature and deep pressure. Light touch may be above the level of the anterior horn cell. Hypotonus, as
assessed with a wisp of cotton; sharp, with a safety pin; related to nerve injury, is characterized by diminished
vibration, with a tuning fork; hot and cold, with test or absent deep tendon reflexes, “floppy” extremities,
tubes filled with hot and cold water, respectively; and and an empty response to quick stretch by the examiner
deep pressure, with a finger. and is associated with lower motor neuron lesions—
The examination should be performed with the lesions below and at the level of the anterior horn cell.
patient first in the supine position and then in the Rigidity—characterized by increased tone in a nonpat-
prone position. Tested areas must be exposed. Con- terned distribution in the limbs, trunk, and face; a
founding sensory data such as draping sheets, air cogwheeling response to quick stretch by the examiner;
blowing from fans, and ambient music should be con- bradykinesia; and festination—is associated with basal
trolled. The examiner needs to provide the patient with ganglia and extrapyramidal impairments. Rigidity may
adequate instruction about the testing method before also be traumatic or medication-induced.
beginning the examination. A corporal representation With movement of the extremities and the axial
form often helps the examiner document the results of skeleton, the nervous system slides and glides relative
the testing. to surrounding structures and is subject to stretch. A
Large-fiber sensory testing is often the most diffi- healthy nervous system can tolerate this loading,
cult to perform. The use of a tuning fork for vibratory whereas low levels of stretch in nerves with epineural
sense is straightforward. A representative “education” or perineural scarring secondary to chronic inflamma-
of the patient as to what sensation is elicited by the tion or nerves compressed by local structures are suf-
tuning fork—typically performed on the chin, man- ficient to generate ectopic impulses from an inflamed
dible, or acromion—is followed by the testing. A sym- nerve. The ectopic impulses typically travel distally in
metrical touching of bony prominences is performed the radicular distribution.106,107 This increased mecha-
beginning in the feet and working proximally, con- nosensitivity is the key characteristic that is evaluated
stantly querying the patient as to whether the intensity in many clinical provocation tests, such as Spurling’s
is equal symmetrically and if the intensity is equal to test for cervical radiculopathy, Tinel’s sign, and the
the “normative” intensity at the location. The testing straight leg–raising test for lumbar radiculopathy.
pattern typically begins at the fifth metatarsal head on The straight leg–raising test108–110 and the femoral
the right, fifth metatarsal head on the left, first meta- nerve test109 in the lower extremity and the various
tarsophalangeal joint on the right, first metatarsopha- upper limb neural tension tests111–116 were designed to
langeal joint on the left, navicular on the right, and so evaluate the mechanosensitivity of the sciatic nerve,
on. Following the testing over two bony prominences, femoral nerve, brachial plexus, median nerve, radial
the tuning fork needs to be re-excited. Proprioception, nerve, and ulnar nerve. A neurodynamic test is consid-
the sense of the position of parts of the body relative ered positive if symptoms can be reproduced and if
to other neighboring parts of the body, is a more dif- symptoms can be altered by structural differentia-
ficult modality to assess reliably than the tactile sensory tion.111,112 Structural differentiation uses static and
modalities. Examiners use a variety of testing active movement at a site remote to the entrapment
methods—all with relevancy but all with confounding area to load further or unload the nervous system.112–115
and uncontrolled variables and with less than hoped An example is the addition of contralateral cervical
for reliability. Some examiners passively position one lateral bend away from horizontal adduction of the
extremity and ask the patient, with eyes closed, to arm; this tests the median nerve. The reliability of
mimic the position with the contralateral extremity. upper and lower limb neurodynamic testing has been
This method requires the patient to have greater than explored widely. Most of these studies investigated
3/5 motor strength and normal tone in all muscles in whether symptom reproduction occurred at a consis-
the contralateral extremity. The Romberg and Sharp- tent point through ROM. The overall view is that
ened Romberg for the trunk and lower extremities and ROM measurement at the point of symptom repro-
the pronator drift for the trunk and upper extremities duction is reliable (Table 14-6).
2560_Chapter 14_0153-0170.indd 161 3/16/2015 4:13:32 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Table 14-6 Large-Fiber Neuropathies Resulting in Loss of Proprioceptive and Kinesthetic Function
Chemotoxic disorders Pyrinuron Immune-mediated Paraneoplastic neuropathy
Metronidazole disorders Sensory neuropathy associated with
Cisplatin sicca syndrome
Vitamin B6 Idiopathic sensory neuropathy
Nitrous oxide Diabetic neuropathy
Infectious disorders Tabes dorsalis Guillain-Barré syndrome
Diphtheritic polyneuropathy Miller-Fisher variant of Guillain-Barré
HIV neuropathy syndrome
Chronic inflammatory demyelinating
polyneuropathy
Multiple sclerosis
Data compiled from Azhary H, Farooq MU, Bhanushali M, Majid A, Kassab MY. Peripheral neuropathy: differential diagnosis and management.
Am Fam Physician. 2010;81(7):887–892; Schroder A, Linker RA, Gold R. Plasmapheresis for neurological disorders. Expert Rev Neurother. 2009;
9(9):1331–1339; Zhang Q, Gu Z, Jiang J, et al. Orthostatic hypotension as a presenting symptom of the Guillain-Barre syndrome. Clin Auton Res.
2010;20(3):209–210; Compston A. Primary sensory neuropathy with muscular changes associated with carcinoma. Editorial. Brain. 2009;
132(Pt 8):1995–1996; Isoda A, Sakurai A, Ogawa Y, et al. Chronic inflammatory demyelinating polyneuropathy accompanied by chronic
myelomonocytic leukemia: possible pathogenesis of autoimmunity in myelodysplastic syndrome. Int J Hematol. 2009;90(2):239–242; Amlie-Lefond
C, Jubelt B. Neurologic manifestations of varicella zoster virus infections. Curr Neurol Neurosci Rep. 2009;9(6):430–434; Lunn MP, Willison HJ.
Diagnosis and treatment of inflammatory neuropathies. J Neurol Neurosurg Psychiatry. 2009;80(3):249–258; Isoda A, Sakurai A, Ogawa Y, et al.
Chronic inflammatory demyelinating polyneuropathy accompanied by chronic myelomonocytic leukemia: possible pathogenesis of autoimmunity in
myelodysplastic syndrome. Int J Hematol. 2009;90(2):239–242; Neiman J, Haapaniemi HM, Hillbom M. Neurological complications of drug
abuse: pathophysiological mechanisms. Eur J Neurol. 2000;7(6):595–606; O’Connor G, McMahon G. Complications of heroin abuse. Eur J
Emerg Med. 2008;15(2):104–106; O’Sullivan JM, McMahon G. Descending polyneuropathy in an intravenous drug user. Eur J Emerg Med.
2005;12(5):248–250; Ziconotide: new drug. Limited analgesic efficacy, too many adverse effects. Prescrire Int. 2008;17(97):179–182; Biondi
DM. Is migraine a neuropathic pain syndrome? Curr Pain Headache Rep. 2006;10(3):167–178; Brouwers EE, Huitema AD, Boogerd W, Beijnen
JH, Schellens JH. Persistent neuropathy after treatment with cisplatin and oxaliplatin. Acta Oncol. 2009;48(6):832–841; Castro M. Peripheral
sensory neuropathy—fighting cold with cold. Lancet Oncol. 2008;9(5):415–416; Dees EC, O’Neil BH, Lindley CM, et al. A phase I and
pharmacologic study of the combination of bortezomib and pegylated liposomal doxorubicin in patients with refractory solid tumors. Cancer
Chemother Pharmacol. 2008;63(1):99–107; Doherty SD, Hsu S. A case series of 48 patients treated with thalidomide. J Drugs Dermatol. 2008;
7(8):769–773; Huang CC. Polyneuropathy induced by n-hexane intoxication in Taiwan. Acta Neurol Taiwan. 2008;17(1):3–10; Coste TC, Gerbi
A, Vague P, Maixent JM, Pieroni G, Raccah D. Peripheral diabetic neuropathy and polyunsaturated fatty acid supplementations: natural sources or
biotechnological needs? Cell Mol Biol (Noisy-le-grand). 2004;50(7):845–853; Di Nardo G, Blandizzi C, Volta U, et al. Molecular, pathological
and therapeutic features of human enteric neuropathies. Aliment Pharmacol Ther. 2008;28(1):25–42; Freeman R. Autonomic peripheral neuropathy.
Neurol Clin. 2007;25(1):277–301; Lacigova S, Bartunek L, Cechurova D, et al. Influence of cardiovascular autonomic neuropathy on atherogenesis
and heart function in patients with type 1 diabetes. Diabetes Res Clin Pract. 2009;83(1):26–31; Manzella D, Paolisso G. Cardiac autonomic
activity and Type II diabetes mellitus. Clin Sci (Lond). 2005;108(2):93–99; Cheer K, Shearman C, Jude EB. Managing complications of the diabetic
foot. BMJ. 2009;339:b4905; Brown PJ, Zirwas MJ, English JC 3rd. The purple digit: an algorithmic approach to diagnosis. Am J Clin Dermatol.
2010;11(2):103–116; Kluger N, Frances C. Cutaneous vasculitis and their differential diagnoses. Clin Exp Rheumatol. 2009;27(1 Suppl 52):
S124–138; and Cohen PR. Primary alopecia neoplastica versus secondary alopecia neoplastica: a new classification for neoplasm-associated scalp
hair loss. J Cutan Pathol. 2009;36(8):917–918.
Because the sensory symptoms of various disease Radicular diseases such as thoracic intervertebral ste-
processes vary in their location, reliable sensory nosis, thoracic compression fractures, and thoracic disc
mapping is extremely useful in assisting with the diag- herniations may result in sensory symptoms along the
nosis. Cobalamin deficiency often manifests as sensory trunk wall.119
disturbances in the upper extremity.117 Guillain-Barré Assessment of the autonomic nervous system is dif-
syndrome1,2 and chronic inflammatory demyelinating ficult to perform in the office, in the clinic, or at the
polyneuropathy118,119 also often begin in the hands. bedside. A hallmark sign of autonomic dysfunction
Unilateral upper extremity involvement may be due to is orthostatic hypotension.121 Orthostatic hypoten-
an isolated mononeuropathy, such as ulnar neuropathy sion is defined as a systolic blood pressure 20 mm Hg
at the elbow, or a more complicated brachial plexus or greater or a diastolic blood pressure 10 mm Hg
neuropathy. or greater with standing after maintaining supine
Examiners should not omit the trunk when per- position at least 5 miniutes.121,122 In patients with
forming a sensory examination. Length-dependent emerging autonomic dysfunction, cardiovagal function
neuropathies such as seen with diabetes often result in may be sufficiently intact to provide a chronotropic
sensory symptoms not only in the typical stocking- response to heart rate to maintain cardiac output. With
glove distribution but also along the anterior truncal long-standing autonomic disease, this response fails to
wall 2 to 4 cm bilateral of midline.120 The distal inter- materialize, and diminished consciousness and poten-
costals and abdominal sensory nerves may also tial for fall result.121–123 Tests involving greater risk to
be affected by length-dependent neuropathies.119,120 the patient or tests requiring additional equipment,
2560_Chapter 14_0153-0170.indd 162 3/16/2015 4:13:32 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
124
Box 14-1
sclerosis. Hyporeflexic responses are often associated
with lower motor neuron dysfunction. Hyporeflexia
Neuropathies Associated With Autonomic Dysfunction may be mononeuropathic or multineuropathic. As a
caveat, early DTR responses to acute upper motor
or Disease neuron injury such as hemorrhagic or thrombotic
Drug-induced neuropathies: paclitaxel, amiodarone, stroke, traumatic brain injury, and spinal cord injury
cisplatin, vincristine may often manifest as hyporeflexic but typically evolve
Alcohol neuropathy to hyperreflexia.124–126
Miller-Fisher variation of Guillain-Barré syndrome Babinski and Clonus Testing
Guillain-Barré syndrome The Babinski and clonus tests are used, often in con-
Paraneoplastic autonomic neuropathy junction with the DTR examination, to assist the
Familial amyloid polyneuropathies
examiner in determining if the symptoms are upper
motor neuron or lower motor neuron. Sensitivity for
Porphyria
the Babinski test has been reported to range from 35%
Chemotoxic neuropathies: thallium, arsenic, mercury, to 96%, and sensitivity for the clonus test has been
organic solvents, hexacarbons
reported to range from 56% to 100%.127–129
Diabetic polyneuropathy Tinel’s Sign
Data compiled from Azhary H, Farooq MU, Bhanushali M, Majid A, Tinel’s sign, named for the French physician Jules
Kassab MY. Peripheral neuropathy: differential diagnosis and Tinel (1879–1952), is often tested in conjunction with
management. Am Fam Physician. 2010;81(7):887–892; Schroder A,
Linker RA, Gold R. Plasmapheresis for neurological disorders. Expert neurodynamic testing.130,131 Tapping of an inflamed,
Rev Neurother. 2009;9(9):1331–1339; Compston A. Primary sensory irritated, entrapped, or reinnervating peripheral nerve
neuropathy with muscular changes associated with carcinoma. may lead to radicular symptoms in the sensory distri-
Editorial. Brain. 2009;132(Pt 8):1995–1996; Layzer R, Wolf J.
Myeloma-associated polyneuropathy responding to lenalidomide. bution of the nerve tested. Tinel’s sign has a fairly high
Neurology. 2009;73(10):812–813; Lunn MP, Willison HJ. Diagnosis sensitivity (70% to 90%) for diagnosis of carpal tunnel
and treatment of inflammatory neuropathies. J Neurol Neurosurg syndrome and ulnar neuropathy at the level of the
Psychiatry. 2009;80(3):249–258; Tatum WO, Bui DD, Grant EG,
Murtagh R. Pseudo-Guillain-Barre syndrome due to “whippet”-induced elbow.130–132
myeloneuropathy. J Neuroimaging. 2010;20(4):400–401; Dees EC,
O’Neil BH, Lindley CM, et al. A phase I and pharmacologic study of Cranial Nerve Examination
the combination of bortezomib and pegylated liposomal doxorubicin in
patients with refractory solid tumors. Cancer Chemother Pharmacol. Cranial nerve examination is an integral part of the
2008;63(1):99–107; Doherty SD, Hsu S. A case series of 48 examination of a patient with suspected peripheral
patients treated with thalidomide. J Drugs Dermatol. 2008;7(8):769– nerve injury (Table 14-7). Anosmia, or loss of smell, is
773; Eksioglu E, Oztekin F, Unlu E, Cakci A, Keyik B, Karadavut IK.
Sacroiliitis and polyneuropathy during isotretinoin treatment. Clin Exp associated with the common diagnoses of diabetic and
Dermatol. 2008;33(2):122–124; Cheer K, Shearman C, Jude EB. hypothyroid-induced peripheral neuropathy1 and with
Managing complications of the diabetic foot. BMJ. the less common diagnoses of cobalamin deficiency117
2009;339:b4905; Brown PJ, Zirwas MJ, English JC 3rd. The purple
digit: an algorithmic approach to diagnosis. Am J Clin Dermatol. and Refsum disease.133 Optic neuritis is often the pre-
2010;11(2):103–116; Kluger N, Frances C. Cutaneous vasculitis senting sign in chronic inflammatory demyelinating
and their differential diagnoses. Clin Exp Rheumatol. 2009;27(1 Suppl polyradiculopathy.5,9 A large pupil that constricts
52):S124–138; and Cohen PR. Primary alopecia neoplastica versus
secondary alopecia neoplastica: a new classification for neoplasm- poorly to light and near vision resulting in a tonic
associated scalp hair loss. J Cutan Pathol. 2009;36(8):917–918. response with poor redilation are signs of tonic pupil,
which is seen in conjunction with widespread or
limited neuropathies such as associated with Guillain-
such as postganglionic sudomotor tests, tilt tests, and Barré syndrome,3,14 Sjögren syndrome,93,94 cancer,134
Valsalva, are better performed in an autonomic reflex and chronic inflammatory demyelinating polyneuropa-
laboratory (Box 14-1). thy.5,9 Facial weakness, with or without pain, is usually
associated with connective tissue diseases such as
Deep Tendon Stretch Examination Sjögren syndrome93 and mixed connective tissue
The deep tendon stretch reflex (DTR) is an excellent disorder.135–137 True facial weakness is often associated
test to assist the examiner in determining upper motor with a focal seventh nerve injury, acquired inflamma-
neuron versus lower motor neuron origin of neuro- tory demyelinating disease, sarcoidosis, and amyo-
pathic symptoms. The examiner should score each trophic lateral sclerosis (Box 14-2).138–144
tendon tap and compare for symmetry, asymmetry, or
unilateral responses. Hyperreflexic responses to tendon Balance Assessment
tap, especially responses accompanied by a positive Postural stability in the dynamic and static state
Babinski sign and clonus, are often indicative of an requires a complex interaction between the somato-
upper motor neuron lesion. Hyperreflexic response sensory system, the vestibular system, and the visual
with the absence of a positive Babinski sign or clonus system within a framework of appropriate musculo-
is rare but may be indicative of amyotrophic lateral skeletal indices and cognition. The goal of the balance
2560_Chapter 14_0153-0170.indd 163 3/17/2015 4:20:53 PM

Process CyanProcess
YellowProcess Black
Table 14-7 Cranial Nerve Testing

Nerve Testing
Olfactory • Test each nostril separately by placing stimuli under one nostril and occluding the other nostril.
Stimuli should be nonirritating, such as cinnamon, toothpaste, or clove.
Optic • Visual acuity is tested in each eye separately via the Snellen eye chart and the near card.
• Visual fields are assessed by asking the patient to cover one eye while the examiner tests the
other. The examiner wiggles a finger in each of the four quadrants, and the patient is asked to
state whether he or she sees the finger in the periphery.
• Pupillary light reflex is tested as the patient stares into the distance as the examiner shines the
penlight obliquely into each pupil. Pupillary constriction should be noted via the consensual and
direct responses.
Oculomotor, trochlear, • Inspect for ptosis, eye position, and nystagmus. Pupil size should be measured with shape and
abducens asymmetry noted. The examiner tests ocular movements by standing 1 m in front of the patient and
asking the patient to follow the target with eyes only. The target is moved in an “H” shape, and
the patient is asked to report diplopia. Nystagmus should be noted.
• The accommodation reflex is testing by moving the target toward the patient’s nose. As the eyes
converge, the pupils should constrict.
Trigeminal • Light touch is tested in the three divisions of the trigeminal nerve on each side of the face using a
cotton wisp. For pain and temperature, a pin (pain) and test tubes of hot and cold water
(temperature) are used.
• The corneal reflex is tested with a wisp of cotton.
• Muscles of mastication (temporalis, masseter) should be inspected for atrophy and symmetry.
Palpate the temporalis and masseter as the patient clenches the jaw. The pterygoids can be tested
by asking the patient to open the mouth against resistance and move the jaw side outside against
resistance. The jaw reflex can be tested by placing a finger over the patient’s chin and tapping
the finger with a reflex hammer.
Facial • Inspect for facial asymmetry, involuntary movements, and fasciculation. The patient shuts eyes
tightly; compare each side.
• The patient grins; compare nasolabial grooves.
• The patient frowns, shows teeth, puffs out cheeks.
Vestibulocochlear • With one of the patient’s ears covered, whisper numbers in the other ear and ask the patient to
repeat the numbers. Conduct the Rinne test and Weber test.
• Weber test: Lateralization. Place 512/1,024 Hz (256 if deaf) vibrating fork on top of patient’s
head/forehead. “Where do you hear sound coming from?” Normal reply is midline.
• Rinne test: Air vs. bone conduction. Place 512/1,024 Hz (256 if deaf) vibrating fork on mastoid
behind ear. Ask the patient to state when he or she stops hearing it. When the patient stops
hearing it, move the vibrating fork to the patient’s ear so that he or she can hear it. Normal: air
conduction (ear) better than bone conduction (mastoid).
Glossopharyngeal • Perform the gag response test to both sides of the soft palate. Assess palatal articulation “KA” and
guttural articulation “GO.”
Accessory • From behind, examine the upper trapezius for symmetry.
• Perform manual muscle test of the upper trapezius and sternocleidomastoid bilaterally.
Hypoglossal • Inspect the tongue for atrophy, fasciculations, or asymmetry with protrusion.
assessment is to identify individuals who, through their Cognitive Examination

impairments, are at risk for falling and require further The most validated of the short forms of cognitive
assessment and ultimately intervention. Peripheral neu- assessment is the Mini-Mental State Examination
ropathy may affect many of the matrices of balance: the (MMSE).149–152 The MMSE provides the examiner
somatosensory system, the vestibular system, the visual with data related to the cognitive ability of the patient.
system, and the musculoskeletal system. A balance If the MMSE score is lower than expected, the patient
screen should have simple and easily understood mea- should be referred for additional cognitive and psycho-
surement tools that reliably and validly identify fall motor assessment. The Beck Depression Inventory is
risk for a given population. Many reliable and well- another validated test to determine the presence of
validated population-specific tools are available.145–148 depression in the patient.153–156 The 36-Item Short
2560_Chapter 14_0153-0170.indd 164 3/16/2015 4:13:32 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Box 14-2
The functional examination is typically scaffolded—
beginning with basic movement patterns that are pre-
Potential Etiologies of True or Apparent Facial Weakness requisites for more complicated patterns and activities.
Scoring is typically nominal either dependent or inde-
Associated With Peripheral Neuropathy pendent or with further delineation such as maximal
Acoustic neuroma assist, moderate assist, minimal assist, contact guard,
Amyotrophic lateral sclerosis or independent. The examiner should also note if
Bell palsy (facial nerve palsy) adaptive equipment such as bracing, prosthetics,
Botulism toxin injection hearing aids, and orthoses are used by the patient
Chronic inflammatory demyelinating polyradiculopathy
during the testing. The examiner should also note
assistive equipment used by the patient at home or
Erb palsy
work, such as walkers, crutches, elevated toilet seats,
Gelsolin amyloidosis shower chairs, and stair glides. The typical functional
HIV examination starting point is bed mobility. Can the
Liposuction patient move to the right, left, up, and down in bed?
Lyme disease Transfers are assessed next. Can the patient transfer
Mastoiditis/mastoidectomy from bed to chair to standing and back to bed? Can
Myasthenia gravis the patient transfer onto a toilet or into a bathtub? The
Parotid gland excision examiner can use visual gait analysis or, if available,
Pseudobulbar palsy quantified measurements of gait performed in a struc-
Sarcoidosis tured gait analysis laboratory to determine impair-
Tangier disease ments in any one or more of the basic subsets of gait.
Facial trauma
Functionally, is the patient able to dress and undress,
perform basic hygiene skills, and don and doff requi-
Data compiled from Bagger-Sjoback D, Remahl S, Ericsson M. site adaptive equipment independently? Fine motor
Long-term outcome of facial palsy in neuroborreliosis. Otol Neurotol.
2005;26(4):790–795; Chernoff WG, Parnes LS. Tuberculous
coordination should be assessed. Validated measures
mastoiditis. J Otolaryngol. 1992;21(4):290–292; Ellis SL, Carter BL, such as the Disabilities of the Arm, Shoulder and
Leehey MA, Conry CM. Bell’s palsy in an older patient with Hand (DASH), Developmental Test of Visual-Motor
uncontrolled hypertension due to medication nonadherence. Ann
Pharmacother. 1999;33(12):1269–1273; Gonzalez-Garcia R,
Integration, and Goodenough Draw-a-Person Test are
Rodriguez-Campo FJ, Escorial-Hernandez V, et al. Complications of helpful in measuring fine motor coordination.161–167
temporomandibular joint arthroscopy: a retrospective analytic study of Standardized functional capacity evaluations provide
670 arthroscopic procedures. J Oral Maxillofac Surg.
2006;64(11):1587–1591; Rainsbury JW, Whiteside OJ, Bottrill ID.
validated information about a patient’s ability to return
Traumatic facial nerve neuroma following mastoid surgery: a case safely to his or her job.
report and literature review. J Laryngol Otol. 2007;121(6):601–605; Validated, generalized functional outcome measures
Smith IM, Mountain RE, Murray JA. An out-patient review of facial
palsy in the community. Clin Otolaryngol Allied Sci. 1994;19(3):198–
and standardized assessment tools such as the Func-
200; and Witt RL. Facial nerve function after partial superficial tional Independence Measure, SF-36, DASH, and the
parotidectomy: an 11-year review (1987–1997). Otolaryngol Head Rancho are useful for documentation of performance
Neck Surg. 1999;121(3):210–213.
and for assessing improvement or regression of symp-
toms and assessing the efficacy of intervention.
Form Health Survey (SF-36) is another validated tool

that measures quality of life indices.157–160
CASE STUDY
Functional Examination J J is a 40-year-old construction worker who specializes
Peripheral neuropathy may result in functional impair- in old paint removal, wood preparation, priming, and
ments. Focal or patterned motor weakness may lead to painting. He has been performing this type of work for
an inability to perform fine and gross motor movement the past 20 years. His hobbies include running,
patterns satisfactorily resulting in loss of an ability to reading, and playing sports with his children. Recently,
accomplish activities of daily living. Secondary impair- he has experienced general numbness in his hands
ments resulting from weakness, loss of endurance, and feet, occasional loss of balance, and a perception
articular and axial joint dysfunction, and disuse atrophy of mild confusion and forgetfulness. His laboratory
may exacerbate the functional loss. Loss of somatosen- work, including hemoglobin, hematocrit, platelets,
sory afferent feedback may lead to loss of static and white blood cells, chemistries, blood sugar, and urine
dynamic standing balance, dyscoordination of the analysis, all came back “normal.” Magnetic resonance
extremities, and neuropathic joints. Loss of protective imaging of his brain, ECG, and chest x-ray were also
sensation may lead to integument injury. “normal.” J J’s primary physician referred him to physical
2560_Chapter 14_0153-0170.indd 165 3/17/2015 4:20:53 PM

Process CyanProcess
YellowProcess Black
therapy for balance assessment and treatment. He 4. Compston A. Primary sensory neuropathy with muscular
reports no medications but has used nitrous oxide in changes associated with carcinoma. Editorial. Brain. 2009;
132(Pt 8):1995–1996.
the past as a recreational drug. 5. Isoda A, Sakurai A, Ogawa Y, et al. Chronic inflammatory
demyelinating polyneuropathy accompanied by chronic
myelomonocytic leukemia: possible pathogenesis of
Case Study Questions autoimmunity in myelodysplastic syndrome. Int J Hematol.
1. After taking the history as detailed in the case study, 2009;90(2):239–242.
6. Layzer R, Wolf J. Myeloma-associated polyneuropathy
would the therapist consider a vestibulopathy as a responding to lenalidomide. Neurology. 2009;73(10):
possible etiology of the balance disorder? 812–813.
a. No, because the patient also complains of numb 7. Amlie-Lefond C, Jubelt B. Neurologic manifestations of
hands and feet varicella zoster virus infections. Curr Neurol Neurosci Rep.
b. Yes, because the patient could have two unrelated 2009;9(6):430–434.
8. Lunn MP, Willison HJ. Diagnosis and treatment of
diagnoses inflammatory neuropathies. J Neurol Neurosurg Psychiatry.
c. No, because patients with vestibulopathies never 2009;80(3):249–258.
have cognitive impairment 9. Isoda A, Sakurai A, Ogawa Y, et al. Chronic inflammatory
d. Yes, because patients with vestibulopathies often demyelinating polyneuropathy accompanied by chronic
have cognitive impairment myelomonocytic leukemia: possible pathogenesis of
autoimmunity in myelodysplastic syndrome. Int J Hematol.
2. Which of the following in J J’s history is a possible 2009;90(2):239–242.
risk factor for neuropathy? 10. Jameson M, Roberts S, Anderson NE, Thompson P. Nitrous
oxide-induced vitamin B(12) deficiency. J Clin Neurosci.
a. Paint removal 1999;6(2):164–166.
b. Running 11. Linstedt U, Jaeger H, Petry A. The neuropathy of the
c. Television watching autonomic nervous system. An additional anesthetic risk in
d. Playing with his children diabetes mellitus [in German]. Anaesthesist. 1993;42(8):
521–527.
3. Risk factors of lead intoxification include which of the 12. Ogundipe O, Pearson MW, Slater NG, Adepegba T,
following? Westerdale N. Sickle cell disease and nitrous oxide-induced
a. Loss of balance, sensory disturbances of the hands neuropathy. Clin Lab Haematol. 1999;21(6):409–412.
13. Richardson PG. Peripheral neuropathy following nitrous
and feet, cognitive impairments oxide abuse. Emerg Med Australas. 2010;22(1):88–90.
b. Blindness, ulcerative colitis, muscle weakness 14. Tatum WO, Bui DD, Grant EG, Murtagh R. Pseudo-
c. Cognitive loss, tremor, skin ulcers Guillain-Barre syndrome due to “whippet”-induced
d. Muscle tenderness, hair loss, cognitive impairments myeloneuropathy. J Neuroimaging. 2010;20(4):400–401.
15. Gay D, Singh A. Cocaine-induced reflex sympathetic
4. If the therapist thinks that lead intoxification belongs dystrophy. Clin Nucl Med. 2000;25(11):863–865.
on the differential list, the therapist should ask the 16. Neiman J, Haapaniemi HM, Hillbom M. Neurological
physician to order which of the following tests? complications of drug abuse: pathophysiological
mechanisms. Eur J Neurol. 2000;7(6):595–606.
a. Repeat brain magnetic resonance imaging 17. O’Connor G, McMahon G. Complications of heroin abuse.
b. Cardiac enzymes Eur J Emerg Med. 2008;15(2):104–106.
c. Serum lead levels 18. O’Sullivan JM, McMahon G. Descending polyneuropathy
d. Blood urea nitrogen in an intravenous drug user. Eur J Emerg Med. 2005;12(5):
248–250.
5. Based on the history alone, additional differential 19. Ziconotide: new drug. Limited analgesic efficacy, too many
diagnoses may include which of the following? adverse effects. Prescrire Int. 2008;17(97):179–182.
a. An undiagnosed neoplasm 20. Biondi DM. Is migraine a neuropathic pain syndrome?
Curr Pain Headache Rep. 2006;10(3):167–178.
b. Multiple sclerosis 21. Brouwers EE, Huitema AD, Boogerd W, Beijnen JH,
c. Nitrous oxide exposure secondary to recreational Schellens JH. Persistent neuropathy after treatment
use with cisplatin and oxaliplatin. Acta Oncol. 2009;48(6):
d. All of the above 832–841.
22. Castro M. Peripheral sensory neuropathy—fighting cold
with cold. Lancet Oncol. 2008;9(5):415–416.
23. Dees EC, O’Neil BH, Lindley CM, et al. A phase I and
References pharmacologic study of the combination of bortezomib and
1. Azhary H, Farooq MU, Bhanushali M, Majid A, Kassab pegylated liposomal doxorubicin in patients with refractory
MY. Peripheral neuropathy: differential diagnosis and solid tumors. Cancer Chemother Pharmacol. 2008;63(1):
management. Am Fam Physician. 2010;81(7):887–892. 99–107.
2. Schroder A, Linker RA, Gold R. Plasmapheresis for 24. Doherty SD, Hsu S. A case series of 48 patients treated
neurological disorders. Expert Rev Neurother. 2009;9(9): with thalidomide. J Drugs Dermatol. 2008;7(8):769–773.
1331–1339. 25. Eksioglu E, Oztekin F, Unlu E, Cakci A, Keyik B,
3. Zhang Q, Gu Z, Jiang J, et al. Orthostatic hypotension as a Karadavut IK. Sacroiliitis and polyneuropathy during
presenting symptom of the Guillain-Barre syndrome. Clin isotretinoin treatment. Clin Exp Dermatol. 2008;33(2):
Auton Res. 2010;20(3):209–210. 122–124.
2560_Chapter 14_0153-0170.indd 166 3/16/2015 4:13:32 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
26. Gdynia HJ, Muller T, Sperfeld AD, et al. Severe 45. Lagueny A. Drug induced neuropathies. Rev Prat. 2008;
sensorimotor neuropathy after intake of highest dosages of 58(17):1910–1916.
vitamin B6. Neuromuscul Disord. 2008;18(2):156–158. 46. Lansdown AB. Critical observations on the neurotoxicity of
27. Hoque R, Chesson AL Jr. Pharmacologically induced/ silver. Crit Rev Toxicol. 2007;37(3):237–250.
exacerbated restless legs syndrome, periodic limb movements 47. Ling SK, Cheng SC, Yen CH. Stonefish envenomation with
of sleep, and REM behavior disorder/REM sleep without acute carpal tunnel syndrome. Hong Kong Med J. 2009;15(6):
atonia: literature review, qualitative scoring, and comparative 471–473.
analysis. J Clin Sleep Med. 2010;6(1):79–83. 48. Majersik JJ, Caravati EM, Steffens JD. Severe neurotoxicity
28. Kautio AL, Haanpaa M, Leminen A, Kalso E, Kautiainen associated with exposure to the solvent 1-bromopropane
H, Saarto T. Amitriptyline in the prevention of (n-propyl bromide). Clin Toxicol (Phila). 2007;45(3):270–276.
chemotherapy-induced neuropathic symptoms. Anticancer 49. Matsuoka M. Neurotoxicity of organic solvents—recent
Res. 2009;29(7):2601–2606. findings. Brain Nerve. 2007;59(6):591–596.
29. Koh C, Kwong KL, Wong SN. Mercury poisoning: a rare 50. Ohnari K, Uozumi T, Tsuji S. Occupation and carpal tunnel
but treatable cause of failure to thrive and developmental syndrome. Brain Nerve. 2007;59(11):1247–1252.
regression in an infant. Hong Kong Med J. 2009;15(1):61–64. 51. Pelclova D, Urban P, Ridzon P, et al. Two-year follow-up of
30. Kumarasamy N, Venkatesh KK, Cecelia AJ, et al. Spectrum two patients after severe thallium intoxication. Hum Exp
of adverse events after generic HAART in southern Indian Toxicol. 2009;28(5):263–272.
HIV-infected patients. AIDS Patient Care STDS. 2008; 52. Puriene A, Janulyte V, Musteikyte M, Bendinskaite R.
22(4):337–344. General health of dentists. Literature review. Stomatologija.
31. Moore A, Pinkerton R. Vincristine: can its therapeutic 2007;9(1):10–20.
index be enhanced? Pediatr Blood Cancer. 53. Sauni R, Paakkonen R, Virtema P, et al. Vibration-induced
2009;53(7):1180–1187. white finger syndrome and carpal tunnel syndrome among
32. Nakamura Y, Tajima K, Kawagoe I, Kanai M, Mitsuhata H. Finnish metal workers. Int Arch Occup Environ Health. 2009;
Efficacy of traditional herbal medicine, Yokukansan on 82(4):445–453.
patients with neuropathic pain. Masui. 2009;58(10): 54. Sethi PK, Khandelwal D. Cadmium exposure: health
1248–1255. hazards of silver cottage industry in developing countries.
33. O’Connor TL, Kossoff E. Delayed seizure associated with J Med Toxicol. 2006;2(1):14–15.
paclitaxel-Cremophor EL in a patient with early-stage 55. Aboussouan LS, Lewis RA, Shy ME. Disorders of
breast cancer. Pharmacotherapy. 2009;29(8):993–996. pulmonary function, sleep, and the upper airway in Charcot-
34. Pierce DA, Holt SR, Reeves-Daniel A. A probable case of Marie-Tooth disease. Lung. 2007;185(1):1–7.
gabapentin-related reversible hearing loss in a patient with 56. Coste TC, Gerbi A, Vague P, Maixent JM, Pieroni G,
acute renal failure. Clin Ther. 2008;30(9):1681–1684. Raccah D. Peripheral diabetic neuropathy and
35. Qi X, Chu Z, Mahller YY, Stringer KF, Witte DP, Cripe polyunsaturated fatty acid supplementations: natural sources
TP. Cancer-selective targeting and cytotoxicity by or biotechnological needs? Cell Mol Biol (Noisy-le-grand).
liposomal-coupled lysosomal saposin C protein. Clin Cancer 2004;50(7):845–853.
Res. 2009;15(18):5840–5851. 57. Di Nardo G, Blandizzi C, Volta U, et al. Molecular,
36. Selvarajah D, Gandhi R, Emery CJ, Tesfaye S. Randomized pathological and therapeutic features of human enteric
placebo-controlled double-blind clinical trial of cannabis- neuropathies. Aliment Pharmacol Ther. 2008;28(1):25–42.
based medicinal product (Sativex) in painful diabetic 58. Freeman R. Autonomic peripheral neuropathy. Neurol Clin.
neuropathy: depression is a major confounding factor. 2007;25(1):277–301.
Diabetes Care. 2010;33(1):128–130. 59. Lacigova S, Bartunek L, Cechurova D, et al. Influence of
37. Singh S, Mukherjee KK, Gill KD, Flora SJ. Lead-induced cardiovascular autonomic neuropathy on atherogenesis and
peripheral neuropathy following ayurvedic medication. heart function in patients with type 1 diabetes. Diabetes Res
Indian J Med Sci. 2009;63(9):408–410. Clin Pract. 2009;83(1):26–31.
38. Toyooka K, Fujimura H. Iatrogenic neuropathies. Curr Opin 60. Manzella D, Paolisso G. Cardiac autonomic activity and
Neurol. 2009;22(5):475–479. Type II diabetes mellitus. Clin Sci (Lond). 2005;108(2):
39. Occupational Medicine Physician’s Guide to Neuropathy in 93–99.
the Workplace Part 3: Case Presentation. J Occup Environ 61. Maule S, Papotti G, Naso D, Magnino C, Testa E, Veglio F.
Med. 2009;51(7):861–862. Orthostatic hypotension: evaluation Cardiovasc Hematol
40. Gimranova GG, Bakiirov AB, Karimova LK. Complex Disord Drug Targets. 2007;7(1):63–70.
evaluation of work conditions and health state of oil industry 62. Mehta A, Ricci R, Widmer U, et al. Fabry disease defined:
workers [in Russian]. Med Tr Prom Ekol. 2009;(8):1–5. baseline clinical manifestations of 366 patients in the Fabry
41. Goffeng LO, Heier MS, Kjuus H, Sjoholm H, Sorensen Outcome Survey. Eur J Clin Invest. 2004;34(3):236–242.
KA, Skaug V. Nerve conduction, visual evoked responses 63. Oka N, Sugiyama H, Kawasaki T, Mizutani K, Matsui M.
and electroretinography in tunnel workers previously Falls in peripheral neuropathy [in Japanese]. Rinsho
exposed to acrylamide and N-methylolacrylamide Shinkeigaku. 2005;45(3):207–210.
containing grouting agents. Neurotoxicol Teratol. 2008;30(3): 64. Sacco IC, Bacarin TA, Canettieri MG, Hennig EM. Plantar
186–194. pressures during shod gait in diabetic neuropathic patients
42. Huang CC. Polyneuropathy induced by n-hexane with and without a history of plantar ulceration. J Am
intoxication in Taiwan. Acta Neurol Taiwan. 2008;17(1): Podiatr Med Assoc. 2009;99(4):285–294.
3–10. 65. Said G. Familial amyloid polyneuropathy: mechanisms
43. Krajnak K, Waugh S, Johnson C, Miller R, Kiedrowski M. leading to nerve degeneration. Amyloid. 2003;10(Suppl 1):
Vibration disrupts vascular function in a model of metabolic 7–12.
syndrome. Ind Health. 2009;47(5):533–542. 66. Vial C, Bouhour F. Vasculitis multiple mononeuropathies
44. Kutlu G, Gomceli YB, Sonmez T, Inan LE. Peripheral [in French]. Rev Prat. 2008;58(17):1896–1899.
neuropathy and visual evoked potential changes in workers 67. Yeung H, Krentz HB, Gill MJ, Power C. Neuropsychiatric
exposed to n-hexane. J Clin Neurosci. 2009;16(10): disorders in HIV infection: impact of diagnosis on economic
1296–1299. costs of care. AIDS. 2006;20(16):2005–2009.
2560_Chapter 14_0153-0170.indd 167 3/16/2015 4:13:32 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
68. Feise RJ, Menke JM. Functional Rating Index: literature and review of the literature. Electromyogr Clin Neurophysiol.
review. Med Sci Monit. 2010;16(2):RA25–36. 2007;47(6):259–271.
69. Longo UG, Loppini M, Denaro L, Maffulli N, Denaro V. 92. Smith MW, Marcus PS, Wurtz LD. Orthopedic issues in
Rating scales for low back pain. Br Med Bull. 2010;94: pregnancy. Obstet Gynecol Surv. 2008;63(2):103–111.
81–144. 93. Giuca MR, Bonfigli D, Bartoli F, Pasini M. Sjogren’s
70. McWilliams LA, Saldanha KM, Dick BD, Watt MC. syndrome: correlation between histopathologic result and
Development and psychometric evaluation of a new measure clinical and serologic parameters. Minerva Stomatol. 2010;
of pain-related support preferences: the Pain Response 59(4):149–157.
Preference Questionnaire. Pain Res Manag. 2009;14(6): 94. Kang JH, Lin HC. Comorbidities in patients with primary
461–469. Sjogren’s Syndrome: a registry-based case-control study.
71. Cheer K, Shearman C, Jude EB. Managing complications of J Rheumatol. 2010; 37(6):1188–1194.
the diabetic foot. BMJ. 2009;339:b4905. 95. Cuthbert SC, Goodheart GJ Jr. On the reliability and
72. Brown PJ, Zirwas MJ, English JC 3rd. The purple digit: an validity of manual muscle testing: a literature review. Chiropr
algorithmic approach to diagnosis. Am J Clin Dermatol. Osteopat. 2007;15:4.
2010;11(2):103–116. 96. Li RC, Jasiewicz JM, Middleton J, et al. The development,
73. Kluger N, Frances C. Cutaneous vasculitis and their validity, and reliability of a manual muscle testing device
differential diagnoses. Clin Exp Rheumatol. 2009; with integrated limb position sensors. Arch Phys Med
27(1 Suppl 52):S124–138. Rehabil. 2006;87(3):411–417.
74. Cohen PR. Primary alopecia neoplastica versus secondary 97. Perry J, Weiss WB, Burnfield JM, Gronley JK. The supine
alopecia neoplastica: a new classification for neoplasm- hip extensor manual muscle test: a reliability and validity
associated scalp hair loss. J Cutan Pathol. 2009;36(8): study. Arch Phys Med Rehabil. 2004;85(8):1345–1350.
917–918. 98. Savic G, Bergstrom EM, Frankel HL, Jamous MA, Jones
75. Mounsey AL, Reed SW. Diagnosing and treating hair loss. PW. Inter-rater reliability of motor and sensory
Am Fam Physician. 2009;80(4):356–362. examinations performed according to American Spinal
76. Trueb RM. Systematic approach to hair loss in women. Injury Association standards. Spinal Cord. 2007;45(6):
J Dtsch Dermatol Ges. 2010; 8(4):284–297, 284–298. 444–451.
77. Ceyhan AM, Yildirim M, Bircan HA, Karayigit DZ. 99. Anderson NE, Mason DF, Fink JN, Bergin PS, Charleston
Transverse leukonychia (Mees’ lines) associated with AJ, Gamble GD. Detection of focal cerebral hemisphere
docetaxel. J Dermatol. 2010;37(2):188–189. lesions using the neurological examination. J Neurol
78. Chauhan S, D’Cruz S, Singh R, Sachdev A. Mees’ lines. Neurosurg Psychiatry. 2005;76(4):545–549.
Lancet. 2008;372(9647):1410. 100. Pullen RL Jr. Neurologic assessment for pronator drift.
79. Huang TC, Chao TY. Mees lines and Beau lines after Nursing. 2004;34(3):22.
chemotherapy. Can Med Assoc J. 2010;182(3):E149. 101. Henriksson NG, Johansson G, Olsson LG, Ostlund H.
80. Lu CI, Huang CC, Chang YC, et al. Short-term thallium Electric analysis of the Romberg test. Acta Otolaryngol. 1966;
intoxication: dermatological findings correlated with Suppl 224:272+.
thallium concentration. Arch Dermatol. 2007;143(1):93–98. 102. Jansen EC, Larsen RE, Olesen MB. Quantitative Romberg
81. Seavolt MB, Sarro RA, Levin K, Camisa C. Mees’ lines in a test. Measurement and computer calculation of postural
patient following acute arsenic intoxication. Int J Dermatol. stability. Ugeskr Laeger. 1978;140(44):2715–2717.
2002;41(7):399–401. 103. Njiokiktjien C, de Rijke W. The recording of Romberg’
82. Zhao G, Ding M, Zhang B, et al. Clinical manifestations test and its application in neurology. Agressologie. 1972;
and management of acute thallium poisoning. Eur Neurol. 13(Suppl C):1–7.
2008;60(6):292–297. 104. Reicke N. The Romberg head-shake test within the scope
83. Marrie TJ, Brown N. Clubbing of the digits. Am J Med. of equilibrium diagnosis [in German]. HNO. 1992;40(6):
2007;120(11):940–941. 195–201.
84. Nguyen K, Aronowitz P. Drumstick digits: a case of 105. Rogers JH. Romberg and his test. J Laryngol Otol. 1980;
clubbing of the fingers and toes. J Hosp Med. 2010; 94(12):1401–1404.
5(3):196. 106. Masear VR, Colgin S. The treatment of epineural scarring
85. Spicknall KE, Zirwas MJ, English JC 3rd. Clubbing: an with allograft vein wrapping. Hand Clin. 1996;12(4):
update on diagnosis, differential diagnosis, pathophysiology, 773–779.
and clinical relevance. J Am Acad Dermatol. 2005;52(6): 107. Palazzi S, Palazzi JL. Neurolysis in compressive
1020–1028. neuropathies. Int Surg. 1980;65(6):509–514.
86. Wu JY, Shih JY. Leg pains, clubbing of digits and lung 108. Davis DS, Quinn RO, Whiteman CT, Williams JD,
mass: what is your call? Can Med Assoc J. 2008;178(4): Young CR. Concurrent validity of four clinical tests used to
395–396. measure hamstring flexibility. J Strength Cond Res. 2008;
87. Gandhi V, Nagral A, Philip S, Malkani RH, Pimputkar R. 22(2):583–588.
Reversal of nail changes after liver transplantation in a child. 109. Mens JM, Pool-Goudzwaard A, Beekmans RE, Tijhuis MT.
Indian J Gastroenterol. 2009;28(4):154–156. Relation between subjective and objective scores on the
88. Huang CC, Sun PL. Superficial white onychomycosis active straight leg raising test. Spine (Phila Pa 1976). 2010;
caused by Trichophyton verrucosum. Int J Dermatol. 2008; 35(3):336–339.
47(11):1162–1164. 110. Rebain R, Baxter GD, McDonough S. A systematic review
89. Ruwan KP, Parakramawansha C, Wijeweera I, Ratnatunga of the passive straight leg raising test as a diagnostic aid for
N, Sumanasekara WG. A case of POEMS syndrome with low back pain (1989 to 2000). Spine (Phila Pa 1976). 2002;
mixed hyaline vascular and plasma cell type Castleman’s 27(17):E388–395.
disease. Ceylon Med J. 2009;54(2):68–69. 111. Kreitz BG, Cote P, Yong-Hing K. Crossed femoral
90. Savage SA, Navarini AA, Trueb RM. Dyskeratosis stretching test. A case report. Spine (Phila Pa 1976). 1996;
congenita; psoriasis. Ther Umsch. 2010;67(4):153–165. 21(13):1584–1586.
91. Mondelli M, Rossi S, Monti E, et al. Long term follow-up 112. Davis DS, Anderson IB, Carson MG, Elkins CL, Stuckey
of carpal tunnel syndrome during pregnancy: a cohort study LB. Upper limb neural tension and seated slump tests: the
2560_Chapter 14_0153-0170.indd 168 3/16/2015 4:13:32 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
false positive rate among healthy young adults without 132. Lifchez SD, Means KR Jr, Dunn RE, Williams EH.
cervical or lumbar symptoms. J Man Manip Ther. 2008;16(3): Intra- and inter-examiner variability in performing Tinel’s
136–141. test. J Hand Surg Am. 2010;35(2):212–216.
113. Heebner ML, Roddey TS. The effects of neural mobilization 133. Levin KH. Variants and mimics of Guillain Barre
in addition to standard care in persons with carpal tunnel Syndrome. Neurologist. 2004;10(2):61–74.
syndrome from a community hospital. J Hand Ther. 2008; 134. Sodhi M, Stoller JK. Small cell carcinoma with
21(3):229–240; quiz 241. paraneoplastic polyneuropathy and tumor embolization: a
114. Nawrot P, Nowakowski A, Kubaszewski L. The usefulness of case report and literature review. Respiration. 2010;79(1):
the provocative tests in nerve monitoring after operative 77–80.
treatment of upper limb neuropathy. Chir Narzadow Ruchu 135. Cortes S, Chambers S, Jeronimo A, Isenberg D. Diabetes
Ortop Pol. 2007;72(2):105–115. mellitus complicating systemic lupus erythematosus—
115. Rubinstein SM, van Tulder M. A best-evidence review of analysis of the UCL lupus cohort and review of the
diagnostic procedures for neck and low-back pain. Best Pract literature. Lupus. 2008;17(11):977–980.
Res Clin Rheumatol. 2008;22(3):471–482. 136. Mellgren SI, Goransson LG, Omdal R. Primary Sjogren’s
116. Sanders RJ, Hammond SL, Rao NM. Diagnosis of thoracic syndrome associated neuropathy. Can J Neurol Sci. 2007;
outlet syndrome. J Vasc Surg. 2007;46(3):601–604. 34(3):280–287.
117. Schiff M, Ogier de Baulny H, Bard G, et al. Should 137. Tzioufas AG, Voulgarelis M. Update on Sjogren’s syndrome
transcobalamin deficiency be treated aggressively? J Inherit autoimmune epithelitis: from classification to increased
Metab Dis. 2010; 33(3):223–229. neoplasias. Best Pract Res Clin Rheumatol. 2007;21(6):
118. Hantson P, Kevers L, Fabien N, Van Den Bergh P. Acute- 989–1010.
onset chronic inflammatory demyelinating polyneuropathy 138. Bagger-Sjoback D, Remahl S, Ericsson M. Long-term
with cranial nerve involvement, dysautonomia, respiratory outcome of facial palsy in neuroborreliosis. Otol Neurotol.
failure, and autoantibodies. Muscle Nerve. 2010;41(3): 2005;26(4):790–795.
423–426. 139. Chernoff WG, Parnes LS. Tuberculous mastoiditis.
119. Jacobs BC, Willison HJ. Peripheral neuropathies: biomarkers J Otolaryngol. 1992;21(4):290–292.
for axonal damage in immune-mediated neuropathy. Nat 140. Ellis SL, Carter BL, Leehey MA, Conry CM. Bell’s palsy in
Rev Neurol. 2009;5(11):584–585. an older patient with uncontrolled hypertension due to
120. Goldberg A, Russell JW, Alexander NB. Standing balance medication nonadherence. Ann Pharmacother. 1999;33(12):
and trunk position sense in impaired glucose tolerance 1269–1273.
(IGT)-related peripheral neuropathy. J Neurol Sci. 2008; 141. Gonzalez-Garcia R, Rodriguez-Campo FJ, Escorial-
270(1–2):165–171. Hernandez V, et al. Complications of temporomandibular
121. Pop-Busui R. Cardiac autonomic neuropathy in diabetes: a joint arthroscopy: a retrospective analytic study of 670
clinical perspective. Diabetes Care. 2010;33(2):434–441. arthroscopic procedures. J Oral Maxillofac Surg. 2006;64(11):
122. Spallone V, Morganti R, Fedele T, D’Amato C, Maiello 1587–1591.
MR. Reappraisal of the diagnostic role of orthostatic 142. Rainsbury JW, Whiteside OJ, Bottrill ID. Traumatic facial
hypotension in diabetes. Clin Auton Res. 2009;19(1): nerve neuroma following mastoid surgery: a case report and
58–64. literature review. J Laryngol Otol. 2007;121(6):601–605.
123. Villavicencio-Chavez C, Miralles Basseda R, Gonzalez 143. Smith IM, Mountain RE, Murray JA. An out-patient
Marin P, Cervera AM. Orthostatic and postprandial review of facial palsy in the community. Clin Otolaryngol
hypotension in elderly patients with chronic diseases and Allied Sci. 1994;19(3):198–200.
disability: prevalence and related factors. Rev Esp Geriatr 144. Witt RL. Facial nerve function after partial superficial
Gerontol. 2009;44(1):12–18. parotidectomy: an 11-year review (1987–1997). Otolaryngol
124. Pop-Busui R. Cardiac autonomic neuropathy in diabetes: Head Neck Surg. 1999;121(3):210–213.
a clinical perspective. Diabetes Care. 2010;33(2):434–441. 145. Boswell-Ruys CL, Sturnieks DL, Harvey LA, Sherrington
125. Spallone V, Morganti R, Fedele T, D’Amato C, Maiello C, Middleton JW, Lord SR. Validity and reliability of
MR. Reappraisal of the diagnostic role of orthostatic assessment tools for measuring unsupported sitting in
hypotension in diabetes. Clin Auton Res. 2009;19(1): people with a spinal cord injury. Arch Phys Med Rehabil.
58–64. 2009;90(9):1571–1577.
126. Villavicencio-Chavez C, Miralles Basseda R, Gonzalez 146. Clark RA, Bryant AL, Pua Y, McCrory P, Bennell K, Hunt
Marin P, Cervera AM. Orthostatic and postprandial M. Validity and reliability of the Nintendo Wii Balance
hypotension in elderly patients with chronic diseases and Board for assessment of standing balance. Gait Posture.
disability: prevalence and related factors. Rev Esp Geriatr 2010;31(3):307–310.
Gerontol. 2009;44(1):12–18 147. Delbaere K, Close JC, Mikolaizak AS, Sachdev PS, Brodaty
127. Berger JR, Fannin M. The “bedsheet” Babinski. South Med J. H, Lord SR. The Falls Efficacy Scale International (FES-I).
2002;95(10):1178–1179. A comprehensive longitudinal validation study. Age Ageing.
128. Ditunno JF, Bell R. The Babinski sign: 100 years on. BMJ. 2010;39(2):210–216.
1996;313(7064):1029–1030. 148. MacIntyre NJ, Stavness CL, Adachi JD. The Safe Functional
129. Ghosh D, Pradhan S. “Extensor toe sign” by various Motion test is reliable for assessment of functional
methods in spastic children with cerebral palsy. J Child movements in individuals at risk for osteoporotic fracture.
Neurol. 1998;13(5):216–220. Clin Rheumatol. 2010;29(2):143–150.
130. Bruske J, Bednarski M, Grzelec H, Zyluk A. The usefulness 149. Bassuk SS, Murphy JM. Characteristics of the Modified
of the Phalen test and the Hoffmann-Tinel sign in the Mini-Mental State Exam among elderly persons. J Clin
diagnosis of carpal tunnel syndrome. Acta Orthop Belg. 2002; Epidemiol. 2003;56(7):622–628.
68(2):141–145. 150. Fabrigoule C, Lechevallier N, Crasborn L, Dartigues JF,
131. Howard M, Lee C, Dellon AL. Documentation of brachial Orgogozo JM. Inter-rater reliability of scales and tests
plexus compression (in the thoracic inlet) utilizing used to measure mild cognitive impairment by general
provocative neurosensory and muscular testing. J Reconstr practitioners and psychologists. Curr Med Res Opin. 2003;
Microsurg. 2003;19(5):303–312. 19(7):603–608.
2560_Chapter 14_0153-0170.indd 169 3/16/2015 4:13:33 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
151. Koch HJ, Gurtler K, Fischer-Barnicol D, Szecsey A, Ibach 160. Bloch MH, Sukhodolsky DG, Leckman JF, Schultz RT.
B. Determination of reliability of psychometric tests in Fine-motor skill deficits in childhood predict adulthood tic
psychiatry using canonical correlation. Psychiatr Prax. 2003; severity and global psychosocial functioning in Tourette’s
30(Suppl 2):157–160. syndrome. J Child Psychol Psychiatry. 2006;47(6):551–559.
152. Marinus J, Visser M, Verwey NA, et al. Assessment of 161. Desrosiers J, Hebert R, Bravo G, Dutil E. Upper extremity
cognition in Parkinson’s disease. Neurology. 2003;61(9): performance test for the elderly (TEMPA): normative data
1222–1228. and correlates with sensorimotor parameters. Test
153. Burkhart BR, Rogers K, McDonald WD, McGrath R, d’Evaluation des Membres Superieurs de Personnes Agees.
Arnoscht O. The measurement of depression: enhancing the Arch Phys Med Rehabil. 1995;76(12):1125–1129.
predictive validity of the Beck Depression Inventory. J Clin 162. Gagnon C, Mathieu J, Desrosiers J. Standardized finger-
Psychol. 1984;40(6):1368–1372. nose test validity for coordination assessment in an ataxic
154. Byerly FC, Carlson WA. Comparison among inpatients, disorder. Can J Neurol Sci. 2004;31(4):484–489.
outpatients, and normals on three self-report depression 163. Neuhauser G. The value of motor tests in neuro-
inventories. J Clin Psychol. 1982;38(4):797–804. developmental diagnosis. Fortschr Med. 1975;93(25):
155. Lightfoot SL, Oliver JM. The Beck Inventory: psychometric 1159–1166.
properties in university students. J Pers Assess. 1985;49(4): 164. Peters LH, Maathuis KG, Kouw E, Hamming M,
434–436. Hadders-Algra M. Test-retest, inter-assessor and intra-
156. Meites K, Lovallo W, Pishkin V. A comparison of four assessor reliability of the modified Touwen examination.
scales for anxiety, depression, and neuroticism. J Clin Psychol. Eur J Paediatr Neurol. 2008;12(4):328–333.
1980;36(2):427–432. 165. Poeta LS, Rosa-Neto F. Motor assessment in school-aged
157. Brazier JE, Walters SJ, Nicholl JP, Kohler B. Using the children with indicators of the attention deficit/hyperactivity
SF-36 and Euroqol on an elderly population. Qual Life Res. disorder. Rev Neurol. 2007;44(3):146–149.
1996;5(2):195–204. 166. Pothmann R, Kurbjuhn A. Assessment of fine motor skills
158. Jacobson AM, de Groot M, Samson JA. The evaluation of in young children and school children. Fortschr Med. 1989;
two measures of quality of life in patients with type I and 107(28):592–595.
type II diabetes. Diabetes Care. 1994;17(4):267–274. 167. Spano M, Mercuri E, Rando T, et al. Motor and perceptual-
159. Jenkinson C, Wright L, Coulter A. Criterion validity and motor competence in children with Down syndrome:
reliability of the SF-36 in a population sample. Qual Life variation in performance with age. Eur J Paediatr Neurol.
Res. 1994;3(1):7–12. 1999;3(1):7–13.
2560_Chapter 14_0153-0170.indd 170 3/16/2015 4:13:33 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
SECTION FOUR
Rehabilitative Procedural Intervention for

Chapter 15
Overview of Rehabilitation
Intervention for Peripheral
Nerve Injury
“Leave all the afternoon for exercise and recreation, which are as necessary
as reading. I will rather say more necessary because health is worth
more than learning.”
—THOMAS JEFFERSON (1743–1826)
Objectives
• Explain the concept of International Classification of Functioning, Disability and Health within the context of
treating a patient with peripheral neuropathy and the commonality of terms when discussing this diagnosis
with other health care practitioners.
• Discuss the use of the Hypothesis-Oriented Algorithm for Clinicians as a model for evaluating patients with
• Identify three paradigm shifts within health care that affect the provision of rehabilitation services to patients
with peripheral neuropathy.
• Describe the focus of therapeutic intervention by rehabilitation services professionals for patients with
Key Terms
• Disability and Health
• Hypothesis-Oriented Algorithm for Clinicians
• International Classification of Functioning
• Intervention
171
2560_Chapter 15_0171-0180.indd 171 3/16/2015 4:13:35 PM

Process CyanProcess
YellowProcess Black
172 Section Four | Rehabilitative Procedural Intervention for Peripheral Nerve Injury
complex medical and surgical care offered throughout
Introduction the continuum of health care services.
Physical and occupational therapy are health care
Medicine is undergoing an accelerated change in
professions involved in ameliorating functional loss
theory, practice, documentation, and reimbursement.
and disability across the health care continuum. Thera-
Rehabilitation services are not immune to these para-
pists assist in identifying persons with functional limi-
digm shifts. The key to being a successful provider of
tation or disability, collect pertinent data, take histories,
health care services is effective management of this
evaluate, assess function, identify problems, develop
change. In the past few years, rehabilitation services
functional goals, and develop and implement a treat-
moved from older disability models such as Nagy to
ment plan (see the next section on “Hypothesis-
the World Health Organization’s International Clas-
Oriented Algorithm for Clinicians”). Services are
sification of Function, Disability and Health. Docu-
performed in collaboration with other health care pro-
mentation for many of us has moved from pen and
fessionals such as physicians, nurses, social workers,
paper to keyboard. The medical record, once a collec-
psychologists, pharmacists, and respiratory therapists;
tion of thousands of paper medical charts, is becoming
with community agencies such as religious organiza-
a secured (hopefully!) connection to the Internet.
tions, support groups, foundations, and agencies; and
Diagnosis, previously the isolated domain of physi-
with the patient’s family members and social support
cians, is now being performed by therapists. Therapists
structure. Therapists are often the primary provider of
working in the inpatient and outpatient arenas are
services for many musculoskeletal and neurological
struggling with decreased lengths of stay and lower
conditions. For others, such as developmental disabili-
facility reimbursement.
ties or internal structural issues, therapists are members
Physical and occupational therapy intervention for
of the care team.
diagnoses related to peripheral neuropathy is provided
With the collaborative nature of health care,
within the aforementioned constraints and process
common language, terminology, and classifications
shifts. Great clinical strides have occurred in recent
must be used as descriptors of patient problems. In
years with the publication of many excellent peer-
many areas of the United States and the world, the
reviewed, evidenced-based studies related to the many
International Classification of Diseases (ICD) is still
possible impairments associated with peripheral neu-
used.2 This classification system and its many iterations
ropathy. One example is the “sickness behavior”
does not meet the need of physical therapists who, by
observed in many clients with neuropathy. Sickness
the nature of the rehabilitation spectrum, require a
behavior is a downstream effect of the elevation
more functional-based system than the diagnosis-
of serum proinflammatory mediators resulting in
based ICD. Even with the shift away from the ICD
anorexia, sleep disturbances, anemia, and depression.
system, reimbursement often remains tied to the ICD
Lifelong learning is mandatory for all practicing
system, and payment, based on a diagnosis, omits the
therapists.1
broad spectrum of severity of functional involvement
This chapter begins with a discussion of the Inter-
that can occur with a particular diagnosis.
national Classification of Functioning, Disability
With the development and implementation of the
and Health (ICF); continues with a short discussion of
International Classification of Functioning, Disability
the use of the Hypothesis-Oriented Algorithm for
and Health (ICF),3 therapists can now rely on a uni-
Clinicians (HOAC), which is a succinct and rational
versal classification system that is equally responsive to
method of evaluating patients with neuropathy; and
all health care personnel in all health care locations
ends with a brief overview of the various therapeutic
along the continuum. The ICF contains lists of catego-
interventions used to treat patients with peripheral
ries organized in two different parts: Functional and
neuropathy. Later chapters expound on each of these
Disability and Contextual Factors. The Functional and
interventions.
Disability category is further subdivided into Body
Function and Structures and Activities and Participa-
International Classification of tion. The Contextual Factors category is also subdi-
vided into Environmental Factors and Personal Factors.
Functioning, Disability and Health Within the hierarchical grading system of the ICF
classification, the ICF categories are designated by the
Functional limitations and disability are universal letters “B” for body function, “S” for body structure, “D”
experiences that affect people of all ages, races, cultures, for domains representing the component activity and
economic levels, and locations. Most persons will expe- participation, and “E” for environmental factors. The
rience functional limitation or disability secondary to grading system is followed by a numeric code stating
an acute or chronic physical or mental illness, trauma, the chapter (1 digit), followed by the second number
or disease at some point in life. Restoring function (1 digit) and the third and fourth levels (1 digit each)
and limiting disability is an important adjunct to the (Table 15-1). The ICF can be employed as a common
2560_Chapter 15_0171-0180.indd 172 3/16/2015 4:13:35 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 15 | Overview of Rehabilitation Intervention for Peripheral Nerve Injury 173
Clinical scripts are pieces of evidence from the sub-
Table 15-1 Classification Rubric for Structure and Function
jective portion of the evaluation or from the review of
of the International Classification of Functioning,
the concurrent available data, including laboratory
Disability and Health
values, radiographic reports, consultations, and neuro-
Parts Part 1: Functioning Part 2: Contextual diagnostic testing, that prompt the clinician to add to
and Disability Factors or remove items from the differential diagnosis list and
Components Body Functions and Environmental
ultimately assist with confirmation of the differential
Structures Factors diagnosis list. Clinical scripts may be classified as
Activities and Personal Factors patient-identified problems (PIPs) or non–patient-
Participation identified problems (NPIPs). A PIP may be concur-
rent. An example of a current PIP is “my left knee
Domains and Items levels Items levels
1st 1st buckles ascending steps” or “my right little finger and
Categories
2nd 2nd ring finger are numb.” PIPs may also be anticipated,
3rd 3rd such as “if my numbness gets any worse I may not be
4th 4th able to type” or “so far I have not fallen down, but I
can see this happening soon if I do not get help.”
NPIPs are problems that are identified by the thera-
pist and often the patient is unaware of the potential
framework across the curriculum and used by all health association of the finding with pathology. For example,
care personnel to provide a detailed diagnostic and a patient may attend rehabilitation services for therapy
functional description of the patient’s illness in a stan- related to a fractured ankle, but the therapist identifies
dard terminology format. Such a set description can weakness in the contralateral ankle. Another example
provide a definition of widely accepted lists of ICF would be a review of laboratory data reveals an aberrant
categories for therapist interventions. hemoglobin A1c test.
Testing criteria are identified by the therapist to
confirm, add to, or remove items from the differential
Hypothesis-Oriented Algorithm diagnosis list. Through the use of testing criteria based
on best evidence such as sensitivity and specificity, the
for Clinicians practitioner can narrow the differential diagnosis list
and eventually arrive at the correct diagnosis. Testing
In 1986, Rothstein and Echternach4 published a criteria are used to examine the correctness of the
clinical decision and documentation guide called hypothesis related to problems that currently exist. For
the Hypothesis-Oriented Algorithm for Clinicians NPIPs and PIPs that are anticipated, the therapist
(HOAC), which offered rehabilitation clinicians a establishes predictive criteria, which, if met, indicate
pragmatic, evidenced-based approach to patient assess- that problems most likely will be avoided because the
ment, intervention, and management (since updated as risk factors were reduced or eliminated. To justify any
the Hypothesis-Oriented Algorithm for Clinicians predictive criterion, the therapist must use appropriate
II5). Since the publication of these seminal works, clinical decision making: best evidence or clinical
radical changes have continued to occur in the U.S. expertise.
health care system. For example, there is now Following the use of testing criteria to narrow the
widespread discussion of the importance of physical differential diagnosis list to the true diagnosis, the
therapists developing diagnoses.6 In addition, thera- therapist can develop a problem list identified by
pists are often required by insurers to refer and use the testing criteria including the functional examina-
practice guides and guidelines developed through tion, the patient’s concerns, and any risk factors identi-
peer-reviewed evidence.7 We argue that what is needed fied throughout the evaluation process. The problem
is a patient management system that involves the list provides the therapist and the patient with talking
patient in decision making and can be used to provide points to assist with determining a mutually agreed-on
payers with better justifications for interventions, list of short-term and long-term goals and approximate
including occasions when therapists may disagree with time frames for accomplishment. Goals must be objec-
practice guidelines. Compatibility with the patient tive, functional, and measurable. Behavioral, problem-
management model in the Guide to Physical Therapist solving, and outcome goals should be included in the
Practice, including the formulation of diagnoses, is goal list. Each identified problem must have a related
also desirable.8 The use of the HOAC provides the short-term or long-term goal. An intervention is then
necessary scaffolding to allow the practicing therapist developed for each goal. Lastly, an ongoing schedule of
to accomplish many of these measures. This tool is reassessments should be established to provide feed-
especially useful in patients with suspected peripheral back about the effectiveness of the intervention in
neuropathy. meeting the pre-established treatment goals.
2560_Chapter 15_0171-0180.indd 173 3/16/2015 4:13:35 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
patient-therapist collaborative relationship as a prereq-
Overview of Intervention uisite to the diagnostic process.
Patient education is an important part of the inter-
Coordination, Communication, vention and must be performed in a collaborative
and Documentation mode. Through the development of the patient-
According to the Guide to Physical Therapist Practice, an therapist relationship, the therapist must determine the
“intervention” is defined as “the purposeful and skilled preferred learning style of the patient and reflect this
interaction of a therapist and the patient/client and, in the method of delivery of the teaching materials. Is
when appropriate, with other individuals involved in the patient a visual learner? Does the patient prefer a
the patient’s clinical care, using various physical therapy cognitive or spiritual approach? Is the patient a mini-
procedures and techniques to produce changes in the malist learner, or does the patient require ancillary
condition consistent with the diagnosis and progno- information?
sis.”8 An intervention consists of five components: A common confounding variable impacting teach-
coordination, communication, documentation, patient- ing is the overestimation the reading and comprehen-
related instruction, and direct interventions. sion ability of patients. Recommendations for the
Coordination, communication, and documentation presentation of health-related information range from
among health care professionals and the patient allow fifth grade to eighth grade reading levels.14 The use of
for a well-defined, goal-oriented, coordinated inter- validated tools such as the Fog index can assist the
vention from many professionals across the health care therapist in determining the reading level of teaching
continuum. Persons with peripheral neuropathic illness handouts.15 Educational materials may be presented to
often not only have impairments related to function the patient in the following ways: orally, handwritten
but also have economic, social, administrative, financial, or typed, preprocessed handouts and brochures,
medical, and relationship issues. Along with therapist custom-made presentations, Web addresses and links,
consultation, patients may also be involved in regular and textbooks. Copies of all teaching materials should
consultation with their primary physician, physician be placed in the medical record. Many physical thera-
specialist, nurse, case manager, counselor, social worker, pists now use telemedicine processes such as live video
and others. Communication must be unimpeded and chats to follow up with patients. Notes should be taken
timely to allow proper coordination of all services. during these sessions and placed in the medical record.
Historically, health care was provided in a context In most areas of the United States, financial pressures
of a “disease-centered model,” in which most decisions on the patient, created by higher copays, higher deduct-
about a patient’s care were made unilaterally by the ibles, and lack of insurance for outpatient rehabilitation
health care professional.9 The disease model focused on services, have added to the importance of teaching and
the particular illness rather than the patient as a whole. the home program. Many patients cannot afford to
Treatment goals were set by the health care practitioner attend outpatient therapy three or four times per week.
rather than in collaboration with the patient. This Often the norm of treatment is one visit per week
model was predicated on the patient complying with with a comprehensive home program and exercise/
100% adherence to the teaching and recommendations performance log with frequent telephone or e-mail
of the health care professional. Lack of program adher- communication between the therapist and the patient.
ence was seen as a fault of the patient rather than as a The importance of a well-written home program is
process issue, a lack of communication on the part of obvious.
the health care professional, or contradictory learning The book Cognition and Curriculum by Eisner16 con-
and teaching styles of the patient and health care pro- taining research on cognition has become a significant
fessional. Over the past decade, outcome data sug- reference point in debates about teaching and curricu-
gested flaws with the authoritarian delivery of teaching, lum making in the United States. Perhaps best
and recommendations for a patient-therapist collab- described as a “cognitive pluralist,” Eisner argues that
orative model have been advanced.10 cognition is frequently approached as a phenomenon
Discussions of a collaborative treatment model have that deals with knowing rather than feeling. For Eisner,
been evolving since the early 1980s in response to vali- knowledge cannot be just a verbal construct (and con-
dated outcome studies and social, cultural, and political strained by the structures of language). This approach
changes.11 Patient-therapist collaboration is the cor- counters the practice of many health care professionals
nerstone to patient-centered care. The characteristics of who teach patients only in the verbal domain. Rather,
a collaborative relationship include an open and trust- knowledge is an intensely variable and personal “event,”
ing relationship, power sharing, and a willingness to something acquired via a combination of one’s senses—
negotiate. Patient-centered care has been associated visual, auditory, tactile, olfactory, gustatory—assembled
with increased patient and therapist satisfaction, according to a personal schema and then made public—
improved outcome measure scores, and adherence.12,13 typically expressed by the same sensory modalities used
Rothstein and Echternach4 list the development of the in the initial acquisition.
2560_Chapter 15_0171-0180.indd 174 3/16/2015 4:13:36 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Table 15-2 Eisner’s Five Philosophical Orientations That Guide Lesson Design
Philosophical Orientation Definition Example
Cognitive process Teaches the patient how to find the data, how to A therapist is asked by a patient’s family
read the data, and how to translate the data to member for information on trigeminal neuralgia.
one’s personal need. Little emphasis on providing The therapist gives the family member the name
clinical information to the patient. of a support group, a website address, and
Teaches the patient how to acquire evidence-based two journal articles. The therapist asks the family
data and incorporate it into his or her lifestyle. member to call the therapist if he has questions.
Academic rationalism A classic approach to learning. Teaches the A patient has a rotator cuff issue. The therapist
“history” of the subject. Little practical application discusses at length the history of physical
but provides a conceptual framework for therapy intervention for tendonitis: heat,
understanding the topic. massage, electrical stimulation, interferential
therapy, manual therapy. Uses evidence-based
language.
Technological Focuses on practical and technical behaviors to The therapist demonstrates, provides, and
facilitate the patient becoming impairment-free. allows the patient to demonstrate a home
Home programs, behavioral modification program of exercises for his chronic shoulder
techniques, precautions. pain that includes frequency and duration.
Social adaptation Patient teaching with a goal of societal The therapist demonstrates the impact of
and social improvement. How may I impact this patient’s maintaining a “healthy” hemoglobin A1c to
reconstruction health in a way that benefits society? minimize complications related to diabetes and
to decrease future health care dollars spent.
Personal relevance Focuses on what is personally important to the “One of my patients had a similar type of
patient. “One of my patients had a similar surgery … he is now doing extremely well.”
problem. At home he …” Used for temporal
confidence building, easing anxiety.
Adapted from Eisner EW. Cognition and Curriculum: A Basis for Deciding What to Teach. New York: Longman; 1982.
For health care professionals, the key to develop- orientations that may be employed by the therapist to
ing knowledge within the patient is to create a varied teach the patient. Based on knowledge gained during
and stimulating environment in which patients become the development of the patient-therapist collaborative
immersed in the subject matter. Therapists also need relationship, the therapist can best define how to
to encourage patients to try make meaning—to read present the teaching information to the patient
(or conceptualize) the situation. Patients do this by (Table 15-2).
constructing images derived from the material the With some peripheral neuropathies, such as those
senses provide and refining the senses as a primary caused by prolonged hyperglycemia or exposure to
means for expanding consciousness—translating the environmental or medication toxins, the primary thera-
data into usable components. Patients require access peutic intervention is to control risk factors. After
to the experience of different forms of representation assessing the patient’s learning style, the therapist
or symbol systems, such as verbal, reading, video, refer- should use aspects of the Eisner philosophical orienta-
ence sources, and personal experience. Trying to make tion to guide teaching of home instructions and risk
sense of these, being encouraged to draw on them and factor modification An example of diabetic neuropathy
play with them, nurtures the imagination and allows risk factor modification taught through the cognitive
patients to be more creative in their responses to the domain may be the therapist providing the patient with
situations in which they find themselves. Patients a website that provides a discussion of the relationship
should also be encouraged to become lifelong learn- between an elevated hemoglobin A1c and the progres-
ers of their chronic diseases, to search out reputable sion of neuropathy. The academic rationalism approach
sources of information and discuss the cogent findings may be used to discuss with the patient the history of
with their health care practitioner. treatment of diabetes from ancient times to today. The
Eisner’s five philosophical orientations that guide technological approach may be providing information
lesson design are an extremely important part of the related to insensate foot precautions, daily foot exami-
preactive teaching process. Cognitive, academic ratio- nations, and a recommendation for monofilament
nalism, technological, social adaptation and recon- examination every 6 months. The social adaptation and
struction, and personal relevance are philosophical social reconstruction approach may be to discuss the
2560_Chapter 15_0171-0180.indd 175 3/16/2015 4:13:36 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
lifetime cost of treating a patient with good diabetes transportation burden; and the need for adaptive and
control versus the cost of treating a patient with poor assistive equipment. Illness incorporates the functional,
control. Lastly, the therapist may use a personal rele- social, and behavioral implications of the diagnosis for
vance approach to risk factor modification providing the patient and the patient’s family. Rehabilitation
exemplars of good diabetes control in patients. interventions must be directed not only at the diagno-
In many instances, interdisciplinary communication sis but also the illness. Each impairment associated
is accomplished through the use of the medical record. with the illness must be designated as a problem and
President George W. Bush established a goal to have have a corresponding goal and intervention.
a universal electronic medical record (EMR) by 2014.17 A wealth of information exists regarding issues of
In 2009, President Obama launched an initiative, the patients experiencing emotional illness related to neu-
Health Information Technology for Economic and ropathic diagnoses.20–23 Emotional response to injury
Clinical Health Act, to move the United States from or illness is a personal reaction to the illness and varies
a paper to paperless system of medical documentation greatly from individual to individual and from one
(the EMR) beginning with the Department of Veter- diagnosis to another.20 Emotional response may be sec-
ans Affairs health care system and then expanding to ondary to pain, impact on the patient’s social structure,
all of the health care continuum.18. The bill included a loss of work, loss of independence, disability, and
$17.2 billion incentive to assist with funding wide- having a “diagnosis.”21 The frequency of an emotional
spread adoption and “meaningful use” of “certified” response to a neuropathic illness or injury that affects
EMR technology. The legislation ties the payments the patient’s functioning has been estimated to be
specifically to the achievement of advances in health 50%.22 The severity of the response to injury or illness
care processes and outcomes. The American Physical may range from minimal to overwhelming. The emo-
Therapy Association cited its support of the electronic tional response to an illness must be identified, noted,
health record in physical therapy through a position and addressed by the treating therapist. Emotional
statement adopted by the House of Delegates in responses, valid or aberrant, have the potential to be a
2008.19 Proliferation and promotion of the EMR confounding variable in the journey to meet clinical
offers many opportunities to enhance clinical effi- goals.
ciency, patient safety, case management, interprofes- Most of the research to date uses a cohort of subjects
sional dialogue, interfacility dialogue, research, and with diabetic peripheral neuropathic pain.20–22 The
outcomes assessment. To date, the initiative is pro- primary challenge to patients with neuropathic pain is
gressing slowly because of implementation cost and the management of the condition precipitating the
the difficulty of multiple systems “talking” to each pain, such as blood sugar control in persons with dia-
other in a common language. At the present time, in betes and inflammation in persons with a rheumato-
many instances, obtaining a checking account balance logical diagnosis. However, disorders associated with
from a bank in the United States while on vacation in emotional pain, especially depression and anxiety, also
Europe is much easier than obtaining a medical record greatly complicate the clinician’s efforts to attain
from the primary care practitioner if one is hospital- optimal outcomes for patients with neuropathy. Jain
ized 10 miles from home. et al.19 reviewed the high rate of comorbidity between
diabetic peripheral neuropathic pain and depression
Direct Intervention: Behavioral Concerns and anxiety with a focus on why this pattern of comor-
Patients with peripheral neuropathic diagnoses present bidity exists and which management tools the clinician
with an unusually wide spectrum of behavioral con- can use to assist with goal accomplishment. There are
cerns, clinical impairments, functional deficits, pain, many physiological similarities between neuropathic
and risk factors. In the development of a goal-based pain and depression and anxiety, and these are reviewed
treatment plan, each of these areas of potential deficits in Chapter 19. Numerous therapist-assessed and self-
may become a confounding variable with regard to reporting tools are available to assist the therapist in
attainment of treatment goals. This textbook contains identifying an emotional component to the neuro-
chapters addressing each of these areas. pathic diagnosis and the severity of the component.
To address behavioral concerns best, the therapist Therapist awareness of these issues assists with program
must be aware of the difference between diagnosis and adherence and intervention. Examples include tools
illness. The diagnosis is the cellular component of a associated with neuropathy severity (Toronto Clinical
pathology resulting in impairment. An intertrochan- Neuropathy Score), pain quantity and quality (Visual
teric hip fracture diagnosis is defined as a trauma or Analogue Scale), pain score (Brief Pain Inventory),
pathology impacting the area of the femur between the quality of life and health status measures (EuroQol
greater and lesser trochanters resulting in loss of bone Instrument 5 Domains), sleep quantity and quality
continuity. The hip fracture illness includes the resul- (Medical Outcomes Sleep Study Scale), anxiety and
tant bed mobility, gait, and transfer dysfunctions; the depression associated with hospital stay (Hospital
loss of income because of inability to work; pain; the Anxiety and Depression Scale), and general health and
2560_Chapter 15_0171-0180.indd 176 3/16/2015 4:13:36 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
quality of life (Short Form 36 Health Survey and the Box 15-1
Health Assessment Questionnaire).23
Depression and anxiety are also common comor- Intervention Principles
bidities in patients with peripheral neuropathies sec-
ondary to chemotherapy drugs. Medications with side Control inflammation and the downstream components:
effects of peripheral neuropathy include taxanes, pain, scarring, edema, angiogenesis
platinum-based drugs, vinca alkaloids, and thalido- Increase flexibility
mide. Chemotherapy-induced peripheral neuropathy Strengthen weakened muscles
may last for months or years after treatment and can Correct posture
affect functional performance and quality of life. Improve movement quality
Tofthagen22 investigated the effects of chemotherapy- Analyze and integrate entire kinetic chain
induced peripheral neuropathy and neuropathic pain Incorporate neuromuscular rehabilitation
on the lives of patients with cancer. Semistructured, Improve functional outcome
private interviews with participants were conducted,
Maintain or improve overall health and fitness
and transcripts were reviewed for symptoms and effects.
Participants often had difficulty describing neuropathic Provide patient education: home program, risk factor
modification, knowledge of diagnosis and pathology
symptoms but reported simultaneous pain or discom-
fort and loss of sensation in the upper and lower Incorporate patient self-management
extremities. Injuries secondary to numbness, muscle Ensure a safe return to function to a maximum level of
weakness, and loss of balance were reported. Neuro- independent function
pathic symptoms interfered with many aspects of daily
life, and participants voiced feelings of frustration,
depression, and loss of life purpose as a result of inabil-
the inflammatory cascade.23 If pathological activity and
ity to perform and participate in enjoyable activities.
irritation continue at the injured site and the inflam-
The results of this study emphasize the importance of
matory cascade is left unchecked, chronic pain and
ongoing assessment and communication with patients
disability may result. The rehabilitation therapist has
about their experiences with peripheral neuropathies.
many modalities available that control the downstream
Direct Intervention: Clinical Concerns effects of the proinflammatory cytokines. These are
easily remembered with the mnemonic PRICEMEM:
Direct interventions are selected based on the findings
protection, rest, ice, compression, elevation, manual
of the evaluation and examination of the patient, diag-
therapy, early motion, and medications.
nosis, prognosis, problem list, patient-therapist collab-
orative goals, anticipated outcomes, time frames, and Protection: Protection is the removal of the
anticipated length of service. Direct interventions are offending stimulus. If the offending stimulus is
performed with or on the patient. Direct intervention repetitive strain from keyboard typing, this is
and teaching represent the largest segments of patient removed. If the offending stimulus is throwing a
care provided by rehabilitative therapists (Box 15-1). baseball, this is removed.
An intervention is most effective when addressing Rest: Rest is the absence of an offending stimulus
functional needs that are mutually agreed on by the and not the absence of movement. Prolonged
patient and therapist. The most successful intervention immobilization may have a deleterious impact
schemas are schemas that combine evidence-based on bone, ligament, nerve, and muscle. Rest is
and clinical expertise–based knowledge and experience. the prescription of selective motions that will
The following interventional principles should be not exacerbate the impairment but allow for
incorporated into any comprehensive rehabilitation normal, or as close to normal as possible,
program. functioning. Rest may be defined as bracing an
Principle 1: Control Inflammation and the injured area; wrapping to control edema;
Downstream Components: Pain, Scarring, non–weight-bearing to protect an injured bone;
Edema, Angiogenesis avoidance of lifting to prevent back pain
High repetition–low force and low repetition–high exacerbation; and avoidance of particular
force injuries to soft tissue result in an immediate motions, such as overhead shoulder elevation, in
migration of macrophages and monocytes to the persons with venous thoracic outlet syndrome.
site of injury. These cells express proinflammatory Ice: Cold thermal therapies are an important
cytokines that activate the inflammatory cascade. adjunct to controlling the acute inflammatory
Pain, edema (secondary to increased vascular permea- process and inflammation developed during the
bility), angiogenesis, scarring, and other “healing” therapeutic rehabilitation process.
activities develop at the injured site. Eventually, anti- Compression: Compression, via wrapping, massage,
inflammatory cytokines are expressed that “turn off ” positioning, or a pneumatic device, helps
2560_Chapter 15_0171-0180.indd 177 3/17/2015 4:20:57 PM

Process CyanProcess
YellowProcess Black
prevent and alleviate edema associated with intervention, movement quality cannot be ignored.
increased capillary permeability. Classic principles of motor acquisition, training, and
Elevation: Used with ice and compression, learning should be employed when there is identified
elevation assists with decreasing edema loss of motor control.
associated with inflammation. For elevation to Principle 5: Analyze and Integrate the
be most effective, consider the heart as the Entire Kinetic Chain
fulcrum for the flow of accumulated fluid. For The movement at one joint often depends on the
elevation to be most successful as a modality to quality of motion and the afferent feedback of the large
decrease edema, the edematous part should be myelinated afferent sensory fibers from the distal and
elevated above the heart. proximal joints. A comprehensive rehabilitation plan
Manual therapy: Manual therapy has many positive encompassing all links along the kinetic chain improves
impacts on inflammation. Stimulation of the outcomes. Emerging research indicates improper
large-fiber afferents assists with pain control. sequencing and activation of motor responses along
The mechanical effect of joint movement assists the kinetic chain to perturbation may be disease-
with regaining joint motion. Prescribed forces specific.26
and force vectors assist with remodeling of Principle 6: Incorporate
connective tissue. Nerve glides and slides are an Neuromuscular Rehabilitation
important modality in assisting with preventing Neuromuscular rehabilitation is the method of training
intraneural and extraneural scarring commonly the enhancement of subconscious motor responses to
seen with inflamed peripheral nerves. normal and aberrant perturbations by simultaneously
Early motion: Early motion is helpful with stimulating afferent signals and central mechanisms
reducing the muscle atrophy associated with responsible for dynamic and static motor control. The
rest, assists with maintaining joint function, and goal of this therapy is to improve the ability of the
assists with preventing ligamentous “creeping.” central nervous system to sequence, control the ampli-
Medications: Although not within the realm of tude of firing, and use proper agonist/antagonist control
physical therapy practices in most locations, the of the muscle response to balance loss and postural
judicious use of steroid and nonsteroidal changes.
medications assists with controlling and limiting Principle 7: Improve Optimal Function
the inflammatory cascade. Short-term and long-term rehabilitation goals must be
functional, objective, and measurable. To meet this end,
Principle 2: Increase Flexibility clinical interventions must be functionally directed.
With the scarring that is a consequence of the inflam- This emphasis on function is an enhancement of past
matory cascade, loss of flexibility—articular, single goals and plans that were written solely to improve
muscle, two joint muscle, and nerve—is an expected metrics such as manual muscle test grade or a degree
complication of injury. Posture and strength are depen- measurement of articular range of motion. All inter-
dent on proper joint mechanics and range of motion. ventions should include a therapeutic functional pro-
With a primary peripheral nerve injury, nerve glides gression along with an exercise progression.
and slides within the symptom-free range are of tan- Principle 8: Maintain or Improve Overall
tamount importance in the rehabilitation plan. Care Fitness and Health
must be taken when performing articular or muscle Whenever possible, the treating therapist should
stretching to avoid tension to injured neural tissue. address, along with the functional limitation, the
Principle 3: Correct Posture downstream impact of risk factors such as inactivity,
With injury, the adaptive shortening and lengthening improper nutrition, tobacco usage, obesity, and an
of tissues coupled with protective and painful position- increased fall risk. As a result of the paradigm shift
ing leads to learning of abnormal, and, if untreated, from the Nagy model to the ICF, standards changes
obligatory, posturing. The restoration of proper posture from The Joint Commission, and amendments to state
in standing, sitting, and lying down assists with allevi- practice acts, the scope of rehabilitation therapy ser-
ating abnormal torque and joint positioning on the vices has expanded to include addressing risk factors
axial and appendicular systems. “Retraining” correct and practices that may affect health.
posture can often be aided by popular therapeutic tech- Principle 9: Provide Patient Education: Home
niques such as Alexander technique, yoga, Feldenkris, Program, Risk Factor Modification, Knowledge
Pilates, and Tai Chi Chuan. of Diagnosis, Pathology
Principle 4: Improve Movement Quality Patient-therapist collaboration is the cornerstone of
Byl24 and Coq et al.25 showed that peripheral injury the therapeutic relationship. The therapist and patient
may result in alteration of the central maintenance work together through the diagnostic journey, the
components of motor control leading to a loss of coor- development of mutually agreed-on goals, the spec-
dination and function. As part of a coordinated plan of trum of the treatment plan, and the schedule for
2560_Chapter 15_0171-0180.indd 178 3/16/2015 4:13:36 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
reassessment. As part of the intervention, the therapist evidence of early chronic kidney disease, elevated
and patient constantly discuss the path from impair- cholesterol and triglycerides, a hemoglobin A1c of 8.6,
ment to health and from disability to functional inde- and a blood sugar of 230 mg/dL.
pendence. The therapist helps mold the patient into an J J also has a chronic wound on his right heel. A
educated consumer of health care, and the patient recent ankle-brachial index of the involved ankle was
assists with educating the therapist about the patient’s 0.72 indicating a significant level of vascular disease.
perceptions of illness and disability. The patient is
taught to self-manage his or her condition and how to
prevent reoccurrences. The home program, an exten-
sion of the clinical relationship, consists of the exercise 1. After reading the patient history, the very first thing
prescription, treatment goals and time frames, risk Kristin should do with this patient is which of the
factor modification, and precautions. A trusting thera- following?
peutic relationship promotes program adherence. a. Take his vital signs
Principle 10: Incorporate Patient Self-Management b. Review his medications and dosages
Many of the patients therapists treat have chronic or c. Speak with his primary care physician
relapsing conditions. As part of the therapeutic inter- d. Develop a trusting patient-therapist collaborative
vention, illness self-management skills are taught to relationship
the patient. Self-management skills include disease-
2. Which of the following should be considered an
specific knowledge of medication, prevention, acute
illness and not a diagnosis?
response to exacerbation, healthy lifestyle choices, and
a. Insulin-dependent diabetes mellitus
intervention.
b. Peripheral vascular disease
Principle 11: Ensure a Safe Return to a Maximum
c. Chronic arterial vascular wound
Level of Independent Function
d. Inability to work secondary to gait instability
A focus of patient teaching is safety. The Joint Com-
mission has taken the lead via the National Patient 3. In developing a written home program and written
Safety Goals encouraging the development of safety as educational material for J J, Kristin should develop
a goal for every patient in the United States. From these at which grade level?
hand washing to fall prevention to documentation a. Undergraduate college
standards mandating the identification of at-risk sui- b. 12th grade
cidal patients, the National Patient Safety Goals c. Eighth grade
encourage therapists to promote a risk-free assessment d. Second grade
and intervention environment.
4. The use of specific tests and measures to add to,
Principle 12: Coordination of Care
remove from, and confirm items on the differential
This is a general principle for all persons providing
diagnosis list is called which of the following?
health care. All care, regardless of the provider, must
a. Hypothesis-oriented algorithm for clinicians
be communicated to the health care stakeholders of
b. International Classification of Functioning, Disability
the patient. These stakeholders vary by patient and
and Health
episode of care. In most cases, the primary care physi-
c. Nagy model
cian, as the gatekeeper of the patient’s care, should be
d. Patient-centered model of health care
informed of all therapeutic interventions. In other
instances, therapists may need to communicate cogent 5. The first principle in the treatment of peripheral nerve
findings to nurses, specialists, social workers, case man- injuries is which of the following?
agers, insurance companies, and other rehabilitation a. Control pain
professionals—all within the scope of patient privacy b. Control inflammation
legislation. c. Maintain function
d. Bracing for rest
CASE STUDY
References
Kristin is a physical therapist in a hospital-based 1. Carp SJ, Barbe MF, Barr AE. Serum biomarkers as signals
outpatient practice. Her first patient of the day is J J, a for risk and severity of work-related musculoskeletal injury.
40-year-old man with a chief complaint of gait Biomark Med. 2008;2:67–79.
dysfunction secondary to large-fiber afferent sensory 2. International Statistical Classification of Diseases and
neuropathy related to his 15-year history of insulin- Related Health Problems: ICD-1. Geneva, Switzerland:
World Health Organization; 1992.
dependent diabetes. J J admits to lack of compliance 3. International Classification of Functioning, Disability and
with his diabetic regimen and medications. Kristin Health: ICF. Geneva, Switzerland: World Health
reviewed his most recent laboratory tests and noted Organization; 1999.
2560_Chapter 15_0171-0180.indd 179 3/16/2015 4:13:36 PM

Process CyanProcess
YellowProcess Black
4. Rothstein JM, Echternach JL. Hypothesis-oriented algorithm 15. Bogert J. In defense of the Fog index. Bulletin of the
for clinicians: a method for evaluation and treatment Association for Business Communication. 1985;48(2):9-11.
planning. Phys Ther. 1986;66:1388–1394. 16. Eisner EW. Cognition and Curriculum: A Basis for Deciding
5. Rothstein JM, Echternach JL. Hypothesis-oriented algorithm What to Teach. New York: Longman; 1982.
for clinicians II (HOAC II): a guide for patient management. 17. Bush GW. 2004 State of the Union Address. January 20,
Phys Ther. 2003;83(5):455–470. 2004. http://www.c-span.org/Transcripts/SOTU-2004.aspx.
6. Delitto A, Snyder-Mackler L. The diagnostic process: Accessed August 14, 2011.
examples in orthopedic physical therapy. Phys Ther. 1995;75: 18. American Physical Therapy Association. Support of electronic
203–211. health record in physical therapy. HOD P06-08-13-11.
7. Feder G, Eccles M, Grol R, et al. Clinical guidelines: using http://www.APTA.org. Accessed August 14, 2011.
clinical guidelines. BMJ. 1999;318:728–730. 19. Jain R, Jain S, Raison CL, Maletic V. Painful diabetic
8. American Physical Therapy Association. Guide to Physical neuropathy is more than pain alone: examining the role
Therapist Practice. Second edition. American Physical of anxiety and depression as mediators and complicators.
Therapy Association. Phys Ther. 2001;81(1):9–746. Curr Diab Rep. 2011;4:275–284.
9. Stanton MW. Expanding patient-centered care to 20. Paliakov I, Toth C. The impact of pain in patients with
empower patient and assist providers. Publication polyneuropathy. Eur J Pain. 2011;15(10):1015–1022.
No. 02-0024. http://archive.ahrq.gov/research/findings/ 21. Stankovic Z, Jasovic-Gasic M, Zamaklar M. Psycho-social
factsheets/patient-centered/ria-issue5/ria-issue5.html. and clinical variables associated with depression in patients
Accessed August 14, 2011. with type 2 diabetes. Psychiatr Danub. 2011;23(1):34–44.
10. Steiner JF, Earnest MA. The language of medication taking. 22. Tofthagen C. Patient perceptions associated with
Ann Intern Med. 2000;132:926–930. chemotherapy-induced peripheral neuropathy. Clin J Oncol
11. Hook M. Partnering with patients—a concept ready for Nurs. 2010;14(3):E22–28.
action. J Adv Nurs. 2006;56:133–143. 23. Barbe MF, Barr AE. Inflammation and pathophysiology of
12. Wolf DM, Lehman L, Quinlin R, Zullo T, Hoffman L. work-related musculoskeletal disorders. Brain Behav Immun.
Effect of patient-centered care on paitent satisfaction and 2006;20:423–429.
quality of care. J Nurs Care Qual. 2008;23:316–321. 24. Byl NN. Focal hand dystonia: a historical perspective from a
13. Fuentes JN, Mislowack A, Bennett J, Paul L, Gilbert TC, clinical scholar. J Hand Ther. 2009;22(2):105–108.
Fontan G. The physician-patient working alliance. Patient 25. Coq JO, Barr AE, Strata F, et al. Peripheral and central
Educ Couns. 2007;66:29–36. changes combine to induce motor behavioral deficits in a
14. Weiss SM, Smith-Siomone SY. Consumer and health moderate repetition task. Exp Neurol. 2009;220(2):234–245.
literacy: The need to better design tobacco-cessation 26. Horak FB, Imitrova D, Nutt JG. Directional specific postural
product packaging, labels, and inserts. Am J Prev Med instability in subjects with Parkinson’s disease. Exp Neurol.
2010;38(3 Suppl):S403–413. 2005;193:504–521.
2560_Chapter 15_0171-0180.indd 180 3/16/2015 4:13:36 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 16
Manual Therapy Techniques
for Peripheral Nerve Injuries
SCOTT BURNS, PT, DPT, OCS, FAAOMPT, AND BILL EGAN, PT, DPT, OCS, FAAOMPT
“Healing is a matter of time, but it is sometimes also a matter of opportunity.”

—HIPPOCRATES (460 B.C.–370 B.C.)
Objectives
• Verbalize the concepts of manual therapy.
• Understand the basic techniques of neural mobilization.
• Describe key manual therapy techniques.
Key Words
• Manual therapy
• Neurodynamic tests
• Passive movement
each region, we focus on key manual therapy tech-

Introduction niques, especially techniques supported by evidence
from the peer-reviewed literature, for common periph-
Manual therapy encompasses treatment interventions eral nerve injuries. Several excellent texts written by
involving the application of skilled passive movement experts and pioneers in the field of manual therapy
techniques. Several types of clinicians are trained in related to neural tissue are available.2–5 The reader is
and apply manual therapy, including chiropractors, directed to these texts for further information and
osteopaths, and physical therapists. There is moderate more detailed coverage of this topic.
evidence that manual therapy, when included as part Manual therapy for peripheral nerve injuries begins
of a multimodal rehabilitation program, is effective in with the assessment and clinical examination of the
the management of many common musculoskeletal patient. For patients with peripheral nerve injuries, the
disorders.1 In the past, manual therapy had mostly clinician should first perform standard orthopedic and
focused on interventions targeting joint articulations neurological testing to assist with making the diagno-
or soft tissue. Over the past 25 years, manual therapy sis. Specific to manual therapy, clinicians can examine
techniques and systems have emerged that purport to the joint articulations and soft tissue structures sur-
assess and mobilize neural tissue directly.2 Research in rounding the injured nerve, also known as the neural
the form of high-quality clinical trials and observa- tissue interface or neural container. Manual therapy
tional studies investigating the effectiveness of manual interventions can be directed to impairments of these
therapy for peripheral nerve injuries has also emerged. interfacing tissues as one method of treatment for
As a result, clinicians frequently use manual therapy in peripheral nerve injuries. Manual therapists can also
the management of peripheral nerve injuries. This attempt to palpate the nerve in question directly, when
chapter begins with an overview of concepts related to possible.6,7 Nerves are not normally sensitive to
manual therapy assessment and management directed mechanical pressure, and increased sensitivity can alert
toward neural tissue and peripheral nerve injuries. For the clinician to an underlying disorder.
181
2560_Chapter 16_0181-0194.indd 181 3/16/2015 4:13:38 PM

Process CyanProcess
YellowProcess Black
To help with the examination and diagnosis of various types of manual therapy techniques for periph-
peripheral nerve injuries, clinicians can use tests and eral nerve injuries are described throughout this chapter.
positions that selectively apply tension to particular The mechanisms of how manual therapy techniques
peripheral nerves based on anatomical and biomechan- produce beneficial effects such as a reduction in pain
ical principles. These tests have been referred to as and improvement in function are poorly understood.
neural tension tests and more recently as neurody- The mechanical effect of manual therapy has been the
namic tests.2 The term “neurodynamic” has been used predominant theory for many years, including the
to reflect that these tests are not simply an assessment notion that displaced joint articulations can be realigned
of the length or flexibility of the nerve, but rather assess or put back in place. Similarly, it was thought that
the sliding and gliding of the nerve within its interfac- neural mobilization techniques had their beneficial
ing tissues. The most commonly known and used neu- effects from stretching shortened neural tissue, releas-
rodynamic test is the straight leg raise. The straight leg ing scarring and adhesions around injured nerve, or
raise increases the tension applied to the lower lumbar improving the gliding of the nerve within its interfac-
nerve roots and sciatic nerve and is used in the assessing tissues. Current research concerning the mecha-
ment of lumbar radiculopathy. If the clinician finds a nisms of manual therapy now supports alternative
limitation of movement with the neural tension test theories.12 Pain modulation through either peripherally
compared with the uninvolved side or the test directly or centrally mediated nervous system effects is now
reproduces the patient’s symptoms, the test is consid- thought to be the predominant mechanism by which
ered positive.8 A positive neural tension test, in isola- manual therapy acts. Nonspecific effects, such as the
tion, does not indicate a peripheral nerve injury. It is patient’s expectations, the patient-provider relation-
also well recognized that in certain pain disorders, such ship, and the placebo effect, cannot be ignored because
as whiplash-associated disorders, there is a frequent they have been shown to be powerful modulators of
occurrence of central pain sensitization.9 Central pain the clinical outcome.13 Manual therapy interventions
sensitization can lead to false-positive test results, are rarely used in isolation. Most research has shown
including neural tension tests.10 that manual therapy is most effective when combined
Aside from mobilizing the interfacing tissues, the with a multimodal program involving active and
manual therapist can also attempt to mobilize the patient-centered interventions such as education,
nerve directly with either passive or active interven- advice, and exercise.14
tions. The neurodynamic test position frequently is
used to initiate the intervention. Techniques for directly
mobilizing nerves can be performed as a static or pro- Common Disorders
longed hold or in an oscillatory fashion known as
neural flossing or gliding. The latter techniques are Cervical Radiculopathy
recommended at first, especially in the management of Cervical radiculopathy is defined as a lesion or disease
acute nerve injuries, because there is less potential for of the cervical nerve root and is most often attributed
further damage to the nerve or irritation of the patient’s to cervical disc herniation or spondylosis.15 The preva-
condition compared with static stretching of an injured lence of cervical radiculopathy has been estimated at
nerve. When a nerve is elongated, there is a decrease 3.3 per 1,000 cases with the peak incidence in the
in the nerve’s vascular supply because of the “wringing- fourth or fifth decade of life.16 Men are typically more
out” effect occurring during elongation of the nerve affected with cervical radiculopathy than women.17
and nerve bed.3 Neural mobilization techniques can be Cervical radiculopathy commonly manifests with
further classified based on the intent of the technique. upper extremity pain or paresthesias, neck pain, head-
Techniques that place tension or stretch on both the aches, or scapulothoracic region pain.18
distal and the proximal end are known as “tension- The diagnosis of cervical radiculopathy is tradition-
ers.”11 Techniques that place tension on one end of the ally made with magnetic resonance imaging (MRI)19,20
nerve while simultaneously releasing or slackening the or electromyography.21,22 The shortcomings of the diag-
other end of the nerve are known as “sliders.” In vitro nostic utility of imaging in spinal conditions when used
and in vivo studies have shown that sliders cause a in isolation has been well documented, and clinicians
greater excursion of the nerve throughout its interfac- should also use an accurate clinical examination to
ing tissues.11 Conversely, tensioners place a greater diagnose cervical radiculopathy.15 Wainner et al.23
strain on the nerve. It is recommended that neural identified a test item cluster of four variables for the
mobilization techniques begin with sliders given the diagnosis of cervical radiculopathy. The four variables
less strain and greater excursion of the nerve. Com- include the Spurling test, neck distraction test, upper
bined manual therapy techniques can also be performed limb neurodynamic test with median nerve bias, and
in which the interfacing tissue is mobilized while the ipsilateral cervical rotation of 60° or less. The presence
nerve is placed in stretch or while the neural tissue is of all four of these variables yields a positive likelihood
actively or passively mobilized. Specific examples of the ratio of 30.3, which shifts the post-test probability of
2560_Chapter 16_0181-0194.indd 182 3/16/2015 4:13:39 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 16 | Manual Therapy Techniques for Peripheral Nerve Injuries 183
cervical radiculopathy being present on electromyogra- clinically meaningful improvements in pain and func-
phy to 90%. In the study by Wainner et al.,23 the supine tion at 6-month follow-up. The patients were treated
upper limb neurodynamic test with median nerve bias using a multimodal approach including cervical lateral
was best at ruling out the presence of cervical radicu- glides in upper limb neurodynamic test position, tho-
lopathy with a sensitivity of 97%. Additional findings racic spine manipulation, intermittent mechanical trac-
on the physical examination that are associated with tion, and deep neck flexor strengthening. In another
cervical radiculopathy include diminished deep tendon case series, 83% of patients had significant reduction
reflexes, sensory deficits, and motor weakness.24 in disability scores following a multimodal treatment
Manual therapy interventions in the management approach including intermittent cervical traction,
of cervical radiculopathy frequently include manipula- thoracic spine manipulation, and deep neck flexor
tion of the cervical and thoracic spine regions (Fig. strengthening.30
16-1).25–28 Manipulation of the thoracic spine region is Intermittent cervical traction has been advocated in
recommended as the initial intervention to avoid the treatment of patients with cervical radiculopa-
potential exacerbation of the radiculopathy from tech- thy.26,31 Raney et al.26 identified predictive variables of
niques targeting the cervical spine (Fig. 16-2). patients who will respond favorably to cervical traction
There is moderate evidence for the effectiveness of and exercise. In this trial, 68 patients received six ses-
thoracic spine manipulation in the treatment of neck sions of intermittent cervical traction and strengthen-
pain including radiculopathy.18,25,27,28 In a case series, ing exercises (two times per week for 3 weeks). Of the
Cleland et al.29 reported 91% of patients experienced subjects, 44% reported a perceived recovery of “a great
deal better” or “a very great deal better.” Five predictive
variables were identified, including peripheralization of
lower cervical (C4–7) with mobility testing, positive
shoulder abduction test, age 55 years or older, positive
upper limb neurodynamic test with median nerve bias,
and positive neck distraction test. A positive upper
limb neurodynamic test with median nerve bias and a
positive neck distraction test are included in the test-
item cluster for detecting the presence of cervical
radiculopathy.23 The age of the patient and peripheral-
ization of symptoms with mobility testing of C4–7
correlate to other signs and symptoms that may be
related to cervical radiculopathy.16
Young et al.32 investigated the outcomes of a manual
therapy and exercise approach with or without inter-
mittent cervical traction. The study comprised 81
patients randomly assigned into one of two groups.
Group 1 included manual therapy, exercise, and inter-
Figure 16-1 Cervical lateral glide manual mobilization. mittent cervical traction, whereas group 2 included
manual therapy, exercise, and sham cervical traction.
The manual therapy techniques used in this study were
either thrust or nonthrust techniques directed to the
upper and middle thoracic spine. In addition to the
thoracic techniques, at least one nonthrust mobiliza-
tion was directed at the cervical spine. The cervical
spine nonthrust techniques included retraction, rota-
tions, and lateral glides in the upper limb neurody-
namic position or posterior-to-anterior mobilizations.
In this trial, the therapist was able to choose the manual
therapy techniques based on patient response and cen-
tralization or reduction of symptoms. The exercises
included in this trial featured deep neck flexion, scapu-
lar stabilization, and cervical retraction or extension. At
least one of the exercises was used during the treatment
session. The subjects in group 1 also received mechani-
cal intermittent cervical traction for 15 minutes with
the on/off cycle set at 50/10. The traction force started
Figure 16-2 Thoracic spine thrust manipulation in supine. at 20 pounds or 10% of the patient’s body weight,
2560_Chapter 16_0181-0194.indd 183 3/16/2015 4:13:39 PM

Process CyanProcess
YellowProcess Black
whichever was less. The force was progressively difficult to interpret. Caution is required when gener-
increased by 2 to 5 pounds each visit. Both groups alizing treatments to all patients with TOS. There is
experienced clinically meaningful improvements in relatively little consensus on the appropriate manage-
pain and function at immediate-term and short-term ment of patients with TOS.33,35,40 General management
follow-up, but there were no differences between strategies include postural education, relaxation exer-
groups. cises, manual therapy, and active exercise programs.39,41
There is a moderate amount of evidence to support There is little evidence for the use of manual therapy
the use of manual therapy techniques directed to the techniques in the management of TOS.39,41 Hooper et
cervical or thoracic spine in patients with cervical al.39,42 provide an excellent review of pathology, exami-
radiculopathy.18,25,27,28,30 Several studies demonstrate nation, and management of patients with TOS. These
the effectiveness of intermittent cervical traction26,30,31; authors recommend the use of first rib mobilization
however, when intermittent cervical traction was com- techniques, glenohumeral mobilization, manual scalene
bined with manual therapy and exercise, there were no stretch, and neural mobilization.39 Additionally, the
significant differences.18 patient is instructed in self-mobilization techniques of
the involved first rib. Smith40 advocated for use of
Thoracic Outlet Syndrome manual therapy techniques directed at the shoulder
Thoracic outlet syndrome (TOS) describes a constel- girdle and sternoclavicular joint, manual stretching of
lation of upper extremity symptoms that occur when the scalene and pectoral muscles, scapular mobiliza-
the neurovascular structures that pass through the tho- tion, and mobilization of the ispilateral first and second
racic outlet become compressed.33 Three main types of ribs in the management of patients with TOS. Smith40
TOS have been identified: neurogenic, venous, and described a treatment protocol including manual
arterial.33,34 In this chapter, we focus on neurogenic therapy techniques in conjunction with postural and
TOS because it involves the peripheral nervous system. body mechanics re-education and therapeutic exer-
Neurogenic TOS accounts for nearly 95% of all cases33 cises. Manual therapy techniques aimed at restoring
and occurs when the nerve roots of the brachial plexus scapula-humeral rhythm and proper scapular kinemat-
become entrapped as they course through the triangle ics have also been recommended.35 In a case series,
formed by the first rib and the anterior and middle Buonocore et al.43 reported that a program using
scalene muscles. There are two variations of neurogenic massage and manual cervical traction techniques
TOS: “true” and “disputed” or symptomatic.34,35 True resulted in the abolishment of all resting symptoms in
neurogenic TOS is rare and typically manifests with 13 patients with TOS. Revel and Amor44 reported 76%
clinical findings isolated within the C8–T1 derma- of patients had excellent to good outcomes with a
tome.34 Disputed or symptomatic neurogenic TOS multimodal approach including massage techniques
accounts for nearly 90% of TOS-related surgeries in directed at the cervicothoracic region and passive
the United States.36 Disputed neurogenic TOS may be mobilizations of the upper quarter.
associated with a traumatic onset or the presence of a
cervical rib. Lateral Epicondylalgia
Clinical signs of neurogenic TOS include pain or Although more commonly known as lateral epicondy-
weakness in the neck, shoulder, or upper extremity34; litis and tennis elbow, lateral epicondylalgia is a more
altered scapular or glenohumeral position and strength; appropriate term because there are no inflammatory
presence of a cervical rib; and possibly traumatic cells associated with the condition.45,46 Occasionally,
onset.34,35 Terao et al.37 reported that in patients with lateral elbow pain results from or is partially attributed
TOS the inclination of the clavicle on the involved side to entrapment neuropathies of the radial nerve around
is 3° lower compared with the uninvolved side. Another the elbow such as radial tunnel syndrome. Clinicians
useful clinical examination tool is the cervical rotation can assess for these entrapment neuropathies using
lateral flexion (CRLF) test to assess for an elevated first standard neurological testing and nerve conduction
rib, which may apply pressure on the neurovascular velocity and electromyography studies. Clinicians can
bundle.38 The CRLF test begins with the patient in the also use a neurodynamic test for the radial nerve to
seated position. The examiner passively rotates the head assist with the diagnosis of radial tunnel syndrome or
away from the affected side and then flexes the neck involvement of the radial nerve in patients with lateral
toward the sternum. The test is considered positive if elbow pain. The diagnostic accuracy of this test for
there is a noticeable decrease in range of motion radial nerve entrapment has not been studied. The test
(ROM) combined with a hard end-feel. A positive is considered positive if there is restricted ROM com-
CRLF test may warrant manual therapy techniques pared with the uninvolved side or if the test reproduces
directed at the first rib in patients with TOS.39 the patient’s chief complaint. Yaxley and Jull47 assessed
TOS may have several different clinical manifes- the radial nerve tension test in 20 patients with unilat-
tations. Given that there are several different varia- eral lateral epicondylalgia. They found reduced ROM
tions without clear diagnostic criteria, the literature is with the test in the involved arm compared with the
2560_Chapter 16_0181-0194.indd 184 3/16/2015 4:13:39 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
53
uninvolved arm in all patients. Additionally, 55% of the elbow flexion plus direct pressure. Elbow flexion
patients’ symptoms were reproduced with the test. The coupled with direct manual pressure over the ulnar
authors postulated that irritation of the radial nerve nerve at the cubital tunnel has a sensitivity of 91%
could be a source or contributing factor to the symp- making it the best screening test.
toms of lateral epicondylalgia. Common nonsurgical interventions for cubital
If the radial neurodynamic test is positive, clinicians tunnel syndrome include bracing, activity modification,
can consider mobilization of the radial nerve as either night splinting, and patient education.49 Surgery is rec-
an active or a passive treatment intervention. Clinicians ommended only for severe or recalcitrant cases. Svern-
can also use manual therapy techniques directed toward löv et al.54 performed a high-quality randomized trial
the cervical spine, thoracic spine, elbow, and wrist to for the conservative treatment of cubital tunnel syn-
address impairments of the tissues interfacing with the drome. They randomly assigned 70 patients with mild
radial nerve. There is no high-quality research support- to moderate cubital tunnel syndrome, based on clinical
ing the effectiveness of neural mobilization techniques findings, into three groups. The three groups were night
in the management of lateral epicondylalgia or radial splinting, active neural gliding exercises, and a control
nerve entrapment. In a case report, Ekstrom and group. All three groups received advice and education
Holden48 described a patient with a 4-month history about the condition and ways to modify activities to
of lateral elbow pain. The patient had a positive radial avoid placing strain on the ulnar nerve. At 6-month
nerve tension test, and the authors attributed her follow-up, 90% of the patients were improved with no
symptoms to mild entrapment of the radial nerve. differences between groups on any outcome measures.
A multimodal program including radial nerve mobi- This study speaks to the self-limiting nature of this
lization was successful in relieving the patient’s condition; most patients with mild to moderate symp-
symptoms. toms can experience improvement with simple advice.
Manual therapy is an option in the management of
Cubital Tunnel Syndrome cubital tunnel syndrome, although there is limited evi-
Cubital tunnel syndrome is the second most common dence at this time. In a case series of seven patients
upper extremity nerve compression syndrome after with mild to moderate cubital tunnel syndrome, Oskay
carpal tunnel syndrome (CTS),49 with an annual inci- et al.55 reported significant reductions in pain, provoca-
dence estimated at 0.8%.50 Originally described in tive testing, and disability in a treatment program that
1954 by Feindel and Stratford,51 cubital tunnel syn- included neural mobilizations and traditional physical
drome typically manifests with medial elbow pain, interventions. These results were maintained over a
sensory complaints within the ulnar nerve distribution 12-month follow-up. In a case report, Coppieters
of the hand, and possibly weakness. In severe cases, et al.56 described an impairment-based approach
wasting of the intrinsic musculature of the hand may including manual therapy and neural mobilizations. In
be present.49 Initially, symptoms tend to be intermit- this case, a 17-year-old student had a traumatic onset
tent in nature, but as severity increases they may become of cubital tunnel syndrome. She presented with medial
constant. elbow pain, symptoms in the ulnar nerve distribution,
A thorough history and assessment of risk factors is negative electrodiagnostic testing, and cervicothoracic
key in the clinical diagnostic process of cubital tunnel segmental dysfunctions. The patient was treated for 6
syndrome. Several risk factors have been identified for sessions consisting of neural gliding, cervicothoracic
individuals who develop cubital tunnel syndrome. thrust, and nonthrust manipulation, with an additional
Cubital tunnel syndrome has been estimated to affect home exercise program. The home exercise program
up to 64% of individuals whose primary occupation consisted of neural gliding and strengthening exercises.
involves computer or repetitive related tasks as well as The patient reported no pain or disability at 6-week
musicians.52 Descatha et al.50 followed 600 subjects for and 10-month follow-up evaluations.
3 years to determine predictive variables for individuals
most likely to develop cubital tunnel syndrome. Carpal Tunnel Syndrome
“Holding a tool in position” (odds ratio, 4.1; confidence CTS is the most common peripheral neuropathy in the
interval, 1.4 to 12.0) and obesity (odds ratio, 4.3; con- upper extremity with an estimated prevalence of 3.8%.57
fidence interval, 1.2 to 16.2) were the only predictive The diagnosis of CTS is typically made with electro-
factors identified. The presence of medial epicondylitis, diagnostic testing; however, clinical diagnosis is pos-
CTS, radial tunnel syndrome, or cervicobrachial neu- sible. Wainner et al.58 developed a clinical prediction
ralgia also increased the chances of developing cubital rule to assist in the clinical identification of CTS. They
tunnel syndrome. Electrodiagnostic testing is a identified five predictor variables, including shaking of
common method of diagnosing cubital tunnel syn- the hands for relief, wrist ratio index greater than 0.67,
drome. Four commonly used provocative tests per- Symptom Severity Scale score greater than 1.9, age
formed during physical examination include Tinel’s older than 45 years, and diminished sensation over the
sign, elbow flexion, direct pressure to the area, and thumb (median nerve distribution). The presence of all
2560_Chapter 16_0181-0194.indd 185 3/16/2015 4:13:39 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
five variables yielded a positive likelihood ratio of 18.3, population may be due partly to the heterogeneity of
which shifts the post-test probability to 90% for the the application of the techniques.69
diagnosis of CTS. In this study, electrophysiological Other manual therapy techniques, such as carpal
testing was used as the reference standard. The wrist bone mobilizations or soft tissue techniques, are pur-
ratio index is the measurement of the anteroposterior portedly effective in patients with CTS. Tal-Akabi and
wrist width divided by the mediolateral wrist width. Rushton64 compared the results of neural mobilization,
This value has been purported to estimate the size of carpal bone mobilization, and no treatment in patients
the carpal canal with larger ratios (greater than 0.70) with CTS. In this study, both neural mobilization and
predisposing individuals to CTS.59 Additional impair- carpal bone mobilization produced better outcomes
ments have been associated with patients with CTS compared with no treatment. There was no significant
including forward head posture and decreased cervical difference between the two intervention groups. Surgi-
ROM.60 cal interventions ultimately were performed in 85% of
Treatment of CTS may range from conservative the patients in the control group compared with 28%
care to surgical management. Numerous interventions and 14% of patients in the neural and carpal bone
have shown short-term efficacy in the conservative mobilization groups, respectively. Moraska et al.66 com-
management of CTS.61 There is strong to moderate pared general massage to the upper quadrant versus
evidence for oral steroids, steroid injections, ultrasound, targeted massage therapy to the potential median nerve
electromagnetic field therapy, night splints, and ergo- entrapment sites of the upper extremity. Targeted
nomic modifications.62 Emerging evidence has dem- massage resulted in a 17.3% increase in grip strength
onstrated the possible efficacy of manual therapy in compared with 4.8% for general massage. Some pro-
the treatment of patients with CTS.63–67 Manual viders advocated for the use of instrumented soft tissue
therapy techniques used in CTS include neural mobi- mobilization techniques. Burke et al.63 investigated
lizations, carpal bone mobilization, and soft tissue instrumented soft tissue mobilization compared with
mobilization. traditional soft tissue mobilization implemented by the
Neural mobilization is a form of manual therapy in clinician’s hands. The authors concluded that there was
which forces are directed at nervous tissue.68 Coppe- no difference in outcomes with the two techniques.
tiers and Butler11 outline two separate neural mobiliza- Given that patients with CTS exhibit greater
tion techniques termed “sliders” or “tensioners.” forward head posture and decreased cervical spine
“Sliders” refers to gliding the nerve through its sheath ROM, it seems plausible that a treatment approach
by selectively placing the joints in certain positions. targeting the cervical and thoracic spine may be useful.
“Tensioners” refers to keeping one end of the nerve A study reported that 48.6% of female patients with
fixed and then placing the joints in position to produce CTS reported a successful outcome immediately fol-
tension within the nerve. The two separate techniques lowing a manual therapy treatment program including
apply different amounts of strain or excursion through targeted soft tissue mobilization techniques, lateral
the nerve. A “tensioning” technique produces roughly cervical glides, and manual sliding neural mobilization
50% of the excursion and nearly seven times the techniques.70 In this study, success was defined at a
amount of strain on the nerve compared with a “sliding” perceived recovery rating of +5 or greater on the Global
technique.11 In systematic reviews regarding the effi- Rating of Change scale, which represents a “quite a bit
cacy of neural mobilization, the results are often incon- better” rating or greater by the patient. Another case
clusive regarding clinical outcomes69; however, typically study reported a complete recovery of pain and dis-
only tensioning techniques were included, and most ability using thrust manipulation techniques that tar-
often these techniques were part of an exercise program. geted the cervical spine and elbow over a 4-week
In a clinical trial, 40 female subjects were randomly period. The role of manual therapy in the management
assigned to receive manual neurodynamic tensioning of CTS appears promising; however, more high-quality
mobilizations or a sham treatment.68 At 3 weeks, the trials are required to determine the effectiveness of
temporal summation of the ulnar nerve was reduced, manual therapy techniques in this population.
indicating a possible neurophysiological effect of ten-
sioning neurodynamic mobilizations. The outcomes of Lumbar Radiculopathy
the two groups in this study did not differ in terms of Lumbar radiculopathy is a common peripheral nerve
pain or disability. In this study, neural mobilization injury in the lower quarter region.71 In patients younger
using “tensioning” techniques produced an effect on than age 50, lumbar radiculopathy usually arises sec-
the nervous system as detected by quantitative sensory ondary to lumbar herniated discs. In patients older
testing; however, there was no change in clinical than 50, radiculopathy is more commonly associated
outcomes compared with sham. It is unclear what with degenerative lateral canal stenosis. Some clini-
effect sliding techniques have on clinical outcomes cians distinguish between lumbar radiculitis involving
or neurophysiological parameters. The equivocal evi- leg or nerve root pain only versus radiculopathy that
dence regarding the use of neural mobilizations in this involves leg pain with neurological signs. The clinical
2560_Chapter 16_0181-0194.indd 186 3/16/2015 4:13:39 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
diagnosis of lumbar radiculopathy is associated with
lancinating leg pain; loss of sensation, reflexes, and
motor function; and positive nerve root tension signs.72
With radiculopathy, the patient’s pain distribution
does not always follow the classic dermatomal distribu-
tion.73 The straight leg–raise test is the most commonly
used clinical test in the assessment of lumbar radicu-
lopathy. However, this test is more applicable to rule
out a radiculopathy because it is a sensitive test but not
very specific. Although the methodological quality of
studies investigating this test is poor, the well or crossed
straight leg–raise test is purported to have greater spec-
ificity to help rule in radiculopathy. Similarly, the neu-
rological tests of sensation, reflexes, and motor function
help to rule in a radiculopathy but do not serve as
adequate screening tests for radiculopathy because of
Figure 16-3 Prone lumbar extension exercise.
their low sensitivity. The most commonly affected
nerve roots in lumbar radiculopathy are the L4–S1
nerve roots. Upper lumbar radiculopathies are rare—
their recognition should alert the clinician to the pos- in the direction that achieved centralization. Patients
sibility of a space-occupying lesion, such as metastatic are also educated about how to avoid positions during
cancer. their daily activities that cause their radicular symp-
Physical therapy management of lumbar radicu- toms to worsen or move toward the periphery. The
lopathies frequently consists of traction, manual therapy, importance of the centralization sign is that patients
and exercise. As with other regions, interventions can who achieve centralization have a more favorable prog-
be directed toward treating the neural interface, directly nosis in terms of recovery of function, decreased pain,
mobilizing neural tissue, or a combination of both. and return to work status compared with patients who
Evidence for conservative or manual therapy manage- do not achieve centralization.76 MDT and directional
ment of lumbar radiculopathy is scarce. A systematic exercise have been studied for patients with low back
review of literature addressing conservative manage- pain, and the results have been favorable compared
ment of a lumbar radiculopathy resulting from lumbar with control groups. Despite these findings, MDT and
herniated disc revealed moderate to weak evidence in directional exercise have not been specifically studied
favor of traction, manipulation, and stabilization exer- in patients with lumbar radiculopathy.77 Nevertheless,
cises.74 Highlights of some of the higher quality it is recommended that repeated directional motion
research in support of manual therapy for lumbar testing be completed in patients presenting with lumbar
radiculopathy follow. radiculopathy before considering other interventions.
Mechanical diagnosis and therapy (MDT), also If the patient’s symptoms centralize, exercises and
known as the McKenzie method, is widely used manual therapy procedures into the direction that pro-
throughout the world in the management of spinal duced centralization should be used because of the
conditions.75 With this method, clinicians ask patients favorable prognosis.77 Not all patients with lumbar
to perform movements of the spine including static, radiculopathy achieve centralization with directional
single, and repeated movements in various planes of exercises, and the exact percentage of patients who can
motion while assessing the patient’s signs and symp- be classified as achieving centralization varies widely
toms (Fig. 16-3). across studies.
The key sign associated with MDT is the centraliza- Fritz et al.78 performed a prospective randomized
tion phenomenon. Centralization is defined as a retreat controlled trial investigating the use of an extension-
of the patient’s symptoms in a distal-to-proximal oriented exercise treatment compared with the same
fashion that occurs during testing and remains after- treatment with the addition of mechanical lumbar
ward.76 An example is in a patient with an S1 radicu- traction. The study enrolled 64 patients 19 to 60 years
lopathy who performs repeated lumbar extension in old with clinical signs of lumbar radiculopathy. Both
standing. If the pain was reported in the calf region at groups received the extension-oriented treatment con-
baseline and retreated proximally to the buttock region sisting of instruction in repeated lumbar extension
during the exercise and stayed in the buttock region exercises in standing and prone and lumbar posterior-
after the completion of the testing, the patient’s symp- to-anterior nonthrust manipulation. Patients were
toms would be classified as centralized. With this instructed as needed to shift their pelvis laterally during
intervention, the patient is prescribed exercises with the exercises to promote extension. Therapists could
the addition of manual therapy procedures as needed also apply overpressure while the patient performed
2560_Chapter 16_0181-0194.indd 187 3/16/2015 4:13:39 PM

Process CyanProcess
YellowProcess Black
prone extension to promote extension ROM. Patients
were instructed to perform the extension exercises
every 4 to 5 hours at home in addition to receiving
supervised treatment in the clinic. Patients were also
told to maintain a neutral lumbar lordosis throughout
their daily activities and to avoid lumbar flexion. This
treatment was provided a maximum of nine times over
a 1-week period. The traction group received mechani-
cal lumbar traction in a prone position. Traction was
performed on a three-dimensional adjustable traction
table with a traction force 40% to 60% of the patients’
body weight for 12 minutes. Clinicians adjusted the
force and the direction of the traction to achieve cen-
tralization of the patients’ symptoms. Patients in the
traction group received 12 treatments over a 6-week
period including traction four times per week during
Figure 16-4 Posterior-to-anterior lumbar manual
the first 2 weeks. At the 2-week and 6-week follow-up
mobilization.
evaluations, both groups achieved clinically and statis-
tically significant improvement in pain and function
with no difference between groups. Further subgroup
analysis found that patients who had a positive crossed could potentially benefit with a low risk of harm. The
straight leg–raise test or had symptom peripheraliza- authors of the study were careful to position the patients
tion with lumbar extension had substantially better so as not to cause peripheralization of the patient’s
outcomes if they received traction. Patients who symptoms during the manipulation. We support this
achieved centralization with extension achieved clini- idea and attempt manipulation in patients with lumbar
cally and statistically better outcomes regardless of radiculopathy only if the position and techniques can
group assignment. A larger prospective study is under be accomplished without peripheralizing the patient’s
way to investigate this question further, but the results symptoms.
suggest that a subgroup of patients with lumbar radicu- Patients older than 50 years of age who have lumbar
lopathy benefit from traction.79 radiculopathy are more likely to have degenerative
McMorland et al.80 compared spinal thrust manipu- lateral canal stenosis compared with lumbar disc her-
lation with microdiskectomy in a group of patients niation. There are few high-quality trials investigating
with lumbar radiculopathy secondary to lumbar disc conservative treatment for patients with lumbar spinal
herniation. Patients were included if they had symp- stenosis. Rates of surgery, including spinal fusion, for
toms for at least 3 months’ duration and had failed lumbar spinal stenosis have been steadily increasing
conservative treatment, positive neurological findings, over the past decade.82 Given the frequent comorbidi-
and MRI findings consistent with lumbar disc hernia- ties in older adults with spinal stenosis, complications
tion. There were 20 patients randomly assigned to the arising from surgery have been increasing as well.
spinal manipulation group consisting of a lumbar Effective nonsurgical management options for patients
thrust manipulation in side-lying, education, and par- with spinal stenosis are crucial. In a high-quality ran-
ticipation in a core stabilization program and 20 domized controlled trial, Whitman et al.83 compared
patients randomly assigned to receive a microdiskec- an exercise-based physical therapy program with
tomy. At 6 weeks after surgery, the patients were pro- a multimodal physical therapy program. These investi-
vided with a similar education and exercise program as gators randomly assigned 58 patients with lumbar
the manipulation group. At 12-week follow-up evalu- spinal stenosis to receive supervised flexion-oriented
ation, both groups had achieved clinically and statisti- exercises plus a level walking program or manual
cally significant improvement in pain and function therapy, exercises, and an unloaded treadmill walking
with no difference between the groups. Of the 20 program. Manual therapy was individually tailored and
patients in the manipulation group, 8 eventually crossed targeted the impairments found during the examina-
over to surgery. Although this was considered a pilot tion (Fig. 16-5).
study, the results are interesting in that some patients Techniques included lumbar thrust and nonthrust
who had failed other forms of nonsurgical care were manipulation and procedures aimed at improving hip
able to benefit from spinal manipulation. It has been mobility. Exercise was designed to promote lumbar
proposed that radiculopathy, including positive neuro- spine flexion, lumbar core stabilization, and hip muscle
logical findings, is a contraindication to manipulation flexibility. Groups received in-clinic treatment two
or that these patients do not benefit from manipulation times per week for 6 weeks and were prescribed a home
(see Fig. 16-4).81 This study showed that some patients exercise program. Both groups achieved clinically and
2560_Chapter 16_0181-0194.indd 188 3/16/2015 4:13:39 PM

Process CyanProcess
YellowProcess Black
buttocks and a positive slump test. Patients were
excluded if they had positive neurological findings or
a positive straight leg raise of less than 45°. Also,
patients could not show signs of peripheralization or
centralization during repeated directional lumbar
ROM testing. Patients in both groups received stan-
dardized lumbar stabilization exercises and posterior-
to-anterior nonthrust manipulation directed to the
lumbar spine two times per week for 3 weeks. Patients
in the slump stretching group also received passive
stretching in the slump position for five bouts of 30
seconds in addition to performing this exercise at home
for two bouts of 30 seconds per day. Both groups
achieved improvement in pain and function at the
completion of the study, but the slump stretching
group achieved clinically and statistically greater
Figure 16-5 Side-lying rotary lumbar thrust manipulation.
improvements. The slump stretch group showed a
greater degree of centralization of leg symptoms at the
end of the treatment. The patients in this study did not
have acute radiculopathy, and their symptoms did not
change with repeated motion testing. The patients in
this study represent a subgroup of patients with chronic
leg pain that likely started as an acute radiculopathy.
Proponents of neural mobilization have recommended
that exercises or passive treatments do not begin with
procedures that place tension on the nerve at both the
proximal and the distal ends,85 particularly in the acute
phase where performing “tensioners” could have an
adverse effect because of the decrease in blood circula-
tion while in the fully stretched position. It is recom-
mended that patients initially perform gentle neural
“flossing” exercises in an oscillatory fashion.
Piriformis Syndrome
Figure 16-6 Clinician-assisted slump stretch. Piriformis syndrome is a controversial diagnosis
because of the commonality of signs and symptoms
between piriformis syndrome and other conditions,
statistically meaningful improvement in pain and func- particularly lumbar radiculopathy. There is currently no
tion at 6-week and 1-year follow-up evaluations, with accepted standard for the clinical diagnosis of pirifor-
the multimodal physical therapy group achieving sig- mis syndrome, and it remains a diagnosis of exclusion.
nificantly better outcomes. It is difficult to separate the Piriformis syndrome is thought to arise from anatomi-
effects of the manual therapy from the other interven- cal anomalies where the sciatic nerve pierces the piri-
tions in this study. In our opinion, key manual therapy formis muscle or from indirect compression of the
techniques for patients with lumbar radiculopathy sciatic nerve in the region of the piriformis caused by
resulting from lumbar stenosis include lumbar manip- trauma or repetitive strain.86 Clinicians should examine
ulation (thrust or nonthrust) and hip stretching/ the lumbar, sacroiliac, and hip joint regions before
mobilization. It is important during these procedures ruling in piriformis syndrome as a potential diagnosis.
to ensure that the patient’s symptoms do not periph- Repeated lumbar movement testing as mentioned
eralize during the technique. earlier should be conducted in attempts to find direc-
Few studies have investigated the effects of direct tions that either centralize or peripheralize the patient’s
neural mobilization in patients with lumbar radicu- pain. If the patient’s symptoms can be centralized with
lopathy. Cleland et al.84 performed a pilot randomized repeated lumbar movement, the diagnosis of piriformis
controlled trial comparing slump stretching with sta- syndrome is unlikely. Tests that purportedly rule in
bilization exercises for 30 patients with low back and piriformis syndrome as a diagnosis include the flexion,
leg pain (Fig. 16-6). adduction, internal rotation (FAIR) test, straight leg
Patients who met the inclusion criteria for the raise, and direct palpation of the piriformis muscle
study had low back pain with symptoms distal to the belly.87 For the FAIR test, the patient is in side-lying
2560_Chapter 16_0181-0194.indd 189 3/16/2015 4:13:40 PM

Process CyanProcess
YellowProcess Black
and the clinician passively flexes, adducts, and inter- who did not. As mentioned previously, it is now recom-
nally rotates with patient’s top leg. The test is positive mended that patients perform neural flossing exercises
if it reproduces symptoms in the piriformis region. A for the sciatic nerve at first, particularly in the acute
systematic review of the literature reported that the phase of injury, and perform static neural stretching as
following signs were most common among studies a progression and only as needed to clear the patient
investigating the diagnosis of piriformis syndrome: fully of sciatic neural tension signs. Another potential
buttock pain, external tenderness over the greater treatment option for hamstring-related sciatic neural
sciatic notch, aggravation of the pain through sitting, irritation is to perform soft tissue mobilization while
and augmentation of the pain with maneuvers that the patient actively stretches the hamstring and flosses
increase piriformis muscle tension.86 Nonrandomized, the nerve.
observational studies reported some benefit from the
injection of the piriformis muscle with botulinum toxin Meralgia Paresthetica
to reduce muscle spasms and relieve pressure on the Entrapment of the lateral femoral cutaneous nerve in
sciatic nerve.88 High-quality trials of physical and the inguinal region, also known as meralgia paresthet-
manual therapy interventions are lacking. General ica, involves paresthesias, numbness, and burning in the
strategies include stretching and direct mobilization of peripheral nerve’s field.94 Common causes include
the piriformis muscle. In addition to treating the obesity, diabetes, direct trauma, pregnancy, radiation,
muscle, sciatic neural mobilization using neural floss- and direct pressure on the nerve from restrictive cloth-
ing or exercises could be attempted. A case report in ing and utility belts. Clinical diagnosis involves testing
the literature indicates that a possible cause of pirifor- sensation in the nerve’s field, palpating the nerve in the
mis syndrome is motor control dysfunction of the lateral inguinal region, and neural tension testing. For
lower extremity whereby the hip and femur on the neural tension testing, the patient is in prone, and the
affected side excessively adducts and internally rotates knee is passively flexed; this places tension on the upper
during functional activities.89 In theory, this movement lumbar nerve roots and femoral nerve. The hip can be
dysfunction places strain on the piriformis muscle adducted to apply further tension to the lateral femoral
which is an external rotator of the hip. In the case cutaneous nerve.3 Typical treatment involves patient
report, correction of this dysfunction with movement education to alter any direct compression on the nerve
re-education and strengthening exercises for the hip from restrictive clothing or belts, injections, and surgery
external rotators and gluteal muscles was beneficial for as a last resort.94 Manual therapy treatment could be
the patient. directed toward the soft tissue in the anterior thigh and
inguinal region. Assessment and manual therapy man-
Hamstring Strains agement of upper lumbar dysfunction could also be
Although hamstring injuries predominantly involve potentially beneficial because the lateral femoral cuta-
muscle strain from sudden high-velocity eccentric con- neous nerve receives its supply from the upper lumbar
traction of the hamstrings during athletic activities, spine. Direct mobilization of the nerve involves knee
there have been reports in the literature of sciatic nerve flexion in an oscillatory fashion either actively by the
involvement.90 During the injury, the sciatic nerve patient or passively by the clinician. Active neural floss-
could become overstretched resulting in a tension neu- ing while performing soft tissue mobilization of the
ropathy. Additionally, the acute inflammatory response anterior thigh or inguinal region is another potentially
in the region of the injured muscle tissue could lead to useful option.
bleeding and scarring around the sciatic nerve. It has
also been proposed that lumbar spine dysfunction, Neuropathies of the Foot and Ankle Region
either as a predisposing factor or as a result of the Aside from diabetic peripheral neuropathy, peripheral
injury, is associated with hamstring injury, and the nerve injuries of the foot and ankle region are uncom-
lumbar dysfunction could result in concomitant sciat- mon. There is no evidence from high-quality random-
ica.91 It has been recommended that all patients with ized trials in the literature concerning manual therapy
hamstring injuries receive an evaluation of the lumbar for peripheral nerve injuries in the foot and ankle
spine, pelvis, and hip joints to assess for impairments region. The major peripheral nerves of the lower leg,
that could be contributing to the signs and symptoms including the posterior tibial, peroneal, and sural nerves,
of hamstring injury.92 In the evaluation of patients with can be evaluated for neuropathy using history and
hamstring injury, the slump test has been recom- physical examination. Part of the physical examination
mended to evaluate the patient for sciatic neural irrita- could involve neural tension testing, making use of the
tion.90 In an experimental study, Kornberg and Lew93 anatomical course of the nerve around the foot and
reported that Australian football players who had sus- ankle region.95–98 For example, to tension the tibial
tained a grade I hamstring injury and also had a posi- nerve selectively, the ankle can be placed in dorsiflexion
tive slump test were able to return to play more quickly and eversion during the straight leg–raise test. To
if they received slump stretching in addition to tradi- apply tension to the peroneal nerve, the ankle can be
tional management compared with a group of players placed in plantar flexion and inversion. Manual therapy
2560_Chapter 16_0181-0194.indd 190 3/16/2015 4:13:40 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
management of peripheral nerve injuries about the foot 3. Manual therapy techniques used in the treatment of
and ankle can involve mobilization of the surrounding carpal tunnel syndrome include all of the following
structures, direct mobilization of the nerve, or a com- except which one?
bination of the two. Based on the examination findings, a. Carpal bone mobilization
tissues that interface with the injured nerve could be b. Lumbar thrust maneuver
targeted with manual therapy interventions. For c. Neural mobilization
example, in patients with plantar heel pain associated d. Soft tissue mobilization
with posterior tibial neuropathy, also known as tarsal
4. Given that patients with CTS syndrome exhibit
tunnel syndrome, the subtalar joint can be passively
greater forward head posture and decreased
manipulated. For direct neural mobilization, the pos-
cervical spine ROM, which of the following
terior tibial nerve can be mobilized using passive ankle
therapeutic techniques may be useful?
dorsiflexion with eversion. For a combination manual
a. Cervical ROM
therapy technique, the subtalar joint can be manipu-
b. Postural retraining
lated while the tibial nerve is on stretch. In another
c. Thoracic manipulation
example, the manual therapist can address the superfi-
d. All of the above
cial peroneal nerve, which can be injured during an
inversion ankle sprain.99 For this injury, the proximal 5. “Sliders” and “tensioners” are two types of which of
and distal tibiofibular joint can be passively manipu- the following?
lated. The superficial peroneal nerve can be directly a. Manipulative thrusts of the thoracic spine
mobilized with passive ankle plantar flexion with inver- b. Manipulative thrust of the cervical spine
sion. The distal tibiofibular joint can be mobilized with c. Neurodynamic treatment techniques
the superficial peroneal nerve on stretch. d. Mobilization techniques for the carpal bones
CASE STUDY References

BR, a 52-year-old man who works as a computer 1. Bronfort G, Haas M, Evans R, Leininger B, Triano J.
programmer for a large software company, presents to Effectiveness of manual therapies: the UK evidence report.
Chiropr Osteopat. 2010;18:3.
outpatient therapy with a chief complaint of a 3-month 2. Butler DS. The Sensitive Nervous System. 1st ed. Adelaide,
history of numbness in his right (dominant hand), South Australia: Noigroup Publications; 2000.
which worsens with computer activity and sleep. An 3. Shacklock M. Clinical Neurodynamics: A New System of
electroneuromyography examination revealed slowing Neuromusculoskeletal Treatment. Oxford, UK: Butterworth-
of the median nerve through the carpal tunnel and Heinemann; 2005.
4. Maitland G, Hengeveld E, Banks K, English K. Maitland’s
mild denervation potentials in the thenar compartment Vertebral Manipulation. 7th ed. Oxford, UK: Butterworth-
musculature. His symptoms were assessed with the Heinemann; 2005.
Symptom Severity Score with a result of 2.2. His 5. Butler D. Mobilisation of the Nervous System. 1st ed.
medical history is otherwise benign. BR does not take Edinburgh: Churchill Livingstone; 1991.
any prescriptive medications. 6. Schmid AB, Brunner F, Luomajoki H, et al. Reliability of
clinical tests to evaluate nerve function and
mechanosensitivity of the upper limb peripheral nervous
Case Study Questions system. BMC Musculoskelet Disord. 2009;10:11.
7. Walsh J, Hall T. Reliability, validity and diagnostic accuracy
1. The clinical prediction rule developed by Wainner of palpation of the sciatic, tibial and common peroneal nerves
et al.58 identified five predictor variables to assess in the examination of low back related leg pain. Man Ther.
2009;14(6):623–629.
the possibility of a CTS diagnosis. Which of the 8. Wainner RS, Fritz JM, Irrgang JJ, et al. Reliability and
following items is not part of the prediction rule? diagnostic accuracy of the clinical examination and patient
a. Weakness of the ipsilateral digiti minimi muscle self-report measures for cervical radiculopathy. Spine. 2003;
b. Shaking of the hand for relief 28(1):52–62.
c. A Symptom Severity Scale score of greater than 9. Nijs J, Van Houdenhove B, Oostendorp RAB. Recognition of
central sensitization in patients with musculoskeletal pain:
1.9 and age older than 45 years application of pain neurophysiology in manual therapy
d. Wrist ratio index greater than 0.67 practice. Man Ther. 2010;15(2):135–141.
10. Scott D, Jull G, Sterling M. Widespread sensory
2. Which of the following tests is the “gold standard” hypersensitivity is a feature of chronic whiplash-associated
test for diagnosing CTS? disorder but not chronic idiopathic neck pain. Clin J Pain.
a. Disability of the Arm, Shoulder and Hand (DASH) 2005;21(2):175–181.
assessment 11. Coppieters MW, Butler DS. Do “sliders” slide and
b. Electroneuromyography “tensioners” tension? An analysis of neurodynamic techniques
and considerations regarding their application. Man Ther.
c. Phalen’s test 2008;13(3):213–221.
d. Symptom Severity Scale score of greater than 1.9 12. Bialosky JE, Bishop MD, Price DD, Robinson ME, George
and age older than 45 years SZ. The mechanisms of manual therapy in the treatment of
2560_Chapter 16_0181-0194.indd 191 3/16/2015 4:13:40 PM

Process CyanProcess
YellowProcess Black
musculoskeletal pain: a comprehensive model. Man Ther. 30. Waldrop MA. Diagnosis and treatment of cervical
2009;14(5):531–538. radiculopathy using a clinical prediction rule and a
13. Bialosky JE, Bishop MD, Cleland JA. Individual expectation: multimodal intervention approach: a case series. J Orthop
an overlooked, but pertinent, factor in the treatment of Sports Phys Ther. 2006;36(3):152–159.
individuals experiencing musculoskeletal pain. Phys Ther. 31. Moeti P, Marchetti G. Clinical outcome from mechanical
2010;90(9):1345–1355. intermittent cervical traction for the treatment of cervical
14. Gross AR, Hoving JL, Haines TA, et al. Manipulation and radiculopathy: a case series. J Orthop Sports Phys Ther. 2001;
mobilisation for mechanical neck disorders. Cochrane Database 31(4):207–213.
Syst Rev. 2004;(1):CD004249. 32. Young IA, Michener LA, Cleland JA, Aguilera AJ, Snyder
15. Wainner RS, Gill H. Diagnosis and nonoperative AR. Manual therapy, exercise, and traction for patients with
management of cervical radiculopathy. J Orthop Sports Phys cervical radiculopathy: a randomized clinical trial. Phys Ther.
Ther. 2000;30(12):728–744. 2009;89(7):632–642.
16. Radhakrishnan K, Litchy WJ, O’Fallon WM, Kurland LT. 33. Brooke BS, Freischlag JA. Contemporary management of
Epidemiology of cervical radiculopathy. A population-based thoracic outlet syndrome. Curr Opin Cardiol. 2010;25(6):
study from Rochester, Minnesota, 1976 through 1990. Brain. 535–540.
1994;117(Pt 2):325–335. 34. Povlsen B, Belzberg A, Hansson T, Dorsi M. Treatment
17. Eubanks JD. Cervical radiculopathy: nonoperative for thoracic outlet syndrome. Cochrane Database Syst Rev.
management of neck pain and radicular symptoms. Am Fam 2010;(1):CD007218.
Physician. 2010;81(1):33–40. 35. Watson LA, Pizzari T, Balster S. Thoracic outlet syndrome
18. Young IA, Michener LA, Cleland JA, Aguilera AJ, Snyder part 2: conservative management of thoracic outlet. Man Ther.
AR. Manual therapy, exercise, and traction for patients with 2010;15(4):305–314.
cervical radiculopathy: a randomized clinical trial. Phys Ther. 36. Wilbourn AJ. The thoracic outlet syndrome is overdiagnosed.
2009;89(7):632–642. Arch Neurol. 1990;47(3):328–330.
19. Larsson EM, Holtås S, Cronqvist S, Brandt L. Comparison 37. Terao T, Ide K, Taniguchi M, et al. The management of
of myelography, CT myelography and magnetic resonance patients with thoracic outlet syndrome (TOS) and an
imaging in cervical spondylosis and disk herniation. Pre- and assistant diagnosis to discriminate between TOS and cervical
postoperative findings. Acta Radiol. 1989;30(3):233–239. spondylosis [in Japanese]. No Shinkei Geka. 2008;36(7):
20. Song K, Choi B, Kim G, Kim J. Clinical usefulness of 615–623.
CT-myelogram comparing with the MRI in degenerative 38. Lindgren KA, Leino E, Manninen H. Cervical rotation
cervical spinal disorders: is CTM still useful for primary lateral flexion test in brachialgia. Arch Phys Med Rehabil.
diagnostic tool? J Spinal Disord Tech. 2009;22(5):353–357. 1992;73(8):735–737.
21. Eisen A. The utility of proximal nerve conduction in 39. Hooper T, Denton J, McGalliard M, Brismee J, Sizer P.
radiculopathies: the cons. Electroencephalogr Clin Neurophysiol. Thoracic outlet syndrome: a controversial clinical condition.
1991;78(3):171–172; discussion 167. Part 2: non-surgical and surgical management. J Man Manip
22. Cho SC, Ferrante MA, Levin KH, Harmon RL, So YT. Ther. 2010;18(3):132–138.
Utility of electrodiagnostic testing in evaluating patients with 40. Smith KF. The thoracic outlet syndrome: a protocol of
lumbosacral radiculopathy: an evidence-based review. Muscle treatment. J Orthop Sports Phys Ther. 1979;1(2):89–99.
Nerve. 2010;42(2):276–282. 41. Vanti C, Natalini L, Romeo A, Tosarelli D, Pillastrini P.
23. Wainner RS, Fritz JM, Irrgang JJ, et al. Reliability and Conservative treatment of thoracic outlet syndrome. A review
diagnostic accuracy of the clinical examination and patient of the literature. Eura Medicophys. 2007;43(1):55–70.
self-report measures for cervical radiculopathy. Spine. 2003; 42. Hooper T, Denton J, McGalliard M, Brismee J, Sizer P.
28(1):52–62. Thoracic outlet syndrome: a controversial clinical condition.
24. Childs JD, Cleland JA, Elliott JM, et al. Neck pain: clinical Part 1: anatomy, and clinical examination/diagnosis. J Man
practice guidelines linked to the International Classification Manip Ther. 2010;18(2):75–83.
of Functioning, Disability, and Health from the Orthopedic 43. Buonocore M, Manstretta C, Mazzucchi G, Casale R. The
Section of the American Physical Therapy Association. clinical evaluation of conservative treatment in patients with
J Orthop Sports Phys Ther. 2008;38(9):A1–A34. the thoracic outlet syndrome [in Italian]. G Ital Med Lav
25. Cleland JA, Childs JD, Fritz JM, Whitman JM, Eberhart SL. Ergon. 1998;20(4):249–254.
Development of a clinical prediction rule for guiding 44. Revel M, Amor B. Rehabilitation of cervico-thoraco-brachial
treatment of a subgroup of patients with neck pain: use of outlet syndromes [in French]. Phlebologie. 1983;36(2):
thoracic spine manipulation, exercise, and patient education. 157–165.
Phys Ther. 2007;87(1):9–23. 45. Vicenzino B, Cleland JA, Bisset L. Joint manipulation in the
26. Raney NH, Petersen EJ, Smith TA, et al. Development of a management of lateral epicondylalgia: a clinical commentary.
clinical prediction rule to identify patients with neck pain J Man Manip Ther. 2007;15(1):50–56.
likely to benefit from cervical traction and exercise. Eur 46. Waugh EJ. Lateral epicondylalgia or epicondylitis: what’s in a
Spine J. 2009;18(3):382–391. name? J Orthop Sports Phys Ther. 2005;35(4):200–202.
27. Cleland JA, Mintken PE, Carpenter K, et al. Examination of 47. Yaxley GA, Jull GA. Adverse tension in the neural system. A
a clinical prediction rule to identify patients with neck pain preliminary study of tennis elbow. Aust J Physiother. 1993;
likely to benefit from thoracic spine thrust manipulation and 39(1):15–22.
a general cervical range of motion exercise: multi-center 48. Ekstrom RA, Holden K. Examination of and intervention for
randomized clinical trial. Phys Ther. 2010;90(9):1239–1250. a patient with chronic lateral elbow pain with signs of nerve
28. Cleland JA, Fritz JM, Whitman JM, Heath R. Predictors of entrapment. Phys Ther. 2002;82(11):1077–1086.
short-term outcome in people with a clinical diagnosis of 49. Szabo RM, Kwak C. Natural history and conservative
cervical radiculopathy. Phys Ther. 2007;87(12):1619–1632. management of cubital tunnel syndrome. Hand Clin. 2007;
29. Cleland JA, Whitman JM, Fritz JM, Palmer JA. Manual 23(3):311–318.
physical therapy, cervical traction, and strengthening exercises 50. Descatha A, Leclerc A, Chastang J, Roquelaure Y. Incidence
in patients with cervical radiculopathy: a case series. J Orthop of ulnar nerve entrapment at the elbow in repetitive work.
Sports Phys Ther. 2005;35(12):802–811. Scand J Work Environ Health. 2004;30(3):234–240.
2560_Chapter 16_0181-0194.indd 192 3/16/2015 4:13:40 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
51. Feindel W, Stratford J. The role of the cubital tunnel in tardy carpal tunnel syndrome who are likely to achieve short-term
ulnar palsy. Can J Surg. 1958;1(4):287–300. success with physical therapy. Exp Brain Res. 2010;207(1–2):
52. Pascarelli EF, Hsu YP. Understanding work-related upper 85–94.
extremity disorders: clinical findings in 485 computer users, 71. Van Boxem K, Cheng J, Patijn J, et al. 11. Lumbosacral
musicians, and others. J Occup Rehabil. 2001;11(1):1–21. radicular pain. Pain Pract. 2010;10(4):339–358.
53. Novak CB, Lee GW, Mackinnon SE, Lay L. Provocative 72. van der Windt DA, Simons E, Riphagen II, et al. Physical
testing for cubital tunnel syndrome. J Hand Surg Am. 1994; examination for lumbar radiculopathy due to disc herniation
19(5):817–820. in patients with low-back pain. Cochrane Database Syst Rev.
54. Svernlöv B, Larsson M, Rehn K, Adolfsson L. Conservative 2010;(2):CD007431.
treatment of the cubital tunnel syndrome. J Hand Surg Eur 73. Murphy DR, Hurwitz EL, Gerrard JK, Clary R. Pain
Vol. 2009;34(2):201–207. patterns and descriptions in patients with radicular pain: does
55. Oskay D, Meriç A, Kirdi N, et al. Neurodynamic the pain necessarily follow a specific dermatome? Chiropr
mobilization in the conservative treatment of cubital tunnel Osteopat. 2009;17:9.
syndrome: long-term follow-up of 7 cases. J Manipulative 74. Hahne AJ, Ford JJ, McMeeken JM. Conservative
Physiol Ther. 2010;33(2):156–163. management of lumbar disc herniation with associated
56. Coppieters MW, Bartholomeeusen KE, Stappaerts KH. radiculopathy: a systematic review. Spine. 2010;35(11):
Incorporating nerve-gliding techniques in the conservative E488–504.
treatment of cubital tunnel syndrome. J Manipulative Physiol 75. May S, Donelson R. Evidence-informed management of
Ther. 2004;27(9):560–568. chronic low back pain with the McKenzie method. Spine J.
57. Atroshi I, Gummesson C, Johnsson R, et al. Prevalence of 2008;8(1):134–141.
carpal tunnel syndrome in a general population. JAMA. 1999; 76. Werneke M, Hart DL. Centralization phenomenon as a
282(2):153–158. prognostic factor for chronic low back pain and disability.
58. Wainner RS, Fritz JM, Irrgang JJ, et al. Development of a Spine. 2001;26(7):758–764; discussion 765.
clinical prediction rule for the diagnosis of carpal tunnel 77. Long A, Donelson R, Fung T. Does it matter which exercise?
syndrome. Arch Phys Med Rehabil. 2005;86(4):609–618. A randomized control trial of exercise for low back pain.
59. Johnson EW, Gatens T, Poindexter D, Bowers D. Wrist Spine. 2004;29(23):2593–2602.
dimensions: correlation with median sensory latencies. Arch 78. Fritz JM, Lindsay W, Matheson JW, et al. Is there a subgroup
Phys Med Rehabil. 1983;64(11):556–557. of patients with low back pain likely to benefit from
60. De-la-Llave-Rincón AI, Fernández-de-las-Peñas C, Palacios- mechanical traction? Results of a randomized clinical trial
Ceña D, Cleland JA. Increased forward head posture and and subgrouping analysis. Spine. 2007;32(26):E793–800.
restricted cervical range of motion in patients with carpal 79. Fritz JM, Thackeray A, Childs JD, Brennan GP. A
tunnel syndrome. J Orthop Sports Phys Ther. 2009;39(9): randomized clinical trial of the effectiveness of mechanical
658–664. traction for sub-groups of patients with low back pain: study
61. Hirata H. Carpal tunnel syndrome and cubital tunnel methods and rationale. BMC Musculoskelet Disord. 2010;11:81.
syndrome [in Japanese]. Rinsho Shinkeigaku. 2007;47(11): 80. McMorland G, Suter E, Casha S, du Plessis SJ, Hurlbert RJ.
761–765. Manipulation or microdiskectomy for sciatica? A prospective
62. Huisstede BM, Hoogvliet P, Randsdorp MS, et al. Carpal randomized clinical study. J Manipulative Physiol Ther. 2010;
tunnel syndrome. Part I: effectiveness of nonsurgical 33(8):576–584.
treatments—a systematic review. Arch Phys Med Rehabil. 81. Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment
2010;91(7):981–1004. of low back pain: a joint clinical practice guideline from the
63. Burke J, Buchberger DJ, Carey-Loghmani MT, et al. A pilot American College of Physicians and the American Pain
study comparing two manual therapy interventions for carpal Society. Ann Intern Med. 2007;147(7):478–491.
tunnel syndrome. J Manipulative Physiol Ther. 2007;30(1): 82. Deyo RA, Mirza SK, Martin BI, et al. Trends, major medical
50–61. complications, and charges associated with surgery for
64. Tal-Akabi A, Rushton A. An investigation to compare the lumbar spinal stenosis in older adults. JAMA. 2010;303(13):
effectiveness of carpal bone mobilisation and neurodynamic 1259–1265.
mobilisation as methods of treatment for carpal tunnel 83. Whitman JM, Flynn TW, Childs JD, et al. A comparison
syndrome. Man Ther. 2000;5(4):214–222. between two physical therapy treatment programs for patients
65. Valente R, Gibson H. Chiropractic manipulation in carpal with lumbar spinal stenosis: a randomized clinical trial. Spine.
tunnel syndrome. J Manipulative Physiol Ther. 1994;17(4): 2006;31(22):2541–2549.
246–249. 84. Cleland JA, Childs JD, Palmer JA, Eberhart S. Slump
66. Moraska A, Chandler C, Edmiston-Schaetzel A, et al. stretching in the management of non-radicular low back
Comparison of a targeted and general massage protocol on pain: a pilot clinical trial. Man Ther. 2006;11(4):279–286.
strength, function, and symptoms associated with carpal 85. Nee RJ, Butler D. Management of peripheral neuropathic
tunnel syndrome: a randomized pilot study. J Altern pain: integrating neurobiology, neurodynamics, and clinical
Complement Med. 2008;14(3):259–267. evidence. Phys Ther Sport. 2006;7(1):36–49.
67. Baysal O, Altay Z, Ozcan C, et al. Comparison of three 86. Hopayian K, Song F, Riera R, Sambandan S. The clinical
conservative treatment protocols in carpal tunnel syndrome. features of the piriformis syndrome: a systematic review.
Int J Clin Pract. 2006;60(7):820–828. Eur Spine J. 2010;19(12):2095–2109.
68. Bialosky JE, Bishop MD, Price DD, et al. A randomized 87. Fishman LM, Dombi GW, Michaelsen C, et al. Piriformis
sham-controlled trial of a neurodynamic technique in the syndrome: diagnosis, treatment, and outcome—a 10-year
treatment of carpal tunnel syndrome. J Orthop Sports Phys study. Arch Phys Med Rehabil. 2002;83(3):295–301.
Ther. 2009;39(10):709–723. 88. Fishman LM, Konnoth C, Rozner B. Botulinum neurotoxin
69. Medina McKeon JM, Yancosek KE. Neural gliding type B and physical therapy in the treatment of piriformis
techniques for the treatment of carpal tunnel syndrome: a syndrome: a dose-finding study. Am J Phys Med Rehabil. 2004;
systematic review. J Sport Rehabil. 2008;17(3):324–341. 83(1):42–50; quiz 51–53.
70. Fernández-de-Las-Peñas C, Cleland JA, Ortega-Santiago R, 89. Tonley JC, Yun SM, Kochevar RJ, et al. Treatment of an
et al. Central sensitization does not identify patients with individual with piriformis syndrome focusing on hip muscle
2560_Chapter 16_0181-0194.indd 193 3/16/2015 4:13:40 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
strengthening and movement reeducation: a case report. 96. Alshami AM, Babri AS, Souvlis T, Coppieters MW.
J Orthop Sports Phys Ther. 2010;40(2):103–111. Biomechanical evaluation of two clinical tests for plantar heel
90. Turl SE, George KP. Adverse neural tension: a factor in pain: the dorsiflexion-eversion test for tarsal tunnel syndrome
repetitive hamstring strain? J Orthop Sports Phys Ther. 1998; and the windlass test for plantar fasciitis. Foot Ankle Int.
27(1):16–21. 2007;28(4):499–505.
91. Hoskins W, Pollard H. The management of hamstring 97. Coppieters MW, Alshami AM, Babri AS, et al. Strain and
injury—part 1: issues in diagnosis. Man Ther. 2005;10(2): excursion of the sciatic, tibial, and plantar nerves during a
96–107. modified straight leg raising test. J Orthop Res. 2006;24(9):
92. Hoskins W, Pollard H. Hamstring injury management—part 1883–1889.
2: treatment. Man Ther. 2005;10(3):180–190. 98. Alshami AM, Babri AS, Souvlis T, Coppieters MW. Strain in
93. Kornberg C, Lew P. The effect of stretching neural structures the tibial and plantar nerves with foot and ankle movements
on grade one hamstring injuries. J Orthop Sports Phys Ther. and the influence of adjacent joint positions. J Appl Biomech.
1989;10(12):481–487. 2008;24(4):368–376.
94. Harney D, Patijn J. Meralgia paresthetica: diagnosis and 99. Nitz AJ, Dobner JJ, Kersey D. Nerve injury and grades II and
management strategies. Pain Med. 2007;8(8):669–677. III ankle sprains. Am J Sports Med. 1985;13(3):177–182.
95. Alshami AM, Souvlis T, Coppieters MW. A review of plantar
heel pain of neural origin: differential diagnosis and
management. Man Ther. 2008;13(2):103–111.
2560_Chapter 16_0181-0194.indd 194 3/16/2015 4:13:40 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 17
The Role of Physical Agents in
JAMES W. BELLEW, PT, EDD, AND EDWARD MAHONEY, PT, DPT, CWS
“When health is absent Wisdom cannot reveal itself, Art cannot

become manifest, Strength cannot be exerted, Wealth is useless and
Reason is powerless.”
—HEROPHILOS (300 B.C.)
Objectives
• Discuss the role of physical agents in patient intervention.
• List the physical agents available to the practicing therapist and note their therapeutic indications.
• Describe the various forms of therapeutic electrical stimulation.
• Develop evidence-based knowledge of the indications, contraindications, and applications of physical
agents.
Key Terms
• Electrical stimulation
• Modality
• Pain modulation
• Physical agents
comprehensive intervention plan. Advances in under-

Introduction standing of the biophysical effects of physical agents
have spurred their continued use in rehabilitation.1–6
The inherent potential of the peripheral nervous system
Although injured peripheral nerves have demonstrated
to undergo autogenic repair after injury or insult is a
the ability to regenerate, physical agents impart specific
compelling impetus both to individuals experiencing
and selective responses to mediate tissue healing that
damage or loss of function and to the practitioners
have led practitioners to select physical agents for
addressing the associated symptoms and impairments.
peripheral nerve injury (PNI) intervention.7
Although it is known that injured peripheral axons
have the ability to regenerate, restoration of func-
tional ability remains less than optimal. Nevertheless,
pursuit of effective and meaningful recovery remains Physical Agents
paramount.
Physical agents, or therapeutic modalities, repre- Role of Physical Agents
sent a spectrum of adjunctive therapies used to comple- Physical agents are complementary, or adjunctive,
ment or supplement other interventions, such as interventions used with other treatment strategies to
exercise, joint or tissue mobilization, strengthening, increase the probability that a desired therapeutic effect
or stretching. Collectively, physical agents and the will be realized. For example, the use of electrical
interventions they supplement comprise the more stimulation (ES) at a wound bed may be used to
195
2560_Chapter 17_0195-0208.indd 195 3/16/2015 4:13:42 PM

Process CyanProcess
YellowProcess Black
attract cells, such as fibroblasts, or influence the orien- due to the pervasive view that healing can occur in
tation of endothelial cells to promote and potentiate peripheral nerves secondary to Schwann cell activity,
wound healing.1,8,9 Physical agents are not intended to whereas oligodendrocytes of the central nervous system
supplant more skilled and selective interventions pro- (CNS) do not demonstrate such repair.10,11 Interven-
vided by practitioners. Rather, physical agents represent tions aimed at accelerating regeneration and improving
a viable supplementary class of tools for influencing reinnervation are of great interest. Herein lies the
healing of injured tissue. impetus for the use of physical agents for PNI—
acceleration of healing. To date, a substantial amount
What Are Physical Agents? of evidence in animal models suggests efficacy for the
Physical agents are means of delivering and using for use of physical agents. Such evidence in humans
therapeutic purpose one or more of several types of remains elusive, but this has not discouraged interest
physical energies. Therapeutic benefits are derived from and use of physical agents for PNI.
the transfer of these energies to patients to stimulate
tissue responses that may not be realized through other Electrical Stimulation
interventions. Physical agents traditionally include ES following PNI has long been considered to promote
thermal modalities (e.g., heat and cold), electromag- nerve regeneration, decrease pain associated with injury,
netic modalities (e.g., ES and diathermy), light modali- and maintain denervated skeletal muscle. The literature
ties (e.g., laser or infrared), and mechanical modalities is replete with optimistic evidence of nerve regenera-
(e.g., traction, compression, and ultrasound [US]). tion after ES of injured peripheral nerves. However,
Table 17-1 summarizes the classes and types of physi- most of this evidence comes from animal models. Such
cal agents with representative examples of clinical uses. evidence has not been produced in humans.
Regeneration of Nerve
Physical Agents for Peripheral In the 1980s, using rat and rabbit models, low-frequency
alternating current (AC) after crush injury was reported
Nerve Injury to accelerate the return of reflex foot withdrawal and
contractile force in reinnervated muscles.12–14 These
Compared with central nerve injury, PNI has received findings served as the impetus for investigations assess-
much less attention from neuroscientists. This is likely ing the effects of ES on nerve regeneration and rein-
nervation, and much of this information has come
from Gordon et al.7,12,15–18 Gordon’s group found that
Table 17-1 Classes of Physical Agents and Clinical Uses after continuous low-frequency (20 pps) stimulation of
the proximal nerve stump for 2 weeks, all motor
Class of Agent Type Examples
neurons that regenerated their axons into the distal
Electromagnetic Electricity High-volt pulsed current; stump eventually regenerated into the appropriate
direct current; endoneurial tubes. A comparison between stimulated
microcurrent; TENS
Electromagnetic Short-wave or pulsed
and nonstimulated nerve regeneration showed that
waves diathermy; PEMF; low-frequency stimulation promoted axon regenera-
ultraviolet radiation tion of all motor neurons over a 25-mm distance within
Light Laser; infrared 3 weeks in contrast to 8 to 10 weeks in the nonstimu-
lated nerves.15 The same 1-hour stimulation of the
Thermal Thermotherapy Hot pack;
(i.e., heat) Fluidotherapy;
proximal nerve stump accelerated sensory nerve regen-
continuous-wave US eration, while directing the axons into the correct
or diathermy sensory nerve pathways.19
Cryotherapy Cold or ice pack To find a more clinically feasible intervention for
(i.e., cold) nerve regeneration, Gordon’s group progressively
Mechanical Sound Continuous or pulsed shortened the stimulation to 1 hour, applied immedi-
US ately after surgical repair of the nerve transection.
Traction Manual or mechanical The degree of regeneration was not diminished. Simi-
traction larly robust findings after 1 hour of stimulation either
Compression Intermittent pneumatic before or after nerve suture have been reported more
compression; recently.12,20
compression wraps From earlier evidence of accelerated regeneration
Hydrotherapy Whirlpool after ES, investigation of human patients with com-
(i.e., water) pressive nerve injury from carpal tunnel syndrome
PEMF, pulsed electromagnetic field; TENS, transcutaneous electrical (CTS) and loss of greater than 50% of functional
nerve stimulation; US, ultrasound. motor units of the median eminence was undertaken.7,17
2560_Chapter 17_0195-0208.indd 196 3/16/2015 4:13:43 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 17 | The Role of Physical Agents in Peripheral Nerve Injury 197
Direct ES of the median nerve proximal to and imme- was observed in 16% to 36% of patients receiving
diately after surgical release for 1 hour at 20 pps was TENS. TENS appeared to be helpful in patients who
effective in promoting reinnervation of muscles within failed to show benefit from amitriptyline, a conven-
9 months. This result is in stark contrast to the nonsig- tional first-line pharmacological intervention.28,29 More
nificant return of functional motor units in control surprising was the observation that the combination of
patients who did not receive stimulation. TENS and amitriptyline resulted in greater pain relief
Collectively, the aforementioned findings demon- than TENS alone.28
strate accelerated axon regeneration in rats and acceler- Treatment conditions across reviewed studies were
ated muscle reinnervation in humans.7,12,15,17,18,21 The similar because they extended from the same research
findings that were the result of 1 hour of stimulation group.28,29,31 A biphasic, exponentially decaying wave-
applied directly to the proximal nerve and immediately form using a 4-msec pulse duration and an amplitude
after surgical repair indicate a relatively narrow window 35 mA or less and 23 to 35 volts was administered 30
of time. If the noted acceleration can be effective in minutes per day for 4 weeks.1 Patients self-selected a
accelerating axon regeneration sufficiently to extend frequency between 2 and 70 pps. Nearly 85% of the
the window of opportunity for regeneration, ES may patients receiving TENS reported substantial reduc-
become a viable intervention to aid and augment tion of pain, and 36% reported complete resolution.28
recovery of function after PNI.18 Reports from human Changes in pain before treatment compared with after
subjects are sparse at this stage of research, which leaves treatment were not noted in the sham-treatment group.
the future use of ES for nerve regeneration question- However, when the sham group later received TENS,
able but hopeful. a significant reduction in pain was observed in 70% of
Bottom line for nerve regeneration after ES: ES has the subjects (Fig. 17-1).29 Prior human studies of
been associated with several findings indicative of TENS for painful diabetic neuropathy reported benefit
nerve regeneration. However, these findings occurred lasting up to 12 weeks; however, the long-term effect
largely under experimental conditions with rodents of TENS is unknown. Forst et al.30 performed a double-
where nerve injury is easily induced, reproducible, and blind randomized study examining 12 weeks of TENS
well controlled. There remains a large divide between versus placebo for mild to moderate painful diabetic
the evidence for regeneration in animals and the func- neuropathy. Of the TENS group, 70% reported
tional recovery in humans. Although the volumes of improvement versus only 29% in the placebo group,
laboratory data touting regeneration of nerve and with benefit noted in the TENS group for up to 12
effects of ES are encouraging, these findings have yet weeks. A retrospective analysis by Julka et al.31 on the
to be realized in clinical situations with humans and
remain essentially intangible for clinical use.
Modulation of Pain
Neuropathic pain secondary to injury or pathology to
peripheral nerves pose a considerable challenge. Trans-
cutaneous electrical nerve stimulation (TENS) has
been used in the management of pain associated with
peripheral neuropathy with widely varying results.
Prior studies of TENS on neuropathic pain are largely
from populations with diabetic peripheral neuropathy,
with TENS reported to reduce pain in 50% to 75% of
patients.22–24
Three systematic and meta-analytic reviews pub-
lished in 2010 and prior studies describing TENS with
neuropathic pain in humans are available.25–30 In a
review of relevant randomized controlled trials of
TENS for painful diabetic neuropathy, Jin et al.26
determined only 3 of 130 studies met appropriate
inclusion criteria.28–-30 Likewise, Pieber et al.27 identi-
fied only 15 relevant studies using ES for painful dia-
betic neuropathy from 3,801 hits during a data search
for “diabetic neuropathy.” Dubinsky and Miyasaki25 Figure 17-1 Electrode configuration for treatment of
determined only 3 of 263 articles met their criteria. neuropathic pain using TENS electrodes placed proximal
Collectively, these reviews concluded that TENS to the patella over the vastus lateralis and medialis oblique,
yielded positive benefits for pain relief lasting up to 12 over the neck of the fibula, and over the proximal
weeks with no adverse effects. Complete relief of pain gastrocnemius distal to the popliteal fossa.28,29
2560_Chapter 17_0195-0208.indd 197 3/16/2015 4:13:43 PM

Process CyanProcess
YellowProcess Black
Figure 17-2 Stimulation over the common peroneal nerve Figure 17-3 A basic TENS unit with controls for pulse
for treatment of painful diabetic peripheral neuropathy.30 frequency, duration, and amplitude may be used to treat
painful diabetic neuropathy. (From Michlovitz S, Bellew J,
Nolan T. Modalities for Therapeutic Intervention. 5th ed.
long-term benefit of TENS used questionnaire data
Philadelphia: FA Davis; 2011.)
regarding pain. Over an average use of 1.7 years, 76%
of the patients using TENS reported a 44% ±
4% subjective reduction of pain with use of TENS therapeutic benefits by delivering both high-frequency
(Fig. 17-2). and low-frequency stimulation. Although many TENS
Information regarding stimulation parameters may units maintain a constant frequency, interferential cur-
be gathered from rat models. Somers and Clemente32 rents employing a reciprocal or integral sweep from low
reported that high-frequency (100 pps) stimulation or frequency to high frequency may be used to deliver
a combination of high-frequency (100 pps) and low- both high-frequency and low-frequency TENS. More
frequency (20 pps) stimulation to the contralateral recent data support this variation for modulation of
limb of rats with unilaterally induced neuropathic pain pain.35,36
prevents the onset of mechanical allodynia. This appears
to occur via distinctly different alterations in dorsal Frequency Rhythmic Electrical
horn neurotransmitter content, which suggests that the Modulation System
mechanism of action of high-frequency stimulation or To date, frequency rhythmic electrical modulation
a combination of high-frequency and low-frequency system (FREMS) has shown promising results for the
stimulation may be unique.32 The TENS stimulator treatment of painful peripheral neuropathy, but it is
used by Somers and Clemente was a readily available still considered a novel intervention modality. FREMS
conventional model, allowing for easy replication of the is high-voltage, biphasic current delivered with a vari-
stimulus parameters with most types of basic TENS able (i.e., rhythmic) pulse frequency, pulse duration,
stimulators (Fig. 17-3). and amplitude. Results from a double-blind, random-
A combination of high-frequency and low-frequency ized, placebo-controlled, crossover study supported the
TENS has also been shown to decrease pain associated use of FREMS for peripheral neuropathy.37 After
with type II complex regional pain syndrome—a treatment, day and night pain scores, vibratory percep-
chronic condition that can develop after PNI.33 TENS tion threshold, monofilament testing, and motor nerve
has shown varying results in rats, with some rats dem- conduction velocity (NCV) improved compared with
onstrating an increase in pain threshold.34 TENS baseline and remained significantly improved at 4
administered contralateral to the nerve injury yielded months. Conversely, none of these parameters improved
the most benefit. Specifically, high-frequency TENS significantly in the placebo group. Conti et al.38 used
(100 pps) reduced the onset of mechanical allodynia, the same study design to assess the effects of FREMS
whereas low-frequency TENS (20 pps) reduced the on cutaneous blood flow. Transcutaneous oxygen
onset of thermal allodynia.33 Clinical administration tension did not change in the initial 3 weeks of treat-
of TENS for neuropathic pain may yield greater ment but at 4 months was significantly higher than
2560_Chapter 17_0195-0208.indd 198 3/16/2015 4:13:43 PM

Process CyanProcess
YellowProcess Black
baseline. Conti et al. suggested that improvement in After denervation, human skeletal muscle, similar to
peripheral neuropathy was the result of increased local an injured nerve, exhibits strategies to promote recov-
blood flow; however, more research is needed to test ery and reinnervation.43 ES is thought to facilitate
this hypothesis. these strategies; however, direct stimulation of dener-
Bottom line on ES for pain associated with peripheral vated skeletal muscle has shown conflicting results. A
neuropathy: Three extensive reviews of TENS on painful study published in 2010 by Gigo-Benato et al.39 exam-
diabetic neuropathy deemed only a modicum of studies ined direct transcutaneously administered cathodal
from hundreds to be worthy of review, evidencing the stimulation to denervated anterior tibialis muscles of
lack of quality data from which to draw clinical rats. ES accentuated muscle atrophy and impaired neu-
conclusions.25–27 Current data generally support the romuscular functional recovery in rats compared with
inclusion of TENS in the comprehensive management nonstimulated controls. Impaired healing after ES was
of painful neuropathy. More specifically, a combination also reported by Baptista et al.,44 who compared high-
of high-frequency and low-frequency stimulation may frequency TENS (100 pps, pulse duration 80 μsec) and
be most effective. Largely enhanced by the lack of low-frequency TENS (4 pps, pulse duration 240 μsec)
adverse effects with TENS, a recommendation to in mice after sciatic crush injury. ES resulted in signs
support use of TENS can be loosely made based on of impaired regeneration, including axonal edema,
the limited number of prior studies. thinner myelinated fibers, and irregular cytoarchitec-
ture with more pronounced impairment in the
Preservation of Denervated Muscle high-frequency group. These findings are particularly
Use of ES for increasing strength, volitional recruit- noteworthy because the TENS was delivered using
ment, re-education, and function in normally inner- surface electrodes and parameters consistent with those
vated but weak skeletal muscle is well known and commonly employed in humans when administering
supported. Use in denervated muscle or muscle await- high-frequency (i.e., conventional) or low-frequency
ing reinnervation secondary to PNI is less certain, with (i.e., acupuncture) TENS.45
few studies offering contradictory results.39–41 As such, The literature is not without contradiction. Dow
ES for denervated muscle after PNI continues to be et al.46 initially reported ES reduced changes in muscle
scrutinized and remains highly controversial.42 It is function related to denervation. However, after pro-
unclear whether nerve growth is suppressed or impaired longed denervation, the same protocol failed to produce
with ES, and this is a dividing point for individuals on optimistic findings suggesting that ES may not attenu-
either side of this issue. ate factors hindering regeneration following a delayed
The differentiation between muscle denervated by reinnervation.47 That the intrinsic rate of endogenous
injury to the peripheral nerve versus denervation sec- reinnervation of injured nerve is slow underlies the
ondary to injury of the CNS, as seen in stroke or spinal significance of this evidence. Although ES may render
cord injury, must be distinguished. Direct injury to the some therapeutic benefit in the initial period after
peripheral nerve results in a lower motor neuron lesion, injury, application following prolonged denervation
whereas injury to the CNS leaves an intact lower motor may not yield such results.
neuron below the level of CNS injury. This differentia- Bottom line for ES to preserve denervated muscle: A
tion is critical. With an intact lower motor neuron, and 2007 review of ES in patients with neurological condi-
assuming appropriate stimulus parameters, ES elicits tions concluded that evidence neither supports nor
muscular contraction by depolarizing the peripheral refutes the use of ES for increasing strength after
nerve as the neurolemma maintains a lower threshold PNI.48 Studies with low methodological quality and
for excitation than the muscle membrane (sarcolemma). large variations in the response of humans to ES make
With an injury to the lower motor neuron, ES may a more conclusive understanding infeasible. Given the
evoke a muscular contraction by direct stimulation and continued clinical interest in the use of ES for dener-
depolarization of the higher threshold sarcolemma. vated muscle, this conclusion is concerning. There is
The stimulus parameters required for the latter differ renewed interest in using ES during gait or other
vastly from the former. Specifically, the pulse duration activities to provide function; however, these applica-
required to evoke a muscular contraction in muscle tions often involve upper motor neuron injury and
denervated by lower motor neuron injury often exceeds cannot be extrapolated to lower motor neuron injury
1 msec, a duration not offered on many clinical stimu- stemming from PNI.49–51 Clinicians are left to make
lators. Consequently, many clinicians are unable to decisions from limited and poorly designed studies or
offer effective ES to patients with PNI. Additionally, are left to draw conclusions from other populations.48
the intensity of the current required to depolarize the
sarcolemma versus the neurolemma is significantly Ultrasound
greater and is often painful. These two factors underlie Use of therapeutic US for PNI has been studied for
much of the unsatisfactory results from stimulation of two distinct effects: (1) reduction of pain and improved
denervated muscle after PNI. function and (2) facilitation of nerve regeneration.52
2560_Chapter 17_0195-0208.indd 199 3/16/2015 4:13:44 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Therapeutic US is classified as thermal or nonthermal. The effect of LIPUS on isolated Schwann cells from
The physiological effects realized from thermal or con- proximal nerve stumps of rats has also been studied
tinuous US generally reflect the thermal effects because Schwann cells appear to aid in myelinating
observed with other thermal agents with two excep- axons and directional guidance of neurons—events
tions: (1) The depth of effect is greater with US than critical to regeneration.64 Following daily 5-minute
other thermal agents except short wave diathermy, and applications of LIPUS at 100 mW/cm2 for 14 days,
(2) the effect is more pronounced in tissues with higher Zhang et al.63 reported that treated Schwann cells
collagen content because these tissues retain more increased cell proliferation and expression of neuro-
sound energy.52,53 Because peripheral nerves possess trophic growth factors (neurotrophin-3 and brain-
high levels of collagen and subcellular organelles derived neurotrophic factor) versus control cells.
throughout the axon, an interest in the use of US for Additional support for the regenerative effects of
nerve healing has encouraged further study.54–56 Non- LIPUS is available.60,61,65 Raso et al.65 reported a sig-
thermal or pulsed US imparts the effects of cavitation, nificantly greater rate of functional recovery and nerve
microstreaming, and acoustic streaming, which are fiber density after crush injury of the sciatic nerve in
believed to facilitate endogenous mechanisms of tissue rats versus untreated injured controls. US was delivered
healing. Understanding of these mechanisms in PNI is daily for 2 minutes at 400 mW/cm2 for 10 days begin-
unclear. ning the day after injury. After 5 minutes of LIPUS at
Studies in animal models using continuous US after 300 mW/cm2 and 1 MHz administered 12 times over
PNI have shed light on the potential for healing.57,58 2 weeks, Chang et al.61 reported a significantly greater
Mourad et al.57 treated rats with complete axonotmetic number and area of regenerated axons.
denervation 3 days after a crush injury with continuous Clinical use of US for PNI in humans has been
US ranging from 0.25 to 5.0 W/cm2. Compared with primarily for CTS. However, only a few randomized
control rats, the US-treated group demonstrated a sig- controlled studies exist. Improvements in median NCV
nificantly greater rate of recovery in function with the and pain were reported by Ebenbichler et al.66 after
most improvement seen in the rats receiving 1-minute pulsed US at 1.0 W/cm2 applied 15 minutes daily
applications of 0.25 W/cm2 US at 1.0 MHz or for 2 weeks versus sham US in mild to moderate
2.25 MHz. Similar findings were reported by Hong et CTS. Piravej and Boonhong67 reported the benefit
al.58 who examined recovery of measures of electro- of continuous low-intensity (0.5 W/cm2) US on
physiological function (compound motor action poten- CTS after 10-minute treatments administered 5 days
tial [CMAP], NCV, and distal motor latency [DML]) per week for 4 weeks. Both the US group and the
following continuous thermal US at 0.5 W/cm2 and control group, who received diclofenac and sham US,
1.0 W/cm2 in rats with compression neuropathy. The showed significant improvements in sensory nerve
recovery rate of DML did not improve, but CMAP action potentials, in addition to a significant difference
and NCV showed significantly faster recovery rates noted in the US group. In contrast, Oztas et al.68 com-
compared with untreated controls. However, these pared US (1.5 W/cm2 or 0.8 W/cm2) with sham
improvements occurred only in the nerves receiving US US and reported no significant change in clinical
at 0.5 W/cm2. With 1.0 W/cm2, the recovery rate of or neurophysiological measures. US therapy (pulsed
the CMAP was slower than in the untreated leg, and 1.0 W/cm2) for CTS was also compared with low-
no significant changes were noted in recovery rate for level laser therapy (LLLT) with both groups showing
NCV and DML. These findings of efficacy for con- benefit, but greater improvement was noted in the US
tinuous low-intensity US (i.e., less than 1.0 W/cm2) group.69
were supported by Lowdon et al.59 comparing From collective examination of studies regarding use
0.5 W/cm2 and 1.0 W/cm2. Collectively, these studies of US for CTS, two factors appear to affect efficacy of
indicate that US less than 1.0 W/cm2 can facilitate US: the duration and severity of symptoms and the
recovery, whereas US greater than 1.0 W/cm2 can power of the US.52,66,68,70 In mild to moderate symp-
retard recovery. toms of lesser duration, treatment benefits appear to be
Use of low-intensity pulsed US (LIPUS; less than derived from US. As the severity and duration of CTS
1.0 W/cm2) has consistently shown accelerated regen- increase, the benefits of US decrease or are absent. For
eration of peripheral nerve in rats despite the lack of intensity, data suggest low-intensity, less than 1.0 W/
understanding of the precise mechanisms.60–63 US was cm2. Studies of both continuous and pulsed US using
studied in rats after complete nerve transection and power less than 1.0 W/cm2 have demonstrated
surgical placement of a grafted nerve conduit to guide improvement in nerve function after injury. Use of
axonal sprouting and regeneration. Using 400 mW/ continuous US with less than 1.0 W/cm2 power is
cm2 applied 2 minutes per day for 8 weeks beginning unlikely to result in a true thermal effect on the treated
24 hours after injury, Park et al.62 demonstrated a nearly tissues. Changes in tissue, cell, and membrane activity
50% greater rate of nerve regeneration, greater axon secondary to the mechanical effects of US likely under-
diameter, and thicker myelin in rats treated with US. lie the observed effects.
2560_Chapter 17_0195-0208.indd 200 3/16/2015 4:13:44 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Bottom line for US and PNI: Considerable evidence studies, LLLT for repair of incomplete PNI is pro-
exists suggesting accelerated regeneration and recov- posed to (1) increase the rate of axonal growth and
ery of function after administration of continuous myelination, (2) prevent or limit degeneration in the
and pulsed US in rat models. The degree to which corresponding motor neurons of the spinal cord,
these findings can be translated to recovery of PNI in (3) offer immediate protective effects to increase func-
humans is speculative. We are not aware of any quality tional activity of the injured nerve, (4) maintain func-
evidence for the regeneration of peripheral nerve in tional activity of injured nerve over time, and
humans after treatment with US. For compressive neu- (5) minimize scar formation.5
ropathy secondary to CTS, low-intensity US (less than Data from animal studies suggest that LLLT sig-
1.0 W/cm2) may attenuate symptoms, but evidence nificantly improves recovery of PNI.83–86 More specifi-
for improved neurophysiological performance remains cally, low-power lasers (632.8 nm and 780 nm
equivocal. Limited evidence suggests improved mea- wavelength) attenuate retrograde degeneration of
sures in neurophysiological function that may reflect neurons in the corresponding segments of the spinal
change in cell and membrane function, alteration cord.85 Shamir et al.84 examined the effect of 780 nm
of intercellular communication, or increase in local helium-neon (HeNe) laser after complete rat sciatic
circulation. nerve transection with anastomosis. LLLT demon-
strated increased regenerative processes and accelerated
Laser axon growth, findings supported by more recent
LLLT is widely used and accepted in several European study.87,88 Consistent findings have also been reported
countries as an adjunctive intervention for tissue after end-to-end anastomosis followed by laser irradia-
healing. Acceptance and use of LLLT in the United tion. In this use, the laser-treated groups had faster
States have been less robust since its initial approval recovery of motor function and remyelination.89
for use in CTS in 2002. However, much discussion However, not all studies support the use of LLLT after
continues with regard to the use of LLLT for tissue PNI. Reis et al.90 examined the effects of gallium-
healing, based on the purported ability of LLLT to aluminum-arsenide (GaAlAs) laser (660 Nm) on
augment or enhance the body’s natural processes of rats after neurotmesis and epineural anastomosis
healing. Conclusive evidence to support widespread and reported no significant changes in functional
use of LLLT in patients with PNI remains elusive. outcomes.
Much of the lack of evidence may be complicated by Compelled by optimistic findings in animal models,
the limited populations for which laser has been Rochkind et al.87 performed a randomized, double-
approved; poor quality of study design; variable treat- blind, placebo-controlled study in 2007 and reported
ment techniques; variable assessment and outcome the effects of low-power 780-nm laser in humans with
measures; and variations in equipment used, including incomplete peripheral nerve and brachial plexus inju-
wavelength and energy density or power. ries for greater than 6 months. Patients with traumatic
Clinical interest in the use of laser for PNI stems nerve injury were treated 5 hours per day for 21 days
from observed responses in the metabolic activity of and later compared with controls. Outcome measures
tissues and cells, such as fibroblasts, endothelial cells, were taken after 21 days, 3 months, and 6 months.
osteoclasts, and neurons, exposed to laser energy in Motor function, recruitment of motor units, and
primarily animal models and in a few human studies. sensory function improved significantly, with no
Acute LLLT has shown decreased production of bra- changes in controls. These findings as well as findings
dykinin, reduced levels of prostaglandin E2, increased by Rochkind et al. while examining LLLT for incom-
secretion of endogenous opioids, increased production plete PNI suggest that at least partial recovery of nerve
of serotonin and nitric oxide, and increased axonal function results from acceleration of nerve conductiv-
sprouting and nerve cell regeneration.71–80 ity, followed by increased myelination in existing nerve
Laser energy, or photoenergy, emits packets of light fibers and partial regeneration of new axons and new
energy, called photons, that are absorbed by receptor synaptic connections.83,85,87,88,91
chromophores within the mitochondria and cell mem- LLLT for compressive nerve injury secondary to
brane of tissues irradiated with laser energy.81,82 Absorp- CTS remains the most studied, albeit still limited,
tion of photoenergy increases cellular metabolism and application of LLLT for PNI. To date, results remain
increases the oxidative production of adenosine tri- equivocal, with no preponderance of evidence available
phosphate (ATP)—a process known as photobiomod- to support or refute its use.70,92–95 Evcik et al.94 per-
ulation. In the presence of injury, ATP is used to formed a prospective, randomized, placebo-controlled
synthesize DNA, RNA, proteins, and enzymes; facili- trial to investigate the efficacy of laser therapy in the
tate cellular mitosis; and increase synthesis of growth treatment of CTS and reported significant improve-
factors to repair compromised tissue. ments in sensory nerve velocity and sensory and motor
As with ES for PNI, most evidence regarding LLLT distal latencies in the laser-treated group versus con-
has been derived from animal models. Based on rat trols. No difference was observed in pain and pinch
2560_Chapter 17_0195-0208.indd 201 3/16/2015 4:13:44 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
grip between the laser-treated group and the control
group. In contrast, Irvine et al.92 compared LLLT with
sham laser in 15 patients with CTS and reported no
significant effect on parameters of electrophysiological
function. Similarly, clinical and electrophysiological
parameters in patients with rheumatoid arthritis and
CTS showed no significant improvement after LLLT
applied 5 days per week for 2 weeks.95 Improvements
in neurophysiological parameters were reported by
Naeser et al.,93 who compared LLLT with TENS with
sham laser with TENS. Significant improvements in
mean sensory latency and pain were noted, with
no difference in mean motor latency. However, exten-
sive criticism of the data analyses of Naeser et al. Figure 17-4 The simultaneous delivery of laser and
leave considerable doubt as to the credibility of their electrical energy to evoke the biophysical responses of each
observations.96,97 modality (MR4; Multi Radiance Medical, Solon, Ohio).
In response to PNI, muscle tissue demonstrates an
accelerated degradation of myoprotein, atrophy, and
decreased contractile mechanics. Through mechanisms Bottom line for laser and PNI: LLLT appears to be a
of photobiostimulation, LLLT is thought to attenuate viable intervention for PNI. A comprehensive 2005
degeneration of muscle until axonal regeneration review reported that all but two experimental studies
results in reinnervation.5 Increased synthesis of cre- showed LLLT to enhance recovery from severely
atine kinase, an enzyme involved in the supply of injured peripheral nerve.100 Likewise, a 2004 meta-
energy to skeletal muscle, and preservation of acetyl- analysis reported laser therapy to have an overall mean
choline receptors observed after administration of treatment effect size of 1.81 for tissue repair and 1.11
LLLT in denervated rat muscle suggest a protective for pain control (an effect size of 0.8 or more indicates
effect of laser.98,99 The synthesis of high-energy phos- a large effect size) and that LLLT is a highly effective
phates via increased mitochondrial rephosphorylation agent for tissue repair and pain.78 Although findings
of ATP is thought to preserve muscle integrity in the for the use of laser therapy for PNI at first glance
initial period after denervation injury by limiting the appear promising, these results are largely from animal
natural degenerative processes that occur in muscle. models and limited randomized controlled trials. Such
Data from rat models suggest that LLLT initiated as promising findings in humans are sparse. Postulated
early as possible after injury may temporarily prevent benefits for humans are predicated on speculative use
denervation-induced biochemical changes as well as from observed responses in animal and isolated cell
the potential restoration of muscle function.5,98,99 There studies. Because of the lack of substantial evidence in
appear to be no deleterious consequences with muscle humans, the specific use of LLLT for PNI in humans
stemming from laser irradiation after PNI. Although can be neither fully endorsed nor completely refuted.
these findings suggest a protective effect of laser, the Laser therapy may one day prove to be an effective
research has yet to be substantiated in humans. Con- intervention, but until then, endorsement is made via
sequently, authors researching LLLT for PNI have hopeful optimism.
suggested that more recent evidence from rat models
should be a strong impetus for broader clinical trials in Pulsed Electromagnetic Field
humans.99–101 Pulsed electromagnetic field (PEMF) energy produced
Given the growing clinical interest in LLLT and by diathermy devices passes through bodily tissues
continuing LLLT research, greater understanding of with minimal reflection at tissue interfaces or at bone,
the effect of laser energy for PNI is imminent. Con- whereby minimal traces of energy accumulate at these
tinuing research and technological advancements make interfaces as it occurs with US.103 Gradually, absorption
LLLT a burgeoning area of physical agents. Techno- of energy by deeper tissues causes increased cellular
logical advancements have made possible the concur- activity.103 Biological effects of PEMF include increased
rent administration of therapeutic ES with LLLT. microvascular perfusion, changes in voltage-dependent
Underlying this advancement are the observed findings ion-ligand binding, and alteration of cell membrane
and potential for healing for ES and laser when deliv- function and cellular activity.104–109 PEMF therapy for
ered as monotherapies. Newly approved by the U.S. 40 to 45 minutes and set to 600 pps has been shown
Food and Drug Administration (FDA) for increasing to increase local blood flow significantly in healthy
local blood flow and pain modulation, combined subjects without pathology and in patients with dia-
therapy with ES and laser delivers electrical and light betic ulceration.110,111 Increased cell mitosis and growth,
energy (Fig. 17-4).102 expression of growth factors in fibroblasts and nerve
2560_Chapter 17_0195-0208.indd 202 3/16/2015 4:13:44 PM

Process CyanProcess
YellowProcess Black
cells, activity of macrophages, and phosphorylation and light. Monochromatic infrared energy (MIRE) is
protein synthesis have been observed after PEMF delivered at a single wavelength (890 nm long, at a rate
therapy.112–114 Despite lack of understanding of the of 292 times per second) from a pad containing 60
mechanisms underlying these effects, PEMF therapy superluminous GaAlAs diodes by a therapeutic device
for PNI has continued. manufactured by Anodyne Therapy, LLC (Tampa,
Initial studies of PEMF therapy for regeneration of Florida).116 Since it was approved by the FDA for the
PNI in cats and rats showed promising results, but such reduction of pain and increasing circulation, numerous
results in humans were not examined until more investigations have been performed on the effective-
recently. Use of PEMF in patients with refractory CTS ness of MIRE.
and patients with diabetic neuropathy was studied in The primary outcome measure of studies assessing
two separate randomized, double-blinded, placebo- MIRE has generally been restoration of protective sen-
controlled trials by Weintraub et al.3,4 No effect of sation, and some cases have included wound recur-
PEMF was noted in measures of neuropathic pain in rence, quality of life, number of falls, and fear of falling
patients with diabetic neuropathy. However, nearly one as outcome measures. Although earlier studies exam-
third of the subjects demonstrated an increase in epi- ined the effects of MIRE on wound healing, the first
thelial nerve fiber density after 3 months—an effect published study specifically aimed at determining the
not observed in the sham group. This finding suggested effectiveness of MIRE on the reversal of peripheral
regenerative capabilities of PEMF and has provided neuropathy was published by Kochman in 2002.117
the impetus for continued interest in PEMF. Subjects Following six treatments of MIRE, 48 of 49 patients
with refractory CTS receiving PEMF reported signifi- had improved sensation, with all demonstrating
cant short-term and long-term pain relief, while also improvement in 12 weeks. Similar results were reported
demonstrating a modest 10% improvement in distal by Prendergast et al.118 Following 10 treatments in 2
nerve conduction latencies. In both studies, the authors weeks, 96% of all subjects had a reduced severity grade
concluded that although neurophysiological measures of sensory impairment after the treatments with MIRE.
showed only modest change, little doubt exits that A primary limitation of the previous studies is the
PEMF yields neurobiological effects that hold great lack of a control group without which improvements
promise. Use of PEMF therapy in patients with chronic secondary to placebo cannot be ruled out. Without a
diabetic polyneuropathy was examined by Musaev control group treated with a sham device, it is difficult
et al. in 2003.115 Significant improvement in conduc- to determine how much of the improvement in sensa-
tion of peripheral nerves and reflex excitability of function could be attributed to a placebo effect. Leonard
tionally diverse motor neurons in the spinal cord and et al.119 addressed this issue by performing a double-
increased amplitudes of muscle potentials and the blind, randomized, placebo-controlled study in patients
number of functioning motor neurons were observed with type 1 or type 2 diabetes who were insensate to
after 10 applications of PEMF therapy. the 5.07 Semmes Weinstein monofilament (SWM).119
At the time of this writing, we are unaware of any Subjects were treated with MIRE on one limb and a
studies examining PEMF therapy in humans after sham device on the other for 2 weeks, followed by
transected PNI or more extensive studies in compres- active treatments to both limbs over the next 2 weeks.
sive nerve pathology. Although initial results from Although sham treatment did not improve sensitivity
patients with diabetic neuropathy and compressive as measured by the number of insensate sites, 2 weeks
pathology following CTS appear encouraging, much of sham treatment did result in significantly reduced
more evidence is needed to support the widespread use Michigan Neuropathy Screening Instrument scores,
of PEMF therapy for PNI in humans. indicating an improvement of peripheral neuropathy.
Bottom line for PEMF and PNI: Evidence for PEMF In subjects considered to have more severe conditions
therapy for PNI is limited and appears largely related (i.e., insensate to 6.65 SWM), there was no significant
to as yet unclear cellular and hemodynamic events (i.e., improvement in sensation, pain, or neuropathic symp-
increased perfusion). The limited evidence in humans toms, but balance did improve moderately.
stems from compressive neuropathy and mild ischemic Two potential issues with the study by Leonard
neuropathy, conditions where increased local perfusion et al. were the short treatment duration and use of only
may underlie observed benefits. Changes in cell activity two sizes of monofilaments. It may be argued that if
and increased local blood flow do not appear to be treatment were for a longer duration or if smaller incre-
unique to PEMF. At this time, there is insufficient ments of monofilament were used, the potential effects
evidence to support use of PEMF as a therapeutic of MIRE would have been more apparent. Arnall
intervention for PNI in humans. et al.120 addressed these issues studying patients with
diabetes treated for 8 weeks with a combination of
Monochromatic Infrared Energy infrared and visible red light. Six monofilaments, rather
The most widely used physical agent for the treatment than two, were used, which improved the ability to
of peripheral neuropathy at the present time is infrared detect small changes in sensation. A sham device was
2560_Chapter 17_0195-0208.indd 203 3/16/2015 4:13:44 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
not used; however, the contralateral limb received no assessing the effect of MIRE on sensation in 39 patients
treatment and served as a control. Subjects initially with peripheral neuropathy showed no significant dif-
sensitive to the 5.07 SWM showed no significant ference between the active and placebo groups at 4
improvements in sensation in either the treatment or weeks because both groups demonstrated statistically
the control limb. In patients insensate to the 5.07 SWM significant improvements in the mean number of sites
at baseline, improvement was noted; however, only sensitive to the 5.07 SWM.125 Similar findings were
changes in the treatment group were significant. Arnall also noted at 8 weeks. Results of this placebo-controlled
et al. likewise examined the effects of infrared light on study suggest that MIRE offers no greater benefit than
the perception of vibratory sensation and found no placebo treatment for peripheral neuropathy.
significant changes in the subject’s ability to perceive A placebo-controlled double-blinded study by
vibration after infrared light therapy. Franzen-Korzendorfer et al.126 also failed to demon-
Numerous retrospective studies are frequently cited strate efficacy for MIRE. In this study, patients had
in support of MIRE for the reversal of peripheral neu- each leg randomly assigned to the sham or active treat-
ropathy. Using questionnaire data from patients with ment group. At the conclusion of the study, there were
diabetic peripheral neuropathy that had improved with no significant differences in pain or sensation levels
MIRE, Powell et al.121 concluded that MIRE reduced between the active and sham groups. Additionally, pain
the incidence of diabetic foot ulcerations when com- scores did not change for either group. Sensation did
paring the incidence of ulceration in their own study significantly improve from baseline for both the control
with the incidence reported in a previous study. Extrap- and sham groups, again suggesting a placebo effect.
olation to the general population of patients with dia- Perhaps the largest placebo-controlled study examin-
betic neuropathy is impossible because patients who ing the effectiveness of MIRE was a double-blinded,
did not benefit from MIRE were excluded. Addition- sham-controlled study by Lavery et al.127 involving 60
ally, only 57% of eligible participants responded to the patients. In contrast to other studies that assigned one
survey, so no conclusion can be made regarding whether limb to the active group and the other to the control
the remaining participants fared as well or did not group, this study had two distinct groups statistically
respond because they were less satisfied with the results. similar at baseline. Six different outcome measures
DeLellis et al.122 reviewed records of 1,047 patients were assessed. No significant differences were noted
with peripheral neuropathy. Based on physician docu- between groups after 3 months of treatment.
mentation, 99% were insensate to the 5.07 SWM in Bottom line for MIRE for peripheral neuropathy: Use
two or more places on both feet before the initiation of MIRE for the restoration of impaired sensation in
of MIRE. After MIRE, 56% of patients regained pro- patients with peripheral neuropathy remains conten-
tective sensation, and the number of insensate sites was tious. Despite early, largely industry-funded, primarily
significantly lessened. Similarly to additional studies of noncontrolled studies that demonstrated positive
MIRE, there was no control group, which must be effects of MIRE, more recent placebo-controlled
considered when interpreting the results. A compara- studies have failed to yield such positive results. Because
ble retrospective chart review of 2,239 patients who a placebo effect seems to be a strong possibility, further
had received MIRE for peripheral neuropathy revealed investigations of MIRE for the treatment of neuropa-
a 67% reduction in pain and a 66% reduction in the thy should be large, independent studies with a sham
number of insensate sites.123 Although the results are control group.
impressive, the possibility of a placebo effect must be
considered because this study was nonblinded and
nonrandomized, and lacked a control group.
The functional benefits of MIRE, specifically the
CASE STUDY
rate of falls in elderly patients with peripheral neuropa- While playing football, SC received a violent blow
thy, have been examined.124 A health questionnaire of from a helmet to his right arm just distal to the
252 patients reporting symptomatic reversal of periph- acromion. He felt his arm immediately “weaken” and
eral diabetic neuropathy was used. Based on survey was pulled from the game. Initial assessment identified
results, a reduction in fear of falling and number of falls a “rotator cuff strain,” and SC was prohibited from
and an increase in quality-of-life rating were apparent practice or playing until the arm healed. After 3 weeks
1 month and 1 year after neuropathy improved. No of rest, the arm was not improving, and he saw a
objective measures of balance were assessed. Addition- physical therapist. The therapist, after evaluation,
ally, fear of falling has been implicated as a risk factor thought the injury was neurological and referred SC to
for falls, and the finding that participants were less a neurologist for an electroneuromyography assessment.
fearful alludes to the functional relevance of this study. The needle examination revealed an axonotmetic lesion
Despite promising results from other studies, several of the right axillary nerve with significant weakness of
placebo-controlled trials have not found such efficacy the right deltoid muscle. SC was referred back to the
for MIRE. A double-blind, placebo-controlled trial physical therapist for intervention.
2560_Chapter 17_0195-0208.indd 204 3/16/2015 4:13:44 PM

Process CyanProcess
YellowProcess Black
Case Study Questions 5. Which of the following statements regarding findings
of current research with LLLT and regeneration is true?
1. SC, after researching “nerve injury” on the Internet,
a. LLLT has no effect on regeneration.
requested of the physical therapist that ES be
b. Based on rat models and cellular models, LLLT is a
performed to his shoulder. “From what I read online,
promising agent as an intervention for nerve injury.
electrical stimulation is the best tool to speed nerve
c. Risk of complications makes LLLT an unsafe
regeneration,” explained SC to his therapist. The
therapy.
therapist’s best response would be:
d. LLLT is a highly effective modality and always
a. “Unfortunately, evidence the effectiveness of
should be considered as a first-line modality for
electrical stimulation in human studies is poor.
nerve injury.
There are more effective interventions we
should try.”
b. “I am not convinced, but let’s try it.”
c. “Most evidence is from rodent studies and is easily References
translated into human results.” 1. Nuccitelli R. A role for endogenous electrical fields in
d. “Electrical stimulation worked for a friend of mine; wound healing. Curr Top Dev Biol. 2003;58:1–27.
2. Raja K, Garcia M, Isseroff R. Wound re-epithelialization:
let’s try it.”
modulating keratinocyte migration in wound healing. Front
Biosci. 2007;12:2849–2868.
2. Three systematic and meta-analytic reviews published 3. Weintraub M, Cole S. A randomized controlled trial of the
in 2010 describing TENS with neuropathic pain are effects of a combination of static and dynamic magnetic fields
available. Which of the following statements is not on carpal tunnel syndrome. Pain Med. 2008;9(5):493–504.
true? 4. Weintraub M, Herrmann D, Smith G, Backonja M, Cole S.
Pulsed electromagnetic fields to reduce diabetic neuropathic
a. TENS and amitriptyline are more effective than
pain and stimulate neuronal repair: a randomized controlled
TENS alone. trial. Arch Phys Med Rehabil. 2009;90:1102–1109.
b. TENS promotes positive pain relief for up to 12 5. Rochkind S. Phototherapy in peripheral nerve injury for
weeks with no adverse effects. muscle preservation and nerve regeneration. Photomed Laser
c. Complete pain relief was found in 16% to 36% of Surg. 2009;27(2):221–222.
6. Volkert W, Hassan A, Hassan M, et al. Effectiveness of
patients who used TENS.
monochromatic infrared photoenergy and physical therapy
d. Pain relief with TENS treatment lasted up to 10 for peripheral neuropathy: changes in sensation, pain, and
years. balance—a preliminary, multicenter study. PhysOccup Ther
Geriatr. 2005;24(2):1–17.
3. Which of the following statements regarding the use 7. Gordon T, Chan K, Sulaiman O, Udina E, Amirjani N,
of ES to preserve denervated muscle is true? Brushart T. Accelerating axon growth to overcome
a. ES, performed twice per day, is an effective limitations in functional recovery after peripheral nerve
injury. Neurosurgery. 2009;65:A132–144.
modality to maintain functional sarcomeres. 8. McCaig C, Rajnicek A, Song B, Zhao M. Controlling cell
b. A 2007 review of ES neither supports nor refutes behavior electrically: current views and future potential.
the use of ES for the preservation of functional Physiol Rev. 2005;85:943–978.
sarcomeres in denervated muscle. 9. Erickson C, Nuccitelli R. Embyonic fibroblast motility and
c. ES has no impact on preserving functional orientation can be influenced by physiological electrical
fields. J Cell Biol. 1984;98:296–307.
sarcomeres in denervated muscle. 10. Fenrich K, Gordon T. Axonal regeneration in the peripheral
d. ES slows, but does not prevent, muscle atrophy in and central nervous systems—current issues and advances.
denervated muscle. Can J Neurol Sci. 2004;31:142–156.
11. Sulaiman O, Gordon T. Effects of short and long term
4. Which of the following statements best describes Schwann cell denervation on peripheral nerve regeneration,
the use of US in the promotion of nerve myelination, and size. Glia. 2000;32:234–246.
12. Gordon T, Udina E, Verge M, de Chaves E. Brief electrical
regeneration? stimulation accelerates axon regeneration in the peripheral
a. US is an effective modality to promote nerve nervous system and promotes sensory axon regeneration in
regeneration in axonotmetic lesions. the central nervous system. Motor Control. 2009;13:412–441.
b. US is an effective modality to promote nerve 13. Nix W, Hopf H. Electrical stimulation of regenerating nerve
healing in neurapraxic lesions. and its effect on motor recovery. Brain Res. 1983;272:21–25.
14. Pockett S, Gavin R. Acceleration of peripheral nerve
c. Although there is considerable evidence of the regeneration after crush injury in rat. Neurosci Lett. 1985;59:
effectiveness of US in promoting nerve 221–224.
regeneration in a rat model, there is no quality 15. Al-Majeed A, Neumann C, Brushart T, Gordon T. Brief
evidence of the effectiveness in humans. electrical stimulation promotes the speed and accuracy of
d. For compressive neuropathy secondary to CTS, motor axonal regeneration. J Neurosci Methods. 2000;20:
2602–2608.
low-intensity US is a highly effective modality in 16. Gordon A, Weistein M. Sodium salicylate iontophoresis in
aiding regeneration and improvement in functional the treatment of plantar warts: case report. Phys Ther. 1969;
performance. 49:869–870.
2560_Chapter 17_0195-0208.indd 205 3/16/2015 4:13:44 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
17. Gordon T, Brushart T, Amirjani N, Chan K. The potential of the rat sciatic nerve. Arch Phys Med Rehabil. 1998;79:
of electrical stimulation to promote functional recovery after 1370–1376.
peripheral nerve injury: comparisons between rats and 35. Bellew J. Foundations of Electrotherapy. 5th ed. Philadelphia:
humans. Acta Neurochir Suppl. 2007;100:3–11. FA Davis; 2011.
18. Gordon T, Brushart T, Chan K. Augmenting nerve 36. Fuentes J, Olivo S, Magee D, Gross D. Effectiveness of
regeneration with electrical stimulation. Neurol Res. 2008;30: interferential current therapy in the management of
1012–1022. musculoskeletal pain: a systematic review and meta-analysis.
19. Brushart T, Jari R, Verge V, Rohde C, Gordon T. Electrical Phys Ther. 2010;90(9):1219–1238.
stimulation restores the specificity of sensory axon 37. Bosi E. Effectiveness of frequency-modulated
regeneration. Exp Neurol. 2005;194:221–229. electromagnetic neural stimulation in the treatment of
20. Franz C, Rustishauser U, Rafuse V. Intrinsic neuronal painful diabetic neuropathy. Diabetologia. 2005;48:817–823.
properties control selective targeting of regenerating 38. Conti M. Frequency-modulated electromagnetic neural
motoneurons. Brain. 2008;131:1492–1505. stimulation enhances cutaneous microvascular flow in
21. Havton L.A lumbosacral ventral root avulsion injury and patients with diabetic neuropathy. J Diabetes Complications.
repair model for studies of neuropathic pain in rats. Methods 2009;23:46–48.
Mol Bio. 2012;851:185–193. 39. Gigo-Benato D, Russo T, Geuna S, Domingues N, Salvini
22. Cauthen J, Renner E. Transcutaneous and peripheral nerve T, Parizotto A. Electrical stimulation impairs early
stimulation for chronic pain states. Surg Neurol. 1975;4: functional recovery and accentuates skeletal muscle atrophy
102–104. after sciatic nerve crush injury in rats. Muscle Nerve. 2010;
23. Johansson F, Almay B, Von Knorring L, Terenius I. 41:685–693.
Predictors for the outcome of treatment with high- 40. McGinnis M, Murphy D. The lack of an effect of applied
frequency transcutaneous electrical nerve stimulation in DC electric fields on peripheral nerve regeneration in the
patients with chronic pain. Pain. 1980;9:55–61. guinea pig. Neuroscience. 1992;51:231–244.
24. Meyler W, de Jongste M, Rolf C. Clinical evaluation of pain 41. Marqueste T, Decherchi P, Dousset E, Berthelin F, Jammes
treatment with electrostimulation: a study on TENS in Y. Effect of muscle electrostimulation on afferent activities
patients with different pain syndromes. Clin J Pain. 1994;10: from tibialis anterior muscle after nerve repair by self-
22–27. anastamosis. Neuroscience. 2002;113:257–271.
25. Dubinsky R, Miyasaki J. Assessment: efficacy of 42. Eberstein A, Eberstein S. Electrical stimulation of
transcutaneous electric nerve stimulation in the treatment of denervated muscle: is it worthwhile? Med Sci Sports Exerc.
of pain in neurological disorders (an evidence-based review): 1996;28(12):1463–1469.
report of the Therapeutics and Technology Assessment 43. Gosztonyi G, Naschold U, Grozdanovic Z, Stoltenburg-
Subcommittee of the American Academy of Neurology. Didinger G, Gossrau R. Expression of Leu-19 (CD56-N-
Neurology. 2010;74:173–176. CAM) and nitric oxide synthase (NOS) I in denervated and
26. Jin D, Xu Y, Geng D, Yan T. Effect of transcutaneous reinnervated human skeletal muscle. Microsc Res Techn. 2001;
electrical nerve stimulation on symptomatic diabetic 55:187–197.
neuropathy: a meta-analysis of randomized controlled trials. 44. Baptista A, Gomes J, Oliveira J, Santos S, Vannier-Santos M,
Diabetes Res Clin Pract. 2010;89:10–15. Martinez A. High- and low-frequency transcutaneous
27. Pieber K, Herceg M, Paternostro-Sluga T. Electrotherapy electrical stimulation delay sciatic nerve regeneration after
for the treatment of painful diabetic peripheral neuropathy: crush injury in the mouse. J Peripher Nerv Syst. 2008;13:71–80.
a review. J Rehabil Med. 2010;42:289–295. 45. Bellew J. Clinical Electrical Stimulaiton: Application and
28. Kumar D, Alvaro M, Julka I, Marshall H. Diabetic Techniques. 5th ed. Philadelphia: FA Davis; 2011.
peripheral neuropathy: effectiveness of electrotherapy and 46. Dow D, Cederna P, Hassett C, Kostrominova T, Faulkner J,
amitriptyline for symptomatic relief. Diabetes Care. Dennis R. Number of contractions to maintain mass and
1998;21:1322–1325. force of a denervated rat muscle. Muscle Nerve. 2004;30(1):
29. Kumar D, Marshall H. Diabetic peripheral neuropathy: 77–86.
amelioration of pain with transcutaneous electrostimulation. 47. Dow D, Cederna P, Hassett C, Dennis R, Faulknet J.
Diabetes Care. 1997;20:1702–1705. Electrical stimulation prior to delayed reinnervation does
30. Forst T, Nguyen S, Forst S, Disselhoff B, Pohlmann T, not enhance recovery in muscle of rats. Restor Neurol
Pfutzner A. Impact of low frequency transcutaneous Neurosci. 2007;25:601–610.
electrical nerve stimulation on symptomatic diabetic 48. Glinsky J, Harvey L, Van Es P. Efficacy of electrical
neuropathy using the new Salutaris device. Diabetes Nutr stimulation to increase muscle strength in people with
Metab. 2004;17:163–168. neurological conditions: a systematic review. Physiother Res
31. Julka I, Alvaro M, Kumar D. Beneficial effects of electrical Int. 2007;12(3):175–194.
stimulation on neuropathic symptoms in diabetes patients. 49. Kern H, Hofer C, Modlin M, et al. Denervated muscles in
J Foot Ankle Surg. 1988;37:191–194. humans: limitations and problems of currently used
32. Somers D, Clemente F. Contra-lateral high or a functional electrical stimulation training protocols. Artif
combination of high- and low-frequency transcutaneous Organs. 2002;26(3):216–218.
electrical nerve stimulation reduces mechanical allodynia 50. Mandl T, Meyerspeer M, Reichel M, et al. Functional
and alters dorsal horn neurotransmitter content in electrical stimulation of long-term denervated, degenerated
neuropathic rats. J Pain. 2009;10(2):221–229. human skeletal muscle: estimating activation using
33. Somers D, Clemente F. Transcutaneous electrical nerve T2-parameter magnetic resonance imaging methods. Artif
stimulation for the management of neuropathic pain: the Organs. 2008;32(8):604–608.
effects of frequency and electrode position on prevention of 51. Modlin M, Forstner C, Hofer C, et al. Electrical stimulation
allodynia in a rat model of complex regional pain syndrom of denervated muscles: first results of a clinical study. Artif
type II. Phys Ther. 2006;86(5):698–709. Organs. 2005;29(3):203–206.
34. Somers D, Clemente F. High-frequency transcutaneous 52. Michlovitz S. Is there a role for ultrasound and electrical
electrical nerve stimulation alters thermal but not stimulation following injury to tendon and nerve? J Hand
mechanical allodynia following chronic constriction injury Ther. 2005;18:292–296.
2560_Chapter 17_0195-0208.indd 206 3/16/2015 4:13:44 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
53. Michlovitz S, Bellew J, Nolan T. Modalities for Therapeutic liver mitochondria irradiated in vitro by helium-neon laser.
Intervention. 5th ed. Philadelphia: FA Davis; 2011. FEBS Lett. 1984;175:95–99.
54. Bunge M, Williams A, Wood P, et al. Comparison of nerve 73. Loevschal H, Arenholt-Bindslev D. Effect of low level
cell and nerve cell plus Schwann cell cultures, with diode laser irradiation of human oral mucosa fibroblasts in
particular emphasis on basal lamina and collagen formation. vitro. Lasers Surg Med. 1994;14:347–354.
J Cell Biol. 1980;84:184–202. 74. Karu T. Molecular mechanisms of the therapeutic effects of
55. Lundborg G, Rydevik B. Effects of stretching the tibial low intensity laser radiation. Lasers Life Sci. 1989;2:53–74.
nerve of the rabbit: a preliminary study of the intraneural 75. Mognato M, Squizzato F, Facchin F, Zaghetto L, Corti L.
circulation and barrier function of the perineurium. J Bone Cell growth modulation of human cells irradiated in vitro
Joint Surg (Br). 1973;55:390–401. with low-level laser therapy. Photomed Laser Surg. 2004;22:
56. Rydevik B, Lundborg G, Nordborg C. Intraneural tissue 523–526.
reactions induced by internal neurolysis. Scand J Plast 76. Moor P, Ridgway T, Higbee R, Howard E, Lucroy M.
Reconstr Surg. 1976;10:3–8. Effect of wavelength on low-intensity laser irradiation-
57. Mourad P, Lazar D, Curra F, et al. Ultrasound accelerates stimulated cell proliferation in vitro. Lasers Surg Med. 2005;
functional recovery after peripheral nerve damage. 36:8–12.
Neurosurgery. 2001;48(5):1136–1141. 77. Ferreira D, Zângaro R, Villaverde A, et al. Analgesic effect
58. Hong C, Liu H, Yu J. Ultrasound thermotherapy effect of He-Ne (632.8 nm) low-level laser therapy on acute
on the recovery of nerve conduction in experimental inflammatory pain. Photomed Laser Surg. 2005;23(2):
compression neuropathy. Arch Phys Med Rehabil. 1988;69: 177–181.
410–414. 78. Enwemeka C, Parker J, Dowdy D, Harkness E, Sanford L,
59. Lowdon I, Seaber A, Urbaniak J. An improved method of Woodruff L. The efficacy of low-power lasers in tissue repair
recording rat tracks for measurements of the sciatic and pain control: a meta-analysis study. Photomed Laser Surg.
functional index of De Medinaceli. J Neurosci Methods. 1988; 2004;22(4):323–329.
24:279–281. 79. Byrnes K, Waynant R, Ilev I, et al. Light promotes
60. Crisci A, Ferreira A. Low-intensity pulsed ultrasound regeneration and functional recovery and alters the immune
accelerates the regeneration of the sciatic nerve after response after spinal cord injury. Lasers Surg Med. 2005;
neurotomy in rats. Ultrasound Med Biol. 2002;28(10): 36(3):171–185.
1335–1341. 80. Yu W, Naim J, McGowan M, et al. Photomodulation of
61. Chang C, Hsu S, Lin F, Chang H, Chang C. Low intensity oxidative metabolism and electron chain enzymes in the rat
ultrasound accelerated nerve regeneration using cell seeded liver mitochondria. Photochem Photobiol. 1997;66:866–871.
poly (D,L-lactic acid-co-glycolic acid) conduits: an in-vivo 81. Abergel R, Meeker C, Lam T, Dwye R, Lesavoy M, Uitto J.
and in-vitro study. J Biomed Mater Res B Appl Biomater. Control of connective tissue metabolism by lasers: recent
2005;75:99–107. developments and future prospects. J Am Acad Dermatol.
62. Park S, Oh S, Seo T, Namgung U, Kim J, Lee J. 1984;11:1142–1150.
Ultrasound-stimulated peripheral nerve regeneration 82. Karu T. Molecular mechanisms of the therapeutic effects of
within asymmetrically porous PLGA/Pluronic F127 low intensity laser radiation. Lasers Life Sci. 1989;2:53–74.
nerve guide conduit. J Biomed Mater Res. 2010;94(2): 83. Rochkind S, Nissan M, Barr-Nea L, Razon N, Schwartz M,
359–366. Bartal A. Response of peripheral nerve to He-Ne laser:
63. Zhang H, Lin X, Wan H, Li J, Li J. Effect of low-intensity experimental studies. Lasers Surg Med. 1987;7:441–443.
pulsed ultrasound on the expression of neurotrophin-3 and 84. Shamir M, Rochkind S, Sandbank J, Alon M. Double-blind
brain-derived neurotrophic factor in cultured Schwann cells. randomized study evaluating regeneration of the rat
Microsurgery. 2009;29(6):479–485. transected sciatic nerve after suturing and postoperative
64. Bhatheja K, Field J. Schwann cells: origins and role in lower power laser treatment. J Reconstr Microsurg. 2001;17:
axonal maintenance and regeneration. Int J Biochem Cell Biol. 133–138.
2006;38:1995–1999. 85. Rochkind S, Rousso M, Nissan M, Villarreal M, Barr-Nea
65. Raso V, Barbieri C, Mazzer N, Fasan V. Can therapeutic L, Reese DG. Systemic effects of low-power laser irradiation
ultrasound influence the regeneration of peripheral nerves? on the peripheral and central nervous system, cutaneous
J Neurosci Methods. 2005;142:185–192. wounds, and burns. Laser Surg Med. 1989;9(2):174–178.
66. Ebenbichler G, Resch K, Funovics M, Nicolakis P, 86. Anders J, Borke R, Woolery S, Van de Merwe W. Low
Wiesinger G, Fialka V. Ultrasound treatment for treating power laser irradiation alters the rate of regeneration of the
carpal tunnel syndrome: randomized “sham” controlled trial. rat facial nerve. Lasers Surg Med. 1993;13:72–82.
BMJ. 1998;316:7315. 87. Rochkind S, Droroy V, Alon M, Nissan M, Ouaknine GE.
67. Piravej K, Boonhong J. Effect of ultrasound thermotherapy The treatment of incomplete peripheral nerve injuries using
in mild to moderate carpal tunnel syndrome. J Med Assoc a new modality-laser phototherapy (780nm). Photomed Laser
Thai. 2004;87(Suppl 2):S100–106. Surg. 2007;25:436–442.
68. Oztas O, Turan B, Bora I, Karakaya M. Ultrasound therapy 88. Rochkind S, Leider-Trejo L, Nissan M, Shamir M,
effects in carpal tunnel syndrome. Arch Phys Med Rehabil. Kharenko O, Alon M. Efficacy of 780nm laser phototherapy
1998;79:1540–1544. on peripheral nerve regeneration after neurotube
69. Bakhtiary A, Rashidy-Pour A. Ultrasound and laser therapy reconstruction procedure (double-blind randomized study).
in the treatment of carpal tunnel syndrome. Aust J Physiother. Photomed Laser Surg. 2007;25:137–143.
2004;50:147–151. 89. Gigo-Benato D, Geuna S, deCastro Rodrigues A, et al. Low
70. Piazzini D, Aprile I, Ferrara P, et al. A systematic review of power laser biostimulation enhances nerve repair after
conservative treatment of carpal tunnel syndrome. Clin end-to-side neurorrhaphy. A double blind randomized study
Rehabil. 2007;21:299–314. in the rat median nerve model. Laser Med Sci. 2004;19:
71. Pinheiro A, Gerbi ME. Photoengineering of bone repair 57–65.
processes. Photomed Laser Surg. 2006;24:169–178. 90. Reis F, Belchior A, Nicolau R, Fonseca T, Carvalho P. Effect
72. Passerella S, Casamassima E, Molinari S, et al. Increase of of gallium-aluminum-arsenide laser therapy (660Nm) on
proton electrochemical potential and ATP synthesis in rat recovery of the sciatic nerve in rats following neurotmesis
2560_Chapter 17_0195-0208.indd 207 3/16/2015 4:13:44 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
lesion and epineural anastomosis: functional analysis. Braz J 111. Mayrovitz H, Larsen P. Effects of pulsed electromagnetic
Phys Ther. 2008;12:215–221. fileds on skin microvascular blood perfusion. Wounds.
91. Rochkind S. Stimulation effects of laser energy on the 1992;4(5):197–202.
regeneration of traumatically injured peripheral nerves. 112. Markov MS, Muechsam DJ, Pilla AA. Modulation of
Morphogen Regen. 1978;83:25–27. Cell-Free Myosin Phosphorylation With Pulsed Radio
92. Irvine J, Chong S, Amirjani N, Chan M. Double blind Frequency Electromagnetic Fields. Singapore: World
randomized controlled trial of low level laser therapy in Scientific; 1995.
carpal tunnel syndrome. Muscle Nerve. 2004;30:182–187. 113. Boonstra J, Skper S, Varons S. Regulation of Na+-K+ pump
93. Naeser M, Hahn K, Lieberman B. Carpal tunnel syndrome activity by nerve growth factor in chick embryo dorsal root
pain treated with low level laser and microamperes ganglia cells. J Cell Physiol. 1982;113:452–455.
transcutaneous electrical nerve stimulation: a controlled 114. Rozengurt E, Mendoza S. Monovalent ion fluxes and the
study. Arch Phys Med Rehabil. 2002;83:978–987. control of cell proliferation in cultured fibroblasts. Ann N Y
94. Evcik D, Kavuncu V, Cakir T, Subasi V, Yaman M. Laser Acad Sci. 1980;339:175–190.
therapy in the treatment of carpal tunnel syndrome: a 115. Musaev A, Guseinva S, Imamverdieva S. The use of pulsed
randomized controlled trial. Photomed Laser Surg. 2007;25: electromagnetic fields with complex modulation in the
34–39. treatment of patients with diabetic polyneuropathy. Neurosci
95. Ekim A, Armagan O, Tascioglu F, Oner C, Colak I. Behav Physiol. 2003;33(8):745–752.
Effect of low level laser therapy in rheumatoid patients 116. Burke T. 5 Questions—and answers—about MIRE
with carpal tunnel syndrome. Swiss Med Wkly. 2007;137: treatment. Adv Skin Wound Care. 2003;16:369–371.
347–352. 117. Kochman A. Symptomatic reversal of peripheral neuropathy
96. Bodofsky E. Treating carpal tunnel syndrome with lasers in patients with diabetes. J Am Podiatr Med Assoc. 2002;92:
and TENS. Arch Phys Med Rehabil. 2002;83:1806–1807. 125–130.
97. Bodofsky E. Follow-up on low level laser and microvolt 118. Prendergast JJ, Miranda G, Sanchez M. Improvement of
transcutaneous electric stimulation. Arch Phys Med Rehabil. sensory impairment in patients with peripheral neuropathy.
2003;84:1402–1403. Endocr Pract. 2004;10:24–30.
98. Bolognani L, Volpi N. Low Power Laser Enzymology: 119. Leonard DR, Farooqi MH, Myers S. Restoration of
Reactivation of Myosin ATPase by GaAs and HeNe Lasers. sensation, reduced pain, and improved balance in subjects
Bari, Italy: Trani; 1991. with diabetic peripheral neuropathy: a double-blind,
99. Rochkind S, Geuna S, Shainberg A. Phototherapy in randomized, placebo-controlled study with monochromatic
peripheral nerve injury: effects on muscle preservation and near-infrared treatment. Diabetes Care. 2004;27:168–172.
nerve regeneration. Int Rev Neurobiol. 2009;87:445–464. 120. Arnall DA, Nelson AG, López L, et al. The restorative
100. Gigo-Benato D, Geuna S, Rochkind S. Phototherapy for effects of pulsed light therapy on significant loss of
enhancing peripheral nerve repair: a review of the literature. peripheral protective sensation in patients with long-term
Muscle Nerve. 2005;31:694–701. type 1 and type 2 diabetes mellitus. Acta Diabetol. 2006;43:
101. Rochkind S. Phototherapy in peripheral nerve regeneration: 26–33.
from basic science to clinical study. Neurosurg Focus. 2009; 121. Powell MW, Carnegie DE, Burke TJ. Reversal of diabetic
26(2):E8, 1–6. peripheral neuropathy and new wound incidence: the role of
102. FDA Clearance: K071445. Trade Name Device: MIRE. Adv Skin Wound Care. 2004;17:295–300.
LaserTENS, Multi Radiance Medical. 122. DeLellis SL, Carnegie DH, Burke TJ. Improved sensitivity
103. Dellagatta E, Nolan T. Electromagnetic Waves: Laser, in patients with peripheral neuropathy: effects of
Diathermy, and Pulsed Electromagnetic Fields. 5th ed. monochromatic infrared photo energy. J Am Podiatr Med
Philadelphia: FA Davis; 2011. Assoc. 2005;95:143–147.
104. Glassman L, McGrath M, Bassett C. Effect of external 123. Harkless LB, DeLellis S, Carnegie DH, Burke TJ. Improved
pulsing electromagnetic fields on the healing of soft tissues. foot sensitivity and pain reduction in patients with
Ann Plast Surg. 1986;16:287–295. peripheral neuropathy after treatment with monchromatic
105. Ryaby J. Clinical effects of electromagnetic and electric infrared photo energy—MIRE. J Diabetes Complications.
fields on fracture healing. Clin Orthop. 1984;355(Suppl): 2006;20:81–87.
205–215. 124. Powell MW, Carnegie DH, Burke TJ. Reversal of diabetic
106. Weintraub M. Magnetotherapy: historical background peripheral neuropathy with phototherapy (MIRE) decreases
with a stimulating future. Clin Rev Phys Rehabil. 2004;16: falls and the fear of falling and improves activities of daily
96–108. living in seniors. Age Ageing. 2006;35(1):11–16.
107. Cameron M. Physical Agents in Rehabilitation. 2nd ed. St. 125. Clifft JK, Kasser RJ, Newton TS, Bush AJ. The effect of
Louis: Saunders; 2003. monochromatic infrared energy on sensation in patients
108. Chiabrera A, Grattarola M, Viviani R. Interaction between with diabetic peripheral neuropathy: a double-blind,
electromagnetic fields and cells: microelectrophoretic effect placebo-controlled study. Diabetes Care. 2005;28:2896–2900.
of ligands and surface receptors. Bioelectromagnetics. 1984;5: 126. Franzen-Korzendorfer H, Blackinton M, Rone-Adams S,
173–178. McCulloch J. The effect of monochromatic infrared energy
109. McLeod B, Liboff A. Dynamic characteristics of low on transcutaneous oxygen measurements and protective
membrane ions in multified configurations of low frequency sensation: results of a controlled, double-blind, randomized
electromagnetic radiation. Bioelectromagnetics. 1986;7: clinical study. Ostomy Wound Manage. 2008;54:16–31.
177–189. 127. Lavery LA, Murdoch DP, Williams J, Lavery DC. Does
110. Mayrovitz H, Larsen P. A preliminary study to evaluate the Anodyne light therapy improve peripheral neuropathy in
effect of pulsed radio frequency field treatment on lower diabetes? A double-blind, sham-controlled, randomized trial
extremity peri-ulcer skin microcirculaiton of diabetic to evaluate monchromatic infrared photoenergy. Diabetes
patients. Wounds. 1995;7(3):90–93. Care 2008;31:316–321.
2560_Chapter 17_0195-0208.indd 208 3/16/2015 4:13:44 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 18
Orthotic Intervention for
ELIZABETH SPENCER STEFFA, OTR/L, CHT
“Illness is the most heeded of all doctors. To goodness and wisdom we make only
promises; to pain we obey.”
—MARCEL PROUST (1871–1922)
Objectives
• List the indications for use of a splint in individuals with peripheral nerve injury.
• Describe the differences between static and dynamic splinting.
• Discuss common orthoses prescribed for individuals with median, ulnar, radial, and plexus injuries.
• Define the concept of three-point pressure.
Key Terms
• Contracture
• Dynamic splint
• Immobilization
• Safe position
• Serial casting
• Static splint
• Three-point pressure
Introduction functional daily activities. The prescription, fabrication,

and fitting of a custom orthosis requires a strong
Using splinting to treat a peripheral nerve injury is understanding of the basic mechanical principles of
important but often challenging. This chapter discusses splinting; knowledge of the mechanical properties of
the basic use of splinting forces as an intervention for splinting materials; knowledge of deep and surface
brachial plexus, radial, median, and ulnar nerve injuries. anatomy; knowledge of the impact of compressive,
Lower extremity nerve injuries are not addressed in tensile, and shear forces on the integument; and a thor-
this chapter; however, the basic splinting concepts may ough understanding of the pathophysiology, diagnos-
be translated to those nerve injuries as well. tics, and treatment of peripheral nerve injury. Therapists
All injuries to peripheral nerves result in possible who use splinting should strive to practice with a “min-
motor loss and subsequent muscle imbalance creating imalistic” approach with emphasis on simplicity, cost
the potential for further loss of function secondary accountability, flexibility, and sustainability in the
to adaptive contractile and noncontractile tissue short- attainment of splint effectiveness. This method of prac-
ening and lengthening. The objectives of splinting tice promotes patient satisfaction and compliance.1 The
include protection of injured tissues, enhancement of ideal splint should be comfortable, lightweight, func-
a healing environment, prevention or minimization of tional, easy to don and doff, and aesthetically “pleasing”
contracture formation, acting as a substitute for lost to the patient while performing the function for which
motor function, and facilitation and enhancement of it was intended.
209
2560_Chapter 18_0209-0218.indd 209 3/17/2015 4:21:00 PM

Process CyanProcess
YellowProcess Black
Classification System was published in an effort to
Splinting Mechanics improve and standardize splinting nomenclature. The
and Terminology standard “wrist splint” is now classified as a “wrist
extension immobilization splint, type 0.”1,4 The wrist
The most frequently used splint for the appendicular extension immobilization splint, type 0, is fabricated at
skeleton is a three-point pressure splint. The proximal two thirds the length of the forearm and two thirds
and distal forces occur in the same direction, and the forearm circumference to distribute the force over a
middle force is in the opposite direction (Fig. 18-1). considerable surface area to minimize integument dis-
The wrist splint uses two points of pressure—one at ruption and increase comfort as well as increase the
the palm and the other along the proximal forearm— splint strength. Because the distance of the lever arm
and an opposite directional point of force at the wrist (the distance between the opposite forces supplied by
(Fig. 18-2). The wrist splint is classified as a first-class the splint) is an integral component of the force vector,
lever.2 Force is defined by type, such as push or pull; the longer the lever arms, the greater resistance the
amount; application angle; and point of application.3 splint can accommodate. The splint prevents wrist
The wrist splint has no moving parts and is commonly motion but does not limit finger flexion or extension.
referred to as a static splint. This term and many other The splint allows full rotational motion and opposition
commonly used splinting terms are misleading. In of the thumb to the base of the little finger.
1992, the American Society of Hand Therapists Splint Splint design should prevent further injury and
promote function whenever possible. Proper position-
ing of a weakened hand facilitates the maintenance of
tissue length and permits a modicum of function.
Speaking of the wrist extension immobilization splint,
James described the “safe position” as follows: “The
metacarpophalangeal joints are safe in flexion and most
unsafe in extension; the PIP joints, conversely, are safe
in extension and exceedingly unsafe if immobilized in
flexion”5 (Fig. 18-3).
The hand and wrist in the safe position splint shown
in Figure 18-3 maintains wrist extension at 30°, which
is the position of functional grip strength. The meta-
carpophalangeal (MCP) joints are in 90° flexion to
maintain MCP ligament length and functional posi-
tion. The proximal interphalangeal (PIP) joints are in
extension to maintain extrinsic muscle length and
prevent intrinsic muscle tightness. The thumb is placed
in palmar abduction to maintain opposition potential
Figure 18-1 Three-point pressure splint. The three-point to one or more digits in prehension. The MCP flexion,
pressure system for the control of abnormal static PIP extension immobilization splint is also called a
positioning of a foot consists of two laterally directed type 1 splint.4 The safe position splint is custom fitted
forces—one at the area of the first metatarsal head and to the flaccid hand and worn in the daytime and at
one at the medial border of the calcaneus—and one night, but it is removed for skin care and hygiene or as
medially directed force just proximal to the base of the permitted after a surgical repair. The splint is retained
fifth metatarsal.
Figure 18-3 Safe position splint uses metacarpophalangeal

Figure 18-2 Three-point pressure wrist extension flexion and interphalangeal extension immobilization in an
immobilization splint. intrinsic plus position.
2560_Chapter 18_0209-0218.indd 210 3/17/2015 4:21:01 PM

Process CyanProcess
YellowProcess Black
Chapter 18 | Orthotic Intervention for Peripheral Neuropathy 211
as a nighttime splint as function begins to return or a
functional daytime splint is used.
A dynamic splint is properly defined as a mobiliza-
tion splint in flexion, extension, or rotation using some
form of traction, such as rubber bands or springs.
Rubber bands exhibit creep over time when subjected
to a constant stress load. Creep results in a change in
the force dynamics. Shorter thicker bands demonstrate
less creep than longer thinner bands. Spring tension is
not subject to creep and allows for the maintenance of
the prescribed forces. Determination of proper length
and tension is difficult to objectify and a hallmark of
clinical expertise. An experienced therapist tends to use
the proper length and tension, whereas an inexperi-
enced therapist tends to fabricate dynamic splints with
excessive forces applied to the soft tissues.6 The rubber
band tension is easy to change, does not easily snag on
Figure 18-4 Plexus injury secondary to multiple trauma
clothing, and is inexpensive. The springs are difficult to
may also include shoulder dislocation, humeral fracture, or
change, catch on clothing, and are more expensive.
crush injury.
Collaboration, teamwork, and communication between
the therapist and patient are important aspects of the
determination of an appropriate tension prescribed in
the dynamic splint. Increased tension may facilitate
healing and function but may cause pain resulting in a
negative impact on patient compliance.
Brachial Plexus Splinting

A preganglionic brachial plexus injury is an injury to
the central nervous system occurring proximal to the
neuron. A preganglionic injury has very poor capacity
for recovery. A postganglionic brachial plexus injury
involves the peripheral nervous system, and if the
injury is neurapraxic or axonotmetic, the nerves are
able to regenerate and are amenable to self-repair. Post-
ganglionic neurotmetic lesions do not heal spontane-
ously and require surgical intervention for recovery
(Figs. 18-4 and 18-5).7 Preganglionic brachial plexus
injury may be associated with head injury or incom-
plete spinal cord injury. Postganglionic plexus injuries
typically result from forceful scapular depression,
shoulder hyperhorizontal abduction, contralateral neck Figure 18-5 Plexus injury secondary to multiple trauma
lateral flexion, or any combination of these motions.8 with shoulder dislocation, humeral fracture, or crush injury
Less common etiologies include injuries related to may require a hemisling support in addition to splinting.
medication, infection, repetitive strain, or radiation.
Plexus injuries secondary to a multiple trauma etiology
may also include shoulder dislocation, fractures, or muscles may require 24 months to reinnervate. In addi-
crush injuries. The splinting program must take into tion, atrophic changes may result in distal muscles
consideration individual cognitive or physical limita- awaiting reinnervation. Muscle scarring, arthropathy,
tions. Knowledge of each individual nerve function and chronic regional pain syndrome, and contracture all are
deficit is essential for splinting. Evaluation is ongoing common complications of proximal nerve lesions. Per-
because the injured or repaired nerves may regain func- manent loss of sarcomeres in the intrinsic hand muscles
tion at different rates or may not recover at all. Recov- may occur if reinnervation does not occur within 6
ery, especially with axonotmetic and neurotmetic months of injury.9 Early splinting to position the
lesions, is a prolonged process. Axonal regeneration injured plexus in the optimum posture for healing
may occur at a slow rate of 1 mm per month. Distal while allowing the spared muscles to function and
2560_Chapter 18_0209-0218.indd 211 3/17/2015 4:21:01 PM

Process CyanProcess
YellowProcess Black
maintenance of soft tissue length is essential for a
favorable rehabilitation outcome.
Radial Nerve Splinting

The radial nerve innervates the triceps, extensor carpi
radialis longus and brevis, brachioradialis, supinator,
extrinsic finger extensors, and thumb extrinsic abduc-
tor muscles. Radial nerve injury commonly occurs with
humeral fracture, elbow dislocation, and Monteggia
fracture. Neuropathy may also result directly or indi-
rectly from systemic disease.10 For instance, tumor may
directly compress the radial nerve or may indirectly
injure the nerve via paraneoplastic syndrome, illness Figure 18-6 Radial nerve injury splinted with Phoenix
related to critical illness neuropathy or myopathy, or wrist extension outrigger using spring tension following
through the effects of chemotherapy medication or external fixator fracture stabilization. Proper outrigger
radiation. Proximal injury to the radial nerve may affect alignment with the wrist joint is essential to prevent wrist
wrist, finger, and thumb extension and produce weak- joint compaction.
ness of supination and thumb radial abduction.9 The
loss of wrist extension prevents tenodesis action and
decreases finger use in power grip or grasp-release
(Figs. 18-6 through 18-19).11
A B
Figure 18-7 A–C, James Sellers, OTR, described the

dorsal splint with elastic digit extension assist for radial
nerve injury. The splint allows full finger flexion. The
C
elastic extension assist requires hand sewing to replace.
2560_Chapter 18_0209-0218.indd 212 3/17/2015 4:21:02 PM

Process CyanProcess
YellowProcess Black
Figure 18-8 Following humeral fracture with radial nerve Figure 18-10 A hand-based finger and thumb extension
injury, a 34-year-old man was splinted for mobilization splint was used as wrist motion returned to permit right
using combined Phoenix wrist and Rolyan adjustable dominant writing and keyboarding for a 21-year-old
outriggers to assist wrist and finger extension and allow university student. She was able to complete all her classes
full finger flexion. The wrist may go into flexion as needed despite her injury and extended recovery.
for activities of daily living or fine motor tasks.
Figure 18-11 The extended Phoenix outrigger is used with

the lightest metacarpophalangeal extension assist force to
Figure 18-9 Radial nerve injury and humeral fracture decrease a tenodesis effect when performing activities of
following a motor vehicle accident was splinted with daily living (zipper pull, buttoning, or shoe tying) that
Phoenix wrist and digit extension mobilization. require going in and out of wrist flexion.
Figure 18-12 A and B, Elbow flexion/wrist/hand

immobilization splint with finger intrinsic plus position
A
and thumb supported in palmar abduction.
2560_Chapter 18_0209-0218.indd 213 3/17/2015 4:21:02 PM

Process CyanProcess
YellowProcess Black
Figure 18-15 A 39-year-old woman sustained a traumatic

shoulder dislocation with a lower brachial plexus injury.
She was initially treated with upper arm immobilization to
the chest wall to place the plexus in a “resting” position,
which eliminated tensile forces. In addition, she was
Figure 18-13 Proximal interphalangeal joint contractures prescribed a safe splint and forearm hemisling. Because the
treated with dynamic splinting. median nerve sustained a neurapraxic injury and the radial
nerve sustained axonal degeneration, conduction returned
to the medial nerve before the radial nerve. She was fitted
with a combined wrist and metacarpophalangeal extension
mobilization splint with spring assist replacing the lost
radial nerve function. Splinting allowed functional
prehension and early use of the intrinsic hand muscles,
which prevented muscle atrophy and joint contractures.
Figure 18-14 A 57-year-old man did not receive

early splinting to maintain the hand and fingers in
the safe position. He was referred to therapy for
metacarpophalangeal flexion splinting after
metacarpophalangeal capsulotomies but did not obtain
functional return.
With radial nerve lesions, the wrist is splinted in 20°

to 30° extension to assist functional grip strength. Figure 18-16 The splint also permitted wrist flexion,
Based on the physical examination, the required splint essential for many activities of daily living tasks, such as
may be a static immobilization splint or a dynamic buttoning, manipulating objects at or below waist level, or
mobilization splint. There are multiple opinions in the using a zipper.
literature. Pearson12 states that a static wrist immobili-
zation splint without dynamic finger extension mobi-
lization assist may be adequate for many patients with The “safe position” splint should be worn during the
proximal radial nerve lesions with motor neuropathy. day and at night. The mobilization splint may use static
Fess and Philips13 state that patients with nonfunc- lines for a tenodesis effect or elastic tension such as
tional radial nerve–innervated muscles should be springs or rubber bands. The thumb may not need to
treated with an external hand support. Dillingham be included in the outrigger because the thumb exten-
et al.14 recommend a hinged wrist orthosis with sors and abductors are located on the dorsoulnar surface
dynamic finger extension assists to compensate for and are not on stretch when wrist extension is provided
muscular deficits resulting from the radial nerve injury. by the splint.10 Mobilization splints are typically worn
2560_Chapter 18_0209-0218.indd 214 3/17/2015 4:21:03 PM

Process CyanProcess
YellowProcess Black
Figure 18-19 Wartenberg’s sign—inability to adduct the

Figure 18-17 As radial nerve axonal regeneration occurred, extended little finger to the extended ring finger because
the splint was converted into a hand-based of lack of intrinsic function.
metacarpophalangeal-mobilization splint for finger
extension. Without the splint, a Wartenberg’s sign could
be elicited and, therefore, the quality of prehension in the
index finger and thumb diminished.
Figure 18-20 Metacarpophalangeal flexion and thumb sling

in palmar abduction prevents contracture formation while
permitting functional prehension.
Figure 18-18 Diminished prehension associated with

intrinsic weakness and a positive Wartenberg’s sign.
during the daytime and changed to a static splint for

nighttime wear.
Median Nerve Splinting

The median nerve innervates the extrinsic pronator
muscles, radial wrist flexor, superficial digit flexors,
index and long finger profundus flexors, and long
thumb flexor through branches exiting early from the
nerve (Figs. 18-20, 18-21, and 18-22). Thumb abduc-
tion and opposition are innervated from branches
exiting distally. Palm and anterior digit tactile and Figure 18-21 The web space splint is worn primarily at
kinesthetic/proprioception sensation are provided by night to maintain thumb adductor length.
2560_Chapter 18_0209-0218.indd 215 3/17/2015 4:21:03 PM

Process CyanProcess
YellowProcess Black
Figure 18-23 Ulnar claw deformity.
Figure 18-22 Soft leather thumb abduction splint allows

tool use without palmar pressure.
the median nerve except for the small finger and ulnar
half of the ring finger.15 Splinting for the high-level
median nerve injury supports the radial fingers in
MCP flexion and the thumb in palmar abduction
opposition. High median nerve palsy typically limits
flexion of the index finger distal interphalangeal (DIP)
joint and the thumb interphalangeal joint decreasing
functional tip prehension. Ring splints may be used to
flex the distal joints of the index finger and thumb to
prevent joint hyperextension and to improve tip pre-
hension. The low-level median nerve injury splint is Figure 18-24 The ulnar claw splint maintains the ring and
used to place the thumb in palmar abduction and to small finger metacarpophalangeal joints in flexion
maintain opposition.9 The unopposed adductor pollicis permitting active interphalangeal joint extension.
muscle may be positioned in a full thumb abduction
web space splint to maintain the muscle length. The
thumb may be held in palmar abduction with a soft that holding straps are loosened at night to prevent
daytime splint that permits functional grip on a handle possible compression secondary to the development of
or tool. nighttime edema. Wider and softer straps may also
Median nerve compression at the wrist level—carpal decrease venous return compression.
tunnel syndrome (CTS)—is a neurological disorder
and may result from trauma, distal radius fracture,
hormone changes during pregnancy, endocrine disor- Ulnar Nerve Splinting
ders such as diabetes, or repetitive wrist motion. CTS
is the most frequent compression neuropathy and The ulnar nerve innervates the flexi carpi ulnaris, the
occurs in 0.7% to 16% of the general population.16 ring and little finger deep flexors and lumbricales,
Evidence-based research has shown that night splint- dorsal and palmar interossei, abductor and opponens
ing alone reduces CTS symptom severity as measured digiti minimi, and adductor pollicis.15 Loss of the
by nerve conduction testing.16 Evidence suggests intrinsic hand muscles produces an ulnar claw defor-
splinting the wrist in neutral improves symptoms more mity with the MCP joints unable to flex and the PIP
than splinting the historical and often used 20° of wrist joints unable to extend, whereas the long flexors remain
extension.16 Surgical intervention provides better long- intact. The extrinsic extensors hyperextend the MCP
term outcomes than splinting alone.17 Courts18 found joints, and the extrinsic flexors flex the PIP and DIP
that using splinting in symptomatic individuals with joints (Figs. 18-23 and 18-24). The volar capsular liga-
CTS during pregnancy increased average grip strength ment structures may elongate and exacerbate the claw
by 5.4 pounds in each of the pinch strengths after just deformity. Clawing may not occur when the flexor
1 week of splinting. When fabricating a static splint digitorum is affected. Splinting the ring and little
for clients with CTS, care should be taken to ensure finger MCP joints in flexion permits active extension
2560_Chapter 18_0209-0218.indd 216 3/17/2015 4:21:03 PM

Process CyanProcess
YellowProcess Black
of the PIP joints and allows functional hand use for
grasp and release. Anticlaw splinting is contraindicated
if contractures are present and the MCP joints cannot
be passively flexed or the interphalangeal joints cannot
be passively extended. Early anticlaw splinting prevents
contracture formation. An ulnar nerve injury proximal
to the wrist may produce a weak interossei muscle
creating Wartenberg’s sign with the little finger in
abduction.15 A minimal “double ring” splint or soft
“trapper” may be used to prevent overstretching with
the little finger in abduction. Hyperflexion of the
thumb when pinching produces Froment’s sign sec-
ondary to a weak adductor pollicis muscle requiring
flexor pollicis longus for power pinch.19
One of the most common etiologies of proximal
ulnar lesions is cubital tunnel syndrome. Bozentka Figure 18-25 The combined ulnar and median nerve
reported that cubital tunnel syndrome is the second laceration injury was splinted with a hand-based splint for
most common peripheral compression neuropathy metacarpophalangeal flexion permitting active
after CTS.20 The etiology of cubital tunnel syndrome interphalangeal finger extension. The thumb spica is in
is varied and includes direct trauma, osseous fracture, palmar abduction. The splint is easily removed for hygiene.
and overuse. For cubital tunnel syndrome with ulnar
nerve compression at the elbow, a soft daytime Neo-
prene splint and a nighttime anterior elbow splint at
20° flexion may be used.
CASE STUDY
Combined Peripheral Nerve Injures Annie is a 50-year-old, previously healthy, right hand
dominant woman who works as a certified public
and Complications accountant. She sustained a traumatic cervical spine
and brachial plexus injury to the right upper extremity
Cases of delayed diagnosis or referral may require as a result of a body surfing accident 1 year ago.
splinting to reduce contractures. Contractures of the Along with orthopedic and integument injuries, Annie
interphalangeal joints are best treated using plaster of sustained C7 through T1 spinal nerve traction injuries
Paris serial casting to hold the joint at end range and resulting in significant upper extremity weakness,
to allow tissue cell growth. If the patient has sufficient sensory loss, and dysfunction. At 1 year after injury,
cognitive and psychomotor skills, he or she may be the latissimus, pectoralis, triceps, and all distal muscle
instructed to change the casting every 2 or 3 days. groups function at grade between 0/5 and 1/5. The
However, replacement casts are applied by the splinting three deltoid divisions, the rotator cuff, and the biceps
therapist in most instances (Fig. 18-25). function at grade 2+/5. Annie now presents with a
Forearm or hand trauma may result in more than flail wrist and hand. There is patchy loss of tactile
one peripheral nerve injury. Combining splinting tech- sense throughout the entire upper extremity. Capillary
niques for each of the injured nerves may be possible. refill is excellent. There is mild hand edema. She
Minimalistic splint design for the combined injury reports no improvement in muscle strength or sensation
may allow preservation of functional hand use. over the past 6 months. She underwent an unsuccessful
The clinical objectives of using splinting in patients brachial plexus surgical exploration 9 months ago.
with a diagnosis of peripheral nerve injury vary from Annie presents at the clinic with an over-the-counter
protection, stabilization, lengthening shortened tissues, sling and over-the-counter cloth glove on her right
shortening lengthened tissues, rest, exercise, and pre- hand. She is experiencing right shoulder pain, which
serving function. Splinting is an important primary she attributes to the sling.
and adjunct intervention for nerve injuries. Much of A custom, lightweight, thermoplastic, foam-lined
the process of splinting revolves around clinical deci- orthosis was fabricated using a Step-Lock elbow joint.
sion making: Splint or no splint? Which type of splint? A prefabricated cock-up splint was fitted to the patient.
Dynamic or static? Material? Fastening mechanism? An over-the-counter compressive sleeve extending from
Wear schedule? An increasing number of evidenced- the fingertips to the wrist was provided to the patient.
based publications address splinting. That being said, Lastly, a figure-of-eight harness was attached to the
clinical expertise and experience remain important elbow orthosis to aid in suspension and ipsilateral limb
components in splinting intervention. comfort.
2560_Chapter 18_0209-0218.indd 217 3/17/2015 4:21:04 PM

Process CyanProcess
YellowProcess Black
Case Study Questions Principles and Process. Philadelphia: Lippincott Williams &
Wilkins; 2003:59–72.
1. The purpose of the Step-Lock elbow joint is which of 4. American Society of Hand Therapists. American Society of
the following? Hand Therapists Splinting Classification System. Chicago:
a. Pain control ASHT; 1992.
5. Fess EE. A history of splinting: to understand the present,
b. Control of edema view the past. J Hand Ther. 2002;15:97–132
c. Skin protection 6. Bell-Krotoski JA, Breger-Stanton DE. Biomechanics and
d. Elbow positioning evaluation of the hand. In: Macklin EJ, Callahan AD,
Skirven TM, Schneider LH, Osterman AL, eds.
2. The compressive glove will provide which function Rehabilitation of the Hand and Upper Extremity. 5th ed.
for the wrist and hand? St Louis: Mosby; 2002:240–252.
a. Protection 7. Trumble TE. Brachial plexus injuries. In: Principles of Hand
b. Decrease dependent edema Surgery and Therapy. Philadelphia: Saunders; 2000:312–344.
8. Hentz DO. Traumatic brachial plexus injury. In: Green DP,
c. Neither a nor b Hotchkiss RN, Penderson WC, Wolfe SW, eds. Green’s
d. Both a and b Operative Hand Surgery. Vol II. 5th ed. Philadelphia:
Churchill Livingstone; 2005:1132–1199.
3. The therapist is addressing the shoulder pain by 9. Robinson LR. Trauma rehabilitation. In: Robinson LR,
which of the following interventions? Spencer Steffa EL, eds. Diagnosis and Rehabilitation of
a. Compressive glove Peripheral Nerve Injuries. Philadelphia: Lippincott Williams
b. Figure-of-eight harness & Wilkins; 2006:299–342
c. The locked elbow 10. Colditz JC. Splinting for radial nerve palsy. J Hand Ther.
1987;1:18–19.
d. The wrist cock-up splint 11. Hannah SD, Hudak PL. Splinting and radial nerve palsy: a
4. Daily skin checks should be performed by the patient single-subject experiment. J Hand Ther. 2001; 14:195–201.
12. Pearson SO. Splinting of the nerve injured hand. In: Skirven,
to assist with identifying which of the following? T, Osterman A, Fedorczyk J, Amadio P (eds.): Rehabilitation
a. Edema of the Hand,. 5th ed. St. Louis: Mosby Elsevier; 2011:
b. Allergic reaction to the splinting materials 567–601.
c. Pressure ulcers 13. Fess EE, Philips CA: Hand Splinting: Principles and Methods.
d. All of the above 2nd ed. St Louis: Mosby, 1978.
14. Dillingham TR, Olaje FH, Belandres PV, Thorn-Vogel MI.
5. Additional educational teaching should be provided Orthosis for the complete median and radial nerve-injured
to the patient regarding which of the following? war casualty. J Hand Ther. 1992; 5:212–217.
15. Kendall FP, McCreary EK, Provance PG. Muscle Testing and
a. Insensate limb precautions Function. 4th ed. Baltimore: Williams & Wilkins; 1993.
b. Edema management 16. Gummesson AI, Johnsson R, McCabe SJ, Ornstein E. Severe
c. Proper skin hygiene carpal tunnel syndrome, potentially needing surgical
d. All of the above treatment in a general population. J Hand Surg Am. 2003;28:
639–644.
17. Muller M, Tsui D, Schnuur R, Biddulph-Deisroth L, Hard J,
MacDermid JC. Effectiveness of hand therapy interventions
in primary management of carpal tunnel syndrome: a
systematic review. J Hand Ther. 2004;17:210–225.
References 18. Courts RB. Splinting for symptoms of carpal tunnel
1. Van Lede P. Minimalistic splint design: a rationale told in a syndrome during pregnancy. J Hand Ther. 1995;8:31–34.
personal style. J Hand Ther. 2002:192–201. 19. Lund AT, Amadio PC. Treatment of cubital tunnel
2. Janson JR. Mechanical principles. In: Fess EE, Gettle KS, syndrome: perspectives for the therapist. J Hand Ther. 2006;
Phillips CA, Jansen JR, eds. Hand and Upper Extremity 19:170–178.
Splinting Principles and Methods. 3rd ed. St Louis: Mosby; 20. Apfel E, Sigafoos GT. Comparison of range-of-motion
2005:161–165. constraints provided by splints used in the treatment of
3. Austin GP, Jacobs ML. Mechanical principles. In: Jacobs cubital tunnel syndrome—a pilot study. J Hand Ther. 2006;19:
ML, Austin N, eds. Splinting the Hand and Upper Extremity 384–391.
2560_Chapter 18_0209-0218.indd 218 3/17/2015 4:21:04 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 19
Counseling and Behavior
Modification Techniques
for Functional Loss and
Chronic Pain
AMY HEATH, PT, DPT, OCS
“Believe you can and you are halfway there.”

—THEODORE ROOSEVELT (1858–1919)
Objectives
• Discuss the relationship between chronic pain and depression.
• Compare and contrast the various behavioral theories and their indication for use in a clinical setting.
• Discuss the term “positive psychology” as it relates to the treatment of chronic pain.
• Define the various methods of behavioral modification that may be applicable to the practicing therapist.
Key Terms
• Behavior therapy
• Depression
• Operant therapy
• Positive psychology
emotional, sociological, financial, and environmental

Introduction factors that influence an individual’s perception of pain.
This mulifaceted concept of pain is so well regarded
Chronic pain and its concomitant functional loss that the Commission on Accreditation of Rehabilita-
requires a multimodal approach in management. tion Facilities will accredit pain management facilities
Medical management seeks to resolve or decrease pain only if they have a mental health specialist on staff.1
with medication, surgery, or a combination of both. To complicate the matter further, individuals with
Therapeutic management entails a variety of disciplines chronic pain are often more likely to experience other
working together with the patient to help the patient psychological disturbances, such as depression.
better cope and function with chronic pain. “Counsel- Researchers have spent much money and time
ing” and “behavior management” are umbrella terms investigating the relationship (specifically the temporal
used to describe strategies used by psychotherapy pro- relationship) between depression and chronic pain.
fessionals working with patients with chronic pain. To date, however, theorists have been able only to
It is well documented that pain is more than just a posit models relating the two. These models enlighten
physiological response to a stimulus—pain is an expe- the psychology behind chronic pain and include
rience. Included in this experience are psychological, the cognitive distortion model, in which individuals
219
2560_Chapter 19_0219-0226.indd 219 3/16/2015 4:13:52 PM

Process CyanProcess
YellowProcess Black
experiencing chronic pain have a “cognitive vulnerabil- of pain, it is a unique experience for each individual.
ity” to depression, and the model of learned helpless- Consequently, research about chronic pain may not be
ness, in which individuals with chronic pain feel as specific to peripheral neuropathy but is still valid, reli-
though they cannot control their own outcomes (related able, and informative.
to pain) and they develop an attitude of helplessness.
The behavioral model, which embraces operant thera-
pies as an intervention, presupposes that depression as Behavior Therapy
a function of chronic pain occurs because of one or a
combination of three reasons: (1) There are fewer posi- Psychological treatments are necessary when treating
tive reinforcers, (2) positive reinforcers that do exist patients with chronic pain and the functional loss that
no longer have an impact, or (3) the individual is inca- may result. The question for clinicians providing these
pable of gaining positive reinforcement. As a means treatments is which intervention is more effective or
to encompass components of each of these models, appropriate? Answering this question is where differ-
the chronic pain experience has evolved to capture ences in approaches become apparent. There is evi-
the individual nature of each person’s chronic pain dence to support the use of multiple approaches,
experience.2 but why choose one over the other? Determining the
As is the case with any form of intervention, psy- best course of treatment for a particular individual can
chotherapeutic approaches to chronic pain and func- best be determined by understanding the foundations
tional loss require a skilled professional. The counseling of each approach. In this section, we review multiple
involved with this type of intervention strategy is psychological approaches, beginning with operant
derived from a positive regard for the client’s personal therapy. Operant therapy is an approach designed
experience, emphasizing empathy and respect.3 A thor- to address the gross motor and cognitive/subjective
ough assessment of the individual is required initially. responses to clinical pain (Tables 19-1 and 19-2).4
This assessment can be used to guide treatment, diag- In the late 1960s and early 1970s, Fordyce proposed
nose any other psychological issues such as anxiety or a concept of clinical pain as more than just neurophysi-
depression, and build a rapport with the patient. Within ological responses of the body. Based on Fordyce’s
the context of the assessment, it is critical for therapists earlier works, Sanders4 defined pain as “an interacting
to understand how the patient conceptualizes his or cluster of individualized overt, covert, and neurophysi-
her pain. This information can be ascertained using ological responses capable of being produced by
standardized questionnaires and open-ended interview
questions. Because of the complex nature of pain, ques-
tions may be directed toward personal values. A perti- Table 19-1 Multiple Response Conceptualization
nent example is religiosity. Because some patients may of Clinical Pain
see their pain as a punishment from a higher being, it
is important to understand this information as a part Response Category Examples
of the individual’s pain experience. If religiosity proves Neurophysiological Afferent A-delta and C nerve
to be a component, it is imperative that the professional ascending excitation
addressing these concerns is competent and knowledg- Neurophysiological Hypothalamic, limbic,
able enough to address the issue properly. Standardized supraspinal/cortical somatosensory excitation
questionnaires can also assist in gathering patient
information. The type of questionnaire chosen depends Neurophysiological Efferent autonomic, pyramidal,
descending extrapyramidal nerve excitation
on the function, pain, and outcomes the therapist is
targeting. Neurophysiological Chemical release of β-endorphin
All of the information gathered from the initial chemical and enkephalin neuropeptides
assessment is essential to develop the patient’s treat- Cognitive/subjective Pain is horrible, unbearable, out
ment plan and the psychological approach that will be thoughts of control
used as an intervention. This chapter focuses on several Cognitive/subjective Perceptions of pain, fear/anxiety,
types of psychotherapeutic interventions and the feelings states anger, sadness/depression
research that supports their use. Interventions that Cognitive/subjective Visualizations of being crippled,
include behavioral modification strategies are addressed images having surgery, losing a job
because these are likely to be used in conjunction with
Gross motor verbal Moaning, crying/yelling, pain
other therapies. Most of the research dealing with
complaints
chronic pain does not specifically include chronic pain
from a peripheral neuropathic etiology. However, neu- Gross motor nonverbal Guarding, squeezing, limping,
ropathic pain is similar to chronic pain from other lying down, taking analgesics
origins in its individual chronic pain experiences— Adapted from Sanders SH. Operant therapy with pain patients:
meaning that because of the multidimensional nature evidence for its effectiveness. Semin Pain Med. 2003;1(2):90–98.
2560_Chapter 19_0219-0226.indd 220 3/16/2015 4:13:53 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 19 | Counseling and Behavior Modification Techniques for Functional Loss and Chronic Pain 221
Table 19-2 Primary and Secondary Pain Responses and Antecedent and Consequent Stimuli by Acute and Chronic Pain States
Prevalent Antecedent Stimuli Initiating and Pain Responses Prevalent Consequent Stimuli Maintaining Responses
Maintaining Responses
Acute state Neurophysiological ↓Subjective pain perception
Tissue damage/irritation Gross motor ↓Tissue damage/irritation
Environmental stressors Cognitive/subjective ↓Environmental stressors
Prior conditioned stimuli ↑Social attention
Pain response models
Chronic state Gross motor ↓Or avoid environmental stressors
Environmental stressors Cognitive/subjective ↓Or avoid subjective pain perception
Conditioned/distinctive stimuli Neurophysiological ↓Or avoid drug withdrawal
Pain response models ↑Social attention
Tissue damage/irritation ↑Economic gains
↓Or avoid tissue damage
Adapted from Sanders SH. Operant therapy with pain patients: evidence for its effectiveness. Semin Pain Med. 2003;1(2):90–98.
relevant tissue damage or irritation, and may also be Table 19-3 Impact of Chronic Pain on the Family:
produced and maintained by other antecedent or
Two Dimensions
consequent stimulus conditions.” Operant therapy
addresses these antecedent or consequent stimulus Person With Pain Family Members
conditions.
In the context of clinical pain, the stimulus condi- Pain that does not Inability to see or feel the pain
show
tions that are present before or after pain are behaviors
that can be modified by the individual’s environment Fluctuating activity Increased responsibility for
or the effects of the behavior. Using operant therapy levels maintaining the home and income
techniques, clinicians work to influence and manipu- Isolation Loss of personal support system
late both the environment and the consequences.4 Cli- Lack of interest Emotional outbursts of the person
nicians manipulate the environment and consequences with pain
using rewards and punishments. Appropriate pain
Doubt about the reality Added daily stress
(well) behaviors are rewarded, and “inappropriate” pain of the pain
behaviors are punished. Punishment is often a decrease
in reinforcement from others, whereas well behaviors Loss of job, friends, Loss of plans and hopes for the
promote reinforcement.5 This type of therapy is diffi- and productivity future
cult when one considers the multiple environmental *Adapted from Cowan P, Kelly N, Pasero C, Covington E, Lidz C.
influences and the multitude of consequences that any Family manual. A manual for families of persons with pain. Rocklin,
one pain behavior may elucidate from any number of CA: American Chronic Pain Association; 1998.
individuals. It is precisely because of this that operant
therapies often include the individuals to whom the According to Lewandowski et al.,6 chronic pain can
patient is most closely connected. Family therapies and affect almost all areas of life and results in serious
psychodynamic approaches are often indicated for a consequences for the family because often the indi-
comprehensive plan. The learned behaviors of the individual with pain or functional loss depends emotionally
vidual with pain can be unknowingly (or knowingly) and physically on others resulting in a change in family
reinforced by the individuals involved in the patient’s roles (Table 19-3).
care. The pain behaviors may result in more attention, One of the most difficult aspects of operant therapy
more care, and distraction from other more negative is the patient’s ability to comprehend the goal of treat-
consequences.5 ment. For individuals with chronic pain, it is likely that
With operant therapy, the individual and family and the goal is not to “cure” the pain but to minimize it to
friends learn to identify the less desirable pain behav- “overcome disability and restore function, despite the
iors. The participants are taught to ignore the pain continuation of some pain.”5 Despite the evidence in
behaviors or to navigate another way to acknowledge support of operant therapy, its use is still widely criti-
the pain behavior while reinforcing well behavior.6 cized.6 Most criticism derives from the approach’s
Family therapy is especially beneficial when one con- inherent inability to be standardized. Its individualized
siders the possible change in relationship dynamics approach makes its successes difficult to replicate.
that may result from functional loss or chronic pain. Additionally, it is argued that operant therapy alone is
2560_Chapter 19_0219-0226.indd 221 3/16/2015 4:13:53 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
not as successful as when used in concert with another the neurophysiological, cogntive, and behavioral pro-
therapy, typically cognitive behavior therapy (CBT). cesses, the counselor can “challenge the reality of the
In recent research, operant therapy (or behavior patient’s pain”3 without defeating the patient. The goal
therapy) used in conjunction with CBT has proved to of psychotherapeutic intervention is for the patient to
be the most successful in helping individuals with gain a sense of control over the pain.3 Cognitive
chronic pain. restructuring, reframing, and reconceptualizing are
strategies that can be very beneficial during episodes
when pain levels increase. They can also be used in
Cognitive Behavior Therapy conjunction with other interventions, such as physical
exercise, relaxation techniques, and other behavior
Although the goals in behavior therapies are to decrease modification and self-regulatory strategies for pain
pain behaviors and promote well behaviors, the goal of management.
CBT is to “moderate the demoralizing and potentially Although it may seem counterintuitive, exercise is
depressive experiences of the person in chronic pain often suggested to patients experiencing chronic pain.
and to encourage self-efficacy through psychological As a result of chronic pain, individuals may decrease
and physical behaviors that help enhance treatment their activity as a means to avert the pain. However,
outcomes.”7 CBT is not just one approach to chronic exercise is actually a great way to prevent and overcome
pain management—it is many different interventions physical deconditioning, which serves to complicate
with the goal of affecting an individual’s pain experi- further the neurophysiological aspect of the pain expe-
ence through the alteration of the individual’s pain- rience. It is important that exercise be closely moni-
related thoughts and actions.3 A few of these strategies tored and supervised. Having the patient exercise as
include cognitive restructuring and reframing, develop- opposed to remaining sedentary can assist in demon-
ing skills to problem solve and cope, assertiveness strating that the activity is not causing the patient
training, reinterpretation of the pain experience, anxiety harm but can help him or her feel better.3
defusion, depression management, and other socioen- Exercise is primarily viewed as a physical interven-
viromental interventions.3,7 Similar to behavior therapy tion; however, because of its “feel good” effects, it may
involving operant therapy principles, the rationale also be viewed as an emotional intervention similar to
behind the use of CBT is that the individual’s pain anxiety defusion and depression management. Anxiety
experience is not just neurophysiological but is the and depression are suspect in their relationship to
result of a combination of neurophysiological, gross chronic pain. It is sometimes difficult to determine
motor, and cognitive/subjective factors. which comes first—the emotional issues or the reported
Professionals using CBT as an intervention gener- levels of increased pain. Either way it is essential that
ally work with patients to educate them regarding anxiety or depression or both are addressed in psycho-
factors that influence their perception of pain and therapeutic sessions for chronic pain. Addressing these
helpful coping techniques. Therapists work to teach emotional concerns can also aid in identifying common
patients new ways of responding to pain and often stressors, which can lead to more straightforward
encourage exercise and increased activity levels.3 All of coping schemes.
these strategies may be used with some patients, and Similar to concerns with operant strategies, signifi-
only a few may be used with others. Similar to operant cant consideration of the individual’s socioenvironment
therapy, some people criticize the use of CBT because is part of the CBT approach. Understanding the rela-
of the inability to structure one program to work with tionship dynamics between individuals with chronic
one, if not all, patients with chronic pain. However, pain and their loved ones can provide insight into the
despite this criticism, the outcomes-based research has goals of the patient and what obstacles may stand in
proved this method of therapy to be effective.7 the way of the goals. Current research shows that
For patients with chronic pain, reinterpreting the chronic pain does not just affect the person with pain
pain experience can be extremely beneficial albeit but also affects other loved ones by increasing depen-
challenging. For these people, distinguishing between dency, shame, attention, or fear. All of these emotions
pain, suffering, and pain behaviors gives them an should be managed with sensitivity; understanding
opportunity to identify and name better the culprit of how these emotions manifest themselves in the indi-
their negative experiences. According to Grant and vidual can be criticial to achieving the goals of CBT.
Haverkamp,3 “pain” is the sensation activated by stimu-
lating nociceptors in the nervous system. “Suffering” is
the affective response to the sensory experience, and Alternative Approaches
“pain behaviors” are the actions elicited when people
are suffering. Understanding how these concepts differ CBT and operant therapies are considered under the
is the first step in being able to restructure one’s own umbrella terms “counseling” and “behavior manage-
thoughts. In using language that differentiates between ment” mentioned previously for psychotherapeutic
2560_Chapter 19_0219-0226.indd 222 3/16/2015 4:13:53 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
approaches generally used by licensed professionals for perception of pain and pain behaviors. The use of
patients with chronic pain. In addition to these two family therapy and support groups is advocated for as
major approaches, there are alternative approaches that part of a comprehensive approach to chronic pain man-
can be used, but they are used less frequently. These agement. Family therapy generally includes partners,
strategies are employed less frequently as a result of a children, and caregivers. Within the therapy sessions,
lack of evidence to support their efficacy or a lack of numerous psychotherapeutic approaches can be used,
understanding about how or why the strategy works. including CBT, operant therapy, and positive psychol-
Although literature to support the success of these ogy. The parties are taught in the sessions the skills to
approaches is limited, this section discusses positive identify pain behaviors and, based on the approach
psychology, support groups and family therapies, being used, to respond accordingly.6,7 Support groups
and eye movement desensitization and reprocessing help individuals with chronic pain, and the people in
(EMDR). their lives feel less alone in their chronic pain experi-
Positive psychology is a relatively new area of ence. Support groups can limit an individual’s feeling
growth in the psychological sciences. It is also an of isolation, give the individual an arena to discuss any
umbrella term incorporating many concepts ranging problems he or she may be having, and lead to increased
from an individual’s personality traits, such as positive motivation through social experience.10 Both of these
affect, optimism, hope, and gratitude, to an individual’s strategies can be a significant additive to a more well-
spirituality and social support. Positive psychology is rounded approach to chronic pain management.
the scientific attempt at a greater understanding of how The final alternative approach reviewed here is
these concepts affect an individual’s personal health— EMDR, an intervention that is designed to “bring the
specifically, for our purposes, how the concepts of client into a more adaptive cognitive and emotional
having a sense of coherence, self-efficacy, positive affect, state.”11 The rationale supporting the use of EMDR is
optimisim, hope, gratitude, spirituality, and social that chronic pain contains physical, cognitive, and
support help an individual with chronic pain and the emotional experiences. EMDR can work to address
supporting rationale.7,8 and reprocess these experiences to allow patients to
The goal of positive psychology is to decrease nega- cope better with the pain. Using EMDR requires a
tive depressive symptoms by increasing emotions to trained clinician to guide the individual. The steps for
which individuals can respond in a positive sense.9 EMDR include focusing on the first pain event, pain
Depressive symptoms frequently appear in concert sensations, or other pain-related distressing experi-
with chronic pain sypmptoms.2 Researchers theorize ences. At this point, the clinician uses bilateral auditory,
that positive psychology has a helpful effect as a result visual, or tactile sensory stimuli to decrease the inten-
of biological, behavioral, or social processes.8 From a sity of the initial event, pain sensations, or other experi-
neurobiological perspective, it is understood that posi- ences. Next, the biliateral stimulation is used to
tive psychology may affect the neuroendocrine and strengthen positive responses, such as increased relax-
immune systems. Behaviorly and socially, positive psy- ation or decreased pain, as a means for the individual
chology may affect how a person can prevent serious to reprocess the experiences himself or herself.11
health issues and promote greater participation in his These alternative approaches to chronic pain man-
or her own rehabilitation processes.8 Individuals with agement in addition to the typical psychotherapeutic
chronic pain who possess a positive psychological well- interventions may prove to help patients cope with
being may be better prepared to deal with their chronic their pain more readily as well as move forward in their
pain.7 Interventions that have been suggested for use ability to function within their societal role. None of
but that are still in the infancy stage with regard to these approaches have been proven to be better than
evidence ask individuals to identify their own stengths, the other, and, generally speaking, they are probably
their “blessings,” and three doors that have opened as most successful when used together. There is no clear-
a result of their experience. Additionally, patients are cut approach to working with an individual with
encouraged to savor enjoyable activities in the hope chronic pain—there are many factors to consider and
that their positive psychological well-being will increase many strategies with which to work.
to manage and deal better with their chronic pain.7
In positive psychology, patients who perceive that
they have a social or familial support system are often Behavior Modification Strategies
best able to manage their pain behaviors and continue
to function with their impairment. As stated previously In addition to psychotherapeutic approaches, multiple
in this chapter, when an individual experiences chronic behavioral modification strategies exist that can be
pain, the pain does not just affect the individual’s life employed to assist individuals with chronic pain. These
but also affects the lives of the people around him or behavior modification strategies in particular are often
her. There may be a change in the dynamic and func- used in conjunction with the counseling approaches
tion of relationships as a result of the individual’s discussed previously.
2560_Chapter 19_0219-0226.indd 223 3/16/2015 4:13:53 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Relaxation training can encompass multiple strate- to support the notion that general relaxation tech-
gies. It is also one of the most common techniques used niques, without the use of biofeedback, can be equally
to help individuals manage their pain.3 According to effective.3,12
Grant and Haverkamp,3 “… relaxation techniques can The final behavior modification technique discussed
include deep breathing, progressive muscle relaxation, in this section is activity planning and exercise. As
relaxing imagery, cue-controlled relaxation, autogenic mentioned previously, it may seem counterintuitive to
relaxation, or hypnosis.” In addition to the sheer individuals with chronic pain to increase their activity
number of relaxation techniques that exist, the number levels or exercise, but there is empirical evidence to
of theories attempting to explain their use and success support that doing so can have multiple positive
also contribute to their dominant presence within the effects.3 The exercise and increased activity levels should
treatment of chronic pain. Arena12 reported that there be supervised by a health care clinician with the skill
are three primary theories explaining why relaxation set to do so. Increasing activity levels and exercise can
strategies are effective. One theory states that with move the individual to a greater understanding of his
chronic pain comes an increase in stress on an indi- or her body as well as the understanding that activity
vidual’s body. If the individual can learn how to control is not causing any increase in tissue damage despite
the stress by using relaxation strategies, the individual what the pain experience may be. Additionally,
can help to decrease his or her own pain. The second increased activity and exercise can prevent further
theory states that increased muscle tension is a con- deconditioned states, which may serve to complicate
tributing factor to most pain, and if an individual can the initial diagnosis of chronic pain.3
use relaxation techniques to decrease muscle tension, If increased activity or exercise is out of the question,
the individual should be able to decrease his or her then, at a minimum, individuals with chronic pain
pain. Finally, the third theory states that individuals should be educated to plan their activities. An indi-
with chronic pain have sympathetic nervous systems vidual experiencing chronic pain often has times of the
that are “stuck” in a flight-or-fight response. Given the day that are worse than others, or there may be certain
appropriate relaxation strategy, the individual may be situations that may cause an increase in pain behaviors.
able to “unstick” himself or herself from this sympa- Allowing individuals to understand and appreciate
thetic nervous system response and decrease his or her these nuances of their own pain experience can lead
pain.12 In combination with other strategies, research them to make better decisions about the timing of their
has shown that relaxation techniques are helpful in activities. For instance, for a particular individual, if the
controlling chronic pain experiences. pain experience is worse in the mornings than in the
Whichever technique is used, one of the keys to evening, it would be important for that individual to
success with this specific intervention is whether or not perform more rigorous activities in the morning when
the patient can generalize the strategy to appropriate he or she is feeling better, leaving the less rigorous
situations outside of the clinic or facility. A patient may activities for the evening.
be able to enact a relaxation strategy in the controlled All of these behavior modification strategies may be
environment of a health care professional’s office. employed with most, if not all, individuals with chronic
However, being able to identify stressors in day-to-day pain. However, to facilitate the most success, the behav-
activities and apply the appropriate relaxation tech- ior modification strategies should not be used in isola-
nique to decrease pain is a difficult task. The task of tion. Instead, incorporating the behavior modification
learning how to generalize can be overcome by practic- strategies in with one (or more) of the psychotherapeu-
ing the technique in different situations.12 tic interventions is likely to provide the most support-
Another behavior modification strategy is biofeed- ive environment to control pain and support a return
back. Similar to other psychotherapeutic techniques, to function for a patient with chronic pain.
biofeedback can be used in conjunction with relaxation
techniques. Biofeedback is used to draw the patient’s
attention, via auditory, visual, or tactile stimulation, to Research
increased stress levels and muscle tension. By drawing
the attention of the individual to these issues, the hope In 1999, Morley et al.13 published a systematic review
is that the individual can work to decrease the stress and meta-analysis of randomized controlled trials in
levels or muscle tension, generally by executing an which CBT and behavior therapy (operant therapy and
additional technique such as one of the psychothera- relaxation training) were used as interventions for all
peutic interventions or a relaxation intervention.12 forms of chronic pain, excluding headaches. In 2001,
Despite the usefulness of biofeedback in drawing an Van Tulder et al.14 published an additional systematic
individual’s attention to areas of issue, there is some review of trials in which behavioral treatments were
concern about its applicability because of its added employed for patients with chronic low back pain. As
expense and the fact that the individual must be trained is the case with most systematic reviews and meta-
to use it appropriately. Additionally, there is evidence analyses, there were many outcome measures used to
2560_Chapter 19_0219-0226.indd 224 3/16/2015 4:13:53 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
capture what the original reasearchers intended to use patient’s pain experiences must direct the interventions
as an objective measurement of pain, function, or well- and treatment planning.
being. Similarly, the interventions within the original Although the research used to support the practice
research included a variety of techniques, often used in of psychotherapeutic interventions with patients expe-
combination. Appreciating these caveats, it seems riencing chronic pain is generally based on patient
exceptional that the authors of the systematic reviews populations without peripheral neuropathy, the evi-
and meta-analyses were able to come to any conclusion dence is compelling and is difficult to refute, even for
at all. However, after grouping and organizing inter- this specific population. The systematic reviews and
ventions and outcome measures, their conclusions meta-analyses all support the use of some sort of psy-
were the same—psychological intervention, regardless chological approach. The pain literature has advanced
of the approach, results in better outcomes for indi- to encompass the idea of the “pain experience” for
viduals compared with individuals who were placed individuals with chronic pain, including physical, emo-
on a waiting list and did not receive psychological tional, and cognitive elements. Even without the
intervention.15 support of empirically based research, heuristically it is
Following the work of Morley et al.13 and Van easy to identify and understand how managing chronic
Tulder et al.,14 McCracken and Turk16 published a lit- pain and the range of symptoms that come with it
erature review, which indicated that combining behav- would be best done with a multimodal approach.
ior therapy and CBT also produces positive effects for Despite the overwhelming support of psychological
all types of chronic pain, not just chronic low back pain. intervention, some people argue against its use. These
Hoffman et al.15 published a meta-analysis of psycho- arguments come from an inability to standardize the
logical interventions for patients with chronic low back psychotherapeutic intervention and the idea that not
pain. Their conclusions further supported the initial everyone will benefit from the same type of interven-
conclusions of Morley et al.13 and Van Tulder et al.,14 tion. In this chapter, we discuss many different
reporting that psychological interventions can reduce approaches to inform professionals who are working
self-reported pain levels, pain-related interference, with this patient population. As the controversy dem-
depression, and disability and can increase health- onstrates, one approach is not going to work with all
related quality of life for patients with chronic low patients. Instead, the professionals managing the care
back pain. of individuals with chronic pain are responsible for
In addition to information regarding behavior knowing what alternatives there are and understanding
therapy, CBT, relaxation training, and biofeedback is the differences and distinctions between them—most
empirical research supporting the efficacy of positive likely using several approaches with one patient.
psychology for patients with chronic pain. Rasmussen, The chronic pain experience is multidimensional,
Scheier, and Sieier16 conducted a meta-analysis review- and it is the clinician’s responsibility to understand
ing how optimism affected the outcome measures used these dimensions and intervene with appropriate strat-
in the the original research. In all domains, optimisim egies. In deciding which strategies to use with a patient
had positive predictive capabilities with regard to with chronic pain, it is essential to perform a thorough
health outcomes, offering additional support to the history and initial assessment. This is a critical part of
argument that chronic pain should be addressed with the care of all patients, particularly patients with chal-
a multimodal approach. lenging diagnoses such as chronic pain. This first step
Despite the fact that few empirical data come from in the process is key to successful treatment planning
a patient population with chronic pain secondary to and should be valued as such. During this initial assess-
peripheral neuropathy, reviewed collectively, the body ment, the clinician can use his or her knowledge of
of literature supporting psychotherapeutic intervention different models of pain processing to interpret which
for patients with chronic pain offers a strong argument intervention is most appropriate. The initial assessment
for clinicians working with these patients regardless of also gives the clinician an opportunity to build trust
the etiology of the pain. Similarly, that these psycho- and a relationship with the patient as well as the oppor-
therapeutic interventions should be viewed as dynamic tunity to explain the process of psychotherapeutic
as opposed to static is implied by the reviewed litera- interventions. Building and maintaining trust is an
ture. As much of the literature implies, there is no essential component to working with patients with
clear-cut, straightforward approach to working with a chronic pain.
patient experiencing chronic pain. As a result, the best
approach to intervention is to start with one approach
keeping in mind applications for other approaches
throughout the treatment. Using appropriate outcome
CASE STUDY
measures can be beneficial in helping to direct the Mary is an 82-year-old woman with chronic mid-back
course of treatment, as can a thorough assessment and pain. She was diagnosed with osteoporosis 5 years
reassessment process. Invariably the patient and the ago, and she fell last year with a resultant compression
2560_Chapter 19_0219-0226.indd 225 3/16/2015 4:13:53 PM

Process CyanProcess
YellowProcess Black
fracture of T12. Mary remains in chronic pain despite 5. The aberrant learned pain behaviors of people with
two courses of physical therapy and two attempts at chronic pain are reinforced by which of the
vertebroplasty. She estimates her pain to be 6/10 at following?
rest and 9/10 with ambulation. She walks functional a. The hardwiring of these behaviors into the cerebral
distances (i.e., 30 feet) with a rolling walker. She cortex
requires moderate assistance with dressing and bathing b. The behavior of the family
because of her pain. She can no longer travel to visit c. Medication
her children and has all but eliminated going out d. Behavioral therapy
socially with her husband. She spends most of her day
in a recliner watching television. She is unable to take
anti-inflammatory medications because of her References
anticoagulant therapy. She uses a topical narcotic 1. Lebovits AH. Psychological interventions with pain patients:
patch over her back that affords “a bit of relief.” evidence for their effectiveness. Semin Pain Med. 2003;1(2):
25–37.
2. Banks SM, Kerns RD. Explaining high rates of depression in
chronic pain: a diathesis-stress framework. Psychol Bull. 1996;
Case Study Questions 119(1):95–110.
3. Grant LD, Haverkamp BE. A cognitive-behavioral approach
1. Mary’s husband is encouraging Mary to return to
to chronic pain management. J Couns Dev. 1995;74:25–32.
physical therapy for a supervised exercise program. 4. Sanders SH. Operant therapy with pain patients: evidence for
Based on the literature, exercise may benefit a its effectiveness. Semin Pain Med. 2003;1(2):90–98.
patient with chronic pain for which of the following 5. Benjamin S. Psychological treatment of chronic pain: a
reasons? selective review. J Psychosom Res. 1989;33(2):121–131.
6. Lewandowski W, Morris R, Burke Draucker C, Risko J.
a. Exercise may prevent disuse atrophy of postural
Chronic pain and the family: theory-driven treatment
muscles. approaches. Issues Ment Health Nurs. 2007;28:1019–1044.
b. Exercise may assist with pain control through the 7. Farrugia D, Fetter H. Chronic pain: biological understanding
expression of endorphins. and treatment suggestions for mental health counselors.
c. Exercise has a direct relationship to the quality of J Ment Health Couns. 2009;31(3):189–200.
8. Aspinwall LG, Tedeschi RG. The value of positive psychology
sleep.
for health psychology: progress and pitfalls in examining the
d. All of the above relation of positive phenomena to health. Ann Behav Med.
2010;39:4–15.
2. For patients with chronic pain, operant therapy is
9. Seligman ME, Rashid T, Parks AC. Positive psychotherapy.
best defined as which of the following? Am Psychol. 2006;61:774–788.
a. Operant therapy is an approach designed to 10. Arthur AR, Edwards C. An evaluation of support groups
address the gross motor and cognitive/subjective for patients with long-term chronic pain and complex
responses to clinical pain. psychosocial difficulties. European Journal of Psychotherapy,
Counselling and Health. 2005;7(3):169–180.
b. Operant therapy is a behavioral therapy used to
11. Grant M, Threlfo C. EMDR in the treatment of chronic
improve risk factor modification. pain. J Clin Psychol. 2002;58(12):1505–1520.
c. Operant therapy is a cognitive therapy to improve 12. Arena JG. Chronic pain: psychological approaches for the
knowledge of the etiology of pain. front-line clinician. J Clin Psychol. 2002;58(11):1385–1396.
d. None of the above 13. Morley S, Eccleston C, Williams A. Systematic review and
meta-analysis of randomized controlled trials of cognitive
3. Examples of manipulating the environment to behavior therapy and behavior therapy for chronic pain in
decrease chronic pain include which of the adults, excluding headache. Pain. 1999;80(1–2):1–13.
14. Van Tulder MW, Ostelo R, Vlaeyen JW, Linton SJ,
following?
Assendelft WJ. Behavioral treatment for chronic low back
a. Maintaining the home at a comfortable pain: a systematic review within the framework of the
temperature Cochrane Back Review Group. Spine (Phila Pa 1976). 2001;
b. Limiting ambient noise such as turning down the 26(3):270–281.
telephone ringer and the television 15. Hoffman BM, Papas RK, Chatkoff DK, Kerns RD. Meta-
analysis of psychological interventions for chronic low back
c. Purchasing a stair lift rather than ascending steps
pain. Health Psychol. 2007;26(1):1–9.
by crawling 16. Rasmussen H, Scheier MF, Greenhouse J. Optimism and
d. All of the above physical health: A meta-analytic review. Ann Behav Med.
2009;37:239–256.
4. The depression and anxiety associated with chronic
pain may be effectively treated with which of the
following modalities?
a. Exercise
b. Medication
c. Talk therapy
d. All of the above
2560_Chapter 19_0219-0226.indd 226 3/16/2015 4:13:54 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
SECTION FIVE
Special Considerations
Chapter 20
Guillain-Barré Syndrome
MEGAN MULDERIG, PT, DPT, NCS
“Through my illness I learned rejection. I was written off. That was the
moment I thought, okay, game on. No prisoners. Everybody’s going down.”
—LANCE ARMSTRONG (1971–)
Objectives
• Discuss possible etiologies of Guillain-Barré syndrome (GBS).
• Discuss the clinical presentation and variations of GBS.
• Develop an evaluative algorithm for individuals with GBS.
• Discuss treatment options for individuals with GBS.
Key Terms
• Guillain-Barré syndrome
• Inflammatory demyelinating polyradiculopathy
pathology of GBS is understood, and effective treat-

Introduction ment methods are available.
GBS is an autoimmune disease that typically is pre-
Guillain-Barré syndrome (GBS) is a relatively ceded by an acute bacterial or viral infection. Although
common acute form of peripheral neuropathy in which the exact cause is unknown, GBS has been shown to
the body ’s immune system suddenly and rapidly attacks be preceded frequently by a respiratory infection or
the peripheral nervous system. More specifically, the stomach virus. In rare cases, GBS may manifest in a
pathology is an inflammatory demyelinating polyra- patient after receiving certain vaccinations. GBS can
diculopathy, a consequence of inflammation of periph- be identified by various degrees of ascending weakness,
eral nerves and spinal nerve roots. GBS most commonly sensory abnormalities, diminished or absent reflexes,
affects the myelin sheaths, but in severe cases, the axons and autonomic dysfunction, all of which occur sym-
are also damaged.1 The exact mechanism by which the metrically and evolve rapidly. GBS often emanates
immune system is attacked is unclear; however, the in the legs, and the associated pain, weakness, and
227
2560_Chapter 20_0227-0238.indd 227 3/16/2015 4:14:00 PM

Process CyanProcess
YellowProcess Black
228 Section Five | Special Considerations
paresthesia can spread quickly to the arms and face patient with GBS so that the patient can achieve
depending on the severity of the disease in a particular optimal functional ability and return to his or her pre-
patient. On average, the disease achieves its most severe morbid quality of life. A patient with GBS presents
neurological state (i.e., its nadir) within 8 days; however, myriad challenges to a clinician because of the com-
the nadir must occur during a period of less than 4 prehensive effect of GBS on body structure and func-
weeks to satisfy the diagnostic criteria of acute GBS.2 tion, activity limitations, participation restrictions,
In the event that symptoms continue to progress environmental factors, and the patient ’s quality of life.
beyond a 4-week period, the diagnostic focus shifts A coordinated approach by all members of the health
from acute GBS to a more chronic form of inflamma- care team providing treatment to the patient is essen-
tory neuropathy known as chronic inflammatory tial to ensuring that the patient achieves a full func-
demyelinating polyneuropathy (CIDP). GBS requires tional recovery.
hospitalization for early recognition and treatment.
The diagnosis of GBS is clinically based; however,
the diagnosis is typically supported by laboratory and Epidemiology
electrophysiological testing to rule out more esoteric
neuropathies. Specific criteria have been established for The annual incidence of GBS is about 1 to 2 per
the diagnosis of GBS.3 It is a syndrome divided into 100,000 persons and is equally dispersed worldwide.6
several subtypes. Consideration of motor, sensory, Lower rates have been reported in children younger
cranial nerve, and autonomic involvement is important than 16 years old, about 0.6/100,000 per year.6 GBS
in differentiating between other neurological diagnoses does not affect a particular race or socioeconomic class
and the following GBS subtypes2,3: more frequently, and its occurrence has not changed
significantly over many years.48 It affects persons of all
● Acute inflammatory demyelinating
ages, although a literature review published in 2009
polyradiculoneuropathy
noted that GBS was most common in elderly adults.6
• Most common—85% of cases
Another study reported that GBS is more common
• Characterized by primary demyelination of
among adults between 30 and 50 years old.7 Men and
sensory and motor nerves
women are equally affected.8 No genetic predisposition
● Acute axonal motor neuropathy and acute
to GBS has been found, and there is no suggestion that
axonal motor and sensory neuropathy
the disease is communicable.9 Age at onset affects mor-
• 5% to 10% of cases
bidity and the setting to which the patient is dis-
• Axonal degeneration with motor or motor
charged after an acute care stay.5 When GBS is
and sensory involvement
diagnosed in individuals younger than age 50, these
• Poorer prognosis with motor and sensory
individuals are most often discharged to home; indi-
symptoms
viduals between 51 and 75 with a new diagnosis of
• Increased frequency of respiratory and bulbar
GBS are most often discharged to a rehabilitation
symptoms
setting or skilled nursing facility. Of patients, 80% are
● Miller-Fisher syndrome
ambulatory 6 months after diagnosis.5 Mortality rates
• 5% of cases
are 3% to 10%, and mortality is most prevalent when
• Rare, more focal form of GBS
GBS is diagnosed in individuals older than age 75.5
• Characterized by areflexia, ataxia, and
Approximately two thirds (40% to 70%) of patients
ophthalmoplegia
with GBS have a preceding infection, which is often
• Symptoms also may include facial weakness,
experienced about 4 to 6 weeks before diagnosis.6,11 The
bulbar signs, ptosis, and pupillary defect
most common preceding infection (up to 70%) is an
GBS is the most common cause of acute nontrau- upper respiratory infection, followed by inflammation
matic neuromuscular paralysis in the world and is a of the stomach or intestines (6% to 26%).6 A preceding
leading cause of disability in the United States.2,4 It infection occurs more frequently in children who
often results in residual effects that influence quality of develop GBS, with a 67% to 85% incidence rate; upper
life, such as pain, fatigue, and emotional disturbances respiratory infection is most common, followed by gas-
for 3 to 6 years after diagnosis.5 The introduction of trointestinal infection.6 In a literature review, no sig-
treatment via immunotherapy has affected how the nificant incidence was found with regard to seasonal
disease is managed and has had a positive influence on occurrence.6 Viruses associated with development of
the functional outcomes of patients with GBS. GBS are cytomegalovirus and Epstein-Barr virus.6 Flu
Rehabilitation of a patient with GBS can be influ- vaccines and HIV have been implicated more recently.12
enced positively by a clinician who is educated about Less than 2% to 3% of individuals who develop GBS
the pathology, effects, and complications of the disease. recently underwent surgery or experienced trauma.2
Overall, the clinician plays an important role in the The reason why some individuals develop GBS and
management of symptoms and rehabilitation of a others do not is unknown, as is the reason why the
2560_Chapter 20_0227-0238.indd 228 3/16/2015 4:14:01 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 20 | Guillain-Barré Syndrome 229
severity of the disease varies among individuals. There Table 20-1 Clinical Diagnostic Indicators for
has been discussion about a connection between vac-
Guillain-Barré Syndrome
cines and GBS in susceptible individuals.11 It is under-
stood that vaccines influence the immune system to Weakness Progressive motor weakness in
produce immunity. Although the etiology of GBS is more than one limb
unknown, it is possible that a vaccine may stimulate Symmetrical weakness pattern
the immune system in a way that triggers an Areflexia
autoimmune-like disease process. There is not suffi- Progression of May continue for 2–4 weeks
cient evidence at the present time to conclude that Symptoms
vaccines are a cause of GBS.13 The discussion arose as
Electrodiagnostic Nerve conduction slowing or block
a result of a slight, but statistically significant, increase
Features Reduced conduction velocity in two
in the incidence of GBS after the H1N1 (swine flu) or more nerves
vaccines in 1976.11,14 Since 1976, studies of vaccines for
influenza have found little to no risk for GBS.11,14 Cerebrospinal Fluid Elevated protein
Preliminary examination of data by the U.S. Centers Adapted from Asbury AK, Arnason B, Karp HR, McFarlin DE. Criteria
for Disease Control and Prevention after H1N1 vac- for diagnosis of Guillain Barré Syndrome. Ann Neurol. 1978;3:
cination in 2009 showed risk similar to that after sea- 565–566.
sonal influenza vaccination (<1 case of GBS per 1
million vaccinations) and incidence much less than the
incidence after the H1N1 vaccination in 1976.15 Vac-
cines aid in preventing the spread of disease and Table 20-2 Clinical Diagnostic Indicators Supporting a
improving disease survival rate across the world, and Diagnosis Other Than Guillain-Barré Syndrome
the benefits of them far outweigh the small risk for
developing GBS. It is recommended that patients in Weakness Nonprogressive acute motor
the acute phase of GBS and for up to 1 year after onset weakness
Asymmetrical weakness pattern
not receive vaccinations.13 Patients with a history of
Hyperreflexia
GBS should be evaluated on an individual basis and
caution should be exercised when determining whether Upper Motor Signs Positive Babinski or clonus
a future vaccine is necessary.15 Additional, more defini- Spasticity
tive research is needed in this area.13 Bowel and Bladder Dysfunction of bowel or bladder
Sensory Symptoms exclusive to sensory
impairment
Clinical Presentation and Diagnosis Adapted from Asbury AK, Arnason B, Karp HR, McFarlin DE. Criteria
for diagnosis of Guillain Barre Syndrome. Ann Neurol. 1978;3:
According to most resources, GBS is classified as a 565–566.
syndrome, rather than a disease, because there is no
evidence of GBS having a specific cause. A syndrome
is characterized by a group of clinically based symp-
toms and laboratory test results without an identifiable may reveal distinct hyporeflexia instead (Tables 20-1
cause. Arriving at a diagnosis of GBS is difficult because and 20-2).3
of variability of presenting signs and symptoms. To A complete electrodiagnostic examination is critical
make an accurate diagnosis, physicians rely on signs to establish the pathology of GBS and to understand
and symptoms along with results of electrophysiologi- the degree of axonal damage.3 Nerve conduction veloc-
cal and laboratory tests. A thorough history and evalu- ity (NCV) studies are most supportive of the diag-
ation should include length of time that symptoms nosis of GBS, especially in the initial stages, because
have been present and discussion of any previous infec- they detect demyelination early in the disease process.4
tions. Laboratory testing includes an evaluation of Electromyography ascertains the integrity of the motor
cerebrospinal fluid via lumbar puncture. Typically, units. The motor portion of the NCV test is found to be
testing shows that individuals with GBS have elevated abnormal in 90% of patients with GBS approximately
protein in the cerebrospinal fluid. 2 weeks after symptom onset and is indicative of an
Two specific features are required for diagnosis of evolving manifestation of the syndrome.3 In the first
GBS—areflexia and progressive motor weakness of 2 to 3 weeks after onset of the most common form of
one limb.3,16 The motor weakness can vary from a mild GBS, acute inflammatory demyelinating polyradiculo-
form in the lower extremities to complete paralysis neuropathy, demyelinating polyneuropathy is the prev-
of all four extremities and the trunk as well as the alent finding, and axonal degeneration is secondary.3
facial and respiratory muscles.3,16 Typically, areflexia is NCV studies, specifically motor NCV, are the most
widespread throughout the limbs; however, mild forms reliable predictor of prognosis when done 4 to 6 weeks
2560_Chapter 20_0227-0238.indd 229 3/16/2015 4:14:01 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
after symptom onset because the features of the syn- management of GBS. PE is a process that involves
drome are clearer at this time.3,4 Common features for removing blood from the body, separating plasma from
confirming the diagnosis of GBS include reduced con- blood cells for treatment to remove disease-causing
duction velocity, conduction block, abnormal temporal antibodies, and returning blood to the body along with
dispersion, prolonged distal latencies, and prolonged or a replacement for plasma and a small concentration
absent F waves and H reflexes.3 The conduction block of albumin to replace protein that may have been lost.17
and temporal dispersion frequently occur at sites of The process is performed on consecutive days for a
entrapment—in the peroneal nerve between the ankle period typically not greater than 5 days.17 A 2010
and fibular head, median nerve between wrist and Cochrane review concluded that PE is more effective
elbow, or ulnar nerve between wrist and elbow.3 In than no treatment and should be started within 2
the primary axonal form of GBS, the primary finding weeks of symptom onset.17 In mild, moderate, and
is decreased muscle action unit potential of a distally severe cases of GBS, up to four sessions of PE have
stimulated nerve, excluding all the aforementioned resulted in a meaningful reduction in the length of
findings of a demyelinated nerve.4 time between nadir and a patient ’s recovery of ambula-
tion without an assistive device.17 These same plasma
treatments also have shown a diminishment in the
Medical Management length of time between nadir and a patient ’s full recov-
ery of strength.17 Research supports the use of PE to
and Treatment lessen the time patients spend on artificial ventilation
and to minimize the residual effects 1 year after diag-
After GBS is diagnosed, immediate medical manage- nosis.17 However, the complex process involved in PE
ment in an acute care hospital is crucial because of the poses a risk for patients who are hemodynamically
risk of symptom progression to a life-threatening unstable; for that reason, medical professionals looked
degree. The care of patients with GBS requires the for another, safer treatment option.
expertise of physicians, nurses, and rehabilitation spe- IVIG therapy is a medical treatment commonly
cialists because morbidity and mortality are closely used to treat autoimmune diseases such as GBS, pedi-
related to the quality of medical management that atric HIV, and CIDP. It consists of intravenous admin-
occurs early in the disease process. Treatment of istration of purified antibodies (immunoglobulins)
primary symptoms and prevention of secondary com- taken from third-party human blood specimens to
plications is the main focus in the acute phase. Three replace antibodies that a patient ’s compromised auto-
phases of GBS typically occur: First, worsening of immune system is unable to produce.1 The immuno-
symptoms to the point of nadir; second, a plateau phase globulins are administered intravenously in high doses
where function remains the same; and third, improve- for 5 days.1 The goal of the treatment is to fight and
ment of function and recovery. Respiratory and circula- prevent further infection.1 IVIG has been shown to
tory problems are the most frequently seen acute speed recovery as effectively as PE when initiated
complications. Patients are commonly admitted to the within 2 weeks of onset of motor symptoms.1 One
intensive care unit (ICU) in the early phase for moni- study showed added benefit when IVIG was combined
toring of respiration and vital signs in the event that with corticosteroids; additional research is necessary to
mechanical ventilation is needed. Because relapses may establish the benefit of these therapies when com-
occur in patients with a more severe course of the bined.1 A combination of IVIG and PE has been
disease, it is crucial for regular neurological evaluations explored as a treatment option for GBS, but it has been
to be done in acute care as well as in the inpatient determined that there is no added benefit.1 When
rehabilitation setting.2 compared with PE, IVIG was determined to be
There is no cure for GBS. Medical management safer, easier to administer, and associated with fewer
focuses on reducing symptoms and attempting to complications, and so IVIG is usually the first treat-
attenuate the patient ’s period of recovery to the extent ment, as determined by physicians, used after GBS is
possible.16 Pharmacological interventions have been diagnosed.1
found to be effective in accelerating recovery and The initial theory behind treatment with corticoste-
reversing nerve damage compared with supportive roids is that they reduce overall inflammation and
treatments alone.17 The most popular pharmacological decrease nerve damage. A 2010 Cochrane review found
treatments are plasmapheresis and intravenous immu- moderate evidence that treatment with steroids alone
noglobulin (IVIG) therapy. Corticosteroids previously does not influence recovery and does not affect the
were thought to be useful; however, there is little evi- future long-term functional outcome.18 Evidence of
dence to support this, and their use is no longer a poor quality suggests that oral corticosteroids may
standard of practice for GBS treatment. postpone recovery.18 Because corticosteroids have not
Plasmapheresis, or plasma exchange (PE), was been shown to have a beneficial effect, they are not
the first treatment known to be effective in the currently used to treat GBS.18
2560_Chapter 20_0227-0238.indd 230 3/16/2015 4:14:01 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
cardiac arrhythmias, diaphoresis, and gastrointestinal
Clinical Implications difficulties.21–23 Symptoms can last throughout the
acute care as well as the rehabilitation stay; it is impor-
Patients with GBS may experience multiple complica-
tant for vital signs to be closely monitored and for any
tions. These complications contribute to prolonged
abnormalities to be communicated immediately to the
recovery time; extended time needed in rehabilitation;
physician.2 Bowel and bladder dysfunction (e.g., con-
and increased restrictions placed on participation in
stipation) is addressed by the physician and improves
family, work, and societal roles.19 Medical and rehabili-
with a consistent continence program; these symptoms
tative management of typical complications are dis-
resolve early in the recovery process.19 Monitoring of
cussed here.
autonomic dysfunction occurs in the ICU and acute
care settings; however, in the rehabilitation and outpa-
Cardiovascular and Respiratory Compromise
tient settings, physical therapists are responsible for
As a result of the loss of peripheral innervation to the monitoring blood pressure and heart rate regularly.
muscles of respiration as well as problems with sup- This monitoring is especially important during changes
porting the airway because of bulbar weakness, one of position from supine to sit and sit to stand as well
third of patients with GBS experience difficulty breath- as after static or dynamic upright activity, such as
ing independently and respiratory restriction.2,8 Respi- walking and activities of daily living (ADLs). Ortho-
ratory complications, most commonly pneumonia, are static hypotension is a common complication second-
associated with morbidity and mortality.20 Artificial ary to autonomic dysfunction and decreased muscle
ventilation is needed in about 50% of cases, typically tone of the lower extremities. There is conflicting evi-
more severe cases of GBS, to maintain a properly func- dence about orthostatic hypotension and whether it
tioning airway.8 The need for ventilatory support is completely resolves during recovery or remains as part
correlated with cranial nerve dysfunction, autonomic of residual disability; however, more research is needed
dysfunction, prolonged immobility, and longer lengths in this area.17,18 When a patient with GBS presents
of stay in the acute care and rehabilitation settings.2 It with dysautonomia, rehabilitative goals should include
is also closely associated with morbidity and mortality. education of the patient and family on effective ways
The risk for aspiration increases in patients with cranial to manage the process, including the reason for use of
nerve involvement secondary to weakness of swallow- compression garments (abdominal binder and antiem-
ing muscles. Patients are weaned from ventilation when bolism compression stockings) and the importance of
strength and lung function have improved. maintaining sufficient hydration.19 To improve toler-
Assessment and intervention by physical therapists ance to the upright position gradually and to assess the
is an important part of the recovery for the cardiore- response from the respiratory, cardiovascular, and auto-
spiratory system. Goals of physical therapy are to nomic systems after prolonged immobility, physical
stimulate clearance of pulmonary secretions, optimize therapists use a tilt table during treatment sessions.19
oxygenation, and reduce the energy expenditure of
breathing. These goals are accomplished with postural Muscle Weakness
drainage, chest percussion techniques, cough stimula- Individuals with GBS often present with weakness and
tion, cough assistance, and inspiratory training.2 Over- flaccid or hypotonic extremities and trunk.2 Weakness,
fatiguing of respiratory muscles should be avoided leading to immobility, is one of the most disabling
because this may induce respiratory failure.2 Respira- symptoms of GBS. Very little research exists to deter-
tory rate and oxygen saturation should be closely mon- mine the effect of muscle strength training in patients
itored during exertion and upright activity, especially with GBS, and there is no evidence to compare and
in the acute care setting while the ventilator is being contrast interventions or to support an effective course
weaned and in the rehabilitation setting when exercise of physical therapy. Assumptions have been made
tolerance is progressing. based on strength and conditioning research done on
patients with other polyneuropathies as well as normal
Autonomic Dysfunction subjects. The main precaution to be discussed here
Dysautonomia reportedly occurs in about 60% to 70% involves avoiding overworking muscles to prevent or
of patients with GBS.21 Clinically, dysautonomia can reduce recurrence or worsening of symptoms.
manifest as a minor disruption or as a life-threatening Strengthening exercises should avoid overworking
complication related to morbidity and mortality. the muscles to the point of fatigue.19 Evidence exists
Patients who present with a more severe form of to support the theory that overworking the motor unit
GBS (up to 20% of patients) and require mechanical may delay recovery.2 There is anecdotal evidence to
ventilation are at higher risk for developing severe dys- support the belief that overworking muscles may lead
autonomia.2 Dysautonomia most often manifests as to relapse of weakness and delayed recovery.23 It is
tachycardia, but symptoms may also include blood believed that intact motor units are at risk for being
pressure instability such as orthostatic hypotension, overworked.
2560_Chapter 20_0227-0238.indd 231 3/16/2015 4:14:01 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
The effect produced by GBS on the peripheral to guide our understanding of the effect of exercise on
nerves leads to an impairment of the ability of the this pathological state.
motor unit to distribute signals and engage muscle
fibers to produce a force and a muscle contraction.23 Pain and Sensory Dysfunction (Dysesthesia)
Because of injury to the myelin or axons or both, weak- Most patients with GBS report pain as a disabling
ness occurs that results from the accessibility of smaller symptom. It is often the first symptom experienced by
numbers of muscle fibers.23 During muscle activity or individuals with GBS, before onset of weakness or
exercise, the available muscle fibers, which are few, are sensory changes.2 Pain most commonly begins in the
at risk for being overworked. proximal musculature, specifically the low back and
The literature has established parameters to guide upper part of the legs, and is most frequently reported
treatment planning and exercise program development in these areas during the acute and recovery phases of
by the physical therapist.23 Before the point of nadir is GBS for up to 1 year.31 The pathogenesis of GBS pain
reached, the role of the physical therapist is to maintain syndromes is unknown. More than three quarters of
passive range of motion. Specific exercise parameters patients with GBS report pain in the acute phase, and
include refraining from overworking the patient to one third experience pain 2 years after diagnosis.32,33
the point of fatigue, avoiding eccentric contractions The severity of pain does not appear to be correlated
because these increase the likelihood of injury, and not with functional recovery but is linked with involvement
emphasizing strength training until muscles are able of sensory nerve fibers.31,33 Moulin et al.33 discussed
to achieve full active motion against gravity.23 Small three variations of pain as described by patients with
studies in patients with neuromuscular disease suggest GBS. The most frequently reported was throbbing and
that a high-resistance exercise regimen increases the aching pain in the low back that radiated to the legs.
probability for a loss of muscle strength.23 A submaxi- Second, patients described dysesthetic pain, noted to
mal exercise program is recommended to avoid regres- be burning or tingling in the extremities. Less com-
sion of symptoms. monly, patients with GBS reported pain related to
Strength returns in a descending pattern as nerves joint aches and stiffness. The visual analog scale is a
regenerate.24 Recovery of strength and other symptoms reliable and valid assessment of patients’ experience
occur quickly during the first 6 months after nadir.24 and perception of their pain. Pain is primarily managed
Clinicians should consider results of electrophysiologi- through pharmacology, specifically with nonsteroidal
cal testing to determine the severity of damage to the anti-inflammatory medications or, for patients with
myelin and axons when considering an exercise pre- disabling pain, narcotics. The best course of pharmaco-
scription.23 The presence and severity of axonal damage logical treatment for each individual patient is deter-
are indicative of long-term strength and functional mined by the physician.
deficits.20,23 Manual muscle testing and handheld Although pain and functional recovery are not
dynamometry are reliable and valid ways of assessing linked, pain should be assessed and managed in the
strength. Gains in strength have been documented rehabilitation setting to ensure patient comfort and full
during the recovery process for 18 months after participation in the therapy sessions. Because of varying
symptom onset.30 This should serve as a guide to the degrees of weakness and immobility of the trunk and
exercise prescription and the need for long-term extremities, pain can be caused by an imbalance of
follow-up of the patient with GBS. strength and flexibility or malalignment of spinal joints.
In the beginning of the recovery stage, passive range Rehabilitation specialists can address pain in the early
of motion and application of resting splints are impor- stages with attention to positioning in the bed and
tant to maintain flexibility to ease return of functional wheelchair. Range of motion exercises are important to
mobility when the patient is able. When the recovery maintain flexibility and prevent joint contractures;
stage begins, assessment of strength and tolerance for however, it has been suggested that lengthening of
upright activity may be initiated. Aerobic exercise is a nerve roots, by means of stretching, may induce addi-
crucial part of the exercise prescription to ensure the tional discomfort.2 Pain-relieving modalities, such as
patient returns to a premorbid level of function and transcutaneous electrical nerve stimulation, and patient
endurance; however, vital signs must be closely moni- education help to relieve symptoms. Referral to a phy-
tored in case of autonomic dysfunction, and a low sician who specializes in chronic pain may be necessary
to moderate exertion level must be maintained.23 if pain persists after strength and endurance deficits
Strengthening should occur within the limits of func- have resolved.
tional activities with emphasis on low repetitions.
Eccentric contractions are safe at a submaximal level Fatigue
and should ideally be performed during functional Fatigue is a common complaint of patients with acute
activities.23 The exercise parameters discussed here GBS and is a major contributor to long-term disability.
should be used as a guideline for exercise prescription It is seen in up to 80% of patients with immune-
in patients with GBS. Additional research is necessary mediated polyneuropathies, CIDP, and GBS.34 Merkies
2560_Chapter 20_0227-0238.indd 232 3/16/2015 4:14:01 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
34
et al. reported that patients describe fatigue as one of weakness, the gait pattern is often affected. In the initial
the three most disabling symptoms that affects their stages of recovery, ambulatory aids such as a walker,
quality of life. The risk for fatigue doubles in patients crutches, or a cane may be needed. Strength and endur-
with muscular weakness and is closely associated with ance training should include functional standing and
pain.35 Fatigue in GBS has been correlated with age walking activities, taking into consideration the need
but is not related to preceding infection, the severity of to avoid overfatiguing the muscles. Persistent lower
symptoms at onset, or the severity of residual neuro- extremity weakness can lead to difficulty with foot
logical deficits.36 At the onset of GBS, peripheral clearance (footdrop) in one leg or both, necessitating
fatigue appears to have a significant influence on com- the need for an orthosis. One study of 69 patients who
plaints of fatigue. After resolution of neurological were admitted for inpatient rehabilitation found that
symptoms, psychosocial dysfunction and dysautono- two thirds of patients required an orthosis at one point
mia contribute to persistent fatigue.36 Despite good during rehabilitation, and one third needed an orthosis
recovery of physical strength and mobility, fatigue is 1 year after diagnosis.17 A case study found neurode-
frequently a long-term effect of GBS that may inter- velopmental sequencing to be an effective treatment
fere with overall daily function and social life.36 technique for a geriatric patient with GBS.40 The use
The causes of fatigue in patients with GBS are of partial body weight support locomotor training was
numerous and may be related to central and peripheral investigated in a limited fashion.19 Research to support
factors. de Vries et al.36 described different causes of the efficacy of physical therapy interventions on gait
fatigue in patients with GBS—fatigue that is perceived and functional recovery is needed.
and felt by the patient (experienced fatigue) and fatigue
that is related to decreased muscle endurance and force Integument
production (peripheral fatigue). The Fatigue Severity Patients with severe weakness and prolonged immobil-
Scale is a valid assessment tool for experienced fatigue, ity are at risk for skin breakdown at areas of bony
with good test-retest reliability and good internal con- prominence. Regular skin checks, pressure relief, and
sistency. Muscle capacity in peripheral fatigue can be patient and caregiver education are imperative for pre-
measured by electrophysiological testing.36 Physical vention of breakdown.41
therapists can use measures of endurance and activity
tolerance, such as the 2-Minute Walk Test or 6-Minute Swallowing and Speech
Walk Test, and manual muscle testing as assessment Patients whose cranial nerves are affected experience
tools for this impairment. difficulties with swallowing and motor speech. A
Treatment of fatigue should focus on underlying speech and language pathologist should be consulted
symptoms and discussion of psychosocial causative for proper assessment and treatment. In rare instances,
factors. Exercise prescribed by a physical therapist can supplementary feeding methods may be required
have a positive impact on fatigue levels. A small study short-term, such as a nasogastric feeding tube or a
of a custom-designed low-impact treatment program percutaneous endoscopic gastrostomy tube.
completed by patients recovered from GBS who expe-
rienced persistent fatigue found that patients reported Deep Vein Thrombosis
fatigue diminished by 20% in addition to overall Roughly 80% to 90% of patients with GBS are non-
improvement of “physical fitness, function and quality ambulatory at one point in the disease process. Because
of life”; this progress was maintained at 2-year of this prolonged immobility, patients with GBS are at
follow-up.37 In light of the fact that consistent exercise risk for developing deep vein thrombosis or pulmonary
improves physical conditioning and muscle strength, embolism.2 The treating clinician should be mindful of
one can deduce that a rehabilitation exercise program the signs and symptoms of this complication. It is
would positively influence the degree of fatigue expe- unclear what percentage of patients experience this
rienced by patients with GBS.38 complication because that has not been studied.2 Pro-
Medications are used to manage fatigue in other phylactic measures routinely used include compressive
demyelinating disorders; however, there is very little stockings, pneumatic stockings, ankle exercises, early
evidence for their use in patients with GBS.36 One ambulation, and antiplatelet therapies such as low-
randomized controlled trial found that amantadine, molecular-weight heparin.
a drug that has many purposes but is commonly
used to improve arousal in patients with neurological Heterotopic Ossification
impairments, had no effect on severe fatigue in patients Heterotopic ossification (HO) is a complication that
with GBS.39 occurs infrequently in patients with GBS. HO is the
formation of bone in soft tissue in the periarticular
Gait space. It typically occurs in patients after trauma to the
As a result of the presence of weakness and imbal- central nervous system. In a prospective study of out-
ance that varies from tetraparesis to symmetrical leg comes in patients with GBS, a very small percentage
2560_Chapter 20_0227-0238.indd 233 3/16/2015 4:14:01 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
of patients were found to have developed HO in the physical therapy as an adjunct to medical care. The
hip region (6%), typically patients with a more severe length of time spent under rehabilitative care has been
course who are admitted to the ICU. HO has been positively correlated with fewer limitations on long-
reported only in the hip joints.42 term functional activity and participation restrictions.1
Because the speed and degree of recovery vary from
Psychosocial Implications person to person, persistent physical and psychological
Because of the rapid onset of weakness and immobility deficits may contribute to decreased overall physical
that is experienced by patients of all ages who have and psychological functioning years after diagnosis.39
GBS, psychosocial function is significantly affected For this reason, rehabilitation should be provided in an
throughout the acute and rehabilitative phases. The adequate time frame to ensure optimal recovery.
most frequently experienced issues are anxiety, depres- Physical therapy should begin during the acute
sion, and pain as well as feeling undereducated about stages to assist in the prevention of decubitus ulcers,
their symptoms.43 The rate and level of physical recov- prevention of contractures, and monitoring of cardio-
ery appear to be related to the level of psychological respiratory issues during strengthening and functional
stress that is present 1 year after diagnosis.43 Cognitive activity.2 Education about the length of time and
issues may be present after prolonged mechanical ven- process for recovery is critical.9 Based on evidence
tilation.19 It is the health care provider’s responsibility from research on other neuromuscular diseases, exer-
to educate the patient and family about symptoms as cise and rehabilitation have a positive influence on
well as to assist their understanding of what to expect strength, endurance, functional activities, ADLs, and
during the course of recovery. An evaluation in the the prominent residual symptoms of fatigue and pain
rehabilitation setting should include an assessment of (Box 20-1).44–46
the patient ’s perception of function and disability as
well as education about the effect of GBS on psycho-
logical health; a reliable and valid tool is the Short Classification of Signs
Form-41 (SF-36).43 If symptoms of depression persist
1 to 2 years after diagnosis, the primary physician and Symptoms
should be alerted; extended depression occurs most
commonly in patients who have not returned to their The International Classification of Functioning, Dis-
premorbid level of physical function. Persistent pain ability and Health (ICF) model was established by the
and fatigue can contribute significantly to emotional
stress, and these symptoms should be addressed by the BOX 20-1
physician and rehabilitation clinician. Psychological
stress may persist 1 to 2 years after diagnosis because Physical Therapy Assessment for an Individual With
of social limitations such as inability to go to work or
attend social functions.43 Understanding that patients Guillain-Barré Syndrome
with GBS may experience lingering physical and psy- History of present illness
chological deficits years after the acute phase will con- Premorbid functional status
tribute to improved quality of care by health care Past medical and surgical history
professionals. More research is needed on the psycho- Medications
logical and social outcomes after GBS. Review of laboratory, electrodiagnostic, and
Support groups in the United States and around the radiographic data
world are beneficial to patients with GBS and their Social status including home support
families. Such groups allow exchange of emotional Vital signs in supine, sitting, and standing before and
after activity
support and coping strategies. Support groups also help
Visual acuity, depth perception, hearing
patients to develop a sense of community, while pro- Speech
viding education and promoting advocacy. The GBS/ Cognition
CIDP Foundation International is a nonprofit volun- Swallowing
teer organization that provides a forum for networking Activity tolerance
and education for patients, families, caregivers, and Integument
health care professionals. Muscle strength, tone, and coordination
Articular and axial range of motion
Reflexes
Rehabilitative Care Bowel and bladder
Balance
Sensory testing
Rehabilitation is an integral component in the recovery
Functional assessment: Bed mobility, transfers,
of premorbid strength, functional mobility, and quality ambulation, wheelchair mobility
of life; however, very little evidence exists to support
2560_Chapter 20_0227-0238.indd 234 3/16/2015 4:14:01 PM

Process CyanProcess
YellowProcess Black
World Health Organization to create universal domains of these measures have been tested or validated in
of assessment associated with the functioning of patients with GBS.
patients with different conditions.47 As discussed, GBS
● Activity limitations: Berg Balance Scale,
has the potential to affect multiple systems throughout
Tinetti Assessment Tool, Functional
the body, which translates to dysfunction on many
Independence Measure, 10-Meter Walk Test,
levels. The signs, symptoms, and clinical effects of GBS
6-Minute Walk Test, Modified Rankin Scale,
can be categorized into different levels according to
Modified Barthel Index
the ICF19,47:
● Participation restrictions: Fatigue Impact Scale,
● Body structure and function: Decreased Fatigue Severity Scale, GBS disability scale,
respiratory capacity, fatigue, pain, muscle Short Form-36, Positive Affect Negative Affect
weakness, decreased range of motion, autonomic Scale, Hughes Disability Scale, Modified
dysfunction, dysphagia Fatigue Impact Scale, Disability Grading Scale
● Activity limitations: Transfers, mobility on level for GBS, Erasmus GBS outcome score7
surfaces and stairs, speech and communication
disorders, ADLs
● Participation restrictions: Difficulty returning to Prognosis, Recovery of Function,
social and family roles and functions, inability
to work
and Quality of Life
The outlook for most patients with a diagnosis of
GBS is positive from a long-term perspective; however,
Examples of Physical Therapy more severe cases may be associated with lasting dis-
Goals for Rehabilitation ability and residual deficits.17 Older age, presence of
comorbidity, onset of autonomic dysfunction, disease
Short-Term Goals severity (specifically the degree of weakness and need
for intubation for ventilatory support), and duration of
● Improve activity tolerance (3 hours of therapy the plateau phase are suggestive of worse overall
in acute rehabilitation) outcome and are related to morbidity and mortal-
● Independence with bed mobility ity.1,10,18 Clinical symptoms are typically more severe in
● Independence with mobility at the patients with preceding gastrointestinal infection.2
wheelchair level Approximately 40% of patients who are admitted to
● Independence with transfers, toileting, dressing, the hospital require inpatient rehabilitation after their
and bathing acute care stay to ensure safe discharge to home.2
● Maximize articular and axial range of motion to Patients admitted for inpatient rehabilitation have
allow performance of ADLs typically experienced medical complications such as
● Complete patient and family education respiratory failure, cranial nerve dysfunction, and auto-
● Maximize muscle strength to permit functional nomic dysfunction.2
activities Most patients recover functional mobility and return
● Promote a safe and acceptable gait pattern with to their premorbid level of activity participation and
or without assistive devices quality of life after receiving timely medical treatment
Long-Term Goals and suitable supportive rehabilitative care. Residual
disability is present in 20% to 50% of patients, some-
● Independence with ADLs times for 3 to 6 years after diagnosis.5,9,48 Residual
● Independent mobility on level and uneven disability is often characterized by pain, fatigue, or
surfaces at premorbid level in the home and weakness, which negatively affect a person in various
community settings aspects of life.19 Individuals with persistent weakness
● Return to work may benefit from ambulation with an orthosis or assis-
tive device.17 However, most patients are able to resume
normal family, work, and social activities within a
Assessment and Outcome Measures 2-year period. The amount of time it takes to recover
depends on the severity of the disease at its nadir.21
More research is needed to evaluate the effect of GBS Patients with GBS score lower than normal on
on activity limitations, functional mobility, strength, quality-of-life outcome measures.45 Following research
gait, and participation in life roles. Following is a list on self-reported residual deficits from patients with
of suggested outcome measures that may be beneficial neuromuscular diseases, Rekand et al.35 concluded that
during evaluation and reporting of progress according these diseases and syndromes, including GBS, “cause
to the domains of the ICF.47 To our knowledge, none long-lasting disability and interfere with the quality of
2560_Chapter 20_0227-0238.indd 235 3/16/2015 4:14:01 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
life.” Up to 50% of patients may experience difficulty 4. Common complications of GBS in the acute stage
participating in social and leisure activities for 3 to 6 include which of the following?
years after diagnosis.48 In general, evidence has shown a. Respiratory compromise
that most patients make a good recovery and return b. Autonomic dysfunction
to functional ambulation within 6 months. Notwith- c. Muscle weakness
standing such gains in basic strength and mobility, a d. All of the above
patient ’s recovery from GBS may entail longer term
5. _______________ has been reported by more than
deficits in quality of life and activities of functional
50% of patients with GBS 2 years after diagnosis.
independence, such as a return to premorbid levels of
a. Pain
participation in leisure and work activities. Despite the
b. Paresthesia
evidence for potential recovery, the condition is multi-
c. Dizziness
faceted and complex, and a cure continues to elude the
d. Inability to walk
medical field. It is essential that an integrated health
care approach be undertaken, with prolonged medical
and rehabilitative care, to ensure proper management
of the pathological process and subsequent recovery. References
1. Hughes RA, Swan AV, van Doorn PA. Intravenous
immunoglobulin for Guillain-Barré syndrome. Cochrane
Database Syst Rev. 2010;(6):CD002063.
2. Meythaler JM. Rehabilitation of Guillain Barré syndrome.
CASE STUDY Arch Phys Med Rehabil. 1997;78:872–879.
3. Asbury AK, Cornblath DR. Assessment of current diagnostic
While on a business trip to Europe, Bill developed a criteria for Guillain Barré syndrome. Ann Neurol. 1990;
severe upper respiratory infection. On the flight home, 27(suppl):S21–24.
he began to experience numbness and tingling of his 4. van Doorn PA. Treatment of Guillain Barré syndrome and
CIDP. J Peripher Nerv Syst. 2005;10:113–127.
toes bilaterally. On leaving the airplane, he had 5. van Doorn P, Ruts L, Jacobs B. Clinical features,
difficulty walking to his car, he noticed his right knee pathogenesis, and treatment of Guillain-Barré syndrome.
buckling by the time he approached his car. When he Lancet Neurol. 2008;7(10):939–950.
arrived home and told his wife about his symptoms, 6. McGrogan A, Gemma CM, Seaman HE, de Vries CS. The
she immediately drove him to the emergency epidemiology of Guillain-Barré syndrome worldwide: a
systematic literature review. Neuroepidemiology. 2009;32:
department of a local hospital. 150–163.
Blood work screening was normal, but based on the 7. Lunn MP, Willison HJ. Diagnosis and treatment in
history, Bill was admitted to the ICU with suspected inflammatory neuropathies. J Neurol Neurosurg Psychiatry.
GBS. In the ICU, his condition rapidly deteriorated, 2009;80(3):249–258.
and within 24 hours of admission, he was placed on 8. Burns TE. Guillain Barré syndrome. Semin Neurol. 2008;28:
152–167.
a ventilator. 9. Pritchard J. What ’s new with Guillain Barré syndrome? Pract
Neurol. 2006;6:208–217.
10. Alshekhlee A, Hussain Z, Sultan B, Katirji B. Guillain-Barré
Case Study Questions syndrome incidence and mortality rates in US hospitals.
1. Which two physical examination criteria are Neurology. 2008;70:1608–1613.
11. Hughes RA, Cornblath DR. Guillain-Barré syndrome.
necessary for a diagnosis of GBS? Lancet. 2005;366:1653–1666.
a. Areflexia and progressive weakness 12. Souayah N, Nasar A, Suri MFK, Qureshi AI. Guillain-Barré
b. Hyperreflexia and posturing syndrome after vaccination in United States: data from the
c. Spasticity and urinary retention Centers for Disease Control and Prevention/Food and Drug
d. Hyporeflexia and a positive Babinski test Administration Vaccine Adverse Event Reporting System
(1990–2005). J Clin Neuromuscul Dis. 2009;11:1–6.
2. Which of the following is the “gold standard” test 13. Haber P, Sejvar J, Mikaeloff Y, DeStefano F. Vaccines and
for GBS? Guillain-Barré syndrome. Drug Saf 2009;32(4):309–323.
14. Lehmann HC, Hartung HP, Kieseier BC, Hughes RA.
a. Magnetic resonance imaging of the brain Guillain-Barré syndrome after exposure to influenza virus.
b. Electroneuromyogram Lancet Infect Dis 2010;10:643–651.
c. Computed tomography scan of the spine 15. Centers for Disease Control and Prevention (CDC).
d. Hemoglobin and hematocrit Preliminary results: surveillance for Guillain-Barré Syndrome
After Receipt of Influenza A (H1N1) 2009 Monovalent
3. Which of the following therapies are the most Vaccine—United States, 2009–2010. MMWR Morb Mortal
effective for the treatment of GBS? Wkly Rep. 2010;59(21):657–661.
a. Antibiotics 16. Pithadia AB, Kakadia N. Guillain Barré syndrome (GBS).
Pharmacol Rep. 2010;64:220–232.
b. Corticosteroids 17. Asbury AK, Arnason BG, Karp HR, McFarlin DE. Criteria
c. Plasmapheresis and IVIG therapy for diagnosis of Guillain-Barré syndrome. Ann Neurol. 1978;
d. Radiation therapy 3:565–566.
2560_Chapter 20_0227-0238.indd 236 3/16/2015 4:14:01 PM

Process CyanProcess
YellowProcess Black
18. Hughes RA, Swan AV, van Doorn PA. Corticosteroids for 33. Moulin DE, Hagen N, Feasby TE, Amireh R, Hahn A. Pain
Guillain-Barré syndrome. Cochrane Database Syst Rev. in Guillain-Barré syndrome. Neurology. 1997;48(2):328–331.
2010;(2):CD001446. 34. Merkies IS, Schmitz PI, Samijn JP, van der Meché FG, van
19. Gupta A, Taly AB, Srivastava A, Murali T. Guillain-Barré Doorn PA. Fatigue in immune-mediated polyneuropathies.
syndrome—rehabilitation outcome, residual deficits and Neurology. 1999;53:1648–1664.
requirement of lower limb orthosis for locomotion at 1 year 35. Rekand T, Gramstad A, Vedeler CA. Fatigue, pain and
follow-up. Disabil Rehabil. 2010;32(23):1897–1902. muscle weakness are frequent after Guillain-Barré syndrome
20. Nicholas R, Playford ED, Thompson AJ. A retrospective and poliomyelitis. J Neurol. 2009;256:349–354.
analysis of outcome in severe Guillain-Barré syndrome 36. de Vries JM, Hagemans ML, Bussmann JB, van der Ploeg
following combined neurological and rehabilitation AT, van Doorn PA. Fatigue in neuromuscular disorders: focus
management. Disabil Rehabil. 2000; 22(10):451–455. on Guillain Barré syndrome and Pompe disease. Cell Mol Life
21. Keoppen S, Kraywinkel K, Wessendorf TE, et al. Long term Sci. 2010;67:701–713.
outcome of Guillain Barré syndrome. Neurocrit Care. 2006;5: 37. Garssen MP, Bussmann JB, Schmitz PI, et al. Physical
235–242. training and fatigue, fitness, and quality of life in Guillain-
22. World Health Organization. The International Classification Barré syndrome and CIDP. Neurology. 2004;63:2393–2395.
of Functioning, Disability and Health (ICF). Geneva: 38. Hughes RA, Wijdicks EF, Benson E, et al. Supportive care
WHO; 2001. for patients with Guillain-Barré syndrome. Arch Neurol. 2005;
23. Rekand T, Gramstad A, Vedeler CA. Fatigue, pain and 62:1194–1198.
muscle weakness are frequent after Guillain-Barré syndrome 39. Bowyer HR, Glover M. Guillain Barré syndrome:
and poliomyelitis. J Neurol. 2009;256:349–354. management and treatment options for patients with
24. Moulin DE, Hagen N, Feasby TE, Amireh R, Hahn A. moderate to severe progression. J Neurosci Nurs. 2010;42(5):
Pain in Guillain-Barré syndrome. Neurology. 1997;48: 288–293.
328–331. 40. Bassile CC. Guillain Barré syndrome and exercise guidelines.
25. Dhar R, Stitt L, Hahn AF. The morbidity and outcome of Neurol Rep. 1996;20(2):31–36.
patients with Guillain-Barré syndrome admitted to the 41. Rudolph T, Larsen JP, Farbu E. The long-term functional
intensive care unit. J Neurol Sci. 2008;264:121–128. status in patients with Guillain-Barré syndrome. Eur J Neurol.
26. Raphael JC, Chevret S, Hughes RAC, Annane D. Plasma 2008;15:1332–1337.
exchange for Guillain Barré syndrome. Cochrane Database Syst 42. Garssen MP, Schmitz PI, Merkies IS, et al. Amantadine
Rev. 2012;(7):CD001798. for treatment of fatigue in Guillain-Barré syndrome: a
27. Karavatas SG. The role of neurodevelopmental sequencing in randomised, double blind, placebo controlled, crossover trial.
the physical therapy management of a geriatric patient with J Neurol Neurosurg Psychiatry. 2006;77:61–65.
Guillain-Barre syndrome. Top Geriatr Rehabil. 2005;21(2): 43. Zeilig G, Weingarden HP, Levy R, Peer I, Ohry A, Blumen
133–135. N. Heterotopic ossification in Guillain-Barré syndrome:
28. Ruts L, Drenthen J, Jongen JL, et al. Pain in Guillain-Barré incidence and effects on functional outcome with long-term
syndrome: a long-term follow-up study. Neurology. 2010;75: follow-up. Arch Phys Med Rehabil. 2006;87:92–95.
1–9. 44. Flachenecker P, Wermuth P, Hartung HP, Reiners K.
29. El Mhandi L, Calmels P, Camdessanche JP, Gautheron V, Quantitative assessment of cardiovascular autonomic function
Feasson L: Muscle strength recovery in treated Guillain- in Guillain-Barré syndrome. Ann Neurol. 1997;42:171–179.
Barré syndrome: a prospective study for the first 18 months 45. Parry GJ, Steinberg JS. Guillain-Barré Syndrome: From
after onset. Am J Phys Med Rehabil. 2007;86:716–724. Diagnosis to Recovery. Saint Paul, MN: AAN Enterprises,
30. Khan F, Ng L. Guillain-Barré syndrome: an update in Inc; 2007.
rehabilitation. Int J Ther Rehabil. 2009;16(8):451–460. 46. Bernsen RA, de Jager AE, Kuijer W, van der Meche FG,
31. Flachenecker P. Autonomic dysfunction in Guillain-Barré Suurmeijer TP. Psychosocial dysfunction in the first year after
syndrome and multiple sclerosis. J Neurol. 2007;254(suppl 2): Guillain Barré syndrome. Muscle Nerve. 2010;41:533–539.
II196–II101. 47. Eldar R, Marincek C. Physical activity for elderly persons
32. Forsberg A, Press R, Einarsson U, de Pedro-Cuesta J, with neurological impairment: a review. Scand J Rehabil Med.
Holmgvist L. Impairment in Guillain-Barré syndrome during 2000;32:99–103.
the first 2 years after onset: a prospective study. J Neurol Sci. 48. Tiffreau V, Rapin A, Serafi R, et al. Post-polio syndrome and
2004;227:131–138. rehabilitation. Ann Phys Rehabil Med. 2010;53(1):42–50.
2560_Chapter 20_0227-0238.indd 237 3/16/2015 4:14:01 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
2560_Glossary_0347-0360.indd 360 3/17/2015 12:11:29 PM
Chapter 21
in the Athlete
“Do not let what you cannot do interfere with what you can do.”
—JOHN WOODEN
Objectives
• Identify common peripheral neuropathies associated with sports.
• Relate specific neuropathy to a specific sport.
• Identify the biomechanical etiologies of sports-related neuropathies.
Key Terms
• Burner
• Inflammation
• Neuropathy
• Repetitive and overuse athletic movements
This chapter reviews the most frequent peripheral

Introduction nerve injuries encountered by athletes. For organiza-
tional purposes and ease of reader understanding, we
The last three decades have witnessed a tremendous
discuss the possible neural injuries in the context spe-
increase in sports participation at all levels. However,
cific to types of athletic participation and, to a lesser
increased sports participation has also increased the
extent, gender, age, and psychological variables that
numbers, and perhaps the incidence, of sport-related
may affect injury.
injuries. Injuries can be due to either acute trauma or
overuse. Acute injuries are defined as a high-force, low-
repetition tissue stress resulting in a wide spectrum of
injury severity—from a simple strain or sprain to Background
trauma affecting multiple body systems—the compli-
cations of which may include shock, respiratory failure, The pathophysiology of nerve injuries can be initiated
or death. Overuse injuries may be defined as a low- by mechanical events involving repetitive and overuse
force, high-repetition tissue stress that subsequently athletic movements, such as overhead throwing,
leads to an inflammatory cascade–initiated impairment running, and jumping, or through direct blunt trauma.1
in tissue reparative mechanisms. Peripheral nerve The tensile or compressive forces exerted on the nerve
injury may result from high-force, low-repetition and stimulate the vasa nervorum, resulting in disruption of
low-force, high-repetition athletic injuries. the microvasculature and the deformation of the con-
In recent years, a rich literature has significantly nective tissue. Irritation potentiates a transient inflam-
contributed to the understanding of the etiologies, matory response (i.e., macrophage/monocyte activity)
types, assessment, intervention, and prevention of that can induce chemosensitive and immunosensitive
peripheral nerve injury related to athletic participation. reactions with prolonged exposure producing a noxious
239
2560_Chapter 21_0239-0252.indd 239 3/16/2015 4:14:04 PM

Process CyanProcess
YellowProcess Black
response.2 The edema produced is a consequence of tendinopathies with documented paratendon inflam-
compromised microcirculation at the endoneural level mation and cellular proliferation, increased production
and may lead to hypoxia, local pain, angiogenesis, of matrix compounds, tendon degeneration, and func-
scarring, and restricted axoplasmic flow.3 Endoneural tional loss. Histological studies of median nerves of rats
edema accumulation is compounded by the lack trained in high-repetition, low-force reaching tasks
of lymph tissue present at this level of the nerve exhibited increased numbers of ED1+ inflammatory
to facilitate flow of fluids.4 Continued mechanical macrophages in the involved limb and signs of epineu-
exposure—in these athletic cases continued participa- ral and perineural fibrosis. Conduction testing revealed
tion in the etiologic activity—potentiates the increased a slight but significant slowing of nerve conduction
nerve mechanosensitivity, propagating inflammatory velocity in the reach limb, which was consistent with
responses inflicting chemosensitivity to the nerve and similar studies indicating histological changes occur-
the surrounding musculature.5 The trauma may result ring before functional change.3,4,8 Biopsy specimens of
in signs and symptoms such as dysesthesia, hyperesthe- rat median nerves involved in high-frequency, low-
sia, hypoesthesia, paresis (hypotonia), and paresthe- force task repetitive strain showed ED1+ macrophages
sia.3,4 Clinical presentations include dysfunction, in portions of the median nerve located within and
fatigability, loss of coordination, and disability.3–5 Pos- adjacent to the site of strain. Increases in these cells
tural dysfunction—primarily muscular, capsular, and were found in the perineural and epineural layers and
ligamentous tightness—also occurs as a result of exces- in association with the axons. Infiltration of the ED1+
sive fibrosis, neural budding, and reflexive muscle tone macrophages is finely graded to the degree of injury as
initiated to protect the injured nerve from further measured by nerve conduction velocity and the degen-
damage.5 Therapeutic management involves eliminat- eration of nerve fibers and myelin. The rat nerves
ing any irritating mechanical stimuli that are present; showed an increase in collagen type I immunoreactivity
decreasing the inflammation; and maintaining muscle, in the epineurium of the median nerve at the wrist in
nerve, and ligamentous range of motion. the trained animals. Progressive thickening of the
Four categories have been reported in the literature internal and external epineurium as well as thickening
to describe the underlying pathophysiology of acute or of the perineurium was also seen.3,4
traumatic peripheral nerve injury. The first category Athletes in the fourth category undergo a high-
consists of patients with underlying systemic or auto- force, low-repetition strain resulting in microinjury and
immune diseases who are thought to have a higher perhaps macroinjury to bone, tendon, muscle, ligament,
risk for connective tissue and neural injury as a result and nerve. The cascade of the inflammatory reaction is
of the impact of the primary disease on collagen struc- similar to that which occurs secondary to high-
tures. Diagnoses that fit this category include lupus repetition, low-force injuries but with the added vari-
erythematosus, psoriatic arthritis, rheumatoid disease, ables of acute instability and pain, weakness, or loss of
diabetes mellitus, chronic kidney disease, and hyper- neural input or output.
parathyroidism. These conditions are thought to cause Athletics-induced neural injury differs greatly from
downstream inflammatory changes that alter the struc- contractile tissue and ligamentous tissue injury. Periph-
ture of the tendon, muscle, ligament, and peripheral eral nerve injury has a length-dependent response to
nerve. Histological examination of the nerves of these repair; the more proximal the injury, the longer the
patients has demonstrated chronic inflammation, isch- time for repair. Axonotmetic and neurotmetic injuries
emia, and amyloid deposition.6 The additional forces often require surgical intervention, such as neurolysis
and stresses of athletic competition in patients with and gap repair. Along with target loss of function, there
these diagnoses may add to the risk of neuropathy. is also a concurrent afferent and autonomic loss. Pro-
The second category includes athletes with single or prioceptive, kinesthetic, and tactile loss can be espe-
multiple dosing of oral or injectable corticosteroids, cially devastating to a competitive athlete. The quality
which are thought to have an association with tendon and quantity of pain with neural injury differ from
rupture and possibly neuropathy. It is believed that the most musculoskeletal pain syndromes because of the
steroids affect collagen synthesis and compromise radicular nature of the presentation. Along with local
blood supply, weakening the tendon and the neural pain resulting from local nerve inflammation, the asso-
connective tissue and placing the athlete at risk for ciated pain often travels distally along the axis of der-
injury.7 matomal and myotomal innervations, expanding the
Patients in the third category exhibit inflammatory area of pain perception and, often in the case of nerves,
and degenerative changes on histological studies attrib- a region of negative or positive symptoms of nerve
uted to microtrauma from chronic overuse. The serial injury. Often immobilization or limited excursion is
body of work by Barr, Barbe, Safadi, Amin, Carp, required for healing of neural injuries, whereas many
and others2–4 in a rat model of high-frequency, musculoskeletal injuries allow for a scaffolding of activ-
low-force repetitive strain tasks and later with transla- ity. As the nerve heals, passive insufficiency of a
tion to human populations revealed repetition-induced damaged nerve is always a serious concern that must
2560_Chapter 21_0239-0252.indd 240 3/16/2015 4:14:05 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 21 | Peripheral Nerve Injury in the Athlete 241
be addressed with neural glide/slide rehabilitation Table 21-1 Frequency Rate of All Specific
techniques.
Musculoneuroskeletal Injuries Occurring in
Collegiate Football Games
Football Injury Frequency Rate of Injury per Game
(per 100 Athletes Participating)
Football has been played competitively at the collegiate
level in the United States for more than 100 years. Knee internal derangements 0.617
Long recognized as a high-risk activity and at the Ankle ligament sprains 0.539
urging of President Theodore Roosevelt, representa- Concussions 0.234
tives from Princeton, Harvard, and Yale met at the
Neck nerve injury 0.180
White House in 1905 to “save” football from its inher-
ent violence. In his opening statements, President Upper leg contusions 0.127
Roosevelt noted that “18 collegiate deaths” occurred as Upper leg strain 0.124
a result of football in 1904 and requested rule changes Acromioclavicular joint sprains 0.098
to improve safety and “save the game.” Ultimately, the
colleges banded together to form the predecessor to Shoulder ligament strain 0.091
the National Collegiate Athletic Association (NCAA) Lower leg contusion 0.063
with the goal of reforming the sport to limit injuries Foot ligament strain 0.011
and fatalities. However, even with ongoing and Hand fracture 0.010
evidence-based regulation directed at equipment—
primarily helmets, safety rules, and the elimination of Data compiled from Albright JP, McAuley E, Martin RK, Crowley ET,
many techniques such as the “flying wedge”—football Foster DT. Head and neck injuries in college football: an eight-year
analysis. Am J Sports Med. 1985;13:147–152; Warren RF.
remains a very high-risk sport for injury to the Neurologic injuries in football. In: Jordan BD, Tsairis P, Warren RF, eds.
participants.9 Sports Neurology. Rockville, MD: Aspen; 1989:235–237; Poindexter
Football is a high-velocity, high-force collision sport DP, Johnson EW. Football shoulder and neck injury: a study of the
“stinger.” Arch Phys Med Rehabil. 1984;65:601–602; and Feinberg
in which injuries are expected to occur. Football ath- JH, Radecki J, Wolfe SW, Strauss L, Mintz DN. Brachial plexopathy/
letes, many of whom weigh more than 300 pounds and nerve root avulsion in a football player; the role of electrodiagnostics.
can run the 40-yard dash in less than 5 seconds, collide HSS J. 2008;4:87–95.
with enormous quantities of force. Football, of all the
common major sports played in the United States, has
the highest number and incidence of injuries.10 Game
injury rates in collegiate football average 3.6 per 100
players per game (Table 21-1). Injury rate during prac-
tice is 1 per 100 players per practice. Musculoskeletal
injuries are the most common football injury reported, Table 21-2 Frequency Rate of All Specific
with knee derangement and ankle sprains having the Musculoneuroskeletal Shoulder Injuries Occurring
greatest frequency of occurrence. Except for the shoul- in Collegiate Football Games
der and knee, current studies are limited in identifying
types of football injuries associated with body part Shoulder Injury Frequency Rate of Injury per Game
(Table 21-2).10,11 No current references are available (per 100 Athletes Participating)
delineating the number of peripheral nerve injuries and Acromioclavicular sprain 0.110
the locations associated with football.
Anterior ligament sprain 0.107
The “burner,” sometimes referred to as “stinger syn-
drome,” is one of the most common peripheral nerve Glenohumeral dislocation 0.101
injuries seen in football.11,12 Frequently underreported Contusion 0.068
by athletes, stingers have been found to affect 65% Muscle/tendon strain 0.064
of college football athletes at least once during their
collegiate career.12 Burner symptoms typically include Nerve injury 0.026
a burning or stinging pain that radiates down one Data compiled from Albright JP, McAuley E, Martin RK, Crowley ET,
of the upper limbs with or without associated pares- Foster DT. Head and neck injuries in college football: an eight-year
thesias and weakness. In most cases, symptoms are analysis. Am J Sports Med. 1985;13:147–152; Warren RF.
Neurologic injuries in football. In: Jordan BD, Tsairis P, Warren RF, eds.
transient and self-limiting. However, recurrences are Sports Neurology. Rockville, MD: Aspen; 1989:235–237; Poindexter
common, and subtle neurological deficits may persist DP, Johnson EW. Football shoulder and neck injury: a study of the
without being detected. Symptoms of burner syndrome “stinger.” Arch Phys Med Rehabil. 1984;65:601–602; and Feinberg
JH, Radecki J, Wolfe SW, Strauss L, Mintz DN. Brachial plexopathy/
that persist may indicate a more serious neurological nerve root avulsion in a football player; the role of electrodiagnostics.
injury.13 HSS J. 2008;4:87–95.
2560_Chapter 21_0239-0252.indd 241 3/16/2015 4:14:05 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Burners typically result from an upper cervical root
(C5–C6) or upper brachial plexus injury. Controversy
exists whether these injuries commonly involve the
cervical roots, the brachial plexus, or a combination of
the two.13 Burners result from nerve traction or direct
compression of the involved nerve fibers. Rare, but
catastrophic, sequelae of severe traumatic upper cervi-
cal nerve root injury has been reported and may result
in permanent nerve root injury—nerve root avulsion.
These injuries are usually limited to high-velocity A
impacts, such as motorcycle collisions, and have been
documented in the literature pertaining to football
injury.14
Burner lexicon defines the injury as a grade 1, 2, or
3 peripheral nerve injury. Grade 1, which constitutes
most burner injuries, is neurapraxia, which is a dis-
ruption of nerve action potential involving partial
demyelinization. Axonal integrity is preserved, and
remyelinization occurs within days to 3 weeks. A grade
2 injury is axonotmesis, which entails actual axonal
B
damage and wallerian degeneration. A grade 3 injury
is neurotmesis, which often results in permanent nerve
damage.14
Three mechanisms of burners have been described
in the literature.13–15 The first mechanism is a traction
injury to the brachial plexus and nerve roots. Traction
injury occurs when any combination of the following
movements occurs: The ipsilateral shoulder and scapu-
lar are depressed; the ipsilateral shoulder is horizontally
abducted past midline; the neck is forced into contra-
lateral lateral flexion. The second mechanism involves C
a direct blow to the supraclavicular fossa—this causes Figure 21-1 Stinger injuries may be caused by
a percussive injury to the upper trunk. The third mech- (A) contralateral flexion resulting in an ipsilateral tension
anism is nerve compression by a combination of neck injury to the plexus, (B) direct trauma to the plexus, and
hyperextension and ipsilateral lateral flexion. Biome- (C) contralateral flexion of the neck with contralateral
chanically, this position mimics the Spurling maneuver, compressive injury to the plexus.
which tests for foraminal stenosis. The third mecha-
nism may, along with brachial plexus injury, injure the
nerve roots. One investigator observed that the most Symptoms lasting longer than minutes to hours or
persistent and severe symptoms from burners occurred symptoms that progressively worsen may be indicative
with this mechanism of injury (Fig. 21-1).14 of an axonotmetic lesion or additional structural
Most burner injuries occur with tackling.15 Shoulder damage in the thoracic outlet. Immediate paralysis
and scapular depression and neck lateral flexion can requires emergent treatment owing to possible nerve
occur as the tackler drives his shoulder into the ball root avulsion or cord injury. Electroneuromyogram
carrier’s body, especially into a thigh or knee. Shoulder testing is unreliable for at least 3 weeks after injury.14
horizontal abduction typically occurs with arm tackling There have been reports in the literature of cervical
lateral to the tackler’s torso. The ball carrier’s momen- nerve root avulsion in football when severe forces later-
tum exceeds the strength of the tackler’s horizontal ally flex the neck, depress the scapula, and horizontally
adductor muscle groups, forcing the shoulder into an abduct the glenohumeral joint.16 This etiology has also
abnormal horizontal abduction position that stretches been well established in other high-velocity impacts
the plexus. Additionally, direct compression of the bra- that may occur with skiing or motorcycle riding.17
chial plexus can occur from contact with the ball car- Feinberg et al.18 reported the case of a 30-year-old
rier’s elbow, knee, or shoulder. semiprofessional football player who sustained a cervi-
Initial symptoms after injury are paresthesias in any cal nerve root avulsion injury. He felt an immediate
combination of the C5 to T1 dermatomes, acute sub- “frostbite” sensation in his right arm and hand. Subse-
clavicular pain, and generalized weakness. In most quent electrodiagnostic and imaging studies revealed a
cases, the symptoms resolve within minutes to hours. complete avulsion of the C6 and C7 nerve roots from
2560_Chapter 21_0239-0252.indd 242 3/16/2015 4:14:05 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
the spinal cord. A nerve graft was eventually performed musculocutaneous nerve palsy. The nerve is at risk with
to bridge the neural gap. open and with arthroscopic procedures and can be
Burners frequently recur. One study reported an stretched by retractor placement on the coracobrachia-
87% chance of recurrence.11 In another study, 36 upper lis muscle for exposure.26
level athletes who missed playing time secondary to a The differential diagnosis for musculocutaneous
burner injury had a 42% chance of having another neck nerve injury includes rupture of the distal biceps tendon
injury that results in loss of playing time.14 The only at the elbow and more diffuse brachial plexus injuries.
valid predictor of burner injury is having a previous Distal biceps tendon rupture is associated with a loss
burner.18 Players with a history of burners are often of the contour of the muscle belly and superior retrac-
fitted with collars (e.g., the Cowboy Collar) that assist tion. The athlete can still contract the muscle, although
with the prevention of severe lateral neck flexion. The a loss of contour is obvious.26
effectiveness of these adaptations has not been thor- The long thoracic nerve is a pure motor nerve to the
oughly studied. serratus anterior muscle, originating directly from the
Axillary nerve injuries most commonly occur after spinal roots of C5, C6, and C7. The long thoracic nerve
anterior glenohumeral dislocation. Glenohumeral dis- passes along the anterior lateral aspect of the chest wall,
locations typically occur in one of two ways: falling supplying branches to all of the digitations of the ser-
backward on an outstretched, extended arm, resulting ratus anterior muscle. The long thoracic nerve is well
in an anterior displacement of the humerus from its protected throughout its proximal course along the
resting glenoid position, or forced lateral rotation of superior chest down to the level of the inferior portion
the humerus. The exact incidence of nerve palsy after of the pectoralis major. The nerve is susceptible to trac-
acute dislocations of the shoulder ranges from 9% to tion injury between its two points of relative fixation:
18%.19–21 Inferior dislocations, although rarer than at the medial scalene muscle at the base of the neck
anterior dislocations, have an even higher rate of axil- and at the superior aspect of the serratus anterior
lary nerve palsy—reported as high as 60%.22 Blunt muscle. In general, injuries to the long thoracic nerve
trauma to the anterior aspect of the shoulder without occur secondary to asynchronous motion of the arm
dislocation has been implicated in axillary nerve trauma and scapula, which can occur with a missed shot in golf,
in sports such as football, wrestling, and gymnastics.21 handball, or tennis or in contact sports in which the
Acute axillary neuropathy has also been associated with arm is jerked into an abnormal position, such as with
backpacking, usually in inexperienced hikers.23 The football tackling.27 A direct blow to the shoulder more
cause of axillary nerve injury in “rucksack palsy” is often results in a diffuse brachial plexus injury than an
thought to be traction caused by depression of the isolated injury of the long thoracic nerve because of the
shoulder from the excessively weighted backpack.24 protected position of the long thoracic nerve along the
Musculocutaneous nerve palsy manifests with chest wall.28 Long thoracic nerve traction injuries have
wasting of the biceps, coracobrachialis, and brachialis been reported secondary to repetitive motions such as
muscles; loss of the biceps reflex; and weakness of swimming, tennis, and prolonged positioning of the
elbow flexion and supination. The athlete reports a arm while shooting a rifle.24 Fatigue of the parascapular
variable loss of sensation along the lateral aspect of the muscles, as seen in ancillary football exercises such as
forearm but generally does not complain of any signifi- rope skipping, upper body ergometer workouts, and
cant pain. Clinical examination reveals atrophy of the weight lifting, can allow abnormal scapular motion on
biceps and brachialis muscles and decreased muscle the chest wall, resulting in a traction injury to the long
tone in patients with partial nerve injury. Elbow flexion thoracic nerve. Weight lifting exercises most com-
is weak but may be possible using the brachioradialis monly associated with long thoracic nerve palsy include
muscle, which is innervated by the radial nerve. Direct behind-the-neck French curls and the bench press. All
trauma to the anterior shoulder, fractures of the of these exercises can result in marked translation of
humerus and clavicle, and anterior shoulder disloca- the scapula on the chest wall, producing a traction
tions25 are common etiologies of musculocutaneous injury to the long thoracic nerve (Box 21-1).24
nerve injury. Tensile forces through the nerve can occur Peroneal nerve compromise has been reported in the
with prolonged overhead throwing as the nerve football literature.29 Etiologies include trauma and
stretches over the anterior shoulder and coracoids. insidious origins. Traumatic causes of peroneal nerve
Musculocutaneous nerve injuries in weight lifters and neuropathy occur in association with musculoskeletal
rowers have been attributed to engorgement of the injury or with isolated nerve traction, compression, or
coracobrachialis muscle.25 Forceful extension of the laceration. Insidious causes include mass lesions, toxic
elbow against resistance, such as when a runner attempts neuropathies, and metabolic syndromes. The peroneal
to prevent the football being torn from his grasp by a nerve is easily injured because of its subcutaneous loca-
defender, has also been implicated in musculocutane- tion at the fibular head, the fact that it is tethered by
ous nerve palsy. Anterior shoulder surgery, especially the tendinous origin of the peroneus longus as it winds
for instability in athletes, has been associated with around the fibular head and passes through the
2560_Chapter 21_0239-0252.indd 243 3/16/2015 4:14:05 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Box 21-1
traction can help to prevent common peroneal nerve
injury during arthroscopic knee surgery.31
Sports Implicated in Long Thoracic Nerve Injury Peroneal neuropathy at the knee has been reported
with ligamentous knee injury.32 In a series of 31 lower
Archery Discus extremity sports injuries, 17 were peroneal nerve inju-
Hockey Squash ries indicating the relative commonality of such an
Backpacking Football injury. Eight of these traumatic injuries were associated
Rope skipping Swimming with ligamentous injury of the knee. Most of these
Ballet Golf involved anterior cruciate ligament rupture; this often
Shooting Tennis occurred in conjunction with injury to the medial col-
Skiing Gymnastics
lateral and posterior cruciate ligaments. Three of the
peroneal neuropathies in this series were associated
Bowling Weight lifting
with ankle injuries (attributed to traction injuries asso-
Basketball Handball ciated with severe inversion).30
Skiing Racquetball Ligamentous or bony injury of the ankle may lead
Bowling Wrestling to peroneal neuropathy. However, nerve damage results
Soccer more often from treatment of ankle fracture than from
Data compiled from Duralde, XA. Neurological injuries to the athlete’s the fracture itself. Treatment of ankle injuries with a
shoulder. J Athl Train. 2000;35:316–328; McIlveen SJ, Duralde XA, below-knee splint or cast can damage the peroneal
D’Alessandro DF, Bigliani LU. Isolated nerve injuries about the shoulder. nerve by additive pressure over the fibular head. Asso-
Clin Orthop Relat Res. 1994;306:54–63; Goodman CE. Unusual
nerve injuries in recreational activities. Am J Sports Med. ciated lower extremity edema, especially immediately
1983;11:224–227; and McIlveen SJ, Duralde XA. Isolated nerve postimmobilization, can exacerbate this complication.
injuries about the shoulder. In: Bigliani LU, ed. Complications of Cast-induced or splint-induced edema can often be
Shoulder Surgery. New York: Williams & Wilkins; 1993:64–68.
avoided by padding the cast or splint in the area of the
fibular head, keeping the superior aspect of the cast at
least 1 inch inferior to the fibular head, avoiding pro-
peroneal tunnel to divide over the fibular neck, and its longed pressure on the lateral knee (as can occur during
location on the lateral aspect of the knee and leg bed rest with lateral rotation of the leg), performing
making it susceptible to traction forces as the knee or frequent neurological checks, avoiding dependency,
ankle is forced into varus.29 Peroneal nerve injury and maintaining elevation.33
results in weakness of ankle dorsiflexion and eversion Ankle sprain is a common cause of morbidity in the
and weakness of great and lesser toe extension. general population, and it is the most commonly
At the hip, nerve fibers that terminate in the pero- injured joint complex among athletes.30 The mecha-
neal nerve may be injured.18 The lateral fibers of the nism of injury in ankle sprain commonly involves
sciatic nerve are the most susceptible to injury. These inversion of a plantar flexed ankle. This position applies
fibers form the common peroneal nerve at the knee. mechanical traction to the peroneal nerve at the fibular
The lateral location of the nerve fibers within the nerve head.33 Peroneal nerve injury after ankle sprain was
trunk, tethering at the fibular head, and the larger size first described by Hyslop in 1941 in a case series of
of the funiculi are likely to be responsible for this three patients.33 The mechanism of injury was pro-
susceptibility.29 Acute dislocation, acetabular fracture, posed as a traction injury of the nerve in the postero-
proximal and midshaft femoral fracture, or operative lateral knee from a sudden force with the patient’s foot
repair of these fractures jeopardizes these nerve fibers. in plantar flexion and inversion. Concurrent ankle
The incidence of peroneal nerve compromise secondary sprain and peroneal neuropathy at the fibular head may
to osseous injury and surgical repair of the hip complex be easily misdiagnosed. Patients with ankle sprain
ranges from 6% to 33%. The most commonly reported often experience lateral ankle pain and eversion weak-
complication of hip osteotomy is sciatic nerve paresis.18 ness from the primary ligamentous injury. In a series
The common peroneal nerve may be injured at the of 66 patients with ankle sprain, electroneuromyo-
knee with a fracture of the distal femur, proximal tibia, graphic studies indicated that 86% of patients with
or proximal fibula.29 There is an approximately 1% inci- grade III sprains and 17% of patients with grade II
dence of peroneal nerve injury with tibial plateau frac- sprains had evidence of peroneal nerve injury on needle
ture.30 Peroneal nerve injury also can occur with examination.33
realignment of the knee extensor mechanism and
arthroscopic meniscal repair—common procedures
among football players. Stretch injury of the peroneal Trampoline
nerve can occur during reduction treatment of a knee
flexion contracture.31 Using a posterolateral incision With increasing popularity of trampolines has come an
and placing a retractor to protect the nerve from increased number of injuries.34 It is unknown whether
2560_Chapter 21_0239-0252.indd 244 3/16/2015 4:14:05 PM

Process CyanProcess
YellowProcess Black
there is an actual increase in the risk associated with (9%) had an injury to the head area—28 were lacera-
trampoline use for the same number of hours of expo- tions, and 20 were scalp contusions. None of the
sure or simply more injuries because of an increased patients were assigned a Glasgow Coma Scale score
number of participants. There is some indication that less than 15. A severe injury, as defined by an Abbrevi-
the number of trampoline injures may be due to ated Injury Scale value greater than 3, was present in
increased recreational (i.e., backyard) and other creative 63 of 556 (11%) patients. Patients injured on the mat
methods of use. Smith35 studied the epidemiology of had a relative risk of 0.07 of a severe injury compared
trampoline-related injuries among children and con- with 0.29 if falling off the trampoline. A total of 70
cluded that they were so common that children should (13%) patients were hospitalized for a mean of 2.2 days
not use trampolines. Furnival et al.36 and Woodward et (range, 1 to 8 days). The most common site of injury
al.37 found dramatically increasing numbers of trampo- among the hospitalized patients was the elbow (27 of
line injuries and recommended a ban of the recre- 70), followed by a fracture of the forearm (14 of 70).
ational use of trampolines. In 2000, Brown and Lee38 There were 23 patients who sustained a supracondylar
reported that trampolines were responsible for more fracture of the humerus, and 3 of these patients reported
than 6,500 pediatric cervical spine injuries in the an ulnar nerve neuropathy in association with the frac-
United States and supported a ban of the use of tram- ture. None of the four patients with elbow dislocations
polines by children. reported a nerve injury, but one patient sustained an
In a 2006 study, Nysted and Drogset34 described injury to the brachial artery. The artery was repaired
trampoline-related injures seen at St. Olav’s University with a vein graft. Two patients with supracondylar frac-
Hospital in Norway from March 2001 to October tures had diminished radial pulse immediately after the
2004. Their study included 556 patients (56% male and accident; however, angiography was normal.
44% female). The mean age was 11 years (range, 1 to
62 years). A lateral ligament injury of the ankle was the
most often reported diagnosis (20%), followed by an Cheerleading
overstretching of ligaments in the neck (8%) and a
fracture of the elbow (7%) (Tables 21-3 and 21-4). The Cheerleading injuries in the United States are increas-
authors observed significantly more fractures and dis- ing and present a significant source of injury to
locations in the upper extremity than in the lower
extremity (P < 0.001). Soft tissue injury accounted for
almost 30% of injuries in the upper extremity com- Table 21-4 Location of Trampoline Injury
pared with 74% of injuries in the lower extremity (P <
0.001). Of the patients, 46 (8%) had a cervical injury— Body Part Number (%)
of which 43 were minor overstretching of ligaments
Head 49 (9)
with mild to moderate radicular neural signs, 2 were
cervical fractures, and 1 was an atlantoaxial subluxation Neck including radiculopathy 46 (8)
without injury to the spinal cord. Of the patients, 49 Trunk/back including radiculopathy 24 (4)
Shoulder 8 (1)
Upper arm including plexopathy 8 (1)
Table 21-3 Main Cause of Trampoline Injury33–36
Elbow 62 (11)
Mechanism of Injury Number (%) Forearm 36 (7)
Awkward landing on the trampoline 292 (53) Wrist/hand 77 (14)
Fall off the trampoline 122 (22) Hip/thigh 10 (2)
Collision with another person 73 (13) Knee 49 (9)
Performing a somersault 59 (11) Leg 15 (3)
Other 5 (1) Ankle 141 (25)
Unknown 5 (1) Foot 31 (6)
Total 551 (100) Total 556 (100)
Data compiled from Nysted M, Drogset JO. Trampoline injuries. Br J Data compiled from Nysted M, Drogset JO. Trampoline injuries. Br J
Sports Med. 2006;40:984–987; Smith GA. Injuries to children in Sports Med. 2006;40:984–987; Smith GA. Injuries to children in
the United States related to trampolines, 1990–1995. Pediatrics. the United States related to trampolines, 1990–1995. Pediatrics.
1998;101:406–412; Furnival RA, Street KA, Schunk JE. Too 1998;101:406–412; Furnival RA, Street KA, Schunk JE. Too many
many trampoline injuries. Pediatrics. 1999;103:1020–1025; and trampoline injuries. Pediatrics. 1999;103:1020–1025; and
Woodward GA, Furnival R, Schunk JE. Trampolines revisited: a review Woodward GA, Furnival R, Schunk JE. Trampolines revisited: a review
of 114 pediatric recreational trampoline injuries. Pediatrics. 1992;89: of 114 pediatric recreational trampoline injuries. Pediatrics. 1992;89:
849–854. 849–854.
2560_Chapter 21_0239-0252.indd 245 3/16/2015 4:14:05 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
participants, most of whom are female.39,40 According shoulder or that a median nerve injury may accompany
to one study,39 the number of cheerleading-related a severe wrist fracture. Additional epidemiological
injuries sustained by children 5 to 18 years old and work is required to assess the number and severity of
treated in U.S. hospital emergency departments more nerve injuries associated with cheerleading.
than doubled from an estimated 10,900 injuries in In a study by Shields and Smith,39 concussions rep-
1990 to an estimated 22,900 injuries in 2002. Cheer- resented only 4% of all cheerleading injuries. A similar
leading was a relatively sedentary, ground-based sport study conducted by Schulz et al.42 concluded that
30 years ago with routines consisting primarily of toe- concussions account for 6% of cheerleading-related
touch jumps, splits, and claps.40 Today, cheerleading injuries. Concussions, if undetected, can expose a
routines incorporate gymnastic tumbling runs and cheerleader to the potential for repetitive traumatic
partner stunts consisting of human pyramids, lifts, brain injury. Repetitive traumatic brain injury occurs
catches, and tosses. The increasing number of cheer- after an individual sustains an initial head injury
leading injuries may be associated with this change to (usually a concussion), followed by a second head injury
more gymnastic-style cheerleading routines.40 An before symptoms associated with the first have fully
increase in the number of cheerleading participants cleared. The second blow may be minor and could
may also be a factor. Although the actual number result in brain swelling. Although repetitive traumatic
of cheerleading participants is unknown, American brain injury is most common in contact and collision
Sports Data Inc.41 reported that the number of U.S. sports such as ice hockey, boxing, and football, it may
cheerleading participants 6 years old and older increased also be sustained when cheerleaders collide with other
from 3,039,000 in 1990 to 3,579,000 in 2003. cheerleaders. However, data do not currently exist to
Compared with injuries in other sports, cheerlead- confirm this. Cheerleaders, their parents, cheerleading
ing injuries have not received the same amount of coaches, athletic trainers, and health care providers
concern in the literature with regard to tracking, sever- should be aware of the signs and symptoms of concus-
ity, type, and reportability. Few epidemiological studies sions and the potential for repetitive traumatic brain
of cheerleading injuries exist in the literature, and none injury.
of the existing studies describe the epidemiology of
cheerleading injuries by type of cheerleading team
(college, high school, middle school, elementary school, Baseball
or recreation league) or type of cheerleading event
(practice, pep rallies, athletic events, or cheerleading Most peripheral nerve injuries occurring in baseball are
competitions). seen with pitchers. The number of pitches thrown in a
Shields and Smith39 were the first to report cheer- given day (as many as 200 including warm-up and
leading injury rates based on actual exposure data by actual game pitches) over the course of a full 8-month
type of team and event. A cohort of 9,022 cheerleaders season; the angular velocity of the pitcher’s arm (mea-
on 412 U.S. cheerleading teams participated in the sured as high as 7,500 degrees per second); and the
study. During the 1-year data-collection period, 567 torque produced at the shoulder, elbow, and wrist with
cheerleading injuries were reported: 83% (467 of 565) throwing curve balls, sliders, and cutters all have been
occurred during practice, 52% (296 of 565) occurred implicated in the relatively high incidence of nerve
while the cheerleader was attempting a stunt, and 24% injury in pitchers.43 In baseball pitchers, nerve injury
(132 of 563) occurred while the cheerleader was basing has been cited in the literature to account for approxi-
or spotting one or more cheerleaders. Lower extremity mately 2% of all diagnosed shoulder injuries.43
injuries (30%; 168 of 565) and strains and sprains Quadrilateral space syndrome represents a chronic
(53%; 302 of 565) were most common. Collegiate compression syndrome of the axillary nerve in throw-
cheerleaders were more likely to sustain a concussion ing athletes. Axillary nerve entrapment occurs insidi-
(P = 0.01, rate ratio [RR] = 2.98, 95% confidence ously in the quadrilateral space without history of
interval [CI] = 1.34, 6.59), and All Star cheerleaders trauma. Fibrous bands at the inferior edge of the teres
were more likely to sustain a fracture or dislocation (P minor have been implicated, as have randomly oriented
= 0.01, RR = 1.76, 95% CI = 1.16, 2.66) than cheer- fibrous bands found in the quadrilateral space. Both the
leaders on other types of teams. Overall injury rates for axillary nerve and the posterior humeral circumflex
practices, pep rallies, athletic events, and cheerleading artery are compressed in the quadrilateral space when
competitions were 1.0, 0.6, 0.6, and 1.4 injuries per the arm is placed in the abducted, externally rotated,
1,000 athlete-exposures. or throwing position.24
From a peripheral nerve injury standpoint, the dis- Posterior interosseous neuropathy (PIN) is a pe-
cussion of the type of injury reported is not of sufficient ripheral nerve injury commonly characterized by a
depth to discern if nerve injury occurred with the sensation of a deep ache in the posterior forearm,
orthopedic-described pathology. It is certainly possible which can be accompanied by weakness of the forearm
that a plexus injury may result with a dislocated extensors and brachioradialis, sensory alterations, or a
2560_Chapter 21_0239-0252.indd 246 3/16/2015 4:14:05 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
combination of both. PIN occurs with less frequency occur as a result of a congenital anomaly, such as a
in the upper extremity than median and ulnar mono- cervical rib or a prefixed plexus; repetitive motion;
neuropathies.44 Among athletes, the incidence of PIN posture; or muscle hypertrophy. Symptoms include arm
is unknown. Mechanical soft tissue injuries can mani- and forearm weakness and pallor, loss of distal pulses,
fest in a self-limiting manner and with symptoms (pain and occasionally sensory loss within the C5–T1 der-
and weakness) similar to a peripheral neuropathy, matomes, owing to the proximity of the plexus to the
which can make differentiating each condition a chal- artery. Exercise including neural glides and soft tissue
lenge. The proposed mechanism for injury in this case stretching is often effective. However, many cases pro-
is the mechanics during the late stages of the throwing gress to conditions that may require surgical neurolysis,
motion—the follow-through. The follow-through is scalenectomy, or first rib resection.
defined as the progression of motion from maximal Following carpal tunnel syndrome, cubital tunnel
shoulder internal rotation to a balanced fielding posi- syndrome is the second most common peripheral nerve
tion after the ball has been released. This is the phase entrapment syndrome in the human body. When
of throwing that exhibits high levels of eccentric appropriately diagnosed in a timely fashion, this condi-
loading at the forearm along with repeated supination- tion may be treated by conservative and operative
pronation as a potential effect that places stress to the means with little or no resultant loss of function. The
soft tissues of the throwing arm. cubital tunnel is formed by the cubital tunnel retinacu-
The muscles involved with the deceleration phase of lum, which straddles a gap of about 4 mm between the
the follow-through are the rotator cuff muscles, deltoid, medial epicondyle and the olecranon. The floor of the
triceps brachii, brachialis, supinator, and forearm exten- tunnel is formed by the capsule and the posterior band
sor muscles. These muscles undergo eccentric loading of the medial collateral ligament of the elbow joint. It
that can theoretically compress or apply excessive tensile contains several structures, the most important of
loading along the course of the radial nerve. This theory which is the ulnar nerve. The ulnar nerve is the termi-
has not been substantiated in the literature. nal branch of the medial cord of the brachial plexus
Upper extremity deep venous thrombosis (UEDVT) and contains fibers from the C8 and T1 spinal nerve
is also known as thrombosis of the axillary-subclavian roots. It descends the arm just anterior to the medial
vein or Paget-Schroetter syndrome.45 It is considered intermuscular septum and later pierces this septum in
a relatively infrequent disorder that occurs predomi- the final third of its length. Progressing underneath the
nantly in young, otherwise healthy individuals who septum and adjacent to the triceps muscle, it traverses
participate in repetitive upper extremity activities that the cubital tunnel to enter the forearm, where it passes
result in subclavian vein irritation.46 From an epide- between the two heads of the flexor carpi ulnaris
miological perspective, the general incidence of muscle.
UEDVT remains low (approximately 2 per 100,000 This anatomical arrangement has two implications
persons per year), even though it is regarded as the for the nerve. First, the ulnar nerve follows a relatively
most common vascular condition among athletes.47 constrained, nonundulating path,50 and second, it
Symptoms are nonspecific, are variable, range in sever- lies some distance from the axis of rotation of the
ity, and may be position dependent. Occasionally, elbow joint.51 Movement of the elbow requires the
patients may be asymptomatic. However, most com- nerve to stretch and slide through the cubital tunnel.
monly, patient complaints include initial “heaviness” in Sliding has the greatest role in this process, although
the affected arm and a dull ache and pain in the neck, the nerve itself can stretch up to 5 mm.50 The unusual
shoulder, or axilla of the involved limb. The differential anatomy of the cubital tunnel and the well-recognized
diagnosis is complex because patients with UEDVT increase in intraneural pressure associated with elbow
typically display compressive signs usually associated flexion are believed to be key issues in the pathogenesis
with thoracic outlet syndrome, contributing to the like- of cubital tunnel syndrome.51 In addition, the shape
lihood that a structure compressing the subclavian vein of the tunnel changes from an oval to an ellipse
may also compress the brachial plexus.48 Other more with elbow flexion. This maneuver narrows the canal
dramatic signs of UEDVT may include ecchymosis by 55%.52
and nonedematous swelling of the shoulder, arm, and The American and Japanese literature places a heavy
hand; functional impairment; discoloration and mottled emphasis on the susceptibility of baseball throwers to
skin; and distention of the cutaneous veins of the cubital tunnel syndrome. Ulnar nerve symptoms during
involved upper extremity.49 Conservative treatment the part of the throwing cycle that involves extreme
including exercise and anticoagulation medication is flexion (late cocking, valgus stress, early acceleration)
often ineffective. Patients with UEDVT commonly are strongly suggestive of the biomechanical etiology
require surgical intervention, including the removal of of cubital tunnel syndrome.53
the first rib or scalene muscles. Arterial thoracic syn- Initial treatment for cubital tunnel syndrome is rest
drome results from the compression of the subclavian and avoidance of the etiological behavior. If rest fails
artery within the thoracic outlet. Compression may to improve symptoms or if the needle examination
2560_Chapter 21_0239-0252.indd 247 3/16/2015 4:14:05 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
becomes positive for distal denervation, surgical explo- tendinoses, flexor-pronator mass injuries, neuritis of
ration is indicated. Neurolysis and transposition ante- the ulnar nerve, posterior impingement, and olecranon
riorly are two common procedures. stress fractures.56 Tennis places the ligamentous,
osseous, musculotendinous, and neural structures of the
elbow at increased risk for various injuries. Proper
Volleyball training and preventive exercise based on sound bio-
mechanical research can result in decrease of loads
The NCAA conducted its first women’s volleyball across the elbow in tennis players.
championship in 1981. In the 1988–1989 academic Knowledge of the kinetic chain of the tennis service
year, 721 schools sponsored varsity women’s volleyball and stroke should be taken into account by tennis
teams comprising 9,486 participants. By 2003–2004, athletic trainers, physical therapists, and instructors.
the number of varsity teams had increased 36% to 982, For example, biomechanical analyses of tennis players
involving 310 participants.54 Participation growth indicated that with more effective knee flexion-
during this time has been apparent in all three divisions extension during the service action, there was less
of college sport, but particularly in Divisions II valgus strain and loading at the elbow.57 The exact
and III.54 impact of this finding is as yet unknown and needs to
Agel et al.55 published an excellent monograph on be studied further.
the epidemiology of volleyball injuries in women. In Internal rotation of the upper arm at the shoulder
games, ankle ligament sprains (44.1%), knee internal during the overhead service and forehand is of utmost
derangements (14.1%), shoulder muscle strains (5.2%), importance—decrease of internal rotation in the shoul-
and low back muscle strains (4.8%) accounted for most der can increase rotatory stress on the elbow. Internal
injuries. In practices, ankle ligament sprains accounted rotation of the upper arm and pronation of the
for 29.4% of all reported injuries, whereas other forearm during the early phase of the follow-through
common injuries were upper leg muscle-tendon strains of the service most likely reduces the forces on the
(12.3%), low back muscle-tendon strains (7.9%), and elbow. Grip size does not seem to play a role in elbow
knee internal derangements (7.8%). A participant had injuries; playing with a “Western grip” can possibly
twice the risk of sustaining a knee internal derange- increase valgus stress on the elbow, especially during
ment in a game (0.46 vs. 0.22 per 1,000 A-Es; acceleration.58
RR = 2.1, 95% CI = 1.8, 2.5) than in a practice. Female The primary peripheral nerve injury associated with
volleyball players also had almost twice the risk of tennis is cubital tunnel syndrome. Ulnar neuritis around
sustaining an ankle sprain in a game than during a the elbow can be the result of compression or traction
practice (1.44 vs. 0.83 per 1000 A-Es; RR = 1.7, 95% from valgus stress and can be seen as an isolated injury
CI = 1.6, 1.9). The rate of ankle sprains has decreased or in combination with UCL insufficiency or chronic
on average per year by 1.8% (P = 0.15) in games flexor-pronator mass tendinosis. Compression can
and 3.0% (P = 0.04) in practices over the 16 years occur as a result of a tight cubital tunnel, osteophytes
of this study. The specific structures injured most from the ulnohumeral joint, muscle hypertrophy, or
frequently during games and practices combined were subluxation of the nerve. In tennis players, the initial
the menisci and collateral ligaments. The authors’ data presentation of ulnar neuritis can be pain along the
did not include concurrent nerve injuries with the medial joint line associated with dysesthesias, paresthe-
reported musculoskeletal injuries, although nerve sias, or even anesthesia in the small and ulnar half of
injury is a common complication of all the diagnoses the ring finger. The degree of sensory and motor
reported.55 changes can vary depending on the severity and dura-
tion of ulnar nerve compression. Functionally, players
lose the ability to grasp the racket properly and lose
Tennis tactile and proprioception sensation in the hand. Surgi-
cal intervention is indicated in cases of progressive
The ligamentous, osseous, musculotendinous, and muscle weakness, persistent muscle weakness for more
neural structures at the posteromedial side of the than 4 months, chronic neuropathy, or failure of a non-
elbow are at risk for various injuries during overhead surgical regimen.59
athletics. Tennis, in particular, subjects an individual to In a cadaver study, the movement of the ulnar nerve
the combination of valgus and extension overloading. at the proximal aspect of the cubital tunnel was signifi-
Motions such as an overhead serve result in tensile cantly increased during all service phases with increased
forces along the medial stabilizing structures, with elbow flexion (P < 0.05). A mean (standard deviation)
compression on the lateral compartment and shear maximum movement of 12.4 (± 2.4) mm was recorded
stress posteriorly. The combination of tensile forces during the wind-up phase with maximum elbow
medially and shear forces posteriorly can result in ulnar flexion. The maximum strain on the ulnar nerve during
collateral ligament (UCL) tears, tendinopathies and the acceleration phase was found to be close to the
2560_Chapter 21_0239-0252.indd 248 3/16/2015 4:14:05 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
60
elastic and circulatory limits of the nerve. The ulnar Because this powerful movement is repeated
nerve is subjected to longitudinal strain in the cubital throughout the game or practice session, decreased
tunnel during the service motion, and this longitudinal endurance or weak muscles could lead to premature
strain is increased as the elbow is in greater flexion.61 fatigue and increased injury risk to the trunk region.
Suprascapular nerve injuries have also been reported McGill65 discussed and advocated the importance of
with tennis players. Symptoms of suprascapular nerve trunk endurance in preventing low back pain (LBP).
palsy generally have an insidious onset and are poorly Lindsay et al.64 found associations in a population of
localized. Athletes with suprascapular neuropathy typi- golfers between poor static trunk extensor endurance
cally have vague posterior shoulder pain, weakness and increased quadriceps inhibition. Quadriceps inhi-
of abduction and external rotation, and atrophy of bition was postulated to be reflective of irritation to
the infraspinatus or supraspinatus (or both) muscle the lumbar structures. Clinical ramifications from the
bellies. Pain may radiate down the radial axis of the present study suggest that muscular endurance exer-
arm. When entrapment of the suprascapular nerve cises focusing on rotation of the trunk should be an
occurs at the spinoglenoid area, pain is an inconsistent important component of rehabilitation programs tar-
finding. Because the suprascapular nerve has no dermal geting golfers with LPB and as prophylaxis in prevent-
distribution, pain is poorly localized and commonly ing LBP.
leads to a delay in diagnosis (on average 12 months). Injuries to the lower back are one of the most
Physical examination of suprascapular nerve entrap- common golf-related problems. The incidence of golf-
ment syndrome can follow repetitive motions, pro- related lower back injury ranges from 15% to 34% in
longed positioning, or single acute events. Entrapment amateur golfers and 22% to 24% in professional
can also occur more distally at the spinoglenoid notch, golfers.65 Collectively, the incidence of lower back pain
which is more commonly seen in athletes whose sports in male golfers is 25% to 36% and 22% to 27% in
require rapid forceful external rotation movements female golfers.64 Despite the high participation rate
such as volleyball.58 The cocking motion for the serve and the large financial support of the golf industry,
results in rapid external rotation of the shoulder. This current data on golf-related injury epidemiology that
rapid motion of the infraspinatus muscle is thought to could specifically direct practitioners in the manage-
pull the suprascapular nerve against the base of the ment of these problems are limited.66 McGill65
scapular spine, resulting in nerve injury at this level. described the play characteristics of golfers who had an
Injury to nerves in the spinoglenoid area has also been injury to their lower back in the course of play or prac-
noted secondary to ganglion cysts. Ganglion cysts in tice in the previous year (12 months). In addition,
athletes appear to be related to posterior labral injuries common injury mechanisms for the back injury were
and may be associated with posterior instability. Pos- sought to determine if factors such as age, sex, and
terior shoulder instability may also result in traction amount of play or practice affected the back injury rate.
injury of the suprascapular nerve without ganglion cyst Finally, the study aimed to report the practitioner uti-
formation.62 lization or back injury management among the golfers
surveyed.
McGill65 reported that of 1,634 Australian amateur
Golf golfers surveyed, 17.6% of golfers sustained at least one
injury in the previous year. The lower back accounted
The effective execution of the golf swing not only for 25% of all golf-related injuries in the previous year,
requires rapid movement of the extremities but also making the lower back the most common site of injury.
substantial strength and power of the trunk muscles. A golfer with a golf-related lower back injury was likely
The torso rotates away from the target (to the right for to have a previous history of lower back injury as well.
a right-handed player; to the left for a left-handed The follow-through phase of the golf swing was
player) at approximately 85 degrees/second on the reported to be associated with the greatest likelihood
backswing, and the powerful downswing involves trunk of injury compared with other phases of the swing.
rotational velocities approaching 200 degrees/second.63 Most of the injured golfers received treatment of their
Pink et al.63 demonstrated relatively high and constant injury with a general practitioner (69%), a physical
activity in the abdominal oblique muscles throughout therapist (49%), or a chiropractor (40%).
most parts of the golf swing of skilled amateur players. Practitioners treating golfers with a history of lower
In a similar study using professional golfers, Lindsay et back injury should evaluate trunk muscle strength
al.64 measured muscle activity in the erector spinae, and evaluate the golf swing—especially the follow-
abdominal oblique, and rectus abdominis. These authors through—to identify potential causes of aggravation to
established that all trunk muscles were relatively active the lower back. Targeted measures, such as spinal
during the acceleration phase of the golf swing with manipulative therapy, soft tissue and back exercise, and
the trail-side abdominal oblique muscles showing the conditioning programs to assist the strength and
highest level of activity. mobility of the golfer, could then be implemented.
2560_Chapter 21_0239-0252.indd 249 3/16/2015 4:14:05 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
2. Bill returns to the clinic 3 days later after having
Ice Hockey magnetic resonance imaging (MRI) of the shoulder
and electrodiagnostic studies. MRI was “normal,” but
The common peroneal nerve separates from the sciatic
the needle portion of the electroneuromyogram
nerve in the upper popliteal fossa. It then passes down-
revealed an axonotmetic lesion of the right axial
ward and laterally through the popliteal fossa, lies
nerve with evidence of mild denervation of the
behind the head of the fibula, winds obliquely around
involved deltoid. Your recommendation would be
the neck of the fibula, and pierces the superficial head
which of the following?
of the long peroneal muscle to enter the anterior
a. Continue to pitch through the pain
compartment of the leg. During its course around
b. Continue to pitch through the pain and begin
the fibula, the nerve is quite superficial and is easily
shoulder strengthening exercises
damaged by trauma. In ice hockey, the two most
c. Stop pitching and rest
common etiologies for common peroneal nerve injury
d. Stop pitching and begin shoulder strengthening
are direct trauma secondary to “boarding,” falls, or
exercise
being hit by the puck or stick and laceration from an
ice skate.67 3. If the therapist had noted edema in the involved
upper extremity along with the nerve lesion, a
possible diagnosis would be which of the following?
a. Venous thoracic outlet syndrome (Pagett-Schroetter
syndrome)
CASE STUDY b. Brachial plexopathy
c. Arterial thoracic outlet syndrome
Bill is a Division I baseball pitcher who has been
d. Carpal tunnel syndrome
averaging 100 pitches per game. He is scheduled to
pitch every fifth day. Late in the season, Bill estimates 4. Possible etiologies for Bill’s problem include which of
that he has started 18 games over the past 3 months. the following?
Bill presents now to the outpatient orthopedic clinic a. Overuse
with a “tired arm.” He feels his velocity is down b. Intrinsic scapular weakness
compared with early in the year, and he has noticed c. Poor pitching technique
what he feels is “atrophy” of his pitching shoulder. The d. All of the above
quality of his pitching as measured statistically has
5. Weakness of which muscle would most likely rule out
decreased over his last two starts. He also complains
a simple axillary nerve injury?
of an “ache” in his pitching shoulder at night that
a. Anterior deltoid
interrupts his sleeping. Bill is quite anxious; he feels he
b. Posterior deltoid
is worsening instead of getting better.
c. Biceps
On examination, there is mild atrophy of the
d. Teres minor
involved shoulder. Pulses in all positions are +2. There
is mild sensory loss over the involved deltoid. Isokinetic
testing reveals an 18% reduction of torque in the
involved anterior deltoid compared with the uninvolved
side. Altogether, muscle groups test within 5% of the References
contralateral limb. Deep tendon reflexes are preserved. 1. Albright JP, McAuley E, Martin RK, Crowley ET, Foster DT.
A cervical spine screen reveals no abnormalities. Head and neck injuries in college football: an eight-year
Volumetric studies reveal no upper extremity edema. analysis. Am J Sports Med. 1985;13:147–152.
2. Barbe MF, Safadi FF, Rivera-Nieves EI, Montara TE, Popoff
SN, Barr AE. Expression of ED1, ED2, IL-1 and COX2 in
Case Study Questions bone and in the rat model of cumulative trauma disorder
(CTD). Paper presented at: American Society for Bone
1. Based on the information documented in the case Mineral Research 21st Annual Meeting; September 30–
study, the best action for you to take as the primary October 4, 1999; St. Louis, MO.
therapist is which of the following? 3. Barr AE, Barbe MF. Inflammation reduces physiological
tissue tolerance in the development of work-related
a. Instruct Bill to “pitch through the pain” and things musculoskeletal disorders. J Electromyogr Kinesiol. 2004;14:
will soon get better 77–85.
b. Begin Bill on a general strengthening regimen 4. Carp SJ, Barbe MF, Winter KA, Amin M, Barr AE.
directed at the shoulder and scapular musculature Inflammatory biomarkers increase with severity of upper-
c. Refer Bill for further testing with a tentative extremity overuse disorders. Clin Sci (Lond). 2007;112;
305–314.
diagnosis of axillary nerve injury 5. Carp SJ, Barbe MF, Barr AE. Serum biomarkers as signals
d. Prescribe a sling and rest with follow-up in for risk and severity of work-related musculoskeletal injury.
1 week Biomark Med. 2008;2:67–79.
2560_Chapter 21_0239-0252.indd 250 3/16/2015 4:14:05 PM

Process CyanProcess
YellowProcess Black
6. DiBennedetto M, Markey K. Electrodiagnostic localization 31. Fukuda H. Bilateral peroneal nerve palsy caused by
of traumatic upper trunk brachial plexopathy. Arch Phys Med intermittent pneumatic compression. Intern Med. 2006;45(2):
Rehabil. 1984;65:15. 93–94.
7. Kepatnas G. The effect of local corticosteroids on healing and 32. Fetzer GB, Prather H, Gelberman RH, Clohisy JC.
biomechanical activity in partially injured tendon sheaths. Progressive peroneal nerve palsy in a varus arthritic knee.
Clin Orthop Relat Res. 1982;163:160–179. J Bone Joint Surg Am. 2004;86(7):1538–1540.
8. Mackinnon SE, Hudson AR, Falk RE, Kline D, Hunter D. 33. Langenhove M, Pollefliet A, Vanderstraeten G. A
Peripheral nerve allograft: an assessment of regeneration retrospective electrodiagnostic evaluation of footdrop in 303
across pretreated nerve allografts. Neurosurgery. 1984;15: patients. Electromyogr Clin Neurophysiol. 1989;29:145–152.
690–693. 34. Nysted M, Drogset JO. Trampoline injuries. Br J Sports Med.
9. Buford K. Native American: The Life and Sporting Legend of 2006;40:984–987.
Jim Thorpe. New York: Alfred A Knopf; 2010:62–64. 35. Smith GA. Injuries to children in the United States related
10. Warren RF. Neurologic injuries in football. In: Jordan BD, to trampolines, 1990–1995. Pediatrics. 1998;101:406–412.
Tsairis P, Warren RF, eds. Sports Neurology. Rockville, MD: 36. Furnival RA, Street KA, Schunk JE. Too many trampoline
Aspen; 1989:235–237. injuries. Pediatrics. 1999;103:1020–1025.
11. Sallis RE, Jones K, Knopp W. Burners: offensive strategy for 37. Woodward GA, Furnival R, Schunk JE. Trampolines
an underreported injury. Phys Sportsmed. 1992;20:47–55. revisited: a review of 114 pediatric recreational trampoline
12. Speer KP, Bassett FJ III. The prolonged burner syndrome. injuries. Pediatrics. 1992;89:849–854.
Am J Sports Med. 1990;18:591–594. 38. Brown PG, Lee M. Trampoline injuries of the cervical spine.
13. Levitz CL, Reilly PJ, Torg JS. The pathomechanics of chronic, Pediatr Neurosurg. 2000;32(4):170–175.
recurrent cervical nerve root neurapraxia. The chronic burner 39. Shields BJ, Smith GA. Cheerleading-related injuries to
syndrome. Am J Sports Med. 1997;25:73–76. children 5 to 18 years of age: United States, 1990–2002.
14. Poindexter DP, Johnson EW. Football shoulder and neck Pediatrics. 2006;117(1):122–129.
injury: a study of the “stinger.” Arch Phys Med Rehabil. 1984; 40. Hutchinson MR. Cheerleading injuries: patterns, prevention,
65:601–602. case reports. Physician Sportsmed. 1997;25(9):83–96.
15. Markey KL, Di Benedetto M, Curl WW. Upper trunk 41. American Sports Data Inc. The Superstudy of Sports
brachial plexopathy. The stinger syndrome. Am J Sports Med. Participation: Volume II. Recreational Sports 2003. Hartsdale,
1993;21:650–655. NY: American Sports Data Inc; 2004.
16. Warren RF. Neurological injuries in football. In: Jordan BD, 42. Schulz MR, Marshall SW, Yang J, Mueller FO, Weaver NL,
Tsairis P, Warren RF, eds. Sports Neurology. Rockville, MD: Bowling JM. A prospective cohort study of injury incidence
Aspen; 1989:235–237. and risk factors in North Carolina high school competitive
17. Hershman EV. Brachial plexus injuries. Clin Sports Med. cheerleaders. Am J Sports Med. 2004;32(2):396–405.
1990;9:311–329. 43. Cumming C, Schneider D. Peripheral nerve injuries in
18. Feinberg JH, Radecki J, Wolfe SW, Strauss L, Mintz DN. baseball players. Neurol Clin. 2008;26:195–215.
Brachial plexopathy/nerve root avulsion in a football player; 44. Robb A, Sajko S. Conservative management of posterior
the role of electrodiagnostics. HSS J. 2008;4:87–95. interosseous neuropathy in an elite baseball pitcher’s return to
19. Archembault JL. Brachial plexus stretch injuries. J Am Coll play: a case report and review of the literature. J Can Chiropr
Health. 1983;31:256–260. Assoc. 2009;53:300–310.
20. Blom S, Dahlback LO. Nerve injuries in dislocations of the 45. Dunant JH. Effort thrombosis, a complication of thoracic
shoulder joint and fractures of the neck of the humerus: A outlet syndrome. Vasa. 1981;10:322–324.
clinical and electromyographical study. Act Chir Scand. 1970; 46. Medler RG, McQueen DA. Effort thrombosis in a young
136:461–466. wrestler, a case report. J Bone Joint Surg Am. 1993;75:
21. Pasila M, Jaroma H, Kiviluoto O, Sundholm A. Early 1071–1073.
complications of primary shoulder dislocations. Acta Orthop 47. Urschel HC, Razzuk MA. Paget Shroetter syndrome:
Scand. 1978;49(3):260–263. what is the best management? Ann Thorac Surg. 2000;69:
22. Meister K. Injuries to the shoulder in the throwing athlete: 1663–1668.
part two: evaluation/treatment. Am J Sports Med. 2000;28: 48. Joffe HV, Goldhaver SZ. Upper-extremity deep vein
587–601. thrombosis. Circulation. 2002;106:1874–1880.
23. Katzman BM, Bozentka DJ. Peripheral nerve injuries 49. Hurley B, Comins SA, Green RM, Canizzaro J. Atraumatic
secondary to missiles. Hand Clin. 1999;15(2):233–244. subclavian vein thrombosis in a collegiate baseball player: a
24. Duralde XA. Neurological injuries to the athlete’s shoulder. case report. J Athl Train. 2006;41:198–200.
J Athl Train. 2000;35:316–328. 50. Kanazawa S, Fujioka H, Kanatani T, et al. The relation
25. McIlveen SJ, Duralde XA, D’Alessandro DF, Bigliani LU. between cubital tunnel syndrome and the elbow alignment.
Isolated nerve injuries about the shoulder. Clin Orthop Relat Kobe J Med Sci. 1994;40:155–163.
Res. 1994;306:54–63. 51. Descatha A, Leclerc A, Chastang JF, et al. Incidence of ulnar
26. Goodman CE. Unusual nerve injuries in recreational nerve entrapment at the elbow in repetitive work. Scand J
activities. Am J Sports Med. 1983;11:224–227. Work Environ Health. 2004;30:234–240.
27. McIlveen SJ, Duralde XA. Isolated nerve injuries about the 52. Kakosy T. Tunnel syndromes of the upper extremities in
shoulder. In: Bigliani LU, ed. Complications of Shoulder workers using hand-operated vibrating tools. Med Lav. 1994;
Surgery. New York: Williams & Wilkins; 1993:64–68. 85:474–480.
28. Burge PD, Rushworth G, Watson NA. Patterns of injury to 53. Aoki M, Kanaya K, Aiki H, et al. Cubital tunnel syndrome in
the terminal branches of the brachial plexus: the place for adolescent base ball players: a report of 6 cases with 3 to 5
early exploration. J Bone Joint Surg Br. 1985;67:630–634. year follow up. Arthroscopy. 2005;21:758.
29. McCrory P, Bell S, Bradshaw C. Nerve entrapments of the 54. 1981/1982–2004/2005 NCAA Sports Sponsorship and
lower leg. Sports Med. 2002;32(6):371–391. Participation Rates Report. Indianapolis, IN: NCAA; 2006.
30. Katirji MB, Wilbourn AJ. Common peroneal 55. Agel J, Palmieri-Smith RM, Dick R, Wojtys EM, Marshall
mononeuropathy: a clinical and electrophysiologic study of SW. Descriptive epidemiology of collegiate woman’s
116 lesions. Neurology. 1988;38:1723–1728. volleyball injuries: National Collegiate Athletic Association
2560_Chapter 21_0239-0252.indd 251 3/16/2015 4:14:05 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Injury Surveillance System, 1988–1989 through 2003–2004. 61. Eisen A, Danon J. The mild cubital tunnel syndrome. Its
J Athl Train. 2007;42:295–302. natural history and indication for surgical intervention.
56. Elliott B, Fleisig G, Nicholls R. Technique effects on upper Neurology. 1974;24:608–613.
limb loading in the tennis serve. J Sci Med Sport. 2004;6: 62. Ferretti A, Cerullo G, Russo G. Suprascapular neuropathy in
76–87. volleyball players. J Bone Joint Surg Am. 1987;69:260–263.
57. Hatch GF 3rd, Pink MM, Mohr KJ, et al. The effect of 63. Pink M, Perry J, Jobe FW. Electromyographic analysis of the
tennis racket grip size on forearm muscle firing patterns. trunk in golfers. Am J Sport Med. 1993;21:385–388.
Am J Sports Med. 2006;34:177–183. 64. Lindsay DM, Horton JF, Paley RD. Trunk motion of male
58. Eygendaal D, Rahussen FTG, Diercks RL. Biomechanics professional golfers using two different golf clubs. J Appl
of the elbow joint in tennis player related to pathology. Biomech. 2002;18:366–373.
Br J Sports Med. 2007;41(11):820–823. 65. McGill SM. Low back exercises: evidence for improving
59. Posner MA. Compressive ulnar neuropathies at the elbow. II. exercise regimens. Phys Ther. 1999;78:754–765.
Treatment. J Am Acad Orthop Surg 1998;6:289–297. 66. Gosheger G, Liem D, Ludwig K, et al. Injuries and overuse
60. Aoki M, Takasaki H, Muraki T, Uchiyama E, Murakami G, syndromes in golf. Am J Sports Med. 2003;31(3):438–443.
Yamashita T. Strain on the ulnar nerve at the elbow and wrist 67. Shevell MI, Steward JD. Laceration of the common
during throwing motion. J Bone Joint Surg Am. 2005;87: peroneal nerve by a skate blade. Can Med Assoc J. 1988;139:
2508–2514. 311–312.
2560_Chapter 21_0239-0252.indd 252 3/16/2015 4:14:05 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 22
Effects of Peripheral
Neuropathy on Posture
and Balance
EMILY A. KESHNER, PT, EDD, AND JILL C. SLABODA, PHD
“Life is like riding a bicycle. In order to keep your balance

you must keep moving.”
—ALBERT EINSTEIN (1879–1955)
Objectives
• Discuss the relationship of afferent and efferent peripheral nerve contributions to normal balance and
postural control.
• Discuss the functional relationship of loss of balance-related sensory pathways.
• Identify the positional and functional impact of diabetic sensory neuropathy.
• Explain the relationship between falls and neuropathy.
Key Terms
• Balance
• Postural compensation
• Postural control
exactly the ones impacted by the presence of peripheral

Introduction neuropathy.
Postural control is the result of a continuous inte-
Falls resulting in significant injury are a major health gration of information from the convergence of mul-
issue for older adults. Instability that results in a fall tiple sensory receptors. Proprioceptive, vestibular, and
is the leading cause of injury-related death and of visual signals have been most frequently identified as
nonfatal injury in the United States.1–3 The probability the primary contributors to postural control, but cor-
that an adult will experience a fall increases with age rective postural responses can also be influenced by
and with age-related disease. It has been reported other somatosensory feedback (e.g., tactile) as well as
that individuals with diabetes mellitus experience sub- feedforward (e.g., prediction of a slippery surface)
jective feelings of instability, and the risk of falling is mechanisms. Because there are so many possible path-
increased by a factor of 15 in patients with diabetic ways that could signal the beginning of a fall, one
neuropathy compared with healthy individuals.4,5 The would think that even if any single input were lost, the
dynamic process of maintaining an upright posture is other pathways would provide sufficient detail for the
vital to the health and independent functioning of the postural response to be appropriate to the task demands.
aging population. However, the mechanisms that are However, each sensory pathway has well-defined sen-
necessary for the maintenance of upright posture are sitivities to environmental stimuli.
253
2560_Chapter 22_0253-0268.indd 253 3/16/2015 4:14:08 PM

Process CyanProcess
YellowProcess Black
emerging treatment approaches for instability resulting
Motor plan
prediction/ from peripheral neuropathy associated with diabetes
perception are presented.
Peripheral Nerve Contributions

Visual Auditory to Posture Control
Somatosensory Signals
The somatosensory system, including proprioception,
touch, pressure, and vibration, is important for precise
detection of body position. It is commonly believed
that automatic postural responses are triggered by pro-
prioceptive inputs in the lower limb.18–20 Many studies
on automatic postural responses to stance perturba-
Somatosensory Vestibular tions have shown stereotypical patterns to occur in the
leg muscles after displacement of the base of support.
These patterns consist of activation of the ankle muscles
followed by the upper leg muscles to bring the center
Figure 22-1 Multiple contributions need to be processed by of mass (COM) back to its initial position. The auto-
the central nervous system during activities in a natural matic postural responses of the leg muscles to base of
environment. support translations were shown to be specific to the
direction of platform perturbation—that is, reactive to
the direction of ankle rotation. These responses were
For example, imagine the cyclists in Figure 22-1. Do termed “functional stretch reflexes.” It was observed
they rely more heavily on their motor plan for advanc- that both horizontal translations and up/down rota-
ing beyond the other cyclists or reacting to what they tions of the base of support rotate the ankle joint but
see and hear the others doing? Or do they pay more with different magnitudes of body sway; yet they
attention to their muscle and joint receptors telling trigger similar patterns of postural response in the leg
them how fast they are pedaling or how fatigued they muscles. It was hypothesized that the initiation of
are getting? With all of this continuous feedback, when these responses was primarily dependent on the ankle
do they focus on the vestibular information that may proprioceptive inputs elicited by the platform move-
be telling them they are starting to tilt? Sensitivities of ment.18 Removal of visual inputs had little effect on the
the pathways for sensory information completely latencies or organization of these leg muscle responses21
overlap,6–8 and experimental studies have been able to further supporting this hypothesis of proprioceptive
exclude any single input (i.e., proprioceptive,9 visual,10 control.
vestibular,11 or plantar cutaneous12) as the primary The determination of whether it is solely ankle pro-
trigger for the automatic postural reactions. Instead, prioception that generates the postural responses
the specialized characteristics of each pathway deter- depends greatly on the actual task. When the muscles
mine whether that pathway more or less modulates the along both the anterior and the posterior aspects of the
delivery of information about the environmental cir- body were recorded from ankle to neck,22 a descending
cumstances encountered during an active lifestyle. To pattern starting from the neck muscles and reorienting
produce a healthy postural response that aligns the the head and trunk to vertical was observed simultane-
body with respect to earth vertical and various body ously with the ascending pattern from the lower limb
parts with respect to each other across a wide variety muscles. The absence of a time delay between the earli-
of task demands, convergence of information from all est response in the neck and the ankle was strongly
of the sensory systems (vestibular, somatosensory, and indicative that inputs other than lower limb proprio-
visual) is preferable.13 ceptors were initiating upper body postural responses.
A large body of evidence demonstrates that the loss Two possible pathways are the vestibular and the visual
of peripheral somatosensory information produces systems.
severe consequences on human balance and locomo-
tion.4,14–17 This chapter presents current opinions about Vestibular Signals
the role of three primary sensory pathways for postural The vestibular system has an ambiguous role in the
control. Modifications in static posture and dynamic control of posture. Although the vestibular system is
balance following the loss of any of these inputs sec- not responsible for initiating automatic postural reac-
ondary to aging or disease are described. Finally, some tions, it is responsible for establishing orientation in
2560_Chapter 22_0253-0268.indd 254 3/16/2015 4:14:08 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 22 | Effects of Peripheral Neuropathy on Posture and Balance 255
23–29 49
space. The somatosensory system provides infor- direction of gaze. Instability as a result of viewing
mation about the position and motion of the body with distance has been reported only for static visual
respect to the support surface and body segments with stimuli.50,51 When spatial orientation and static pos-
respect to each other, whereas the vestibular system tural sway were examined in the presence of a looming
provides information with respect to gravity and other visual environment,52–54 it was found that visual inputs
inertial forces. dominated the response in the lower (0.1 Hz) fre-
Otolith function is relatively more resistant to quency range.7 When there is some unexpected cir-
damage than horizontal and vertical canal function and cumstance, such as a tilting room, individuals cannot
often remains intact even after injury to the semicircu- distinguish between full visual field motion and motion
lar canals. The vestibular otoliths, which detect linear of the body.24,55 These conflicts often lead to visual illu-
forces acting on the head, are believed to be responsible sions that may be exacerbated when vestibular infor-
for identifying vertical orientation through sensitivity mation is lost or unreliable.
to the gravity vector. In addition, reflex responses Studies of locomotion with combined central and
related to dynamic stimulation of the otolith organs are peripheral radial flow demonstrated that central and
more robust than reflex responses related to static stim- peripheral regions of the visual field are sensitive to
ulation of the otolith organs. However, even if the optic flow and differentially influence postural sta-
otoliths remain intact with labyrinthine loss, the ability bility in healthy subjects and patients with vestibu-
to identify an upright orientation may be impaired.30 lar disorders.56–58 Current findings contradict prior
Lateral head oscillations that were not correlated with assumptions that visual information is redundant to
eye movements during locomotion suggested that the postural control system unless both vestibular and
oscillopsia was an inability to detect spatial orientation somatosensory inputs were lost.59 Both the quality and
during head or body movements rather than a mere the location of the visual information evidently influ-
blurring of vision.31 It was also observed that subjects ence quiet stance and active motion.
with bilateral labyrinthine loss standing on a rotating
platform were progressively unable to regain an upright
posture even though they were repositioned in vertical Postural Adaptation to Loss of
after each trial.10 This observation suggests an inability
to create or maintain an internal vertical reference in a Sensory Pathway
the absence of labyrinthine inputs.
Sensory Reweighting
Visual Signals The sensory weighting hypothesis2 suggests that the
When vision is removed in a healthy adult, there is no CNS multiplies each sensory input by some weight
effect on balance other than some increased sway.10,21,32 depending on the importance of that input to the
It was generally believed that this lack of effect on task.60 The weighted variables are summed to produce
balance indicated that visual information was unneces- a response modulated to the relevancy of the incoming
sary for the control of balance. However, visual inputs afferents (Fig. 22-2). If this is correct and the CNS is
have a strong impact on the maintenance of balance using a weighted sum of all inputs in the production
and orientation in space if the parameters of the of postural behaviors, when one sensory cue is absent
visual field do not match the velocity of the physical or inappropriate, other, more reliable cues would be
motion parameters.21,32–37 Motion of the visual field expected to become more heavily weighted.61–64 The
induces body motion,37–40 and the presence of a stable situation might arise in which an individual relies on
focal image in the visual field helps diminish body slower sensory feedback (e.g., vision) to produce pos-
motion.41–43 However, during a visual tracking task, tural stabilization if faster, more direct feedback (e.g.,
inappropriate peripheral visual inputs increased the proprioception) has become distorted or diminished.65
amplitude of postural sway, whereas appropriate periph- If a sensory pathway is damaged or lost, we might
eral visual inputs decreased postural sway44 revealing expect that through adaptation to this impairment, the
that the stabilizing effect of an object in the central CNS would weight the remaining inputs more heavily
visual field was reduced when there was a conflict in and rely on those signals to generate motor responses.
the peripheral visual region. These response charac- For example, an individual with a bilateral labyrinthine
teristics demonstrate that the central nervous system deficit would weight visual and somatosensory inputs
(CNS) does not suppress the effects of inappropriate more heavily to maintain postural orientation in space.
visual motion even when the visual field motion does There is evidence that reliance between the available
not match the actual physical motion feedback. sensory inputs shifts during postural tasks. There is also
During quiet stance, motion of the peripheral visual evidence that, in healthy subjects, this dependence may
field was found to induce body sway.33,37,45,46 Postural be due to an individual’s perceptual choice or a sam-
instability was caused by changes in the velocity pling between the modalities rather than exist solely
and frequency of the visual field motion47,48 and the an adaptation to sensory dysfunction.66 In complex
2560_Chapter 22_0253-0268.indd 255 3/16/2015 4:14:09 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Perception of
Prediction/expectation orientation
Visual/transducer Sensory
Internal Model
(retina) Integration
Physical transducers
(muscle, spindles,
Internal Model
joint and skin receptors
canals and otoliths)
Motor command Sensory – Motor

Transformation
Current body orientation
Figure 22-2 Block diagram of the processes involved in producing postural orientation in a
natural environment. The individual receives external (visual) and internal (somatosensory and
vestibular) information about the position of the body relative to the environment. This
information is matched to the internal model of body orientation formed by past experience.
The difference between where the individual is and where the individual expected to be is
calculated, and the difference is transformed into a motor correction from the current body
orientation to the desired body orientation in space.
tasks, healthy and elderly adults exposed to both visual 15 Young adults
and base of support disturbances simultaneously incor- Older adults
porated specific parameters from each input, rather Angular Deviation (deg) 12
than diminishing responses to either of them as would
be expected with sensory weighting.67 When healthy
9
young adults stood on a reduced base of support in
front of a visual field that translated sinusoidally in the
anterior-posterior direction, many of them could not 6
maintain a continuous stance and needed to take a step
to stabilize themselves.68,69 The effect was greatest on 3
their head and whole body COM values (Fig. 22-3).
Greater spectral power at the frequency of the visual 0
stimulus in these individuals, combined with whole Vertical Horizontal
body delays in the motion of the COM, suggested
Rod Alignment
greater visual field dependency of the steppers. These
results imply that the thresholds for shifting from a Figure 22-3 (Left) Picture of the projected rod within a
reliance on visual information to somatosensory infor- tilted frame. (Right) Bar graph showing mean angular
mation can differ even within a healthy population and deviations (with standard deviations) from pure vertical
strongly point to a role of visual perception in the suc- and horizontal in young and elderly adults.
cessful organization of a postural response.
The measure of visual field dependence with a
Rod and Frame test has been shown to be a good gravitational cues.75 Elderly individuals with a history
predictor of a subject’s reliance on visual reafference of falling and patients who have had a stroke have been
for stabilizing posture.70–75 In this test, subjects are found to be significantly more visual field dependent
instructed to ignore the tilted box (frame) that encloses than healthy young adults.76 Labyrinthine-deficient
the rod and to attempt to align the rod either to pure individuals who, it is assumed, become more sensitive
horizontal or to pure vertical (Fig. 22-4). Visual field– to visual inputs secondary to the loss of vestibular
dependent subjects primarily use visual cues for esti- suppression77–82 have been shown to increase their
mating subjective vertical and body orientation; visual visual field dependence and their postural deviation
field–independent subjects relied on egocentric or when faced with a tilted visual frame of reference.83
2560_Chapter 22_0253-0268.indd 256 3/16/2015 4:14:09 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Visual scene motion
100 48 48
Displacement (mm)
Normalized Power
Normalized Power
0
32 32
⫺100 Step initiation
16 16
⫺200
⫺300 0 0
15 20 25 30 0.05 0.1 0.15 0.2 0.05 0.1 0.15 0.2
Time(s) Frequency (Hz) Frequency (Hz)
Figure 22-4 (Left) Example of displacement of the center of mass just before taking a step in a
healthy young adult standing on a reduced base of support during anterior-posterior translation
of the visual field. (Center) Power of the center of mass in adults who did not take a step is
negligible at all frequencies. (Right) Center of mass responses match the frequency of visual field
motion in adults needing to take a step on both a wide (dashed line) and a narrowed (solid line)
platform.
When a specific input is lost or unreliable, shifting the gastrocnemius muscle response amplitudes in the
dependence (or sensory reweighting) to the more reli- individuals with blindness were smaller than those of
able inputs seems to occur. sighted subjects with eyes closed, no significant onset
latency differences were found between blind and
Loss of Individual Inputs sighted adults. Also, there were no significant differ-
Loss of either vestibular or somatosensory inputs does ences in the amplitudes of postural sway between blind
not result in delayed or disorganized postural responses. and sighted subjects with eyes open or closed. These
However, both types of sensory deficits alter the type results suggest that the automatic postural response
of postural response selected. Somatosensory loss system is unaffected by the absence of vision from birth
resulted in an increased hip strategy84 for postural cor- and that long-term absence of visual information does
rection, similar to the movement strategy used by need to be substituted by other sensory inputs during
control subjects while standing on a shortened surface.85 rapid, transient postural disturbances.94
Vestibular loss resulted in a normal ankle strategy with
absence of a hip strategy, even when required for the Intramodal Dependencies
task of maintaining equilibrium on a shortened During daily activities, we receive continuously varying
surface.86,87 Patients who lost vestibular function in signals from multiple sensory channels that must be
infancy did not show normal early hip torque patterns, integrated by the CNS. The outcome is our individual
suggesting that in the absence of vestibular informa- perception of self-motion and spatial orientation,95
tion these individuals select movement patterns that which is used for planning subsequent motor actions
reduce the motion of their upper body. (see Fig. 22-2). Although we could orient our body
Loss of vestibular information can occur with posture to a visual, somatosensory, or vestibular refer-
destruction of the labyrinths through disease, trauma, ence, the inputs to which we respond most strongly
or chemical intervention. Vertigo, dizziness, and often depend on the particular task and behavioral
instability are frequently the result. Some of these goals. We also work from an internal estimate of our
impairments are not easily compensated for, and dis- current body orientation with respect to the environ-
orientation when moving in a dynamic moving envi- ment, incorporating the expected multisensory inputs
ronment, such as walking along a crowded street88 or with our postural reactions for each task.96,97 Results
driving,89 is common. Although kinematic adaptations from studies in a virtual environment demonstrated
of lower limb postural reactions have been observed in that converging inputs organized the postural orienta-
patients with labyrinthine deficit,90–92 these individuals tion during rotations of the visual scene in pitch and
still evidence a great deal of instability. Adaptation to roll.98 The head and trunk were linked in magnitude
support surface inputs alone is not an effective com- and phase, whereas the ankle produced small compen-
pensatory process. sations that were largely out of phase with the upper
Individuals who had congenital total blindness were body. The authors concluded that the upper body was
examined for the effects of the absence of vision from controlled by visual-vestibular signals, whereas the
birth on automatic postural responses to platform ankle responded to proprioception and changes in
displacements during stance.93 Postural disturbances ground reaction forces, which is suggestive of the dual
included forward and backward translations and toe up ascending and descending systems of postural organi-
and down rotations of the base of support. Although zation control mentioned previously.99,100
2560_Chapter 22_0253-0268.indd 257 3/16/2015 4:14:09 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
If all of an individual’s sensory pathways have been were observed when two conflicting inputs were
operating effectively, a sudden loss or dysfunction of combined.67–103
any one pathway would have an impact on the calcula- These results support therapeutic interventions that
tion of where the individual is in space and how to train patients to cope with other modal inputs to adapt
move toward the next motor goal. When the relevant to some sensory loss. When the task requires that the
inputs are signaling similar circumstances, the move- CNS calculate differences between conflicting signals
ment is not likely to be affected greatly by an absence to determine the appropriate response, the responses
of a single pathway. For example, adults who are blind shaped to fit a single input often do not completely
stood in a room that could be moved around them. A meet the demands of the task.
sound source moved with the room, simulating the
acoustic consequences of body sway. Body sway was
greater when the room moved than when it was sta- Neuropathic Effects on Balance
tionary, suggesting that acoustic feedback may have
been used to control stance.101 In another study, when Automatic Postural Reactions
the support surface was stable and visual information Although postural orientation, or the final calculation
matched the performer’s expectation (i.e., visual motion of one’s position in space, depends on the integration of
feedback was the same as physical motion feedback), somatosensory inputs with vestibular feedback,63,104–106
the visuo-ocular signals fully substituted for lost ves- the importance of direct ankle angle information to
tibular inputs.102 When healthy young and elderly postural control cannot be ignored. Disruption of ankle
adults received fore-aft translations of the immersive, angle feedback has been shown to be more destabiliz-
wide field-of-view visual environment that did not ing than disruption of COM or center of pressure
match amplitude or frequency of the anterior-posterior (COP) feedback in healthy subjects and in patients
translations of the support surface, the response to the with diabetic peripheral neuropathy who stood on a
visual input was strongly potentiated by the addition rotating platform.107 All subjects showed the greatest
of the physical motion (Fig. 22-5). With only support amount of sway when surface rotation was rotated in
surface translation, segmental responses were small proportion to ankle angle, and patients with somato-
and mostly opposed the direction of sled translation. sensory loss had higher sway velocities in all conditions
When only the visual scene was moving, segmental than healthy subjects. Even when the vision and vestib-
responses were negligible in the young adults, but the ular systems were intact, altered or reduced somatosen-
elderly adults and labyrinthine-deficient subjects were sory information46,59,87 produced delayed compensatory
clearly responsive. When the inputs were presented responses and increased instability. These results suggest
coincidentally, response amplitudes were significantly that the nervous system relies heavily on ankle position
increased for all subjects. Intramodal dependencies to control posture and that pressure sensation in the
Healthy Adults LD Adult
3 Sled alone 3
Scene alone
Both
2 2
RMS
1 1
0 0
Head Trunk Ankle COP Head Trunk Ankle COP
Figure 22-5 Root mean square (RMS) values of head, trunk, ankle, and center of pressure (COP)
displacement in healthy young adults (left) and a labyrinthine-deficient (LD) patient (right) when
standing on a platform (sled) that was translating in the anterior-posterior direction at 0.25 Hz, in front
of a visual scene translating at 0.1 Hz, or with both combined. The patient had no responses to motion of
the visual scene alone.
2560_Chapter 22_0253-0268.indd 258 3/16/2015 4:14:09 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
feet, which was absent in the patients with diabetic centrally initiated responses that create the inertial
neuropathy, also contributes to postural orientation. forces necessary to counterbalance an oncoming
The extent to which automatic postural responses balance disturbance.116–118 If the pathways that gener-
are triggered by lower leg proprioception has been ate these responses are damaged, it has been demon-
examined in the lower limbs of patients with diabetic strated that new anticipatory responses can be learned
polyneuropathy.9,108,109 Varying combinations of base of through practice to compensate for predictable pos-
support translations and rotations were used to deter- tural disturbances.119 Although patients with periph-
mine the contribution of lower leg proprioception to eral neuropathy lacked a particular compensatory trunk
the automatic postural responses. The expectation was motion that was present in healthy subjects, they were
that healthy subjects would modulate their responses able to adapt their motion to platform movement by
to these conditions, whereas responses in patients with increasing the distance they traveled and producing
polyneuropathy would be absent. earlier anticipatory muscular activity in the lower
Patients with neuropathy exhibited the same distal- limb.120
to-proximal muscle activation patterns as normal sub- Visual information also may strengthen and shape
jects. However, the timing and amplitude of the the anticipatory control of balance because of the many
compensatory responses were diminished and delayed. cues in the visual flow field that can be used in antici-
Increased background muscle activity levels and patory processing. Although visual information is
decreased trunk flexibility and lateral instability were processed too slowly to have a direct impact on the
also observed in the patients compared with a healthy triggered automatic postural reactions appearing within
population.110,111 The automatic postural response could 150 msec of a base of support disturbance, compensa-
be triggered by somatosensory receptors located at the tory behaviors following these automatic reactions are
knee, hip, or trunk as well as the ankle. Patients also greatly modified by visual flow.121 Healthy subjects
demonstrated an impaired ability to scale the magni- were observed to overshoot their initial vertical orien-
tude of ankle torque to the velocity and the amplitude tation toward the direction of visual motion with
of surface translations, suggesting that somatosensory amplitudes that increased as visual velocity increased,
information from the legs may be necessary for pro- exhibiting a direct relationship between orientation in
ducing the correct response magnitudes of automatic space and motion of the visual world.122 Postural sway
postural responses.109 can be reduced by focusing on a stationary visual target
There is also evidence112–114 that correct alignment or by having prior knowledge of a forthcoming visual
of the head with the trunk and with the gravitoinertial displacement.123
vertical requires that the vestibular system receive
somatosensory inputs. Postural responses to sinusoidal Assessing the Risk of Falls With
platform perturbations in patients with bilateral hori- Peripheral Neuropathy
zontal canal dysfunction were unable to stabilize the Polyneuropathy is a neurological disorder that occurs
trunk in space, and the patients lost balance during when many peripheral nerves throughout the body
high-frequency oscillations of the base of support malfunction simultaneously. Patients may experience
when their eyes were closed.115 Most likely to align the unusual sensations (paresthesias), numbness, and pain
body with respect to earth vertical, a convergence of in their hands and feet. In addition, there may be weak-
sensory information from the vestibular and somato- ness of the muscles in the feet and hands and balance
sensory systems is needed. Patients with bilateral ves- problems that appear as difficulty when walking on
tibular loss did not use a hip strategy to control posture uneven surfaces or in the dark. Symptoms of dizziness
when on an altered support surface. However, when and instability can also occur because of diminished
translated on a normal support surface, patients with sensitivity of joint receptors combined with decreased
adult-onset vestibular loss exhibited normal abdominal sensitivity of the vestibular labyrinths.124
muscle activation latencies and early patterns of hip Two systematic reviews identified neuropathy, par-
torque indicating that they could initiate a hip strategy ticularly peripheral neuropathy, as the primary factor
when the support surface was unaltered. These results causing increased postural instability in individuals
indicate that somatosensory information is critical if with diabetes.125,126 Patients with diabetes mellitus who
the vestibular system is to stabilize the trunk on an did not exhibit strong clinical measures of neuropathy
unstable platform and that vestibulospinal inputs con- were still identified as having a high risk of falls.127–129
tribute to the compensatory responses of patients with Acceleration measures of the lumbar spine and ankle
polyneuropathy.10,99 during quiet stance revealed that diabetic patients with
peripheral neuropathy had higher acceleration values
Anticipatory Postural Compensation than healthy individuals and diabetic patients without
Anticipatory postural adjustments maintain postural peripheral neuropathy.130
stability by compensating for expected destabilizations Quantitative measures of postural sway during
as a result of movement of the limbs or body. They are quiet stance are generally believed to be useful as a
2560_Chapter 22_0253-0268.indd 259 3/16/2015 4:14:09 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
COP AP-ML COP AP-ML

4 4
3 3
2 2
1 1
AP
AP
0 0
⫺1 ⫺1
⫺2 ⫺2
⫺3 ⫺3
⫺4 ⫺4
⫺1 ⫺2 0 2 1 ⫺1 ⫺2 0 2 1
ML Noise ML
Force plate Force plate
Figure 22-6 Illustrative diagram of the change of center of pressure in both the anterior-
posterior and the lateral directions in a healthy young adult standing on a force platform
with eyes open. A noisy vibration signal at the soles of the feet produces reduced center
of pressure displacements in both directions and improved postural stability.
longitudinal measure of the risk of falling (Fig. 22-6).131 consistently reported. Larger measures of COP and
However, a review of 28 research studies of patients trunk velocity have been observed, especially on a foam
with diabetic neuropathy does not support this point surface.134 The time lag between the head and feet was
of view and instead argues that no single test effectively also found to be significantly greater in patients with
explains the relationship between peripheral neuropa- diabetic neuropathy than in healthy individuals when
thy and postural dyscontrol.125 These authors report standing on a sinusoidal moving platform.119 A com-
that there is insufficient evidence to conclude that pos- parison of patients with diabetes and healthy adults
tural differences with neuropathy arise from differences revealed that all subjects increased their postural sway
in postural strategies. with their eyes closed. However, the difference in the
In 19 of the 28 articles, participants performed quiet sway of the patient group with eyes closed or open was
standing, and the other 9 articles involved perturba- greater, especially in the lateral plane.135 The severity
tions of upright standing or other movements in of peripheral neuropathy correlated with the amplitude
addition to upright standing. The predictive capacity of the postural sway along the anterior-posterior and
of subjective sensory discrimination measures versus lateral planes.136
objective neural responsiveness measures were clearly Because nonspecific aspects of diabetes (e.g., high
dependent on the task. Sensory discrimination was blood pressure, loss of hearing) may affect balance, one
more accurate during quiet stance, and neural respon- must be cautious about attributing instability strictly
siveness was more accurate during dynamic tasks. For to peripheral neuropathy. Other factors associated with
example, when neuropathy was characterized objec- diabetes that are not directly related to sensory loss can
tively through an electrophysiological assessment and also affect balance. Body mass index, aging, and loss of
subjectively by assessing the threshold of vibration per- muscle strength in the lower extremities137,138 have
ception, neither healthy individuals nor individuals been cited as the primary factors contributing to an
with diabetes exhibited any significant correlation increase in falls. Among women with diabetes, the
between neural responsiveness and COP indices of presence of musculoskeletal pain, high body mass
postural sway on either a firm or a foam base of index, and reduced strength in the lower extremities
support.132 Neuropathy assessed with subjective sensory were independently associated with an increased likeli-
testing revealed large fluctuations in the COP path hood of recurrent falls.139,140 Up to 10% of patients with
length in patients with diabetic neuropathy.133 Neural diabetes have orthostatic hypotension, possibly sec-
responsiveness did not correlate with changes in the ondary to autonomic neuropathy, reduced baroreflex
COP, but age was a significant factor in all sensory sensitivity, or hypotensive medication, which correlates
discrimination measures. with an increased risk of falls.141 Finally, a strong and
Despite inconsistencies in the reports about how significant correlation between dorsiflexion muscle
postural behaviors are best assessed, certain differences strength and gait velocity was observed in individuals
in the amount of postural sway of patients with with diabetes older than 55 years old.142 Logistic
neuropathy compared with healthy individuals are regression analysis determined that walking velocity,
2560_Chapter 22_0253-0268.indd 260 3/16/2015 4:14:09 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
strength of ankle dorsiflexors, and degree of neuropa- noise added to the foot for a 60-minute period resulted
thy accurately predicted 75% of the self-reported in decreases in the threshold of vibration perception
“fallers” in this group. (or increased sensitivity to the vibration inputs) when
measured immediately after the application of a noisy
signal to the feet in individuals with neuropathy sec-
New Treatments and Interventions ondary to diabetes.158 The addition of noisy vibration
has been shown to strengthen the recognition of signals
for Instability Caused by Neuropathy that would not normally be detected.156,159–161
Several different researchers have developed shoe
Cutaneous mechanoreceptors in the foot and proprio- insoles that deliver random vibrations to the heel
ceptive signals from the muscles and joints of the lower and ball of the foot at varying bandwidths of
limbs provide important information on pressure dis- frequencies.160–162 An application of constant vibration
tributions and joint position that are essential for to the ball or the heel of the foot results in compensa-
maintaining balance.143–145 In a study that anesthetized tory sway responses in the direction opposite the
the feet of healthy adults and exposed them to unex- applied stimulation (i.e., vibration on the heel produces
pected platform translations, afferents in the foot were a forward shift of the COP).163–165 The amplitude of
found to be responsible for sensing the limits of the the vibration typically chosen is below the threshold
COM, sensing foot contact and weight transfer, and for perception of the input or at amplitudes that cor-
controlling stability during single limb support.12 respond to 90% of the level that the person reports just
Similar studies revealed that gait patterns were more feeling the vibration. When random vibration signals
cautious and motion was modified in multiple lower were applied to the feet, reductions in postural sway
limb segments146 when the feet were anesthetized in were found during quiet stance and during dual tasking
healthy adults. Shifts in the compensatory torque in individuals with neuropathy.154,157 Reductions in
responses from the ankle to the hip during postural stride, swing, and stance time variability during gait
translations were also observed.147,148 Body sway were also found when random vibrating insoles were
increased and longer latencies of adaptation to the placed on the feet of elderly adult fallers during a task
galvanic stimulation were found when galvanic stimu- that required them to walk for 6 minutes. The results
lation of the vestibular system was combined with suggest that this intervention can potentially reduce
anesthetized feet.149,150 the factors that lead to falls166 making it a valuable
intervention for postural instability.
Vibrating Insoles and Whole Body Vibration Whole body vibration167–170 has also been proved to
In patients with neuropathy, cutaneous and proprio- be effective for reduction of postural sway with and
ceptive information in the foot can deteriorate as a without vision in patients who have had a stroke,
result of disease or the combination of disease and patients with diabetic neuropathy, and elderly adults.
aging, which results in greater postural instability and Interventions that used whole body vibration required
a greater risk for falls. More recent treatment interven- quiet stance on a stable platform while it vibrated at a
tions that focus on simulating receptors in the foot frequency of about 20 Hz171 or standing on a platform
demonstrate promising results. One such intervention tilting side to side while vibrating at 15 to 25 Hz.172,173
is based on the theory of stochastic resonance151–153 A single session of whole body vibration reduced gait
suggesting that subthreshold, random noise (via vibra- variability in elderly adults who had a history of falls166
tion inputs) to the feet of adults with neuropathy and increased knee extensor torque and muscle activa-
increases somatosensory information and decreases tion in patients with stroke.167,168 Improvements in
postural instability.154–157 functional measures such as the Timed Up and Go test
The premise guiding this treatment is that an and rising from a chair were also found in elderly adults
increased risk of falls is believed to be associated with after a 6-week intervention that included whole body
weakened somatosensory signals in individuals with vibration 3 days a week. Although vibration does not
neuropathy, in particular, diminished detection and shorten the time to react to instability, it can decrease
feedback of pressure changes in the feet. The lack of the amplitude of fluctuation between the controlled
signal detection may indicate a decrease in the number body segment and the unstable surface increasing the
of mechanoreceptors in the feet of patients with neu- likelihood that a corrective response will be effective.174
ropathy resulting in increased tactile thresholds on the Longer term studies on the effectiveness of the vibra-
plantar side of the feet compared with healthy indi- tion interventions and the amount of dosage required
viduals. A consequence of this increased tactile sensa- to reduce instability are needed.
tion threshold is that weaker signals are ignored,
ultimately leading to a loss in signal transmission to Rocker Shoes
the CNS, which may increase the likelihood that In some patients with neuropathy, particularly related
balance corrective responses will not occur. Mechanical to diabetes, ulcers or sores are a major concern to the
2560_Chapter 22_0253-0268.indd 261 3/16/2015 4:14:09 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
health of their feet and can limit their ability to ambu- lateral stability were found in elderly adults with
late or maintain balance. Therapeutic shoes such as sensory loss unrelated to neuropathy, and this benefit
rocker shoes have been largely successful in reducing continued at assessment after 12 weeks of wearing the
pressure on high-risk areas on the foot by redistribut- insoles.189
ing the pressure in the foot175,176 without adversely There is little doubt that individuals with peripheral
impacting gait.177 The purpose of rocker shoes is to neuropathy are at a high risk for postural instability
rock the foot from heel strike to toe off during gait and falling. Symptoms of instability are exacerbated
without requiring that the shoe bend.177 Various rocker when vision is obstructed, with decreased visual acuity,
shoes have been developed, including heel negative, or when approaching and having to compensate gait
double rocker, and toe-only rocker.178 The design of the around uneven ground and obstacles. New understand-
shoe has an impact on the pressure distribution and ing about how individuals might be trained to shift
can shift the COP while standing and during gait.179 their reliance to other sensory pathways to compensate
The concept of the rocker shoe goes back at least to for impaired inputs offers potential for new therapeutic
1981 when an article was published on the use of the interventions. In addition, new technologies that
rocker shoe as a walking aid for patients with multiple directly modify the feedback from the lower limbs
sclerosis.180 The authors found that these shoes allowed during functional activities demonstrate great promise
for normal velocity and stride characteristics combined in reducing instability and consequently protecting
with a marked decrease in energy cost. However, the individuals with neuropathy from the risk of greater
impact of rocker shoes on gait and postural stability in injury through falls.
healthy adults showed mixed results. Only small
changes in kinematics and little to no change in walking
speed were found in healthy young adults.181 Healthy
young adults were also greatly destabilized during an
CASE STUDY
unexpected backward translation of a support surface Over the past 5 years, Carolyn’s retinopathy, which is
when wearing rocker shoes.182 related to diabetes mellitus, has worsened to the point
Kinematic changes in gait are found at the ankle where she is functionally blind. She can see “shadows”
with all types of rocker shoes,183 but modifications at and “figures” but cannot identify faces, objects, curbs,
the hip and knees were also found with double rocker or stairs. She uses a cane for ambulation. Carolyn
and toe-only rocker shoes.184,185 Reports about changes works as a counselor at a drug rehabilitation facility.
in the hip or knee with heel-negative rocker shoes are She uses public transportation to travel to and from
contradictory.186,187 Toe-only rocker shoes result in work. She lives alone in a two-story home.
increased cadence and decreased stride length,181
whereas the heel-negative shoes produced no increase
in stride length but increased cadence.187 Decreases in
double limb support and increases in heel strike in 1. If Carolyn, with her limited visual acuity, were to
double rocker shoes were found compared with regular walk on a spongy surface such as a shag carpet
athletic shoes, but no changes in cadence, velocity, with high nap (mimicking proprioceptive negative
single limb support, or swing-stance ratios emerged.188 feet), what result would this have on her dynamic
The evidence seems to support that rocker shoes are ambulation balance?
effective for reducing pressure in the foot but have a a. None
limited impact on gait kinematics. b. Minimal
c. Severe
Limiting Lateral Motion d. Unable to tell from the information provided
When the limit of stability is reached during gait, the
2. Which of the following is the primary cause of
cutaneous mechanoreceptors are stimulated by indent-
postural instability in persons with diabetes?
ing the skin on the foot, which should lead to a balance
a. Blindness
correction.189 If the receptors are not functioning prop-
b. Afferent peripheral neuropathy
erly, lateral instability increases. Typically, reducing
c. Elevated blood sugar
lateral instability involves assistive devices such as
d. Loss of proximal muscle mass
canes or ankle orthoses, but these devices also alter the
body mechanics and might produce long-term postural 3. Anticipatory postural adjustments maintain postural
misalignments. Insoles with a raised ridge around the stability by compensating for which of the following?
outside of the foot were developed more recently to a. Expected destabilizations as a result of movement
decrease lateral instability.189 This insole was developed of the body limbs
as an alternative to vibrating insoles because the vibrat- b. External sounds
ing insoles require a large amount of power that may c. Orthopedic maladies such as arthritis
not be feasible for use in everyday life. Decreases in d. Unexpected ground perturbations
2560_Chapter 22_0253-0268.indd 262 3/16/2015 4:14:09 PM

Process CyanProcess
YellowProcess Black
4. Persons with neuropathy exhibit which type of 14. Dingwell JB, Cusumano JP, Sternad D, Cavanagh PR.
aberrant compensation to external variables Slower speeds in patients with diabetic neuropathy lead to
improved local dynamic stability of continuous overground
impacting balance? walking. J Biomech. 2000;33(10):1269–1277.
a. Timing of compensatory activities 15. Griffin JW, Cornblath DR, Alexander E, et al. Ataxic
b. Amplitude of compensatory activities sensory neuropathy and dorsal root ganglionitis associated
c. Lateral trunk instability with Sjogren’s syndrome. Ann Neurol. 1990;27(3):304–315.
d. All of the above 16. Katoulis EC, Ebdon-Parry M, Lanshammar H, Vileikyte L,
Kulkarni J, Boulton AJ. Gait abnormalities in diabetic
5. Research has shown that the primary impact of neuropathy. Diabetes Care. 1997;20(12):1904–1907.
Carolyn’s blindness on her posture is which of the 17. Koski K, Luukinen H, Laippala P, Kivela SL. Risk factors
for major injurious falls among the home-dwelling elderly
following? by functional abilities. A prospective population-based study.
a. Increased lateral sway during quiet stance Gerontology. 1998;44(4):232–238.
b. Decreased step length 18. Nashner LM. Adapting reflexes controlling the human
c. Ataxia posture. Exp Brain Res. 1976;26(1):59–72.
d. Tremor 19. Nashner LM. Fixed patterns of rapid postural responses
among leg muscles during stance. Exp Brain Res. 1977;30(1):
13–24.
20. Nashner LM, Woollacott M, Tuma G. Organization of
rapid responses to postural and locomotor-like perturbations
References of standing man. Exp Brain Res. 1979;36(3):463–476.
1. Alexander BH, Rivara FP, Wolf ME. The cost and frequency 21. Nashner L, Berthoz A. Visual contribution to rapid motor
of hospitalization for fall-related injuries in older adults. Am responses during postural control. Brain Res. 1978;150(2):
J Public Health. 1992;82(7):1020–1023. 403–407.
2. Gryfe CI, Amies A, Ashley MJ. A longitudinal study of falls 22. Keshner EA, Woollacott MH, Debu B. Neck, trunk and
in an elderly population: I. incidence and morbidity. Age limb muscle responses during postural perturbations in
Ageing. 1977;6(4):201–210. humans. Exp Brain Res. 1988;71(3):455–466.
3. Talbot LA, Musiol RJ, Witham EK, Metter EJ. Falls in 23. Dichgans J, Brandt T, Held R. The role of vision in
young, middle-aged and older community dwelling adults: gravitational orientation. Fortschr Zool. 1975;23(1):255–263.
perceived cause, environmental factors and injury. BMC 24. Dichgans J, Held R, Young LR, Brandt T. Moving visual
Public Health. 2005;5:86. scenes influence the apparent direction of gravity. Science.
4. Cavanagh PR, Derr JA, Ulbrecht JS, Maser RE, Orchard TJ. 1972;178(66):1217–1219.
Problems with gait and posture in neuropathic patients with 25. Barmack NH, Yakhnitsa V. Vestibular signals in the
insulin-dependent diabetes mellitus. Diabet Med. 1992;9(5): parasolitary nucleus. J Neurophysiol. 2000;83(6):3559–3569.
469–474. 26. Guedry FE. Perception of motion and position relative
5. Greene DA, Sima AF, Pfeifer MA, Albers JW. Diabetic to the earth. An overview. Ann N Y Acad Sci. 1992;656:
neuropathy. Annu Rev Med. 1990;41:303–317. 315–328.
6. Kuo AD. An optimal state estimation model of sensory 27. Guedry FE, Rupert AH, McGrath BJ, Oman CM. The
integration in human postural balance. J Neural Eng. 2005; dynamics of spatial orientation during complex and
2(3):S235–249. changing linear and angular acceleration. J Vestib Res. 1992;
7. Dichgans J, Mauritz KH, Allum JH, Brandt T. Postural 2(4):259–283.
sway in normals and atactic patients: analysis of the 28. Wright W, Horak F. Perception of verticality during
stabilising and destabilizing effects of vision. Agressologie. dynamic postural tasks in healthy and vestibular loss subjects
1976;17(C spec no):15–24. [abstract]. Soc Neurosci. 2005;168:19.
8. Peterson BW, Goldberg J, Bilotto G, Fuller JH. 29. Young LR, Jackson DK, Groleau N, Modestino S.
Cervicocollic reflex: its dynamic properties and interaction Multisensory integration in microgravity. Ann N Y Acad Sci.
with vestibular reflexes. J Neurophysiol. 1985;54(1):90–109. 1992;656:340–353.
9. Bloem BR, Allum JH, Carpenter MG, Verschuuren JJ, 30. Halmagyi GM, Curthoys IS. Otolith function tests. In:
Honegger F. Triggering of balance corrections and Herdman SJ, ed. Vestibular Rehabilitation. 2nd ed.
compensatory strategies in a patient with total leg Philadelphia: FA Davis; 2000:195–214.
proprioceptive loss. Exp Brain Res. 2002;142(1):91–107. 31. Takahashi M, Okada Y, Saito A, et al. Roles of head, gaze,
10. Keshner EA, Allum JH, Pfaltz CR. Postural coactivation and spatial orientation in the production of oscillopsia.
and adaptation in the sway stabilizing responses of normals J Vestib Res. 1990;1(3):215–222.
and patients with bilateral vestibular deficit. Exp Brain Res. 32. Vidal PP, Berthoz A, Millanvoye M. Difference between eye
1987;69(1):77–92. closure and visual stabilization in the control of posture in
11. Carpenter MG, Allum JH, Honegger F. Vestibular man. Aviat Space Environ Med. 1982;53(2):166–170.
influences on human postural control in combinations of 33. Dokka K, Kenyon RV, Keshner EA. Influence of visual
pitch and roll planes reveal differences in spatiotemporal scene velocity on segmental kinematics during stance. Gait
processing. Exp Brain Res. 2001;140(1):95–111. Posture. 2009;30(2):211–216.
12. Perry SD, McIlroy WE, Maki BE. The role of plantar 34. Guerraz M, Bronstein AM. Mechanisms underlying visually
cutaneous mechanoreceptors in the control of compensatory induced body sway. Neurosci Lett. 2008;443(1):12–16.
stepping reactions evoked by unpredictable, multi-directional 35. Keshner EA, Kenyon RV, Dhaher Y. Postural research and
perturbation. Brain Res. 2000;877(2):401–406. rehabilitation in an immersive virtual environment. Conf
13. Horak FB, Macpherson JM. Postural orientation and Proc IEEE Eng Med Biol Soc. 2004;7:4862–4865.
equilibrium. In: Rowel JL, Shepard J, eds. Handbook of 36. Previc FH. The effects of dynamic visual stimulation on
Physiology. New York: Oxford University Press; 1996: perception and motor control. J Vestib Res. 1992;2(4):
255–292. 285–295.
2560_Chapter 22_0253-0268.indd 263 3/16/2015 4:14:09 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
37. Previc FH, Kenyon RV, Boer ER, Johnson BH. The effects magnification factor of restricted visual fields. Exp Brain Res.
of background visual roll stimulation on postural and 1994;99(3):501–506.
manual control and self-motion perception. Percept 57. Redfern MS, Furman JM. Postural sway of patients with
Psychophys. 1993;54(1):93–107. vestibular disorders during optic flow. J Vestib Res. 1994;4(3):
38. Ferman L, Collewijn H, Jansen TC, Van den Berg AV. 221–230.
Human gaze stability in the horizontal, vertical and 58. Bardy BG, Warren WH Jr, Kay BA. The role of central and
torsional direction during voluntary head movements, peripheral vision in postural control during walking. Percept
evaluated with a three-dimensional scleral induction coil Psychophys. 1999;61(7):1356–1368.
technique. Vision Res. 1987;27(5):811–828. 59. Dichgans J, Mauritz KH. Patterns and mechanisms of
39. Kotaka S, Okubo J, Watanabe I. The influence of eye postural instability in patients with cerebellar lesions. Adv
movements and tactile information on postural sway in Neurol. 1983;39:633–643.
patients with peripheral vestibular lesions. Auris Nasus 60. Peterka RJ. Sensorimotor integration in human postural
Larynx. 1986;13(suppl 2):S153–S159. control. J Neurophysiol. 2002;88(3):1097–1118.
40. Previc FH, Donnelly M. The effects of visual depth and 61. Ravaioli E, Oie KS, Kiemel T, Chiari L, Jeka JJ. Nonlinear
eccentricity on manual bias, induced motion, and vection. postural control in response to visual translation. Exp Brain
Perception. 1993;22(8):929–945. Res. 2005;160(4):450–459.
41. Bronstein AM, Buckwell D. Automatic control of postural 62. Cenciarini M, Peterka RJ. Stimulus-dependent changes in
sway by visual motion parallax. Exp Brain Res. 1997;113(2): the vestibular contribution to human postural control.
243–248. J Neurophysiol. 2006;95(5):2733–2750.
42. Crane BT, Demer JL. Gaze stabilization during dynamic 63. Mergner T, Maurer C, Peterka RJ. A multisensory posture
posturography in normal and vestibulopathic humans. Exp control model of human upright stance. Prog Brain Res.
Brain Res. 1998;122(2):235–246. 2003;142:189–201.
43. Jahn K, Strupp M, Brandt T. Both actual and imagined 64. Carver S, Kiemel T, Jeka JJ. Modeling the dynamics of
locomotion suppress spontaneous vestibular nystagmus. sensory reweighting. Biol Cybern. 2006;95(2):123–134.
Neuroreport. 2002;13(16):2125–2128. 65. Speers RA, Kuo AD, Horak FB. Contributions of altered
44. Keshner E, Kenyon RV, Dhaher YY, Streepey JW. sensation and feedback responses to changes in coordination
Employing a virtual environment in postural research and of postural control due to aging. Gait Posture. 2002;16(1):
rehabilitation to reveal the impact of visual information. 20–30.
Paper presented at: International Conference on Disability, 66. Lambrey S, Viaud-Delmon I, Berthoz A. Influence of a
Virtual Reality, and Associated Technologies; September sensorimotor conflict on the memorization of a path
20–22, 2004; Oxford, UK. traveled in virtual reality. Brain Res Cogn Brain Res.
45. Black FO, Nashner LM. Postural disturbance in patients 2002;14(1):177–186.
with benign paroxysmal positional nystagmus. Ann Otol 67. Keshner EA, Kenyon RV, Langston J. Postural responses
Rhinol Laryngol. 1984;93(6 pt 1):595–599. exhibit multisensory dependencies with discordant visual
46. Black FO, Wall C 3rd, Nashner LM. Effects of visual and and support surface motion. J Vestib Res. 2004;14(4):
support surface orientation references upon postural control 307–319.
in vestibular deficient subjects. Acta Otolaryngol. 1983; 68. Streepey JW, Kenyon RV, Keshner EA. Visual motion
95(3–4):199–201. combined with base of support width reveals variable field
47. Dijkstra TM, Schoner G, Gielen CC. Temporal stability of dependency in healthy young adults. Exp Brain Res. 2007;
the action-perception cycle for postural control in a moving 176(1):182–187.
visual environment. Exp Brain Res. 1994;97(3):477–486. 69. Streepey JW, Kenyon RV, Keshner EA. Field of view and
48. Masson G, Mestre DR, Pailhous J. Effects of the spatio- base of support width influence postural responses to
temporal structure of optical flow on postural readjustments visual stimuli during quiet stance. Gait Posture. 2007;25(1):
in man. Exp Brain Res. 1995;103(1):137–150. 49–55.
49. Gielen CC, van Asten WN. Postural responses to simulated 70. Asch SE, Witkin HA. Studies in space orientation;
moving environments are not invariant for the direction of perception of the upright with displaced visual fields and
gaze. Exp Brain Res. 1990;79(1):167–174. with body tilted. J Exp Psychol. 1948;38(4):455–477.
50. Dijkstra TM, Gielen CC, Melis BJ. Postural responses to 71. Asch SE, Witkin HA. Studies in space orientation. II.
stationary and moving scenes as a function of distance to Perception of the upright with displaced visual fields and
the scene. Hum Mov Sci. 1992;11:195–203. with body tilted. J Exp Psychol Gen. 1992;121(4):407–418;
51. Paulus W, Straube A, Krafczyk S, Brandt T. Differential discussion 404–406.
effects of retinal target displacement, changing size and 72. Isableu B, Ohlmann T, Cremieux J, Amblard B. Selection of
changing disparity in the control of anterior/posterior and spatial frame of reference and postural control variability.
lateral body sway. Exp Brain Res. 1989;78(2):243–252. Exp Brain Res. 1997;114(3):584–589.
52. Brooks JN, Sherrick MF. Induced motion and the visual 73. Isableu B, Ohlmann T, Cremieux J, Vuillerme N, Amblard
vertical: effects of frame size. Percept Mot Skills. 1994; B, Gresty MA. Individual differences in the ability to
79(3 pt 2):1443–1450. identify, select and use appropriate frames of reference
53. Howard IP, Childerson L. The contribution of motion, the for perceptuo-motor control. Neuroscience. 2010;169(3):
visual frame, and visual polarity to sensations of body tilt. 1199–1215.
Perception. 1994;23(7):753–762. 74. Isableu B, Ohlmann T, Cremieux J, Amblard B. Differential
54. Lestienne F, Soechting J, Berthoz A. Postural readjustments approach to strategies of segmental stabilisation in postural
induced by linear motion of visual scenes. Exp Brain Res. control. Exp Brain Res. 2003;150(2):208–221.
1977;28(3–4):363–384. 75. Luyat M, Ohlmann T, Barraud PA. Subjective vertical
55. Lackner JR, DiZio P. Visual stimulation affects the and postural activity. Acta Psychol (Amst). 1997;95(2):
perception of voluntary leg movements during walking. 181–193.
Perception. 1988;17(1):71–80. 76. Lord SR, Webster IW. Visual field dependence in elderly
56. Straube A, Krafczyk S, Paulus W, Brandt T. Dependence of fallers and non-fallers. Int J Aging Hum Dev. 1990;31(4):
visual stabilization of postural sway on the cortical 267–277.
2560_Chapter 22_0253-0268.indd 264 3/16/2015 4:14:09 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
77. Bronstein AM. Visual vertigo syndrome: clinical and 98. Keshner EA, Kenyon RV. The influence of an immersive
posturography findings. J Neurol Neurosurg Psychiatry. virtual environment on the segmental organization of
1995;59(5):472–476. postural stabilizing responses. J Vestib Res. 2000;10(4–5):
78. Bronstein AM. The visual vertigo syndrome. Acta 207–219.
Otolaryngol. 1995;520(pt 1):45–48. 99. Buchanan JJ, Horak FB. Emergence of postural patterns as a
79. Furman JM, Jacob RG. A clinical taxonomy of dizziness and function of vision and translation frequency. J Neurophysiol.
anxiety in the otoneurological setting. J Anxiety Disord. 1999;81(5):2325–2339.
2001;15(1–2):9–26. 100. Keshner EA, Peterson BW. Motor control strategies
80. Guerraz M, Yardley L, Bertholon P, et al. Visual vertigo: underlying head stabilization and voluntary head
symptom assessment, spatial orientation and postural movements in humans and cats. Progr Brain Res. 1988;76:
control. Brain. 2001;124(pt 8):1646–1656. 329–339.
81. Peterka RJ. Simple model of sensory interaction in human 101. Stoffregen TA, Villard S, Kim C, Ito K, Bardy BG.
postural control. In: Mergner T, Hlavacka F, eds. Coupling of head and body movement with motion of
Multisensory Control of Posture. New York: Plenum Press; the audible environment. J Exp Psychol. 2009;35(4):
1995:282–288. 1221–1231.
82. Peterka RJ, Benolken MS. Role of somatosensory and 102. Schweigart G, Heimbrand S, Mergner T, Becker W.
vestibular cues in attenuating visually induced human Perception of horizontal head and trunk rotation:
postural sway. Exp Brain Res. 1995;105(1):101–110. modification of neck input following loss of vestibular
83. Oltman PK. A portable rod-and-frame apparatus. Percept function. Exp Brain Res. 1993;95(3):533–546.
Motor Skills. 1968;26(2):503–506. 103. Bugnariu N, Fung J. Aging and selective sensorimotor
84. Horak FB, Hlavacka F. Somatosensory loss increases strategies in the regulation of upright balance. J Neuroeng
vestibulospinal sensitivity. J Neurophysiol. 2001;86(2): Rehabil. 2007;4:19.
575–585. 104. Mergner T, Huber W, Becker W. Vestibular-neck interaction
85. Horak FB, Nashner LM. Central programming of postural and transformation of sensory coordinates. J Vestib Res.
movements: adaptation to altered support-surface 1997;7(4):347–367.
configurations. J Neurophysiol. 1986;55(6):1369–1381. 105. Mergner T, Nardi GL, Becker W, Deecke L. The role of
86. Diener HC, Dichgans J, Guschlbauer B, Bacher M, Rapp canal-neck interaction for the perception of horizontal trunk
H, Langenbach P. Associated postural adjustments with and head rotation. Exp Brain Res. 1983;49(2):198–208.
body movement in normal subjects and patients with 106. Mergner T, Rosemeier T. Interaction of vestibular,
parkinsonism and cerebellar disease. Rev Neurol (Paris). somatosensory and visual signals for postural control and
1990;146(10):555–563. motion perception under terrestrial and microgravity
87. Horak FB, Nashner LM, Diener HC. Postural strategies conditions—a conceptual model. Brain Res Brain Res Rev.
associated with somatosensory and vestibular loss. Exp Brain 1998;28(1–2):118–135.
Res. 1990;82(1):167–177. 107. Horak FB, Dickstein R, Peterka RJ. Diabetic neuropathy
88. Cohen HS. Vestibular disorders and impaired path and surface sway-referencing disrupt somatosensory
integration along a linear trajectory. J Vestib Res. 2000;10(1): information for postural stability in stance. Somatosens Mot
7–15. Res. 2002;19(4):316–326.
89. Page NG, Gresty MA. Motorist ’s vestibular disorientation 108. Inglis JT, Kennedy PM, Wells C, Chua R. The role of
syndrome. J Neurol Neurosurg Psychiatry. 1985;48(8): cutaneous receptors in the foot. Adv Exp Med Biol. 2002;
729–735. 508:111–117.
90. Allum JH, Honegger F, Pfaltz CR. The role of stretch and 109. Inglis JT, Horak FB, Shupert CL, Jones-Rycewicz C. The
vestibulo-spinal reflexes in the generation of human importance of somatosensory information in triggering and
equilibrating reactions. Progr Brain Res. 1989;80:399–409; scaling automatic postural responses in humans. Exp Brain
discussion 395–397. Res. 1994;101(1):159–164.
91. Allum JH, Pfaltz CR. Visual and vestibular contributions to 110. Horlings CG, van Engelen BG, Allum JH, Bloem BR. A
pitch sway stabilization in the ankle muscles of normals and weak balance: the contribution of muscle weakness to
patients with bilateral peripheral vestibular deficits. Exp postural instability and falls. Nat Clin Pract. 2008;4(9):
Brain Res. 1985;58(1):82–94. 504–515.
92. Curthoys IS, Halmagyi GM. Clinical changes in vestibular 111. Van de Warrenburg BP, Bakker M, Kremer BP, Bloem BR,
function with time after unilateral vestibular loss. In: Allum JH. Trunk sway in patients with spinocerebellar
Herdman SJ, ed. Vestibular Rehabilitation. 2nd ed. ataxia. Mov Disord. 2005;20(8):1006–1013.
Philadelphia: FA Davis; 2000:172–194. 112. Gdowski GT, Boyle R, McCrea RA. Sensory processing in
93. Nakata H, Yabe K. Automatic postural response systems in the vestibular nuclei during active head movements. Arch
individuals with congenital total blindness. Gait Posture. Ital Biol. 2000;138(1):15–28.
2001;14(1):36–43. 113. Gdowski GT, McCrea RA. Neck proprioceptive inputs to
94. Schmid M, Nardone A, De Nunzio AM, Schieppati M. primate vestibular nucleus neurons. Exp Brain Res. 2000;
Equilibrium during static and dynamic tasks in blind 135(4):511–526.
subjects: no evidence of cross-modal plasticity. Brain. 114. Imai T, Moore ST, Raphan T, Cohen B. Interaction of the
2007;130(pt 8):2097–2107. body, head, and eyes during walking and turning. Exp Brain
95. Wright WG, Schneider E, Glasauer S. Compensatory Res. 2001;136(1):1–18.
manual motor responses while object wielding during 115. Buchanan JJ, Horak FB. Vestibular loss disrupts control of
combined linear visual and physical roll tilt stimulation. head and trunk on a sinusoidally moving platform. J Vestib
Exp Brain Res. 2009;192(4):683–694. Res. 2001;11(6):371–389.
96. Gurfinkel VS, Ivanenko Yu P, Levik Yu S, Babakova IA. 116. Bouisset S, Zattara M. A sequence of postural movements
Kinesthetic reference for human orthograde posture. precedes voluntary movement. Neurosci Lett. 1981;22:
Neuroscience. 1995;68(1):229–243. 263–270.
97. Massion J. Postural control system. Curr Opin Neurobiol. 117. Jeannerod M. The contribution of open-loop and closed-
1994;4(6):877–887. loop control modes in prehension movements. In: Kornblum
2560_Chapter 22_0253-0268.indd 265 3/16/2015 4:14:09 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
S, Requin J, eds. Preparatory States and Processes. Hillsdale, 136. Corriveau H, Prince F, Hebert R, et al. Evaluation of
NJ: Lawrence Erlbaum Associates; 1984:323–338. postural stability in elderly with diabetic neuropathy.
118. Layne CS, Abraham LD. Interactions between automatic Diabetes Care. 2000;23(8):1187–1191.
postural adjustments and anticipatory postural patterns 137. Gutierrez EM, Helber MD, Dealva D, Ashton-Miller JA,
accompanying voluntary movement. Int J Neurosci. 1991; Richardson JK. Mild diabetic neuropathy affects ankle motor
61(3–4):241–254. function. Clin Biomech (Bristol, Avon). 2001;16(6):522–528.
119. Nardone A, Grasso M, Schieppati M. Balance control in 138. van Sloten TT, Savelberg HH, Duimel-Peeters IG, et al.
peripheral neuropathy: are patients equally unstable under Peripheral neuropathy, decreased muscle strength and
static and dynamic conditions? Gait Posture. 2006;23(3): obesity are strongly associated with walking in persons with
364–373. type 2 diabetes without manifest mobility limitations.
120. Bunday KL, Bronstein AM. Locomotor adaptation and Diabetes Res Clin Pract. 2911;91(1):32–39.
aftereffects in patients with reduced somatosensory input 139. Schwartz AV, Hillier TA, Sellmeyer DE, et al. Older women
due to peripheral neuropathy. J Neurophysiol. 2009;102(6): with diabetes have a higher risk of falls: a prospective study.
3119–3128. Diabetes Care. 2002;25(10):1749–1754.
121. Keshner EA, Dhaher Y. Characterizing head motion in 140. Volpato S, Leveille SG, Blaum C, Fried LP, Guralnik JM.
three planes during combined visual and base of support Risk factors for falls in older disabled women with diabetes:
disturbances in healthy and visually sensitive subjects. Gait the Women’s Health and Aging Study. J Gerontol. 2005;
Posture.2008;28(1):127–134. 60(12):1539–1545.
122. Wang Y, Kenyon RV, Keshner EA. Identifying the control 141. Mayne D, Stout NR, Aspray TJ. Diabetes, falls and
of physically and perceptually evoked sway responses with fractures. Age Ageing. 2010;39(5):522–525.
coincident visual scene velocities and tilt of the base of 142. Macgilchrist C, Paul L, Ellis BM, Howe TE, Kennon B,
support. Exp Brain Res. 2010;201(4):663–672. Godwin J. Lower-limb risk factors for falls in people with
123. Guerraz M, Gianna CC, Burchill PM, Gresty MA, diabetes mellitus. Diabet Med. 2010;27(2):162–168.
Bronstein AM. Effect of visual surrounding motion on body 143. Schlee G, Milani TL, Sterzing T, Oriwol D. Short-time
sway in a three-dimensional environment. Percept Psychophys. lower leg ischemia reduces plantar foot sensitivity. Neurosci
2001;63(1):47–58. Lett. 2009;462(3):286–288.
124. Agrawal Y, Carey JP, Della Santina CC, Schubert MC, 144. Thompson C, Belanger M, Fung J. Effects of plantar
Minor LB. Diabetes, vestibular dysfunction, and falls: cutaneo-muscular and tendon vibration on posture and
analyses from the National Health and Nutrition balance during quiet and perturbed stance. Hum Mov Sci.
Examination Survey. Otol Neurotol. 2010;31(9):1445–1450. 2011;30(2):153–171.
125. Bonnet C, Carello C, Turvey MT. Diabetes and postural 145. Roll R, Kavounoudias A, Roll JP. Cutaneous afferents from
stability: review and hypotheses. J Mot Behav. 2009;41(2): human plantar sole contribute to body posture awareness.
172–190. Neuroreport. 2002;13(15):1957–1961.
126. Kars HJ, Hijmans JM, Geertzen JH, Zijlstra W. The effect 146. Eils E, Behrens S, Mers O, Thorwesten L, Volker K,
of reduced somatosensation on standing balance: a Rosenbaum D. Reduced plantar sensation causes a cautious
systematic review. J Diabetes Sci Technol. 2009;3(4):931–943. walking pattern. Gait Posture. 2004;20(1):54–60.
127. Liu MW, Hsu WC, Lu TW, Chen HL, Liu HC. Patients 147. Meyer PF, Oddsson LI, De Luca CJ. Reduced plantar
with type II diabetes mellitus display reduced toe-obstacle sensitivity alters postural responses to lateral perturbations
clearance with altered gait patterns during obstacle-crossing. of balance. Exp Brain Res. 2004;157(4):526–536.
Gait Posture. 2010;31(1):93–99. 148. Meyer PF, Oddsson LI, De Luca CJ. The role of plantar
128. Sawacha Z, Cristoferi G, Guarneri G, et al. Characterizing cutaneous sensation in unperturbed stance. Exp Brain Res.
multisegment foot kinematics during gait in diabetic foot 2004;156(4):505–512.
patients. J Neuroeng Rehabil. 2009;6:37. 149. Magnusson M, Enbom H, Johansson R, Pyykko I.
129. Sawacha Z, Gabriella G, Cristoferi G, Guiotto A, Avogaro Significance of pressor input from the human feet in
A, Cobelli C. Diabetic gait and posture abnormalities: a anterior-posterior postural control. The effect of
biomechanical investigation through three dimensional gait hypothermia on vibration-induced body-sway. Acta
analysis. Clin Biomech (Bristol, Avon). 2009;24(9):722–728. Otolaryngol. 1990;110(3–4):182–188.
130. Turcot K, Allet L, Golay A, Hoffmeyer P, Armand S. 150. Magnusson M, Johansson R, Wiklund J. Galvanically
Investigation of standing balance in diabetic patients with induced body sway in the anterior-posterior plane. Acta
and without peripheral neuropathy using accelerometers. Otolaryngol. 1990;110(1–2):11–17.
Clin Biomech (Bristol, Avon). 2009;24(9):716–721. 151. Collins JJ, Chow CC, Capela AC, Imhoff TT. Aperiodic
131. Schilling RJ, Bollt EM, Fulk GD, Skufca JD, Al-Ajlouni stochastic resonance. Phys Rev E Stat Phys Plasmas Fluids
AF, Robinson CJ. A quiet standing index for testing the Relat Interdiscip Topics. 1996;54(5):5575–5584.
postural sway of healthy and diabetic adults across a range 152. Collins JJ, Imhoff TT, Grigg P. Noise-enhanced information
of ages. IEEE Trans Biomed Eng. 2009;56(2):292–302. transmission in rat SA1 cutaneous mechanoreceptors via
132. Bergin PS, Bronstein AM, Murray NM, Sancovic S, aperiodic stochastic resonance. J Neurophysiol. 1996;76(1):
Zeppenfeld DK. Body sway and vibration perception 642–645.
thresholds in normal aging and in patients with 153. Priplata A, Niemi J, Salen M, Harry J, Lipsitz LA, Collins
polyneuropathy. J Neurol Neurosurg Psychiatry. 1995;58(3): JJ. Noise-enhanced human balance control. Phys Rev Lett.
335–340. 2002;89(23):238101.
133. Simoneau GG, Ulbrecht JS, Derr JA, Becker MB, Cavanagh 154. Hijmans JM, Geertzen JH, Zijlstra W, Hof AL, Postema K.
PR. Postural instability in patients with diabetic sensory Effects of vibrating insoles on standing balance in diabetic
neuropathy. Diabetes Care. 1994;17(12):1411–1421. neuropathy. J Rehabil Res Dev. 2008;45(9):1441–1449.
134. Dickstein R, Shupert CL, Horak FB. Fingertip touch 155. Hijmans JM, Geertzen JH, Dijkstra PU, Postema K. A
improves postural stability in patients with peripheral systematic review of the effects of shoes and other ankle or
neuropathy. Gait Posture. 2001;14(3):238–247. foot appliances on balance in older people and people with
135. Ahmmed AU, Mackenzie IJ. Posture changes in diabetes peripheral nervous system disorders. Gait Posture.
mellitus. J Laryngol Otol. 2003;117(5):358–364. 2007;25(2):316–323.
2560_Chapter 22_0253-0268.indd 266 3/16/2015 4:14:09 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
156. Khaodhiar L, Niemi JB, Earnest R, Lima C, Harry JD, of community-dwelling older adults. J Strength Cond Res.
Veves A. Enhancing sensation in diabetic neuropathic 2009;23(5):1508–1513.
foot with mechanical noise. Diabetes Care. 2003;26(12): 173. Rittweger J. Vibration as an exercise modality: how it may
3280–3283. work, and what its potential might be. Eur J Appl Physiol.
157. Priplata AA, Patritti BL, Niemi JB, et al. Noise-enhanced 2010;108(5):877–904.
balance control in patients with diabetes and patients with 174. Milton JG, Small SS, Solodkin A. On the road to
stroke. Ann Neurol. 2006;59(1):4–12. automatic: dynamic aspects in the development of expertise.
158. Cloutier R, Horr S, Niemi JB, et al. Prolonged mechanical J Clin Neurophysiol. 2004;21(3):134–143.
noise restores tactile sense in diabetic neuropathic patients. 175. Bus SA, Ulbrecht JS, Cavanagh PR. Pressure relief and load
Int J Low Extrem Wounds. 2010;8:6–10. redistribution by custom-made insoles in diabetic patients
159. Richardson KA, Imhoff TT, Grigg P, Collins JJ. Using with neuropathy and foot deformity. Clin Biomech (Bristol,
electrical noise to enhance the ability of humans to detect Avon). 2004;19(6):629–638.
subthreshold mechanical cutaneous stimuli. Chaos. 1998; 176. Frykberg RG, Bailey LF, Matz A, Panthel LA, Ruesch G.
8(3):599–603. Offloading properties of a rocker insole. A preliminary study.
160. Gravelle DC, Laughton CA, Dhruv NT, et al. Noise- J Am Podiatr Med Assoc. 2002;92(1):48–53.
enhanced balance control in older adults. Neuroreport. 2002; 177. Janisse DJ, Janisse E. Shoe modification and the use of
13(15):1853–1856. orthoses in the treatment of foot and ankle pathology. J Am
161. Dhruv NT, Niemi JB, Harry JD, Lipsitz LA, Collins JJ. Acad Orthop Surg. 2008;16(3):152–158.
Enhancing tactile sensation in older adults with electrical 178. Brown D, Wertsch JJ, Harris GF, Klein J, Janisse D. Effect
noise stimulation. Neuroreport. 2002;13(5):597–600. of rocker soles on plantar pressures. Arch Phys Med Rehabil.
162. Priplata AA, Niemi JB, Harry JD, Lipsitz LA, Collins JJ. 2004;85(1):81–86.
Vibrating insoles and balance control in elderly people. 179. Xu H, Akai M, Kakurai S, Yokota K, Kaneko H. Effect of
Lancet. 2003;362(9390):1123–1124. shoe modifications on center of pressure and in-shoe plantar
163. Kavounoudias A, Roll R, Roll JP. The plantar sole is a pressures. Am J Phys Med Rehabil. 1999;78(6):516–524.
‘dynamometric map’ for human balance control. Neuroreport. 180. Perry J, Gronley JK, Lunsford T. Rocker shoe as walking aid in
1998;9(14):3247–3252. multiple sclerosis. Arch Phys Med Rehabil. 1981;62(2):59–65.
164. Kavounoudias A, Roll R, Roll JP. Specific whole-body shifts 181. Van Bogart JJ, Long JT, Klein JP, Wertsch JJ, Janisse DJ,
induced by frequency-modulated vibrations of human Harris GF. Effects of the toe-only rocker on gait kinematics
plantar soles. Neurosci Lett. 1999;266(3):181–184. and kinetics in able-bodied persons. IEEE Trans Neural Syst
165. Kavounoudias A, Roll R, Roll JP. Foot sole and ankle Rehabil Eng. 2005;13(4):542–550.
muscle inputs contribute jointly to human erect posture 182. Albright BC, Woodhull-Smith WM. Rocker bottom soles
regulation. J Physiol. 2001;532(pt 3):869–878. alter the postural response to backward translation during
166. Galica AM, Kang HG, Priplata AA, et al. Subsensory stance. Gait Posture. 2009;30(1):45–49.
vibrations to the feet reduce gait variability in elderly fallers. 183. Wang CC, Hansen AH. Response of able-bodied persons to
Gait Posture. 2009;30(3):383–387. changes in shoe rocker radius during walking: changes in
167. Tihanyi TK, Horvath M, Fazekas G, Hortobagyi T, Tihanyi ankle kinematics to maintain a consistent roll-over shape.
J. One session of whole body vibration increases voluntary J Biomech.2010;43(12):2288–2293.
muscle strength transiently in patients with stroke. Clin 184. Long JT, Sirota N, Klein JP, Wertsch JJ, Janisse D, Harris
Rehabil. 2007;21(9):782–793. GF. Biomechanics of the double rocker sole shoe: gait
168. van Nes IJ, Geurts AC, Hendricks HT, Duysens J. Short- kinematics and kinetics. Conf Proc IEEE Eng Med Biol Soc.
term effects of whole-body vibration on postural control in 2004;7:5107–5110.
unilateral chronic stroke patients: preliminary evidence. Am J 185. Long JT, Klein JP, Sirota NM, Wertsch JJ, Janisse D, Harris
Phys Med Rehabil. 2004;83(11):867–873. GF. Biomechanics of the double rocker sole shoe: gait
169. van Nes IJ, Latour H, Schils F, Meijer R, van Kuijk A, kinematics and kinetics. J Biomech. 2007;40(13):2882–2890.
Geurts AC. Long-term effects of 6-week whole-body 186. Boyer KA, Andriacchi TP. Changes in running kinematics
vibration on balance recovery and activities of daily living in and kinetics in response to a rockered shoe intervention.
the postacute phase of stroke: a randomized, controlled trial. Clin Biomech (Bristol, Avon). 2009;24(10):872–876.
Stroke. 2006;37(9):2331–2335. 187. Myers KA, Long JT, Klein JP, Wertsch JJ, Janisse D, Harris
170. Rees SS, Murphy AJ, Watsford ML. Effects of whole body GF. Biomechanical implications of the negative heel rocker
vibration on postural steadiness in an older population. J Sci sole shoe: gait kinematics and kinetics. Gait Posture. 2006;
Med Sport. 2009;12(4):440–444. 24(3):323–330.
171. Cheung WH, Mok HW, Qin L, Sze PC, Lee KM, Leung 188. Peterson MJ, Perry J, Montgomery J. Walking patterns of
KS. High-frequency whole-body vibration improves healthy subjects wearing rocker shoes. Phys Ther.
balancing ability in elderly women. Arch Phys Med Rehabil. 1985;65(10):1483–1489.
2007;88(7):852–857. 189. Perry SD, Radtke A, McIlroy WE, Fernie GR, Maki BE.
172. Furness TP, Maschette WE. Influence of whole body Efficacy and effectiveness of a balance-enhancing insole.
vibration platform frequency on neuromuscular performance J Gerontol. 2008;63(6):595–602.
2560_Chapter 22_0253-0268.indd 267 3/16/2015 4:14:09 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
2560_Glossary_0347-0360.indd 360 3/17/2015 12:11:29 PM
Chapter 23
Brachial Plexopathies
STEVEN WHITENACK, MD, PHD
“Do you not see how necessary a world of pains and troubles is to school an
intelligence and make it a soul?”
—JOHN KEATS (1795–1821)
Objectives
• From a historical perspective, discuss the origin of the various terms related to thoracic outlet syndrome and
the surgical and conservative interventions used to treat this condition.
• Explain the relationship of the structures within the thoracic outlet to the etiology of the various types of
thoracic outlet syndrome.
• Relate the signs and symptoms to the etiological anatomical structures.
• Differentiate between arterial, venous, and neurological thoracic outlet syndrome.
Key Terms
• Scalene muscle
• Subclavian vessels
• Thoracic outlet syndrome
numbness, paresthesias, headaches, weakness of the

Introduction arm and hand, ischemia, and arm swelling. The term
engenders a great deal of controversy in the literature,
Brachial plexopathy can be divided into the same especially neurology, because of the difficulty in defin-
variety of nerve pathologies as other nerve “syndromes.” ing it. TOS may be viewed as a clinical complex that
These pathologies may be caused by acute or chronic includes four parts: neuropathy of the brachial plexus,
compression, stretch injury, ischemic injury, electrical compression vasculopathy of the subclavian vessels,
injury, radiation injury, and various direct injuries. The complex regional pain syndrome (CRPS) or reflex
management of brachial plexopathies theoretically sympathetic dystrophy (RSD), and cervicothoracic and
does not differ from management of other nerve inju- brachial myofasciitis. Conversely, some authors would
ries. However, brachial plexopathy is more difficult to choose to limit the use of the term TOS to problems
understand and treat. This difficulty is largely due to involving only the lower portions of the plexus—the
the variation in manifestations caused by the more C8 and T1 nerve roots, lower trunk, and medial cord.
complex anatomy of the plexus than, for instance, the Manifestations of compromise of the neurological
median nerve at the wrist; the extensive range of elements associated with the thoracic outlet differ from
motion of the shoulder; and the complex anatomy of the manifestations seen in compromise of the vascular
the other associated structures intimately related to the elements of the thoracic outlet. However, because the
brachial plexus. Most patients presenting with brachial term TOS is so well entrenched in the literature, this
plexopathy fit the entity known as thoracic outlet syn- chapter attempts to broaden the understanding of the
drome (TOS). various manifestations of TOS rather than use an
The term thoracic outlet syndrome encompasses entirely new nomenclature. This broader understand-
various clinical entities involving structures around ing should improve the diagnosis and treatment of this
the shoulder girdle. Symptoms can include pain, difficult entity.
269
2560_Chapter 23_0269-0288.indd 269 3/16/2015 4:14:12 PM

Process CyanProcess
YellowProcess Black
The variability in presentation of TOS, which causes
great debate and misunderstanding, can be explained
rationally if time is taken to comprehend fully the
complex anatomy of the thoracic outlet region. The
variation in mechanism of injury and variation in
anatomy of the structures surrounding the brachial
plexus cause the lack of a “typical clinical profile”
desired by many neurologists. There are many typical
profiles, which can be explained and thoroughly under-
stood when these anatomical variations are studied.
TOS is also a dynamic entity. Alterations in posture
and activity can profoundly affect the clinical picture.
Historical Background
Many different and distinct entities have been grouped
together under the term TOS. Rob is generally credited
with coining the term “thoracic outlet compression
syndrome.”1 Peet et al.2 first grouped cervical rib
syndrome, scalenus-anticus syndrome, subcoracoid- Figure 23-1 Aelius Galenus (A.D. 129–200), commonly
pectoralis minor syndrome, costoclavicular syndrome, known as Galen, was a prominent physician, philosopher,
and first thoracic rib syndrome into the TOS. Other and surgeon of Greek ethnicity. Galen contributed greatly
authors have added the scalenus medius syndrome, to the understanding and appreciation of numerous
Paget-Schroetter syndrome (effort thrombosis of disciplines including anatomy, pathology, physiology, and
subclavian vein), rucksack palsy, droopy shoulder neurology. Courtesy of the National Library of Medicine.
syndrome, and hyperabduction syndrome. Although
including these separate etiologies under one heading
can obscure the important differences in diagnosis and
treatment, such a grouping is more likely to aid in The next step in surgical thinking led to the resec-
understanding TOS. tion of the anterior scalene in the absence of a cervical
The history of TOS has been well documented in rib. Scalenus-anticus syndrome, as credited to Naffziger
many prior excellent reviews. The first recognition of by Ochsner et al.,9 became a common diagnosis, and
cervical ribs dates to Galen (Fig. 23-1) and Vesalius. scalenotomy became a common procedure. Over time,
Willshire is generally credited as the first to make the the failures in treatment in patients with “Naffziger’s
diagnosis of “cervical rib syndrome.”3 Coote4 reported syndrome” led to disenchantment with scalenotomy.
the first successful cervical rib resection in 1861. W.W. However, other upper extremity pain syndromes had
Keen5 and Halsted6 wrote extensive reviews and not yet been described, and many failures may have
described surgical results. been in diagnosis rather than procedure. Cervical
Patients later were described with similar or identi- radiculopathy was described in 1943 by Semmes and
cal symptoms in the absence of a cervical rib. In 1910, Murphy.10 It was not until 1950 that Phalen11 described
Murphy7 was the first to resect a normal first rib and carpal tunnel syndrome or until 1953 that Kremer
achieve relief of symptoms. In 1927, Brickner8 was the et al.12 defined the nerve conduction abnormalities at
first to describe resection of the normal first rib in the the carpal tunnel.
American literature. Also in 1927, Adson and Coffey1 Other etiological factors were also described to
initiated a shift in thinking with their belief that the explain the symptoms being attributed to scalenus
symptoms were related to the relationship of the ante- anticus syndrome. in 1934. Lewis and Pickering13
rior scalene to the cervical rib and not the rib itself. implicated compression of the neurovascular bundle
Adson was “convinced that it was not necessary to between the clavicle and the first rib as the cause of
remove cervical ribs routinely, and that the chief etio- the symptoms. This condition was later termed the
logical element was the scalenus anticus muscle.”1 This “costoclavicular compression syndrome” by Falconer
belief was based on operative findings, surgical results, and Weddell.14 In 1945, Wright15 added the concept of
and the fact that most cervical ribs were asymptomatic. hyperabduction of the arms causing neurovascular
Adson’s operative procedure consisted of section of the compression at two levels. In addition to the similarly
anterior scalene, removal of any tendinous bands, and described costoclavicular compression, he added the
occasionally removal of the cervical rib. Adson’s sign concept of compression by the posterior border of
was described at that time.1 the pectoralis minor against the anterior border of
2560_Chapter 23_0269-0288.indd 270 3/16/2015 4:14:12 PM

Process CyanProcess
YellowProcess Black
Chapter 23 | Brachial Plexopathies 271
the upper ribs. Wright ’s test was also described at Middle scalene muscle
that time.15
In 1953, Lord added the concept of resection of the Phrenic nerve
clavicle for relief of the costoclavicular compression Internal
syndrome.16 Scalenotomy remained the preferred pro- Anterior scalene
muscle jugular vein
cedure, but because of disenchantment with results as
described by Raaf,17 scalenotomy fell into disfavor. Suprascapular
Clavicle
Falconer and Li14 were the first to support direct resec- artery
tion of the first rib in 1962. Later that same year, Thyrocervical
Clagett18 solidified the importance of the first rib as trunk
the common denominator in the pathophysiology External jugular
of TOS during the presidential address before the vein
American Association for Thoracic Surgery. Clagett ’s
approach was a posterior, thoracoplasty-type resection Sternocleidomastoid
of the first rib, befitting a thoracic surgeon trained in muscle (cut)
tuberculosis surgery.
Figure 23-2 The intimate relationship between the
A major advancement in the surgical approach to
subclavian vasculature and the elements of the brachial
TOS was reported by Roos19 in 1966. The transaxillary
plexus.
first rib resection that he described rapidly became the
standard procedure for patients with TOS. The 93%
improvement rate reported by Roos was reaffirmed by
other authors, including Urschel et al.20 and Sanders.21 Arterial Thoracic Outlet Syndrome
Roos22–25 also was primarily responsible for redirecting
attention away from the vascular compression and to Symptomatic arterial manifestations of TOS are rep-
the brachial plexus compression. In addition, Roos24 resentative of either acute or chronic compression (Fig.
carefully classified the many different types of congeni- 23-2). Chronic compression of the subclavian artery
tal bands that contribute to TOS. can cause both occlusive and aneurysmal disease.
Nerve compression has remained the central concept Aneurysms and arterial occlusive disease are relatively
for the etiology of symptoms of TOS by most authors. rare. Dense fascial bands running forward and inferi-
Scar fixation of the nerves causing traction and fixation orly from a cervical rib or elongated transverse process
of the brachial plexus rather than compression as the of C7 are the usual structural anomalies that predispose
primary pathological process is the latest concept to aid to arterial manifestations of TOS. These bands may
understanding of this complex problem. Sunderland26 create positional compression with motion of the arm.
attempted to help define the difference between nerve The Adson, Wright, and Halstead maneuvers are used
compressive problems and nerve entrapment and wrote to demonstrate arterial compression. However, the
“the key to the pathogenesis of the entrapment nerve presence of the capacity to obliterate the pulse at the
lesion is the local inflammatory reaction that occurs in wrist with arm motion does not in itself define TOS.
response to repeated mechanical irritation during limb Many completely asymptomatic individuals are able to
movements.” Simple “decompressive” procedures may shut off their pulse, particularly at the extremes of
be inadequate to relieve the pathological process found range of motion of the shoulder.
in many of these complex cases. The symptoms of arterial compression are generally
described as having a “dead arm” or fatigue with use.
The symptoms may be positional and may interfere
with occupations requiring overhead arm use. The
Vascular Syndromes absence of pulses with a completely abducted arm is
likely to cause fatigue when trying to perform overhead
Vascular manifestations of TOS are rare. Of reported activity. With appropriate accommodation, many of
cases of TOC, 3% to 5% are vascular, with only 1% these types of activities may be continued without cre-
being arterial. These percentages are probably over- ating undue risk of repetitive trauma to the artery. For
stated, as the recognition of neurogenic TOS involving example, use of extension devices can allow continued
the upper plexus has increased. The misunderstanding productive work to be accomplished.
of the relationship between the vascular diagnostic The sequelae of repetitive trauma to the artery are
signs and the neurological manifestations of TOS is intimal damage to the vessel, leading to thrombosis,
one of many aspects of this problem that create the occlusive disease with poststenotic dilation, or occa-
controversy that surrounds this diagnosis. Vascular syn- sionally aneurysm formation.27 The initial symptoms of
dromes are divided into arterial and venous types. Pure subclavian artery occlusion depend on the rapidity of
lymphatic disorders have not been described. the occlusion. A slowly progressive occlusion may allow
2560_Chapter 23_0269-0288.indd 271 3/16/2015 4:14:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
time for adequate collateral circulation to develop. In resection, resection of abnormal bands, and possible
this situation, the patient may have complaints only scalenectomy should be done at the same time. Rib
when the arm is used excessively. A more rapid occlu- resection can be delayed 2 to 3 months after throm-
sion, representing acute thrombosis, causes the patient bolysis is performed, maintaining the patient on anti-
to have symptoms of arm claudication, with muscle coagulation until surgery. A residual stricture in the
cramping after minimal use or at rest. Before complete vein after resection of the compressive bands some-
occlusion occurs, examination reveals diminished to times responds to balloon dilation. There is a high
absent pulses in the involved arm and a bruit in the failure rate if angioplasty of the vein is done before
infraclavicular space. decompression. Intraluminal stent placement should
The presenting symptoms of aneurysmal disease28 be avoided if the etiology of the venous occlusion is
are usually related to distal embolization to the arm, external compression.31
hand, or fingers. This embolization is caused by frag- Short-term anticoagulation should be considered
ments of the clotted material within the aneurysm for all forms of vascular TOS.30 Warfarin (Coumadin)
breaking loose and lodging in the distal vessels. The therapy for a minimum of 3 months provides a lower
symptoms may vary from acute ischemia of the arm incidence of post-thrombotic complications and should
with pain, pallor, paresthesias, and pulselessness to fin- be used unless there is a clear contraindication (e.g.,
gertip necrosis suggestive of Raynaud’s phenomenon. bleeding diathesis, active ulcer disease).
The presence of a pulsatile mass in the supraclavic-
ular fossa should raise the question of a subclavian
aneurysm. Neurogenic symptoms infrequently may be
caused by pressure from the aneurysm. An ultrasound
Neurological Thoracic
study can usually confirm the presence of an aneurysm. Outlet Syndromes
Venous Thoracic Outlet Syndrome Most thinking on TOS originally centered on lower
Acute venous occlusion of the subclavian vein results plexus pathology resulting in ulnar mediated com-
in sudden painful swelling of the arm, often with a plaints in the arm and hand. These symptoms are gen-
bluish discoloration. Most commonly, this subclavian erally more clear-cut and easily defined than with other
venous thrombosis is the result of sudden maximal arm types of symptoms and consequently have been more
use and is known as effort thrombosis or Paget- accepted over time. At the present time, most patients
Schroetter syndrome. If the thrombosis is more insidi- with TOS have been involved in some type of signifi-
ous in onset, the sudden painful swelling does not cant trauma, particularly with a flexion-extension com-
occur, but rather swelling with significant use occurs. ponent. The delayed onset of symptoms 1 to 3 months
Other etiologies of intravascular thrombosis must be after this type of injury should be expected if the
considered, including factor V (Leiden), antithrombin natural consequences of scar contraction and fibrosis
III or anticardiolipin antibodies, and protein C and are considered and the anatomical abnormalities
protein S abnormalities.29 Spontaneous development described later in this chapter are understood. The use
of any venous thrombosis without obvious cause should of the term “whiplash” carries many of the same nega-
also raise the question of occult malignancy. Subclavian tive connotations as TOS, a position it does not deserve.
venous catheters for intravenous access and particularly More recent observations will perhaps elevate the
dialysis are the most common etiology of subclavian understanding of both of these complex problems.30,31
thrombosis or stenosis at the present time. The neurology literature has been characterized by
an aggressive attack on thoracic outlet diagnoses.32,33
Treatment of Vascular Thoracic The neurologist ’s bias has been made clear by using the
Outlet Syndrome terms “true neurogenic” and “disputed” to differentiate
The treatment of vascular manifestations of TOS can types of TOS. One can also consider the more com-
be divided into immediate and long-term therapy. In monly accepted definitions of TOS in the surgical lit-
the presence of distal arterial embolization, heparin erature as “classic” TOS.
therapy is instituted rapidly. If the embolus is in
the larger vessels, embolectomy is indicated. Subse- “True Neurogenic” Thoracic Outlet Syndrome
quent thoracic outlet decompression and repair of the The most clearly defined subset of TOS has been
arterial pathology with a vein graft or patch should labeled by Wilbourn and Porter34 as “true neurogenic”
soon follow.30 TOS. These patients have atrophy of the ulnar intrinsic
Venous thrombectomy can be effective if performed hand muscles (particularly the thenar eminence and
in the first few days after onset of symptoms. Throm- first dorsal interosseous muscles), numbness and par-
bolysis with streptokinase or urokinase infusion is more esthesias in the ulnar distribution, and clear peripheral
likely to be beneficial if the diagnosis is delayed.30 electromyography evidence of neuron loss, always asso-
When operative thrombectomy is performed, rib ciated with the presence of a cervical rib. The rib itself
2560_Chapter 23_0269-0288.indd 272 3/16/2015 4:14:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
or a tight musculotendinous band emanating from the foramen to the junction of the anterior and posterior
end of the rib causes the compressive neuropathy. Pain divisions. The symptoms mirror the point of entrap-
is often remarkably absent in this variation of TOS, ment, and the expression of the upper extremity com-
perhaps because of the selective compression of only plaints can be manifest in any of the peripheral nerves
the C8 nerve root. This syndrome variety is also called of the shoulder girdle and arm that ultimately arise
“motor type” neurogenic TOS, and because it was first from these nerves.
electrically defined accurately by Gilliat in 1970, this Mackinnnon36,37 continued the work of Sunder-
type of TOS is also called Gilliat ’s disease.35 land26 and showed that the response of nerves to com-
Because of the symptoms of hand weakness, carpal pression passes through many stages. Initially, there is
tunnel syndrome commonly is mistakenly diagnosed in periodic ischemia related to interruption of local blood
these cases. Any time the diagnosis of carpal tunnel flow. Microscopically, there is subperineural edema.
syndrome is made in a teenager who has thenar wasting, More chronic ischemia results in reactive thickening of
it is imperative to rule out TOS (usually related to a the perineural tissues. The most external nerve fascicles
cervical rib) before proceeding with carpal tunnel alone initially show degeneration, whereas the central
surgery. It must be reemphasized that the fine motor fibers remain intact. The implications of these findings
intrinsic function of the hand is mediated more via the are not to be underestimated. There can be variation in
ulnar nerve than the median. the peripheral manifestations of more proximal nerve
The “true neurogenic” variation is rare in its most compression based on local anatomical factors.
narrow form in most reported series as well as our own. The arguments of Wilbourn32 requiring a fixed set
In my experience, the C8 nerve root compression seen of criteria in all patients that can be uniformly repro-
at surgery has been extreme in these cases, to the point duced indicate a lack of appreciation for clinical evalu-
that the nerve has a gelatinous appearance from demy- ation of patients. In entities such as appendicitis, it is
elination when observed at surgery. The onset of symp- well recognized that the entire picture of the patient
toms is usually in the late teens or early 20s, presumably including history, physical examination, and laboratory
secondary to the decreasing bony flexibility and angu- studies must be considered together to establish a diag-
lation of the cervical rib. The compression seen in these nosis. Not all patients with appendicitis have identical
cases is severe, and electromyography and other nerve presentations. It seems unrealistic to expect all patients
studies can easily make the diagnosis. with TOS to have fixed criteria for diagnosis. Nelems38
developed a set of subjective criteria that are divided
Classic Thoracic Outlet Syndrome into “must have, may have, and can’t have” criteria. This
Cases of TOS that do not fulfill the restrictive criteria is a useful methodology when approaching nearly all
of “true neurogenic” TOS have been labeled “disputed” pain-mediated syndromes.
TOS. The central issue in these arguments is the vari- Patient complaints in cases of TOS can be broadly
ability in symptoms in patients who do not fit precisely grouped into upper and lower plexus components.
into the “true neurogenic” category. A corollary argu- They have become clearly separable in our evaluations,
ment centers on the lack of “uniform” criteria for the along with other secondarily associated manifestations
physical examination. When a full understanding of brought about by misuse of the arm and shoulder
the anatomical basis for TOS is reached, the concerns girdle. The anatomy of the brachial plexus must be
of the detractors can be put aside. There is no dispute repeatedly studied to comprehend the various nerve
if the pathophysiology is understood. Figure 23-2 symptoms that are possible. The distribution of symp-
shows the full distribution of the nerves that ultimately toms can follow any of the nerves derived from all
derive from the brachial plexus. Compromise at any branches of the brachial plexus. It is most important
level of the plexus creates a symptom complex in the to understand that the symptoms caused by proximal
anatomical distribution of the involved nerve. Descrip- plexus compression and entrapment can be distributed
tions of symptoms being on a “nonanatomical” basis to multiple sites distally.
usually indicate a lack of understanding of the brachial
plexus anatomy. Lower Brachial Plexus Syndromes
The extensive anatomical studies of Roos and (Lower Thoracic Outlet Syndrome)
others21–26 documented the variety of muscle anomalies The symptoms of lower trunk plexus involvement
and fibrous bands found in these patients. The nearly involve various combinations of pain and other sensory
infinite minor variations in the location, path, severity disturbances in the arm and hand and mild weakness
of compression, and density of these muscles and bands of the hand and arm. In the so-called true neurogenic
are responsible for the differences in symptoms from variety, pain is remarkably absent, and motor symptoms
one patient to another. Fascial bands leading from the predominate. Pain is the central feature of the remain-
C7 transverse process to the pleura and first rib may der of TOS cases that involve the lower plexus.
compress the C8 or T1 nerve roots either separately or The pain of lower plexus TOS is often described as
together and anywhere from immediately distal to the beginning at the base of the neck and supraclavicular
2560_Chapter 23_0269-0288.indd 273 3/16/2015 4:14:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
fossa and heading to the area just inferomedial to the The most common constellation of complaints in
deltopectoral groove, which is the path of the nerve upper plexus cases involves pain along the trapezius
after passing under the acromion. The pain then extends ridge, into the suprascapular notch, and along the
variably down the arm in the ulnar distribution. Usually medial scapular border. There is also pain running pos-
numbness and paresthesias extending into the fourth teriorly up the back of the neck to the occipital protu-
and fifth fingers are more prominent distally. Elevation berance and headaches that pass from the back of the
of the arm laterally and above the head places traction skull forward toward the eye. Pain into the pectoral
on the lower plexus and almost always reproduces the region that is often burning in quality is also commonly
patient ’s symptoms. Careful history and sensory testing found. Pain along the distribution of the long thoracic
show that the numbness generally involves the ulnar nerve, with winging of the scapula, is seen less often.
aspect of the middle finger.39; this is helpful in differ- In many long-standing cases, patients have facial
entiating TOS from pure ulnar nerve compression. pain that is interpreted as a “TMJ” (temporomandibu-
Sunderland26 believed that the usual descriptions of lar joint) symptom. They may also develop what appear
the peripheral sensory distribution of the nerve roots to be sympathetic mediated swelling of the unilateral
of the brachial plexus were misrepresented in the face, occasional lid droop, and eye pain. This group of
forearm. The usual presentation of nerve root sensory patients also commonly complains of difficulty with
distribution shows C6 supplying the index and thumb. night vision.
Sunderland’s view shows C6 to have almost no sensory To the skeptics of upper plexus–type TOS, these
distribution distal to the wrist, with C7 supplying the multiple manifestations of nerve compromise are
index and thumb. The distribution in the radial forearm ignored; discarded; or placed into diagnostic categories
is described as C5–6 (upper trunk) and in the ulnar such as fibromyositis, migraine equivalent, and any
forearm and hand as C8–T1 (lower trunk), rather than variety of shoulder pathology. If one clearly and dispas-
as separate nerve roots. This description fits more sionately reviews the anatomy of the brachial plexus, it
clearly the distribution of sensory complaints in these becomes apparent that all of the aforementioned com-
patients. In our experience, the lower trunk seems to plaints are in the ultimate distribution of C5, C6, and
split the long finger in patients with lower trunk the upper trunk or portions of the cervical plexus
sensory complaints,40 rather than involve the whole involved by scalene spasm and scarring. The pectoral
finger as described by Sunderland.26 symptoms come from the medial and lateral pectoral
Variations in the ulnar and median nerves must be nerves, the periscapular symptoms come from the
understood when differentiating plexus-level from suprascapular and long thoracic nerves, and the radial
distal neuropathies.22,25 Absence of thenar wasting with sensory and first through third finger symptoms more
a distal injury to the median nerve at the wrist can obviously come from the final peripheral nerve distri-
occur if both a Martin-Gruber and a Riche-Cannieu bution of the lateral cord.
anastomosis are present. These communications gener- The occipital pain can be mediated through the irri-
ally contain motor neurons only. The Martin-Gruber tation of the greater occipital nerve as it passes through
anastomosis occurs distal to the elbow. The sensory the posterior musculature of the neck, which may be
findings in the hand should still correlate appropriately secondarily in spasm.41 Although often referred to as
with the other findings of plexus-level pathology. “migraine” headaches, there is usually no aura preceding
The motor complaints of lower trunk TOS are the headache, and nausea and vomiting seldom occur.
usually described as fatigue of the hand, loss of pen- In Britain, these types of post-traumatic headaches
manship, or loss of the ability to write for lengthy have been labeled “footballer’s migraine.”42 There also
periods. Wasting of the ulnar intrinsic and thenar appears to be a referred pain aspect to these complaints
muscles seldom occurs but must be watched for care- mediated through communications with the cervical
fully in patients who are being followed in a therapy plexus. Known subcortical crossover pathways may
program. Development of atrophy is an indication for explain the origin of contralateral pain in some
immediate surgical intervention. instances. These pathways at the spinal and mid-brain
level may also explain the complaints of ipsilateral pain
Upper Brachial Plexus Syndromes or numbness in equivalent fingers and toes that are
(Upper Thoracic Outlet Syndrome) occasionally reported. In the teaching of acupressure
There are many recognizable forms of upper plexus techniques for relief of these posterior headaches, pres-
involvement with TOS that fall into repeatable pat- sure is placed alternately over the occipital protuberance
terns of complaint. To decipher these complaints, one and the web space of the thumb with excellent result.
must evaluate all aspects of the history, including the
exact mechanism of injury, history of prior injuries, the Mixed Plexus Syndromes
precise nature of prior treatment and therapy, details of As understanding of the complexities of the brachial
the conditions of the workplace, and other similar plexus improves, it is increasingly evident that the
details. upper and lower plexus symptoms become intertwined.
2560_Chapter 23_0269-0288.indd 274 3/16/2015 4:14:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Patients with diffuse arm and shoulder symptoms must importance of understanding the interrelationship
not be written off as having “nonanatomical” com- between TOS and these other associated problems
plaints. The anatomical abnormalities described by cannot be understated. Many major orthopedic texts
Roos22 that are repeatedly confirmed at surgery make do not have even cursory mention of TOS, which
it clear that the distribution of complaints depends on further adds to the lack of understanding and recogni-
the mixture of anamolies found in any given individual, tion of a patient with TOS.
particularly with alteration of arm position. There is
marked variability in the involvement of C7 and the Impingement Syndrome (Rotator Cuff Tear)
middle trunk with either the upper or the lower trunk, The diagnosis of rotator cuff tear has been made and
symptomatically as well as anatomically. Considering surgery performed in many patients who eventually are
that injury is usually the basis of modern plexopathy, it referred for unrelenting arm and hand symptoms.45 The
is well to consider that with lower plexus injury C7 suprascapular nerve as it comes off the upper trunk is
may be involved in dense scar fixation to the lower the site of significant fibrous fixation in patients with
trunk. A “sausage casing” type of material can envelope upper plexus TOS. This fibrous fixation can lead to
the middle and lower trunk. The symptoms may overlap dysfunction of the supraspinatus and infraspinatus
in the median nerve distribution. In upper plexus inju- muscles and laxity of the rotator cuff. The sensory
ries, C5 and C6 may be bound with C7, or the middle branches supply the articular surfaces of the shoulder
trunk, to create symptoms and findings overlapping the joint. Impingement also occurs in patients with TOS
median nerve with the upper plexus, lateral cord dis- because of the forward displacement of the scapulo-
tribution. The “prefixed” plexus, which has contribution thoracic articulation at the shoulder. As a result of this
from C4, and the “postfixed” plexus, which has contri- forward displacement, the structures in the supra-
bution from T2, create further variability in the “usual” humeral space (the tendon of the long head of the
manifestations of TOS.22 With a prefixed or postfixed biceps, the supraspinatus tendon, the subacromial
plexus, nerve roots and trunks do not conform to the bursa, and the superior aspect of the joint capsule) may
same ultimate distribution, and the symptoms may be become impinged between the greater tuberosity of the
variable. humerus and the acromion as the arm is abducted.
Typically, the signs of impingement include pain
Parsonage-Turner Syndrome referred within the C5 dermatome, a classic “painful
A rare type of brachial plexopathy that most com- arc,” and loss of range of motion at the glenohumeral
monly involves the upper plexus has become known joint.46
as Parsonage-Turner syndrome.43 It has also been Appropriate shoulder posture and strengthening of
called neuralgic amyotrophy, patchwork amyotro- the rotator cuff muscle group, particularly the supra-
phy, shoulder-girdle syndrome, and numerous terms spinatus muscle, can rapidly improve this entity. There
using the name of the muscle involved with pain and are multiple causes of rotator cuff injuries not related
wasting.44 Parsonage-Turner syndrome often begins as to TOS. Patients who do have TOS must be recog-
a sudden pain in the shoulder girdle region lasting 10 nized because surgery on the rotator cuff is unsuccess-
to 14 days before weakness and then atrophy of the ful in most cases until the underlying upper plexus
muscles of the particular nerve involved occur. The pain pathology is appropriately treated.
usually decreases as the atrophy begins. Recovery takes
several months to years and is generally good. Trapezius Spasm
The etiology of Parsonage-Turner syndrome is The trapezius is innervated by the C11 (spinal acces-
believed to be immune and inflammatory related often sory) nerve and plexus pathology cannot be directly
following a viral or bacterial illness, vaccinations, or implicated in the sometimes severe pain in the trape-
systemic illness. There is no specific treatment other zial ridge. The forward-sloping shoulder causes an
than supportive to prevent limitation of shoulder imbalance in the shoulder girdle muscles. When the
motion or secondary injury as a result of the muscle shoulder is elevated in a shrugging motion, the trape-
weakness. Involvement of the phrenic nerve is worri- zius works alone if the shoulder is forward. The rhom-
some in individuals with severe chronic obstructive boids and levator scapulae do not adequately assist the
pulmonary disease.44 trapezius. The trapezius fatigues and tends to spasm.
Appropriate posture, massage, and deep heat often
relieve this problem over time.
Associated Musculoskeletal Biceps Tendonitis
Problems Similar to the previous discussion, biceps tendonitis
occurs as the tendon partially subluxes out of the
Numerous musculoskeletal complaints are common in groove when the arms are used laterally and the shoul-
patients with TOS and require further elucidation. The der is again positioned forward. This entity responds
2560_Chapter 23_0269-0288.indd 275 3/16/2015 4:14:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
quickly to anti-inflammatory agents in concert with Numerous structures are at risk of compromise in
proper shoulder positioning. When tendonitis is very the thoracic outlet, including the brachial plexus, the
severe, steroids may be used, but repetitive injections subclavian artery, and the subclavian vein. The etiology
should be avoided. The more proximal biceps tendon of the resultant brachial plexus compression neuropa-
can also be involved in shoulder impingement. thies is multifactorial, but certain risk factors predis-
pose to this entity. Three broad categories of risk factors
Trigger Points are congenital-structural, post-traumatic structural,
Patients who have the other ancillary manifestations and post-traumatic postural. When an inciting event
almost always have painful areas along the medial occurs, a clinically significant compromise of the bra-
scapular border, along the posterior neck, and in the chial plexus can result. The degree of congenital pre-
trapezial insertion into the scapula. These points of disposition and the nature of the inciting event
irritation are areas of periosteal inflammation at muscle determine the severity and the clinical course of the
insertions or areas of chronic muscle tension from neuropathy or vasculopathy.
either spasm or improper use of the muscle caused by When there has been significant trauma to the neck,
poor posturing of the shoulder girdle; this may also be particularly flexion-hyperextension type, resulting in
manifest as motor end plate sensitivity that becomes tearing of the scalene muscle bundles, two potential
involved in a circus reflex within the spinal column. problems occur that directly affect the nerves of the
With improvement in the overall position of the shoul- plexus. First, contraction and fibrosis of the muscle
der girdle, the tender areas gradually improve.46 Moist bundles can increasingly compress the nerve roots and
heat, ultrasound, and massage may be beneficial. Resis- trunks. Because scar is an active tissue and undergoes
tant areas can be injected with local anesthetic and progressive contraction for 18 to 24 months, it is
steroids, but this should not be repeated often. understandable that symptom progression often begins
and continues many months after an injury.
Lateral Epicondylitis Even more poorly understood is the fixation of the
nerves to the muscle fascia of the scalene anomalies.
Symptoms at the lateral elbow are commonly associ- This fixation is extremely common and occurs at all
ated with TOS. Chronic use of the extremity in abnor- levels of the plexus. It is most likely caused by bleeding
mal posture with the shoulders forward causes the from the torn muscle and epineural connective tissue
patient to use the extensor muscles of the forearm causing adherence of the muscle fascia to the epineural
inappropriately. Chronic improper use of these muscles tissues. This adherence interferes with the basic need
causes irritation at the muscle insertion into the lateral for the roots and trunks to have separate and free
epicondyle. Treatment consists of retraining of shoul- mobility with arm shoulder and neck motion that
der posture and appropriate use of the arms in lifting allow the shoulder to function in a 360-degree arc.
and with repetitive actions. Anti-inflammatory agents Repetitive traction injury causes anatomical deformity
and local modalities sometimes are needed. Surgery of the plexus and results in inflammatory repair, adhe-
should be avoidable with proper preventive measures. sion, and progression of the painful neuropathy. This
Symptoms referable to radial nerve entrapment in the scarring also is likely to progress over time.
proximal forearm are often confused with lateral epi- Machleder et al.48 reported significant abnormal
condylitis. The radial nerve is exquisitely tender at the histological patterns of the anterior and middle scalene
border of the extensor carpi radialis. in patients with traumatic TOS. Sanders et al.49 found
atrophy of type II fibers and increase in the average
number of type I fibers. Also, the percentage of con-
Pathophysiology nective tissue was increased by a mean of 36%. The
importance of these findings should not be underesti-
To understand TOS is to understand the various ana- mated. The fibrous tissue content of the scalene muscles
tomical abnormalities and pathophysiological changes is often clinically apparent at the time of surgery as the
that are a consequence of these abnormalities. In a muscle is transected.
study of the thoracic outlet, Roos47 compared the
anatomy of cadaver specimens with the anatomy at Embryology
surgery in patients with TOS. This study helped define During the embryonic development of the upper
the numerous findings at surgery. However, Roos’ study extremity, numerous changes occur as the limb bud
underestimated the abnormalities found at surgery, forms that ultimately may become manifest in the
particularly at the level of the upper plexus. The inter- problems encountered in patients with TOS. The
digitating fibers of the anterior scalene between the scalene muscles form as one confluent muscle mass.
C5, C6, and C7 nerve roots found in cases of upper This scalene muscle mass becomes separated into spe-
plexus TOS that we have explored have been severely cific muscles only as the neurovascular structures pen-
underestimated. etrate it. Some argument remains whether the scalenus
2560_Chapter 23_0269-0288.indd 276 3/16/2015 4:14:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
minimus variant arises from this original scalene mass. upward in the neck and may tether portions of the
The muscle abnormalities found at surgery represent cervical plexus to create the neck and facial symptoms
the variable fragmentation of the scalene mass as the often found with upper plexus TOS cases. Roos47
structures of the limb bud pass through it.50 found this type of abnormality in 76% of dissections
A C7 rib also forms in the early embryo and then in patients with TOS.
regresses variably. The residual cervical rib may vary Perhaps the most important anomaly to recognize
from a complete rib to an elongated C7 transverse is the complete posterior position (Fig. 23-4) of the
process. There may be a dense fibrous band left in the anterior scalene, which places the C5 and C6 nerve
place of the supernumerary rib. Some authors believe roots in jeopardy for injury by an inexperienced surgeon
that the presence of a cervical rib also signals the pres- during anterior approaches to the plexus.51 We have
ence of a prefixed type of plexus (small T1 nerve and seen many cases in which nerve roots were transected
major contribution to the plexus from C4). My opera- when this anatomical variation was not recognized by
tive findings support this finding only occasionally. the prior surgeon.
There are occasionally unusual medial origins of the
Anterior Scalene Anomalies anterior scalene. The most inferior of these may com-
The many abnormal origins and insertions of the ante- press the subclavian artery.
rior scalene muscle are the “linchpin” on which the
remaining plexus anomalies are built. The anterior Middle Scalene Anomalies
scalene is described in every textbook of anatomy to Middle scalene anomalies are less well recognized than
take origin from the anterior tubercles of the third anterior anomalies but are equally important.52 The
through sixth cervical vertebrae and lies in its entirety insertion commonly extends well forward on the first
anterior to the plexus. The insertion is on the scalene rib, occasionally forward of the anterior scalene
tubercle of the first rib. The scalene muscles assist in insertion. This extension may throw the entire plexus
flexion and lateral flexion of the neck. The function of forward, into anterior scalene abnormalities, and even
the scalene as an accessory muscle of respiration has against the clavicle. With the arms abducted and supi-
been questioned. The nerve supply to the scalene nated, any motion of the arms in a plane posterior to
muscles is from the cervical plexus. the midline causes the nerves of the plexus to be
Abnormalities of the anterior scalene can affect stretched taut over the forward-placed middle scalene.
the low plexus or the high plexus. The low plexus These abnormalities are particularly important when
anomalies have been well described since the begin- the anterior border of the muscle is fibrous and sharply
ning of the understanding of TOS.1,16 The importance demarcated—the so-called middle scalene band. There
of the upper plexus muscle anomalies has been recog- may be slips of the middle scalene origin that arise
nized only more recently as has the variability of symp- anterior to the plane of the lower portions of the plexus
toms related to minor variations in the exact nature of and trap the lower plexus against the anterior scalene.
the compression.
The insertion of the anterior scalene may be anoma- Congenital Fibromuscular Bands
lously attached posteriorly and laterally on the first rib Roos47 described and categorized 10 types of tissue
or onto the pleura (actually Sibson’s fascia). This attach- bands that contribute to the compromise of the nerves
ment serves to fix the lower plexus posteriorly and is of the brachial plexus. Type 1 passes from the tip of a
more of an inciting factor when there are other struc- short cervical rib to the first rib. Type 2 is a dense band
tures posterior to the plexus that force it anteriorly. The that passes in the position of a cervical rib from the tip
insertion may be split, with a portion of the muscle of an elongated transverse process of C7. Type 3 is a
posterior to the artery, which also fixes the plexus rib-to-rib band that passes from the posterior to ante-
posteriorly. rior first rib, elevating the lower trunk or T1 nerve root.
Anomalies of the muscle origin superiorly are Roos believed that type 3 was the most common
extremely common. The most frequent anomaly is a anomaly he encountered. Type 4 is the above-mentioned
splitting of fibers around the C5 nerve root; this can forward abnormal middle scalene attachment to the
vary from a tiny slip of tendinous tissue to a large mass first rib. Types 5 and 6 are the scalenus minimus anoma-
of muscle. The muscle origins may also pass beneath lies. Type 7 is a thin tendinous band that passes from
C6 (Fig. 23-3) and affect the proximal C5, C6, or C7 the middle scalene muscle to the sternum under the
nerve roots. The fibrous fixation of these proximal subclavian vessels. Type 8 is similar and arises from the
anomalies also may extend superiorly and create fixa- anterior scalene. Type 9 is a dense broad band of tissue
tion to the nerves of the cervical plexus. The fusion of that is like a drumhead through which the T1 nerve
the muscle bundles to the C5 and C6 nerve roots may root must pass; this is what Sunderland26 believed was
be congenital or may be related to injury with scar fixa- the extension of Sibson’s fascia. Type 10 is similar to
tion. The fibrous tethering restricts nerve gliding. The type 3 but extends to the back of the sternum or costal
layer of fascia that invests the anterior scalene extends cartilage.
2560_Chapter 23_0269-0288.indd 277 3/16/2015 4:14:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
C1 C1
C2 C2
Middle scalene muscle C3 Middle scalene muscle C3
Anterior scalene muscle Anterior scalene muscle

C4 C4
Phrenic nerve Phrenic nerve
C5 C5
C6 C6
C5 C5
C6 C7 C6 C7
C7 C7
T1 T1
C8 C8
T2 T2
A 1st rib 1st rib
C1
C2
Middle scalene muscle C3
Anterior scalene muscle

C4
Phrenic nerve
C5
C6
C5
C6 C7
C7
T1
C8
T2
Figure 23-3 Typical anatomy of the scalene

B 1st rib muscles within the thoracic outlet.
Scalenus Minimus and Pleuralis pleura. Uncommonly, the scalenus pleuralis variant
Scalenus minimus and scalenus pleuralis are muscles may pass between the C8 and T1 nerve roots, in which
that arise from the anterior transverse processes of C7 case the lower trunk is not formed until the roots pass
and occasionally C6 and insert onto either the first rib beyond the first rib. These muscles vary greatly in their
(Fig. 23-5) or the pleura. These muscles, also known as mass, angle of origin and insertion, and fibrous content.
the Albinus muscles, are variably present, unrelated The exact nature and position of the lower plexus
to the presence of any of the other described anomalies. entrapment may vary significantly.
The scalenus minimus muscle passes anterior to the
lower trunk or the C8 and T1 nerve roots to insert onto Axillary Arch Muscles
the first rib. A scalenus pleuralis variation may be iden- The axillary arch muscle of Langer and the sternalis
tical except for inserting onto the pleura anteriorly. muscle are two muscles of the lateral chest that can
Occasionally, there is a double insertion onto rib and cause peripheral nerve compression lateral to the
2560_Chapter 23_0269-0288.indd 278 3/16/2015 4:14:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
axilla just distal to the plexus and cause symptoms
similar to lower trunk or medial cord entrapment. Sup-
posedly present in 2% to 3% of the population, the
muscle of Langer was found only twice in our series
and has seldom been described in modern texts. The
presence of this anomaly should be considered in
Middle scalene patients with immediate treatment failures after supra-
muscle clavicular plexus dissections.
Anterior scalene Radiation Fibrosis
muscle
Radiation therapy is a well-known cause of scarring
Posterior scalene and fibrosis. The plexus may be included in the radia-
muscle tion field in the treatment of breast cancer and in the
treatment of the mediastinum in lung cancer and lym-
phomas. Acute radiation injury to the plexus is uncom-
mon in the modern era. The delayed scarring that
occurs after radiation therapy progresses slowly over
time. There is danger in dissection of the plexus after
radiation therapy from interference with the blood
supply within the nerves, which may result in severely
Figure 23-4 The path of the median nerve is pictured as it
compromised nerve function.54
enters the forearm and hand.
Other Fibrous Anomalies
Fixation of C7 and C8 in a dense fibrous sheath that
appears almost like sausage casing is frequently
found.25,33,47 This type of anomaly may extend out to
Middle scalene
fuse the entire middle and lower trunks. Similarly, the
upper plexus can be entrapped in this dense matting.
Scalene minimus C7 Based on its location, we have labeled this tissue meso-
Anterior scalene epineural fibrosis. This mesoepineural fixation is due to
Transverse trauma, where hemorrhage and oxidative reaction
Inferior trunk process
of plexus of C7 results in fixed scarring. These types of fixation are
extremely important in patients with symptoms associ-
Subclavian ated with arm motion. When the arm is abducted, the
artery and nerves of the lower plexus are required to move dif-
vein
ferential distances similar to the reins of a team of
First rib horses. When the nerve roots and trunks are fixed
together, significant traction on the nerves occurs with
motion. These fibrous sheaths also create significant
compression when placed under traction, similar to the
tightening of a Chinese finger trap.
Clavicle Abnormalities
Figure 23-5 The scalenus minimus and pleuralis (also Clavicular fractures may heal with exuberant callus or
known as the Albinus muscles) arise primarily from the may heal improperly with posterior angulation.55 This
transverse processes of C7 and insert on the first rib or posterior angulation can easily cause pressure on the
occasionally the pleura and are variably present. These brachial plexus with entrapment against the first rib.
muscles vary greatly in their insertion, angle of origin, and First rib resection rather than clavicle resection is gen-
fibrous content. erally recommended to relieve the plexus-level com-
pression in active patients.
Cervical Rib Anomalies
53
“thoracic outlet.” The muscle of Langer is a broad flat Cervical ribs are the most easily understood congenital
muscle that originates from the tendon of the latissi- anomaly and the most easily documented. Anteropos-
mus and passes anteriorly to insert anterior to the terior and oblique cervical radiographs are the best way
bicipital groove next to the pectoralis major insertion. to document a cervical rib.50,56 However, the clinician
It may trap the ulnar and median nerves high in the needs to view the radiographs personally, rather than
2560_Chapter 23_0269-0288.indd 279 3/16/2015 4:14:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
accept a report of “normal cervical spine.” The rib may the development of TOS after some type of inciting
go unnoticed in a search for more serious acute pathol- event.
ogy. A chest x-ray is not optimal for evaluation of
cervical rib anomalies because the standard posteroan- Elongated C7 Transverse Process
terior view throws the shoulders forward and may hide Cervical spine films should always be carefully inspected
the extra rib behind the first rib. for the presence of an elongated transverse process of
Cervical spine radiographs are much more sensitive the C7 vertebra. This process is defined as a projection
at the present time for rib anomalies than computed beyond the plane of the transverse process of T1 and
tomography and magnetic resonance imaging scans. is easily visualized and measured. The importance lies
The “slices” viewed on magnetic resonance imaging and in the anomalous attachments of scalenus minimus,
computed tomography images make it difficult to scalenus pleuralis, and fibrous bands, which are com-
reconstruct mentally the presence of these types of rib monly found associated with these elongated processes.
anomalies in three dimensions. Computer programs In the angled cervical spine films, the space-occupying
that reconstruct the images in three dimensions can nature of this anomaly can be appreciated.57
enhance the workup of patients with TOS through
visualization of these anomalies and the ability to prove First Rib Anomalies
more clearly their impact on the surrounding nerves Deformity of the first rib is much less common than
and vessels. the presence of a cervical rib.58,59 However, a surprising
The radiographs of the spine should be obtained in number of first rib deformities exist. Fusion of the first
at least four views. The oblique views of the spine to second rib at a point even with the location of the
are enlightening and often give a much better idea for scalene tubercle occurs most commonly. The insertion
how far the rib may be angled forward to interfere with of the anterior scalene is most obvious, but the middle
the nerves of the plexus (Fig. 23-6). The cervical rib scalene also may be significantly displaced, and the
may occasionally be entirely within the substance of possibility of pressure on (particularly the lower) plexus
the middle scalene and not directly causative of any may occur. The first rib may also be displaced superi-
pathology. orly, which lessens the already compromised space at
The length of cervical ribs is often discussed relative the thoracic inlet (outlet); this particularly predisposes
to the likelihood of the ribs causing symptoms. A short the lower plexus to the effects of downward traction
rib that is angled forward is more likely to cause severe of the arm.
deficits than a long rib, which may even be fused to the Tumors of the first rib as a cause of TOS have been
first rib. The few cases of “true neurogenic” TOS that described by Melliere et al.60 Fracture of the first rib
I have seen have had sharp, forward-pointing ribs that may heal with protuberant callus, which may also com-
indent the C8 nerve root from behind. All rib anoma- promise the thoracic outlet. First rib fractures are
lies must be considered a significant predisposition to usually associated with severe trauma, and injury to the
scalene muscles and direct plexus injury can easily
occur.
Postural Abnormalities
Postural abnormalities can contribute significantly to
the development of TOS. Most clinicians recognize
Cervical rib the concept of the “droopy shoulder syndrome.”61
C7 When the angle of the clavicle is below parallel from
the junction with the sternum, the entire shoulder
girdle causes traction on the plexus. When there is an
T1
underlying congenital structural abnormality, the mal-
positioned shoulder may in and of itself create the
onset of symptoms. Distal injuries in the arm can also
Normal
“first” rib
contribute greatly to the development of new-onset
TOS symptoms. The weight of a heavy forearm cast
can create downward forces on the arm.
Fatigue of the scapular elevator muscles in large-
breasted women may eventually create drag on the
plexus over the first rib. Breast reduction surgery may
be warranted in some cases if a trial of physical therapy
Figure 23-6 The presence of cervical ribs (unilaterally or is unsuccessful at improving the posture and the symp-
bilaterally) may predispose an individual to vascular and toms. Pregnancy may similarly initiate symptoms in
neurogenic dysfunction within the outlet. susceptible individuals as the breasts enlarge. Breast
2560_Chapter 23_0269-0288.indd 280 3/16/2015 4:14:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
reconstructive surgery can also lead to compromise of the C5, C6 roots, upper trunk, or lateral cord leads to
the plexus by altering the space at the distal plexus, manifestation of symptoms when this position is exag-
behind the pectoralis minor.62,63 gerated. Similarly, with the arm held laterally at 90°
Unusual positioning for long periods can also cause and with the palm extended, the fixation at the C8, T1
severe problems at the plexus level. There have been roots, lower trunk, and medial cord level results in
many descriptions of lower plexus neurogenic and reproducible symptoms in the appropriate distribu-
acute arterial occlusive events occurring after coronary tions. Close study of the anatomy of the brachial plexus
bypass surgery and lateral thoracotomies. The com- and its terminal nerves enables understanding of the
monly accepted wisdom has been to implicate improper symptoms caused by traction and the resultant scarring
positioning and overzealous sternal retraction causing or fixation of the various areas of the plexus.
direct clavicle–to–first rib compression. It is more rea- With the contribution that traction and compressive
sonable to think that the problems arise in individuals forces and fixation impairments add to the more easily
who have an anatomical predisposition from one of the understood concepts of compressive neuropathy of
many types of tissue bands. Particularly in the lateral the plexus, one can explore the interaction associated
thoracotomy position, an axillary roll or beanbag to with symptoms originating from the more distal ter-
elevate the chest wall away from the operating table is minal nerves. The concepts of “double crush” and “triple
imperative. crush” injuries are somewhat disputed. However, if the
The pivotal concept that unites these various etiolo- symptoms caused by variations in posturing as noted
gies of TOS is that TOS is often a dynamic problem. earlier are considered, it is easy to understand how
Until an event, or series of events, occurs that causes injury and subsequent fixation at other points along the
an alteration in the microanatomy of the tissues sur- peripheral nerves create additive symptoms in different
rounding the plexus, patients may have no symptoms positions.
of any kind.
Complex Regional Pain Syndrome
Traction Plexopathy The International Association for the Study of Pain68
The main focus of the TOS type of brachial plexopathy proposed a new term, complex regional pain syndrome,
discussed to this point has focused on compressive to replace RSD. CRPS is a poorly understood symptom
forces on the nerves. Duchenne64 described traction complex that affects a small but important group of
brachial palsy in 1872, referring to an obstetrical injury patients who have had some type of trauma to the
to the upper plexus. Later Erb65 described injury to the upper extremity. “Shoulder-hand syndrome” and “cau-
upper plexus in adults secondary to trauma, of which salgia” are two of the more common terms used inter-
motorcycle accidents are the predominant cause at the changeably with CRPS.69,70 “Causalgia” is derived from
present time. These injuries are often generally lumped the Greek words causos meaning “heat” and algos
into “Erb’s palsy” or “Erb-Duchenne palsy.” Klumpke66 meaning “pain.” The term “causalgia” was coined and
subsequently described traction injury to the lower the first full description was written by Weir Mitchell
plexus. A severe injury may result in avulsion of the during the Civil War.71 Many other terms have been
nerve root from the spine. The plexus may also rupture used, which further enforces the misunderstanding
within the brachial plexus. Less severe traction or (Box 23-1).
trauma results in a stretch injury, also known as a
neurapraxia, from which there can be near-complete
recovery. The sequelae of a stretch or neurapraxic injury
BOX 23-1
may result in scarring and fixation of the nerves of the
plexus. The same injury may cause a stretch injury of
any of the other soft tissue structures near the plexus, Common Synonyms Found in the Literature for Complex
causing bleeding, scarring, and fixation of the adjacent Regional Pain Syndrome
nerves. Horsley67 is credited with the idea that brachial Reflex sympathetic dystrophy
plexus lesions are caused by injuries that tend to spread Sudeck’s atrophy, reflex
the head and shoulders apart and to stretch the plexus. Reflex neurovascular dystrophy
The scarring and fixation of different portions of the Shoulder-hand syndrome
plexus are easily seen at surgery and help explain some Algoneurodystrophy
of the reasons why brachial plexus/TOS is misunder- Causalgia
stood. Decompressive-only procedures (first rib resec- Vasomotor atrophy
tion or scalenotomy), which do not address the scarring Pseudomotor atrophy
and fixation of the nerves, result in continued symp- Steinbrocker syndrome
Erythromelalgia
toms with full range of motion of the shoulder. The
Algodystrophy
upper plexus is placed under maximum stretch with Posttraumatic dystrophy
the “waiter’s tip” position of the arm. Scarring around
2560_Chapter 23_0269-0288.indd 281 3/16/2015 4:14:13 PM

Process CyanProcess
YellowProcess Black
CRPS is further divided into two types.69 Type 1 Classically, development of CRPS follows a traumatic
represents cases classically referred to as RSD. Type 2 injury to peripheral nerve.76 The injury frequently is
corresponds to causalgia. The essential differentiating caused by the hand being caught in some type of
feature between the two types using this nomenclature machinery such as a punch press or roller. A neuroma
is that causalgia is associated with a major nerve injury. or peripheral nerve entrapment may precede the devel-
The trauma believed to be associated with RSD is often opment of the RSD symptoms.69 Careful history of the
considered “trivial.” There is no definitive test for RSD, injury may show that the injury resulted in traction to
causalgia, or CRPS. the brachial plexus as the patient attempted to extract
It is common for patients to be labeled with the the hand from the machinery. The weight of a cast
diagnosis of RSD or CRPS because of slight mottling on the arm may cause traction to the plexus.
of the hand, unexplained pain, pain with arm motion, Fixation of the C7 nerve root (middle trunk) to the
edema, sweating, or similar complaints that may be C8 nerve root or lower trunk is also found almost
associated with RSD.72 RSD should be excluded if a universally in these patients.72 The traction or fixation
more definitive diagnosis can be made, and a diligent signs that are elicited by the provocative postures on
search for other causes should be undertaken before examination have profound implications. It is probably
allowing this diagnosis of exclusion to be made. safe to say that these signs do not develop unless the
Drucker et al.73 divided RSD into three stages patient has more than one point of traction and fixa-
based on clinical presentation. Stage 1 is a reversible tion along the length of the nerve (i.e., the “double
state characterized by hyperhydrosis, warmth, ery- crush” phenomenon).
thema, rapid nail growth, and edema of the hand. Other authors have clinically implicated sympa-
Resolution of symptoms may occur after treatment or thetic dysfunction as a significant problem in patients
spontaneously. In stage 2, there is mottling and cold- with TOS. Urschel and Kourlis77 performed a sympa-
ness of the skin associated with brittle nails and thectomy in all patients during transaxillary rib resec-
increased pain. Osteoporosis is always present. Spon- tion. This adjunct to surgery was found to be of limited
taneous resolution is rare, and response blocks or sym- value early in my experience and was ended in 1983.
pathectomy is less likely to be beneficial. Stage 3 The residual neurological complaints after transaxillary
shows a fixed atrophic hand with severe osteoporosis. rib resection appear in most cases to be related more
There is seldom any response to therapy. There is to incomplete decompression and failure to release the
clearly some overlap between the various stages, but traction or fixation at areas of the plexus not treated
this framework serves to divide the syndrome reason- with transaxillary rib resection than the presence of
ably to allow appropriate expectations from interven- sympathetic dystrophy.
tions to be forwarded. Schwartzman et al.74 published Several issues remain confusing. The severity of
an excellent review in 1987. injury is not clearly related to the severity of CRPS.
CRPS remains a series of symptom complex descrip- The response to therapy is extremely variable. Finally,
tions, not a freestanding diagnosis, in most patients. A untreated CRPS usually “burns out” after several years,
patient presenting with CRPS-type symptoms should and the pain eventually begins to subside, although the
be thoroughly evaluated for evidence of plexus-level hand may remain nearly functionless.
pathology. The relationship between plexus injuries and
the development of RSD was recognized in the past
but has been understated in more recent literature. To Surgery
quote from Barnes’ 1952 article on causalgia in Sed-
don’s text75: “Multiple nerve injuries are commonly Failure of conservative therapy is an indication for
present and causalgia may be associated with all. In the surgery if the symptoms are severe enough to warrant
upper limb there is always an incomplete lesion of the intervention. There are a few instances in which surgery
lower trunk or medial cord of the brachial plexus or should be undertaken rapidly, sometimes without a
the median nerve.” Although our practice may see a trial of physical therapy. Development of muscle
skewed population, there has been evidence of signifi- atrophy is an indication for immediate intervention
cant plexus conduction deficits in all cases of “true before further loss of motor units ensues rapidly.
RSD” that we have studied. The findings at surgery in Immediate surgery is indicated in cases of venous and
this group of patients uniformly show extensive fixa- arterial thrombosis. In these instances, decompression
tion of the plexus to the surrounding tissues, particu- of the vessels should begin soon after clot removal or
larly at the level of the lower trunk secondary to the lysis. We also believe that extremely positive vascular
presence of a Roos band or scalenus minimus type of occlusive signs with minimal arm motion should
anomaly; this fits the type of injury usually seen. prompt early intervention because of the risk of arterial
The most confusing aspect of CRPS is that the complications.
development and severity of CRPS have not been The type of procedure recommended is based on
directly correlated with the severity of the injury. many factors. There are presently two major approaches
2560_Chapter 23_0269-0288.indd 282 3/16/2015 4:14:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
to surgical decompression of the thoracic outlet: trans- supraclavicular resection of residual scalene muscle is
axillary first rib resection and comprehensive supra- indicated.
clavicular plexus decompression with scalenectomy.
Other procedures such as scalenotomy are of historical Scalenotomy and Scalenectomy
interest only. Division of the anterior scalene or partial resection as
In cases of lower trunk compression only, without a practiced for many years as first described by Adson
history of significant trauma, the transaxillary approach and Coffey1 relieves symptoms in a moderate number
described by Roos19 is the approach of choice. When of patients. It is difficult to predict which patients with
there has been significant trauma of the “whiplash” isolated lower trunk symptoms will respond to scale-
type, the likelihood of fibrous fixation of the upper nectomy alone. As has been well documented by
plexus makes transaxillary resection of the first rib a numerous anatomical studies, there are many other
poor choice. In this instance, we prefer a supraclavicu- structures that can create lower plexus symptoms other
lar approach. A few surgeons prefer performing first than anomalous attachments of the anterior scalene. In
rib resections via a posterior approach. These proce- patients with only posterior displacement of the scalene
dures should be performed only by surgeons with spe- attachments to the first rib or pleura, the resection of
cific interest in this field. the scalene should relieve lower plexus compression.
When combined with resection of other anomalous
bands, scalenectomy increases the likelihood of satis-
Transaxillary First Rib Resection factory decompression of the lower plexus. Other
problems cannot be resolved by partial lower anterior
Roos19 described the transaxillary approach for resect- scalenectomy, which has resulted in development of the
ing the first rib in 1966. Before this time, the posterior concept of total plexus decompression.
thoracotomy approach was favored, similar to rib resec-
tion for thoracoplasty for tuberculosis. The transaxillary Total Brachial Plexus Decompression
approach proved to be much easier technically and Limitations of the transaxillary first rib resection led to
came into favor by most chest and vascular surgeons. reevaluation of scalenectomy. The original scalenotomy
The theory for first rib resection lies in the concept that procedure of Naffziger and Grant80 consisted simply of
TOS is a disease of the lower trunk and medial cord division of the anterior scalene above its attachment to
of the plexus, caused by numerous anomalous struc- the first rib. When scalenectomy was performed in the
tures that attach to the first rib or pleura and are acces- past, it was divided from the first rib and resected above
sible through this approach. the C7 level. Recurrences particularly at the level of the
Roos19,23,24 described this approach in great detail in upper plexus were common enough to cause continu-
many publications and more recently made a videotape ing reevaluation of the procedure. The concept of
of the procedure, which should be reviewed by anyone traction and fixation of the lower plexus was clearly
who plans to use this technique. The written descrip- understood; however, continuing symptoms from the
tion in Rutherford’s Textbook of Vascular Surgery78 is upper plexus remained an issue. The interdigitating
very clearly presented and is recommended for the bundles of anterior scalene between the roots of the
many technical details of the procedure. Urschel and upper trunk and middle trunk eventually received the
Razzuk79 suggested using a videoscope to assist visual- attention they warranted.
ization of the nerves and vessels at the apex. The patient is placed supine on the operating table.
In the hands of experienced surgeons such as Roos, Nonparalyzing general endotracheal anesthesia is
the transaxillary approach is safe, and the risk of nerve administered so that nerves can be tested throughout
injury or vascular injury is minimal. However, for the procedure. The endotracheal tube should be brought
surgeons with less experience with the procedure, the out of the nonoperative side of the mouth to avoid
risks are quite high. It is very common to see on kinking and provide access for the anesthesiologist. The
follow-up cervical spine films that a long length of head is tilted away from the operative side approxi-
first rib has been left in place posteriorly. When this mately 20°, and the chin is elevated. We use a vacuum
type of radiological evidence is found, one can be beanbag to hold the head in place. The entire neck,
sure that an inadequate decompression of the lower anterior chest, and arm are prepared and draped. The
plexus has been performed. Other problems encoun- impervious stockinet that has been placed on the arm
tered with the transaxillary approach are inadequate is clipped to the chest wall to keep it in place through-
removal of the myofascial bands and the very annoying out the procedure. Slight downward traction is placed
incidence of intercostobrachial nerve neuralgia. Patients on the arm by clipping a Kling wrap that has been
with fixed adhesions of the upper plexus (traction or wrapped about the stockinet to the drapes.
fixation injury) may have increased symptoms after The incision, which splits the lateral border of the
transaxillary first rib resections as the scalene muscle sternocleidomastoid, is made in the skin line 2 to 3 cm
retracts superiorly. If this retraction occurs, an early above the clavicle depending on the size of the patient.
2560_Chapter 23_0269-0288.indd 283 3/16/2015 4:14:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
The incision is taken through the platysma muscle. and is also encircled with a vessel loop. Any anomalies
Hemostats are obtained with electrocautery. The lateral of the middle scalene are resected at this time. When
border of the sternocleidomastoid is mobilized exten- the middle scalene has a firm fibrous anterior border,
sively, and the dissection is carried down to the deep it is partially resected. There are also quite commonly
cervical investing fascia. The fascia is opened superior portions of the origins of the middle scalene that pass
to the omohyoid muscle and is widely separated; this forward to lie in a plane anterior to the nerve roots.
exposes the scalene fat pad. An avascular plane is devel- These slips of muscle are also resected.
oped either medially or laterally around the fat pad to When a cervical rib is present, it is now resected
avoid venous and lymphatic vessels. along with any muscle attachments. The periosteum is
The fat pad is retracted in a self-retaining retractor. removed with the rib to avoid the possibility of regrowth
The anterior scalene can now be seen. The position of of the rib. Kerrison rongeurs are used to remove the rib
the phrenic nerve is immediately carefully noted. proximally so that the nerves can be fully visualized as
At this time, the upper trunk of the plexus can be the rib is removed.
encountered lying anterior to the scalene, which must When all of the muscle anomalies have been resected,
be recognized. When the phrenic nerve lies on the attention is directed to the nerves themselves. The
anterolateral aspect of the scalene, it must be mobilized fusion of C7 to either the upper or the lower trunk is
with its surrounding fascia over its full length so that quite common. The mesoepineural fixation of the
it can be carefully kept medial out of harm’s way various trunks must be separated to allow the nerves
throughout the procedure. When the phrenic nerve of the plexus to move through the full ranges of shoul-
originates directly off of the upper trunk, it is quite der motion. The need to release this fixation is apparent
short, and the dissection must tediously work around when the arm is moved during surgery. The tension on
it because it cannot be retracted. the various trunks is assessed at different positions
The medial and lateral aspects of the lower anterior during motion. Nerves that are significantly taut either
scalene are freed exposing the subclavian artery. A require further mobilization and relief of the mesoepi-
plane is developed between the artery and the muscle neural fixation or are fixed at other levels distally. The
with a large right-angled clamp. A Kocher clamp is roots, trunks, and divisions of the plexus can be mobi-
placed across the muscle, carefully observing the lized without fear of devascularization. There is never
phrenic nerve. A bipolar cautery is used to detach the any bleeding from the nerves when the dense scar
anterior scalene from the first rib, and the muscle is is removed, indicating that the blood supply of the
retracted superiorly. nerves is internal at this level. Equally important is the
There are usually numerous small vessels along the complete lack of any nerve functional loss when this
medial aspect of the muscle, which are also divided type of dissection is done. This is not an internal
with the bipolar cautery. Any aberrant portions of the neurolysis.
muscle distally are removed with the specimen. As the Assessment of the need for a first rib resection is
dissection continues superiorly, the anterior scalene made. If there is compression of the plexus between the
origins from the transverse processes of C4, C5, and first rib and clavicle or if there is evidence of the lower
C6 almost constantly split and pass between the C5, trunk being pulled tight over the rib with arm motion,
C6, and C7 nerve roots. These anomalies occur in a first rib resection is done. The first rib resection can
almost every case of upper plexus TOS. Using blunt be accomplished safely via this same incision except in
and sharp dissection as appropriate, these slips of extremely muscular individuals. The middle scalene
muscle are dissected away from the upper nerve roots attachments to the first rib are cleared from the supe-
and divided at the origins from the transverse pro- rior surface of the rib. Care must be taken to be sure of
cesses. The use of bipolar electrocautery makes this the position of the long thoracic nerve, which often
dissection safe and hemostatic. Care is taken to avoid passes through the substance of the middle scalene. The
the branches to the long thoracic nerve, which emanate most posterior aspect of the first rib is transected seri-
from the posterior aspect of C5, C6, and usually C7. ally with Kerrison rongeurs. The intercostal muscle is
After the anterior scalene is totally removed, the C7 separated from the first rib by dissection with either
nerve root/middle trunk is identified and encircled blunt or sharp scissors. A good view of the anterior rib
with a vessel loop. Sometimes C7 is fused to C8 with can be obtained by forward displacement of the shoul-
a dense matted epineural fixation that must be dis- der. Using angled duckbill or Kerrison rongeurs, the rib
sected away to free the nerves completely. The subcla- is transected anteriorly and removed. In some cases,
vian artery is encircled with a vessel loop. If there are piecemeal resection is necessary.
any branches of the subclavian passing through the A sympathectomy is easily done from this approach
lower plexus, they are divided with silk ties. if required. The pleura is bluntly separated from the ribs
If a scalenus minimus muscle is present, it is encoun- at the posteromedial rib and retracted forward. Finger
tered at this time and is resected. Any other anterior palpation easily identifies the sympathetic chain at
Roos bands are resected. The lower trunk is exposed the level of the second rib. The sympathetic chain is
2560_Chapter 23_0269-0288.indd 284 3/16/2015 4:14:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
elevated on a right angle clamp and grasped with the prompted conversion to ties for all vessels. The thoracic
right angle. Dissection is the taken distally at least to duct on the left and the accessory duct on the right
the fourth rib, and the chain is divided. Through this must be avoided at the inferomedial end of the scalene
approach, the stellate ganglion is easily seen. The effer- fat pad. If a significant amount of chyle is seen in the
ent branch to the T1 nerve root can be seen, and the drain postoperatively, the incision should be reexplored.
chain is divided at this level. In theory, there should The proteinaceous fluid of a chylous leak leaves
never be a Horner’s syndrome if the sympathetic chain extremely dense scar around the plexus if not repaired
is divided at this level. I have seen several cases in immediately.
which there were no eye symptoms but there was Phrenic nerve injury occurs in a few cases despite
absence of facial sweating on the operated side and two careful attention to detail and attempts to avoid undue
cases of mild permanent Horner’s syndrome despite traction by retractors. Diaphragmatic palsy usually
carefully dividing the sympathetic chain at a level that recovers over several months. There were only two cases
was clearly below the stellate ganglion. of permanent palsy in our series.
The wound is drained with a 7-mm silicone drain, There were two cases of permanent plexus injury in
which is brought out lateral to the external jugular vein. our series. Both occurred in patients who had prior
The scalene fat pad is tacked back in place over the radiation therapy for carcinoma of the breast. Supracla-
plexus. The platysma is closed with 3-0 absorbable vicular brachial plexus dissection should be undertaken
polyglactin suture. The skin is closed with a 4-0 pull- with extreme caution in patients who have undergone
out polypropylene. The drain is left in place until there prior radiation therapy near the plexus. If possible, radi-
is minimal drainage over a 24-hour period. Therapy is ation therapy ports should be adjusted to avoid the
begun on the first postoperative day. The initial goal of plexus in patients with a diagnosis of TOS. Another
therapy is to maintain full range of motion and proper patient who had a diagnosis of stage 3 RSD experi-
posture. enced significant motor dysfunction of the entire upper
extremity despite conduction studies which showed
Combined Anterior and that function had returned to normal and lack of
Transaxillary Procedure atrophy. Temporary motor dysfunction occurs occasion-
Because of dissatisfaction with the completeness of ally, more likely involving the upper trunk from traction
plexus decompression that could be accomplished on the nerves as they are dissected from the dense scar
with the transaxillary and the anterior approach, the tissue. Injury to the long thoracic nerve can easily occur
concept of a combined procedure was introduced. if the nerve is displaced anteriorly within the substance
Roos25 continued to recommend the combined proce- of the middle scalene. Care must be taken to section
dure, largely because of comfort with the transaxillary the muscle serially over a right angle clamp or similar
approach to rib resection. The first rib can be removed technique to prevent winging of the scapula.
from the anterior approach, but this is technically dif- Mild numbness and paresthesias are common from
ficult in heavyset or muscular individuals. When rib manipulation of the plexus early after plexus decom-
resection is deemed necessary, it should be performed pression, but recovery is rapid. There is sometimes
by whatever technique with which the surgeon is most hypersensitivity in the peripheral nerve distribution as
comfortable. the distal signals return.
Pneumothorax from pleural entry should not be
Robotic Surgery problematic if a Jackson-Pratt type of drain that has a
Robotic surgery gives remarkable views of the plexus one-way valve at the bulb is used. At the time of drain
and vessels of the thoracic inlet area. As instrumenta- removal, the drain site must be treated like a chest tube
tion is developed that aids in the proper dissection and and covered with an occlusive dressing.
protection of the nerves and vessels, the precision Horner’s syndrome may occur after sympathectomy,
allowed will undoubtedly add to the ability of surgeons even if the division of the sympathetic chain is carefully
trained in these techniques to obtain excellent results. done below the efferent nerve to the T1 nerve root.
Interestingly, with surgical sympathectomy there is
Complications often absence of the expected unilateral facial sweating
Numerous postsurgical complications can occur. Most with miosis or lid droop. According to anatomical
can be avoided with careful attention to surgical detail. descriptions, this should not occur. There is more varia-
Careful hemostasis prevents significant hematoma for- tion in the level of fibers involved in development of a
mation, which increases the likelihood of recurrent Horner’s syndrome than has been appreciated.
scar fixation. Permanent silk ties should be used for Vascular injury is rare but potentially hazardous. If
ligatures rather than surgical clips. Clips can get caught the artery has been severely entrapped by anomalous
in the surgical drain and be pulled out when the bands or muscles, it may become fragile to manipula-
drain is removed. An infected pseudoaneursym of the tion as in the original description of scalenotomy by
subclavian artery resulted in one such case and Adson and Coffey.1 Some slight subintimal dissection
2560_Chapter 23_0269-0288.indd 285 3/16/2015 4:14:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
occurs infrequently and has presented no significant to accept some responsibility by avoiding avocations
sequelae. Manipulation of the artery should be kept to that would be likely to cause reinjury.
a minimum. Venous injury most commonly occurs as A small number of patients experience recurrence
the anterior scalene is being removed from the first rib despite careful follow-up and compliance. In the series
in the anterior approach. During transaxillary rib resec- by Sanders et al.33, the delayed poor results occurred
tion, the subclavian vein is at greatest risk during resec- equally with transaxillary rib resection, anterior scale-
tion of the anterior portion of the rib. Control of the nectomy, and supraclavicular rib resection. The imme-
vein when injured during an anterior supraclavicular diate improved results showed a 93% cumulative
approach usually requires a subclavicular counterinci- success rate at 3 months, 81% at 1 year, and 74% at 5
sion. There has been only one significant venous injury years. Our data mirror the report of Sanders et al.33 if
in our series. limited to TOS procedures only.
Some of the 1-year failures reported by Roos23,24 and
Results Sanders et al.33 represent less a failure of the primary
The success of surgical procedures for TOS can be TOS surgery than a failure to recognize the signifi-
divided into short-term and long-term results. The cant associated peripheral neuropathy (“double crush”).
success rate has been shown to deteriorate over time Early in my experience, the number of immediate fail-
through the first 2 years because of numerous factors.30 ures from transaxillary rib resection despite a techni-
Recurrent injury and failure to conform to the therapy cally satisfactory procedure caused a reevaluation of the
program are the most common causes of failure. Rear- approach. It became apparent after study that upper
end automobile collisions are the leading cause of TOS plexus involvement was found in these post-traumatic
as well as the leading cause of treatment failure.33 cases and that transaxillary rib resection alone wors-
Although the concept that postoperative therapy is ened the upper plexus symptoms in a large number of
equally important as the surgery is stressed from the patients. The nearly constant anterior scalene anoma-
initial consultation, one of the most frustrating prob- lies at the upper plexus level had not been previously
lems we see are patients who stop the daily exercise recognized. Marked relief of upper plexus symptoms,
program after 3, 4, or 5 months because they are headache, and facial pain can be achieved only if com-
“feeling fine.” pleted decompression of the upper plexus is performed.
Successful surgical results depend on the definition
used for determination of success. Several points must
be stressed. Complete relief of symptoms is unlikely
except in nontraumatic cases limited to the lower
CASE STUDY
plexus. In this instance, a transaxillary rib resection can SC is a starting pitcher for his college baseball team.
achieve superior results that are likely to be permanent. Now 21 years old, SC has been pitching
Recurrent scarring about the upper plexus is unlikely, competitively for 15 years. He has averaged 200
and the likelihood of new-onset upper plexus symp- innings each of the past 2 years, which is a marked
toms secondary to muscle abnormalities is low. When increase over his workload the prior 3 to 5 years.
there are upper plexus symptoms, there are muscle Over the past 6 months, SC has noticed that his right
abnormalities. These cases, in which transaxillary rib (throwing) hand feels cooler than his left. The right
resection is recommended, manifest in a more straight- hand sometimes appears blue and mottled after much
forward manner and tend to have fewer of the ancillary pitching. There is no swelling of the hand. SC
manifestations described in this chapter. Cases related approached the trainer with his concerns and was
to post-traumatic and repetitive injuries are more likely referred to a vascular specialist. After an extensive
to have other associated problems, be of a more chronic physical examination, the vascular surgeon determined
nature, and have more significant perineural traction the working diagnosis to be arterial TOS secondary to
and fixation. chronic overuse of the upper extremity and possible
If return to prior levels of activity is required for aberrant congenital fascial bands within the thoracic
inclusion as a good or excellent result, a large number outlet. Diagnostic imaging tests were ordered. SC was
of patients would be eliminated. Demands that patients instructed to stop pitching immediately.
resume such occupations as assembly line work, heavy
construction, or overhead activities cannot often be
met without significant likelihood of recurrence. When
there is willingness on the part of insurance companies, 1. Which of the following arteries is most likely involved
businesses, and the patients themselves to aid the in arterial TOC in SC?
patient ’s return to the workplace with appropriate a. Subclavian artery
accommodation, rather than limit the patient to the b. Brachial artery
preinjury status, the entire workers’ compensation c. Aorta
process is improved. It is also incumbent on the patient d. Radial artery
2560_Chapter 23_0269-0288.indd 286 3/16/2015 4:14:13 PM

Process CyanProcess
YellowProcess Black
2. Aberrant congenital bands associated with arterial 11. Phalen CM. The carpal-tunnel syndrome. Seventeen years’
TOC typically originate on which structures? experience in diagnosis and treatment of six hundred
fifty-four hands. J Bone Joint Surg Am. 1966;48(2):
a. First rib and spinous process 211–228.
b. First rib and transverse process 12. Kremer M, Gilliat RW, Golding JSR, Wilson TG.
c. Spinous process and transverse process Acroparasthesia in the carpal tunnel syndrome. Lancet. 1953;
d. Transverse process and coracoid process 2:590–595.
13. Lewis M, Pickering DC. Pressure at the cervicobrachial
3. In arterial TOS, which of the following tests would outlet. Br Med J. 1947;3:341–342.
typically be negative? 14. Falconer MA, Li FWP. Resection of the first rib in
a. Halstead costoclavicular compression of the brachial plexus. Lancet.
1962;1:59–63.
b. Wright 15. Wright IS. The neurovascular syndrome produced by
c. Adson hyperabduction of the arm. Am Heart J. 1945;29:1–19.
d. Shoulder impingement 16. Lord JW, Urschel HC Jr. Total claviculectomy. Surg Rounds.
1988;11:17–27.
4. Arterial TOS is often confused with which of the 17. Raaf J. Surgery for cervical rib and scalenus anticus syndrome.
following conditions? JAMA. 1955;157:219.
a. CRPS 18. Clagett OT. Presidential address: Research and prosearch.
b. Raynaud’s phenomenon J Urol Nephrol (Paris) 1962;44:153–166.
19. Roos DB. Transaxillary approach for first rib resection to
c. Multiple sclerosis relieve thoracic outlet syndrome. Ann Surg. 1966;163(3):
d. Venous TOS 354–358.
20. Urschel HC Jr, Razzuk MA, Albers JE, Wood RE, Paulson
5. The presence of which of the following diagnostic DL. Reoperation for recurrent thoracic outlet syndrome. Ann
signs may lead to a diagnosis of subclavian artery Thorac Surg. 1976;21(1):19–25.
aneurysm? 21. Sanders RJ. Thoracic Outlet Syndrome: A Common Sequela of
a. Hypoactive deep tendon reflexes in the Neck Injuries. Philadelphia: Lippincott; 1991.
involved arm 22. Roos DB. Congenital anomalies associated with thoracic
outlet syndrome. Am J Surg. 1976;132:771–778.
b. A supraclavicular pulsatile mass 23. Roos DB. Thoracic outlet syndromes: update 1987. Am J Surg.
c. Hand and wrist edema 1987;154:568–573.
d. Supraclavicular Tinel’s sign 24. Roos DB. The place for scalenectomy and first-rib resection
in thoracic outlet syndrome. Surgery. 1982;92(6):1077–1085.
25. Roos DB. Historical perspectives and anatomic
considerations. Thoracic outlet syndrome. Semin Thorac
Cardiovasc Surg. 1996;8(2):183–189.
26. Sunderland S. The anatomy and physiology of nerve injury.
References Muscle Nerve. 1990;13:771–784.
1. Adson AW, Coffey JR. Cervical rib: a method of anterior 27. Adams JT, De Weese JA. “Effort” thrombosis of the axillary
approach for relief of symptoms by division of the scalenus and subclavian veins. J Trauma. 1971;11(11):923–930.
anticus. Ann Surg. 1927;85:839–857. 28. Greenhalgh RM, Powell JT. Endovascular repair of
2. Peet RM, Hendriksen JD, Anderson TP, Martin GM. abdominal aortic aneurysm. N Engl J Med. 2008;358:
Thoracic outlet syndrome: evaluation of the therapeutic 494–501.
exercise program. Proc Mayo Clin. 1956;31:281–287. 29. Braverman AC, Thompson RW, Sanchez LA. Diseases of the
3. Borchardt M. Symptomatologie und Therapie der Halsrippen. aorta. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds.
Berl Klin Wochenschr. 1901;38:1265. Braunwald ’s Heart Disease: A Textbook of Cardiovascular
4. Coote H. Pressure on the axillary vessels and nerves by an Medicine. 9th ed. Philadelphia: Saunders; 2011.
exostosis from a cervical rib; interference with the circulation 30. Urschel HC Jr, Razzuk MA. Neurovascular compression in
of the arm; removal of the rib and exostosis, recovery. Med the thoracic outlet: changing management over 50 years. Ann
Times Gaz. 1861;2:108. Surg. 1998;228(4):609–617.
5. Keen WW. The symptomatology, diagnosis and surgical 31. Urschel HC Jr, Razzuk MA. Improved management of the
treatment of cervical ribs. Am J Med Sci. 1907;133:173–218. Paget-Schroetter syndrome secondary to thoracic outlet
6. Halsted WS. An experimental study of circumscribed dilation compression. Ann Thorac Surg. 1991;52(6):1217–1221.
of an artery immediately distal to a partially occluding band, 32. Wilbourn AJ. Thoracic outlet syndrome: a neurologist ’s
and its bearing on the dilation of the subclavian artery perspective. Chest Surg Clin N Am. 1999;9:821–839.
observed in certain cases of cervical rib. J Exp Med. 1916;24: 33. Sanders RJ, Hammond SL, Rao NM. Thoracic outlet
271–286. syndrome: a review. Neurologist. 2008;14:365–373.
7. Murphy T. Brachial neuritis caused by pressure of first rib. 34. Wilburn AJ, Porter JM. Thoracic outlet syndrome. Spine.
Aust Med J. 1910;15:582–585. 1988;2:598.
8. Brickner WM. Brachial plexus pressure by the normal first 35. Tender GC, Thomas AJ, Thomas N, Kline DG. Gilliatt-
rib. Ann Surg. 1927;858:1927. Sumner hand revisited: a 25-year experience. Neurosurgery.
9. Ochsner A, Gage M, DeBakey M. Scalenus anticus 2004;55(4):883–890.
(Naffziger) syndrome. Am J Surg. 1935;28:699. 36. Mackinnon SE. Thoracic outlet syndrome: introduction.
10. Semmes RE, Murphy F. The syndrome of unilateral rupture Semin Thorac Cardiovasc Surg. 1996;8(2):175.
of the 6th cervical intervertebral disc with compression of the 37. Mackinnon SE. Thoracic outlet syndrome. Chest Surg Clin N
seventh cervical nerve root; report of 4 cases simulating Am. 1999;9:701.
coronary artery disease. JAMA. 1943;121:1209–1214. 38. Nelems W. On subjectivity. Can Med Assoc J. 1994;150:65.
2560_Chapter 23_0269-0288.indd 287 3/16/2015 4:14:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
39. Urschel HC Jr, Razzuk MA, Wood RE, Perekh M, Paulson with the scalene tubercle of the first rib. J Vasc Surg. 2012;
DL. Objective diagnosis (ulnar nerve conduction velocity) 55(5):1495.
and current therapy of the thoracic outlet syndrome. Ann 60. Melliere D, Ben Yahia NE, Etienne G, Becquemin JP, de
Thorac Surg. 1971;12(6):608–620. Labareyre H. Thoracic outlet syndrome caused by tumor of
40. Jaeger SH, Singer DI, Whitenack SH, Mandel S. Nerve the first rib. J Vasc Surg. 1991;14(2):235–240.
injury complications. Management of neurogenic pain 61. Al-Shekhlee A, Katirji B. Spinal accessory neuropathy, droopy
syndromes. Hand Clin. 1986;2(1):217–234. shoulder, and thoracic outlet syndrome. Muscle Nerve. 2003;
41. Adson AW. Surgical treatment for symptoms produced by 28(3):383–385.
cervical ribs and the scalenus anticus muscle. Clin Orthop 62. Iwuagwu OC, Bajalan AA, Platt AJ, Stanley PR, Drew PJ.
Relat Res. 1986;207:3–12. Effects of reduction mammoplasty on upper-limb nerve
42. Mathews WB. Footballer’s migraine. Br Med J. 1972;5809: conduction across the thoracic outlet in women with
326–327. macromastia: a prospective randomized study. Ann Plast Surg.
43. Spillane JD. Localised neuritis of the shoulder girdle: a report 2005;55(5):445–448.
of 46 cases in the MEF. Lancet. 1943;242:532–535. 63. Rubio PA, Rose FA. Thoracic outlet syndrome caused by a
44. Fabero K, Hawkins R, Jones M. Neuralgic amyotrophy. latissimus dorsi flap for breast reconstruction. Chest. 1990;
J Bone Joint Surg Am. 1987;69:195–198. 97(2):494–495.
45. Brown KE, Stickler L. Shoulder pain and dysfunction 64. Duchenne G. De l’électrisation localisée et de son application
secondary to neural injury. Int J Sports Phys Ther. 2011;6(3): à la pathologie et la thérapeutique. Paris: JB Ballière et fils;
224–233. 1872.
46. Kirchhoff C, Imhoff AB. Posterosuperior and anterosuperior 65. Erb W. Ueber eine eigenthümliche Localisation von
impingement of the shoulder in overhead athletes—evolving Lähmungen im Plexus brachialis. Verhandlungen des
concepts. Int Orthop. 2010;34(7):1049–1058. naturhistorisch-medicinischen Vereins zu Heidelberg. 1874;2:
47. Roos DB. Congenital anomalies associated with thoracic 130–137.
outlet syndrome. Anatomy, symptoms, diagnosis, and 66. Klumpke A. Contribution a l’etude des paralysies radicularies
treatment. Am J Surg. 1976;132(6):771–778. de plexus brachial. Rev Med (Paris) 1885;5:591–790.
48. Machleder HI, Moll F, Verity A. The anterior scalene muscle 67. Horsley V. Brachial plexus injuries. Practitioner. 1899;
in thoracic outlet compression syndrome. Histochemical and 63:131.
morphometric studies. Arch Surg. 1986;212:1141–1144. 68. Harden NR, Bruehl S, Perez R, et al. Validation of proposed
49. Sanders RJ, Jackson CG, Banchero N, Pearce WH. Scalene diagnostic criteria (the “Budapest Criteria”) for complex
muscle abnormalities in traumatic thoracic outlet syndrome. regional pain syndrome. Pain. 2010;150(2):268–274.
Am J Surg. 1990;159:231–236. 69. de Mos M, de Bruijn AG, Huygen FJ, Dieleman JP, Stricker
50. Ferrante MA. The thoracic outlet syndromes. Muscle Nerve. BH, Sturkenboom MC. The incidence of complex regional
2012;45(6):780–795. pain syndrome: a population-based study. Pain.
51. Wayman J, Miller S, Shanahan D. Anatomical variation of 2007;129:12–20.
the insertion of scalenus anterior in adult human subjects: 70. Ribbers GM, Geurts AC, Stam HJ, Mulder T. Pharmacologic
implications for clinical practice. J Anat. 1993;183(pt 1): treatment of complex regional pain syndrome I: a conceptual
165–167. framework. Arch Phys Med Rehabil. 2003;84:141–146.
52. Thomas GI, Jones TW, Stavney LS, Manhas DR. The middle 71. Pearce JMS. Silas Weir Mitchell (1829–1914). J Neurol
scalene muscle and its contribution to the thoracic outlet Neurosurg Psychiatry. 1992;55:924.
syndrome. Am J Surg. 1983;145(5):589–592. 72. Stanton-Hicks M, Baron R, Boas R, et al. Complex regional
53. Clarys JP, Barbaix E, Van Rompaey H, Caboor D, Van Roy P. pain syndromes: guidelines for therapy. Clin J Pain. 1998;14:
The muscular arch of the axilla revisited: its possible role in 155–166.
the thoracic outlet and shoulder instability syndromes. Man 73. Drucker WR, Hubay CA, Holden WD, et al. Pathogenesis of
Ther. 1996;1(3):133–139. post traumatic sympathetic dystrophy. Am J Surg. 1959;97:
54. Mullins GM, O’Sullivan SS, Neligan A, et al. Non-traumatic 454–461.
brachial plexopathies, clinical, radiological and 74. Schwartzman RJ, Liu JE, Smullens SN, Hyslop T, Tahmoush
neurophysiological findings from a tertiary centre. Clin Neurol AJ. Long-term outcome following sympathectomy for
Neurosurg. 2007;109(8):661–666. complex regional pain syndrome type 1 (RSD). J Neurol Sci.
55. Skedros JG, Hill BB, Pitts TC. Iatrogenic thoracic outlet 1997;150:149–152.
syndrome caused by revision surgery for multiple subacute 75. Seddon H. Surgical Disorders of the Peripheral Nerves. London:
fixation failures of a clavicle fracture: a case report. J Shoulder Harcourt Brace/Churchill Livingstone; 1972.
Elbow Surg. 2010;19(1):e18–e23. 76. Wilder RT. Management of pediatric patients with
56. Brintnall ES, Hyndman OR, Van Alien WM. Costoclavicular complex regional pain syndrome. Clin J Pain. 2006;22:
compression associated with cervical rib. Ann Surg. 1956; 443–448.
144:921. 77. Urschel HC, Kourlis H. Thoracic outlet syndrome: a 50-year
57. Le Forestier N, Moulonguet A, Maisonobe T, Léger JM, experience at Baylor University Medical Center. Proc (Bayl
Bouche P. True neurogenic thoracic outlet syndrome: Univ Med Cent). 2007;20(2):125–135.
electrophysiological diagnosis in six cases. Muscle Nerve. 78. Cronenwett JL, Johnston W, eds. Rutherford ’s Vascular Surgery.
1998;21(9):1129–1134. 7th ed. Philadelphia: Saunders; 2010.
58. Kirschbaum A, Palade E, Csatari Z, Passlick B. Venous 79. Urschel HC Jr, Razzuk MA. Neurovascular compression in
thoracic outlet syndrome caused by a congenital rib the thoracic outlet: changing management over 50 years. Ann
malformation. Interact Cardiovasc Thorac Surg. 2012;15(2): Surg. 1998;228(4):609–617.
328–329. 80. Naffziger HC, Grant WT. Neuritis of the brachial plexus
59. Balakrishnan A, Coates P, Parry CA. Thoracic outlet mechanical in origin: the scalenus syndrome. Surg Gynecol
syndrome caused by pseudoarticulation of a cervical rib Obstet. 1938;67:722–730.
2560_Chapter 23_0269-0288.indd 288 3/16/2015 4:14:13 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 24
Entrapment Neuropathy in the
Forearm, Wrist, and Hand
TERI O’HEARN PT, DPT, CHT
“If you can force your nerve, heart and sinew to serve you long after they are
gone, and so hold on when there is nothing in you except the will which says to
them: ‘Hold on!’ ”
—RUDYARD KIPLING (1865–1936)
Objectives
• Describe the anatomical course of each upper extremity peripheral nerve.
• Identify common nerve entrapment sites in the upper extremity.
• Discuss the signs and symptoms of common tunnel syndromes of the upper extremity.
• Discuss the possible functional loss attributed to each neuropathy.
Key Terms
• Compressive neuropathy
• Entrapment
• Tensile neuropathy
• Tunnel syndrome
the symptoms may provide the name, such as gleno-

Introduction humeral hyperabduction syndrome. “Tunnel” is often
in the name, such as carpal tunnel syndrome (CTS)
With the undulating course of peripheral nerves from or tarsal tunnel syndrome. The nerve may be the
the central nervous system distally to the end organs, descriptor, such as ilioinguinal syndrome. Lastly, the
nerves pass through bony, fibrous, osteofibrous, and etiological structure may be the descriptor, such as pro-
fibromuscular tunnels risking injury from compression, nator teres syndrome.
entrapment, and tensile forces. Because most periph- Although the diagnostic names may vary, all entrap-
eral nerves carry motor, sensory, and autonomic fibers, ment, compressive, and tensile neuropathies originate
the potential spectrum of impairment is impressive. from a lesion to the peripheral nerve and associated
Careful linking of the presenting signs and symptoms structural elements in a narrow anatomical space. Neu-
assists the clinician in identifying a list of differential ropathy may be compressive, such as from a hypertro-
diagnoses that, through examination and testing, can phied muscle, aberrant bone or bone formation, or
be confirmed, disproved, or added to. tumor. Traumatic neuropathy may occur from a missile,
The nomenclature of the etiology of entrapment, laceration, repetitive use, or blunt contact. Metabolic
compressive, and tensile neuropathies is diverse. etiologies include diabetes mellitus or hyperthyroid-
Some syndromes are named after the describing author, ism. Toxic neuropathies occur with lead and mercury
such as Kiloh-Nevin syndrome. Some are named intoxication or with some prescriptive medications.
after an anatomical area, such as metatarsalgia and Infections may produce space-occupying lesions or
thoracic outlet syndrome. The movement producing neural necrosis via bacteria and viruses. Tensile causes
289
2560_Chapter 24_0289-0310.indd 289 3/16/2015 4:14:17 PM

Process CyanProcess
YellowProcess Black
include stretching over or around aberrant anatomy. accelerated in individuals with diabetes.4 Appreciating
Anatomical variations may affect nerves, such as a the occurrence of diminished sensation that is common
post-fixed brachial plexus or a cervical rib. In this in patients with diabetes, the risk of complications such
chapter, we concentrate on entrapment, compressive, as ulcerations or other injuries is especially great. Use
and tensile neuropathic sites of injury. Other chapters of diagnostic testing, such as electromyography (EMG)
provide more detailed descriptions of the etiology of and nerve conduction velocity (NCV) studies, is helpful
the neuropathy. in distinguishing a nerve compression from diabetic
For this chapter, the term “tunnel syndromes” indi- neuropathy and is important in the provision of appro-
cates all entrapment, compressive, and tensile neuropa- priate treatment. Predictably, recovery rate is often slow
thies. Although there are a large number of tunnel compared with individuals without diabetes and is
syndromes in the upper extremity, this chapter focuses greatly influenced by glycemic control.4
only on the more common syndromes in the upper
extremity. This text also includes chapters detailing
tunnel syndromes in the lower extremity and thoracic Pathogenesis of Tunnel Injuries
outlet syndrome.
Lundborg1 stated: “For a peripheral nerve to func- Narrowing of the osteofibrous or fibrous neurovascular
tion properly, two basic requirements must be met: 1, tunnel is a major risk factor in the development of
its connection with the mother cells in the central tunnel syndromes. Intrinsic or extrinsic factors may
nervous system must remain undisturbed; and 2, it precipitate tunnel syndromes (Table 24-1). Extrinsic
must receive a continuous and adequate supply of causes are systemic events that happen outside the
oxygen through the intraneural vascular system.” Com- tunnel; intrinsic causes are systemic events that happen
pression or entrapment of a nerve blocks its ability to within the tunnel. Many tunnel syndromes are classi-
exchange essential nutrients, resulting initially in dys- fied as idiopathic. The Seddon classification of severity
function and ultimately in nerve tissue destruction. of tunnel syndrome as related to nerve injury is the
This chapter highlights commonly encountered most commonly used designation (Table 24-2).
neuropathies, such as radial tunnel, posterior interos- Neurapraxic lesions to nerve are the most common
seous nerve, pronator, anterior interosseous nerve, nerve injury and result in the mildest symptoms. Typi-
carpal tunnel, cubital tunnel, and Guyon’s canal (ulnar cally, there is only a temporary loss of function, and
tunnel) syndromes. However, entrapment can occur there is no structural neural disruption. Recovery occurs
anywhere along the course of the peripheral nerve. in minutes to weeks. Axonotmetic lesions result in
Recognition of symptoms helps to locate the site of the axonal and sheath disruption with preservation of the
lesion, but treatment depends on reversing the mecha-
nism of entrapment and facilitating normal physiologi-
cal neural function. According to a study by Ochoa2 Table 24-1 Intrinsic and Extrinsic Causes of Tunnel Syndrome
conducted in 1972, “the differences in pressures
between the compressed and uncompressed nerve gen- Category Examples
erate longitudinal forces that tend to extrude exoplasm External to Tunnel
like toothpaste from a tube.” Axonal flow, designed to Congenital Cervical rib, post fixed plexus
be unidirectional, is imperative to nerve function.
Nerve entrapment syndromes commonly occur where Trauma Elbow dislocation, fracture
anatomical restrictions, natural or otherwise, diminish Infectious Herpes zoster
the ability of the nerve to maintain optimal pressure Neoplasm Pancoast tumor, osteogenic sarcoma
gradients and mobility.3
Metabolic Diabetes mellitus, hyperthyroidism
Tissue loading can result in elevated extraneural
pressures within minutes or hours, restricting blood Hormonal Pregnancy
flow and axonal transport; this may result in endoneu- Toxic Lead intoxification, some medications
ral edema and increased intrafascicular pressure. There Iatrogenic Surgical injury, casting, wrapping
is evidence that the amount of endoneural edema is
related to the degree of axonal injury.3 Internal to Tunnel
In addition to the physical aspect of nerve entrap- Congenital Anomalous scalene muscle
ment related to mechanical forces, comorbidities, such Infectious Tuberculosis, abscess
as diabetes, increase the risk of development of neu- Neoplasm Schwannoma, hemangioma, myeloma
ropathy. It is estimated that nearly one third of patients
with diabetes are affected with nerve entrapment, Hormonal Pregnancy
although it is difficult to distinguish this from diabetic Toxic Lead intoxication, some medications
neuropathy.4 The rate of progression from initial injury Iatrogenic Surgical injury
to onset as well as severity of symptoms appears to be
2560_Chapter 24_0289-0310.indd 290 3/16/2015 4:14:18 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 24 | Entrapment Neuropathy in the Forearm, Wrist, and Hand 291
connective and structural elements. Wallerian degen- clinician can correctly diagnose the syndrome only
eration occurs distal to the site of injury. Recovery time through a valid and reliable physical examination and
is related to the distance the neural elements need to aided by radiographic, laboratory, and electrodiagnostic
regrow to reach the effector organ. Neurotmetic lesions studies.
are the most severe and result in a complete anatomical Diagnosis begins with a thorough document review
disruption of the nerve and the associated connective (i.e., laboratory results, imaging results, consultations)
structures. There is no spontaneous recovery. Surgical before the patient encounter, history, and physical
intervention is required. examination. The document review, history, and physi-
cal examination provide clinical scripts to the clinician
Clinical Symptoms and Signs that assist with building a differential diagnosis list.
Because most peripheral nerves carry motor, sensory, Further questioning and physical assessment tech-
and autonomic fibers from and to multiple myotomes niques complemented by radiographic, laboratory, and
and dermatomes, the spectrum of presenting signs and electrodiagnostic tests assist in adding to, removing, or
symptoms can be quite varied (Table 24-3). The astute confirming the items on the differential diagnosis list
(Figs. 24-1 and 24-2). Eventually, through meticulous
Table 24-2 Seddon Classification of Peripheral Nerve Injuries
Table 24-3 Symptoms and Signs of Peripheral Neuropathy
Lesion Definition Recovery Potential
Neurapraxia Temporary loss of Excellent without Type Symptoms and Signs
function; no neural intervention Sensory Loss of tactile discrimination, sharp, dull,
disruption vibration, kinesthesia, proprioception, light
Axonotmesis Disruption of axon and Good to excellent touch, pain, paresthesia, hyperesthesia,
sheath; connective with length- hypoalgesia, pain
sheath intact dependent Motor Myalgia, weakness, paralysis, hypoactive
variability deep tendon reflexes, atrophy
Neurotmesis Complete anatomical Poor to fair; Autonomic Vegetative disturbances, trophic nails, abnormal
disruption of nerve requires surgical hair growth, cool or warm skin, erythema,
intervention blanching, hyperhidrosis, hypohidrosis
Anterior View Posterior View
Medial brachial Upper lateral brachial

cutaneous and cutaneous nerve
intercostobrachial
nerves Posterior brachial
cutaneous and lower
lateral brachial Medial brachial
cutaneous nerve cutaneous and
intercostobrachial
nerves
Posterior antebrachial
cutaneous nerve
Lateral antebrachial
cutaneous nerve
Medial
antebrachial Medial
cutaneous Radial nerve antebrachial
nerve cutaneous
nerve
Ulnar nerve Ulnar

nerve
Median nerve
Figure 24-1 Mapping of the peripheral dermatomes of the upper extremity delineating
the nerve name and geographic distribution.
2560_Chapter 24_0289-0310.indd 291 3/16/2015 4:14:18 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Anterior View Posterior View
C2
C2 C3
C3 C4
C4 C5
C5
C6
C6
C7
T1
T1
Figure 24-3 Rule-of-nine test. Square grid, proximal aspect
is volar elbow flexion crease, with lateral-medial and distal
borders of equal length. Nine equal points within the grid
are palpated; a subjective report of pain at a specific point
or points that correlates with the posterior interosseous
nerve indicates a positive test. (Note: Photo is intended to
illustrate the test layout and is not meant to be used in
C8 C8 actual testing; the bottom of the photo represents the
proximal volar left arm.)
C7
Figure 24-2 Mapping of the segmental dermatomes of the

The classic presentation of RTS is reported pain at
upper extremity delineating the nerve name and
the lateral aspect of the proximal forearm without motor
geographic distribution.
weakness. The Rule-of-Nine test is a method of identi-
fying radial nerve irritation in the forearm (Fig. 24-3).9
The patient typically complains of a deep burning ache
about 4 to 5 cm distal to the lateral epicondyle over the
evaluation and assessment, the clinician arrives at the mobile wad of extensor carpi radialis longus (ECRL),
correct diagnosis. See Chapter 14 for a specific evalu- extensor carpi radialis brevis (ECRB), and brachiora-
ation algorithm. dialis (BR). Increased pain is commonly reported after
activities that include wrist extension combined with
forearm supination. Pain at night and at rest may also
Radial Nerve be reported.6 This pain may result in limited ability to
achieve complete active wrist extension and forearm
Radial Tunnel Syndrome pronation and often is accompanied by the patient ’s
Presentation complaint of needing to modify normal movement or
Radial tunnel syndrome (RTS) was first described in depend more on others to accomplish tasks.6
1956.5 The etiology of RTS may include pressure to Many publications seem to use the terms RTS and
the radial nerve caused by tumors or other lesions that posterior interosseous nerve (PIN) syndrome inter-
impose on the space occupied by the nerve, edema and changeably; however, the hallmark difference is that
inflammation, or blunt trauma to the proximal forearm. RTS involves pain over the radial aspect of the proxi-
More commonly, the development of RTS appears to mal forearm, whereas PIN syndrome is associated with
be correlated to activity that involves vigorous or repet- motor weakness at the wrist and digits (see section on
itive elbow, forearm. and wrist motion.6 RTS com- PIN syndrome later).6–9
monly is misdiagnosed as atypical lateral epicondylitis, In contrast to PIN compression, radial tunnel com-
or tennis elbow, although the two conditions often pression symptoms typically include forearm pain
coexist.7 located distal to the lateral epicondyle of the humerus.
Studies have listed risk factors related to RTS to PIN syndrome is not always associated with pain;
include occupations that involve maintaining the elbow marked weakness of the finger and wrist extensors is
in extension between 0° and 45°, especially when com- the typical presentation.9 It has been hypothesized that
bined with forearm supination; engagement of the RTS pain is a predecessor to PIN compression, which
supinator muscle imposes a compressive force on the results in motor deficits.10
nerve as it is tensioned across the radiocapitellar joint. Anatomy
Roquelaure et al.8 reported that factory workers who Continuing from the posterior cord, the radial nerve is
exerted regular force of at least 1 kg more than 10 times the largest terminal branch of the brachial plexus and
per hour were at risk for development of RTS.6 carries the C5–T1 nerve fibers, directly providing
2560_Chapter 24_0289-0310.indd 292 3/16/2015 4:14:18 PM

Process CyanProcess
YellowProcess Black
innervation to the triceps, anconeus, BR, and ECRL Typical reported patient history may include trauma to
muscles and possibly innervating the ECRB.11 The the lateral forearm, repetitive manual work, and lengthy
nerve descends behind the axillary and upper brachial time spent at the computer, and the condition is highly
arteries and courses in front of the latissimus dorsi and correlated with rheumatoid arthritis. A common pre-
teres major tendons. It crosses from the medial to the sentation is weakness of finger extension, thumb abduc-
lateral aspect of the humerus between the medial and tion, and wrist extension. EMG studies often show
lateral heads of the triceps and continues distally to increased differential latency of the PIN.10 BR, ECRB,
pierce the lateral intermuscular septum, passing and ECRL, which are innervated by more proximal
between the brachialis and BR muscles. At the level of branches of the radial nerve, are typically spared,13
the lateral epicondyle of the elbow, the radial nerve resulting in a presentation of active wrist extension
divides into deep and superficial branches.6 combined with radial deviation. The extensor carpi
The proximal aspect of the radial tunnel lies near the ulnaris and extensor digitorum communis are inner-
level of the radiocapitellar joint where the nerve rests vated by the PIN and, with compression of the motor
on the joint capsule. A surgical capsular release or other neuron, may become unable to produce adequate force
trauma at this location may injure the nerve. The medial to accomplish active neutral alignment of the wrist. The
border of the tunnel is formed by the BR muscle proxi- patient may also report pain at the proximal forearm,
mally and the biceps tendon distally. The lateral border but this is more likely related to RTS, which may coin-
and roof of the tunnel is provided by the ECRB and cide with PIN compression. PIN syndrome, in itself, is
ECRL. The tunnel extends to the distal aspect of the not associated with sensory deficits (see section on
supinator muscle.6 Wartenberg’s syndrome).11 Although the PIN is con-
Compression of the radial nerve may occur any- sidered to be a motor nerve, it does supply innervation
where along this pathway. In the forearm, areas of to the dorsal capsule of the wrist, providing proprio-
compression may be: ceptive and nociceptive sensation. As innervation is
supplied to the extensor pollicis longus, a branch to the
● Most commonly, at the proximal margin of the
distal radioulnar joint enters the fourth dorsal extensor
deep and superficial layers of the supinator
compartment and further divides into three or four
muscle.12
smaller branches at the dorsal wrist capsule. Patients
● At the proximal ECRB at the level of the
presenting with symptoms of the deep terminal sensory
radiocapitellar joint and may be associated with
branch of the PIN complain of a deep, dull ache in the
arthrosis.9
wrist, which may be exacerbated with forcefully resisted
● At the fibrous bands at the level of the radial
wrist extension. The patient may also report pain with
head.10
deep palpation of the forearm in combination with
● At the radial recurrent vessels (leash of Henry).6,12
wrist flexion.14 A study investigating the possibility of
● At the ligament/arcade of Frohse or at the
proprioceptive deficits related to PIN neurectomy after
distal border of the supinator muscle, or both.10
surgeries to treat conditions such as carpal instability,
The anatomy of the radial nerve at the forearm is distal radius fracture, and distal radioulnar joint pathol-
considered to be highly variable, making accurate diag- ogy concluded there were no significant proprioceptive
nosis a challenge.6 changes when the surgical population of the study was
Manual tests for RTS include the following: compared with the healthy, nonsurgical control group.15
The loss of active extension of the fingers associated
● Resisted middle finger12
with PIN paralysis may mimic extensor tendon rupture
• Pain is reported at the dorsal forearm over
in patient presentation. The use of tenodesis (passive
the radial tunnel with resisted middle finger
wrist flexion) to elicit digital extension can allow the
extension; this assists in differential diagnosis
therapist to rule out rupture of the extensor tendons
of RTS versus resistant tennis elbow (lateral
and validate suspicion of PIN paralysis.
epicondylitis).
The literature reviewed in this chapter suggests pain
● Resisted forearm supination10
related to RTS precedes motor dysfunction related to
• With elbow held in flexion, isometric
PIN syndrome, and onset of symptoms is often seen
forearm supination with patient report of
in individuals who engage in repetitive manual upper
pain over the radial tunnel is considered a
extremity activity.10
positive test for RTS.
Anatomy
Distal to the anconeus muscle, the radial nerve contin-
Posterior Interosseous Nerve Syndrome ues to the dorsal forearm, lateral to the radius, and
Presentation pierces the supinator muscle at the arcade of Frohse.
Patients demonstrating motor deficits and resulting The deep branch of the radial nerve is also referred to
functional impairment of the extensors of the wrist and as the PIN. A further division results in the medial and
digits may be affected with compression of the PIN. lateral branches.
2560_Chapter 24_0289-0310.indd 293 3/16/2015 4:14:18 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
The level of bifurcation of the radial nerve into the 1932. He suggested the term cheiralgia paraesthetica, an
posterior (deep) and superficial branches is variable and obsolete term for pain and paresthesia in the hand.17,18
not entirely reliable when it comes to diagnosing the SBRN entrapment is also known as handcuff neuritis/
site of PIN entrapment. The position of the forearm neuropathy/neurapraxia and wristlet watch neuritis.19
influences the location of the PIN; as the forearm Individuals who wear tight gloves or wristwatches
rotates from supination into pronation, the nerve may and athletes who use tape, archery guards, or straps
move 1.0 cm lateral to medial.12 with a racquetball racket may present with symptoms
The PIN provides motor innervation to the ECRB, of this type of compression. Entrapment of the SBRN
supinator, extensor carpi ulnaris, extensor digiti minimi, may be seen in patients who have had traumatic injury,
all extensor digitorum communis, extensor indicis, such as Colles’ fracture; repeated exposure to cold; or
extensor pollicis brevis, abductor pollicis longus, and other external compression at the wrist, such as from
extensor pollicis longus muscles. The terminal branch a cast.17 A soft tissue mass, such as a lipoma, or other
of the PIN supplies pain and proprioceptive innerva- anatomical variations, such as tight fascial bands, have
tion to the wrist. been reported in association with Wartenberg’s syn-
As the PIN continues distally on the interosseous drome.17 Athletes who participate in activities such as
membrane anterior to the extensor pollicis longus and batting, throwing, or rowing or in contact sports such
onto the wrist, it provides sensory fibers to the liga- as football, lacrosse, and hockey may experience nerve
ments of the wrist joint.10 The ECRB may be inner- injury secondary to direct trauma.14
vated by the radial nerve or by the PIN.11 The patient typically reports dorsoradial wrist, hand,
Entrapment of the PIN may occur: thumb, and index finger pain, numbness, and paresthe-
sias.14 Symptoms are often misdiagnosed as de Quer-
● Most commonly, at the proximal edge of the
vain’s stenosing tendovaginitis, although the two
supinator muscle.11
diagnoses are often seen concurrently. The rate of asso-
● Within or at the distal aspect of the supinator
ciation between the two diagnoses has been reported
muscle.
as 50%.20 Sensory testing, absence of edema and ten-
● As a result of radial head fracture or dislocation.
derness at the radial styloid, positive Tinel’s sign over
● Secondary to a mass imposing pressure onto the
the SBRN, or electrodiagnostic studies can distinguish
nerve (e.g., ganglion cyst, lipoma, synovitis).
Wartenberg’s syndrome from de Quervain’s stenosing
● As a complication after surgery, such as open
tendovaginitis.20
reduction with internal fixation of a proximal
Anatomy
radius fracture.13
The SBRN travels deep to the BR tendon, emerging
● After bifurcation into the medial and lateral
through the fascia that connects the BR and the ECRL
branches,
tendons at the middle to distal third of the forearm.20,21
• Involvement of the medial branch may
The nerve can become compressed between these
manifest as paralysis of extensor carpi ulnaris,
tendons, especially during forearm pronation. Dellon
extensor digiti minimi, and extensor
et al. described this type of compression as a scissoring
digitorum communis or
effect as the nerve becomes superficial.14 As the SBRN
• If the lateral branch is compressed, paralysis
continues distally after piercing the deep fascia, it
may be seen in abductor pollicis longus,
further divides into the five dorsal digital nerves.21
extensor pollicis brevis, extensor pollicis
The SBRN supplies cutaneous innervation to the
longus, and extensor indicis proprius, but
dorsoradial hand over the first, second, and third rays.
compression of both medial and lateral
The patient typically reports paresthesia and numbness
branches is uncommon.11
at this region. Sensory disturbance over the first exten-
Congenital anatomical anomalies resulting in sor compartment may be associated with overlapping
increased risk of PIN entrapment have been reported. innervation between the SBRN and the lateral cutane-
In a study reported by Prakash et al.16 in 2008, absence ous nerve of the forearm, which is a continuation of
of the ECRB was discovered and two tendons extend- the musculocutaneous nerve. Because of the superficial
ing from the ECRL into the second compartment of location of the nerves, entrapment neuropathies are
the extensor retinaculum deep to the abductor pollicis common.19
longus. The authors thought this anomaly further
increased the chance of PIN entrapment.
Median Nerve
Wartenberg’s Syndrome
Entrapment of the superficial branch of the radial Pronator Syndrome
nerve (SBRN) is also known as Wartenberg’s syn- Presentation
drome. The condition was first described as an inflam- A patient complains of forearm pain and numbness
mation of the SBRN by Wartenberg, a neurologist, in that makes his job as a dental hygienist very difficult.
2560_Chapter 24_0289-0310.indd 294 3/16/2015 4:14:18 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
There is no particular event that seems to have caused postural deficits; absence of forearm pain; and EMG
these symptoms, which were gradual in onset. Range findings that may or may not reveal an abnormality.25
of motion in the forearm, wrist, and hand is within Ericson25 emphasized the essential component of
normal limits but difficult because of pain. addressing the entire person, as opposed to focusing on
Symptoms of pronator syndrome may mimic CTS, the location of the symptoms, as a CTR may be inef-
but PS is much less common and is often considered fective in resolution of symptoms because the proximal
to be a reason patients do not respond as expected after problem has not been addressed or has not resolved.
carpal tunnel release (CTR) or may exist in combina- Ericson25 attributed the development of median nerve
tion with a double crush phenomenon.22 The diagnos- entrapment in the forearm to the following “critical
tic contrast to CTS is the absence of nocturnal sum” of etiology, which should be considered in appro-
symptoms. priate diagnosis and treatment:
The cardinal signs of PS are:
● Normal aging process
● Pain in the proximal forearm. ● Chronic hand pain
● Paresthesias in the digits. ● Sustained or repetitive forearm pronation
● Numbness in the palm associated with the ● Thoracic outlet symptoms
palmar cutaneous branch of the median nerve. • Postural deficits increase the amount of hand
Exacerbating activities may include forced or repeti- pain experienced
tive forearm pronation and supination, repetitive grasp- ● Cervical spondylosis/radiculopathy
ing, or direct pressure at the volar forearm. Studies have ● Obesity
investigated populations at risk for development of PS, ● Depression
which may include assembly line workers, carpenters, ● Ligamentous laxity
weightlifters, tennis players, forklift drivers, musicians, Anatomy
dentists and dental hygienists, and people who provide The median nerve is formed by lateral (C5–7) and
child care that involves cradling a baby on the volar medial (C8–T1) cords of the brachial plexus. Lying
forearm.14 Patients often present with symptoms in the anterior to the brachialis, deep to the lacertus fibrosus,
fifth decade, but onset of symptoms may be influenced the nerve passes between the superficial (humeral) and
by the intensity or frequency of the exacerbating activi- deep (ulnar) head of the pronator teres in the proximal
ties and medical comorbidities and general health of one third of the forearm. The nerve crosses lateral to
the individual. Athletes who participate in sports that the ulnar artery, separated by the deep and superficial
include repetitive, forceful forearm pronation and grip- heads of the pronator teres muscle. It proceeds poste-
ping may be at increased risk for development of PS. rior to the fibrous arch formed by two heads of the
Included in this population are pitchers, weightlifters, flexor digitorum superficialis (FDS) and emerges in the
archers, tennis players, arm wrestlers, and rowers. distal one third of the forearm along the lateral FDS.
Patients typically present with volar forearm pain, The median nerve innervates pronator teres, flexor
which is exacerbated with the activity and is relieved carpi radialis, palmaris longus, and FDS.
with rest, as well as occasional hand pain.14 The anterior interosseous nerve (AIN) branch of the
PS is considered to be a rare condition compared median nerve originates 5 to 8 cm distal to the medial
with CTS. It has been reported to be seen more com- epicondyle of the elbow, distal to the proximal border
monly in women than in men.23 of the superficial head of the pronator teres. Together,
Compression of the median nerve may occur the AIN and median nerves go through the fibrous
between the superficial and deep heads of the pronator arch of the FDS. The palmar cutaneous branch of the
teres and has been noted between both heads in 4.6% median nerve arises from the lateral aspect of the
of cases. It has been reported that the deep head of nerve approximately 7 cm proximal to the distal wrist
the pronator teres may be absent in 21.7% of the crease and runs deep to the antebrachial fascia close to
population.24 the medial border of the flexor carpi radialis, innervat-
The condition termed “pronator syndrome,” as pre- ing the skin over the palm proximal thenar eminence
viously described in the medical literature, has been (Fig. 24-4).
suggested to be nonexistent; rather, the appropriate The three most common sites for median nerve
term for this malady is “median nerve entrapment in compression associated with PS are as follows:
the forearm.”25 The clinical presentation includes subtle
weakness that may be unnoticed by the patient other ● Bicipital aponeurosis, otherwise known as
than on clinical examination; vague hand pain or lacertus fibrosus; its fascia is intimately
numbness in the median nerve distribution that may connected with pronator teres14
be intermittent (noticed distally, as opposed to at the • This site of compression is most common
compression site at the elbow), commonly seen with when the pronator teres origin is especially
concurrent diagnosis of CTS or with demonstration of proximal14
2560_Chapter 24_0289-0310.indd 295 3/16/2015 4:14:18 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
compensatory proximal interphalangeal joint
hyperflexion.
• Hyperextension at the thumb interphalangeal
joint is combined with hyperflexion at the
metacarpophalangeal joint.26
There is no reported paresthesia, which is the key

differentiating symptom from CTS. Clinically, AIN
is considered a pure motor nerve, but it has sensory
branches at distal radioulnar and radiocarpal joints.26
The development of AIN syndrome may be associated
with chronic (repetitive or prolonged) forearm prona-
Figure 24-4 Path of the median nerve as it enters the
tion or elbow flexion or acute trauma, such as fracture.27
forearm and hand.
Weakness of the muscles innervated by the AIN, in
itself, is rare with incidence reportedly less than 1% of
all peripheral neuropathies of the upper extremity.26,28
● At the site of the pronator teres as the nerve
There is continued question as to whether AIN syn-
passes between the humeral and ulnar heads
drome is a neuritis, compression/entrapment neuropa-
• This site is often associated with muscle
thy, or both.26
hypertrophy, fibrous bands within the muscle,
Electrodiagnostic studies may assist in differentiat-
or anomalous course of the nerve, which has
ing between main median nerve trunk and AIN
been seen below or piercing the humeral
entrapment. In a case study of a young Coast Guards-
head14
man who had lost functional pinch, motor and sensory
● Below thickened fibrous arch of the FDS14
conduction assessment was performed to determine
● Less commonly, deep to the ligament of
the site of neural lesion. An assessment of the median
Struthers, which spans the supracondylar process
nerve from axilla to wrist revealed normal conduction
and medial epicondyle at the distal humerus
in the main median nerve trunk, but no evoked action
● Persistent median artery
potentials were elicited in the FPL, indicating probable
● Rarely, secondary to an enlarged bursa at the
entrapment at the proximal aspect of the AIN. Surgical
bicipital tuberosity14
decompression resulted in resolution of symptoms.29
Anterior Interosseous Nerve Syndrome AIN syndrome, although a rare condition, should be
considered whenever a patient presents with a history
Presentation
of forearm pain in association with hand or forearm
AIN syndrome is associated with loss of flexor pollicis
weakness that may be the result of acute trauma.27 Loss
longus (FPL), flexor digitorum profundus (FDP)
of digital flexion may be the result of tendon rupture
(index and occasionally middle, ring, and small fingers),
related to diagnoses such as rheumatoid arthritis, Kien-
and pronator quadratus in severe cases.26 Forearm pain,
böck’s disease, and scaphoid nonunion. To rule out
often described as “vague” or “aching,” which may
rupture and validate suspicion of AIN syndrome,
develop over several hours, leads to weakness and
passive wrist flexion and extension produce the teno-
motor dysfunction in the thumb and index finger and
desis effect of FPL and FDP.30
potentially affects forearm pronation. Pain may be
Anatomy
experienced at rest but is exacerbated with activity.26
The AIN is the largest branch of the median nerve,
Weakness results in difficulty with handwriting because
which arises about 5 to 8 cm distal to the medial epi-
of inability to achieve functional tip pinch.
condyle of the elbow from the posterior aspect of the
● Incomplete syndrome is characterized by loss of median nerve.26 Lying anterior to the brachialis muscle
FPL or index finger FDP strength. and deep to lacertus fibrosus, it is crossed by the deep
● Complete syndrome is characterized by head of the pronator teres in the proximal one third of
weakness of FPL, FDP of index and middle the forearm. It may lie deep to ulnar collateral vessels,
fingers, and pronator quadratus. an accessory muscle from the FDS (Gantzner’s muscle),
• All FDP muscles may be innervated by the and an accessory muscle from the FDS to FPL. As the
AIN, resulting in weakness in all fingers.26 nerve continues distally, it passes lateral to the ulnar
● “Classic attitude” of weak pinch and inability to artery and between the FDP and FPL, along the
make “0” sign is associated with late stages of volar surface of the interosseous membrane with the
AIN syndrome.6 interosseous artery. Continuing distally, it travels pos-
• With attempted index finger–thumb terior to the fibrous arch formed by the two heads of
opposition, the index finger distal FDS, emerging in the distal third of the forearm. The
interphalangeal joint hyperextends with AIN provides motor innervation to the FDP of the
2560_Chapter 24_0289-0310.indd 296 3/16/2015 4:14:18 PM

Process CyanProcess
YellowProcess Black
index and middle fingers, FPL, and pronator quadratus extremes of wrist flexion and extension and resisted
muscles.31 grip,41 and pressure increases are greater in patients
Possible compression sites of the AIN include, but with a diagnosis of CTS compared with healthy control
are not limited to, the following: individuals.42 Although the carpal tunnel has openings
at either end, it maintains its unique tissue pressure
● Deep head of pronator teres
levels as though it were a closed compartment.26,43
● Fibrous tissue arcade of FDS
The debate regarding the etiology of CTS makes
● Gantzner’s muscle (accessory head of FPL),
determining the cause of this condition challenging.
flexor carpi radialis brevis26
Authors have attributed risk for development of CTS
● Tendinous origin of palmaris profundus
to vocation, occupation, lifestyle, gender, and genetics.
• Rare anomaly of the forearm, originating
There does not appear to be any direct correlation of
from the radial aspect of the common flexor
cause and effect that has substantiating evidence.
tendons in the proximal forearm and
Although CTS has historically been a common workers’
inserting at the palmar aponeurosis32
compensation issue, it is difficult for the physician to
● Accessory lacertus fibrosus
declare clearly the relationship of one’s occupation to
● Direct physical compression of nerve or vascular
injury in the case of CTS.
supply by blood vessel
Increased risk factors that are not related to vocation
• Ulnar recurrent vessels
include thyroid disease, diabetes mellitus, rheumatoid
• Aberrant radial artery
arthritis, alcoholism, obesity, and pregnancy.33,44 There
• Anomalous median artery
appears to be a correlation with greater weight and
• Anterior interosseous vessels as they cross
female gender.33 Other factors that may compromise
the AIN
the space within the carpal tunnel include, but are not
• Enlarged bursae, tumors, accessory bicipital
limited to, cysts, tumors, osteophytes, fractures, or
aponeurosis26
hypertrophic synovial tissue. According to a literature
review conducted by Falkiner and Myers38 in 2002,
Carpal Tunnel Syndrome primary risk factors for development of CTS are female
Presentation gender, menopausal age, obesity or physically unfit,
CTS is the most common peripheral nerve compres- diabetes including family history of diabetes, osteoar-
sive disorder in the upper extremity.33–36 CTS is con- thritis of the first carpometacarpal joint, smoking, and
sidered to be responsible for the highest rate of work alcohol abuse. It was concluded that the disease process
missed by affected employees37 and, in a report released was not correlated with work except in cases of cold
in 2002, accounted for $2 billion in annual surgical environments, such as butchery, but was correlated
costs.38 Although CTS is commonly thought of as a with general health and lifestyle.
work-related condition, the evidence supporting this The literature suggests three causes of CTS related
assumption is lacking. to compression of the neurovascular structures within
CTS is defined by the American Academy of Ortho- the carpal tunnel:
paedic Surgeons as a symptomatic compression neu-
ropathy of the median nerve at the level of the wrist, ● Compromised oxygen delivery and resulting
characterized physiologically by evidence of increased ischemia
pressure within the carpal tunnel and decreased func- ● Decreased longitudinal excursion of the
tion of the nerve at that level.39 The condition affects median nerve
male and female individuals of varying ages and is not ● Injury or compression to carpal structures
specific to ethnic or occupational factors.39 Plenty of secondary to mechanical influence26
attention has been paid to this common pest of medical Because evidence supporting the reliability of diag-
diagnoses, but progress has been slow in developing nostic evaluation for CTS is lacking, no particular test
methods of prevention, diagnosis, and treatment. is considered a gold standard for diagnosis of CTS.
Complaints associated with CTS include numbness EMG and NCV testing are commonly used as an
and tingling in the thumb and index, middle, and radial objective augmentation to clinical diagnosis, which
half of the ring fingers; burning pain at night; and, in may otherwise be based on subjective information
advanced cases, distal forearm pain, diminished grip (Figs. 24-5 and 24-6).39
and pinch strength, and loss of sensation. Symptoms Manual tests considered to be reliable in screening
may vary from day to day.35,39 Median nerve irritation for CTS include the following:
associated with position and activity is well docu-
mented. Compression on the median nerve within the ● Tinel’s percussion test33
carpal tunnel compromises oxygen delivery to the nerve • The Tinel percussion test was developed by
and may result in mechanical injury.40 Increases in pres- Tinel in 1915. Gingerly tapping over an
sure within the carpal tunnel have been measured with irritated nerve may produce paresthesias at
2560_Chapter 24_0289-0310.indd 297 3/16/2015 4:14:18 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
together for 60 seconds; a positive test result
is symptom reproduction in median nerve
distribution. (Reverse Phalen test is
conducted in “praying hands” fashion,
achieving wrist hyperextension.)
● Carpal compression test40
• In 1991, Durkan developed this simple test.
It is performed by applying direct pressure
on the carpal tunnel for up to 1 minute. The
test is considered to be positive if the subject
reports paresthesia/dysesthesia in the median
nerve distribution.
CTR surgery is considered an effective treatment for

Figure 24-5 In a pure anterior interosseous nerve lesion, CTS. Postoperative complications are infrequent but
there may be weakness of the flexor pollicis longus and the may pose a frustrating challenge to the patient and the
flexor digitorum profundus I and II as revealed by the treating therapist. Pillar pain, tenderness superficial to
abnormal posturing associated with a pinch. Classic attitude the carpal tunnel, thenar, or hypothenar areas after
of a weak pinch: thumb metacarpophalangeal hyperflexion CTR, is sometimes encountered but poorly under-
combined with interphalangeal hyperextension, index finger stood. The pain is not experienced with activity and
proximal interphalangeal hyperflexion combined with distal may be accompanied by swelling. It is not commonly
interphalangeal hyperextension. associated with sensory disturbance.45 Scar sensitivity,
neuromas of cutaneous nerve endings, changes in
carpal arch dynamics or thenar and hypothenar muscle
origins, and decreased median nerve gliding may be
factors in development of pillar pain, which often
results in the patient having difficulty returning to
work.45
Taizo and Hiroyuki46 studied patients after CTR
who experienced pillar pain; spontaneous resolution of
symptoms occurred within 1 month in 58% (n = 146
hands), and the pain continued 3 to 9 months in 9%
(n = 13 hands). Women recovered more quickly than
men, but men were significantly younger and more
active. The authors suggested that pillar pain “might be
caused by a continuous synovitis by mechanical stimu-
lation” after CTR.46 (See the section on treatment later
for a discussion of the treatment of pillar pain.)
Figure 24-6 Compression test for median neuropathy is Anatomy
performed by pressing on the median nerve at the level of The median nerve arises from the lateral and medial
the distal palmar crease. A positive test elicits paresthesia cords of the brachial plexus. After it descends the prox-
over the dorsal cutaneous distribution of the median nerve. imal arm, the nerve crosses the antecubital fossa deep
Manual pressure is applied directly over the carpal tunnel to the biceps aponeurosis between the biceps tendon
flexor retinaculum for up to 1 minute; the test is positive if and pronator teres, lying on the distal brachialis muscle.
the subject reports paresthesia or dysesthesia in the median It continues beneath the two heads of the FDS, emerg-
nerve distribution. ing between FDS and FDP at the distal forearm. The
nerve route becomes ulnar to the flexor carpi radialis
and deep to the palmaris longus tendon, entering the
the percussion site and in the nerve carpal tunnel superficial to the flexor tendons.
distribution. This test is not used exclusively The floor of the carpal tunnel is formed by the eight
to test for CTS and is often used generally carpal bones; the roof of the tunnel is the transverse
to test for nerve irritation. carpal ligament, a strong fibrous band that is bordered
● Phalen’s test35 by the hamate and pisiform ulnarly and the scaphoid
• Phalen, an American hand surgeon (1966), and trapezium radially. The median nerve and the nine
developed and named this test. Increased tendons of the FDS, FDP, and FPL muscles are con-
carpal tunnel pressure is achieved as the tained within the tunnel. Also to be considered is the
patient is positioned in bilateral wrist often additional presence of the proximal aspects of
hyperflexion by pressing dorsal hands the lumbrical muscles, which are attached to the FDP
2560_Chapter 24_0289-0310.indd 298 3/16/2015 4:14:18 PM

Process CyanProcess
YellowProcess Black
tendons. It has been suggested that lumbrical tightness, ● Adjacent to the hook of the hamate
resulting in proximal migration, contributed signifi- • Commonly observed with CTR as hourglass
cantly to the etiology of CTS and was correlated with deformity in the nerve
occupations that involved repetitive hand motions.47 ● Space-occupying lesion
Two separate layers of fascia span the volar carpal • Flexor tenosynovitis
canal, the most superficial being the antebrachial fascia • Fracture-dislocation of carpal or radius bones
proximally and palmar fascia distally; the deep layer is • Tumors
the flexor retinaculum.26 Superficial to the flexor reti- • Ganglia
naculum (not within the carpal tunnel) lies the pal-
Edema and vascular sclerosis are seen concurrently
maris longus muscle and ulnar nerve, and the radial
with CTS but may be secondary factors rather than
artery is located lateral to the flexor retinaculum.
primary causes for entrapment neuropathy.26
The palmaris profundus is a muscle that arises from
the lateral edge of the radius, lateral to the FDS and
deep to the pronator teres. Its distal tendon passes
beneath the flexor retinaculum, broadening in the palm Ulnar Nerve
and inserting into the palmar aponeurosis. It has also
been termed musculus comitans nervi mediani because Cubital Tunnel Syndrome
the tendon of palmaris profundus and the median Presentation
nerve are often enveloped in a common sheath. This Cubital tunnel syndrome, the entrapment of the ulnar
muscle was first described by Frohse and Fraenkel in nerve at the elbow, may manifest with motor and
1908 (Die muskeln des menschlichen Armes) and may be sensory impairments in the forearm and hand.50 It is
found with or in the absence of the palmaris longus.32 considered to be the most common ulnar nerve entrap-
Because of its proximity to the median nerve, entrapment neuropathy and the second most common
ment at this site is possible and often overlooked, entrapment neuropathy in the arm, second to CTS.50–52
which may result in suboptimal results from CTR.48 Early in the disease process, the patient typically com-
The deep motor branch of the median nerve emerges plains of numbness in the small finger and ulnar aspect
within or just distal to the flexor retinaculum and typi- of the ring finger, which often is exacerbated by pro-
cally provides innervation to the thenar muscles longed flexion of the elbow, such as while sleeping, as
(abductor pollicis brevis, opponens pollicis, superficial well as with repeated external pressure over the nerve.
and deep heads of the flexor pollicis brevis and adduc- Individuals who lean their elbows on hard surfaces,
tor pollicis) and the lumbricals of the index and middle such as desktops, wheelchair arm rests, or an automo-
fingers. The abductor pollicis brevis has a separate bile window frame while driving, are at risk. Occupa-
muscle belly, but the opponens pollicis, superficial and tional hazards include prolonged telephone use and
deep heads of flexor pollicis brevis, and adductor pol- operation of vibrating tools.50 The symptoms progress
licis are more closely connected as the deep thenar from being occasional, while the position or activity is
muscle group and receive innervation from branches of taking place, to becoming constant and unrelenting
the recurrent nerve and accessory recurrent nerve from anesthesia.50 Additionally, patients often report pain at
the median nerve as well as terminal branches of the the medial aspect of the elbow, related to extensive
deep branch of the ulnar nerve.49 Variations in motor wrist flexion, specifically with extensive use of flexor
and sensory innervation have been reported, further carpi ulnaris (FCU).50
increasing diagnostic challenges.26 Cubital tunnel syndrome is not limited to individu-
The sensory branches of the median nerve supply als who commonly assume static postures that impose
the thumb; index, middle, and radial aspect of the ring sustained tension or compression on the ulnar nerve.
fingers; and radial aspect of the palm of the hand. The Athletes who engage in repeated throwing are suscep-
palmar cutaneous nerve arises from the median nerve tible to ulnar nerve irritation at the elbow. The litera-
about 5 cm proximal to the wrist crease, coursing sepa- ture reports diagnosis and treatment for cubital tunnel
rately under the antebrachial fascia between the pal- syndrome in baseball players ranging from Little
maris longus and flexor carpi radialis tendons, providing League through professional levels. Instability of the
sensory innervation to the thenar eminence. As it elbow secondary to repetitive valgus stress, which has
becomes more superficial, it divides into a radial and been suggested to contribute to ulnar nerve compres-
one or more ulnar branches and may be encountered sion, also is seen in throwing athletes. Repetitive
in a routine CTR.26 throwing is believed to result in the forward-medial
The common areas of median nerve compression movement of the hypertrophic medial head of the
within the carpal tunnel are as follows:32,33,44–48 triceps when the elbow is flexed greater than 90°. The
triceps imposes pressure on the nerve, increasing com-
● Proximal edge of the transverse carpal ligament pression under the arcuate ligament of Osborne.51,53,54
• Exacerbated by wrist flexion, validating In addition to throwing athletes, individuals at risk
Phalen’s test for development of cubital tunnel syndrome include
2560_Chapter 24_0289-0310.indd 299 3/16/2015 4:14:18 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
assembly line workers; violinists; and individuals with
occupations that involve concussive activity such as
hammering or shoveling, heavy lifting, and exposure to
extensive vibration. In a study by Kakosy55 of individu-
als whose occupations involved use of hand-arm vibra-
tion tools, it was reported that a significant number of
the population studied displayed signs and symptoms
of cubital tunnel syndrome, suggesting that use of such
tools increased the risk of developing ulnar neuropathy
at the elbow.50
Bony changes resulting from fractures or other
pathologies such as Paget ’s disease, rheumatoid arthri-
tis, or osteoarthritis can make the ulnar nerve more
vulnerable to external pressure. The normally narrow
configuration of the cubital tunnel becomes further
compromised as the condylar groove space is affected
by osteophytes or other deformity. Soft tissue compres-
sion on the nerve at the condylar groove may also
impair function owing to the presence of ganglia, fibro-
lipomas, epidermoid cysts, or thickened synovium
associated with rheumatoid arthritis, giant cell tumors,
Figure 24-7 The elbow flexion test is a poorly standardized
synovial cysts, or tophaceous gout.50
test for cubital tunnel syndrome. The test consists of the
The cause of cubital tunnel syndrome typically has
examiner passively flexing the elbow with full extension of
been attributed to longitudinal traction associated with
the wrist and fingers for 3 minutes. A positive test is
position or activity resulting in friction force and volar
defined as an indication of one or more of the following
subluxation of the nerve. As the elbow is flexed, the
symptoms: pain, numbness, or tingling. The elbow is
nerve becomes stretched across the bony surface,
positioned in maximum flexion, with the wrist neutral,
becoming narrowed and flattened within the condylar
while the therapist palpates over the ulnar nerve proximal
groove. Prolonged elbow flexion, such as during
to the cubital tunnel; this is sustained for 1 minute. The
immobilization/casting, use of a sling after injury, or
test is considered positive if the patient describes pain or
repetitively (e.g., while sleeping in a fetal position), has
paresthesias in the ulnar nerve distribution.
been associated with development of cubital tunnel
syndrome.50 Mechanical compression related to prior
trauma, such as supracondylar fracture, and swelling at
the medial elbow after injury or surgery may also result
in ulnar nerve compression.51
Hand weakness secondary to intrinsic muscle
impairment and resulting contractures are indications
of more advanced stages of ulnar nerve entrapment.50,51
Muscle atrophy associated with cubital tunnel syn-
drome is four times as likely to occur compared with
atrophy related to CTS.51 However, muscle impair-
ment without reported paresthesias is more likely to be
related to C8–T1 nerve root involvement as opposed
to cubital tunnel syndrome.50 Initially, motor deficits
manifest with the patient demonstrating impaired Figure 24-8 Path of the ulnar nerve in the forearm and
dexterity in the hand and reporting feeling “clumsy.” If hand as it courses distally from the cubital tunnel.
the compression is not relieved, the patient may even-
tually lose grip and pinch strength. Froment ’s sign, the
compensatory hyperflexion of the thumb interphalan- hyperflexion deformity ( Jeanne’s sign). Wartenberg’s
geal joint with attempted adduction (e.g., holding sign, the patient’s inability to adduct the small finger,
a pen in the thumb-index finger web space), is the results from paralysis of the interosseous muscles and
result of adductor pollicis paralysis (Figs. 24-7 and ulnar lumbricals and unopposed ulnar insertion of
24-8). Instability at the thumb metacarpophalangeal extensor digiti minimi (Fig. 24-9).
joint is a common occurrence because of adductor Advanced stages of ulnar neuropathy are associated
weakness resulting in unopposed thumb extension; with visible atrophy of the intrinsic hand muscles.
unopposed thumb flexors lead to interphalangeal joint Unopposed extensors, owing to paralysis of interosseous
2560_Chapter 24_0289-0310.indd 300 3/16/2015 4:14:18 PM

Process CyanProcess
YellowProcess Black
tunnel. Pressure and position are sustained for up to
1 minute. The test is considered to be positive if the
subject reports pain/paresthesia in the ulnar nerve
distribution.56
Anatomy
The ulnar nerve originates as a terminal branch of the
medial cord of the brachial plexus at the C8 (occasion-
ally C7) to T1 nerve root levels. At the middle to distal
third of the proximal arm medial to the axillary artery,
the ulnar nerve pierces the intermuscular septum at the
brachialis and triceps muscle borders and enters the
posterior/extensor compartment. It continues distally
between the aponeurosis of the two heads of the FCU,
Figure 24-9 To elicit Wartenberg’s sign, the patient is which blend with the arcuate ligament of Osborne,
directed to extend the fingers; abduction or clawing of the forming the roof of the cubital tunnel as it joins the
little finger occurs. As the patient attempts to adduct the medial epicondyle of the humerus and olecranon
fingers, the small finger (and, in this case, the ring finger process. This bridge stretches approximately 5 mm for
to a degree) remains abducted. each 45° of elbow flexion, which results in a flattening
and narrowing of the nerve in the cubital tunnel.50 The
medial collateral ligament of the elbow provides the
and ulnar lumbrical muscles, manifest as clawhand floor of the tunnel; as the elbow flexes, the medial col-
deformity, also known as benediction posture or main lateral ligament becomes slack and bulges into the
en griffe, and inability to form a functional grip.50 tunnel, further invading the cubital tunnel space.
The four most common sites of ulnar nerve com- The nerve becomes subcutaneous as it emerges from
pression and resulting compromise to intraneural the extensor/posterior compartment of the arm to the
microcirculation are the following:50–56 flexor compartment of the forearm within the epicon-
dylar groove of the distal humerus. It enters the forearm
● Arcade of Struthers
between the two heads of the FCU and gives off small
• The arcade of Struthers is a thick fascial band
branches that innervate the FCU and the ulnar half of
located approximately 8 to 10 cm proximal to
the FDP muscles. Approximately 5 cm proximal to the
the medial epicondyle of the elbow, which
pisiform, the nerve emerges at the medial border of the
runs from the medial head of the triceps to
FCU. It bifurcates into the dorsal and palmar cutane-
the medial intermuscular septum. Entrapment
ous branches supplying the dorsal ulnar side of the
of the ulnar nerve takes place between the
hand and fourth and fifth digits and the ulnar side of
muscles and the ligamentous sheath.
the palm. At the level of the wrist, the ulnar nerve,
● Humeroulnar arcade (cubital tunnel)
together with and medial to the ulnar artery, continues
• Traction force caused by hyperflexion of the
through the ulnar tunnel, otherwise known as Guyon’s
elbow results in flattening of the ulnar nerve,
canal. The canal is formed by the hamate and pisiform
which has been considered to be the most
bones of the wrist. Within the canal, the nerve bifur-
common cause of cubital tunnel syndrome.
cates into its terminal deep and superficial branches.
● Ulnar groove
The superficial branch of the ulnar nerve provides
• The nerve is vulnerable to traumatic impact
motor innervation to the palmaris brevis and cutaneous
and pressure as well as bony or soft tissue
innervation over the hypothenar eminence and ulti-
irregularities, including mass lesions, fibrosis
mately divides into digital branches supplying the volar
and scarring, abnormalities such as cubitus
small finger and ulnar ring finger (Fig. 24-10).
valgus, and injuries such as radial head
The deep branch of the ulnar nerve emerges between
anterior dislocation.
the abductor and flexor digiti minimi muscles and pro-
● FCU aponeurosis
vides motor innervation to the hypothenar eminence,
• Location of entrapment is approximately 5 to
ring and small finger lumbricals, interosseous muscles,
7 cm distal to the medial epicondyle of the
adductor pollicis, and deep head of the flexor pollicis
elbow. During elbow flexion, the aponeurosis
brevis.50
tightens, constricting the cubital tunnel space
and compressing the ulnar nerve. Guyon’s Canal Syndrome
The elbow flexion test is considered to be reliable (Ulnar Tunnel Syndrome)
in screening for cubital tunnel syndrome. The exam- Presentation
iner positions the subject’s elbow in full flexion while Guyon’s canal syndrome, also known as ulnar tunnel
palpating the ulnar nerve proximal to the cubital syndrome, is a result of entrapment of the ulnar nerve
2560_Chapter 24_0289-0310.indd 301 3/16/2015 4:14:19 PM

Process CyanProcess
YellowProcess Black
syndrome, which may exist proximally. A study by
Smith et al.52 suggested concurrent thoracic outlet syn-
drome in cyclists and altered axonal transport second-
ary to compression or tension loading of the brachial
plexus resulted in increased vulnerability to pressure at
the cubital tunnel or Guyon’s canal or both. Etiology
must be fully considered in diagnosis as well as
treatment.
Anatomy
Guyon’s canal is triangular in shape and is located at
the proximal aspect of the ulnar palm. It is bordered
laterally by the hook of the hamate and transverse
carpal ligament and medially by the pisiform and
attachments of the pisohamate ligament.
Figure 24-10 The ulnar claw, also known as the claw hand, The ulnar nerve continues down the forearm between
is an abnormal resting position of the hand that develops the muscle bellies of the FDS and FDP and enters the
secondary to an ulnar nerve lesion. The hand in ulnar claw canal along with the ulnar artery.13 The passageway is
has the fourth and fifth fingers drawn toward the back of about 4 cm in length. The proximal border is the trans-
the hand at the metacarpophalangeal joint and flexed at verse carpal ligament, and the distal border is the apo-
the interphalangeal joints. Classic intrinsic hand wasting is neurotic arch of the hypothenar muscles. The nerve
associated with ulnar neuropathy. divides into the deep motor and superficial sensory
branches at the level of the pisiform bone.57 The deep
motor branch proceeds between the abductor digiti
minimi and flexor digiti minimi brevis, pierces the
at the wrist as it passes through the narrow fibro- opponens digiti minimi, and continues beneath the
osseous opening between the palmar carpal ligament flexor tendons into the palmar arch.57
at the pisiform bone and origin of the hypothenar About 5 to 6 cm proximal to the wrist, the ulnar
muscles at the level of the hamate bone.57 This pas- nerve contributes to the branch of the dorsal cutaneous
sageway is known as Guyon’s canal or the ulnar tunnel. nerve, which passes deep to the FCU, pierces through
For the sake of simplicity, the term “Guyon’s canal” is the deep fascia, and continues to the dorsoulnar aspect
used henceforth. of the wrist and hand. It divides into two dorsal digital
Initial symptoms commonly include numbness and branches, one supplying the ulnar aspect of the small
tingling and occasionally pain in the ulnar distribution finger and the other providing sensory innervation to
of the palm, the small finger, and ulnar aspect of the the radial aspect of the small finger and ulnar aspect of
ring finger. Sensitivity to cold may also be reported. As the ring finger. The radial aspect of the ring finger and
muscle function is affected, the hand becomes clumsy, ulnar aspect of the ring fingers are mainly supplied by
and muscle atrophy may be observed. the superficial radial nerve but are assisted by the ulnar
At risk for development of Guyon’s canal syndrome digital nerve. The dorsal cutaneous branch of the ulnar
are individuals who have experienced concussion or nerve does not enter Guyon’s canal.
compression at the area; hammering (with or without The deep branch provides motor innervation to the
a hammer), forced gripping, and use of crutches may muscles of the hypothenar eminence, as follows:
impose trauma to the nerve. Use of power tools that
● The abductor digiti minimi is the most
excessively jar or vibrate (e.g., a jackhammer) the area
superficial.
of the hamate and pisiform bones are often associated
● The flexor digiti minimi lies lateral to the
with the etiology of Guyon’s canal syndrome. Also at
abductor digiti minimi.
risk are cyclists who weight-bear on the hands for
● The opponens digiti minimi lies deep to the
prolonged periods of time or ride through rough
abductor digiti minimi and flexor digiti minimi.
terrain. Acute trauma, such as fracture of the hook of
the hamate, may result in the collapse of the tunnel, Innervation is also provided by the deep branch of
compromising the narrow space that is occupied by the the ulnar nerve to all interossei muscles, which abduct
nerve and artery. Soft tissue compression may result and adduct the fingers; third and fourth lumbricals,
from the presence of tumors/lipomas, ganglia, anoma- which flex the fourth and fifth metacarpophalangeal
lous muscle bellies of palmaris brevis hypertrophy, joints; adductor pollicis; and medial head of flexor pol-
thrombosis or aneurysm of the ulnar artery, and, more licis brevis. The superficial branch lies deep and medial
rarely, arteriovenous malformation.58–60 to the ulnar artery, superficial to the hypothenar fascia,
A common mistake the therapist may make is not providing sensation to the small finger and ulnar aspect
recognizing contributing factors to Guyon’s canal of the ring finger.
2560_Chapter 24_0289-0310.indd 302 3/16/2015 4:14:19 PM

Process CyanProcess
YellowProcess Black
Treatment of Entrapment
Neuropathies
Manual Therapy
As therapists, we have the gift of our hands to assist
our patients in their healing process. Extensive study
and practice are required to develop the art and science
of manual therapy. Understanding of anatomy, the
mechanism of injury, and nerve physiology assists in
providing appropriate manual intervention. However,
this is not simply a matter of a mechanical influence
on neural function; symptoms related to neuropathies
have a strong emotional component. Butler61,62 referred
Figure 24-11 Myofascial release is a form of soft tissue
to research that revealed that injured neural tissue
therapy used to treat somatic dysfunction and resultant pain,
expressed more adrenaline-sensitive ion channels, and
dysesthesia, and limited mobility. The therapist is applying
sympathetic fibers sprouted, resulting in increased
stress across the scar: sustained and combined distal and
adrenaline sensitivity. He stated that two facts must be
proximal glide on the flexor surface of the forearm.
considered: (1) Ion channels are produced reactively to
the brain’s response to stress, and (2) stress reduction
can rapidly influence the sensitivity of the peripheral
nerve as the ion channels degrade and reproduce over
a short period of time.61,62 With this in mind, the
therapist must be appreciative of the potential influ-
ence of manual therapy on the neural tissue and avoid
exacerbation of symptoms, which may result from
overly exuberant or otherwise inappropriate delivery of
technique. Following are some widely accepted manual
strategies for the treatment of entrapment neuropa-
thies of the upper extremity.
Myofascial Release
Fascia, connective tissue that is present throughout the
body, covers virtually every corporal structure. Injury
secondary to postural changes, inflammation, and
trauma may result in alterations in pressure on struc- Figure 24-12 A myofascial technique using traction forces
tures, including neural tissue, resulting in dysfunction across a scar. Light tractioning gently encourages
of the entrapped nerve or nerves. Mobilization of the myofascial mobility.
fascia is directed at restoring functional mobility and
nutrition to the affected structures (Figs. 24-11 through
Fig. 24-14).63 pain. For example, pillar pain after CTR seems to be
General contraindications to performing myofascial a mysterious phenomenon that has challenged thera-
release: pists’ abilities; research that supports any particular
etiology or intervention is lacking. It has been sug-
● Malignancy gested that tendon and nerve gliding and use of thera-
● Aneurysm peutic modalities intended to decrease peri-incisional
● Acute rheumatoid arthritis
inflammation may be helpful in the treatment of
Considered regional contraindications: pillar pain.45
● Hematoma
The following online discussion excerpts list certi-
● Open wounds
fied hand therapists’ experiences and techniques in the
● Healing fracture
treatment of pillar pain after CTR. The following
entries are not based on published research studies and
Before attempting to perform myofascial release,
reflect the online opinions and experiences of various
instruction by a qualified professional is required to
participating hand therapists.64
provide appropriate treatment to the patient and mini-
mize risk of accidental injury. ● Vigorous soft tissue mobilization (helps relieve
Soft tissue mobilization is often used by manual pillar pain): having the patient wear a (scar pad)
therapists to facilitate tissue extensibility and to relieve around the incision site at night for 3 to 4
2560_Chapter 24_0289-0310.indd 303 3/16/2015 4:14:19 PM

Process CyanProcess
YellowProcess Black
continue metabolic activity, the mobilization of an
entrapped nerve is intended to restore optimal func-
tion. Normal neural mobility becomes impaired when
inflammation results in intraneural edema, producing
increased intraneural pressure and interrupting vital
blood flow, which provides oxygen and nutrient deliv-
ery to the nerve.65
In addition to cumulative or acute nerve trauma,
iatrogenic injury may occur as a result of tourniquet
use during surgery, casting, or splinting. Immobiliza-
tion during the early remodeling phase after injury has
been reported to hinder optimal joint and soft tissue
loading, impairing nutrient exchange. Nerve compres-
sion from the orthosis secondary to a tightly fitting
device or unpadded cast may occur. Neural tension and
Figure 24-13 Kinesio Taping provides support to impaired flattening of the nerve related to positioning, such as
joints without affecting circulation or range of motion. immobilization in elbow flexion, has been reported to
Indications include muscular facilitation of inhibition, lead to the development of neuropathy.65
pain, edema, ligament injury, muscle strain, and prevention Surgical neural mobilization may be indicated in
of injury. Light tractioning is used to encourage gently severe cases, but conservative treatment using nerve
myofascial mobility. gliding techniques may facilitate recovery in mild to
moderate cases.35,65 Neural mobilization after surgical
intervention is also appropriate to prevent or minimize
postsurgical scarring, which may impair normal nerve
excursion. Scar mobilization, when intended to facili-
tate neural gliding, should be performed in one direc-
tion at a time to avoid tractioning (tensioning) of the
nerve. It is reported that increased neural tension leads
to increased intraneural pressure, which impairs nutri-
ent exchange and nerve function.65,66
Terms associated with manual neural mobilization
include “flossing,” “gliding,” “neurodynamic mobiliza-
tion,” or “neural sliding,” and the actions these terms
describe are intended to reduce symptoms related to
restricted oxygenation to the nerve by increasing neural
excursion and decreasing adhesions.35,67 Neural mobi-
lization techniques were introduced in the treatment
Figure 24-14 Myofascial release technique using tacky of pain and radiculopathy more than 25 years ago.67,68
fabric. The patient may be instructed to use this technique Controversy surrounding nerve gliding techniques
as a component of home exercise program. perhaps should cause us to rethink the methods we
may have been taught in the past.65 Neural mobiliza-
tion techniques should focus on the restoration of
normal physiological glide, as opposed to tensioning of
weeks (has resulted in reduction of tenderness the nerve through stretch, which results in the length-
and scar firmness). ening of the structure. Increasing tension on the nerve
● Vigorous massage: between 4½ and 5 weeks increases intraneural pressure, which may result in an
(postoperatively) decreases pillar pain and scar inflammatory response and increased pain.67 The goal
firmness/tenderness of neural mobilization is to restore excursion of the
● One session of vigorous massage between 4½ nerve during activity of the individual, minimizing
and 5 weeks (postoperatively) and instruction in (ideally, eliminating) tension, which interrupts neural
“golf ball massage” (included in) home program function.67 Exercises may be instructed and prescribed
(four times daily) 5 to 10 minutes: patients have for the patient to perform independently as an aug-
reported quick and lasting results. mentation to manual techniques performed in the
clinic.
Neural Mobilization A sliding technique involves limiting the combined
Considering the intrinsic structure of the nerve and its tension placed on a nerve by reducing the number of
inherent dependence on gliding as the body moves to joints involved; rather than tensioning the nerve across
2560_Chapter 24_0289-0310.indd 304 3/16/2015 4:14:19 PM

Process CyanProcess
YellowProcess Black
two or more joints, sliding is accomplished by unload-
ing the nerve across one or more joints. This technique
was used in a report by Coppieters et al.65 with the
objective of reducing intraneural and extraneural
edema, increasing vascular and neural mobility. It was
discovered in a cadaveric study of radial nerve excur-
sion that about 15 mm of unimpeded nerve glide at
the elbow and about 10 mm at the wrist is required to
perform full motions that involve the shoulder, elbow,
wrist, and fingers.69 If there is an increase in tension
greater than approximately 15% of normal, direct
mechanical damage to the nerve may result because of
Figure 24-15 Myofascial release technique using Kinesio
ischemia.69
Taping for carpal tunnel syndrome.
In a study by Dilley et al.70 ultrasound imaging of
healthy subjects measured neural strain, nerve trunk
and fascicular folding, and excursion of the median
nerve. It was discovered the nerve moved proximally as Therapeutic Taping
the arm abducted from 10° to 90°, with the greatest Products such as KinesioTape and Physiotape may
excursion in the final 40° to 50°. Median nerve excur- assist in the treatment of nerve compression disorders
sion when measured with contralateral cervical flexion by improving vascular and lymphatic flow, facilitating
was variable among subjects without correlation to age neurological function.72–74 In acute cases, symptom
or height; the study found significantly less nerve relief is expected soon after application; in chronic
movement at 30° shoulder abduction compared with cases, prolonged treatment and retaping may be indi-
90°. Elbow extension resulted in the nerve moving cated. Consultation with a physician is advised to
distally in the upper arm and proximally in the forearm ensure appropriate management of symptoms relative
from 90° flexion to full extension with the shoulder to compression neuropathy (Fig. 24-15).
abducted at 90°, resulting in no significant strain. Wrist
extension resulted in the median nerve gliding distally
up to 6 mm. The study determined that with the arm Therapeutic Modalities
positioned at 90° abduction combined with full elbow
extension, the median nerve “behaved like a continuous Applying the principles of wound healing, facilitation
spring under tension” with stretch occurring through- of the processes leading to recovery of a tissue may be
out the length of the nerve. Unloading of the nerve enhanced by use of therapeutic modalities.75 However,
occurred when the shoulder was positioned at less than evidence supporting use of modalities specifically for
45° abduction in combination with 90° elbow flexion.70 treatment of entrapment neuropathies is lacking, and
In a study by Akalin et al.,71 median nerve and tendon more research is needed to provide therapists and other
gliding combined with night splinting resulted in providers with a broader base for sound clinical deci-
improved pinch strength and patient satisfaction for 5 sion making. Three common treatment modalities are
to 11 months after a 4-week study. Although the study addressed in this section.
had design limitations, the information lends support
to the potential benefits of this type of conservative Ultrasound
treatment. Ultrasound treatment to facilitate tissue regeneration
Coppieters et al.65 conducted a study on nerve and healing has been studied and found to be a viable
gliding in conservative treatment of cubital tunnel syn- augmentation to conservative and nonconservative
drome and found that a movement-based treatment treatment protocols. Bone stimulation to facilitate frac-
plan resulted in substantial improvement; there was ture healing using ultrasound has been reported to
no recurrence in symptoms within the 10-month reduce healing time.76 There appears to be evidence
follow-up. Illustrating the undesired maximum trac- that pulsed ultrasound positively influences nerve
tion on the ulnar nerve that occurs with the arm posi- regeneration; in animal studies focusing on the effects
tioned in shoulder abduction, elbow hyperflexion, and of ultrasound after sciatic neurotomy, rapid nerve
wrist extension combined with forearm supination, regeneration was observed and attributed to ultrasound
treatment was conducted to avoid this cumulative treatments.77,78 Animal studies have been conducted
tension by unloading the nerve at adjacent joints. Nerve with the hope of establishing safe and effective human
gliding with care to minimize loading was accom- treatment parameters using ultrasound for facilitating
plished by performing manual passive range of motion nerve recovery. Accelerated nerve regeneration was
and assigning ulnar nerve mobilizations as part of the observed in traumatically injured sciatic nerves in
home exercise program. rats treated with ultrasound.77–79 Despite evidence of
2560_Chapter 24_0289-0310.indd 305 3/16/2015 4:14:19 PM

Process CyanProcess
YellowProcess Black
enhanced tissue healing in these studies, there are no mechanical effects of ultrasound on tissue physiology
human studies on the use of ultrasound for treatment is necessary to choose this modality.
of entrapment neuropathies. In a study comparing
ultrasound treatment with placebo, Oztas et al.80 con- Laser Therapy
cluded outcomes to be comparable and reported sus- “Low level laser therapy (LLLT) is a light source treat-
picion that ultrasound may have a negative effect on ment that generates light of a single wavelength. LLLT
motor nerve function. Appropriate treatment param- emits no heat, sound, or vibration. Instead of producing
eters must be selected; increasing tissue temperature a thermal effect, LLLT may act via nonthermal or
through use of high or continuous duty cycle and deliv- photochemical reactions in the cells, also referred to as
ery of excess ultrasound energy may result in an inflam- photobiology or biostimulation.”86 Also known as cold
matory response as the body attempts to cool the laser therapy, this treatment modality is theorized to
tissues to normal levels. increase mitochondrial activity, resulting in increased
The effects of nonthermal ultrasound, achieved at cellular oxygen consumption as well as lymphatic flow,
intensities of less than 0.3 to 1 W/cm2, include cavita- resulting in decreased edema, enhancing recovery of
tion and streaming, the formation and flow created by damaged nerve tissue.86,87
ultrasound energy. These effects have been reported to The regeneration and recovery of damaged nerves
produce changes in membrane permeability and is one of the most promising indications for use of
metabolite perfusion, reducing the time of the inflam- laser therapy.87 Reduction in edema through enhance-
matory phase of healing and facilitating the prolifera- ment of lymphatic vessel regeneration has also been
tive phase.75 With this source of clinical reasoning, reported.87
exploration of the use of ultrasound in treatment of In a study published in 2007 by Evcik et al.,88 posi-
neuropathies has been ongoing. tive effects on hand grip and pinch strengths were
Mild to moderate idiopathic CTS may respond achieved using treatment parameters of 7 J of LLLT
favorably to ultrasound treatment, inducing biophysi- over the course of 2 minutes five times per week for 2
cal effects that result in decreased tissue inflamma- weeks. Laser therapy for CTS was one of the first
tion.81–84 Ebenbichler et al.81 used treatment parameters indications to receive approval from the U.S. Food and
of 1 MHz, 1.0 W/cm2 pulsed at 25% for 15 minutes Drug Administration, being limited to “adjunct use” in
over the carpal tunnel for 20 sessions; the initial 10 obtaining temporary pain relief.87 In selection of laser
sessions were performed at a frequency of 5 sessions therapy for compression neuropathies, it is recom-
per week, and the final 10 treatments were performed mended to refer to the individual product manual for
twice weekly for 5 weeks. The study suggested that by guidance because various laser therapy systems are cur-
controlling inflammation and excess pressure within rently on the market.
the carpal tunnel, the healing process and nerve recov-
ery may be facilitated. In response to the study by Electrical Stimulation
Ebenbichler et al., alarm was expressed from a hand Regeneration of injured peripheral nerves may be
surgeon’s perspective relative to choosing use of assisted by use of electrical stimulation modalities, but
ultrasound versus CTR in treatment for CTS. The studies on research in humans are scarce. When edema
authors responded by reiterating that the purpose of is suspected to be imposing pressure on a nerve, electri-
their study was to explore the efficacy of ultrasound cal modalities may be helpful for edema management.
treatment for CTS because research is lacking in this Animal studies have reported positive results rela-
area, not to recommend ultrasound as an alternative to tive to edema reduction and nerve regeneration using
CTR. As stated by Ebenbichler et al.,81 optimal treat- direct current.89,90 Human studies on edema manage-
ment schedules and parameters have not been reliably ment employing high volt pulsed current using nega-
established. tive polarity resulted in reduction in edema compared
In a study by Bakhtiary and Rishidy-Pour85 pub- with using positive polarity; the literature suggested
lished in 2004, ultrasound was compared with low level treatment parameters that included 120 pulses per
laser therapy (LLLT) in treatment of CTS with similar second, and that submotor intensity may result in
parameters used in the study by Ebenbichler et al.81 some improvement in edema and range-of-motion
and infrared laser parameters of 9 J, 830 nm, each for measurements.91 Although the mechanism that results
15 treatment days. The study concluded that ultra- in edema reduction when high volt pulsed current is
sound was more effective than LLLT in treatment of used with a negative polarity is not completely under-
CTS.81,85 (Note recommendations regarding selection stood, it is hypothesized that the conduction of nega-
of laser treatment parameters in the following section tively charged electrical current repels the like-charged
on laser therapy.) plasma proteins associated with edema, a phenomenon
In selecting treatment parameters for compression known as “cataphoresis.”92
neuropathies, there are no clear recommendations rela- The mechanism of electrical stimulation resulting in
tive to the use of ultrasound. Understanding of the edema reduction is not completely understood, but it
2560_Chapter 24_0289-0310.indd 306 3/16/2015 4:14:19 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
is speculated that edema formation is retarded because 5. To quantify the neuropathy based on the Seddon
of reduced microvessel permeability to plasma macro- classification, which diagnostic test would be the
molecules.93 Further research is needed to understand most helpful?
better and use this treatment modality appropriately. a. Phalen’s
b. Electroneuromyogram
c. Magnetic resonance imaging of the elbow
CASE STUDY d. X-ray of the elbow
BR is a long distance runner averaging more than 25
miles per week. He has noticed over the past few months
that at the 5-mile point of his run his left hand becomes References
numb. The numbness continues to worsen the longer he
1. Lundborg G. Structure and function of the intraneural
runs and extends from his two medial fingers along the microvessels as related to trauma, edema formation, and nerve
outside of his wrist to just below his elbow. When he function. J Bone Joint Surg Am. 1975;57:938–948.
stops running, the numbness gradually abates after a few 2. Ochoa J. Nerve fiber pathology in acute and chronic
hours. He also notes a constant dull ache behind his compression. In: Omer G, Spinner M, VanBeek A, eds.
elbow. He does not perceive any weakness in the hand. Management of Peripheral Nerve Problems. 2nd ed.
Philadelphia: Saunders; 1998:475–483.
On physical examination, the only “hard” finding 3. Rempel D, Dahlin L, Lundborg G. Pathophysiology of nerve
uncovered by the therapist is a positive Tinel sign over compression syndromes: response of peripheral nerves to
the olecranon fossae. During the examination, the loading. J Bone Joint Surg Am. 1999;81(11):1600–1610.
therapist could not identify any focal weakness, loss of 4. Tapadia M, Mozaffar T, Gupta R. Compressive neuropathies
deep tendon reflex, or tactile sensory loss. There was of the upper extremity: update on pathophysiology,
classification, and electrodiagnostic findings. J Hand Surg Am.
no evidence of upper motor neuron involvement. 2010;35:668–677.
Cranial nerves were intact. 5. Michele AA, Krueger FJ. Lateral epicondylitis of the elbow
treated by fasciotomy. Surgery. 1956;39:277–284.
6. Standard of Care: Radial Tunnel Syndrome. Copyright 2007
Case Study Questions The Brigham and Women’s Hospital, Inc., Department of
Rehabilitation Services. All rights reserved.
1. Based on the subjective complaints of the patient, 7. Stanley J. Radial tunnel syndrome: a surgeon’s perspective.
the symptoms appear to be associated with which J Hand Ther. 2006;19:180–185.
nerve? 8. Roquelaure Y, Raimbeau G, Saint-Cast Y, Martin YH,
a. Ulnar Pelier-Cady MC. Occupational risk factors for radial tunnel
b. Median syndrome in factory workers. Chir Main. 2003;22(6):293–298.
9. Loh YC, Lam WL, Stanley JK, Soames RW. A new clinical
c. Anterior interosseus test for radial tunnel syndrome—the Rule-of-Nine test:
d. Posterior interosseus a cadaveric study. J Orthop Surg. 2004;12(1):83–86.
10. Tennent TD, Woodgate A. Posterior interosseous nerve
2. Which of the following would be a differential dysfunction in the radial tunnel. Curr Orthop. 2008;22(3):
diagnosis for this impairment? 226–232.
a. Ulnar nerve impingement at the tunnel of Guyon 11. Stern M. Radial nerve entrapment. Medscape Web site.
b. C8–T1 cervical radiculopathy http://emedicine.medscape.com/article/1244110-overview.
c. Ulnar nerve impingement at the olecranon fossa Updated September 2, 2009. Accessed July 12, 2010.
12. Thomas SJ, Yakin DE, Parry BR, Lubahn JD. The anatomical
d. All of the above relationship between the posterior interosseous nerve and the
3. If the correct diagnosis is ulnar nerve impingement at supinator muscle. J Hand Surg Am. 2000;25:936–941.
13. Wilhelmi B, Naffziger R, Neumeister M. Hand, nerve
the elbow and if there is muscle weakness related to compression syndromes. Medscape Web site. http://
the impingement, which muscle would have the emedicine.medscape.com/article/1285531-overview. Updated
highest probability of exhibiting weakness? May 31, 2009. Accessed July 12, 2010.
a. Flexor carpi radialis 14. Dillon AL, Mackinnon SE. Chronic nerve compression
b. Pronator teres model for the double-crush hypothesis. Am Plast Surg. 1991;
26:259–265.
c. Abductor digiti minimi 15. Patterson RW, van Niel M, Shimko P, Pace C, Seitz WH Jr.
d. Opponens pollicis Proprioception of the wrist following posterior interosseous
sensory neurectomy. J Hand Surg Am. 2010;35:52–56.
4. If the correct diagnosis is ulnar nerve impingement at 16. Prakash, Rai R, Ranade AV, Prabhu LV, Pai MM, Singh G.
the elbow, which behavioral change may be Multiple variations of extensor muscles of forearm in relation
indicated? to the radial nerve: a case report and review. Int J Morphol.
a. Encourage sleeping with the elbow extended 2008;26(2):447–449.
b. Avoid leaning on the elbow when sitting at a 17. Tosun N, Tuncay I, Akpinar F. Entrapment of the sensory
branch of the radial nerve (Wartenberg’s syndrome): an
desk unusual cause. Tohoku J Exp Med. 2001;193:251–254.
c. Maintain elbow extension when running 18. Stedman’s Medical Dictionary. Baltimore: Lippincott, Williams
d. All of the above & Wilkins; 2006.
2560_Chapter 24_0289-0310.indd 307 3/16/2015 4:14:19 PM

Process CyanProcess
YellowProcess Black
19. Lanzetta M, Foucher G. Entrapment of the superficial outcome study of adjunct exercises. J Okla State Med Assoc.
branch of the radial nerve (Wartenberg’s syndrome). Int ;95(1):7–14.
Orthop. 1993;17:342–345. 42. Luchetti R, Schoenhuber R, Nathan P. Correlation of
20. Szabo R. Entrapment and compression neuropathies. In: segmental carpal tunnel pressures with changes in hand and
Green DP. Hotchkiss RN, Pederson WC, eds. Green’s wrist positions in patients with carpal tunnel syndrome and
Operative Hand Surgery. Vol 2. 4th ed. Philadelphia: Churchill controls. J Hand Surg Eur. 1998;23(5):598–602.
Livingstone; 1998:1439. 43. Cobb TK, An Kai-Nan, Cooney W. Externally applied forces
21. Surendran S, Bhat SM, Krishnamurthy A. Compression of to the palm increase carpal tunnel pressure. J Hand Surg.
radial nerve between the split tendon of brachioradialis 1995;20(2):181–185.
muscle: a case report. Neuroanatomy. 2006;5:4–5. 44. Geoghegan JM, Clark DI, Bainbridge LC, Smith C,
22. Pronator syndrome discussion. EHand.com: The Electronic Hubbard R. Risk factors in carpal tunnel syndrome. J Hand
Textbook of Hand Surgery Web site. http://www.eatonhand Surg Eur. 2004;29(4):315–320.
.com/dis/dis315.htm. Accessed July 22, 2010. 45. Rodner C, Katarincic J. Open carpal tunnel release. Tech
23. Hagert S, Englund J. Pronator syndrome: a retrospective Orthop. 2006;21(1):3–11.
study of median nerve entrapment at the elbow in female 46. Taizo K, Hiroyuki H. Clinical analysis of pillar pain after
machine milkers. J Agric Saf Health. 2004;10(4):247–256. endoscopic carpal tunnel release: the Okutsu method. J Jpn
24. Lee M, LaStayo P. Pronator syndrome and other nerve Soc Surg Hand. 2005;22(2):6–9.
compressions that mimic carpal tunnel syndrome. J Orthop 47. Siegel D, Kuzma G, Eakins D. Anatomic investigation of the
Sport Phys Ther. 2004;34:601–609. role of the lumbrical muscles in carpal tunnel syndrome.
25. Ericson WB. Median nerve entrapment in the forearm: J Hand Surg. 1995;20(5):860–863.
diagnosis and treatment. Poster presented at: ASSH March 48. Gwynne D. Bilateral palmaris profundus in association with
13–16, 2004, San Francisco, CA. bifid median nerve as a cause of failed carpal tunnel release.
26. Koo JT, Szabo RM. Compression neuropathies of the median J Hand Surg. 2006;31(5):741–743.
nerve. Journal of the American Society for Surgery of the Hand. 49. Homma T, Sakai T. Thenar and hypothenar muscles and their
2004;4(3):156–175. innervation by the ulnar and median nerves in the human
27. Collins D, Weber E. Anterior interosseous nerve syndrome. hand. Acta Anat. 1992;145:44–49.
South Med J. 1983;76(12):1533–1537. 50. Robertson C, Saratsiotis J. A review of compressive ulnar
28. Nigst H, Dick W. Syndromes of compression of the median neuropathy at the elbow. J Manipulative Physiol Ther. 2005;28:
nerve in the proximal forearm (pronator teres syndrome: 345.e18.
anterior interosseous nerve syndrome). Arch Orthop Trauma 51. Palmer B, Hughes T. Cubital tunnel syndrome. J Hand Surg
Surg. 1979;93:307–312. Am. 2010;35:153–163.
29. Nelson R, Currier D. Anterior interosseous syndrome: a case 52. Smith T, Sawyer S, Sizer P, Brismee J. The double crush
report. J Phys Ther. 1980;60:194. syndrome: a common occurrence in cyclists with ulnar nerve
30. Mody B. Tenodesis effect: a simple clinical test to neuropathy—a case control study. Clin J Sport Med. 2008;18:
differentiate rupture of flexor pollicis longus and incomplete 55–61.
anterior interosseous paralysis. J Hand Surg Br. 1992; 53. Aoki M, Takasaki H, Muraki T, Uchiyama E, Murakami G,
17:510. Yamashita T. Strain on the ulnar nerve at the elbow and wrist
31. Farber J, Bryan R. The anterior interosseous nerve syndrome. during throwing motion. J Bone Joint Surg Am. 2005;87(11):
J Bone Joint Surg Am. 1968;50:521–523. 2508–2514.
32. Stark E, Dell M, Wisco J. A case report: a variation of the 54. Aoki M, Kanaya K, Aiki H, Wada T, Yamashita T, Ogiwara
palmaris profundus muscle. IJAV. 2010;3:36–38. N. Cubital tunnel syndrome in adolescent baseball players: a
33. Bickel K. Carpal tunnel syndrome. J Hand Surg Am. 2010;35: report of six cases with 3- to 5-year follow-up. Arthroscopy.
147–152. 2005;21(6):758e1–758e6.
34. Moscony AMB. Common peripheral nerve problems. In: 55. Kakosy T. Tunnel syndromes of the upper extremities in
Cooper C, ed. Fundamentals of Hand Therapy: Clinical workers using hand-operated vibrating tools. Med Lav. 1994;
Reasoning and Treatment Guidelines for Common Diagnoses of 85:474–480.
the Upper Extremity. Philadelphia: Mosby; 2007:201–250. 56. Gelberman RH, Yamaguchi K, Hollstien S, et al. Changes in
35. Medina McKeon J, Yancosek K. Neural gliding techniques interstitial pressure and cross-sectional area of the cubital
for the treatment of carpal tunnel syndrome: a systemic tunnel and of the ulnar nerve with flexion of the elbow: an
review. J Sport Rehabil. 2008;17:324–341. experimental study in human cadavera. J Bone Joint Surg Am.
36. Silverstein B, Fine L, Armstrong T. Occupational factors 1998;80:492–501.
and carpal tunnel syndrome. Am J Ind Med. 1987;11(3): 57. Zeiss J, Jakab E, Khimji T, Imbriglia J. Ulnar tunnel at the
343–358. wrist (Guyon’s canal): normal MR anatomy and variants. AJR
37. U.S. Department of Labor. Occupational Injuries and Illnesses: Am J Roentgenol. 1992;158:1081–1085.
Counts, Rates, and Characteristics. Bulletin 2538. Washington, 58. Chalidis B, Sachinis N, Dimitriou C. Ulnar nerve penetration
DC: U.S. Bureau of Labor Statistics; 2001. by a volar ganglion in the Guyon canal. Plast Reconstr Surg.
38. Falkiner S, Myers S. When exactly can carpal tunnel 2009;124(5):264e–266e.
syndrome be considered work-related? Aust N Z J Surg. 2002; 59. Sierakowski A, Zweifel CJ, Payne S. Compression of the
72:204–209. ulnar nerve in Guyon’s canal caused by a large hypothenar
39. American Academy of Orhopaedic Surgeons Work Group cyst. ePlasty. 2009;10:32–36.
Panel. Clinical guidelines on diagnosis of carpal tunnel 60. Rohilla S, Yadav R, Dhaulakhandi D. Lipoma of Guyon’s
syndrome. www.aaos.org/research/guidelines/CTS_guideline canal causing ulnar neuropathy. J Orthop Traumatol. 2009;10:
.pdf. Accessed July 12, 2010. 101–103.
40. Werner R, Andary M. Carpal tunnel syndrome: 61. Butler DS. The Sensitive Nervous System. South Australia:
pathophysiology and clinical neurophysiology. Clin Noigroup Publications; 2000.
Neurophysiol. 2002;113(9):1373–1381. 62. Butler D. Neurodynamics—Physical Neural Health Web site.
41. Seradge H, Parker W, Baer C, Mayfield K, Schall L. http://noineurodynamics.blogspot.com. Updated July 23,
Conservative treatment of carpal tunnel syndrome: an 2008. Accessed July 12, 2010.
2560_Chapter 24_0289-0310.indd 308 3/16/2015 4:14:19 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
63. Barnes JF. Myofascial Release: The Search for Excellence. A neurotomy in rats. Ultrasound Med Biol. 2002;28(10):
Comprehensive Evaluatory and Treatment Approach. Paoli, PA: 1335–1341.
MFR Seminars; 1990. 78. Mourad PD, Lazar D, Curra FP, et al. Ultrasound accelerates
64. Fedorczyk J. Online discussion: Clinical treatment issues. functional recovery after peripheral nerve damage.
Subject: re: Pillar pain (e-mail communication, October 13, Neurosurgery. 48:1136–1141, 2001.
2010). 79. Chang C-J, Hsu S-H. The effects of low-intensity ultrasound
65. Coppieters M, Bartholomeeusen K, Stappaerts K. on peripheral nerve regeneration in poly (DL-lactic acid-Co-
Incorporating nerve-gliding techniques in the conservative glyconic acid) conduits seeded with Schwann cells. Ultrasound
treatment of cubital tunnel syndrome. J Manipulative Physiol Med Biol. 2004;30(8):1079–1084.
Ther. 2004;27:560–568. 80. Oztas O, Turan B, Bora I, Karakaya MK. Ultrasound therapy
66. Wehbe M, Schlegel J. Nerve gliding exercises for thoracic effect in carpal tunnel syndrome. Arch Phys Med Rehabil.
outlet syndrome. Hand Clin. 2004;20:51–55. 1998;79(12):1540–1544.
67. Coppieters M, Hough A, Dilley A. Different nerve-gliding 81. Ebenbichler G, Resch K, Nicolakis P, et al. Ultrasound
exercises induce different magnitudes of median nerve treatment for treating the carpal tunnel syndrome:
longitudinal excursion: an in vivo study using dynamic randomised “sham” controlled trial. BMJ. 1998;316:731–735.
ultrasound imaging. J Orthop Sports Phys Ther. 2009;39(3): 82. Barnett SB, Ter Haar GR, Ziskin MC, Nyborg WL, Maeda
164–171. K, Bang J. Current status of research on biophysical effects of
68. Elvey RL. Treatment of arm pain associated with abnormal ultrasound. Ultrasound Med Biol. 1994;20:205–218.
brachial plexus tension. Aust J Physiother. 1986;32:225–230. 83. El Hag M, Coghlan K, Christmas P, Harvey W, Harris M.
69. Wright T, Glowczewskie F, Cowin D. Radial nerve excursion The anti-inflammatory effects of dexamethasone and
and strain at the elbow and wrist associated with upper- therapeutic ultrasound in oral surgery. Br J Oral Maxillofac
extremity motion. J Hand Surg Am. 2005;30:990–996. Surg. 1985;23:17–23.
70. Dilley A, Lynn B, Greening J, DeLeon N. Quantitative in 84. Dyson M. Mechanisms involved in therapeutic ultrasound.
vivo studies of median nerve sliding in response to wrist, Physiotherapy. 1987;73:116–120.
elbow, shoulder and neck movements. Clin Biomech. 2003;18: 85. Bakhtiary AH, Rashidy-Pour A. Ultrasound and laser therapy
899–907. in the treatment of carpal tunnel syndrome. Aust J Physiother.
71. Akalin E, El O, Peker O, et al. Treatment of carpal tunnel 2004;50:147–151.
syndrome with nerve and tendon gliding exercises. Am J Phys 86. Wang G. Low level laser therapy (LLLT) technology
Med Rehabil. 2002;81:108–113. assessment. http://www.lni.wa.gov/ClaimsIns/Files/OMD/
72. Kase K, Hashimoto T, Okane T, Kinesio Taping Association. LLLTTechAssessMay032004.pdf. Updated May 3, 2004.
Kinesio Taping Perfect Manual: Amazing Taping Therapy to Accessed July 16, 2010.
Eliminate Pain and Muscle Disorders. Boston, MA: Kinesio 87. Tuner J, Hode L. Laser Therapy: Clinical Practice and Scientific
USA;1998. Background. Tallinn, Estonia: UP Print; 2002.
73. Thelen MD, Dauber JA, Stoneman PD. The clinical efficacy 88. Evcik D, Kavuncu V, Cakir T, Subasi V, Yaman M. Laser
of Kinesio tape for shoulder pain:A randomized, double therapy in the treatment of carpal tunnel syndrome: a
blinded, clinical trial. Journal of Orthop and Sports Physical randomized controlled trial. Photomed Laser Surg. 2007;25(1):
Therapy. 2008;38:389–395. 34–39.
74. Kase K, Hashimoto T. Changes in the volume of the peripheral 89. Mendal FC, Fish DR. New perspectives in edema control via
blood flow by using Kinesio taping. San Francisco, CA:Kinesio electrical stimulation. J Athl Train. 1993;280(1):63–74.
Taping Association International; 1998. 90. Dolan MG, Mendel FC. Clinical application of
75. Hess C, Howard M, Atringer C. A review of mechanical electrotherapy. Athl Ther Today. 2004;9:11–16.
adjuncts in wound healing: hydrotherapy, ultrasound, negative 91. Sandoval MC, Ramirez C, Camargo DM, Salvini TF. Effect
pressure therapy, hyperbaric oxygen and electrostimulation. of high-voltage pulsed current plus conventional treatment on
http//hessplasticsurgery.net/pdf/wound-healing.pdf. Accessed acute ankle sprain. Rev Bras Fisioter, São Carlos. 2010;14(3):
July 15, 2010. 193–199.
76. Kristiansen TK, Ryaby JP, McCabe J, Frey JJ, Roe LR. 92. Cosgrove KA, Alon G, Bell SF, et al. The electrical effect of
Accelerated healing of distal radial fractures with the use of two commonly used clinical stimulators on traumatic edema
low-intensity ultrasound. A multicenter, prospective, in rats. Phys Ther. 1992;72(3):227–233.
randomized specific, double-blind, placebo-controlled study. 93. Reed B. Effect of high voltage pulsed electrical stimulation
J Bone Joint Surg Am. 1997;79:961–973. on microvascular permeability to plasma proteins: a possible
77. Crisci AR, Ferreira AF. Low-intensity pulsed ultrasound mechanism in minimizing edema. Phys Ther. 1988;68(4):
accelerates the regeneration of the sciatic nerve after 491–495.
2560_Chapter 24_0289-0310.indd 309 3/16/2015 4:14:19 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
2560_Glossary_0347-0360.indd 360 3/17/2015 12:11:29 PM
Chapter 25
Entrapment Neuropathies in
the Foot and Ankle
JOHN P. SCANLON, DPM, CRYSTAL N. GONZALEZ, DPM,
BENJAMIN R. DENENBERG, DPM, AND KRUPA J. TRIVEDI, DPM
“The human foot is a masterpiece of engineering and a work of art.”

—LEONARDO DA VINCI (1452–1519)
Objectives
• Describe the anatomical pathways of the major peripheral nerves in the lower extremity.
• Identify possible sites of entrapment of the major peripheral nerves in the lower leg.
• Discuss the pathogenesis of peripheral nerve injury.
• Discuss the possible etiologies of lower extremity peripheral nerve entrapment.
• Describe the surgical and conservative interventions for each lower extremity nerve entrapment site.
• Include peripheral nerve entrapment as a potential differential diagnosis for lower extremity impairments
during the clinical evaluation.
Key Terms
• Entrapment neuropathy
• Neurolysis
• Neuroma
• Peripheral nerve
connective tissue disease, infection, peripheral vascular

Introduction disease, psychiatric disturbances, hormonal imbalances,
toxins, overuse, and metabolic illnesses. The diagnosti-
Symptoms of nerve compression in the lower extremi-
cian must have a good understanding of the anatomy
ties account for a large percentage of patients visiting
of the lower extremity including the nerve paths. In
their primary physician and being referred to a special-
addition, content knowledge of the endocrine, neural,
ist. Because of the myriad symptoms reported by
musculoskeletal, integument, renal, gastrointestinal,
patients with potential lower extremity neuropathy, the
and cardiopulmonary systems often is relevant to the
list of potential differential diagnoses is long. Lack of
diagnosis and interventions associated with lower
proper diagnostic testing and assessment may lead to
extremity neurological symptoms.
inappropriate referral, chronic pain, disability, and sur-
geries that are not helpful or indicated. Complicating
the diagnostic process is that low back pain often
accompanies tunnel syndromes in the lower extremity Anatomy
through systemic or multiple nerve involvement or as
a direct result of gait compensation secondary to lower The lower extremity receives sensory and motor inner-
extremity antalgia. Lower extremity neuropathic symp- vation from branches of the sciatic nerve along with
toms may also be the indirect result of neoplasm, the saphenous nerve. The sciatic nerve is the only nerve
311
2560_Chapter 25_0311-0320.indd 311 3/16/2015 4:14:22 PM

Process CyanProcess
YellowProcess Black
in the lower extremity arising from the lumbar plexus. Box 25-1
Branches of the sciatic nerve include the common
peroneal nerve and tibial nerve. The common peroneal Seddon and Sunderland Classifications of Severity of
nerve branches further to form the superficial peroneal
nerve and the deep peroneal nerve. The superficial Peripheral Nerve Injury
peroneal nerve provides cutaneous innervation to the Seddon’s Classification
anterior and anterolateral aspect of the foot and Neurapraxia: Temporary interruption of conduction
ankle and provides motor innervation to the muscles without loss of axonal continuity; endoneurium,
in the lateral compartment of the leg. The deep pero- perineurium, and epineurium are intact.
neal nerve innervates muscles of the anterior compart- Axonotmesis: Involves loss of relative continuity of the
ment of the leg and intrinsic musculature of the dorsal axon and its covering of myelin, but preservation of the
foot and provides cutaneous innervation to the first connective tissue framework of the nerve; epineurium
interspace. The tibial nerve branches into the sural and perineurium are preserved. Wallerian
degeneration occurs.
nerve, medial plantar nerve, lateral plantar nerve, and Neurotmesis: Total severance or disruption of the entire
medial calcaneal nerve. The sural nerve provides cuta- nerve fiber.
neous innervation to the lateral aspect of the foot. The Sunderland’s Classification
medial plantar nerve innervates the plantar intrinsic First degree: Seddon’s neurapraxia.
musculature of the foot. The lateral plantar nerve Second degree: Seddon’s axonotmesis.
innervates the lateral plantar intrinsic musculature of Third degree: Interruption of the nerve fiber with
the foot. epineurium and perineurium intact. Recovery is possible
The saphenous nerve, the largest cutaneous branch with surgical intervention.
of the femoral nerve, exits from the adductor canal, Fourth degree: Interruption of the nerve fiber with only
descends under the sartorius muscle, and winds around the epineurium intact. Surgical repair is required.
the posterior edge of the sartorius muscle at its tendi- Fifth degree: Complete transection of the nerve.
nous portion. The infrapatellar branch pierces the sar-
torius muscle and crosses anteriorly to the infrapatellar
region. The descending branch passes down the medial
aspect of the leg and at the lower third of the Pathology
leg divides into two branches. One of the branches
of the descending portion of the nerve courses along Entrapment neuropathy is a generalized term fre-
the medial border of the tibia and ends at the quently used to describe common nerve pathology
ankle, whereas the other branch passes anteriorly to involving compression of a peripheral nerve; another
the ankle and is distributed to the medial aspect of the term often used is “tunnel neuropathy.” Although
foot, reaching the metatarsophalangeal joint of the entrapment neuropathy is not directly defined or
great toe. described by the Seddon and Sunderland classification
Variables such as anatomical path, location of adja- systems, there is a definite correlation between the
cent structures, tension, superficiality, size, composi- severity of the nerve lesion and the mechanism of
tion, and vascular supply subject the peripheral nerve injury. Entrapment neuropathies tend to develop as a
to a spectrum of injury types. Seddon and Sunderland result of external or internal compressive or occlusive
individually developed nomenclature systems for the factors. Internal factors, such as narrow fibro-osseous
severity of injury to peripheral nerves. Seddon1 defined tunnels through which the nerves pass and space-
three types of nerve injuries, including neurapraxia, occupying lesions such as an osteophyte or tumor may
axonotmesis, and neurotmesis. Sunderland2 described disrupt the nerve and precipitate axonal damage leading
five degrees of nerve injuries, which correlate with Sed- to neuropathy. External factors, including nerve damage
don’s classification (Box 25-1). With the progression secondary to trauma, biomechanical factors, toxin
from neurapraxic to axonotmetic to neurotmetic ingestion, medication, endocrine disease, and systemic
lesions, the mechanism of injury, the severity of the disease (e.g., rheumatoid arthritis, systemic lupus ery-
symptoms, and the healing time all tend to escalate. thematosus, Sjögren’s disease), are also relevant con-
Neurapraxic lesions tend to be the mildest of lesions tributing features. Systemic diseases may contribute to
with transitory sensory symptoms that last from a pathology described in 1973 by Upton and McComas3
minutes to weeks. Healing is spontaneous. There is no and later by Osterman4 known as “double crush syn-
denervation. The hallmark of axonotmetic lesions is drome.” Double crush occurs when a proximal nerve is
axonal injury with frank denervation. Depending on compressed altering axonal transport and contributing
the location of these injuries, recovery, although typi- to a secondary distal entrapment. A concomitant cervi-
cally spontaneous, may require months or years. Neu- cal nerve root lesion is found in 70% of patients with
rotmetic lesions often require surgical intervention, symptomatic carpal tunnel or ulnar neuropathy via
and the prospect of recovery is guarded. electroneurophysiological testing.3 With all individuals
2560_Chapter 25_0311-0320.indd 312 3/16/2015 4:14:23 PM

Process CyanProcess
YellowProcess Black
Chapter 25 | Entrapment Neuropathies in the Foot and Ankle 313
with a suspected peripheral nerve lesion, a thorough knee. The slump test is performed in three parts. The
and comprehensive physical and electrophysiological patient should be seated in a chair and asked to slump
evaluation must be performed before contemplating the lower back. If this movement does not elicit pain,
any intervention not only to rule out differential diag- flexion at the neck may be added to elicit a response.
noses but also to ascertain if additional sites of entrap- Finally, the addition of extending the knee with con-
ment may be present. comitant dorsiflexion of the foot may be the final
maneuver to elicit sciatic nerve tension.5
Palpation of the path of the peripheral nerve should
Examination be performed. Typically, nerves, contractile tissues, and
noncontractile tissues are not painful to light palpation.
The physical examination begins at first contact with Pain may indicate a problem. Particular emphasis
the patient. The practitioner should identify postural or should be directed at palpating where the nerve passes
gait abnormalities, which may act as “clinical scripts” into the subcutaneous tissue, is adjacent to a bony
to assist with guiding the interview and physical structure, or passes through a fibro-osseous tunnel. Fol-
examination. lowing light palpation, the nerve should be percussed,
After establishing a relationship with the patient, which may elicit various symptoms. A Tinel sign occurs
the nerve examination should begin with a series of when a nerve is tapped and paresthesias are elicited
questions to pinpoint the origin of entrapment. The distal to the area of percussion. Sensation should be
previous medical and surgical history should be docu- tested through multiple modalities, including light
mented with special regard to items related to systemic touch, pin, and vibration. Balance assessment can be
illness or prior neuropathy diagnoses. The medication performed by using validated tests such as the Berg,
history should be obtained and should not be limited Romberg, or Timed Up and Go.6 Large-fiber afferent
to current medications. Because medication-related neuropathy, which is a presenting sign of diabetic neu-
neuropathies are common and may last for a significant ropathy, is often identified by decreased static and
period of time or forever, medications taken over the dynamic standing balance.
past 5 years should be identified and researched for The next area of focus during the examination is the
potential neuropathic complications. The use of over- biomechanical and visual component. Range of motion
the-counter, herbal, and illegal medications and drugs of all the joints distal and proximal to the nerve should
should be queried. The practitioner should attempt to be examined for impairment. Alignment should also
identify any behavioral, vocational, occupational, or be noted, especially as related to the back, hip, knee,
biomechanical stresses that have an impact on the and foot. Long-term abnormal alignment almost
severity of the neuropathic symptoms. always results in abnormal soft tissue stresses. The
For lower extremity symptoms, the physical exami- joints should also be examined in the weight-bearing
nation begins with a screening manual muscle test. position. Misalignment may be present only during
Choosing specific muscles that capture each segmental weight bearing. In addition, positional change and
and peripheral myotome is mandatory. If focal weak- weight bearing may exacerbate symptoms. The patient
ness is identified, additional muscles should be tested should be asked to fan the toes in weight-bearing and
to confirm the involved myotome. Range-of-motion non–weight-bearing positioning. The inability to
screening should be performed to identify overt articu- perform this task as well as the presence of digital
lar and axial abnormalities. Screening can be performed deformities could indicate weakness of the intrinsic
via commands such as “squat down,” “raise up,” “bend,” musculature.
“straighten up,” “stand on your toes,” and “stand on your The biomechanical examination should include a
heels.” gait analysis because weakness in the muscles and
Next, the physical examination moves to the origin range of motion of joints can be more clearly identified
of the peripheral nerve at the spinal cord. Herniated through the phases of gait. Ambulation should be
discs or arthritis can be the primary etiology for nerve assessed on level ground, at various speeds, up a ramp,
pain secondary to compression and entrapment of the down a ramp, ascending and descending steps, and
peripheral nerve roots that stem from the lumbar ascending and descending curbs. Electromyography is
plexus and innervate the lower extremity. To test another diagnostic tool that is helpful in arriving at
for lumbar nerve root entrapment/compression, the a definitive diagnosis of entrapment neuropathy.
straight leg raise or slump test can be performed. Both This test is performed with the insertion of a needle
tests stretch the sciatic nerve to tension eliciting pain. into the muscle innervated by the nerve to assess elec-
Both tests should elicit a “soft tissue end-feel.” Elicit- trical potentials within the motor unit at rest, with
ing neurological symptoms such as radicular pain or minimal contraction, and with maximal contraction.
paresthesias is considered a positive test. The straight Nerve conduction velocity testing performed serially
leg raise is performed with the patient positioned with electromyography provides important informa-
supine and lifting the leg vertically without flexing the tion regarding conduction time and nerve latency.
2560_Chapter 25_0311-0320.indd 313 3/16/2015 4:14:23 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
These data can be compared with and correlated to the Tibial nerve
normative values. For practitioners whose state licens- Common
ing rules permit, a diagnostic block using local anes- peroneal nerve
thetic may be performed to obtain further diagnostic
Medial sural
information or to confirm a differential diagnosis. cutaneous nerve
Lateral sural
cutaneous nerve
Intervention Overview
Small
Conservative and surgical treatments may be effective saphenous
vein Sural nerve
depending on the particular clinical case. Neurapraxic
lesions of the common peroneal nerve typically heal
with conservative treatment. Conversely, neuropathy
associated with long-term poor glycemic control typi-
cally has a poor long-term prognosis.
A sound conservative therapeutic regimen involves
correction of the biomechanical deformities through Achilles Lateral
the use of physical therapy modalities and prescribed tendon malleolus
exercises, orthotic devices, and bracing. Because the
symptoms of entrapment may not fully resolve with
conservative measures alone, surgery may be the next
consideration. Surgical options include, but are not Figure 25-1 Anatomy of the sural nerve.
limited to, neurolysis or a release of the fibro-osseous
tunnels and decompression and release of fibrotic
adhesions around the nerve.
If conservative intervention is not effective, surgical medial and lateral heads of the gastrocnemius muscle,
intervention for the treatment of entrapment neuropa- piercing the deep fascia to anastomose with the sural
thies may be indicated. Several procedures have been communicating nerve at the middle of the posterior
described, including decompression, neurolysis, nerve leg forming the sural nerve. Continuing distally, it tra-
wrapping, and nerve grafting. Decompression often verses along the lateral border of the Achilles tendon
involves careful anatomical dissection and release of to pass along the posterior border of the lateral malleo-
adhesions and fascial constraints. Neurolysis refers to lus approximately where it splits into its two terminal
the surgical resection of a portion of the fibrosed nerve. branches, the lateral dorsal cutaneous nerve and the
Another viable addition to corrective procedures is lateral calcaneal nerve (Fig. 25-1).
nerve wrapping. The primary purpose of this procedure Entrapment of the sural nerve can occur at any point
is to minimize re-entrapment and prevent fibrosis by along its length. Intrinsically, this may be seen along
providing an autogenous tissue such as a vein or syn- changes in fascial planes or along fibro-osseous tunnels.
thetic material to serve as a protective barrier. Other In our practice, sural nerve compression is common in
techniques that have been described include fat grafts runners with tight crural fascia presenting with chronic
and rerouting of the nerve, which allow the nerve to compartment syndrome of the leg. In addition,
heal in an adhesion-free environment.7 impingement may occur secondary to trauma where
blunt force compresses the nerve against a bony struc-
ture.7,8 Athletes, particularly soccer players who sustain
Entrapment Neuropathy of Specific kicks to the posterior aspect of the leg, often experience
entrapment of the sural nerve.9 Plantar flexion inver-
Lower Extremity Nerves sion injuries with concomitant fifth metatarsal frac-
tures have also been described as an etiology.9 Recurrent
Sural Nerve ankle sprains or twisting injuries may lead to fibrosis
The sural nerve is largely responsible for the cutaneous of the nerve sheath, creating an entrapment.10 Similar
innervation of the dorsal lateral aspect of the foot and entrapment scenarios are evident with the presence of
heel and articular innervations to the inferior tibiofibu- ganglions of the peroneal sheath or calcaneocuboid
lar joint, talocrural joint, and talocalcaneal joints. Mea- joint and Achilles peritendonitis.11
suring approximately 2 cm in diameter, it comprises The sural nerve should be examined from the pop-
the medial sural nerve—a branch of the tibial nerve— liteal fossa to the toes. Patients may report numbness
and the sural communicating nerve, which is a branch and paresthesias. Local tenderness along with a posi-
of the common peroneal nerve. Originating at the pop- tive Tinel sign running along the course of the nerve
liteal fossa, the medial sural nerve courses between the is characteristic of this syndrome.
2560_Chapter 25_0311-0320.indd 314 3/16/2015 4:14:23 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Superficial Peroneal Nerve Deep Peroneal Nerve
A branch of the common peroneal nerve, the superfi- The deep peroneal nerve, measuring 1 to 3 mm in
cial peroneal nerve provides cutaneous innervations to diameter, serves as cutaneous innervation to the first
the dorsal aspect of the foot spanning from the medial interspace and provides motor innervation to the ante-
aspect of the fifth toe to the medial aspect of the great rior leg compartment muscle group and the common
toe excluding the first interspace. Muscular innervation short extensor muscle of the foot. Originating from the
to the lateral compartment of the leg, including pero- common peroneal nerve in the popliteal fossa, the deep
neus (fibularis) longus and brevis muscles, is provided peroneal nerve pierces the extensor digitorum longus
by the superficial peroneal nerve. Coursing around the (EDL) muscle as it courses distally. As it descends the
fibular head, the nerve travels in the lateral compart- leg, it is found between the EDL and tibialis anterior
ment and pierces the fascia approximately 12 cm above in the upper third of the leg. Further distally, in the
the tip of the lateral malleolus. Extending distally in middle third of the leg, it courses between the tibialis
the subcutaneous layer, it branches into the intermediate anterior and extensor hallucis longus (EHL) and
and medial dorsal cutaneous nerves, which end in the toward the lower third of the leg between the EHL
terminal digital branches. and EDL. At approximately 1 cm above the talocrural
Common areas of entrapment include at the junc- joint, it separates into lateral and medial branches. The
tion where it egresses from the deep fascia and at loca- medial branch extends distally alongside the dorsalis
tions of fascial defect with muscle herniation. Chronic pedis artery underneath the inferior extensor retinacu-
ankle sprains may predispose to nerve entrapment as lum. It continues distally between the extensor hallucis
repeated ankle sprains stretch the nerve (Fig. 25-2). brevis and EHL to provide innervation to the first
Entrapment elicits symptomatic pain over the distal interspace. The lateral branch extends in an anterior-
calf and dorsum of the foot. Patients may report pain lateral direction penetrating the extensor digitorum
at the distal third of the leg with or without the pres- brevis muscle, terminating into smaller branches that
ence of edema. A significant percentage of patients make up the second and fourth dorsal interosseous
report numbness or paresthesias along the nerve dis- nerves, which provide articular innervations to the tar-
tribution. Pain is typically exacerbated with physical sometatarsal, metatarsophalangeal, and interphalangeal
activities including walking and running. A previous joints of the lesser digits (Fig. 25-3).
history of trauma, most commonly ankle sprains, is The nerve may become compressed and entrapped
present in 25% of all patients with superficial peroneal at the location where the medial branch traverses
nerve entrapment.12 underneath the inferior extensor retinaculum. This is
A few provocative tests have been described by Styf the most common location for deep peroneal entrap-
for the evaluation of this syndrome. First, the patient ment, and entrapment in this location is often referred
is asked to actively dorsiflex and evert the foot against to as anterior tarsal tunnel syndrome. Entrapment may
resistance while the examiner palpates the nerve
impingement site. Then the examiner passively plantar
flexes and everts the foot without pressure over the
Common peroneal nerve
nerve and then with percussion along the length of
the nerve.13
Deep peroneal nerve
Superficial peroneal Tibialis anterior
nerve (cut)
Fibula Tibia
Anterior Extensor hallucis

tibiofibular longus
ligament Medial ligament
Calcaneofibular
ligament Peroneus tertius
Anterior talofibular
ligament Extensor digitorum
brevis
Cutaneous First dorsal
Distribution interosseous
Figure 25-2 Ankle sprain. Chronic plantar flexion/inversion Dorsal digital
cutaneous nerve
ankle sprains may lead to a tensile neuropathy involving
the superficial peroneal nerve. Figure 25-3 Anatomy of the deep peroneal nerve.
2560_Chapter 25_0311-0320.indd 315 3/16/2015 4:14:23 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
also occur where the nerve passes underneath the
extensor hallucis brevis. Compression may also occur Tibialis posterior
in areas where underlying bony prominences exist. Tibial artery
Dorsal osteophytes of the talonavicular joint or os Tibia
intermetatarseum between the first and second meta- Tibial nerve
Flexor digitorum
tarsals may predispose to the development of this syn- longus tendon Flexor
drome. Trauma may also contribute to the development retinaculum
of entrapment. Recurrent ankle sprains have been
identified as a contributing etiology because as the foot Flexor hallucis
longus tendon
plantar flexes and supinates, the nerve is placed under
Calcaneus
significant stretch. This repetitive stretch can lead to bone
nerve inflammation and scarring as previously described.
Tarsal Tunnel
External compression is a very important factor to
consider in the development of this syndrome and is Figure 25-4 Anatomy of the tarsal tunnel.
most commonly seen with athletes. Wearing tight-
fitting shoes, ski boots, and running shoes with tight
lacing at the area of the nerve and performing certain
activities such as push-ups or sit-ups with feet hooked tibial tendon, the flexor digitorum longus tendon, the
under a rigid weight all contribute to the compression flexor hallucis longus tendon, and the posterior tibial
of the nerve and symptomatic presentation.12 artery and vein. A high degree of anatomical variability
Patients most often present with a complaint of pain exists when considering the contents of the tarsal
along the dorsum of the foot with possible radiation to tunnel because the posterior tibial nerve may branch
the first interspace. The pain is often described to occur within the tunnel or distally to the tunnel. Because of
during the aforementioned athletic activities and tends the narrow structural anatomy of the tarsal tunnel,
to subside with rest and removal of external compres- entrapment of the tibial nerve within the tarsal tunnel
sion such as shoes. Physical examination may reveal is common. More common causes of entrapment
hypoesthesia or loss of sensation to the first interspace. include space-occupying lesions, coalitions, biome-
Pain may also be elicited with dorsiflexion and plantar chanical dysfunction, and bony prominences or exos-
flexion of the foot. Weakness of the EDB may also be toses.14 Patients may present with entrapment
noted depending on the area of entrapment. symptoms to the areas of distribution for the medial
calcaneal, medial plantar, or lateral plantar nerves.
Posterior Tibial Nerve Symptoms include hypoesthesias, paresthesias, and
Arising from the sciatic nerve, the posterior tibial nerve symptoms associated with an individual nerve
branches into the lateral sural cutaneous nerve, medial (described in further detail later).15
sural cutaneous nerve, medial calcaneal nerve, and Ganglion cysts are the most common space-
medial and lateral plantar nerve. It is responsible for occupying lesions to occur in the tarsal tunnel.15 Many
the cutaneous innervation of the posterior aspect of the theories exist regarding the development of these
leg and the plantar and plantar medial aspect of the lesions, including displacement of synovial tissue
foot. It provides motor innervation to the superficial during embryogenesis, proliferation of pluripotent
and deep posterior muscle compartment of the leg. In mesenchymal cells, degeneration of connective tissue
the proximal leg, the nerve is situated between the tibi- after trauma, and migration of synovial fluid.16 Gan-
alis posterior muscle and flexor hallucis longus muscle glion cysts causing entrapment syndrome at the tarsal
in the deep posterior muscle compartment. Distally, it tunnel may arise from the subtalar joint; ankle joint; or
is situated between the flexor hallucis longus and flexor tibialis posterior, flexor digitorum longus, and flexor
digitorum longus. In the inferior leg, the nerve enters hallucis longus tendons. Other space-occupying enti-
the subcutaneous layer traversing the tarsal tunnel ties causing similar symptoms include, but are not
along with the posterior tibial artery and venae com- limited to, synovial chondromatosis, schwannomas,
mitantes. The tarsal tunnel is formed by the medial and and varicose veins.17 Conservative treatments include
posterior aspect of the calcaneus, the posterior talus, rest, NSAIDs, bracing, and icing. However, conserva-
the distal tibia, the medial malleolus, the flexor reti- tive treatments often fail because the cause is not
naculum (laciniate ligament), and the abductor hallucis addressed. Surgical intervention is considered a better
muscle (Fig. 25-4). option because the actual etiology is addressed. Proce-
As it emerges from the fibro-osseous tarsal tunnel, dures involve anatomical dissection, ligation of vascular
the posterior tibial nerve separates into the medial supply, and resection of the impingement-causing
plantar nerve, the lateral plantar nerve, and the medial lesion.17 When resecting a ganglion cyst, it is essential
calcaneal nerve.10 The structures within the tarsal to identify the stalk, or the area where the cyst invests
tunnel include the posterior tibial nerve, the posterior in the capsule or tendinous sheath, and carefully ligate
2560_Chapter 25_0311-0320.indd 316 3/16/2015 4:14:23 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
it so as to disrupt the synovial flow. Ganglion cysts also aggravate the medial plantar nerve leading to
generally have a high recurrence rate, and as such it is entrapment symptoms.
possible to have a recurrent tarsal tunnel syndrome.17 Patients typically present with pain radiating distally
Osseous etiological factors, such as coalitions and into the medial toes and proximally into the ankle. Pain
exostoses, increase compartment pressure by decreasing is reportedly worse when running on flat ground, espe-
compartment size, creating an entrapment syndrome. cially when turning corners and during stair workouts.
Surgical decompression by resection of the offending On examination, tenderness can be noted most typi-
exostosis or coalition is a successful treatment modality. cally in the medial plantar arch and in the area of the
Biomechanical dysfunction is a significant causative navicular tuberosity. The examiner may test for symptom
factor in the development of tarsal tunnel syndrome.15 reproducibility by everting the heel or by having the
Examples include excessive subtalar and midtarsal joint patient stand on the ball of the foot. Hypoesthesia and
pronation which result in internal rotation of the tibia, loss of sensation is usually noted after the patient has
plantar flexion, and adduction of the talus; a decrease been jogging. Tinel’s sign may also be present.19
in the calcaneal pitch; and a flattening of the medial
longitudinal arch of the foot. This biomechanical dys- Lateral Plantar Nerve
function causes increased motion in the foot, which The lateral plantar nerve travels in the lower segment
leads to increased stress on all the structures in the foot of the tarsal tunnel entering the deep central plantar
and leg. Increased stress and strain can cause an space between the quadratus plantae and flexor digito-
increased risk of nerve damage and greater likelihood rum brevis. Traveling forward in an anterior-lateral
of nerve entrapment. The goal of treatment in this case direction, the nerve passes plantar to the quadratus
is to address excessive motion in the foot and leg by plantae and along the lateral plantar vessels. At this
means of reconstructive surgery to correct the overpro- point, it penetrates the lateral intermuscular septum,
natory movement by creating a more rigid lever arm. and at the level of the fifth metatarsal base it terminates
Bracing and the use of orthoses can also aid in decreas- into the deep and superficial end branches. The super-
ing pronation during gait. ficial branch divides into the fourth common digital
nerve and the lateral plantar cutaneous nerve of the
Medial Plantar Nerve fifth toe. The deep branch subsequently provides artic-
Larger than the lateral plantar nerve, the medial plantar ular branches to the tarsal and tarsometatarsal joints as
nerve is one of the terminal branches off the posterior well as muscular branches to the lateral lumbricales,
tibial nerve. Situated anteriorly, the nerve travels along interossei, and adductor hallucis.
with the medial plantar artery and passes superior to Although not commonly occurring as a single entity,
the lateral plantar artery. The nerve leaves the tarsal the lateral plantar nerve can become compressed alone
tunnel, passing along the intersection of the long flexors or along with the tibial nerve as previously described
in the second muscle compartment of the foot at the with tarsal tunnel syndrome. Typically, the patient
master knot of Henry. As it continues distally, the experiences loss of sensation to the lateral third of the
nerve is located in the medial portion of the deep plantar aspect of the foot. Because the lateral plantar
compartment of the foot. It divides into its terminal nerve innervates the abductor digiti minimi, functional
branches, three common digital nerves, at the level of loss of this muscle may also be noted, as is seen with
the first metatarsal base. The medial plantar nerve cuta- Baxter’s neuritis.20 Baxter’s neuritis is a syndrome that
neously innervates the medial sole of the foot. The is caused by the entrapment of the nerve to the abduc-
muscular branches of the medial plantar nerve supply tor digiti minimi. Symptoms often include heel pain,
the abductor hallucis, flexor digitorum brevis, flexor typically not associated with a heel spur. Entrapment
hallucis brevis, and first lumbrical. The nerve provides of this nerve is believed to occur between the deep
articular innervation to the talonavicular and cuneona- fascia of the abductor hallucis muscle and the medial
vicular joints and vascular innervations to the medial head of the quadratus plantae muscle. Patients tend
plantar artery. to be athletes presenting with tenderness along the
Entrapment of the medial plantar nerve is typically anteromedial heel along with inability to abduct the
thought to occur in joggers and is often referred to as fifth toe. Treatment entails surgical sectioning of
“jogger’s foot.”18 This type of entrapment occurs at the the deep fascia to release the entrapment.20
location of the master knot of Henry. Most patients
presenting with this syndrome tend to run with exces- Saphenous Nerve
sive heel valgus or hyperpronation. The pathology The saphenous nerve, a branch of the femoral nerve,
often coincides with a history of previous ankle injury travels in the thigh in the subsartorial canal. It pierces
or chronic ankle instability. Excessive abduction or the sartorius muscle and travels in the subcutaneous
adduction at the talonavicular joint may result in com- tissue to innervate the medial knee and leg. It provides
pression of the nerve at the master knot of Henry sensory innervation from the medial aspect of the knee
leading to entrapment syndrome. Arch supports may extending down to the medial aspect of the hallux.10
2560_Chapter 25_0311-0320.indd 317 3/16/2015 4:14:23 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Being so superficial, the saphenous nerve does not patient is weight bearing and the toes associated with
have a high tendency to become impinged secondary the affected interspace spread.12 Treatment for neuro-
to internal factors. However, trauma to the surrounding mas often begins with accommodative devices such as
areas, especially in and around the adductor canal, can metatarsal pads that serve to keep the metatarsals sepa-
cause perineural fibrosis, leading to entrapment syn- rated during the gait cycle to decrease the irritation to
drome. Chief complaints of saphenous nerve entrap- the nerve. Injections at the site of the neuroma are
ment include medial knee or leg pain after prolonged often considered along with accommodative devices.
standing or walking in the distribution of the saphe- Practitioners often concoct a combination of a local
nous nerve. Symptoms may also be exacerbated by anesthetic and corticosteroid to inject; the combination
lower extremity hip adduction or knee extension of substances that is injected is based on practitioner
strengthening exercises. Treatment options are limited preference. Another injectable used to treat neuromas
to the surgical release of fibrotic tissue and adhesions. that is controversial is an alcohol sclerosing agent. A
4% alcohol solution, usually mixed with a local anes-
Neuroma thetic, is injected in small quantities, usually 0.5 to
A neuroma, also referred to as perineural fibrosis, is 1 mL per injection for a total of three treatments.
hypertrophy of a given common digital plantar nerve Surgical treatment includes resection of the neuroma.
as it courses between the condyles of the proximal Detailed knowledge of the nerve origin, course, and
phalanges (Fig. 25-5). The exact mechanism causing area of innervation is essential for appropriate diagno-
neuromas is unknown. However, many causes have sis and understanding of entrapment neuropathies.
been described. One theory attributes friction and sub- Understanding the different etiological factors that
sequent trauma that occurs when the condyles engage contribute to the development of symptoms allows the
with one another during the gait cycle. Another theory practitioner to diagnose and treat these conditions
suggests trauma occurring at the nerve as a result of accurately. Nerve entrapment in the foot and ankle has
the pressure exerted on the nerve by the deep transverse several presentations, all of which have been described
intermetatarsal ligament during propulsion.21 Patients in detail in this chapter. Conservative and surgical
often present with complaints of burning, numbness, treatment options are aimed at correcting or limiting
and tingling in the area of the neuroma. Often patients the cause of entrapment and reducing the severity of
describe experiencing a sensation in having a pebble in axonal loss and impairment. With early and accurate
their foot or as though they are walking on a pebble. diagnosis and appropriate treatment, most patients
On physical examination, a Mulder click, which is a experience complete resolution of symptoms.
palpable click, may be palpated by laterally squeezing
the forefoot and manually manipulating the intermeta-
tarsal space. Another indicator of the presence of a
neuroma is the presence of Sullivan’s sign. Sullivan’s
sign is a clinical marker that can be seen when the
CASE STUDY
JD, an electrician, presented to the physical therapist
with a chief complaint of pain and neuralgic symptoms
(tingling, burning, numbness) of his right second and
third toes and the space between the toes. JD states
that the symptoms have been present for about a year
but have increased recently. He can “bring out” the
symptoms by passively dorsiflexing his toes. Kneeling is
also an issue. As an electrician, he is often kneeling,
Bones
and this position worsens his symptoms. JD also states
that symptoms are exacerbated by standing on his toes
Nerves
on a stepladder. He has self-treated with NSAIDs and
aspirin without success.

Neuroma
1. From the clinical scripts presented in the history,
which diagnosis appears to be the leading
differential diagnosis?
a. L5–S1 radiculopathy
b. Morton’s neuroma
c. Deep peroneal nerve entrapment
Figure 25-5 Typical location of interdigital neuroma pain. d. Sural nerve entrapment
2560_Chapter 25_0311-0320.indd 318 3/16/2015 4:14:23 PM

Process CyanProcess
YellowProcess Black
2. If the correct diagnosis is an interdigital neuroma, 5. Johnson EK, Chiarello CM. The slump test: the effects of
which clinical sign would be present? head and lower extremity position on knee extension.
J Orthop Sports Phys Ther. 1997;26:310–317.
a. Erythema along the second toe
6. Fiatarone CL, Singh MA, Bundy A, et al. Integration of
b. An ulceration of the second toe balance and strength training into daily life activity to reduce
c. A positive Tinel sign between the second and third rate of falls in older people (the LiFE Study): randomized
metatarsal heads parallel trial. BMJ. 2012;345:4547.
d. Weakness of the anterior tibialis muscle 7. Anseimi SJ. Common peroneal nerve compression. J Am
Podiatr Med Assoc. 2006;5(69):413–417.
3. All the following are appropriate treatments for an 8. Gross JA, Hamilton WJ. Isolated mechanical lesions of the
interdigital neuroma except: sural nerve. Muscle Nerve. 1989;3:248–249.
9. Baxter DE: Functional nerve disorders in the athlete’s foot,
a. Orthoses.
ankle, and leg. The Lower Extremity in Sports. 2008;34:
b. Corticosteroid injection. 185–194.
c. Sclerosing alcohol injection. 10. Lawrence SJ, Bott MJ. The sural nerve in the foot and ankle:
d. Electrical stimulation. an anatomic study with clinical a surgical implications. Foot
Ankle Int. 1994;15:490–494.
4. JD is an electrician. Which job-related factors may 11. Pringle RM, Protheroe K, Mukherjee SK. Entrapment
have contributed to the formation of an interdigital neuropathy of the sural nerve. J Bone Joint Surg. 1974;56:
neuroma? 465–468.
12. Lorei MP, Hershman EB. Peripheral nerve injuries in
a. Constant kneeling
athletes. Treatment and prevention. Sports Med. 1993;16:
b. The use of a ladder 130–147.
c. Standing on toes 13. Barrett SL, Dellon AL, Rossen GD, Walters L. Superficial
d. All of the above peroneal nerve: the clinical implications of anatomic
variability. J Foot Ankle Surg. 2006;45:174–176.
5. Which of the following is a factor thought to be the 14. Tsang AM, Mackenney PJ, Adepado AO. Tarsal tunnel
cause of women having a higher incidence of syndrome: a literature review. Foot Ankle Surg. 2012;18:
interdigital neuroma than men? 149–152.
15. Gould JS. Tarsal tunnel syndrome. Foot Ankle Clin.
a. Women tend not to participate in contact sports
2011;16:275–286.
b. Women have a higher incidence of age-related 16. Ahn JH, Choy WS, Kim HY. Operative treatment for
osteoporosis than men ganglion cysts of the foot and ankle. J Foot Ankle Surg.
c. Women wear tighter shoes than men 2010;49:442–445.
d. Women often wear high-heeled shoes 17. Spinner RJ, Delton AL, Rosson GD, Anderson SR, Amrami
KK. Tibial intraneural ganglion in the tarsal tunnel. J Foot
Ankle Surg. 2007;46:27–31.
18. Trafton PG. Jogger’s foot. Clin Orthop Relat Res. 1979;141:
308–309.
19. Beltran LS, Bencardino J, Ghazikhanian V, Beltran J.
References Entrapment neuropathies in the lower extremity III. Semin
1. Seddon HJ. Classification of nerve injuries. BMJ. 1942;2:237. Musculoskelet Radiol. 2010;14:501–511.
2. Sunderland S. A classification of peripheral nerve injury 20. Fuhrmann RA, Frober R. Release of the lateral plantar nerve
producing loss of function. Brain. 1951;74:491–516. in case of entrapment. Oper Orthop Traumatol. 2010;22:
3. Upton AR, McComas AJ. The double crush in nerve 335–343.
entrapment syndromes. Lancet. 1973;18:359–362. 21. Title CL, Schon LC. Morton neuroma: primary and
4. Osterman AL. The double crush syndrome. Orthop Clin North secondary neurectomy. J Am Acad Orthop Surg. 2008;16:
Am. 1988;19:147–155. 550–557.
2560_Chapter 25_0311-0320.indd 319 3/16/2015 4:14:23 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
2560_Glossary_0347-0360.indd 360 3/17/2015 12:11:29 PM
Chapter 26
Fall Risk and Fall Prevention
Strategies for Individuals With
ROBERTA A. NEWTON, PT, PHD, FGSA, AND DENNIS W. KLIMA, PT, MS, PHD, GCS, NCS
“Our greatest glory is not in never falling but in rising every time we fall.”
—CONFUCIUS (551–479 B.C.E.)
Objectives
• List possible fall etiologies.
• Identify fall risks.
• Discuss the fall risk impact of medications.
• Develop a comprehensive fall prevention program.
Key Terms
• Fall prevention
• Fall prevention program
• Fall risk assessment
• Somatosensation
and older.1 The cost of these unintentional falls can be

Introduction a financial burden on the health care system and the
individual and family and a loss of revenue generation.
Two of the most important capabilities of an individual, Balance, mobility impairments, and falls are
regardless of physical, health, or cognitive status, are the commonly reported in older adults who have periph-
ability to navigate the environment and the ability to eral neuropathy associated with diabetes mellitus.2–5
perform social roles. Physiological mechanisms sup- However, studies found that not all older women who
porting these capabilities include postural alignment, have diabetes mellitus and peripheral neuropathy fall.6,7
balance, and mobility, all of which depend on sensation Although these impairments are typically not reported,
and strength in the lower extremities. Impairment they may be secondary consequences for other types of
among these entities resulting from peripheral neu- pathologies resulting in peripheral neuropathy. For the
ropathy increases the likelihood of an individual expe- purpose of this chapter, a fall is defined as an unex-
riencing a fall. Unintentional falls in all age groups pected event during which the person comes to rest on
(excluding ages 15 to 24 years) are the leading cause of the ground, floor, or lower level.8
nonfatal injuries treated in hospital emergency depart- The purposes of this chapter are to provide (1) an
ments; falls rank as the leading cause of death from overview of mechanisms leading to fall risk in indi-
injury in adults older than age 65 years. In 2007, greater viduals with lower extremity peripheral nerve dysfunc-
than 8 million individuals were seen in emergency tion; (2) guidelines for assessment of balance and falls;
departments for treatment related to unintentional falls, and (3) guidelines for interventions to maintain or
of which more than 2.6 million were adults 55 years old regain balance or strategies to compensate for sensory
321
2560_Chapter 26_0321-0330.indd 321 3/16/2015 4:14:25 PM

Process CyanProcess
YellowProcess Black
and motor neuron loss, reducing the risk of falls. medical condition. Inferences regarding fall risk can be
Detailed descriptions of pathologies leading to periph- made by examining the medical condition and mecha-
eral nervous system dysfunction are not included in nisms contributing to a fall.
this chapter but do appear in Chapters 3 through 13.
Table 26-1 provides some examples of peripheral nerve
dysfunction and potential mechanisms that increase Mechanisms Contributing to Falls
the likelihood of falling. As is evident from the litera-
ture, fall risk is not specifically discussed because falling In a 6-month span, the absolute risk of falls occurring
may be considered a secondary consequence of the in individuals with peripheral neuropathy is 55%. Two
Table 26-1 Examples of Impairments Contributing to Fall Risk

Condition Mechanism Sensory Neuromotor Joints and Foot
Charcot-Marie- Peripheral sensory Subclass CMT1: decrease Distal, symmetrical High-arched pes cavus
Tooth disease or and motor neurons: or loss in cutaneous muscle weakness foot deformity;
hereditary motor demyelization sensation and evident in hammertoes
and sensory and axonal proprioception below dorsiflexors and
neuropathy degeneration knee evertors; atrophy;
decreased DTRs
Diabetic mellitus: Slow, progressive Sensory neuropathy: Bilateral, Foot deformity: flatfoot
diabetic loss of sensory, sensations of tingling, asymmetrical with valgus of
neuropathy motor, and burning, numbness; distal muscle midfoot, claw toes,
autonomic function complete loss of sensation weakness collapse of
in feet; pain owing to longitudinal arch
alteration of foot
biomechanics; ulceration
Guillain-Barré Acute inflammatory Acute sensory ascending Progressive paralysis Residual distal
syndrome: demyelinating neuropathy exhibits and areflexia; weakness may be
variants have polyneuropathy greater sensory changes proximal to distal present following
differing than muscle weakness recovery recovery trajectory
characteristics
HIV (AIDS) Peripheral nerve Primarily sensory: distal Bilateral symmetrical Residual ankle
damage secondary symmetrical peripheral and motor loss weakness may lead
to HIV, related neuropathies; to muscle imbalance
opportunistic proprioceptive loss
infections spreads distal to proximal;
(e.g., CMV), or tingling or burning pain;
medications contact sensitivity
Pernicious anemia Symmetrical sensory Late manifestation of vitamin Sensory loss leads
secondary to neuropathy B12 deficiency: loss of to decreased
vitamin B12 beginning in lower motor function balance abilities
deficiency extremities and feet
Postpolio Hypothesized latent Muscle atrophy; decline in Weakness typically Resultant contractures
syndrome aging effects strength, particularly knee asymmetrical, from postpolio
superimposed on extensor strength; often exacerbating syndrome or
reduced alpha decreased endurance and muscle groups hypermobile joints
motor neuronal fatigue affected during owing to
pool from initial initial infection compensatory
polio attack strategies
Lumbar Irritation of nerve Sensory roots may result in Motor decline Compensatory
radiculopathy roots, particularly low back pain and owing to motor mechanisms to
affecting lumbar radiating pain into one or roots at level of relieve pain: postural
disc disruption both legs; sensory decline rupture and realignment or more
owing to sensory root at adjacent nerve sedentary behavior:
level of rupture and roots both strategies lead
adjacent nerve roots to balance instability
CMV, Cytomegalovirus; DTRs, deep tendon reflexes.
2560_Chapter 26_0321-0330.indd 322 3/16/2015 4:14:26 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 26 | Fall Risk and Fall Prevention Strategies for Individuals With Peripheral Neuropathy 323
studies calculated odds ratios for falls in individuals the foot against the shoe. These sensory and biome-
with peripheral neuropathy as 6.3 and 17.9 Risk factors, chanical impairments underlie fall risk.
alone or in combination, may be sufficient to produce
balance instability and falls. These risk factors are cat- Neuromotor Dysfunction in
egorized as intrinsic (individual), extrinsic (e.g., medi- the Lower Extremities
cations, footwear), and environmental. A risk factor Declines in the number of alpha motor axons can result
present in one individual may not be a risk factor for in decreased scaling of force and power as well as
another individual. The impact of a risk factor is viewed decreased timing and sequencing of muscle activity,
in context of the individual’s health; the type, severity, decreasing the ability to produce coordinated muscle
and progression of the individual’s medical condition; synergies to accomplish a particular task. These declines
any comorbidities; and the psychological and mental are evident by decreased muscle strength, dropfoot,
health of the individual. instability in balance and gait, trips, and falls. Similar
to somatosensation declines, compensatory strategies
Peripheral Sensory Declines may offset motor function degradation until a critical
Decreased somatosensation (e.g., the foot in contact threshold is reached and alternative compensatory
with the floor) and decreased proprioception (joint strategies are needed. If the medical condition results
position and muscle length) decrease the ability of the in an abrupt change in peripheral sensory and motor
individual to detect the relationship of the lower systems, the ability of the individual to respond quickly
extremity to the trunk and to the support surface, to perturbations is decreased, causing a potential loss
reducing the ability to locate the center of mass for of balance and perhaps falling. In addition to the rate
postural alignment and balance. Additionally, there is of decline in the peripheral sensorimotor systems, the
a decreased ability to detect the condition of the critical threshold is also based on contributory factors
support surface (e.g., hard or compliant, slippery or such as age, health, progression of the medical condi-
resistive, even or uneven). tion, and prescription medications.
Decreased somatosensation as measured by vibra- Muscle weakness secondary to the medical condi-
tory threshold perception is higher in women with tion can lead to altered foot biomechanics, impaired
diabetes and a history of falls compared with women balance and postural control, and walking difficulties.
with diabetes and no fall history (21.0 volts vs. 17.9 Decreased muscle strength linked with decreased range
volts). Individuals with diabetic peripheral neuropathy of motion, particularly distally (ankle and foot), limits
also demonstrate decreased tactile sensitivity10 and the individual’s ability to adapt to changes in the
decreased proprioception as measured by ankle and walking surface. Weakness is due to either a decline in
great toe joint movement detection.11,12 the number of functioning motor units (motor axon
If sensory loss is gradual, redundant but unique con- and associated muscle cells) or a decreased capability
tributions of the other sensory systems (vestibular and of intact motor units to produce sufficient force to
vision) compensate for the somatosensory losses. These accomplish the same task as a muscle with a normal
compensatory strategies may be sufficient until a criti- complement of motor units would.
cal threshold is reached at which time these strategies Depending on the specific condition, muscle weak-
become insufficient, resulting in balance and dysfunc- ness may be evident as a symmetrical distal muscle
tion and increased probability for falls. The use of an weakness in the dorsiflexors and evertors as observed
assistive device may help compensate for balance dys- in clients with Charcot-Marie-Tooth disease, or hered-
function by increasing the base of support as well as itary motor and sensory neuropathy, the most fre-
providing additional touch information through the quently inherited peripheral neuropathy.14 Footdrop
device to provide cues for upright stance.13 An under- secondary to muscle weakness of the dorsiflexors
standing of the mechanism of sensory decline and the decreases the ability of the foot to clear the floor during
ability of other sensory systems to compensate underlie swing phase of gait, leading to walking difficulties and
guidelines for assessment and treatment protocols for increased frequency of tripping. Similarly, individuals
fall risk reduction. may be unable to lower the foot during the loading
Depending on the severity of the condition, loss of phase of gait and subsequently trip over uneven terrain.
sensation predisposes the joints to repeated trauma, Diabetic peripheral neuropathy has been shown to
and progressive loss of joint proprioception results in impair ankle strength, balance, and walking stability.15
Charcot disease or arthropathy, particularly in indi- Foot deformity, a consequence of muscle weakness and
viduals with diabetes mellitus. Continued joint trauma postural malalignment, leads to secondary conditions
can cause subluxation of the tarsal and metatarsal joints such as foot pain and ulceration and results in balance
resulting in a rocker-bottom foot deformity. This alter- instability and falls. Mauer et al.16 followed 139 nursing
ation in biomechanics of the foot increases joint stress, home residents for 299 days and noted that 78% of
particularly at the midtarsal and tarsometatarsal joints, residents with diabetes fell compared with 30% of resi-
and may result in ulceration secondary to the stress of dents without diabetes.
2560_Chapter 26_0321-0330.indd 323 3/16/2015 4:14:26 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Continued declines in the number of motor neurons
and their associated muscle cells (motor units) can
Elements of a Fall
overburden the remaining motor units and produce Prevention Program
fatigue. For example, postpolio syndrome is defined as
newly acquired neuromotor weakness in clients with a The following eight principles provide a guide to
prior diagnosis of polio.17 Symptoms include muscle implement a fall prevention program.
atrophy, decline in the strength of the affected muscles
particularly knee extensor strength, decreased endur- 1. The causes of a fall in one individual may not
ance, and fatigue with activity, all of which contribute cause a fall in another individual.
to decreased balance abilities, tripping, and fall risk. 2. Falls are generally due to an individual and
Depending on the severity of these symptoms, these environmental mismatch where the individual
individuals may restrict their activity and may use an is unable to recover balance, resulting in a
assistive device (cane or wheelchair). movement of the body to a lower surface (chair,
bed, floor, or against the wall).
Lifestyle and Activity Level 3. Deficits in physiological factors, such as
Peripheral sensory and motor pathology may result in somatosensation, muscle and skeletal strength,
decreased endurance and fatigue with activity, limiting balance, and gait, are associated with an
the mobility of the client and his or her ability to carry increased risk for falling. The risk of falls
out social roles and participate as a productive member increases with the number of physiological risk
of the workforce.18,19 Compensatory mechanisms to factors, the number of medications, and the
relieve pain (e.g., clients with lumbar radiculopathy) number of functional impairments. These
include postural realignment or the assumption of factors are important to identify in terms of fall
more sedentary behavior. Both of these strategies may risk and potential fall-related injuries as well as
lead to balance dysfunction. to prevent or reduce the impact of a fall.
More than 60% of clients with a neuromotor condi- 4. Falls can lead to a fear of falling and a fear of
tion such as hereditary motor and sensory neuropathy the inability to get back up after falling.
type I, postpolio syndrome, or Guillain-Barré syn- 5. Inactivity is a fall risk behavior and includes the
drome experience severe fatigue.20 The peripheral neu- spectrum from prolonged bed rest to a chosen
romotor pathology as well as the client ’s psychological or medical condition–related inactive lifestyle.
state may contribute to fatigue and may lead to a more 6. An individual may not be committed to make
sedentary lifestyle. The resultant spiral includes the sec- the recommended changes in lifestyle or home
ondary consequences of the medical condition, result- environment for various social, cultural,
ing in increased inactivity; declines in strength, balance, financial, or personal reasons.
and mobility; and increased fall risk. 7. No program can guarantee a reduction in falls
if the information is not relevant or the person
Medications does not actively take part to reduce his or her
Single medications and medication combinations may risks.
result in muscle weakness, dizziness, and balance 8. A fall prevention program should include a
instability. Certain classes of drugs are known to screening component, an education component,
produce dizziness, balance instability, and falls via dif- and an activity component.24 Education alone is
ferent mechanisms. These mechanisms include the not sufficient.
metabolism of the individual, which may alter the Generally, fall prevention programs have been
absorption and half-life of the drug; polypharmacy; custom-designed for specific settings, and multiple fall
and medication scheduling. If an individual is taking a prevention programs, rather than a single reliable and
diuretic in the evening, nighttime fall risk increases valid program, exist. The purpose of any fall prevention
because the individual may walk to the bathroom in program is to inform and motivate adults to make
the dark. necessary adaptations to their lifestyles and home envi-
In older adults, benzodiazepines, antidepressants ronment to reduce the risk for falls.
(particularly tricyclic antidepressants and selective
serotonin reuptake inhibitors), antiepileptics, and anti-
hypertensive medications increase fall risk; taking four
or more medications also increases fall risk.21,22 Com-
Guidelines for Assessing Individuals
binations of medications taken for HIV management at Risk for Falls
may cause neuropathy and subsequent falls. Antiretro-
viral medications containing dideoxynucleosides (“d- To determine appropriate interventions for balance
drugs”), such as didanosine and stavudine, may induce dysfunction and to decrease the risk of falls, a compre-
peripheral neuropathy.23 hensive assessment of sensory integrity, range of
2560_Chapter 26_0321-0330.indd 324 3/16/2015 4:14:26 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
motion, muscle strength, balance, and functional Handicap Inventory, assesses perceived disability
mobility and assessments of physical activity and secondary to symptoms of unsteadiness or
health-related quality of life are indicated. Depending dizziness.35
on the medical and health status of the individual,
disease-specific and behavioral assessments are also Integumentary and Foot Posture
recommended. Assessment of the home environment ● Trophic changes include dryness of the skin,
is discussed in conjunction with strategies to reduce fall distribution of hair growth, and condition of
risk in the home. Assessments are briefly outlined in the toenails.
this chapter. Selection of the appropriate assessments ● Pressure areas caused by shoes range from
depends on the client’s status, the practitioner’s exper- redness to ulceration.
tise, and the ability to identify the risk factors that are ● Foot deformities include hammertoes, fallen
modifiable. arches.
Fall History and Fear of Falling Deep Tendon Reflexes and
Obtaining a fall history starts with simply asking if the Electromyographic Examination
person has fallen within the past month, 3 months, or Review of findings is performed to determine the
6 months.25 The circumstances surrounding the fall or extent of peripheral nerve and muscle pathology.
falls should be determined, noting time of day, medica-
tion schedule, activity surrounding the fall, and loca- Range of Motion and Muscle Strength
tion of the fall inside or outside the house. Although range of motion and muscle strength can be
A single dichotomous question can be asked, “Do tested separately,36 they can be observed during physi-
you have a fear of falling?” This question can be fol- cal performance testing (balance and gait).
lowed by the question, “Does this fear restrict your
activities?”26 A more detailed assessment determines ● The Five Times Sit to Stand Test is used in
the confidence an individual has to perform routine older adults to obtain an indication of lower
activities. Assessments developed for older adults are extremity muscle strength. Performance on this
the Falls Efficacy Scale,27 which is used for frail or test may be influenced by pain.
homebound individuals, and the Activities-specific
Health Status and Measure of Physical
Balance Confidence Scale, which is used for more
Performance and Ability to Accomplish
active individuals.28
Activities of Daily Living
Medical and Medication History Self-report of the person’s perception of his or her
Medical history, including acute or chronic conditions health is obtained by asking the question, “How do you
and comorbidities, may solely or in combination con- perceive your health?” The rating is excellent, good, fair,
tribute to falls. The use of a mobility aid such as a cane or poor.
or walker is also noted. Medication type, dose, and Functional Mobility and Gait
frequency and adherence to taking the medication29 are
documented. Over-the-counter medications are also ● The Short Physical Performance Battery (SPPB)
noted. test consists of three components: balance (feet
together, semitandem, tandem), timed 4-m walk,
Sensory Integrity and five chair stands.37 The SPPB predicts the
loss of ability to walk 400 m.38
Bilateral examination of the lower extremities and foot
● The Timed Up and Go test records the time an
to obtain baseline measurements is necessary, particu-
individual stands from a chair, walks 10 ft (3 m)
larly for individuals with an asymmetrical sensory loss.
at his or her preferred speed, returns to the
● Cutaneous sensation is measured with 5.07g chair, and sits down. The TUG test has
Semmes-Weinstein monofilament. Gradation established concurrent validity with the Berg
measures the perception of light touch to loss of Balance Scale (BBS), gait speed, and Barthel
protective sensation.30 Proprioceptive testing Index and excellent reliability (intraclass
includes passive joint movement (yes/no correlation coefficient = 0.99).39
response to movement) or matching joint ● The Dynamic Gait Index assesses the ability of
positions.31 the individual to walk under different
● Pain in the lower extremity and foot is conditions including changes in gait speed and
measured using a visual analog scale32 or the negotiating obstacles.40
McGill Pain Questionnaire.33 ● The gait stability ratio measures the number of
● Vision acuity is assessed using the Snellen steps per meter and is a measure of stability
chart,34 and a vestibular screen, the Dizziness during walking.41
2560_Chapter 26_0321-0330.indd 325 3/16/2015 4:14:26 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
● Gait speed is obtained from timed walk tests tool not specific to any one condition or disease
ranging from 4- to 10-m distances. The 6 and is considered a generic health-related
Minute Walk Test42,43 is used to measure quality of life scale,51 whereas the Fear-
functional endurance. Avoidance Beliefs Questionnaire focuses on the
client’s perception about the effect of physical
Balance Assessments activity and work on low back pain.52
● The Multi-Directional Reach Test (MDRT) ● The Borg Rating of Perceived Exertion
measures limits of stability by having the person documents the perceived level of fatigue.53 This
reach in the forward, right, and left directions tool can monitor perceived exertion during
and lean backward. The MDRT demonstrates physical activity programs to reduce fall risk.
strong test-retest reliability and internal ● The Physical Activity Scale for the Elderly
consistency (Cronbach α = 0.842), along with assesses physical activity including participation
concurrent validity with the BBS and TUG.44 in sports, recreational activities, and housework
● The Four Square Step Test measures an as well as participation in seated activities.54
individual’s ability to negotiate a four-square ● Prochaska and DiClemente55 developed the
matrix created by straight canes affixed to the transtheoretical model to explain behavioral
floor.45 Facing forward through the entire change. The stages include precontemplation—
sequence and beginning in the upper left no intention to change behavior;
“square,” the person enters each of the four contemplation—intention to change;
quadrants while stepping over the four canes. preparation—beginning to make an effort
The sequence is in a clockwise direction and is for change within 30 days; action—actively
repeated in the counterclockwise direction. engaged in the activity; and maintenance—
Time scores slower than 15 seconds are sustain activity for at least 6 months. More
indicative of fall risk. The test is particularly recently, the transtheoretical model has been
challenging for individuals with peripheral applied to fall prevention programs for older
neuropathy because of the requisite cane adults.56
clearance involved with the stepping sequence.
● The BBS assesses balance during performance
of 14 in-home and out-of-home tasks.46 Fall Prevention Strategies
Scoring is on a 5-point scale from 0, unable to
perform, to 5, able to meet the criteria When addressing modifications to an individual’s life-
independently for the test item. The BBS has a style or the environment, practitioners should consider
Cronbach α value of 0.96 and excellent the health and medical condition of the individual, the
interrater (intraclass correlation coefficient individual’s culture, the individual’s finances, relevance
= 0.98) and intrarater (intraclass correlation of behavioral change to the individual, and willingness
coefficient = 0.99) reliability. In community- of the individual to change. Generally, people are more
dwelling older adults, a score of less than 45 willing to change the environment than change them-
predicts assistive device use.47 selves. Evidence-based activity programs exist for older
● The multi-item stance test evaluates the ability adults; impairment-specific rehabilitative programs,
of the person to maintain balance under such as for low back pain,57 incorporating activities
conditions of narrowing the base of support: designed to improve muscle strength, endurance, func-
feet together, semitandem, tandem, and single tion, and mobility can reduce fall risk. Level II evidence
leg stance. The client assumes and maintains the was used to confirm the combination of strengthening
position for up to 30 seconds. Loss of balance and aerobic exercise for individuals with peripheral
or movement away from the test position neuropathy.58 Elements of fall prevention programs are
warrants termination of the test. Instrumented detailed next.
balance assessment can differentiate postural
sway in healthy individuals and individuals with Education and Activity
diabetes.48 Sensory Loss and Footwear
● Understand how reduced lower leg sensation,
Social, Occupational, Leisure, particularly proprioception, can impair balance,
and Functional Status particularly when walking on uneven or
● Disease-specific or global assessments of health- compliant surfaces.
related quality of life provide an indication of ● Wearing shoes with low heels and firm
the impact of the medical condition on the rubber soles may enhance proprioceptive
ability of the individual to participate in societal, input from the feet. Studies have investigated
employment, and recreational activities.49,50 The the use of vibratory insoles to facilitate foot
36-Item Short Form Health Survey is a valid sensation.59
2560_Chapter 26_0321-0330.indd 326 3/16/2015 4:14:26 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
● Areas with reduced sensation are inspected daily recreational activities. Activities can include, but are
to determine pressure areas and potential not limited to, the following:61–65
ulceration.
● Low-impact exercises including the use of
● Use of an assistive device (e.g., cane or rolling
resistive bands,66 stationary bike, and aquatic
walker) improves stability by creating a wider base
exercise67
of support and enhancing tactile input for balance.
● Stretching activities, particularly at the ankle, to
Activity Program improve balance strategies68
Selecting an activity program is influenced by factors ● Dancing, gardening, walking, yoga,69 tai chi
such as age, culture, employment status, and attitudes chuan,70–73 and tae kwon do74
toward participating in exercise or leisure and recre- ● Wii or other video games promoting movement
ational activities. The activity program is graded in or balance75
intensity and frequency to meet the client’s goals and ● Borg Scale of Perceived Exertion can be used to
to avoid fatigue or exacerbation of symptoms such as monitor effort
pain. Identifying barriers to activity participation and
establishing an activity contract monitored by the How to Get Up From the Floor
client and health care professional may facilitate adher- Many clients need a strategy to get up after a fall has
ence.60 An activity program can be custom designed occurred, particularly if assistance is unavailable or not
and may include rehabilitative interventions such as close by (e.g., phone out of reach). The client can prac-
functional electrical stimulation to facilitate muscle tice in the safety of a clinic setting or with a health care
activity, such as the anterior tibialis muscle to decrease professional in the home setting. Box 26-1 is an instruc-
footdrop. An activity program may be part of an indi- tion sheet used to teach this maneuver in a group
vidual intervention or incorporated into leisure and setting.
Box 26-1
Teaching Clients to Get Up From the Floor

Following is a general scripted instruction sheet for • Moving can occur by pulling oneself along, crawling,
helping clients get up from the floor after a fall. Personal or scooting.
experience or other hints are encouraged to make the • Get into a side-sitting position. Once in this position,
talk appropriate to the audience. pause a second to get your bearings (orient yourself
The longer a person remains on the floor after a fall, and catch your breath).
the greater the chances for secondary complications • Kneel with support of the chair or sofa. Once in this
resulting from lying there. It is a given that everyone falls. position, pause a second to get your bearings (orient
Before the person attempts to get up, determine if yourself and catch your breath).
someone is available to assist. If the individual is living • Use the stronger knee to push yourself onto the chair
with someone, it is better to call for assistance, even if it or sofa. Putting your forearms on the chair or sofa seat
means waking the person up. The fall may have caused also helps to get some leverage. Once in this
an injury or badly shaken the individual. In all cases, the position, pause a second to get your bearings (orient
key is to move slowly, remain calm, and run through your yourself and catch your breath).
mind the next step in getting up.
First, check to see if anything is broken—does the It is important to emphasize doing this slowly and not
bone feel broken, or does it just really hurt a lot? impulsively because the person is embarrassed that a fall
Generally, broken bones are associated with severe occurred.
pain. If the person is living alone and believes that Once sitting in a chair or on the sofa, take time to
something was broken, the person needs to move on the calm down, catch your breath, and decide the next
floor to reach a telephone. This is done slowly. course of action—do I need to call a friend, neighbor,
Ask the audience, how they would get up from the relative, ambulance, or 911 for help? Do I just need to
floor if they have fallen. If the floor is clean (always bring talk to someone for assurance?
a floor covering) lie down and have the group problem- For individuals who may be reluctant to learn to get
solve how you would get up. This way they see the up because of fear, anxiety, or the belief that they do not
demonstration as well as being actively involved by have the physical capability to get up, other strategies
providing hints. (I find that most groups like this and will are needed. For example, some individuals may be able
provide additional hints.) to afford some type of alarm system. For all people,
The steps include moving along the floor to a sturdy recommend a buddy system—that is, have someone call
chair that will not move or the sofa or some other fixed the person at least once a day. Also, recommend
support (not a bathroom sink because it could pull away placing the telephone in easy reach and not attached to
from the wall). a kitchen wall where one has to stand to use it.
Modified and reprinted with permission from RA Newton, Fall Prevention Project, 1998.
2560_Chapter 26_0321-0330.indd 327 3/16/2015 4:14:26 PM

Process CyanProcess
YellowProcess Black
Modifications to the Environment
An individual with peripheral neuropathy may have CASE STUDY
the capability but may be unable to participate
Mary is a 75-year-old woman who has been admitted to
(perform) because of environmental barriers. If the
the acute care hospital with a urinary tract infection. She
work or residence environment is modified and the
has a fever, and her white blood cell count is elevated. Her
person can perform within the limits of his or her
past medical history is significant for Parkinson disease.
health condition, individual participation and perfor-
She was admitted for administration of intravenous
mance levels may improve.
antibiotics for the urinary tract infection. A physical
Making the interior and exterior of the living area
therapy evaluation was also ordered for identification
safe can be achieved by doing a room-by-room assess-
of fall risk. Mary tells the physical therapist that she has
ment or examining commonalities (e.g., lighting,
been falling “once a week.” She lives alone and states that
support surface, stairs). Willingness to make the modi-
she “walks around the house very unsafely.” Her house is
fication and financial constraints are potential barriers
one story. An aide helps her with housework, shopping,
for making environmental changes. The following list
and meal preparation (she cannot do any of these on her
outlines strategies to improve the home environment
own). She also receives Meals on Wheels from a local
and potentially to reduce fall risk.
volunteer group. Her lawyer handles all financial matters.
Lighting: Sufficient illumination and location in Mary spends her day watching TV and reading.
stairs and frequently traveled areas are Functional evaluation by the physical therapist reveals
considerations. contact guard for transfers and contact guard for
Support surface: Thick carpet and underpadding ambulation with a cane. Ambulatory distance is 30 feet
decrease the ability of a person with decreased limited by fatigue. Mary’s gait is slow with a marked
foot sensation to detect the support surface. The decreased stride length. The BBS score is 44, markedly
carpet can be removed, or the client can use worse than the accelerated risk of falling score of 49.
additional support to travel through these areas.
Scatter rugs should be removed or firmly Case Study Questions
secured. Ramps and stairs may pose a problem 1. When performing the physical and functional
for individuals with anterior tibialis weakness. evaluation, which of the following would you consider
Furniture: Low and soft-cushioned furniture poses to be the most important evaluative data point as a
difficulty when sitting and standing up. predictor of overall health, well-being, and safety?
Modifications include higher and more firm- a. Stair-climbing assessment
cushioned furniture and tables. Furniture may b. Deep tendon reflexes
become an obstacle if it is located in the most c. BBS
frequently traveled path. Tables with glass or d. Upper extremity manual muscle test
clear tops may be difficult to see.
Bathroom: There should be an appropriate number 2. The assistive device most indicated for Mary to use
and position of grab bars for the toilet, bathtub, at home now is:
and shower. A sturdy bench seat that extends a. No device.
from inside the bathtub into the bathroom b. Standard walker.
alleviates the need to step over the bathtub to c. Quad cane.
enter or exit. d. Wheeled walker.
Frequently used items: These should be located 3. With Mary’s diagnosis of Parkinson disease, you
between shoulder and knee height to avoid most likely would expect to find which of the
potential unexpected perturbations when following on evaluation?
reaching or moving items. a. Spasticity, positive Babinski sign, resting tremor
Falls can be a secondary consequence of impairments b. Rigidity, no confusion, resting tremor
associated with peripheral neuropathy. Often, the c. Hypotonus, negative Babinski sign, confusion, no
medical status and medical management of clients are resting tremor
the primary focus, and falls tend to be an afterthought. d. Flaccidity, no confusion, no resting tremor
As noted, multiple fall risk factors exist and include 4. As an intervention related to the goal of improving
impairments, medication management, and environ- the ankle strategy, the most indicated, safest, and
mental factors. A fall prevention program includes most appropriate for Mary is:
assessment, education, physical activity program, and a. Outdoor distance walking around a track.
environmental modifications. Such a program not only b. Heel-to-toe ambulation.
reduces the risk of falls but also may improve overall c. Catching and tossing a volleyball.
strength, endurance, and functional mobility in the d. TheraBand for strengthening the anterior tibialis and
client to maintain his or her quality of life. the gastrocnemius/soleus in the seated position.
2560_Chapter 26_0321-0330.indd 328 3/16/2015 4:14:26 PM

Process CyanProcess
YellowProcess Black
5. The score on the BBS was 44 indicating a high risk diabetic peripheral neuropathy. Arch Phys Med Rehabil. 2004;
for fall. Taken at face value and without the 85:245–252.
16. Mauer MS, Burcham J, Cheng H. Diabetes mellitus is
performance of other tests and measures, the BBS associated with an increased risk of falls in elderly residents
results indicate to the physical therapist that the fall of a long-term care facility. J Gerontol. 2005;60A:1157–1162.
risk is due to: 17. Stolwijk-Swüste J, Beelen A, Lankhorst J, Nollet F. The
a. Age. course of functional status and muscle strength in patients
b. Musculoskeletal weakness. with late-onset sequelae of poliomyelitis: a systematic review.
Arch Phys Med Rehabil. 2005;86:1693–1701.
c. Parkinson disease. 18. Gálvez R, Marsal C, Vidal J, Ruiz M, Rejas J. Cross-sectional
d. The BBS alone cannot determine the cause of fall evaluation of patient functioning and health-related quality of
risk. life in patients with neuropathic pain under standard care
conditions. Eur J Pain. 2007;11:244–255.
19. Willén C, Thoren-Jönsson A-L, Grimby G, Sunnerhagen KS.
Disability in a 4-year follow-up study of people with
References postpolio syndrome. J Rehabil Med. 2007;39:175–180.
1. CDC Center for Injury Prevention and Control. http:// 20. Zwarts MJ, Bleijenberg G, van Engelen BGM. Clinical
www.cdc.gov/injury/index.html. Accessed May 31, 2010. neurophysiology of fatigue. Clin Neurophysiol. 2008;119(1):
2. Richardson JK. Factors associated with falls in older patients 2–10.
with diffuse polyneuropathy. J Am Geriatr Assoc. 2002;50: 21. Hartikainen S, Lönnroos E, Louhivuori K. Medication as a
1767–1773. risk factor for falls: critical systematic review. J Gerontol A Biol
3. Menz HB, Lord SR, St George R, Fitzpatrick RC. Walking Sci Med Sci. 2007;62(10):1172–1181.
stability and sensorimotor function in older people with 22. Berlie HD, Garwood CL. Diabetes medications related to an
diabetic peripheral neuropathy. Arch Phys Med Rehabil. 2004; increased risk of falls and fall-related morbidity in the elderly.
85:245–252. Ann Pharmacother. 2010;44:712–717.
4. Richardson JK, Thies SB, DeMott TK, Ashton-Miller JA. Gait 23. Hung CF, Gibson SA, Letendre SL, et al. Impact of
analysis in a challenging environment differentiates between long-term treatment with neurotoxic dideoxynucleoside
fallers and nonfallers among older patients with peripheral antiretrovirals: implications for clinical care in resource-
neuropathy. Arch Phys Med Rehabil. 2005;86:1539–1544. limited settings. HIV Med. 2008;9:731–737.
5. Patel S, Hyer S, Tweed K, et al. Risk factors for fractures and 24. AGS/BGS Clinical Practice Guideline: Prevention of Falls in
falls in older women with type 2 diabetes mellitus. Calcif Older Persons. 2010. http://www.americangeriatrics.org/
Tissue Int. 2008;82:87–91. health_care_professionals/clinical_practice/clinical_guidelines
6. Volpato S, Leveille SG, Blaum C, Fried LP, Guralnik JM. _recommendations/prevention_of_falls_summary_of
Risk factors for falls in older disabled women with diabetes: _recommendations. Accessed May 31, 2010.
the Women’s Health and Aging Study. J Gerontol A Biol Sci 25. Lamb SE, Jorstad-Stein EC, Hauer K, Becker C, on behalf
Med Sci. 2005;60:1539–1545. of the Prevention of Falls Network Europe and Outcomes
7. Franklin GM, Kahn LB, Baxter J, Marshall JA, Hamman RF. Consensus Group. Development of a common outcome data
Sensory neuropathy in noninsulin dependent diabetes set for fall injury prevention trials. The Prevention of Falls
mellitus: the San Luis Valley Diabetes Study. Am J Epidemiol. Network Europe Consensus. J Am Geriatr Soc. 2005;53:
1990;131:633–643. 1618–1622.
8. Hauer K, Lamb SE, Jorstad EC, Todd C, Becker C 26. Jørstad EC, Hauer K, Becker C, Lamb SE; ProFaNe Group.
(on behalf of the ProFane-group). Systematic review of Measuring the psychological outcomes of falling: a systematic
definitions and methods of measuring falls in randomised review. J Am Geriatr Soc. 2005;53:501–510.
controlled fall prevention trials: systematic review. Age Ageing. 27. Tinetti ME, Richman D, Powell L. Falls efficacy as a measure
2006;35:5–10. of fear of falling. J Gerontol. 1990;45(6):P239–P243.
9. Hurman DJ, Stevens JA, Rao JK. Practice Parameter: 28. Myers AM, Fletcher PC, Myers AH, Sherk W.
Assessing patients in a neurology practice for risk of falls Discriminative and evaluative properties of the activities-
(an evidence-based review): report of the Quality Standards specific balance confidence (ABC) scale. J Gerontol A Biol Sci
Subcommittee of the American Academy of Neurology. Med Sci. 1998;53:M287–M294.
Neurology. 2008;70:473–479. 29. Berry SD, Quach L, Procter-Gray E, et al. Poor adherence to
10. Holewski JJ, Stess RM, Graf PM, Grunfeld C. Aesthesiometry: medications may be associated with falls. J Gerontol A Biol Sci
quantification of cutaneous pressure sensation in diabetic Med Sci. 2010;65A(5):553–558.
peripheral neuropathy. J Rehabil Res Dev. 1988;25:1–10. 30. Despande N, Metter J, Ferrucci L. Validity of clinically
11. Kars HJ, Hijmans JM, Geertzen JH, Zijlstra W. The effect of derived cumulative somatosensory impairment index. Arch
reduced somatosensation on standing balance: a systematic Phys Med Rehabil. 2010;91:226–232.
review. J Diabetes Sci Technol. 2009;3(4):931–943. 31. Deshpande N, Connelly DN, Culham EG, Costigan PA.
12. Simoneau G, Derr J, Ulbrecht J, Becker M, Cavanagh P. Reliability and validity of ankle proprioceptive measures. Arch
Diabetic sensory neuropathy effect on ankle joint movement Phys Med Rehabil. 2003;84:883–889.
perception. Arch Phys Med Rehabil. 1996;77:453–460. 32. Maio RF, Garrison HG, Spaite DW, et al. Emergency
13. Dickstein R, Shupert CL, Horak FB. Fingertip touch Medicine Services Outcomes Project (EMSOP) IV: pain
improves postural stability in patients with peripheral measurement in out-of-hospital outcomes research. Ann
neuropathy. Gait Posture. 2001;14:238–247. Emerg Med. 2002;40(2):172–179.
14. Chetlin RD, Gutmann L, Tarnopolsky M, Ullrich IH, Yeater 33. Possidente CJ, Tandan R. A survey of treatment practices in
RA. Resistance training effectiveness in patients with diabetic peripheral neuropathy. Prim Care Diabetes. 2009;3(4):
Charcot-Marie-Tooth disease: recommendations for exercise 253–257.
prescription. Arch Phys Med Rehabil. 2004;85:1217–1223. 34. Davidson JA, Ciulla TA, McGill JB, Kles KA, Anderson PW.
15. Menz HB, Lord SR, St George R, Fitzpatrick RC. Walking How the diabetic eye loses vision. Endocrine. 2007;32(1):
stability and sensorimotor function in older people with 107–116.
2560_Chapter 26_0321-0330.indd 329 3/16/2015 4:14:27 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
35. Jacobson GP, Newman CW. The development of the 57. Hayden JA, van Tulder MW, Tomlinson G. Systematic review:
dizziness handicap inventory. Arch Otolaryngol Head Neck strategies for using exercise therapy to improve outcomes in
Surg. 1990;116:424–427. chronic low back pain. Ann Intern Med. 2005;142:776–785.
36. Kendall FP, McCreary EK, Provance PG, Rodgers MM, 58. Cup EH, Pieterse AJ, ten Broek-Pastoor JM, et al. Exercise
Romani WA. Muscles: Testing and Function. 5th ed. Baltimore, therapy and other types of physical therapy for patients with
MD: Lippincott Williams & Wilkins; 2005. neuromuscular diseases: a systematic review. Arch Phys Med
37. Guralnik JM, Ferrucci L, Pieper CF, et al. Lower extremity Rehabil. 2007;88:1452–1464.
function and subsequent disability: consistency across studies, 59. Priplata AA, Niemi JB, Harry JD, Lipsitz LA, Collins JJ.
predictive models, and value of gait speed alone compared Vibrating insoles and balance control in elderly people.
with the short physical performance battery. J Gerontol A Biol Lancet. 2003;362:1123–1124.
Sci Med Sci. 2000;55:M221– M231. 60. Robinson L, Dawson P, Newton J. Promoting adherence with
38. Vasunilashorn S, Coppin AK, Patel KV, et al. Use of the exercise-based falls prevention programs. In: Vincent ML,
short physical performance battery score to predict loss of Moreau TM, eds. Accidental Falls: Causes, Prevention and
ability to walk 400 meters: analysis from the InCHIANTI Intervention. New York: Nova Science Pub, Inc; 2008:283–298.
study. J Gerontol A Biol Sci Med Sci. 2009;64(2):223–229. 61. National Council on Aging. The Creative Practices in Home
39. Podsiadlo D, Richardson S. The timed “up and go”: a test of Safety Assessment and Modification Study and State
basic functional mobility for frail elderly persons. J Am Coalitions on Fall Prevention: A Compendium of Initiatives.
Geriatr Soc. 1991;39:142–147. http://www.ncoa.org/news-ncoa-publications/publications/.
40. Shumway-Cook A, Baldwin M, Pollisar N, Gruber W. Accessed May 21, 2010.
Predicting the probability of falls in community-dwelling 62. Sherrington C, Whitney JC, Lord SR, Herbert RD,
adults. Phys Ther. 1997;77:812–819. Cumming RG, Close JC. Effective exercise for the prevention
41. Cromwell RL, Newton RA. Relationship between balance of falls: a systematic review and meta-analysis. J Am Geriatr
and gait stability in healthy older adults. J Aging Phys Act. Soc. 2008;56(12):2234–2243.
2004;12:90–100. 63. Callahan LF. Physical activity programs for chronic arthritis.
42. Guyatt GH, Thompson PJ, Berman LB, et al. Assessment Curr Opin Rheumatol. 2009;21(2):177–182.
of respiratory function in patients with chronic obstructive 64. White CM, Pritchard J, Turner-Stokes L. Exercise for people
airways disease. Thorax. 1979;34:254–258. with peripheral neuropathy. Cochrane Database Syst Rev.
43. Rogers HL, Cromwell RL, Newton RA. Association of 2004;(4):CD003904.
balance measures and perception of fall risk on gait speed: a 65. Gillespie LD, Gillespie WJ, Robertson MC, et al.
multiple regression analysis. Exp Aging Res. 2005;31:191–203. Interventions for preventing falls in elderly people. Cochrane
44. Newton RA. Validity of the multi-directional reach test: Database Syst Rev. 2003;(4):CD000340.
a practical measure for limits of stability in older adults. 66. Ruhland JL, Shields RK. The effects of a home exercise
J Gerontol A Biol Sci Med Sci. 2001;56:M248–M252. program on impairment and health-related quality of life
45. Dite W, Temple VA. A clinical test of stepping and change of in persons with chronic peripheral neuropathies. Phys Ther.
direction to identify multiple falling older adults. Arch Phys 1997;77(10):1026–1039.
Med Rehabil. 2002;83:1566–1571. 67. Bartels EM, Lund H, Hagen KB, Dagfinrud H, Christensen
46. Berg KO, Wood-Dauphinee SL, Williams KI, Gayton D. R, Danneskiold-Samsøe B. Aquatic exercise for the treatment
Measuring balance in the elderly: preliminary development of of knee and hip osteoarthritis. Cochrane Database Syst Rev.
an instrument. Physiother Can. 1989;41:304–311. 2007;(4):CD005523.
47. Bogle-Thorbahn L, Newton RA. Can Berg’s balance test 68. Bird ML, Hill K, Ball M, Williams AD. Effects of resistance
predict falls in the elderly. Phys Ther. 1996;76:576–585. and flexibility exercise interventions on balance and related
48. Schilling RJ, Bollt EM, Fulk JD, Skufca JD, Al-Ajlouni AF, measures in older adults. J Aging Phys Activity. 2009;17(4):
Robinson CJ. A quiet standing index for testing the postural 444–454.
sway of healthy and diabetic adults across a range of ages. 69. Schmid AA, Van Puymbroeck M, Koceja DM. Effect of a
IEEE Trans Biomed Eng. 2009;56(2):292–302. 12-week yoga intervention on fear of falling and balance in
49. McDowell I. Measuring Health: A Guide to Rating Scales and older adults: a pilot study. Arch Phys Med Rehabil. 2010;91(4):
Questionnaires. 3rd ed. New York: Oxford University Press; 576–583.
2006. 70. Richerson S, Rosendale K. Does Tai Chi improve plantar
50. Huang IC, Hwang CC, Wu MY, et al. Diabetes-specific or sensory ability? A pilot study. Diabetes Technol Ther. 2007;9(3):
generic measures for health-related quality of life? Evidence 276–286.
from psychometric validation of the D-39 and SF36. Value 71. McCain NL, Gray DP, Elswick RK, et al. A randomized clinical
Health. 2008;11(3):450–461. trial of alternative stress management interventions in persons
51. Contopoulos-Ioannidis DG, Karvouni A, Kouri I, Ioannidis with HIV infection. J Consult Clin Psychol. 2008;76(3):431–441.
JPA. Reporting and interpretation of SF-36 outcomes in 72. Hall A, Maher C, Latimer J, Ferreira M. The effectiveness
randomised trials: systematic review. BMJ. 2009;338:a3006. of Tai Chi for chronic musculoskeletal pain conditions: a
52. Waddell G, Newton M, Henderson I. A Fear-avoidance Beliefs systematic review and meta-analysis. Arthritis Rheum. 2009;
Questionnaire (FAB-Q) and the role of fear-avoidance beliefs 61(6):717–724.
in chronic low back pain and disability. Pain. 1993;52:157–168. 73. Lelard T, Doutrellot PL, David P, Ahmaidi S. Effects of a
53. Borg G. Psychological bases of perceived exertion. Med Sci 12-week Tai Chi Chuan program versus a balance training
Sports Exerc. 1982;14:377–381. program on postural control and walking ability in older
54. Washburn RA, Smith KW, Jette AM, Janney CA. The people. Arch Phys Med Rehabil. 2009;1(1):9–14.
Physical Activity Scale for the Elderly (PASE): development 74. Cromwell RL, Meyers PM, Meyers PE, Newton RA. Tae
and evaluation. J Clin Epidemiol. 1993;46(2):153–162. Kwon Do: an effective exercise to improve balance and
55. Prochaska JO, DiClemente CC. Stages and processes of walking ability in healthy older adults. J Gerontol A Biol Sci
self-change in smoking: toward an integrative model of Med Sci. 2007;62A:641–646.
change. J Consult Clin Psychol. 1983;51:390–395. 75. Graves LE, Ridgers ND, Williams K, Stratton G, Atkinson
56. Snodgrass SJ, Rivett DA, Mackenzie LA. Perceptions of older G, Cable NT. The physiologic cost and enjoyment of Wii Fit
adults about fall injury prevention and physical activity. Aust J in adolescents, young adults, and older adults. J Phys Act
Ageing. 2005;24(2):114–118. Health. 2010;7(3):393–401.
2560_Chapter 26_0321-0330.indd 330 3/16/2015 4:14:27 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Chapter 27
Peripheral Neuropathies in
Individuals With HIV Disease
DAVID M. KIETRYS, PT, PHD, OCS, AND MARY LOU GALANTINO, PT, PHD, MSCE
“The global HIV/AIDS epidemic is an unprecedented crisis that requires

an unprecedented response. In particular it requires solidarity—between
the healthy and the sick, between rich and poor, and above all,
between richer and poorer nations. We have 30 million orphans already.
How many more do we have to get, to wake up?”
—KOFI ANON (1938–), GHANIAN DIPLOMAT and FORMER SECRETARY GENERAL
OF THE UNITED NATIONS
Objectives
• Discuss the role of antiretroviral medication in the treatment of HIV/AIDS.
• List the various neuropathies associated with HIV/AIDS.
• Describe the signs and symptoms of distal symmetrical polyneuropathy associated with HIV/AIDS.
• List the risk factors associated with the development of distal symmetrical polyneuropathy in individuals with
HIV/AIDS.
• Discuss the role of complementary and alternative medicines used to treat HIV/AIDS–related polyneuropathy.
Key Terms
• Antiretroviral medications
• Distal symmetrical polyneuropathy
• Highly active antiretroviral therapy
• Human immunodeficiency virus (HIV)
untreated HIV/AIDS. As a result of advances in medi-

Introduction cations used to treat this disease, people with HIV
disease are living longer and leading more active lives.
Following acute infection with human immunodefi- Successful treatment with antiretroviral drugs allows
ciency virus (HIV), people who are untreated gradu- many people to live out their natural life span, but
ally progress from a period of being asymptomatic to many of the drugs have adverse side effects. As people
having advanced HIV disease, or acquired immunode- live longer with the disease, comorbidities may develop
ficiency syndrome (AIDS). This progression may take that complicate medical management and adversely
several months or years. If left untreated, HIV/AIDS affect quality of life. Common conditions, injuries, or
eventually leads to death. HIV/AIDS causes cata- other problems related to aging might affect long-term
strophic levels of immunosuppression, increasing the survival, especially in cases of advanced disease. Finally,
risk of acquiring life-threatening opportunistic infec- a diagnosis of HIV disease may complicate medical
tions. Such infections are the leading cause of death in management of preexisting health conditions.
331
2560_Chapter 27_0331-0346.indd 331 3/16/2015 4:14:29 PM

Process CyanProcess
YellowProcess Black
Antiretroviral medications to treat HIV disease HAART with low CD4 counts (<50 to 100 cells/μL)
have been available since the 1980s. The first antiret- and patients for whom HAART is initiated soon after
roviral drug, AZT (zidovudine), came into widespread treatment for an opportunistic infection is begun.4
use in the United States in 1986. Adverse side effects Immune reconstitution inflammatory syndrome may
and toxicities associated with AZT as a monotherapy further complicate the symptom presentation or be
soon emerged. Later, “cocktails” of at least three differ- associated with the development of peripheral neu-
ent antiretrovirals from at least two different drug ropathies.5 DSP and other neuropathies also may
classes became the standard of care. Treatment of HIV emerge in patients with untreated disease. In addition,
disease with multiple antiretrovirals is known as highly subclinical neuropathy is common in patients with
active antiretroviral therapy (HAART). Because of HIV disease; 30% of asymptomatic patients may have
HAART, HIV disease is now a chronic and generally clinical signs of DSP.6,7
manageable disease, assuming that patients have access DSP is believed to be related to immunological dys-
to and are adherent to HAART. Although HIV/AIDS function associated with HIV infection or exposure to
is not curable at the present time, pharmaceutical dideoxynucleosides, nucleoside reverse transcription
agents for the successful management of this disease inhibitor (NRTI) antiretroviral drugs. In addition, other
continue to evolve and improve. risk factors and mechanisms of interaction with comor-
bid conditions exist.8 Reports of prevalence of DSP
range from 30%9 to greater than 50%10 to 62%11 in
Overview of HIV/AIDS–Associated patients with AIDS and between 8% and 30% in all
infected individuals.12 This variation may be explained
Neuropathies partly by variance in definitional criteria. Before the
emergence of HAART, patients with advanced disease
As with other chronic diseases, complications and and advanced immunosuppression had a high incidence
comorbidities may emerge over time. Distal symmet- of DSP.8 In a study of 1,539 HIV-infected individuals,
rical polyneuropathy (DSP) is the most common neu- most of whom were receiving HAART, Ellis et al.13
rological complication of HIV/AIDS1,2 accounting for found clinical evidence of HIV-associated sensory neu-
approximately 90% of neuropathies seen in patients ropathy in 57% of patients. Of those, 38% reported
with HIV/AIDS,3 and this neuropathy is the focus of neuropathic pain, and 61% reported at least one sensory
this chapter. Other, less common neuropathies are symptom (pain, paresthesia, or loss of sensation). In this
reviewed briefly toward the end of the chapter. The study, pain had a negative effect on quality of life and
types of neuropathies seen in patients with HIV/AIDS function. Other studies reported 50% to 60% of patients
are listed in Box 27-1. with DSP experienced pain as a key symptom.14,15 DSP
Peripheral neuropathies in patients receiving may affect 34% of children with HIV disease.16
HAART are challenging to diagnose and treat because Prolonged life expectancies in individuals treated
of overlap of symptoms with comorbidities. Some with HAART and occurrences of new HIV infections
patients recently placed on HAART experience in older individuals have resulted in increased numbers
immune reconstitution inflammatory syndrome. The of older patients with HIV disease. Greater frequency of
risk of this syndrome is highest for patients who start DSP may occur in older patients with HIV because of
greater immune compromise or comorbidities associ-
Box 27-1 ated with aging.8 A study of comorbidity prevalence in
adults with HIV across each decade of life found that
Types of Peripheral Neuropathy Associated With HIV/AIDS the greatest prevalence of peripheral neuropathy
occurred in the oldest cohort (≥60 years old).17
Distal sensory polyneuropathy Since the advent of HAART, central nervous system
Autonomic neuropathy complications of the disease have declined, but the
Acute inflammatory demyelinating polyneuropathy incidence and prevalence of peripheral neuropathies,
(Guillain-Barré syndrome) especially DSP, remain high and may be increasing for
Chronic inflammatory demyelinating polyneuropathy two main reasons.18 First, because of HAART, survival
Mononeuropathy multiplex or mononeuropathy rates for individuals infected with HIV have increased
Neuropathy associated with diffuse infiltrative and for some individuals may approach normal life
lymphomatosis syndrome expectancy, resulting in prolonged disease duration.
Progressive polyneuropathy Second, certain NRTIs may have a neurotoxic effect.
Neuropathies associated with opportunistic infections NRTIs have been used in many individuals as part of
Progressive polyradiculopathy (associated with HIV management. DSP attributable to NRTI toxicity
cytomegalovirus) is sometimes referred to antiretroviral toxic neuropa-
Herpes zoster thy19,20 and is sometimes considered as a different
pathology than HIV-related DSP. DSP associated
2560_Chapter 27_0331-0346.indd 332 3/16/2015 4:14:30 PM

Process CyanProcess
YellowProcess Black
Chapter 27 | Peripheral Neuropathies in Individuals With HIV Disease 333
with neurotoxic antiretroviral drugs can occur in 21% DSP in HIV disease is a matter of ongoing investiga-
of individuals receiving dideoxynucleosides as part of tion. In general, early initiation of HAART therapy
their HAART regimen.21 These two factors (long-term may reduce the risk of developing DSP24 because it
survival and use of potentially neurotoxic drugs) often reduces viral load and minimizes long-term exposure
exist concurrently and help explain why the incidence to the virus. Small-fiber dysfunction of peripheral
of peripheral neuropathy is still a major concern in the nerves sometimes precedes clinical manifestations of
management of patients with HIV disease. Although DSP.25 Although DSP symptoms first occur in the
disease progression and host factors are associated with distal extremities, peripheral sensitization, central sen-
increased risk of developing DSP, these same factors sitization, and chronic pain emerge as the disease
may predispose some individuals to the neurotoxic progresses.22
effects of certain HAART medications.5 It is widely believed that peripheral nerves are not
The most disabling component of DSP is pain, which directly infected, and such a mechanism is not the
may be either spontaneous or evoked.22 Neuropathic cause of DSP.3,7 However, HIV replication does occur
pain accounts for 25% to 50% of all pain-related clinic in macrophages and supporting cells of the dorsal root
visits by patients with HIV disease.23 Clinically, the signs ganglion (DRG), nerve roots, and peripheral nerves.25
and symptoms of DSP are similar regardless of whether A relatively direct mechanism is proposed to exist.
the pathology is related to HIV disease or NRTI toxic- Nerve cell exposure to an HIV envelope protein, gp120,
ity. Symptoms include bilateral pain, burning, numbness, may have a neurotoxic effect and is associated with
paresthesias, allodynia, and leg cramping (Box 27-2). allodynia and hyperalgesia.5 Possible Schwann cell–
Pain may not have a stimulus (i.e., it may occur sponta- mediated neurotoxicity from gp120 has been
neously), or it may have a stimulus, with a lowered described.10 The binding of gp120 glycoproteins to
threshold to noxious stimuli and allodynia.9 receptors on Schwann cell membranes causes release
Weakness in intrinsic muscles of the foot may be of RANTES (regulated upon activation, normal T-cell
seen in severe cases.10,18 As disease progresses, sleep expressed, and secreted). Chemokine ligand 5 (CCL5)
disturbances and difficulties with activities of daily is a protein that is encoded by a5 gene and then binds
living may emerge.9 Symptoms usually occur in lower to receptors on sensory neurons and induces a tumor
extremities first, with involvement of upper extremities necrosis factor alpha–mediated axonal degeneration
in later stages.18 and apoptotic cell death.20 The gp120 glycoproteins can
also bind directly to receptors on sensory nerves and
the DRG,26 disturbing the regulation of intercellular
Pathophysiology and Risk Factors calcium and inducing upregulation of other proinflam-
matory cytokines.27 Other toxic HIV accessory pro-
The pathogenesis of DSP is likely multifactorial, teins, such as viral protein R (Vpr), also play a role in
although the precise mechanisms are not well under- causing peripheral nervous system injury.28
stood.5 Understanding of the mechanisms that lead to Indirect, or parainfectious, mechanisms associated
with chronic infection and inflammation are also
believed to play a key role in the development of DSP,
BOX 27-2 via a cascade of events associated with neuroimmune
activation.29 DSP may be due to indirect damage from
Signs and Symptoms of HIV-Related Distal Sensory products of immune activation after HIV infection.30
Polyneuropathy These events lead to myelin and axon damage in
peripheral nerves, loss of unmyelinated fibers, and mac-
Sensory disturbances (paresthesias, numbness; rophage infiltration in peripheral nerve and DRG.9,31
stocking/glove distribution)
Macrophages are possibly drawn to peripheral nerves
Impaired sensation (vibration, pain, light touch, as a result of nutritional deficiencies and axonal damage
temperature; stocking/glove distribution)
from infectious agents.32 Injured nerves demonstrate
Pain (burning; stocking/glove distribution) adverse excitability changes and can evoke spontaneous
Decreased deep tendon reflexes (Achilles) peripheral ectopic activity leading to spontaneous sen-
Allodynia sations such as burning.9 Neural tissue may be injured
Hyperalgesia as a result of the presence perivascular macrophages,
Leg cramping satellite cells, Langerhans cells, and proinflammatory
Weakness in intrinsic muscles (in advanced cases) cytokines (e.g., tumor necrosis factor alpha, interferon
Sleep disturbances gamma, interleukin-1 and interleukin-6) with resident
Difficulty with activities of daily living macrophages in nerve and adjacent to nerve mediating
Gait dysfunction the damage.9,10,23,30
Impaired balance
The axonal damage/degeneration, or “dying back,”
of primary afferent fibers occurs in multiple peripheral
2560_Chapter 27_0331-0346.indd 333 3/16/2015 4:14:30 PM

Process CyanProcess
YellowProcess Black
nerves. The first fibers affected are small myelinated Another possible contributing mechanism to DSP
and unmyelinated fibers of nociceptive axons,5,10,27 with in individuals with HIV disease is side effects of
larger fibers affected as the disease progresses.9 In the NRTIs, especially “d-drugs” (dideoxynucleoside reverse
DRG, the Nageotte nodules that appear are cellular transcriptase inhibitors) such as didanosine (ddI), zal-
proliferations, consisting mostly of lymphocytes and citabine, dideoxycytidine (ddC), and stavudine (d4T).
activated macrophages.22 Several possible relationships Peripheral neuropathy associated with these drugs is
may exist between the DRG and peripheral nerve known as antiretroviral toxic neuropathy; it is clinically
fibers. Disturbed function of the DRG leads to axon indistinguishable from HIV-related DSP.22,35 Neuro-
damage/degeneration (dying-back phenomenon) and toxic effects of d-drugs are estimated to occur in 15%
spinal cord changes characterized by degeneration of to 30% of patients who receive them.5 Antiretroviral
the gracile tracts.27 Conversely, axonal damage can lead toxic neuropathy appears to be dose dependent, with
to changes in DRG. In addition, some patients with ddC having the greatest neurotoxic potential.23 Use of
HIV have antisulfatide antibodies to myelin glycolip- multiple “d-drugs” may have a synergistic neurotoxic
ids.33 There is also evidence that elevated levels of effect.8 In antiretroviral toxic neuropathy, interference
inflammatory cytokines that occur with HIV infection with nerve DNA synthesis and mitochondrial dysfunc-
can injure mitochondria in muscle and nerve, interfer- tion are believed to be causal factors.10,31,38 These drugs
ing with normal metabolic processes and function of may interfere with mitochondrial gamma DNA poly-
these tissues.34 merase, leading to impairment of mitochondrial DNA
Peripheral and central sensitization occurs via synthesis, mDNA depletion, disruption of cristae, and
numerous mechanisms. The production of cytokines, interference with mitochondrial function.39,40 Individ-
chemokines, and surface antigens and upregulation of uals with mitochondrial haplotype T have a greater risk
membrane channels in injured nerve and DRG leads to for developing DSP.41 The adverse effects of d-drugs
spontaneous discharge and lower activation thresholds. on mitochondrial function may increase serum lactate
In addition, the multifocal inflammation and products concentrations and pose an increased risk of lactic aci-
of macrophage activation result in abnormal spontane- dosis and other disorders such as myopathy.34,35 There
ous activity of neighboring uninjured nociceptive fibers is conflicting evidence as to whether the use of d-drugs
(peripheral centralization).35 Neuron degeneration and depletes levels of acetyl-L-carnitine, but it is known
macrophage and lymphocyte activation also occur in that depletion of carnitine disrupts mitochondrial
the DRG5 and centrally directed extensions of sensory metabolism.41,42
neurons.27 The sprouting of sympathetic axons around Differentiation between HIV-related DSP and neu-
cell bodies also leads to an exaggerated response to rotoxic neuropathy is challenging; the temporal asso-
discharges. The alterations in neuronal sodium and ciation between the onset of DSP symptoms and the
calcium channel expression in DRG (that contribute initiation of HAART treatment that includes NRTIs
to ectopic impulse generation/hyperexcitability) cause may be helpful.18,35 For example, rapid onset of DSP
central remodeling within the dorsal horn, owing to symptoms after initiation of NRTIs or clinical improve-
A-fiber sprouting and synaptic formation with pain ment in DSP symptoms after cessation of NRTI use
fibers in lamina II.35,36 Second-order neurons in spinal may incriminate NRTIs as a causal factor.3 Some
cord fire spontaneously secondary to activation of patients demonstrate a transient “coasting effect” (i.e.,
N-methyl-D-aspartate receptors and subsequent down- a temporary worsening of DSP symptoms) after ces-
regulation of gamma-aminobutyric acid receptors.23 sation of NRTI; this finding also incriminates NRTIs
Secondary hyperalgesia, originating in dorsal root as a causal factor. Assessment of blood lactate levels
ganglia and second-order neurons in the dorsal horn, (indicative of mitochondrial dysfunction) or serum
extends up to brainstem, cortex, periaqueductal gray acetyl-L-carnitine levels may be helpful in determining
and rostral ventromedial medulla,37 ultimately affecting if DSP in HIV-infected individuals is due to the HIV
ascending and descending pathways. Increased sub- itself or a side effect of medications because elevated
stance P enhances excitation of spinal interneurons.23 serum lactate levels have been found in patients with
The perception of pain is facilitated and the analgesia DSP prescribed d4T,1 and decreased levels of acetyl-L-
is inhibited as the spinal cord and brain become sen- carnitine have been noted in some studies.11 Toxic neu-
sitized.9 The perpetuation of the cascade of inflam- ropathy risk related to d-drugs is magnified in the
matory events, leading to changes in ascending and presence of a high HIV viral load; combination use of
descending neural pathways involving the spinal cord d-drugs in patients with advanced disease; hydroxy-
and brain, is an important mechanism in the develop- urea; older age; malnutrition; anemia; or presence of
ment of chronic pain.9,38 These central changes may neuropathies from other causes such as alcoholism,
play a role in the propagation of chronic pain secondary vitamin B12 deficiency, or diabetes.3 Although many
to changes in pain processing capabilities or increased studies found that use of d-drugs may cause or exac-
sensitivity of sensory nerves. Such spinal cord changes erbate neuropathy, some studies reported that use of
may contribute further to axonal degeneration.35 d-drugs did not increase the risk for development of
2560_Chapter 27_0331-0346.indd 334 3/16/2015 4:14:30 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
11,43,44
neuropathy. Nonetheless, cases of neuropathy BOX 27-3
related to d-drug toxicity have been reported. There is
evidence that HIV-positive patients with certain mito- Risk Factors for Distal Sensory Polyneuropathy in Patients
chondrial haplotypes have a higher risk of d-drug neu-
rotoxic neuropathy,41 but precise mechanisms explaining With HIV/AIDS
variance in susceptibility to developing d-drug–related Older age
neuropathy are unclear. The use of d-drugs has been Nucleoside reverse transcriptase inhibitors (in particular,
reduced in recent years because of the availability of “d-drugs”)
comparably effective and less toxic agents. Severity of HIV disease (high viral load and low CD4
Protease inhibitors, such as indinavir, saquinavir, and counts in pre-HAART era or in untreated individuals)
ritonavir, have also been associated with neuropathy2,10 Diabetes
because of their neurotoxic properties and inhibition Elevated triglycerides
of mDNA polymerase.42,44 However, in a multivariate Autoimmune diseases
analysis that included other risk factors, neither the Renal, liver, or thyroid impairment or disease
duration of protease inhibitor use nor exposure to
Abnormal serum hemoglobin or albumin levels
individual protease inhibitor drugs was associated
with DSP.38 Poor nutrition
Generally, long-term survival (and chronicity of the Weight loss
disease) goes hand in hand with HAART. Long-term Vitamin B12 or thiamine deficiency
survival is attributable to successful management of Alcohol consumption, dependency/abuse
HIV disease with HAART. The emergence of DSP in Other neurological abnormalities/diseases
long-term survivors is potentially related to a com- Medications with neurotoxic side effects
bined effect or interaction between chronic HIV infec- Opiate or methamphetamine abuse
tion and neurotoxic effects of some drugs. Long-term Co-infection with hepatitis C (conflicting evidence, but
HIV infection coupled with long-term use of HAART hepatitis C neuropathy manifests with similar signs and
may make some patients especially vulnerable to DSP. symptoms)
The risk of development of DSP in a patient with Protease inhibitors (unclear; risk is likely small)
HIV disease may also include a history of very low
HAART, Highly active antiretroviral therapy.
CD4 counts or high viral loads, although the evidence
for this is conflicting. Some studies have reported HIV
disease severity (in particular, CD4+ cells counts <50
cells/mm3 and viral load >10,000 copies/mL) is a toxins, co-infection with hepatitis C or syphilis,
predictor of increased risk for DSP,24,32,45 although impaired glucose tolerance, weight loss, abnormal
findings of other studies had disputed this.11 The dis- serum hemoglobin and albumin levels, renal or liver
crepancies may be related to the timing and use of impairment, thyroid dysfunction, other neurological
HAART: Subjects from the pre-HAART era showed abnormalities, alcohol abuse, and opiate or metham-
correlations between HIV disease severity and DSP, phetamine abuse.7,10,11,19,24,32,38,39,44,46–51 Box 27-3 sum-
whereas correlations in subjects in the current HAART marizes risk factors associated with the development
era are not evident.5,11,44 In general, it is believed that of DSP in patients with HIV disease.
DSP risk is greater with worse disease severity or
delayed initiation of HAART.32
Drugs other than antiretrovirals are sometimes used Diagnosis
to treat comorbidities or infections and may have neu-
rotoxic effects.23 For example, isoniazid, used to treat Clinically, it is difficult to distinguish between DSP
tuberculosis, may have neurotoxic effects. Vitamin B6 associated with HIV disease and NRTI toxicity neu-
(pyridoxine) may be used in conjunction to mitigate ropathy because the symptoms are similar.18 Distin-
the neurotoxic effects of isoniazid, but excessively high guishing between these two causal factors was described
doses of vitamin B6 (>200 mg/day) may produce a in the prior section. Although DSP is the most common
neurotoxic effect. Metronidazole, an antibiotic used in form of neuropathy in patients with HIV disease, it is
treatment of Clostridium difficile may have neurotoxic important to make a sound differential diagnosis.
effects. A complete medical history and list of medica- Other forms of neuropathy, such as uremic neuropathy,
tions are important in determining if exposure to diabetic neuropathy, toxic neuropathy, alcoholic neu-
certain medications may be factors in patients with ropathy, or vitamin B12 deficiency–associated neuropa-
HIV disease and DSP. thy, need to be ruled out or treated accordingly if
Other risk factors for DSP in general include present. Other forms of HIV-related neuropathies may
advancing age, poor nutrition, diabetes, other autoim- exist. HIV-related neuropathies other than DSP are
mune diseases, malignancy, exposure to environmental described later in this chapter.
2560_Chapter 27_0331-0346.indd 335 3/16/2015 4:14:30 PM

Process CyanProcess
YellowProcess Black
DSP is primarily a clinical diagnosis based on sub- nerve conduction velocity results, and quantitative
jective complaints of bilateral pain, burning (dysesthe- sensory testing.55 However, Evans et al.56 found that a
sia), numbness, and paresthesias in a stocking/glove model including only assessment of pain sensitivity,
distribution (because all peripheral nerves are involved) tendon reflexes, and quantitative sensory testing had
that begins distally and creeps proximally over time.10,18 85% sensitivity and 80% specificity. They found that
Symptoms typically appear first in the lower extremi- the addition of nerve conduction velocity or epidermal
ties, and walking or applying pressure to the feet (e.g., nerve fiber density testing did not add significant diag-
with socks or bed sheets) may aggravate symptoms.9 nostic value. Robinson-Papp et al.57 reported that
Hyperesthesia (increase in contact sensitivity) may HIV-infected patients presenting with distal lower
become so severe that the patient cannot tolerate extremity neurological symptoms usually have objec-
wearing shoes or socks.23 Pain symptoms often increase tive evidence of sensory neuropathy on neurological
in the evening.22 The patient’s gait pattern may be examination or nerve conduction velocity testing, but
antalgic secondary to pain with weight bearing. Pain subjective complaints had only 52% sensitivity for
may or may not depend on a stimulus, and allodynia detecting the presence of sensory abnormality.
(painful sensation evoked by nonpainful stimuli) may Nerve conduction velocity and electromyography
be present. Pain scales, such as visual analog, numerical, (EMG) can be used to help diagnose DSP; however,
or Wong-Baker scales, should be used on an ongoing these electrodiagnostic tests have low sensitivity
basis to document the level of perceived pain. As a because DSP primarily involves small fibers. When
measure of pain, Simpson et al.11 advocated calculating these tests are positive, findings include decreased or
a 7-day median of pain ratings on a 10-cm visual absent sensory nerve action potentials and other
analog scale or the Gracely pain scale used twice a day, changes in the distal lower extremity that are indicative
separated by 12 hours, for 7 consecutive days. of axonal loss.9,20 The most sensitive finding in patients
Typical physical examination findings include with HIV-related DSP is reduced or absent sural nerve
decreased sensation for temperature, pain (pinprick), sensory potential amplitude.22 In severe cases, abnor-
vibration, and pain sensitivity to cold.10,25 Monofila- mal (decreased) motor conduction, late responses on
ment testing may also show impairment.52 Often pro- nerve conduction velocity, and denervation of distal
prioception is relativity unimpaired.10 Achilles’ jerk muscles on EMG are seen.5,10 The most robust tools to
reflex is absent or diminished.10 In addition, a loss of diagnose DSP might include a combination of subjec-
hair and tightness in skin of the lower leg may be tive symptoms, clinical signs, and electrodiagnostic
observed.10 Although muscle strength is usually pre- study results.
served, patients with severe DSP may exhibit weakness Epidermal skin punch biopsy can be used to help
in toe flexion, extension, or abduction (owing to weak- diagnose or predict DSP. In patients with DSP,
ness in the foot intrinsic); rubor; and pedal edema.2,10 decreased epidermal nerve fiber density is seen,58 and
The Brief Peripheral Neuropathy Screen11,53,54 is a epidermal nerve fiber density assessment has been cor-
validated instrument that includes questions regarding related with clinical and electrophysiological severity
symptoms (pain, aching, burning, paresthesias, or of DSP.59 Skin biopsy may be helpful for early detec-
numbness) in legs or feet, great toe vibration sensation tion before the onset of symptoms and in evaluating
testing with a 128-Hz tuning fork, and ankle deep specific types of neuropathy.31 In asymptomatic
tendon reflex assessment. Ellis et al.54 used this tool to patients, nerve fiber density of less than 11 fibers/mm
diagnose DSP in subjects with a history of advanced is predictive of developing symptomatic DSP within 6
HIV disease if they demonstrated either a mild loss of to 12 months.7 Nerve biopsy, although not commonly
vibratory sensation in both great toes or impaired ankle used as a diagnostic test, would likely show axonal
(Achilles jerk) reflexes (relative to the knee/patellar degeneration and some demyelination, with greater
tendon). The Brief Peripheral Neuropathy Screen had fiber loss in distal fibers (“dying back”); perivascular
a sensitivity of 80% and specificity of 59%. An alterna- infiltration by T lymphocytes and macrophage may
tive version of the screening tool required vibration also be noted.9,20
sensation impairment and decreased reflexes; with
those criteria, sensitivity was considerably worse (49%),
but specificity was much better (88%). Positive findings
of vibration sensation and reflex test, along with sub-
Medical Management and
jective complaints, are highly suggestive of DSP, but Pharmacological Interventions
about half of patients with DSP demonstrate false-
negative findings when only those criteria are applied. Effective treatment of HIV disease with HAART may
A more sensitive instrument with excellent intrarater slow the progression of DSP in some cases or even lead
and interrater reliability is the Total Neuropathy Score. to improvement, provided that the drugs used in the
This instrument includes questions regarding presence HAART regimen do not have a neurotoxic effect.20
of pain, aching, burning, paresthesia, or numbness, Replacement of neurotoxic antiretrovirals with other
2560_Chapter 27_0331-0346.indd 336 3/16/2015 4:14:30 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
retroviral drugs should be considered, if feasible. If such as morphine or fentanyl may be needed for
genotype or phenotype testing of the patient’s viral management of severe pain. When opioids are pre-
strain suggests that other antiretroviral drugs with less scribed, tolerance over time often leads to increased
neurotoxicity would be effective (i.e., the virus strains dosing and physical dependency.18 Patients on long-
are not resistant to other antiretroviral drugs), a change term opioid therapy must also be monitored for
in the combination therapy may be helpful in averting side effects such as constipation and respiratory depres-
further progression of the DSP. However, DSP symp- sion. Techniques such as contracts or agreements
toms may persist or transiently worsen for several between the patient and the physician may be needed
weeks after cessation of neurotoxic antiretroviral to minimize aberrant behaviors such as drug abuse or
medications; this phenomenon is known as the “coast- diversion.
ing effect.”12,60 Patients typically do not return to an Because there are no drugs approved by the U.S.
asymptomatic state even on cessation of NRTIs.20 Food and Drug Administration for treatment of HIV-
Adjustments in HAART regimens used to minimize related DSP, several drugs have been used “off label”
DSP must still provide effective virologic control. If for treatment of symptoms of DSP. Antiepileptic drugs
DSP symptoms persist beyond several weeks after such as pregabalin (Lyrica) or gabapentin (Neurontin)
modification of the HAART regimen and elimination may benefit patients with HIV-related DSP.63,64
or dose reduction of neurotoxic agents, symptoms are Common side effects of pregabalin include dizziness
likely related to HIV-associated neuropathy. For and drowsiness, although these side effects may be
patients suspected to have an antiretroviral neurotoxic minimized by reducing the dosage of the drug.10 Gaba-
cause of neuropathy, carnitine supplementation may be pentin, an older drug with similar metabolic pathway,
helpful.61 mechanism of action, and common effects as pregaba-
Reversible causes of DSP should be addressed. For lin, has also been used in patients with HIV DSP.10
example, effective medical management of diabetes, Gabapentin and lamotrigine were found to be more
recovery from alcoholism, or supplementation for effective than placebo in reducing pain or sleep inter-
nutritional vitamin (vitamin B12 or thiamine) deficien- ference in several trials.63,65 Other antiepileptic drugs
cies would be needed if any of those potential causal that are less commonly used for HIV-related DSP
factors exist. Effective management of such conditions include phenytoin, carbamazepine, lamotrigine, and
may be beneficial in mitigating the progression of DSP. valproate. In general, antiepileptic drugs need to be
However, there is no known cure or effective reversal prescribed and monitored carefully because of risk of
of DSP.10 renal or hepatic stress or interactions with protease
Because direct treatments of DSP are lacking, phar- inhibitors.66
macological treatment of DSP is geared toward Antidepressant drugs, including tricyclic antide-
symptom management (i.e., controlling pain, burning, pressants (TCAs) and selective serotonin reuptake
and paresthesias), preservation of physical function, inhibitors (SSRIs), are also used “off label” in the treat-
and enhancement of quality of life. Palliative therapy ment of HIV-related DSP. Antidepressants impart an
for persistent or worsening symptoms of DSP is often analgesic effect, most likely secondary to enhancement
needed, albeit it is sometimes underused because of of central descending pain inhibition pathways.10
concerns over addiction or dependency, patient reluc- Common TCAs such as amitriptyline and nortripty-
tance to report pain, or inefficiencies in the health care line have been available for treatment of depression for
system. Neuropathic pain is often underrecognized and decades. Common side effects include, but are not
undertreated.3,62 Breitbart et al.62 reported that greater limited to, sedation, confusion, orthostatic hypoten-
than 80% of patients with HIV disease–related pain sion, urinary retention, dry mouth, blurred vision, and
were receiving inadequate analgesia. Despite numerous cardiac arrhythmia.66 Common SSRIs include dulox-
pharmacological options, drugs used to manage neuro- etine (Cymbalta), escitalopram (Lexapro), and sertra-
pathic pain in patients with HIV disease do not fully line (Zoloft). Common side effects of SSRIs include,
ameliorate the pain. Rather, they are used to help but are not limited to, apathy, nausea, drowsiness,
control pain to, it is hoped, a tolerable level. Mono- insomnia, vivid dreams, headache, bruxism, and tinni-
therapy generally reduced pain only by 30% to 50%, tus. Prescription and dosing of antidepressant drugs in
whereas polypharmacy using different drugs with dif- patients the HIV-related DSP must be carefully
ferent mechanisms of action may be more effective.3 administered and monitored, not only to determine
For mild symptoms of DSP, nonopioid analgesics such effectiveness in management of DSP symptoms but
as acetaminophen or NSAIDs such as ibuprofen may also because of the possibility of less common but more
be used. For more chronic, moderate to severe pain, serious side effects and the potential for drug interac-
prescription of long-acting opioids such as oxycodone tions with other medications that the patient may be
or methadone or transdermal fentanyl, with additional taking. For example, certain TCAs and SSRIs are
shorter acting agents (e.g., codeine or hydrocodone) for metabolized in the liver and have potential interactions
breakthrough pain, may be needed. Stronger opioids with antiretroviral drugs that are metabolized along the
2560_Chapter 27_0331-0346.indd 337 3/16/2015 4:14:30 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
same pathway.10 When used to manage symptoms of and recombinant human nerve growth factor, but not
HIV-related DSP, antidepressants may be concurrently with amitriptyline, gabapentin, pregabalin, prosaptide,
used to manage depression in these same patients. peptide T, acetyl-L-carnitine, mexiletine, or lamotri-
Referral to a psychiatrist is often indicated. gine. Cognitive-behavior therapy or supportive psy-
Topical medications, typically delivered via a cream chotherapy has been shown to have a beneficial effect
or patch, may also be used in the treatment of DSP. on pain in patients with HIV-related peripheral neu-
Topical applications are attractive because the potential ropathy, but feasibility and acceptability may be an
for side effects and drug interactions is minimized issue for some patients.71
compared with orally administered drugs. Specific
topical agents include lidocaine and high-concentration
capsaicin. In general, their effectiveness has not been Physical Therapy Interventions
well established.18 Simpson et al.67 reported significant
reductions in pain for up to 12 weeks after a one-time There is a paucity of literature regarding effective phys-
dose of a high-concentration capsaicin patch. ical therapy interventions for patients who have HIV-
Depending on the individual patient’s needs and related DSP. Two case reports described favorable
responsiveness to pharmacological therapies, analge- outcomes in pain and function using an impairment-
sics, antiepileptics, antidepressants, and topical agents based approach and microcurrent electrical stimula-
may be used in combination for management of symp- tion.72 In a patient with HIV-related DSP, a thorough
toms associated with DSP, with the therapeutic goal of physical therapy examination is recommended to
sustained analgesia. Multiple drugs from several classes determine the nature and magnitude of any impair-
are commonly used to achieve adequate analgesia, ments that may exist. Although DSP is generally con-
although controlled studies to confirm efficacy are sidered a progressive disease, some impairments may
lacking.5 Even with successful long-term analgesia, be reversible. A comprehensive physical therapy
some individuals experience episodes of transient program can potentially yield positive results in an
breakthrough pain, and short-term use of opioids such individual patient. Table 27-1 lists potential impair-
as oxycodone with acetaminophen (Percocet) or fen- ments and proposed physical therapy interventions.
tanyl may be prescribed to help manage breakthrough Because patients with neuropathic foot pain may
pain.10 Any prescription of opioids must be carefully self-limit their weight-bearing activities to avoid pain,
administered and monitored because of the risk of it is quite plausible that impairments associated with
addiction and physical dependency, especially in reduced activity, such as heel cord tightness and ankle/
patients with a prior history of recreational drug use or foot hypomobility, may exist. Manual therapy proce-
addiction issues. dures and exercises should be used to address any spe-
Medical cannabis (marijuana) may be beneficial for cific impairments in soft tissue and joint mobility that
HIV-related neuropathy. Smoked cannabis combined are identified on examination. Examination should also
with analgesic therapy was found to be effective in include assessment of balance. The Dynamic Gait
controlling refractory pain in patients with HIV- Index, or other commonly used balance assessment
associated DSP.68–70 In addition, medical cannabis may tests such the Romberg balance test or standing on one
be helpful in treatment of nausea, stimulation of appe- leg with eyes open or eyes closed, can be used for this
tite, management of anxiety, and management of purpose. If balance impairments are identified, the
depression.69 One drawback is that marijuana use has physical therapy program should include balance exer-
a negative impact on adherence to HAART.71 Medical cises and activities. Although muscle weakness does
cannabis is available by prescription in a limited number not appear in early stages of DSP, in advanced stages,
of states in the United States. Criticisms of medical strengthening exercises, particularly for intrinsic mus-
cannabis include the potential side effect of altered culature of the foot, may be indicated.10
memory-related brain function and the common Physical therapy modalities and patient education
method of delivery via smoking. Smoking comes with can be an effective adjunct to comprehensive pain
its own set of risks, including potential for abuse. management. Such interventions should be adminis-
However, vaporizers, pill forms (dronabinol [Marinol]), tered with knowledge of the patient’s current medical
and edible forms are also available. Individuals consid- and pharmacological treatment of pain, and commu-
ering the use of medical cannabis for treatment of DSP nication with the patient’s physician is important for
should ascertain the legality of possession and use of coordinated care. The patient may need lifestyle modi-
this substance in their state of residence. fications or adjustments in activities of daily living,
Other pharmaceuticals are also under investigation. such as avoidance of long periods of walking or stand-
A 2010 systematic review and meta-analysis of ran- ing in unsupportive footwear or avoiding restrictive or
domized controlled trials of pharmacological treatment tight-fitting shoes. Common recommendations for
of HIV-related DSP found greater efficacy than self-treatment of pain include warm soaks, rest, exer-
placebo with smoked cannabis, topical capsaicin (8%), cise, elevation, and massage of feet, depending on
2560_Chapter 27_0331-0346.indd 338 3/16/2015 4:14:30 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Table 27-1 Possible Impairments in Patients With HIV-Related Distal Sensory Polyneuropathy and Proposed Physical
Therapy Interventions
Impairments That May Exist in Patients With HIV-Related Distal Proposed Physical Therapy Interventions
Sensory Polyneuropathy
Pain; sensory changes • Trial of electrical stimulation (various forms)
• Patient education in self-management techniques (heat, ice massage,
rest, elevation, exercise)
• ROM exercises
• Neural mobilization/gliding exercises
• Massage
• Lower extremity night splint
Hypersensitivity or allodynia • Desensitization (e.g., brushing skin with terrycloth towel after a
warm soak)
Heel cord tightness or other impairments in flexibility • Soft tissue mobilization
• Stretching exercises
Joint hypomobility (talocrural, subtalar, mid-tarsal, • Joint mobilization/manipulation
tarsal-metatarsal, intertarsal, metatarsophalangeal) • ROM exercises and activities
Excessive pronation; compromised dynamic arch • Taping
support associated with intrinsic muscle weakness • Arch supports
• Orthoses
Weakness • Strengthening exercises
• Functional activities
Balance impairments • Balance exercises and activities
Impaired endurance • Reconditioning exercises (with consideration of patient tolerance for
weight bearing)
Gait dysfunction • Address soft tissue, joint, and biomechanical issues that may be
affecting gait
• Gait training
• Assistive device use (if needed)
Impaired function or activities of daily living • Functional training
• Activity modification as needed
ROM, Range of motion.
patient preferences.2 A pilot study73 reported the individual patient after a particular form of stimulation,
effects of use of a lower extremity night splint in ongoing treatment with a home electrical stimulation
patients with HIV disease and painful peripheral neu- unit should be considered. There is evidence in the
ropathy. After 3 weeks of nightly use, splint wearers literature that transcutaneous electrical stimulation or
had significantly less pain and an improved sleep index high-frequency muscle stimulation is effective in
score compared with a control group. The authors pro- reducing pain in patients with diabetic peripheral
posed that the improvements in sleep quality may neuropathy.74–76 However, differences in pathophysiol-
prove beneficial breaking the vicious cycle of inter- ogy of HIV-related peripheral neuropathy and diabetic
rupted sleep and nocturnal pain, possibly enhancing peripheral neuropathy suggest caution should be used
the patient’s quality of life. when applying results of outcomes studies performed
Gale74 reported favorable outcomes with microcur- on patients with diabetic peripheral neuropathy to
rent electrical stimulation in two cases, and Galantino patients with HIV-related neuropathy. Several studies
et al.72 reported improvement in functional activities have reported the effects of monochromatic infrared
and decreased muscle response latency after treatment photoenergy (MIRE) therapy on patients with diabetic
with electroacupuncture. Randomized controlled trials peripheral neuropathy. To date, the outcomes of these
on effectiveness of electrotherapeutic and other modal- reports have provided conflicting evidence regarding
ities in patients with HIV disease and DSP have not the effectiveness of MIRE therapy on pain and sensi-
been published. A trial of various forms of electrical tivity.77 No published studies have reported on the
stimulation is recommended in an individual patient. effectiveness of MIRE therapy in patients with HIV-
If a clinically meaningful decrease in pain occurs in an related peripheral neuropathy.
2560_Chapter 27_0331-0346.indd 339 3/16/2015 4:14:30 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
period of individual acupuncture therapy delivered in
Pain Management Integrative a group setting.83 When needles are unavailable, the
Modalities: Acupuncture, Mind- use of electroacupuncture is another option for patients
as they are instructed in the proper placement of elec-
Body Therapy, and Supplements trodes over specific acupuncture points. In one pilot
study, low-voltage noninvasive electroacupuncture was
Use of complementary and alternative medicine administered with skin electrodes over leg points BL60,
(CAM) is prevalent among HIV-positive individuals ST36, K1, and LIV3 for 20 minutes every day for 30
despite the success of antiretroviral treatments and days. Significant findings in the MOS-HIV 30-item
limited evidence of the safety and efficacy of CAM.2,78,79 quality-of-life instrument and H-reflex parameters
A systematic review of 40 studies of CAM use among were noted and support the use of low-voltage elec-
HIV-positive people was conducted in 2008.79 Find- troacupuncture to improve DSP.84 Further clinical
ings confirmed that 60% of HIV-positive individuals trials of acupuncture with improved methodological
report CAM use, and it is more common among indi- quality are needed to determine dose, duration, and
viduals who are men who have sex with men, nonmi- mode of administration of acupoints for HIV DSP
nority, better educated, and less impoverished. Other pain management.
research found that former drug use, visits to a mental When balance and strength impairments arise as a
health professional, and a college education are factors result of HIV-related neurological underpinning, the
associated with higher likelihood of CAM use.78 In use of yoga and tai chi chuan may play a role in
2005, a systematic review of randomized clinical trials the rehabilitation process. Tai chi chuan has been
assessing the effectiveness of complementary therapies shown to have an impact on function, quality of life,
for HIV and HIV-related symptoms found 30 trials and psychosocial variables in individuals living in
(between 1989 and 2003) that met predefined inclu- various stages of HIV/AIDS.85–87 A review summa-
sion and exclusion criteria; most trials were small and rized research on the physical and psychological ben-
of limited methodological rigor.78,79 efits of tai chi chuan and found improved balance and
The use of CAM is associated with longer disease muscular strength as well as improved sleep and atten-
duration and greater severity of HIV symptoms. HIV- tiveness and reduced anxiety.
positive users of CAM report that they use these Stress management may prove to be an effective way
modalities to prevent or alleviate HIV-related symp- to reduce pain and increase quality of life in individuals
toms, reduce treatment side effects, and improve quality with HIV/AIDS.88 Mindfulness-based stress reduc-
of life. Findings regarding the association between tion (MBSR) for stress management in people living
CAM use, psychosocial adjustment, and adherence to with HIV/AIDS is a behavioral intervention that prac-
conventional HIV medications are mixed.78,79 Although tices insight-oriented (or mindfulness) meditation.
the reviewed studies are instrumental in describing the Although research is limited, MBSR may be effective
characteristics of HIV-positive CAM users, the litera- in the management of stress and anxiety for HIV-
ture lacks a conceptual framework to identify causal positive patients, as it has been with many other disease
factors involved in the decision to use CAM or explain conditions.89 Massage also has been shown to have
implications of CAM use for conventional HIV care.79 similar benefits on the immune system as the MBSR
Because of the long-term and often worsening symp- approach. Massage may lower stress levels by reducing
toms of DSP, patients often seek use of CAM inter- cortisol levels, which increases CD4 and CD8 cells and
ventions to promote analgesia. improves the general function of the immune system.90
Acupuncture has been shown in many studies to be A widening body of research indicates alternative
effective for reducing pain related to a variety of dif- supplements may be beneficial for HIV-related pain.
ferent medical conditions, as noted by the National Alpha lipoic acid, acetyl-L-carnitine, benfotiamine,
Institutes of Health.80 A clinical trial in the Journal of methylcobalamin, and topical capsaicin are among the
the American Medical Association81 reporting use of acu- most well-researched alternative options for the treat-
puncture and amitriptyline in HIV-infected patients ment of DSP.91 Other potential nutrient or botanical
concluded that there was no effect for either acupunc- therapies include vitamin E, glutathione, folate, pyri-
ture or amitriptyline on neuropathic pain compared doxine, biotin, myo-inositol, omega-3 and omega-6
with placebo. However, in a reanalysis of the data, fatty acids, L-arginine, L-glutamine, taurine, N-
acupuncture was effective in reducing attrition and acetylcysteine, zinc, magnesium, chromium, and St.
mortality in this sample, especially when health status John’s wort.92,93 Although some CAM therapies have
was taken into account, but results for pain relief were been shown to increase the quality of life of HIV-
mixed.82 In another study, the effect of acupuncture positive patients, other therapies have been shown to
treatment comprising 5 weeks of 10 sessions of 30 to be detrimental.94 Nutritional supplements and herbal
45 minutes in a group setting on DSP found subjective remedies must be used with caution because some
pain and symptoms of DSP were reduced during the over-the-counter nutritional supplements may interact
2560_Chapter 27_0331-0346.indd 340 3/16/2015 4:14:30 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
10
with drugs used in HAART. For example, St. John’s and erectile dysfunction (in men). The proposed eti-
wort, an herbal supplement used to improve mood, is ology of autonomic neuropathy includes an autoim-
known to interact adversely (owing to similar meta- mune response or direct HIV infection of autonomic
bolic pathways) with certain protease inhibitors and nervous system structures.10 Medical management of
nonnucleoside reverse transcriptase inhibitors that are the effects of autonomic neuropathy is often needed.
commonly used in HAART. Patients should be advised
to disclose and discuss use of any nutritional or herbal Inflammatory Demyelinating Neuropathies
supplements with their infectious disease physician. Acute inflammatory demyelinating polyneuropathy
Health care professionals need to be aware of the ben- (AIDP), a condition very similar to Guillain-Barré
efits and risks of herbal and nutritional supplements syndrome, may occur (albeit rarely) during the period
so that patients are properly informed and safety is of seroconversion and high CD4 counts (typically
ensured. a few weeks after acute infection with HIV). This
Decisions about using CAM in conjunction with immune-mediated disorder may also occur in patients
HAART therapy are often poorly informed. Safety with advanced HIV/AIDS and advanced immunosup-
risks and potential drug interactions are frequently pression, especially when the opportunistic infection
ignored because people who use HAART prefer to cytomegalovirus (CMV) is present.3,10,38 AIDP, pri-
focus on the physical and mental benefits of using marily affecting motor fibers, is associated with demy-
selected CAM therapies to promote their quality of elination and axonal loss mediated by macrophages and
life.95 Researchers used a culture-centered approach to lymphocytic infiltrates.20 On EMG, demyelination and
understand the experiences of people with treatment axon degeneration is evidenced by prolonged distal
options for HIV-related peripheral neuropathy. motor and F-wave latencies, reduced conduction veloc-
Although participants reported that biomedical pills ity, partial conduction blocks, and other abnormalities20
were an important context for understanding decision suggestive of a demyelinating neuropathy. Cerebrospi-
making regarding neuropathy treatment, they also nal fluid shows high protein content and mild mono-
expressed deep resentment and frustration with bio- nuclear pleocytosis.43 In HIV-positive patients with
medically prescribed pills. Complaints about the pills AIDP, cerebrospinal fluid lymphocytic pleocytosis is a
worked to frame the holistic alternatives of acupunc- common finding; this particular finding does not occur
ture and massage therapy as better options for neu- in HIV-negative individuals with AIDP.20 Nerve
ropathy and to establish a foundation for understanding biopsy shows segmental demyelination with onion
how participants made particular health treatment bulb formations, macrophage activation, mononuclear
decisions. As life expectancy increases, it is important cell infiltration of nerve fascicles, and endoneural
for health professionals to be knowledgeable about the edema.5 Patients with AIDP typically present with a
prevention, assessment, and treatment of HIV symp- rapid onset of progressive weakness, especially in the
toms and treatment side effects of conventional and lower extremities, and absent or diminished deep
CAM treatments. Given the growing trend of using tendon reflexes. Sensory symptoms are minor. Weak-
CAM by the general population, it is also important ness may progress to involve facial and respiratory
to understand the appropriate use of CAM for muscles. Diagnosis is confirmed with nerve conduction
symptom management in HIV/AIDS care. studies, EMG, and lumbar puncture for detection of
cerebrospinal fluid abnormalities. Medical interven-
tions typically include intravenous immunoglobulin or
Other Types of Neuropathy plasmapheresis.10 Corticosteroids are used with caution
in patients with HIV disease because of their immu-
Associated With HIV Disease nosuppressive effect. Recovery, which may be full or
incomplete, typically occurs gradually over 1 to 2 years.
Less common forms of neuropathy occur in patients Chronic demyelinating neuropathy shares many fea-
with HIV disease and are related to the stage of illness tures with AIDP, with a more protracted onset (>8
and the degree of immunodeficiency. Although DSP weeks), periods of remission or relapse, and longer or
is still quite prevalent, the advent of effective HAART incomplete recovery time.20
has led to a decline in many of these neuropathies.95 HIV-associated neuromuscular weakness syndrome,
a clinically similar condition, includes other symptoms,
Autonomic Neuropathy such as nausea, abdominal distention, lipodystrophy,
Autonomic dysfunction, involving sympathetic and and hepatomegaly, and is associated with hyperlactate-
parasympathetic nerve fibers, may be present in patients mia and lactic acidosis syndrome. This condition
with HIV disease. Autonomic neuropathy is more has been associated with treatment of HIV disease
likely in individuals with HIV/AIDS and may include with NRTIs, which are thought to have a toxic effect
symptoms such as hypotension, syncope, cardiac on mitochondria.5,10 This condition is thought to
arrhythmias, anhidrosis, diarrhea, urinary dysfunction, involve interplay between HIV-induced effects and
2560_Chapter 27_0331-0346.indd 341 3/16/2015 4:14:30 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
drug toxicity.3 In some cases, it can lead to severe mor- Lumbar magnetic resonance imaging with contrast
bidity or death.3 enhancement may reveal enhancement of lumbosa-
cral nerve roots.23 Electrophysiological studies show
Mononeuropathies widespread denervation in paraspinal muscles and leg
Mononeuropathy involving one peripheral or cranial muscles.5 Spinal fluid shows polymorphonuclear pleo-
nerve (typically cranial nerve VII or V) or mononeu- cytosis, elevated protein levels, and low glucose. This
ropathy multiplex (involving two or more peripheral or condition requires concurrent management of HIV
cranial nerves) is a rare complication in individuals and CMV. Prompt treatment of CMV with ganciclo-
with HIV disease that may occur in early stages of vir, foscarnet, or cidofovir often results in resolution
HIV disease.10,38,43 Nerve involvement may be asym- of symptoms over several weeks.5 Polyradiculopathies
metrical.23 Mononeuropathies that occur in early stages may also have other causes, such as syphilis, lympho-
of HIV disease are thought to be due to autoimmune matous meningitis, herpesvirus, syphilis, cryptococ-
mechanisms10,23 or vasculitis of peripheral nerves.5,20 cus, tuberculosis, or lymphoma.20,23 Identification of
Treatment may include corticosteroids, intravenous these potential causes and appropriate treatment are
immunoglobulin, or plasmapheresis.10,38 Neuropathies indicated.
may occur around the time of seroconversion, when
antibody production reaches measurable levels (typi- Neuropathies Related to
cally a few weeks after acute infection), and may resolve Opportunistic Infections
spontaneously.20,23 Signs and symptoms include sensory Patients with HIV disease are at greater risk than the
and motor impairments associated with the peripheral general population for herpes zoster (shingles) exacer-
nerves involved. Electrophysiological studies show a bation, which typically causes pain and rash along the
multifocal pattern of reduction in evoked sensory distribution of a dermatome, cranial nerve, or periph-
and motor compound muscle action potential ampli- eral nerve. Although acute flares are often successfully
tudes,5 suggesting axon degeneration. Severe cases may managed with anti–varicella-zoster medication, some
require treatment with corticosteroids, plasmapheresis, individuals may have incomplete resolution, and symp-
or intravenous immunoglobulin.23 When mononeu- toms may persist as a postherpetic neuralgia, resulting
ropathies occur in patients with advanced disease, they in chronic and persisting symptoms.10
may be related to CMV infection, varicella zoster, or
other opportunistic infections, and medical manage-
ment of the opportunistic infection is indicated.3,10,23
CASE STUDY
Neuropathy Associated With Infiltrative ML is a 48-year-old biomechanical engineer who
Lymphomatosis Syndrome learned he was HIV-positive 11 years ago. He had no
Infiltrative lymphomatosis syndrome is an uncommon HIV testing before that and does not know when he
systemic illness caused by hyperlymphomatosis of was initially infected. At the time he was diagnosed,
CD8 lymphocytes, with infiltration into visceral organs his CD4 count was 575 cells/mm3, and viral load
and epineurium and endoneurium of peripheral was 8,000 copies/mL. ML was prescribed HAART 8
nerves.5,20 It typically occurs in the early stages of HIV years ago and has been fully adherent with his
infection.20 Peripheral sensorimotor neuropathies may medications since that time. At the time HAART was
result from infiltration of CD8 cells into axons and initiated, his CD4 count was 350 cells/mm3, and his
is associated with parotidomegaly, sicca syndrome, viral load was 12,000 copies/mL. Currently, his CD4
lymphadenopathy, and splenomegaly. Pain is typically count is 650 cells/mm3, and his viral load is
multifocal and symmetrical,5 although one third of undetectable (<40 copies/mL).
patients have asymmetrical symptoms at onset.1 Cranial Since his diagnosis, ML has remained active. He
nerve involvement may occur, typically in cranial nerve currently runs 2 miles three times a week and takes an
VII. Therapies include HAART and steroid therapy.5,20 occasional yoga class. ML complains of a recent onset
of intermittent numbness and burning-type pain in both
Progressive Polyradiculopathy feet, including all toes. His pain ranges from 2 cm to
Patients with advanced disease and CMV may present 5 cm on a 10-cm visual analog pain scale. Although
with progressive polyradiculopathy, a rare disorder often present at rest or at night, he reports that the pain
affecting the lumbosacral nerve roots that causes a in the plantar surfaces of his feet is worse after running.
subacute onset of low back and lower extremity pain To help manage this pain, he takes NSAIDs after
and paresthesias, lower extremity weakness, and cauda running. As a runner and biomechanical engineer, he
equine syndrome.10,20 Low back pain and leg pain may has done some research on his own and is suspicious
precede sphincter and lower extremity weakness.20 that his long-standing overpronation pattern may now
Rapid progression leads to flaccid paraplegia and, be causing tarsal tunnel syndrome. He comes to the
in some cases, involvement of the upper extremities. physical therapist for advice on management of his
2560_Chapter 27_0331-0346.indd 342 3/16/2015 4:14:30 PM

Process CyanProcess
YellowProcess Black
symptoms and to be evaluated for orthoses. Past Palpation: No pain with passive extension of first
medical history includes mild anxiety, which he metatarsophalangeal joint in standing; no tenderness
manages with meditation and yoga. along plantar fascia or at medial tubercle of
Most recent laboratory values are CD4 count of calcaneus or elsewhere
650 cells/mm3 and viral load undetectable (<40
copies/mL). All other laboratory values are normal. Case Study Questions
ML’s medications include HAART (Atripla) and over-the- 1. What differential diagnoses need to be considered
counter NSAIDs as needed. ML lives with his wife and in this case?
three children in a two-story home with several steps to a. DSP alone
enter the home. His wife and children have been b. Bilateral tarsal tunnel syndrome alone
tested for HIV and are negative. ML is independent in c. DSP and bilateral tarsal tunnel syndrome
all activities of daily living and is working full-time as a d. All of the above
biomedical engineer at a research university. His goals
are to return to running pain-free and achieve relief of 2. Which of the following statements is most true
symptoms. regarding ML’s prognosis if tarsal tunnel syndrome is
Systems review of ML shows the following: diagnosed?
a. The prognosis is poor because tarsal tunnel
Cardiovascular/pulmonary: Heart rate 76 beats/min, syndrome in individuals with HIV/AIDS is a
blood pressure 125/85 mm Hg, respiratory rate 14 progressive disease.
Integumentary: Dry cracked skin along medial b. Tarsal tunnel syndrome tends to be self-limiting and
longitudinal arch gets better without intervention.
Musculoskeletal: Gross strength, range of motion c. Antiretroviral drugs, in addition to their impact on
(ROM), and symmetry within normal limits (WNL) immunosuppression, have a positive effect on
Neuromuscular: Transfers, gait, and gross motor neuropathy regardless of etiology.
function WNL; upper and lower quarter screening d. The prognosis is excellent with appropriate
reveals slight decrease in light touch perception in all physical therapy.
toes (nondermatomal distribution) and sluggish ankle 3. Interventions for DSP include which of the following?
jerk (1+) reflexes bilaterally a. Electrical stimulation
Communication, affect, learning: WNL b. Intrinsic muscle lengthening and strengthening
Tests and measures performed during examination c. Mobilization of mid-tarsal joints that exhibit
show the following: decreased mobility
Posture and alignment (assessed in standing): Forward d. All of the above
head with forward rounded shoulders, decreased
lumbar lordosis, excessive bilateral calcaneal valgus 4. What would be appropriate topics for patient
and pes planus, mild hallux valgus bilaterally education at this time?
Gait: Excessive pronation observed after weight a. ML needs to be informed that his symptoms may
acceptance and at midstance be due to two different problems (i.e., tarsal tunnel
ROM: WNL except for dorsiflexor passive ROM (with syndrome and DSP), and he should be educated
0° knee), which is limited to 5° owing to heel cord regarding the nature and prognosis of these
tightness bilaterally problems.
Manual muscle test: Upper extremity WNL; lower b. ML should be taught to do frequent skin integrity
extremity WNL checks, especially after running, and to change
Balance: 22 (out of 24) on Dynamic Gait Index running shoes periodically.
Sensation (additional testing performed because of c. Discussion of self-management of DSP symptoms is
deficits noted on lower quarter screening): 10g needed.
monofilament testing confirmed decreased light touch d. All of the above
over all toes and decreased light touch sensation 5. Which of the following would be considered an
over dorsal and plantar surfaces of the feet; vibration inappropriate referral for ML?
sensation (128-Hz tuning fork) was diminished in the a. Referral for custom-made orthoses if taping and
same areas over-the-counter orthoses prove helpful but
Proprioception: WNL nonetheless inadequate
Special tests order showed the following: b. Referral to an herbalist for a prescription for St.
Positive lower extremity neural tension test (straight leg John’s wort
raise with dorsiflexion): Provoked pain and c. Referral to a neurologist or pain specialist
paresthesias in the plantar surfaces of the feet d. Referral for EMG and nerve conduction velocity
Positive (bilateral) Tinel test over tarsal tunnel: studies to confirm suspected diagnoses
Reproduced paresthesias along medial arches
2560_Chapter 27_0331-0346.indd 343 3/16/2015 4:14:30 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
22. Verma S, Estanislao L, Mintz L, Simpson D. Controlling
References neuropathic pain in HIV. Curr HIV/AIDS Rep. 2004;1(3):
1. Nicholas PK, Mauceri L, Slate Ciampa A, et al. Distal 136–141.
sensory polyneuropathy in the context of HIV/AIDS. J Assoc 23. Verma S, Estanislao L, Simpson D. HIV-associated
Nurses AIDS Care. 2007;18(4):32–40. neuropathic pain: epidemiology, pathophysiology and
2. Baker WC. HIV-associated neuropathies. Not a necessary management. CNS Drugs. 2002;19(4):325–334.
consequence of HIV infection. Adv Nurse Pract. 2003;11(11): 24. de Freitas MR. Infectious neuropathy. Curr Opin Neurol.
83–86, 89–90. 2007;20(5):548–552.
3. Verma S, Micsa E, Estanislao L, Simpson D. Neuromuscular 25. Martin C, Solders G, Sonnerborg A, Hansson P. Painful and
complications in HIV. Curr Neurol Neurosci Rep. 2004;4(1): non-painful neuropathy in HIV-infected patients: an analysis
62–67. of somatosensory nerve function. Eur J Pain. 2003;7(1):
4. French MA. HIV/AIDS: immune reconstitution 23–31.
inflammatory syndrome: a reappraisal. Clin Infect Dis. 26. Oh SB, Tran PB, Gillard SE, Hurley RW, Hammond DL,
2009;48(1):101–107. Miller RJ. Chemokines and glycoprotein120 produce pain
5. Ferrari S, Vento S, Monaco S, et al. Human immunodeficiency hypersensitivity by directly exciting primary nociceptive
virus-associated peripheral neuropathies. Mayo Clin Proc. neurons. J Neurosci. 2001;21(14):5027–5035.
2006;81(2):213–219. 27. Jones G, Zhu Y, Silva C, et al. Peripheral nerve-derived
6. Gonzalez-Duarte A, Cikurel, K, Simpson DM. Managing HIV-1 is predominantly CCR5-dependent and causes
HIV peripheral neuropathy. Curr HIV/AIDS Rep. 2007;4(3): neuronal degeneration and neuroinflammation. Virology.
114–118. 2005;334(2):178–193.
7. Gonzalez-Duarte A, Robinson-Papp J, Simpson DM. 28. Acharjee S, Noorbakhsh F, Stemkowski PL, et al. HIV-1 viral
Diagnosis and management of HIV-associated neuropathy. protein R causes peripheral nervous system injury associated
Neurol Clin. 2008;26(3):821–832. with in vivo neuropathic pain. FASEB J. 2010;24(11):
8. Luciano CA, Pardo CA, McArthur JC. Recent developments 4343–4353.
in the HIV neuropathies. Curr Opin Neurol. 2003;16(3): 29. Simpson DM. Selected peripheral neuropathies associated
403–409. with human immunodeficiency virus infection and
9. Dorsey SG, Morton PG. HIV peripheral neuropathy: antiretroviral therapy. J Neurovirol. 2002;8(Suppl 2):33–41.
pathophysiology and clinical implications. AACN Clin Issues. 30. Schifitto G, McDermott MP, McArthur JC, et al. Markers of
2006;17(1):30–36. immune activation and viral load in HIV-associated sensory
10. Robinson-Papp J, Simpson DM. Neuromuscular neuropathy. Neurology. 2005;64(5):842–848.
complications of human immunodeficiency virus infection. 31. Pardo CA, McArthur JC, Griffin JW. HIV neuropathy:
Phys Med Rehab Clin N Am. 2008;19(1):81–96. insights in the pathology of HIV peripheral nerve disease.
11. Simpson DM, Kitch D, Evans SR, et al. HIV neuropathy J Peripher Nerv Syst. 2001;6(1):21–27.
natural history cohort study: assessment measures and risk 32. Lichtenstein KA, Armon C, Baron A, Moorman AC, Wood
factors. Neurology. 2006;66(11):1679–1687. KC, Holmberg SD. Modification of the incidence of
12. Wulff EA, Wang AK, Simpson DM. HIV-associated drug-associated symmetrical peripheral neuropathy by host
peripheral neuropathy: epidemiology, pathophysiology and and disease factors in the HIV outpatient study cohort. Clin
treatment. Drugs. 2000;59(6):1251–1260. Infect Dis. 2005;40(1):148–157.
13. Ellis RJ, Rosario D, Clifford DB, et al. Continued high 33. Petratos S, Turnbull VJ, Papadopoulos R, Ayers M, Gonzales
prevalence and adverse clinical impact of human MF. Antibodies against peripheral myelin glycolipids in
immunodeficiency. Arch Neurol. 2010;67:552–558. people with HIV infection. Immunol Cell Biol. 1998;76(6):
14. Fuller G, Jacobs J, Guiloff R. Nature and incidence of 535–541.
peripheral nerve syndromes in HIV infection. J Neurol 34. Moyle G. Mitochondrial toxicity: myths and facts. J HIV
Neurosurg Psychiatry. 1993;56:372–381. Ther. 2004;9(2):45–47.
15. Martin C, Pehrsson P, Osterberg A, Sonnerborg A, Hansson 35. McArthur JC, Brew BJ, Nath A. Neurological complications
P. Pain in ambulatory HIV-infected patients with and of HIV infection. Lancet Neurol. 2005;4(9):543–555.
without intravenous drug use. Eur J Pain. 1999;3: 36. Nagano I, Shapshak P, Yoshioka M, Xin K, Nakamura S,
157–164. Bradley WG. Increased NADPH-diaphorase reactivity and
16. Araujo AP, Nascimento OJ, Garcia OS. Distal sensory cytokine expression in dorsal root ganglia in acquired
polyneuropathy in a cohort of HIV-infected children over immunodeficiency syndrome. J Neurol Sci. 1996;136(1–2):
five years of age. Pediatrics. 2000;106(3):E35. 117–128.
17. Vance DE, Mugavero M, Willig J, Raper JL, Saag MS. Aging 37. Melzack R, Coderre TJ, Katz J, Vaccarino AL.Central
with HIV: a cross-sectional study of comorbidity prevalence neuroplasticity and pathological pain. Ann N Y Acad Sci. 2001;
and clinical characteristics across decades of life. J Assoc Nurses 933:157–174.
AIDS Care. 2011;22(1):17–25. 38. Letendre S, McCutchan JA, Ellis RJ. Highlights of the 15th
18. Nicholas PK, Kemppainen JK, Canaval GE, et al. Symptom Conference on Retroviruses and Opportunistic Infections.
management and self-care for peripheral neuropathy in HIV/ Neurologic complications of HIV disease and their treatment.
AIDS. AIDS Care. 2007;19(2):179–189. Top HIV Med. 2008;16(1):15–22.
19. Ferrari LF, Levine JD. Alcohol consumption enhances 39. Cherry CL, McArthur JC, Hoy JF, Wesselingh SL.
antiretroviral painful peripheral neuropathy by mitochondrial Nucleoside analogues and neuropathy in the era of HAART.
mechanisms. Eur J Neurosci. 2010;32(5):811–818. J Clin Virol. 2003;26(2):195–207.
20. Hoke A, Cornblath DR. Peripheral neuropathies in human 40. Cherry CL, Wesselingh SL. Nucleoside analogues and HIV:
immunodeficiency virus infection. Suppl Clin Neurophysiol. the combined cost to mitochondria. J Antimicrob Chemother.
2004;57:195–210. 2003;51(5):1091–1093.
21. Scarsella A, Coodley G, Shalit P, et al. Stavudine-associated 41. Hulgan T, Haas DW, Haines JL, et al. Mitochondrial
peripheral neuropathy in zidovudine-naive patients: effect of haplogroups and peripheral neuropathy during antiretroviral
stavudine exposure and antiretroviral experience. Adv Ther. therapy: an adult AIDS clinical trials group study. AIDS.
2002;19(1):1–8. 2005;19(13):1341–1349.
2560_Chapter 27_0331-0346.indd 344 3/16/2015 4:14:30 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
42. Simpson DM, Katzenstein D, Haidich B, et al. Plasma 63. Hahn K, Arendt G, Braun JS, et al. A placebo-controlled trial
carnitine in HIV-associated neuropathy. AIDS. 2001;15(16): of gabapentin for painful HIV-associated sensory
2207–2208. neuropathies. J Neurol. 2004;251(10):1260–1266.
43. Moore RD, Wong WM, Keruly JC, McArthur JC. Incidence 64. Rosenstock J, Tuchman M, LaMoreaux L, Sharma U.
of neuropathy in HIV-infected patients on monotherapy Pregabalin for the treatment of painful diabetic peripheral
versus those on combination therapy with didanosine, neuropathy: a double-blind, placebo-controlled trial. Pain.
stavudine and hydroxyurea. AIDS. 2000;14(3):273–278. 2004:110(3):628–638.
44. Schifitto G, McDermott MP, McArthur JC, et al. Incidence 65. Simpson DM, McArthur JC, Olney R, et al. Lamotrigine for
of and risk factors for HIV-associated distal sensory HIV-associated painful sensory neuropathies: a placebo-
polyneuropathy. Neurology. 2002;58(12):1764–1768. controlled trial. Neurology. 2003;60(9):1508–1514.
45. Childs EA, Lyles RH, Selnes OA, et al. Plasma viral load and 66. Lee K, Vivithanaporn P, Siemieniuk RA, et al. Clinical
CD4 lymphocytes predict HIV-associated dementia and outcomes and immune benefits of anti-epileptic drug therapy
sensory neuropathy. Neurology. 1999;52(3):607–613. in HIV/AIDS. BMC Neurol. 2010;10:44.
46. Ances BM, Vaida F, Rosario D, et al. Role of metabolic 67. Simpson DM, Brown S, Tobias J. Controlled trial of
syndrome components in HIV-associated sensory neuropathy. high-concentration capsaicin patch for treatment of painful
AIDS. 2009;23(17):2317–2322. HIV neuropathy. Neurology. 2008;70(24):2305–2313.
47. Banerjee S, McCutchan JA, Ances BM, et al. 68. Cherry CL, Affandi JS, Imran D, et al. Age and height
Hypertriglyceridemia in combination antiretroviral-treated predict neuropathy risk in patients with HIV prescribed
HIV-positive individuals: potential impact on HIV sensory stavudine. Neurology. 2010;73(4):315–320.
polyneuropathy. AIDS. 2006;25(2):F1–6. 69. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful
48. Schifitto G, McDermott MP, McArthur JC, et al. Incidence HIV-associated sensory neuropathy: a randomized placebo-
of and risk factors associated for HIV-associated distal controlled trial. Neurology. 2007;68(7):515–521.
sensory polyneuropathy. Neurology. 2002;58:1764–1768. 70. Corless IB, Lindgren T, Holzemer W, et al. Marijuana
49. Ellis RJ, Marquie-Beck J, Delaney P, et al. Human effectiveness as an HIV self-care strategy. Clin Nurs Res.
immunodeficiency virus protease inhibitors and risk for 2006;18(2):172–193.
peripheral neuropathy. Ann Neurol. 2008;64(5):566–572. 71. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal
50. Estanislao LB, Morgello S, Simpson DM. Peripheral cannabis for neuropathic pain in HIV: a randomized,
neuropathies associated with HIV and hepatitis C crossover clinical trial. Neuropsychopharmacology. 2009;34(3):
co-infection: a review. AIDS. 2005;19(Suppl 3):S135–139. 672–680.
51. Lopez OL, Becker JT, Dew MA, Caldararo R. Risk modifiers 72. Galantino ML, Eke-Okoro ST, Findley TW, Condoluci D.
for peripheral sensory neuropathy in HIV infection/AIDS. Use of noninvasive electroacupuncture for the treatment of
Eur J Neurol. 2004;11(2):97–102. HIV-related peripheral neuropathy: a pilot study. J Altern
52. Cettomai D, Kwasa J, Kendi C, et al. Utility of quantitative Complement Med. 1999;5(2):135–142.
sensory testing and screening tools in identifying HIV- 73. Littlewood RA, Vanable PA. Complementary and alternative
associated peripheral neuropathy in Western Kenya: pilot medicine use among HIV-positive people: research synthesis
testing. PLoS One. 2010;5(12):e14256. and implications for HIV care. AIDS Care. 2008;20(8):
53. Cherry CL, Wesselingh SL, Lal L, McArthur JC. Evaluation 1002–1018.
of a clinical screening tool for HIV-associated sensory 74. Gale J. Physiotherapy intervention in two people with HIV
neuropathies. Neurology. 2005;65(11):1778–1781. or AIDS-related peripheral neuropathy. Physiother Res Intl.
54. Ellis RJ, Evans SR, Clifford DB, et al. Clinical validation of 2003;8(4):200–209.
the NeuroScreen. J Neurovirol. 2005;11(6):503–511. 75. Phillips KD, Skelton WD, Hand GA. Effect of acupuncture
55. Cornblath DR, Chaudhry V, Carter K, et al. Total neuropathy administered in a group setting on pain and subjective
score: validation and reliability study. Neurology. 1999;53(8): peripheral neuropathy in persons with human
1660–1664. immunodeficiency virus disease. J Altern Complement Med.
56. Evans SR, Clifford DB, Kitch DW, et al. Simplification of 2004;10(3):449–455.
the research diagnosis of HIV-associated sensory neuropathy. 76. Hamza MA, White PF, Craig WF, et al. Percutaneous
HIV Clin Trials. 2008;9(6):434–439. electrical nerve stimulation: a novel analgesic therapy for
57. Robinson-Papp J, Morgello S, Vaida F, et al. Association diabetic neuropathic pain. Diabetes Care. 2000;23(3):365–370.
of self-reported painful symptoms with clinical and 77. Harkless LB, DeLellis S, Carnegie DH, Burke TJ. Improved
neurophysiologic signs in HIV-associated sensory neuropathy. foot sensitivity and pain reduction in patients with peripheral
Pain. 2010;151(3):732–736. neuropathy after treatment with monochromatic infrared
58. Herrmann DN, McDermott MP, Sowden JE, et al. Is skin photo energy-MIRE. J Diabetes Complications. 2006;20(2):
biopsy a predictor of transition to symptomatic HIV 81–87.
neuropathy? A longitudinal study. Neurology. 2006;66(6): 78. Mill E, Wu P, Ernst E. Complementary therapies for the
857–861. treatment of HIV: in search of the evidence. Int J STD AIDS.
59. Zhou L, Kitch DW, Evans SR, et al. Correlates of epidermal 2005;16(6):395–403.
nerve fiber densities in HIV-associated distal sensory 79. Josephs JS, Fleishman JA, Gaist P, Gebo KA. Use of
polyneuropathy. Neurology. 2007;68(24):2113–2119. complementary and alternative medicines among a multistate,
60. Berger AR, Arezzo JC, Schaumburg HH, et al. multisite cohort of people living with HIV/AIDS. HIV Med.
2′,3′-Dideoxycytidine (ddC) toxic neuropathy: a study of 52 2007;8(5):300–305.
patients. Neurology. 1999;43(2):358–362. 80. National Institutes of Health Concensus Conference.
61. Hart AM, Wilson ADH, Montovani C, et al. Acetyl-l- Acupuncture. JAMA.1998;280:1518–1524.
carnitine: a pathogenesis based treatment for HIV-associated 81. Shlay JC, Chaloner K, Max MB, et al. Acupuncture and
antiretroviral toxic neuropathy. AIDS. 2004;18(11): amitriptyline for pain due to HIV-related peripheral
1549–1560. neuropathy: a randomized controlled trial. JAMA. 1998;
62. Breitbart W, Rosenfeld BD, Passik SD, McDonald MV, 280(18):1590–1595.
Thaler H, Portenoy RK. The undertreatment of pain in 82. Shiflett SC, Schwartz GE. Statistical reanalysis of a
ambulatory AIDS patients. Pain. 1996;65(2–3):243–249. randomized trial of acupuncture for pain reveals positive
2560_Chapter 27_0331-0346.indd 345 3/16/2015 4:14:31 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
effects as well as adverse treatment interactions on pain, 89. Palmer R. Use of complementary therapies to treat patients
attrition, and mortality. Explore (NY). 2010;6(4):246–55. with HIV/AIDS. Nurs Stand. 2008;22(50):35–41.
83. Shiflett SC, Schwartz GE. Effects of acupuncture in reducing 90. Head KA. Peripheral neuropathy: pathogenic mechanisms and
attrition and mortality in HIV-infected men with peripheral alternative therapies. Altern Med Rev. 2006;11(4):294–329.
neuropathy. Explore (NY). 2011;7(3):148–154. 91. Cornblath DR, Hoke A. Recent advances in HIV neuropathy.
84. Authier FJ, Gheradi RK. Peripheral neuropathies in HIV- Curr Opin Neurol. 2006;19(5):446–450.
infected patients in the era of HAART. Brain Pathol. 2003; 92. Hasan S, Anwar M, Ahmadi K, Ahmed S, Choong C, See C.
13(2):223–228. Reasons, perceived efficacy, and factors associated with
85. Galatino ML, Shepard K, Krafft L, et al. The effect of complemenatary and alternative medicine use among
group aerobic exercise and t’ai chi on functional outcomes Malaysian patients with HIV/AIDS. J Altern Complement
and quality of life for persons living with aquired Med. 2010;16(11):1171–1176.
immunodeficiency syndrome. J Altern Complement Med. 93. Hoogbruin A. Complementary and alternative therapy
2005;6:1085–1092. (CAT) use and highly active antiretroviral therapy
86. Robins JL, McCain NL, Gray DP, Elswick RK, Walter JM, (HAART): current evidence in the literature, 2000–2009.
McDade E. Research on psychoneuroimmunology: tai chi as J Clin Nurs. 2001;5(1):48–53.
a stress management approach for individuals with HIV 94. Ho EY, Robles JS. Cultural resources for health participation:
disease. Appl Nurs Res. 2006;19(1):2–9. examining biomedicine, acupunture, and massage therapy for
87. Field T. Tai Chi research review. Complement Ther Clin Pract. HIV-related peripheral neuropathy. Health Commun. 2001;
2001;17(3):141–146. 26(2):135–146.
88. Jam S, Imani A, Foroughi M, Alinaghi S, Koochak H, 95. Cornblath DR, McArthur JC, Kennedy PG, Witte AS,
Mohraz M. The effects of mindfulness-bases stress reduction Griffin JW. Inflammatory demyelinating peripheral
(MBSR) program in Iranian HIV/AIDS patients: a pilot neuropathies associated with human T-cell lymphotropic
study. Acta Med Iran. 2010;48(2):101–106. virus type III infection. Ann Neurol. 1997; 21(1):32–40.
2560_Chapter 27_0331-0346.indd 346 3/16/2015 4:14:31 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
GLOSSARY TERMS
A to prevent viral resistance, production of enzymes known

Alcohol: Chronic alcohol organizations such as the NIH as DNases, which destroy the
ingestion is a common etiology emphasize the importance of DNA in the nucleus of the cell.
of neuropathy (alcoholic involving patients in therapy An analogy is roadies breaking
polyneuropathy). The disorder is choices and recommend down the stage in an arena after
defined by a length-dependent analyzing the risks and the a major band has been through
axonal degeneration of motor potential benefits to patients town. The cell shrinks and
and sensory neurons. Although with low viral loads. Standard sends out distress signals, which
the direct toxic effect of the antiretroviral therapy (ART) are answered by vacuum
alcohol on the nerve or the consists of the combination of cleaners known as macrophages.
by-products of the metabolism at least three antiretroviral The macrophages clean away
of the alcohol are two potential (ARV) drugs for maximal the shrunken cells, leaving no
etiologies, research has shown suppression of HIV and to stop trace, so these cells have no
that vitamin deficiency as a the progression of HIV disease. chance to cause the damage
complication of chronic alcohol Huge reductions have been seen that necrotic cells do.
ingestion plays a leading part in in rates of death and suffering Arsenic: Arsenic is a metallic
the development of the when a potent ARV regimen is compound known for its use as
neuropathy. used, particularly in early stages a poison in homicide and
Antiretroviral medications: The of the disease. Expanded access suicide, but toxicity may also
management of HIV/AIDS to ART can also reduce HIV occur as a result of low-level
normally includes the use of transmission at the population exposure from various sources
multiple medications known as level, impact orphanhood, and including the smelting of ores
antiretroviral drugs in an preserve families. to the manufacture of
attempt to control the infection. Apoptosis: There are two integrated circuits. In some
There are several classes of methods of cellular death: areas, arsenic is a groundwater
antiretroviral agents that act on necrosis and apoptosis. Necrosis contaminant. Symptoms are
different stages of the HIV life occurs when a cell is damaged dose dependent and include
cycle. The use of multiple drugs by an external force, such as a gastrointestinal disturbances,
that act on different viral targets toxin, a medication, bodily arrhythmia, hypotension,
is known as highly active injury, an infection, or an cognitive changes, and
antiretroviral therapy ischemic event such as a stroke. peripheral neuropathy.
(HAART). HAART decreases Necrosis results in an Assessment: An assessment is a
the patient’s total burden of inflammatory cascade, which plan of care that identifies the
HIV, maintains function of the may cause additional local or specific needs of the client and
immune system, and prevents systemic events. Apoptosis is how those needs will be
the development of often referred to as addressed by the health care
opportunistic infections that programmed cell death (PCD), system. The assessment is
often lead to death. The and the process of apoptosis developed by a correlative
National Institutes of Health follows a controlled, predictable process: the systematic review
(NIH) recommends offering routine. When a cell is of all health-related data
antiretroviral treatment to all compelled to initiate the including the subjective history
patients with HIV. Because of process of PCD, proteins called provided by the patient,
the complexity of selecting and caspases go into action. previous medical records,
following a regimen, the Caspases break down the laboratory tests, radiological
severity of the side effects, and cellular components needed for tests, and physical assessment;
the importance of compliance survival, and they spur discussion with consultants;
347
2560_Glossary_0347-0360.indd 347 3/16/2015 4:15:02 PM

Process CyanProcess
YellowProcess Black
348 Glossary Terms
mutual goal setting by the is most often caused by traction function over time. The primary
health providers and the or compression of the upper function of the kidneys is to
patient; and knowledge of the trunk of the brachial plexus or remove waste and excess water
effectiveness of the proposed the fifth or sixth cervical nerve from the body. There may be no
interventions. Interventions roots. Burners are typically symptoms initially. The loss of
may range from preventive to transient, but they can cause function usually takes months
therapeutic to palliative. prolonged weakness resulting in or years to occur. It may be so
time loss from athletic slow that symptoms do not
B participation. Also, they often appear until kidney function is
Balance: Balance is the ability to recur. Treatment consists of less than one tenth of normal.
maintain the body’s center of restoring range of motion, The final stage of CKD is called
mass within the base of support improving strength, and end-stage renal disease (ESRD).
with minimal sway. Sway is a providing protective equipment. At this stage, the kidneys are no
horizontal movement of the Return to sports participation longer able to remove enough
center of gravity when a person depends primarily on wastes and excess fluids from
is standing stationary. re-establishment of pain-free the body. The patient requires
Maintaining balance requires motion and full recovery of dialysis or a kidney transplant.
coordinated input from the strength and functional status. CKD and ESRD affect more
visual, somatosensory than 2 out of every 1,000 people
(kinesthetic/proprioceptive), and C in the United States. Diabetes
vestibular systems. Impairments Capillary filtration coefficient: mellitus and uncontrolled high
of any of these systems results Urine formation results from blood pressure are the two
in decreased balance. glomerular filtration, tubular most common causes of CKD.
Behavior therapy: Behavior reabsorption, and tubular Many other diseases and
therapy is a broad term that secretion. Rates at which conditions can damage the
refers to either psychosocial or different substances are excreted kidneys, including autoimmune
behavior analytical intervention in urine represent the sum of disorders (e.g., systemic
or a combination of the two three renal processes: (1) lupus erythematosus and
therapies. In the broadest sense, glomerular filtration, (2) scleroderma), congenital defects
the methods focus on just reabsorption of substances from of the kidneys (e.g., polycystic
behaviors or behaviors in renal tubules into blood, and (3) kidney disease), toxic chemicals,
combination with thoughts and secretion of substances from glomerulonephritis, injury or
feelings. Behavior therapy blood into renal tubules. This trauma, renal calculi and
consists of three disciplines: can be expressed infection, and ischemic kidney
applied behavioral analysis, mathematically as follows: disease.
habit reversal training, and Urinary excretion rate = Classification of peripheral nerve
cognitive-behavior therapy. filtration rate − reabsorption injury: Classification of
Applied behavioral analysis rate + secretion rate. peripheral nerve injury assists in
focuses on operant conditioning Glomerular filtration rate determining the severity,
in the form of positive and (GFR) is determined by the prognosis, and intervention
negative reinforcement. Habit sum of hydrostatic and colloid strategy. Classification of nerve
reversal training uses osmotic forces across the injury was described by Seddon
interventions to decrease glomerular membrane, which in 1943 and by Sunderland in
habit-like behaviors. Cognitive- gives the net filtration pressure 1951. Generally, the lowest
behavior therapy focuses on the and glomerular capillary degree of nerve injury, in which
thoughts and feelings behind filtration coefficient, Kfc. the nerve remains intact, but
mental health diagnoses with This can be expressed there is a transient nerve
treatment plans in mathematically as follows: conduction block, is called
psychotherapy to remediate the GFR = Kfc × net filtration neurapraxia. The second degree
issues. pressure. Net filtration pressure of injury, in which the axon is
Burner: A burner is also often is the sum of hydrostatic and damaged, but the surrounding
referred to as a “stinger.” A colloid osmotic forces that connecting tissue remains
burner is a common nerve either favor or oppose filtration intact, is called axonotmesis.
injury resulting from trauma to across the glomerular capillaries. The last degree of injury, in
the neck and shoulder. Burners Chronic kidney disease: Chronic which both the axon and the
typically occur during a kidney disease (CKD) is the connective tissue are damaged,
sporting competition. The injury progressive loss of kidney is called neurotmesis.
2560_Glossary_0347-0360.indd 348 3/16/2015 4:15:03 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Glossary Terms 349
Compression: Nerve enforced bed rest often some are caused by
compression, often called a accompanies critical illness. autoimmune reactions, and
trapped nerve or entrapment Critical illness myopathy: some are caused by unknown
neuropathy, results from Critical illness myopathy factors.
external compressive forces (CIM) is a syndrome of Diabetes: Diabetes mellitus is a
affecting a single nerve resulting widespread muscle weakness group of chronic metabolic
in impairment of conduction of and neurological dysfunction diseases in which there are high
the afferent, efferent, and that can develop in critically ill levels of glucose in the blood as
autonomic fibers. Nerve patients on prolonged bed rest. a result of the pancreas not
compression may result from CIM is often distinguished supplying sufficient insulin or
trauma, congenital injury, largely on the basis of because cells do not respond to
abnormal development, overuse, specialized electrophysiological insulin that is produced. There
repetitive strain, and disease. testing or muscle and nerve are three main types of
Connective tissue disorders: biopsy, and its causes are diabetes: gestational diabetes,
Connective tissue disorders unknown, although they are type 1 diabetes mellitus, and
(often referred to as connective thought to be a possible type 2 diabetes mellitus.
tissue diseases) results in injury neurological manifestation of Untreated or undertreated
to the target tissue. Connective systemic inflammatory response diabetes can result in many
tissue is any biological tissue syndrome. Major risk factors complications, including
that has an extensive include administration of diabetic ketoacidosis, nonketotic
extracellular matrix of intravenous corticosteroids and hyperosmolar coma,
supporting structures to neuromuscular junction blocks. cardiovascular disease, chronic
facilitate function and Previously a defined entity, and acute kidney disease,
protection. Some connective CIM is now considered to be retinopathy, stroke, and a
tissue disorders are heritable, part of a larger diagnostic spectrum of peripheral
whereas others are acquired. category referred to as critical neuropathies.
Most autoimmune diseases have illness myopathy/ Diagnostic testing: Diagnostic
a connective tissue component. polyneuropathy. testing is a process of using
Contracture: A contracture is a Critical illness polyneuropathy: valid and reliable procedures to
permanent shortening of a Previously a defined entity, confirm the presence of a
contractile or noncontractile critical illness polyneuropathy is disease, to rule out a disease, or
articular or nonarticular tissue. now considered to be part of a to screen for a disease. The
Contracture is usually in larger diagnostic category diagnostic journey is often
response to prolonged referred to as critical illness begun with “screening” tests—
immobilization, disuse, myopathy/polyneuropathy. tests that broadly evaluate for
hypertonic spasticity in a the presence of abnormalities
concentrated muscle area, D but are typically not diagnostic.
congenital deformity, ischemia, Demyelination: Demyelination is Screening tests are followed by
or an inflammatory disease. a process resulting from a specific tests and measures with
When a contracture has demyelinating disease. A a high sensitivity or specificity
matured, surgical release is demyelinating disease is any to rule in or rule out specific
often indicated. Physical disease of the nervous system in disease processes.
therapy and occupational which the myelin sheath of Disability and health: Persons
therapy interactions are very neurons is damaged. with and without disability may
effective in the prevention of Demyelination impairs the be healthy and well. Disability
contracture. conduction of signals in the is an umbrella term that
Critical illness: Critical illness is affected nerves, causing includes impairments, activity
the branch of medicine impairment in sensation, motor limitations, and participation
concerned with the diagnosis control, autonomic regulation, restriction. Impairment is a
and management of life- cognition, or other functions problem in body function or
threatening conditions requiring depending on which nerves are structure. An activity limitation
sophisticated and invasive involved. Demyelination is a difficulty encountered by
monitoring. Examples include describes the effect of the an individual in executing a
respiratory compromise disease, rather than its cause; task or action. A participation
requiring ventilator support, some demyelinating diseases are restriction is a problem
acute renal failure, and acute caused by genetics, some are experienced by an individual in
cardiac arrhythmia. Prolonged caused by infectious agents, involvement in life situations
2560_Glossary_0347-0360.indd 349 3/16/2015 4:15:03 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
350 Glossary Terms
and relationships. Disability is a electromyograph, which consists physically separates the
complex phenomenon, of recording electrodes, an fascicles. It provides two basic
reflecting an interaction amplifier, and an oscilloscope, functions: assisting the external
between features of a person’s to produce a record called epineurium in providing truncal
body and features of the society an electromyogram. An protection from compressive
in which the person lives. electromyograph detects the forces and, more importantly,
Health is the level of metabolic electrical potential generated by facilitation of gliding between
and functional efficiency of a muscle cells when these cells the fascicles. As nerves stretch
living being; it is intrinsic to are electrically or neurologically and rebound, fascicles glide
the organism. activated. The signals can be within the base collagen matrix
Distal symmetrical analyzed to detect medical of the nerve trunk. There is a
polyneuropathy: Distal abnormalities, activation level, direct relationship between the
symmetrical polyneuropathy or recruitment order or to diameter of the nerve and the
(DSP) is the most common analyze the biomechanics of volume of epineurium. There is
form of peripheral neuropathy, a human or animal movement. also greater epineurium content
disorder of the peripheral Often EMG is used to describe in peripheral nerves as they
nervous system affecting more the entire diagnostic process cross joints and as they pass
than 20 million Americans. for nerve or muscle injury. under or near fibrous bands,
DSP is the most common type Tests in addition to EMG such as the flexor retinaculum
of peripheral neuropathy in include nerve conduction at the wrist. The external
people with HIV disease. It is velocity tests and somatosensory epineurium surrounds the nerve
characterized by paresthesia, tests. To avoid ambiguity, a trunk and provides protection
motor neuropathy, and sensory better term to describe the from compressive and tensile
neuropathy especially in the diagnostic procedure is forces.
hands and feet. electroneurodiagnostic Evaluation: The use of validated
Dynamic splint: A dynamic testing. tests and measures with high
splint is any splint that Endoneurium: The innermost sensitivity and specificity to rule
incorporates springs, elastic layer of connective tissue in a in, rule out, or add to the
bands, hydraulics, or other peripheral nerve, forming an differential diagnosis list begun
materials to produce a constant interstitial layer around each during the clinical scripting
active force to counteract individual fiber outside the process.
inherent resistance in a neurolemma, is the
biological tissue. endoneurium. The matrix of F
tightly bound connective tissue Fall prevention: Fall prevention
E also contains capillaries, mast modalities are evidence-based
Electrical stimulation: Electrical cells, Schwann cells, and interventions that decrease fall
stimulation is the therapeutic fibroblasts. The endoneurium risk. These include, but are not
use of electricity to decrease appears to have two primary limited to, somatosensory
pain, improve range of motion, functions: to maintain the rehabilitation, vestibular therapy,
increase strength, improve endoneurial space and fluid biomechanic/postural
coordination, normalize tone, pressure—a homeostatic nerve modification, visual acuity
assist with wound healing, and fiber environment. A slightly maximization, home
decrease edema. By varying the positive pressure is maintained modifications, strengthening,
rate, amplitude, duration, within the endoneurial tube. and education.
waveform, and type of current, The collagen within the Fall prevention program: A fall
practitioners are able to elicit endoneurial tube is primarily prevention program uses
numerous physiological effects longitudinal, evidence evidence-based medicine and
to improve healing. supporting the fact that the best practice designation to
Electromyography: endoneurium assists with assist communities and
Electromyography (EMG) is a protecting the neuron from individuals with reducing fall
technique for evaluating and tensile challenges. risk. Fall prevention programs
recording the electrical activity Epineurium: The epineurium, a range from individual
produced by skeletal muscles loose connective tissue, is consultations, assessments, and
during rest, minimal subdivided into internal and interventions to community-
contraction, and maximal external components. The wide educational programs
contraction. EMG is performed internal epineurium is the base targeting specific cohorts at risk
using an instrument called an collagenous tissue that for falls.
2560_Glossary_0347-0360.indd 350 3/16/2015 4:15:03 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Glossary Terms 351
Fall risk assessment: Fall risk late responses because they are (e.g., milliliters per minute
assessment is the use of responses that occur later than [mL/min]). Several different
validated fall risk assessment the CMAP. techniques are used to calculate
tools to determine an or estimate GFR (GFR or
individual’s risk of falling. If the G eGFR). The following formula
benchmark for fall risk is met, Gestational diabetes: Gestational applies to GFR calculation only
referral is made to a fall diabetes is a condition in which when it is equal to the clearance
prevention program, and fall a pregnant woman with no rate: GFR = urine
prevention modalities are prior diagnosis of diabetes concentration × urine flow/
prescribed. exhibits higher than expected plasma concentration.
Fibrosis: Fibrosis is the concentrations of blood glucose. Guillain-Barré syndrome:
formation of excess fibrous Gestational diabetes is a disease Guillain-Barré syndrome is an
connective tissue in an organ or of the insulin receptors, most acute polyneuropathy that
tissue. Fibrosis is a hallmark likely related to factors such as affects the peripheral nervous
event of the inflammation the presence of human placental system and spares the central
cascade. Initiated by trauma and lactogen that interferes with nervous system. Hallmarks
regulated by cytokine susceptible insulin receptors. including ascending lower
concentration, excessive and Women with gestational motor neuron paralysis with
aberrant tissue along with diabetes have an increased risk subtle sensory changes and pain
angiogenesis occurs at the site of developing preeclampsia, more distal than proximal.
of injury. Fibrosis may occur delivery by cesarean section, Autonomic dysfunction is often
intrinsic or extrinsic to the delivering macrosomal infants, present. The disease may be
nerve. Intrinsic fibrosis may and developing type 2 diabetes. life-threatening especially if the
lead to adaptive shortening, and Glomerular filtration rate: respiratory muscles are
extrinsic fibrosis may lead to Glomerular filtration rate compromised. Diagnosis is
aberrant connections between (GFR) is the volume of fluid made by the clinical picture,
the nerve and the adjacent filtered from the renal cerebrospinal fluid analysis, and
structures. glomerular capillaries into electroneurodiagnostic studies.
F wave: When a motor nerve is Bowman’s capsule per unit time. The etiology is unknown, but
stimulated and the electrical GFR is equal to the clearance the disorder is usually
response of a muscle that it rate when any solute is freely precipitated by a viral or
innervates is displayed on an filtered and is neither bacterial illness. Treatment
oscilloscope, several responses reabsorbed nor secreted by the includes intravenous
can be observed. The initial kidneys. The rate measured is immunoglobulins and
response is the largest in the quantity of the substance in plasmapheresis, and the
amplitude and is termed the the urine that originated from a outcome is usually good.
compound muscle action calculable volume of blood.
potential (CMAP). After the Relating this principle to an H
CMAP, several smaller equation, for the substance Hemodialysis: The two main
responses are seen. These are used, the product of urine types of dialysis are
called F waves. Action concentration and urine flow hemodialysis and peritoneal
potentials in the motor nerve equals the mass of substance dialysis. Dialysis removes wastes
fibers that are caused by excreted during the time that and excess water from the blood
electrical stimulation travel in urine has been collected. This in different ways. Hemodialysis
two directions. The action mass equals the mass filtered at functions to remove wastes and
potentials that travel directly the glomerulus because nothing water by circulating the blood
from the point of stimulation to is added or removed in the outside the body through an
the muscle elicit the CMAP. nephron. Dividing this mass by external filter, called a dialyzer,
Some action potentials travel in the plasma concentration gives that contains a semipermeable
the other direction on the nerve the volume of plasma from membrane. The blood flows in
fibers, all the way to the motor which the mass must have one direction, and the dialysate
neuron cell bodies in the spinal originally come and the volume flows in the opposite direction.
cord. These action potentials of plasma fluid that has entered The countercurrent flow of the
then travel back down to the Bowman’s capsule within the blood and dialysate maximizes
nerve fibers to stimulate the aforementioned period of time. the concentration gradient of
muscles a second time, after a The GFR is typically recorded solutes between the blood and
brief delay. F waves are called in units of volume per time dialysate, which helps to
2560_Glossary_0347-0360.indd 351 3/16/2015 4:15:03 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
352 Glossary Terms
remove additional urea and shellfish, or drinking active virus and in some cases
creatinine from the blood. The contaminated water. Hepatitis can reduce the number of active
concentrations of solutes (e.g., B virus may result in an acute virus until it is undetectable by
potassium, phosphorus, urea) or chronic infection. current blood testing
are undesirably high in a Transmission of the virus is techniques.
patient with kidney disease but typically through sexual contact, Human immunodeficiency virus
low or absent in the dialysis sharing of needles for (HIV): HIV is a slowly
solution. Constant replacement intravenous drug abuse with an replicating retrovirus that causes
of the dialysate ensures that the infected person, tattooing, and acquired immunodeficiency
concentration of undesired sharing personal items such as syndrome (AIDS). AIDS is a
solutes is kept low on this side toothbrushes with an infected progressive failure of the
of the membrane. The dialysis person. Chronic hepatitis B can immune system, allowing
solution has levels of minerals lead to liver damage. The cancers and opportunistic
such as potassium and calcium hepatitis B vaccine is the best infections to develop and thrive.
that are similar to their natural way to prevent infection. HIV infection is spread
concentration in healthy blood. Hepatitis C infection is caused through needle sharing and the
For another solute, bicarbonate, by hepatitis C virus (HCV). transfer of blood or blood
the dialysis solution level is set Virus transmission is similar to products, semen, pre-ejaculate,
at a slightly higher level than in hepatitis B infection. Most vaginal fluid, and breast milk.
normal blood, to encourage persons with HCV have no Hypothesis-Oriented Algorithm
diffusion of bicarbonate into symptoms. Long-term for Clinicians (HOAC):
the blood to act as a pH buffer complications include cirrhosis Originally developed by
to neutralize the metabolic and the need for a liver Rothstein and Enternach
acidosis that is often present. transplant. HCV infection is (Rothstein JL, Enternach JL.
The levels of the components of often associated with The hypothesis-oriented
dialysate are typically prescribed cryoglobulinemia. Peripheral algorithm for clinicians: a
by a nephrologist according to neuropathy (PN) is a relatively method for evaluation and
the needs of the individual common complication of treatment planning. Phys Ther.
patient. In peritoneal dialysis, cryoglobulinemia associated 1986;66:1388–1394), the
wastes and water are removed with HCV infection, and it is HOAC is designed to aid
from the blood inside the body thought to be attributable to practitioners in clinical decision
using the peritoneal membrane nerve ischemia. PN has been making and patient
as a natural semipermeable reported in only a few patients management. The HOAC
membrane. Wastes and excess with HCV and consists of two parts: a
water move from the blood, cryoglobulinemia. The finding sequential guide to evaluation
across the peritoneal membrane, of HCV RNA in nerve biopsy and treatment planning and a
and into a dialysis solution specimens has suggested a branching program used for
called dialysate. possible direct role of HCV in re-evaluation and a systematic
Hepatitis: Hepatitis refers to the pathogenesis of PN. measure of intervention
three disorders that affect the Highly active antiretroviral effectiveness. The HOAC
liver. Hepatitis A virus is found therapy: Highly active requires the clinician to state a
in the stool of persons with antiretroviral therapy hypothesis list (differential
hepatitis A and is a short-lived (HAART) is the name given to diagnoses) and use diagnostic
infection. Most cases resolve aggressive treatment regimens testing to rule in, rule out, or
within weeks or months, but used to suppress HIV viral add to the hypothesis list.
some may have relapsing replication and the progression
symptoms for up to 9 months. of HIV disease. The usual I
Patients rarely develop acute HAART regimen combines Immobilization: Immobilization
liver failure. Hepatitis A is three or more different drugs, is the process of holding a joint
spread by contact, often by such as two nucleoside reverse or bone in place with a splint,
putting something in the transcriptase inhibitors (NRTIs) cast, or brace. The purpose of
mouth that has been in contact and a protease inhibitor, two immobilization is to prevent
with infected stool. Hepatitis A NRTIs and a nonnucleoside injury or to prevent movement
may also be spread by eating reverse transcriptase inhibitor, to facilitate healing.
fruits or vegetables or other such combinations. Infection: Infection is the
contaminated during handling, HAART regimens have been invasion of body tissues of a
eating contaminated fish or proven to reduce the amount of host organism by
2560_Glossary_0347-0360.indd 352 3/16/2015 4:15:03 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Glossary Terms 353
disease-causing organisms such fatigue, and abnormal disability at individual and
as bacteria, prions, viruses, sensations. CIDP is closely population levels. The ICF was
viroids, parasites, and fungi. related to Guillain-Barré officially endorsed by all 191
Many infectious organisms may syndrome, and it is considered WHO Member States in the
lead to the complication of the chronic counterpart of that Fifty-fourth World Health
peripheral neuropathy. acute disease. Treatment for Assembly on May 22, 2001
Inflammation: Inflammation CIDP includes corticosteroids (resolution WHA 54.21).
(from the Latin “to ignite or set such as prednisone, which may Intervention: When a valid
afire”) is part of the be prescribed alone or in diagnosis has been established,
inflammatory cascade affecting combination with interventions (therapeutic
vascularized tissues as a immunosuppressant drugs. modalities and treatments)
response to trauma, infection, Plasmapheresis and intravenous determined by the evidence and
illness, or repetitive injury. The immunoglobulin therapy are clinical expertise are employed
cardinal signs of inflammation effective. The course of CIDP to remediate the impairment.
are pain, warmth, rubor, edema, varies widely among individuals. The effectiveness of the
and loss of function. When a Some may have a bout of intervention is determined by
tissue is traumatized, CIDP followed by spontaneous an outcome measure.
macrophages, monocytes, recovery, whereas others may
dendritic cells, histiocytes, have many bouts with partial L
Kupffer cells, and mastocytes recovery in between relapses. Laboratory testing: Laboratory
release potent inflammatory The disease is a treatable cause testing is part of the diagnostic
mediators, which initiate the of acquired neuropathy, and process to rule in, rule out, or
inflammatory cascade. These early initiation of treatment to add to the differential diagnosis
mediators facilitate vasodilation, prevent loss of nerve axons is list. Laboratory tests may be
angiogenesis, the laying down recommended. However, some considered screening
of fibrous tissue, and vascular individuals are left with residual (nondiagnostic), such as
permeability. They also mediate numbness or weakness. complete blood count and
the release of bradykinin and Insulin: Insulin is produced by sedimentation rate, or
other mediators that increase the beta cells of the pancreas diagnostic, such as culture and
the sensitivity to pain. and is the hormone responsible sensitivity and enzyme
Inflammatory demyelinating for regulating carbohydrate and immunoassay test for syphilis.
polyradiculopathy: fat metabolism and ultimately Lead: Lead toxicity is a leading
Inflammatory demyelinating the concentration of glucose in cause of neuropathy in children
polyradiculopathy, also called the blood. When control of but may occur in persons of all
chronic inflammatory insulin fails, diabetes mellitus ages. Exposure is through
demyelinating develops. ingestion and inhalation. The
polyradiculopathy (CIDP), is a International Classification of most common sources of
neurological disorder Functioning: The International toxicity are from paint in homes
characterized by progressive Classification of Functioning, built between 1920 and 1970
weakness and impaired sensory Disability, and Health, known and occupational settings such
function in the legs and arms. more commonly as ICF, is a as battery manufacturers, auto
The disorder, which is classification of health and radiator refurbishing, silver
sometimes called chronic health-related domains. These refining, and home demolition.
relapsing polyneuropathy, is domains are classified from Neuropathy is typically more
caused by damage to the myelin body, individual, and societal motor than sensory and more
sheath (the fatty covering that perspectives by means of two distal than proximal. There may
wraps around and protects lists: a list of body functions be associated cognitive loss,
nerve fibers) of the peripheral and structure and a list of abdominal pain, headache,
nerves. Although it can occur at domains of activity and fatigue, and anemia.
any age and in both genders, participation. Because an Lower motor neuron: As a
CIDP is more common in individual’s functioning and method of classification of nerve
young adults and in men. It disability occur within a injury and nerve injury
often manifests with tingling or context, the ICF also includes a prognosis, motor nerves are
numbness (beginning in the list of environmental factors. considered upper or lower motor
toes and fingers), weakness of The ICF is the framework of neurons. Lower motor neurons
the arms and legs, loss of deep the World Health Organization are typically the final neuron in
tendon reflexes (areflexia), for measuring health and the pathway from the motor
2560_Glossary_0347-0360.indd 353 3/16/2015 4:15:03 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
354 Glossary Terms
cortex to the target muscle. Manual therapy: Manual therapy, living organisms. There are
Injury to the lower motor also known as manipulative seven major minerals: calcium,
neuron results in flaccid therapy, is a physical phosphorus, potassium, sulfur,
paralysis, hypoactive deep intervention used primarily to sodium, chlorine, and
tendon reflexes, and hypotonus. treat neurological and magnesium. An additional
Examples of lower motor neuron musculoskeletal impairments to group of minerals are known as
disease include Guillain-Barré remediate pain and disability. “trace” minerals, and this list
syndrome, polio, carpal tunnel The scope of manual therapy is includes cobalt, copper, zinc,
syndrome, and L1 root lesion. typically defined by the and iron. Mineral deficiency
Lyme disease: Lyme disease is profession using the practice may lead directly or indirectly
caused by a bite from the (for legal purposes) and by to peripheral neuropathy.
blacklegged tick, which infects individual state practice acts. Modality: A modality is a
the host with the bacterium Mercury: Peripheral neuropathy therapeutic intervention.
Borrelia burgdorferi. The tick from mercury exposure Modalities include medications,
becomes infected by biting mice commonly involves distal manual therapy, exercise,
or deer that are infected with latency sensory slowing for physical interventions such as
Lyme disease. The first reported short-term exposure and motor ultrasound or electrical
case was in Old Lyme, slowing for long-term exposure. stimulation, teaching,
Connecticut, in 1975. Stage I is Central nervous system effects counseling, and functional
where the infection is localized are very common. Mercury retraining.
to the bite area. Symptoms are toxicities, once quite common, Motor nerve conduction: The
minimal but may include a are now mostly limited to motor nerve conduction test is
“bull’s-eye” expanding rash at industrial accidents. There part of the overall nerve
the site of the tick bite. Stage II continues to be concern related conduction study (NCS). The
is called early disseminated to mercury in dental amalgams NCS is a test commonly used
Lyme disease, and symptoms and preservatives such as to evaluate the function,
may include chills, malaise, thimerosal. especially the ability of
itching, articular and muscle Mesoneurium: The mesoneurium electrical conduction, of the
pain, arrhythmia, and paralysis is one of the connective tissues motor and sensory nerves of the
of the bulbar musculature. supporting peripheral nerve human body. Nerve conduction
Stage III is called late trunks. It is classified as loose velocity (NCV) is a common
disseminating Lyme disease, and areolar and is the entry measurement made during this
and symptoms include portal for many of the arteries test. NCV often is used to
abnormal muscle synergies, that supply the vasa nervorum, mean the actual test, but this
dysarthria, motor neuropathy, the highly anastomosing venous may be misleading because
and disseminated sensory and arterial network within the velocity is only one
neuropathy. nerve trunk. The function of the measurement in the test menu.
mesoneurium is not fully Motor NCS are performed by
M understood; however, the electrical stimulation of a
Macronutrient: Three primary “slippery” surface of the peripheral nerve and recording
macronutrients are defined as mesoneurium limits frictional from a muscle supplied by this
being the classes of chemical forces with longitudinal and nerve. The time it takes for the
compounds consumed in the side-to-side movement of the electrical impulse to travel from
largest quantities by humans nerve trunk against local the stimulation to the recording
and that provide bulk energy. structures. There may also be site is measured. This value is
These are protein, fat, and substantial “sliding” motion called the latency and is
carbohydrate. Carbohydrates between the mesoneurium and measured in milliseconds (ms).
include starches and simple and the external epineurium The size of the response, called
complex sugars. Proteins are facilitating the extensibility the amplitude, is also measured.
foods that contain the standard characteristics of nerve. The Motor amplitudes are measured
amino acids. Fats include mesoneurium may also provide in millivolts (mV). By
saturated fats, monounsaturated limited protection from stimulating in two or more
fats, polyunsaturated fats, and compressive and tensile forces different locations along the
essential fatty acids. Failure to affecting the nerve trunk. same nerve, the NCV across
meet macronutrient needs may Minerals: Minerals, also known different segments can be
lead directly or indirectly to as dietary minerals, are common determined. Calculations are
peripheral neuropathy. chemical elements required by performed using the distance
2560_Glossary_0347-0360.indd 354 3/16/2015 4:15:03 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Glossary Terms 355
between the different Neuropathies: Neuropathies are spasticity, fecal and urinary
stimulating electrodes and the a group of diseases and incontinence, and clonus.
difference in latencies. disorders that either directly or Nutrient: A nutrient is a
indirectly result in damage to a chemical, molecule, or
N nerve. Peripheral neuropathy compound that an organism
Neurodynamic tests: refers to damage outside the requires to live and grow or a
Neurodynamic tests or testing central nervous system; central substance used in an organism’s
refers to a group of physical neuropathy refers to damage metabolism that must be taken
maneuvers to assess for passive within the central nervous in from its environment.
insufficiency and adaptive system. Neuropathies may Nutrients are used to build and
shortening of neural tissue. involve one nerve repair tissues and regulate body
Neural tissue may be shortened (mononeuropathy) or many processes and are converted to
by the inflammatory cascade as nerves (polyneuropathy). specific compounds, which are
a result of trauma or infection, Neuropathies may involve the used as energy. Methods for
intraneural or extraneural sensory, autonomic, and motor nutrient intake vary, with
scarring, and aberrant tissue nerves. animals and protists consuming
connecting the neural tissue to Neuropathy: Neuropathy is foods that are digested by an
adjacent structures. Examples damage to one or more nerves internal digestive system; most
include the median nerve as a result of trauma, illness, plants ingest nutrients directly
tension test, straight leg raise repetitive strain, or infection, from the soil through their roots
test, and Kernig test. which leads to motor, sensory, or from the atmosphere.
Neurolysis: Neurolysis refers to and autonomic dysfunction. Organic nutrients include
the degradation of nerve tissue There are hundreds and perhaps carbohydrates, fats, proteins, and
from injury or disease; the thousands of causes of vitamins. Inorganic chemical
therapeutic destruction of neuropathy. Some disorders compounds, such as dietary
neural tissue via chemicals, result in local neuropathy, and minerals, water, and oxygen, may
surgery, or radiofrequency some result in patterned or also be considered nutrients. A
ablation to block nerve systemic neuropathy. nutrient is said to be “essential”
pathways temporarily or Nitrous oxide: Nitrous oxide, if it must be obtained from an
permanently to relieve pain or used as an anesthesia, industrial external source, either because
spasticity; or the surgical additive, and recreational drug, the organism cannot synthesize
removal of extraneural scarring was reported in 1978 as a it or because the organism
or perineural adhesions potential source of peripheral produces insufficient quantities.
tethering neural tissue to neuropathy. Most neuropathies Nutrients needed in very small
adjacent structures. currently reported secondary to amounts are micronutrients, and
Neuroma: Neuromas can be nitrous oxide abuse are related nutrients that are needed in
differentiated into neoplastic to recreational usage. As a larger quantities are called
and nonneoplastic neuromas. recreational drug, nitrous oxide macronutrients. The effects of
Neoplastic neuromas are tumors may cause analgesia, nutrients are dose dependent,
involving neural tissue affecting depersonalization, and shortages are called
the neurons of the central and de-realization, dizziness, deficiencies. Deficiencies in
the peripheral nervous systems. euphoria, and sound distortion. nutrients may lead to disease,
Neoplastic neuromas may be Similar to other N-methyl-D- which may directly or indirectly
benign or malignant. aspartate antagonists, nitrous result in neuropathy.
Nonneoplastic neuromas are oxide has been demonstrated to Nutritional deficiency:
typically the result of acute or produce neurotoxicity in the Nutritional deficiency results
chronic injury to a nerve. Many form of Olney’s lesions. With from a shortfall of the intake of,
neuromas occur after a surgical chronic use, a subacute or the compounds that are
intervention. The injured nerve degeneration of the spinal cord, manufactured into, essential
fibers form an area of as described in classic vitamin nutrients. Nutritional deficiency
ineffective, random, and B12 deficiency, occurs. The may lead to disease, which may
unregulated nerve regeneration. posterior white columns are directly or indirectly result in
They are often palpable and involved with loss of position peripheral neuropathy.
painful. Nonneoplastic neuroma and vibratory sense, ataxia, and
treatment ranges from occasionally Lhermitte sign. O
conservative therapies to Motor tract involvement may Operant therapy: Operant
surgical excision. also occur with weakness, therapy uses the principles of
2560_Glossary_0347-0360.indd 355 3/16/2015 4:15:03 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
356 Glossary Terms
operant conditioning translated to humans by an central nervous system (brain
(punishment and reward) to insect vector and results in and spinal cord). The peripheral
change behavior. Operant Chagas disease. nervous system includes nerves
conditioning is based on the Paresthesia: Paresthesia is a related to sensation, motor
premise that reinforced subjective sensation of tickling, control, and autonomic
behaviors tend to continue and tingling, burning, pricking, regulation. In contrast to the
behaviors not reinforced tend formication, hot, cold, or central nervous system, the
gradually to end. numbness of a person’s skin. peripheral nerves are typically
Overuse: High-force, low- Paresthesia is often described not protected by bone.
repetition and low-force, by the patient as a feeling of Peripheral nerves may be
high-repetition movements “pins and needles” or of a limb injured from various sources,
above the injury threshold of “falling asleep.” The mani- including trauma, overuse,
tissue result in overuse injuries. festations of paresthesia medication, toxins, radiation,
Overuse injury may affect may be transient or chronic. congenital deformity, and
nerve, muscle, tendon, enthesis, Paresthesia may be benign, vitamin deficiency.
ligament, and paratendon areas. secondary to a minor Peripheral neuropathy:
neurapraxia lesion, or a Peripheral neuropathy is
P symptom of a much more transient or permanent damage
Pain modulation: Most, if not serious injury or illness. to an autonomic, sensory, or
all, ailments of the body cause Passive movement: Passive motor neuron outside the
pain. Pain is interpreted and movement is the movement of central nervous system. The
perceived in the brain. Pain is a tissue or tissue structure that injury may be primary (direct
modulated by physical is not directly caused by muscle trauma to a nerve—e.g., median
modalities, medication, and contraction. Tissues are often neuropathy associated with
counseling. Two primary classes differentiated into contractile or carpal tunnel syndrome) or
of medications work on the noncontractile tissues. By secondary (as a complication of
brain: analgesics and definition, when a a disease process—e.g., diabetes
anesthetics. The term analgesic noncontractile tissue lengthens mellitus). Peripheral neuropathy
refers to a drug that relieves or shortens, it is passive may affect one nerve
pain without loss of movement. The lengthening or (mononeuropathy) or many
consciousness. The term central shortening may be caused by nerves (polyneuropathy).
anesthetic refers to a drug that gravity or inertia or indirectly Physical agent: Physical agents
depresses the central nervous by associated muscle or physical agent modalities
system. Central anesthesia is contraction. When a muscle (PAMs) have been a
characterized by the absence of contracts, this is termed active component of interventional
all perception of sensory motion. physical therapy for decades.
modalities, including loss of Perineurium: Each fascicle is PAMs traditionally include
consciousness without loss of surrounded by a layered sheath therapeutic ultrasound, electrical
vital functions. Physical known as the perineurium. The stimulation, short wave
modalities that modulate the perineurium has three primary diathermy, and light. PAMs
perception of pain include heat, functions: to protect the work by transmitting energy
cold, massage, electrical endoneurial tubes from normal into tissues to stimulate them
stimulation, ultrasound, and articular movement patterns; to in ways that are not possible
laser. Counseling indirectly protect the endoneurial tube with patient exercise or manual
affects pain through the from external trauma; and to therapy techniques. Original
reduction of anxiety and the use serve as a molecular diffusion research and systemic reviews
of behavioral modification. barrier, keeping certain have provided a large paradigm
Parasite: A parasite resides in potentially neurotoxic shift in the effectiveness and
close relationship with its host compounds away from the indication of PAMs. Most
and causes the host harm. The perineurial and endoneurial often, PAMs are adjunctive to a
parasite depends on the host for environment via the blood- comprehensive plan of therapy
its life functions. Many parasitic nerve barrier and the care. They may be particularly
infections may result in the perineurial diffusion barrier. effective in the earlier stages of
complication of peripheral Peripheral nerve: Peripheral the treatment plan for
neuropathy. An example is the nerves are neurons and the numerous conditions, including
flagellate protozoan associated connective sheath reducing pain and edema,
Trypanosoma cruzi, which is that are located outside the encouraging wound healing,
2560_Glossary_0347-0360.indd 356 3/16/2015 4:15:04 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Glossary Terms 357
and encouraging muscle plasma flow, which is the plexus, pathology related to the
contraction. PAMs allow volume of blood plasma scalenes and their first rib
therapists to treat symptoms delivered to the kidneys per insertion (scalene triangle) has
and facilitate the introduction unit time. been implicated in the
of other therapy interventions Repetitive and overuse athletic development of neurogenic,
to achieve more rapid movements: Repetitive and venous, and arterial thoracic
functional gains. The overuse athletic motions, also outlet syndrome.
introduction of externally known as repetitive strain Screening: The diagnostic process
powered prostheses, orthoses, injuries or work-related of ruling in, ruling out, or
and exoskeletons not only for musculoskeletal disorders, are adding to the differential
therapeutic exercise but also to either high-repetition/low-force diagnosis list with the aim of
improve and maintain function movements or low-repetition/ determining the correct
has added to the PAM menu of high-force movements. Either diagnosis often begins with
offerings. type has the potential of screening tests. Screening tests
Positive psychology: Positive incurring tissue injury resulting are nondiagnostic for a
psychology is a newer branch of in the inflammatory cascade particular disease but are
psychology that is used to with the hallmark local and capable of ruling in or out large
complement and not replace systemic impact. classes of disease.
traditional areas of psychology. Sensory nerve conduction: The
Positive psychologists attempt S motor nerve conduction test is
to find and nurture genius and Safe position: With regard to part of the overall nerve
talent, rather than merely hand positioning, the safe conduction study (NCS). The
treating mental illness. position is also known as the NCS is a test commonly used
Postural compensation: Postural intrinsic plus position. The to evaluate the function,
compensation is one of the purpose of immobilizing in this especially the ability of
goals of balance rehabilitation position is to allow the hand to electrical conduction, of the
for patients with visual, rest in this position without motor and sensory nerves of the
vestibular, or somatosensory developing as much stiffness as human body. Nerve conduction
loss. Patients are instructed how would occur if the digits were velocity (NCV) is a common
to use the remaining balance positioned differently. In the measurement made during this
function, to develop intrinsic plus position, the test. NCV often is used to
compensatory mechanisms to metacarpophalangeal joints are mean the actual test, but this
use those balance functions, and flexed at 60° to 70°, the may be misleading because
to identify efficient and effective interphalangeal joints are fully velocity is only one
postural movement strategies. extended, and the thumb is in measurement in the test menu.
Postural control: Postural control the fist projection. The wrist is Sensory NCS are performed by
is the ability to sustain the held in extension at 10° less electrically stimulating a
necessary background posture than maximal. peripheral nerve and recording
to carry out a skilled task Scalene muscle: The scalene from a purely sensory portion
efficiently, such as walking, muscles (from the Greek of the nerve, such as distally on
running, dressing, reading, or meaning “uneven”) are a group a finger or toe. The recording
handwriting. The ability to of three pairs of muscles in the electrode is the more proximal
stabilize the trunk and neck lateral neck: anterior, middle, of the two electrodes. Similar to
underlies the ability to develop and posterior scalene muscles. motor studies, sensory latencies
efficient eye and hand They originate on the transverse are on the scale of milliseconds.
movements. processes of C2–C7 and insert Sensory amplitudes are much
on the first and second ribs. The smaller than motor amplitudes,
R scalenes are innervated by the usually in the microvolt (μV)
Renal blood flow: Renal blood fourth through sixth spinal range. The sensory NCV is
flow is the volume of blood nerves. Together, they elevate calculated based on the latency
delivered to the kidneys per the first and second ribs; and the distance between the
unit time. In humans, the ipsilaterally laterally flex the stimulating and recording
kidneys together receive neck; contralaterally rotate the electrodes.
approximately 22% of cardiac neck; and, acting bilaterally, flex Serial casting: Serial casting is a
output, amounting to 1.1 L/min the neck. Because of the noninvasive procedure that
in a 70-kg man. Renal blood intimate relationship with the helps children and adults
flow is closely related to renal subclavian vessels and brachial improve specific joint range of
2560_Glossary_0347-0360.indd 357 3/16/2015 4:15:04 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
358 Glossary Terms
motion to allow improved Subclavian vessels: The foramina and the insertion of
performance of daily activities. subclavian vessels consist of the pectoralis minor on the
Serial casting is a process in the subclavian artery and the humerus. Injury may be
which a well-padded cast is subclavian vein. Because of the secondary to trauma, overuse,
used to provide a mild extrinsic proximity to the first rib and congenital abnormality, tumor,
force to a restricted joint in a scalene muscles, these vessels fracture, or maladaptive posture.
specific direction to improve may be injured acutely or Three-point pressure: The
range of motion. The cast is chronically secondary to trauma controls incorporated in
applied and removed on a or cervical spine and orthotic systems are based on
frequent basis. Each cast glenohumeral overuse three-point force systems that
gradually increases the range of syndromes. affect alignment by controlling
motion in the affected joint. two adjacent skeletal segments.
Seronegative T The corrective force is located
spondyloarthropathies: Also Tension: Tension neuropathy is on the convex side of the curve
referred to seronegative the result of a longitudinal at the joint addressed. Two
spondyloarthritis, seronegative pulling force typically caused by counteractive forces are
spondyloarthropathies are a aberrant, forceful, and excessive positioned on the opposite side
group of related diseases that range of motion of an articular above and below the corrective
have an inflammatory joint on a peripheral nerve. If force. Increasing the distance
component but are negative for the tensile forces are greater of the counteractive forces from
rheumatoid factor. These than the elastic ability of the the corrective force increases
diseases have a common nerve, deformation results the lever arms and the
spectrum of signs and leading to injury of the effectiveness. Based on the
symptoms including a relation functional and connective tissue principle of pressure = total
to HLA-B27, an inflammatory components of the peripheral force/area of force application,
axial/articular arthritis, nerve, resulting in loss of the objective is to distribute the
oligoarthritis, a hereditary afferent, efferent, and autonomic forces over a larger area to
component, and enthesitis. nerve fiber conduction. Tension decrease the resultant pressures,
Examples include psoriatic is the opposite of compression. which may result in skin
arthritis and Reiter syndrome. Slackening is the reduction of breakdown. A well-fitting total
Somatosensation: tension. contact orthosis that avoids
Somatosensation includes the Thallium: Thallium toxicity has bony prominences and uses an
components of the central and been noted to produce appropriate and effective
peripheral nervous systems that dysesthesia, allodynia, distal three-point force system assists
receive and interpret sensory muscle weakness, and sensory in achieving this objective.
information from organs in the impairment. Pesticides and
joints, ligaments, muscles, and rodenticides were historically V
skin. This system processes common sources of thallium Vasa nervorum: All peripheral
information about the length, poisoning, but these are no nerves and the ganglia where
degree of stretch, tension, and longer commonly used. the cell bodies of the autonomic
contraction of muscles; pain; Although industrial occupations nerves are located are
temperature; pressure; and joint may result in exposure to surrounded by small-diameter
position and provides real-time thallium, this is usually a blood vessels (arterioles and
information related to joint low-level and chronic exposure. venules) known as vasa
position and muscle length Consumption of contaminated nervorum, which supply the
during motion and at rest. food and water continues to be blood necessary for the function
Impairment of somatosensation a common source of thallium of the neurons. All nerve
may result in fall risk. exposure. The classic sign of trunks, from large ones such as
Static splint: A static splint is thallium intoxication is alopecia. the sciatic nerve to small ones
indicated to restrict active and Thoracic outlet syndrome: such as the cavernous nerve,
passive range of motion of a Thoracic outlet syndrome is a have their own vasa nervorum.
joint to facilitate healing and constellation of signs and The vasa nervorum of the
prevent further injury. Materials symptoms related to an peripheral nerve trunks can be
used in the fabrication of static impingement of the brachial divided into three groups:
splints tend to be rigid and plexus, subclavian artery, or epineurial, perineurial, and
include steel, aluminum, high- subclavian vein between the endoneurial. Epineurial and
density plastics, and plaster. cervical spine intervertebral perineurial blood vessels form a
2560_Glossary_0347-0360.indd 358 3/16/2015 4:15:04 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Glossary Terms 359
complex network known as the compound (or related set of neuron’s cell body degenerates
epineurial plexus. The epineurial compounds) is called a vitamin distal to the injury. A related
plexus has prominent when it cannot be synthesized process known as wallerian-like
arteriovenous shunts, supplies in sufficient quantities by an degeneration occurs in many
the endoneurial vascular organism and must be obtained neurodegenerative diseases,
compartment, and is innervated from the diet or environment. especially diseases in which
by autonomic nerves such as The term is conditional on the axonal transport is impaired.
sympathetic and peptidergic circumstances and on the Wallerian degeneration occurs
nerves. Injury to the vasa particular organism. For after axonal injury in both the
nervorum may result in example, vitamin C is a vitamin peripheral nervous system and
ischemic (arterial) or for humans but not for most the central nervous system. It
compressive (venous) nerve other animals. Vitamins are occurs in the axon stump distal
fiber injury. classified by their biological and to a site of injury and usually
Vasculitic disorders: Vasculitic chemical activity, not their begins within 24 to 36 hours
disorders, often referred to as structure. Each “vitamin” refers of a lesion, but the process
the vasculitides, refer to a group to a number of vitamer may take 3 weeks. Before
of disorders that target the compounds that all show the degeneration, distal axon
vascular system: lymph, arteries, biological activity associated stumps tend to remain
and veins. A common variable with a particular vitamin. Such electrically excitable. After
of these disorders is the a set of chemicals is grouped degeneration, the distal end of
frequent association with under an alphabetized vitamin the portion of the nerve fiber
common antibodies. “generic descriptor” title. proximal to the lesion sends
Classification of disorders may out sprouts toward the intact
be by etiology, location, or type W connective tissue, and these
or size of the blood vessel Wallerian degeneration: sprouts are attracted by growth
impacted. Examples include Wallerian degeneration is a factors produced by Schwann
temporal arteritis, Behçet process that results when a cells in the tubes. If a sprout
syndrome, and Buerger disease. nerve fiber sustains an reaches the tube, it grows into
Vitamin: A vitamin is an organic axonotmetic or neurotmetic it and advances about 1 mm
compound required by an injury secondary to per day, eventually reaching
organism as a vital nutrient. compression, tension, or disease. and reinnervating the target
Any required organic chemical The axon separated from the tissue.
2560_Glossary_0347-0360.indd 359 3/16/2015 4:15:04 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
2560_Glossary_0347-0360.indd 360 3/17/2015 12:11:29 PM
Appendix: Case Study Answers
Chapter 1: The Anatomy and 4. d. All of the above

5. c. Skin breakdown
Physiology of the Peripheral Nerve
1. d. Nerve Chapter 7: Diabetes Mellitus and
2. a. Axillary
3. c. Axonotmesis Peripheral Neuropathy
4. b. Teres minor
5. c. 2 months 1. b. Monofilament testing
2. d. Hemoglobin A1c
3. c. Inability to sweat
Chapter 4: Peripheral Neuropathy 4.
5.
a. Painful paresthesias
d. Ankle
and Vasculitic, Connective
Tissue, and Seronegative Chapter 8: Peripheral Neuropathy
Spondyloarthropathic Disorders and Infection
1. d. All of the above 1. b. Lyme disease
2. c. Electroneuromyogram 2. a. Erythema migrans
3. a. A functional wrist splint placing the wrist in 3. b. Borrelia burgdorferi
a neutral radial/ulnar deviation posture 4. d. All of the above
4. d. All of the above 5. a. Antimicrobials
5. a. Rheumatoid vasculitis
Chapter 5: Environmental Chapter 9: Peripheral Neuropathy

Toxic Neuropathies Associated With Nutritional
Deficiency
1. a. Ingesting lead-based paint
2. d. Poorly healing wounds 1. a. Beriberi
3. a. Amy’s mother may also have lead 2. d. Skin rash
intoxication and may have passed the high level 3. c. Peripheral edema and congestive heart failure
of lead to Amy while Amy was in utero. 4. b. Guillain-Barré syndrome
4. d. All of the above 5. a. Wernicke-Korsakoff Syndrome
5. d. All of the above
Chapter 10: Peripheral Neuropathy

Chapter 6: Critical Illness and Chronic Kidney Disease
Polyneuropathy
1. d. Urinary tract infection 2. c. Electroneuromyogram of both upper
2. d. All of the above extremities
3. a. Electrodiagnostic studies 3. a. Lack of lower extremity symptoms
361
2560_Appendix_0361-0364.indd 361 3/16/2015 4:13:08 PM

Process CyanProcess
YellowProcess Black
362 Appendix: Case Study Answers
Chapter 15: Overview of
Rehabilitation Intervention for
Chapter 11: Medication- Peripheral Nerve Injury
Induced Neuropathy 1. d. Develop a trusting patient-therapist
collaborative relationship
1. a. Medication-induced neuropathy is a common 2. d. Inability to work secondary to gait instability
side effect of pharmaceutical intervention, the 3. c. Eighth grade
symptoms may have a great impact on the 4. a. Hypothesis-oriented algorithm for clinicians
quality of life of the patient, and effective 5. b. Control inflammation
treatment may be difficult to attain.
3. b. Peripheral neurons Chapter 16: Manual Therapy
5. a. A tactile sensory neuropathy involving the Techniques for Peripheral
hands and feet Nerve Injuries
1. a. Weakness of the ipsilateral digiti minimi
Chapter 12: Electroneurodiagnostic muscle
Assessment and Interpretation 2.
3.
b. Electroneuromyography
b. Lumbar thrust maneuver
1. d. All of the above 4. d. All of the above
2. a. Wrist 5. c. Neurodynamic treatment techniques
4. a. Neurapraxia, neurotmesis, axonotmesis
5. a. Myotonia
Chapter 17: The Role of Physical
Agents in Peripheral Nerve Injury
Chapter 13: Laboratory 1. “Unfortunately, the evidence of the effectiveness
of electrical stimulation in human studies is
Investigation of Suspected poor. There are more effective interventions we
Peripheral Neuropathy should try.”
2. a. TENS and amitriptyline are more effective
1. d. The therapist cannot, with the current than TENS alone.
information presented, rule out diabetes as a 3. b. A 2007 review of ES neither supports nor
cause of the falls. refutes the use of ES for the preservation of
2. a. Hemoglobin A1c functional sarcomeres in denervated muscle.
3. d. Complete blood count 4. c. Although there is considerable evidence of
4. b. Urinalysis the effectiveness of US promoting nerve
5. d. 3 months regeneration in a rat model, there is no quality
evidence of the effectiveness in humans.
5. b. Based on rat models and cellular models,
Chapter 14: The Examination: LLLT is a promising agent as an intervention
for nerve injury.
Evaluation of the Patient With
Suspected Peripheral Neuropathy Chapter 18: Orthotic Intervention
1. b. Yes, because the patient could have two for Peripheral Neuropathy
unrelated diagnoses
2. a. Paint removal 1. d. Elbow positioning
3. a. Loss of balance, sensory disturbances of the 2. d. Both a and b
hand and feet, cognitive impairments 3. b. Figure-of-eight harness
4. c. Serum lead levels 4. d. All of the above
5. d. All of the above 5. d. All of the above
2560_Appendix_0361-0364.indd 362 3/16/2015 4:13:09 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Appendix: Case Study Answers 363
4. b. Raynaud’s phenomenon
Chapter 19: Counseling and 5. b. A supraclavicular pulsatile mass
Behavior Modification Techniques
for Functional Loss and Chapter 24: Entrapment
Chronic Pain Neuropathy in the Forearm,
1. d. All of the above Wrist, and Hand
2. a. Operant therapy is an approach designed to
address the gross motor and cognitive/ 1. a. Ulnar
subjective responses to clinical pain. 2. c. Ulnar nerve impingement at the olecranon
3. d. All of the above fossa
4. d. All of the above 3. c. Abductor digiti minimi
5. b. The behavior of the family 4. d. All of the above
5. b. Electroneuromyogram
Chapter 20: Guillain-Barré

Chapter 25: Entrapment
Syndrome
Neuropathies in the Foot and Ankle
1. a. Areflexia and progressive weakness
2. b. Electroneuromyogram 1. b. Morton’s neuroma
3. c. Plasmapheresis and IVIG therapy 2. c. A positive Tinel sign between the second and
4. d. All of the above third metatarsal heads
5. a. Pain 3. d. Electrical stimulation
5. d. Women often wear high-heeled shoes
Chapter 21: Peripheral Nerve
Injury in the Athlete Chapter 26: Fall Risk and Fall
1. c. Refer Bill for further testing with a tentative Prevention Strategies for
diagnosis of axillary nerve injury
2. d. Stop pitching and begin shoulder
Individuals With Peripheral
strengthening exercise Neuropathy
3. a. Venous thoracic outlet syndrome
(Pagett-Schroetter syndrome) 1. c. BBS
4. d. All of the above 2. d. Wheeled walker
5. c. Biceps 3. b. Rigidity, no confusion, resting tremor
4. d. TheraBand for strengthening the anterior
tibialis and the gastrocnemius/soleus in the
Chapter 22: Effects of Peripheral seated position
Neuropathy on Posture and Balance 5. d. The BBS alone cannot determine the cause
of fall risk.
1. c. Severe
2. b. Afferent peripheral neuropathy
3. a. Expected destabilizations as a result of
Chapter 27: Peripheral
movement of the body limbs Neuropathies in Individuals
5. a. Increased lateral sway during quiet stance With HIV Disease
Chapter 23: Brachial Plexopathies 2. d. Excellent with appropriate physical therapy
1. a. Subclavian artery 4. d. All of the above
2. b. First rib and transverse process 5. b. Referral to an herbalist for a prescription for
3. d. Shoulder impingement St. John’s wort.
2560_Appendix_0361-0364.indd 363 3/16/2015 4:13:09 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
2560_Glossary_0347-0360.indd 360 3/17/2015 12:11:29 PM
INDEX
Page numbers followed by “f ” denote figures, “t” denote tables, and “b” denote boxes
A Arthritis mutilans, 46b somatosensory signals involved in, 254

Abducens nerve testing, 164t Aseptic synovitis, 39f vestibular signals involved in, 254–255
Abetalipoproteinemia, 108 Asymmetric psoriatic arthritis, 46b visual signals involved in, 255
Academic rationalism, 175t Ataxia with vitamin E deficiency, 111 Bannwarth syndrome, 91
Accessory nerve testing, 164t Athletes Barry–Perkins–Young syndrome, 62
Acetaldehyde, 63 acute injuries in, 239–240 Baseball injuries, 246–248
Acid-base balance, 116 axillary nerve injuries in, 243 Basic metabolic panel, 146t, 146–147
Action potentials axonotmetic injuries in, 240 Baxter’s neuritis, 317
back propagating, 4 background on, 239–241 Bechterew syndrome. See Ankylosing spondylitis (AS)
viscoelasticity effects on, 8 baseball, 246–248 Beck Depression Inventory, 164
Activated partial thromboplastin time (APTT), “burner” injuries in, 241–243, 242f Bedrest, 72, 72b, 72f
147 cervical nerve root avulsion in, 242–243 Behavior modification, 223–224
Active range of motion, 160 cheerleading, 245–246 Behavior therapy, 220t–221t, 220–222, 224
Activity planning, 224 common peroneal nerve injuries in, 244, 250 Behavioral change, transtheoretical model of, 326
Acupuncture, 340 cubital tunnel syndrome in, 247–248, 299 Behavioral model, 220
Acute axillary neuropathy, 243 football, 241–244 Behçet disease. See Adamantiades-Behçet disease
Acute axonal degeneration, 11–12 golf, 249 Berg Balance Scale (BBS), 325–326
Acute inflammatory demyelinating polyneuropathy ice hockey, 250 Beriberi, 108–109
(AIDP), 341 long thoracic nerve injury in, 243, 244b Beta-2-microglobulin, 119
Adamantiades-Behçet disease, 43, 43f low back pain in, 249 Bicarbonate, 147
Adductor pollicis paralysis, 300, 300f musculocutaneous nerve palsy in, 243 Biceps brachii, 160, 160f
Adenosine triphosphate (ATP), 201 neurotmetic injuries in, 240 Biceps tendonitis, 275–276
Afferent pathways, 15–16 overuse injuries in, 239 Bicipital aponeurosis, 295
African trypanosomiasis, 99 peroneal nerve compromise in, 243–244 Bilharziasis, 98
AIDS, 92 suprascapular nerve injuries in, 249 Bilirubin, 149t
Alanine aminotransferase (ALT), 148, 149t sural nerve entrapment in, 314 Biofeedback, 224–225
Alcohol dehydrogenase, 63 tennis, 248–249 Biotin, 109
Alcoholism, 63, 108 trampoline injuries, 244–245, 245t Blood alcohol content (BAC), 63–64, 64t
Alcohol-related neuropathy, 53, 63–65, 108 upper extremity deep vein thrombosis in, 247 Blood glucose, 147
Aldose reductase, 80–81 volleyball, 248 Blood lead levels (BLL), 56–57, 57t
Algorithm, 144f Autoantibodies Blood sugar, 147
Alzheimer disease, 3 description of, 38 Blood urea nitrogen (BUN), 147
American trypanosomiasis, 98 in Sjögren’s syndrome, 42 Blood-brain barrier, 125
Amino acids, 106 Autonomic dysfunction, 231 Borg Rating of Perceived Exertion, 326
Amiodarone, 126t, 128–129 Autonomic function testing, 144–145 Borrelia burgdorferi, 90, 90f
Amyloidosis, dialysis-related, 119–120 Autonomic nervous system (ANS) Bortezomib, 126t, 127
Anesthetic agent neuropathies, 54–55 assessment of, 162 Brachial plexopathy
Aneurysmal disease, 272 deep tendon stretch reflex, 163 description of, 269
Angiogenesis, 177 description of, 16 thoracic outlet syndrome. See Thoracic outlet
Ankle neuropathies. See also Lower extremity, lupus, 41 syndrome
entrapment neuropathies of neuropathies associated with dysfunction of, Brachial plexus
manual therapy for, 190–191 163b injuries of
superficial peroneal nerve, 315, 315f Autonomic neuropathy postganglionic, 211
Ankle sprain, 244, 315, 315f description of, 120 preganglionic, 211
Ankylosing spondylitis (AS), 39, 44, 44f, 45b HIV-associated, 341 splinting of, 211f, 211–212
Anorexia nervosa, 108 Axillary arch muscles, 278–279 Parsonage-Turner syndrome involvement of, 275
Anterior interosseous nerve Axillary nerve injuries, 243 radiation fibrosis of, 279
anatomy of, 295–296 Axolemma, 5 splinting of, 211f, 211–212
syndrome involving, 296–297 Axon total decompression of, 283–285
Anterior scalene, 277, 278f–279f anatomy of, 4–5 Brachial plexus syndromes
Anterior tarsal tunnel syndrome, 315 granular disintegration affected by, 12 lower, 273–274
Anticlaw splinting, 217 regenerating, 19 mixed, 274–275
Antidepressants, for HIV-related distal symmetrical unmyelinated, 17 upper, 274
polyneuropathy, 337–338. See also Tricyclic Axon hillock, 5, 16 Braden Scale, 72
antidepressants Axonal regeneration, 18, 211 Breast reduction surgery, 280
Antiepileptic drugs, for HIV-related distal symmetrical Axonotmesis Brief Peripheral Neuropathy Screen, 336
polyneuropathy, 337 characteristics of, 9t, 11 Brief small abundant polyphasic potentials (BSAPPs),
Antifreeze poisoning. See Ethylene glycol definition of, 10, 18, 137, 312b 141
Antineutrophil cytoplasmic antibodies (ANCA), 36 description of, 312 British antilewisite, for arsenic poisoning, 61
Antinuclear antibodies, 41, 148 etiology of, 18 Bruns–Garland syndrome, 82
Antiretroviral medications, 332, 334–335 illustration of, 11f Bulbar polio, 92
Anti-tumor necrosis factor alpha drugs, 128 neurotmesis versus, 137 “Burner,” 241–243, 242f
Apoptosis, 127 Axonotmetic lesions, 290–291 Burning foot syndrome, 120
Arcade of Struthers, 301 Axoplasm, 5 Burning mouth syndrome, 107
Arsenic, 53, 60–61, 61b AZT, 332
Arsenic trioxide, 60
Arteriovenous fistula, 118 C
Arteriovenous shunt, 119f B C7
Arthritis Babinski test, 163 elongated transverse process of, 280
enteropathic, 47–48 Back propagating action potentials, 4 fixation of, 279, 282
juvenile idiopathic, 39–40, 40b Balance Calciferol, 111
psoriatic, 46b, 46–47, 47f assessment of, 163–164, 313, 326 Calcitriol, 116
reactive, 44–46, 45t, 46f diabetes mellitus effects on, 260 Cannabis, for HIV-related distal symmetrical
rheumatoid, 38–39, 39f neuropathic effects on, 258–261 polyneuropathy, 338
365
2560_Index_0365-0372.indd 365 3/17/2015 4:21:09 PM

Process CyanProcess
YellowProcess Black
366 Index
Capillary filtration coefficient, 116 relaxation training for, 224 etiology of, 300
Carbon dioxide, 147 responses to, 220t–221t hand weakness associated with, 300
Carboplatin, 126t Circinate balanitis, 45, 46f high-risk populations for, 247–248, 299–300
Cardiac enzymes, 148 Cisplatin, 126t muscle atrophy associated with, 300
Cardiovascular disease, 118 Clavicular fractures, 279 sites of, 301
Carpal compression test, 298 Clofazimine, 101 in tennis players, 248
Carpal tunnel release, 295, 298, 303 Clonus test, 163 Culture (laboratory test), 150
Carpal tunnel syndrome (CTS) Clotting studies, 147 Cyanocobalamin, 109
anatomy of, 298–299 Cobalamin deficiency, 55, 162 Cytokines
clinical presentation of, 297–298 Cocaine, 156 description of, 27, 30f, 177
compression test for, 298f Coccygeal nerve, 3f mechanical hypersensitivity and, 30
definition of, 297 Cognition, 174 Cytomegalovirus, 228, 341–342
in dialysis-related amyloidosis, 120 Cognitive behavior therapy (CBT), 222, 224–225
electrical stimulation for, 196–197 Cognitive dysfunction, in systemic lupus erythematosus,
incidence of, 25–26 41 D
low-level laser therapy for nerve injury secondary to, Cognitive examination, 164–165 Dactylitis, 47–48, 48f
201–202 Cognitive restructuring, 222 Dapsone, 101
manual therapy for, 185–186 Collaborative treatment model, 174 Deep peroneal nerve, 315f, 315–316
as mononeuropathy, 122 Collateral branches, 5 Deep tendon stretch reflex, 163, 325
Phalen’s test for, 298 Common peroneal nerve injuries Deep vein thrombosis (DVT)
pronator syndrome versus, 295 description of, 312 in Guillain-Barré syndrome, 233
risk factors for, 297 in football athletes, 244 prophylaxis against, 72, 73f
splinting for, 216 in ice hockey athletes, 250 upper extremity, 247
tests for, 297–298, 298f Compartment syndrome, 314 Demyelination, 125
Tinel’s test for, 297–298 Complementary and alternative medicine therapies, Dendrites, 3–4
ultrasound for, 200, 306 340–341 Dendritic zone, 17
Causalgia, 281 Complete blood count (CBC), 145t, 145–146 Denervated muscle, physical agents for preservation of,
Cell body, 3, 5f, 17f Complex regional pain syndrome (CRPS), 269, 281b, 199
Center of mass (COM), 254, 256, 258 281–282 Depression
Center of pressure (COP), 258, 260f Compound muscle action potential (CMAP), chronic pain and, 219–220
Central nervous system (CNS) 136–138 positive psychology for, 223
arsenic poisoning effects on, 61 Compression, 177–178 Developmental Test of Visual-Motor Integration,
components of, 2 Compressive neuropathies, 72b 165
nitrous oxide effects on, 54 Computed tomography, 144 Diabetes mellitus (DM)
nutrition for, 106–107 Concussions, 246 balance affected by, 260
oxygen requirements of, 6 Congenital fibromuscular bands, 277 cardiovascular complications of, 78
poliomyelitis involvement of, 91 Connective tissue disorders cerebrovascular complications of, 78, 79f
Central sensitization, 31, 334 Adamantiades-Behçet disease, 43, 43f complications of, 76–79
Centralization, 187 autoantibodies associated with, 38 definition of, 75
Cervical nerve root avulsion, 242–243 juvenile idiopathic arthritis, 39–40, 40b demographics of, 79–80
Cervical nerves, 3f–4f neuropathies associated with, 38 fall risks in, 253, 259, 322t
Cervical radiculopathy, 72, 182–184, 183f peripheral neuropathies associated with, 21 focal motor neuropathy secondary to, 83f
Cervical rib anomalies, 279–280, 280f rheumatoid arthritis, 38–39, 39f gestational, 75–76
Cervical rotation lateral flexion (CRLF) test, 184 Sjögren’s syndrome, 41–43 ocular complications of, 76–77
Cervical spine nonthrust techniques, 183 systemic lupus erythematosus, 40–41 pathophysiology of, 75–76
Cestodes, 97 Continuous renal replacement therapy (CRRT), 119 peripheral neuropathy caused by, 20
Chagas disease, 98–99 Coordination of care, 179 skin care in, 77–78, 78b, 78f
Charcot neuropathy, 82, 82f Copper, 111–112 tuberculosis and, 95
Charcot-Marie-Tooth disease, 322t, 323 Corticosteroids type 1, 75–76
Cheerleading injuries, 245–246 Guillain-Barré syndrome treated with, 230 type 2, 75–76, 79
Chemokine ligand 5, 333 in HIV-positive patients, 341 ulcerations caused by, 77, 77f
Chemotherapeutic agents, 126t, 126–127, 177 Costoclavicular compression syndrome, 270–271 vascular complications of, 77, 77f
Chief complaint, 153–154 Counseling, 220 Diabetes polyneuropathy, 20
Children Cranial mononeuropathy, 81–82 Diabetic neuropathic cachexia, 81
Guillain-Barré syndrome in, 228 Cranial nerves Diabetic neuropathies
lead poisoning in, 57 description of, 2 asymmetrical, 79t, 81–82
Chloride, 147 examination of, 163, 164t autonomic, 81
Chronic fatigue syndrome (CFS), 99–100 C-reactive protein (CRP), 147–148 characteristics of, 78–79, 81–82, 322t
Chronic inflammatory demyelinating Creatine kinase, 70, 148 Charcot neuropathy, 82, 82f
polyradiculoneuropathy (CIDP), 93–94 Creatine kinase-MB, 148 classification of, 79t, 81–82
Chronic kidney disease (CKD) Creatinine, 147 cranial mononeuropathy, 81–82
autonomic neuropathy in, 120 Critical illness myopathy (CIM) definition of, 79
cardiovascular disease associated with, 118 corticosteroids effect on prevention of, 71 diabetic neuropathic cachexia, 81
economic costs of, 117 deep vein thrombosis prophylaxis in, 72, 73f diabetic radiculoplexus neuropathy, 82
electroencephalography of, 119 etiology of, 69 diabetic thoracic radiculoneuropathy, 82
electrophysiological studies of, 122 overview of, 69–70 distal symmetrical sensorimotor polyneuropathy, 81
etiology of, 115, 117, 117t pathophysiology of, 70–71 early recognition and management of, 79
hemodialysis for, 118 prevention of, 71–73 etiology of, 79
neuropathy induced by, 119–122 signs and symptoms of, 70 fall risk associated with, 322t
paradoxical heat sensation in, 120–121 treatment of, 71–73 glycemic control for, 82–83, 83b
peripheral neuropathy induced by, 119–122 Critical illness polyneuropathy (CIP) hospitalizations for, 79–80
peritoneal dialysis for, 118–119 corticosteroids effect on prevention of, 71 incidence of, 79
prevalence of, 115, 117 deep vein thrombosis prophylaxis in, 72, 73f intervention for, 82–84
restless legs syndrome in, 120, 122 etiology of, 69 microvascular theory of, 80
stages of, 117, 118t overview of, 69–70 nonenzymatic glycosylation theory of, 80–81
symptoms of, 115 pathophysiology of, 70–71 onset of, 154
uremic neuropathy, 119, 121, 121t prevention of, 71–73 pathophysiology of, 80–81
Chronic pain signs and symptoms of, 70 physical therapy for, 83
alternative management strategies for, 222–223 treatment of, 71–73 polyol pathway in, 80
behavior modification strategies for, 223–224 Crohn’s disease, 43, 47 risk factor modification for, 175
behavior therapy for, 220–221, 224 Cubital tunnel syndrome small-fiber neuropathy, 81, 83–84
biofeedback for, 224–225 advanced stages of, 300–301 somatic mononeuropathies, 82
cognitive behavior therapy for, 222, 224–225 anatomy of, 301 symmetrical, 79t, 81
description of, 219–220 in baseball players, 247–248, 299 tricyclic antidepressants for, 83
“experience” of, 225 clinical presentation of, 299–301 Diabetic radiculoplexus neuropathy, 82
family effects of, 221t description of, 185, 217 Diabetic retinopathy, 76–77
operant therapy for, 220–221 elbow flexion test for, 300f, 301 Diabetic thoracic radiculoneuropathy, 82
2560_Index_0365-0372.indd 366 3/17/2015 4:21:10 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Index 367
Diagnosis pathology-specific findings, 138t Extension-oriented exercise treatment, for lumbar
algorithm used in, 144f process of, 136 radiculopathy, 187
illness versus, 176 repetitive nerve stimulation, 138–139 Extensor carpi radialis brevis (ECRB), 292–293
Dialysis-related amyloidosis, 119–120 sensory nerve conduction studies, 137–138, 138t Extensor carpi radialis longus (ECRL), 292–293
Didanosine, 334 Electroneuromyography studies Extensor digitorum longus (EDL), 315
Dideoxycytidine, 334 alcohol-related neuropathy findings, 64–65 Extensor hallucis longus (EHL), 315
1,25-Dihydroxyvitamin D, 116 arsenic poisoning findings, 61 Exteroceptors, 18
Direct intervention, 176–179 critical illness myopathy findings, 70 Eye movement desensitization and reprocessing
Disabilities of the Arm, Shoulder, and Hand (DASH), critical illness polyneuropathy findings, 70 (EMDR), 223
165 diagnostic uses of, 144
Disease-centered model, of health care, 174 ethylene glycol poisoning findings, 63
Disease-modifying antirheumatic drugs (DMARDs), 39 lead poisoning findings, 58 F
Distal interphalangeal joint-predominant arthritis, 46b nitrous oxide peripheral myeloneuropathy findings, F waves, 138
Distal sensory peripheral neuropathy, 93, 93t, 120 55 Facial nerve testing, 164t
Distal symmetrical polyneuropathy, HIV-associated Electronic medical record (EMR), 176 Facial weakness, 165b
antidepressants for, 337–338 Elevation, 178 Fall(s)
antiepileptic drugs for, 337 Emotional response to injury or illness, 176 definition of, 321
cannabis for, 338 Encephalopathy, 119 description of, 204
central sensitization associated with, 334 Endocrine system, 2 in diabetes mellitus patients, 253, 259, 322t
diagnosis of, 335–336 Endoneural edema, 240 environmental considerations, 324, 328
“dying back” of primary afferent fibers in, 333–334 Endoneurium fear of, 324–325
electromyography of, 336 anatomy of, 18 getting up from the floor after, 327, 327b
epidermal skin punch biopsy for, 336 functions of, 5–6 impairments contributing to, 322t, 328
impairments associated with, 339t End-stage renal disease (ESRD), 115, 117, 118t instability that causes, 253
infection mechanisms associated with, 333 Enteropathic arthritis, 47–48 mechanisms contributing to
medical management of, 336–338 Enthesitis-related arthritis, 40b, 47–48 lifestyle and activity level, 324
muscle weakness associated with, 333 Entrapment neuropathies lower extremities neuromotor dysfunction, 323–324
nerve conduction velocity studies of, 336 carpal tunnel syndrome. See Carpal tunnel syndrome medications, 324–325
neurotoxic neuropathy versus, 334–335 deep peroneal nerve, 315f, 315–316 peripheral sensory declines, 323
nucleoside reverse transcriptase inhibitor side effects definition of, 312 peripheral neuropathy as risk factor for, 259–261, 322
as cause of, 334 electrical stimulation for, 306–307 prevalence of, 321
pain associated with, 333, 336–337, 340–341 Guyon’s canal syndrome, 301–302 somatosensory system’s role in, 261
pathophysiology of, 332, 333–335 lateral plantar nerve, 317 Fall history, 325
peripheral sensitization, 334 low-level laser therapy for, 306 Fall prevention
pharmacological interventions for, 336–338 manual therapy for, 303 activity program for, 327
physical examination findings for, 336 medial plantar nerve, 317 assistive devices for, 327
physical therapy interventions for, 338–339, 339t median nerve, 294–299 education and activity strategies for, 326–327
protease inhibitors associated with, 335 myofascial release of, 303f–304f, 303–304 environmental modifications for, 328
reasons for increases in, 332–333 neural mobilization of, 304–305 getting up from the floor after fall, 327, 327b
reversible causes of, 337 overview of, 289–290 program for, 324, 328
risk factors for, 335, 335b pathophysiology of, 312 strategies for, 326–328
topical medications for, 338 posterior interosseous nerve syndrome, 292–294 Fall risk
tricyclic antidepressants for, 337 posterior tibial nerve, 316f, 316–317 assessment of, 324–326
Distal symmetrical sensorimotor polyneuropathy, 81 radial nerve, 292–294 balance assessments and, 326
Dizziness Handicap Inventory, 325 saphenous nerve, 317–318 description of, 321–323
DNase1, 41 superficial peroneal nerve, 315, 315f impairments contributing to, 322t
Docetaxel, 126t, 127 sural nerve, 314, 314f inactivity and, 324
Dorsal rami, 3 therapeutic taping for, 304f–305f, 305 medications and, 324–325
Dorsal root ganglia treatment of, 303–307 physiological deficits and, 324
description of, 333 ulnar nerve, 299–302 sensory integrity assessments, 325
neurons of, 126 ultrasound for, 305–306 Familial Mediterranean fever, 40
Dorsal root ganglioneuropathy, 42 Wartenberg’s syndrome, 294 Family therapy, 221, 221t, 223
“Double crush syndrome,” 312 Environment modifications, for fall prevention, 328 Fanconi syndrome, 58
“Droopy shoulder syndrome,” 280 Environmental toxic neuropathies Fascicles, 3–6, 17
Dry beriberi, 108 alcohol-related neuropathy, 63–65 Fasciculation potentials, 140
Dynamic Gait Index, 325, 338 anesthetic agents, 54–55 Fastest motor nerve conduction velocity, 137
Dynamic splint, 211, 214f arsenic, 53, 60–61, 61b “Fat baby syndrome,” 76, 76f
Dysautonomia, 231 chemical toxicities, 62–65 Fatigue, 232–233, 324
Dysesthesia, 232 ethylene glycol, 62–63, 63t Fear of falling, 324–325
heavy metals, 55–62 Fibrillation potentials, 139f, 140
lead. See Lead; Lead poisoning Fibromuscular bands, congenital, 277
E mercury, 61–62 Filtration fraction, 117
Echinococcus, 97 nitrous oxide, 53–55 First rib
Edema, 177, 244, 306 overview of, 53–54 anomalies of, 280
Efferent neurons, 7 thallium, 53, 59t, 59–60, 60f transaxillary resection of, 283–286
Efferent pathways, 15–16 Enzymes Flexibility, 178
Elbow flexion test, 300f, 301 cardiac, 148 Flexion, adduction, internal rotation (FAIR) test, 189
Elbow flexion/wrist/hand immobilization splint, 213f liver, 148, 149t Flexor carpi ulnaris (FCU), 301
Electrical stimulation (ES) Epidermal skin punch biopsy, for distal symmetrical Flexor digitorum profundus (FDP), 295
denervated muscle preservation using, 199 polyneuropathy, 336 Flexor digitorum superficialis (FDS), 295
description of, 195–196 Epineurium Flexor pollicis longus (FPL), 296
edema reduction using, 306 description of, 2, 17–18 Flukes, 97, 98f
entrapment neuropathies treated with, 306–307 external, 6, 17 Focal motor neuropathy, 83f
nerve regeneration after, 196–197 functions of, 6 Folic acid, 110
transcutaneous electrical nerve stimulation, internal, 6, 17 Foot deformities, 323, 325
197f–198f, 197–199 Epstein-Barr virus, 228 Foot neuropathies, 190–191. See also Lower extremity,
Electroencephalography (EEG), 119 Erb’s palsy, 281 entrapment neuropathies of
Electrolytes, 111 Erosions, in psoriatic arthritis, 47 Football athletes, 241–244
Electromyography (EMG), 136, 139–141, 313, 325, 336 Erythema migrans, 90, 90f “Footballer’s migraine,” 274
Electroneurodiagnostic studies Erythrocyte sedimentation rate (ESR), 147–148 Footdrop, 111, 323
abbreviations used in, 137t Ethanol, 63 Footwear, 326–327
clinical uses of, 136 Ethylene glycol, 62–63, 63t Four Square Step Test, 326
diagnostic uses of, 144 Examination Frequency rhythmic electrical modulation system
electromyography, 139–141 history-taking. See History-taking (FREMS), 198–199
F waves, 138 laboratory testing. See Laboratory testing Froment’s sign, 300
motor nerve conduction studies, 136–137 physical. See Physical examination Functional examination, 165
overview of, 135–136 Exercise, 224 Functional limitations, 172
2560_Index_0365-0372.indd 367 3/17/2015 4:21:10 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
368 Index
Functional mobility assessments, 325–326 Health Information Technology for Economic and Homeostasis
Functional stretch reflexes, 254 Clinical Health Act, 176 definition of, 2
Health-related quality of life, 326 peripheral neuropathy effects on, 2
Heavy metal poisoning sensory loss effects on, 15–16
G arsenic, 53, 60–61, 61b Horner’s syndrome, 285
Gait lead. See Lead; Lead poisoning Human African trypanosomiasis, 99
analysis of, 313, 325–326 mercury, 61–62 Humeroulnar arcade, 301
description of, 262 thallium, 53, 59t, 59–60, 60f Hyperglycemia, 79
in Guillain-Barré syndrome, 233 Hematocrit, 145t, 146 Hyperkalemia, 146–147
Gait speed, 326 Hemodialysis, for chronic kidney disease, 116, 118 Hyperphacosorbitomycopicosis, 77
Gait stability ratio, 325 Hemoglobin, 145t Hyperreflexic response, 163
Galenus, Aelius, 270f Hemoglobin A1c, 79, 150, 150t, 175 Hypoglossal nerve testing, 164t
Gamma-glutamyltransferase (GGT), 148 Hemostasis, 147 Hypokalemia, 146
Ganglion cysts, 316–317 Henoch-Schönlein purpura, 36 Hyporeflexic response, 163
Gastric bypass surgery, 154 Hepatitis C virus, 94 Hypothesis-Oriented Algorithm for Clinicians
Giant motor unit potentials, 141 Hereditary motor and sensory neuropathy, 323 (HOAC), 143, 144f, 173
Glenohumeral dislocations, 243 Herpes zoster, 342 Hypotonus, 161
Glenohumeral hyperabduction syndrome, 289 Herpes zoster ophthalmicus, 96
Glomerular filtration rate (GFR), 116–117, 119 Heterotopic ossification, 233–234
Glossopharyngeal nerve testing, 164t Hexacarbons, 154 I
Glucose Highly active antiretroviral therapy (HAART) Ice hockey injuries, 250
blood, 147 complementary and alternative medicine therapies Ice therapy, 177
in urine, 149–150 used with, 340–341 Illness
Gluten-free diet, for celiac disease, 48 description of, 92, 126t, 128 diagnosis versus, 176
Glycemic control, for diabetic neuropathies, 82–83, distal symmetrical polyneuropathy and, 332, 334–337 emotional response to, 176
83b History of the present illness, 154 Immunological tests, 148–149
Golf injuries, 249 History-taking Impingement syndrome, 275
Goodenough Draw-a-Person Test, 165 chief complaint, 153–154 Impotence, neurological, 21
Guillain-Barré syndrome (GBS) falls, 325 Inactivity, 324
age of onset, 228 history of the present illness, 154 Infections
areflexia associated with, 229 occupational history, 154–156, 155t chronic fatigue syndrome, 99–100
assessment measures, 235 past medical history, 154 Guillain-Barré syndrome onset after, 227–228
autonomic dysfunction caused by, 231 past surgical history, 154 hepatitis C virus, 94
cardiovascular compromise caused by, 231 review of systems, 156, 156t–157t HIV, 92t, 92–94
characteristics of, 322t social history, 154, 156 leprosy, 100–101, 101f, 101t
in children, 228 HIV Lyme disease, 90f, 90–91
clinical presentation of, 229–230 acute inflammatory demyelinating polyneuropathy overview of, 89–90
corticosteroids for, 230 associated with, 341 parasitic, 97f–98f, 97–99
deep vein thrombosis in, 233 antiretroviral medications for, 332 Parsonage-Turner syndrome, 100
definition of, 227 autonomic neuropathy associated with, 341 poliomyelitis, 91–92
description of, 21, 63, 92–93, 162 characteristics of, 322t tuberculosis, 94–95
diagnosis of, 228–230, 229t complementary and alternative medicine therapies varicella-zoster virus, 95–97, 96f
dysautonomia associated with, 231 for, 340–341 Infiltrative lymphomatosis syndrome, 342
dysesthesia associated with, 232 description of, 92t, 92–94, 331 Inflammation, 147–148, 177–178, 240
epidemiology of, 228–229 distal symmetrical polyneuropathy in Inflammatory bowel disease, 43, 47
fall risk associated with, 322t antidepressants for, 337–338 Inflammatory demyelinating neuropathies, 341–342
fatigue caused by, 232–233 antiepileptic drugs for, 337 Inflammatory demyelinating polyradiculopathy, 227
gait affected by, 233 cannabis for, 338 Inspiratory muscle strength training (IMST), 72–73
heterotopic ossification in, 233–234 central sensitization associated with, 334 Integument
HIV-associated, 94 diagnosis of, 335–336 examination of, 158–160, 159f
H1N1 vaccine and, 229 “dying back” of primary afferent fibers in, 333–334 Guillain-Barré syndrome effects on, 233
incidence of, 228 electromyography of, 336 Interleukin-6, 26
infection as precipitating factor for, 227–228 epidermal skin punch biopsy for, 336 Intermittent cervical traction, 183
inflammatory demyelinating polyradiculopathy as impairments associated with, 339t Intermittent claudication, 77
pathology of, 227 infection mechanisms associated with, 333 International Classification of Disease (ICD), 172
integument effects of, 233 medical management of, 336–338 International Classification of Functioning, Disability
intravenous immunoglobulin for, 230 muscle weakness associated with, 333 and Health (ICF), 172–173, 173t
medical management of, 230 nerve conduction velocity studies of, 336 International normalized ratio (INR), 147
nerve conduction studies of, 229 neurotoxic neuropathy versus, 334–335 Interneurons, 7
neuropathy caused by, 154 nucleoside reverse transcriptase inhibitor side Interoceptors, 18
outcome measures, 235 effects as cause of, 334 Interphalangeal joint contractures, 217
pain syndromes associated with, 232 pain associated with, 333, 336–337, 340–341 Intertrochanteric hip fracture, 176
paralysis caused by, 228 pathophysiology of, 332, 333–335 Intervertebral foramen, 2
phases of, 230 peripheral sensitization, 334 Intravascular thrombosis, 272
physical therapy for, 234b, 235 pharmacological interventions for, 336–338 Intravenous immune globulin, 94, 230
plasmapheresis for, 230 physical examination findings for, 336 Ischemia, 20
prognosis for, 235 physical therapy interventions for, 338–339, 339t Isoniazid
progressive motor weakness associated with, 229–230 protease inhibitors associated with, 335 neurotoxic effects of, 335
psychosocial implications of, 234 reasons for increases in, 332–333 for tuberculosis, 95
quality of life effects of, 235–236 reversible causes of, 337 Ixodes scapularis, 90
recovery of function from, 235 risk factors for, 335, 335b
rehabilitation of, 228, 234 topical medications for, 338
respiratory compromise caused by, 231 tricyclic antidepressants for, 337 J
signs and symptoms of, 234–235 fall risk associated with, 322t Jeanne’s sign, 300
support groups for, 234 highly active antiretroviral therapy for, 332 “Jogger’s foot,” 317
swallowing and speech affected by, 233 infiltrative lymphomatosis syndrome, 342 Juvenile idiopathic arthritis ( JIA), 39–40, 40b
treatment of, 230 inflammatory demyelinating neuropathies associated
viruses associated with, 228 with, 341–342
weakness caused by, 229–232 mononeuropathies associated with, 342 K
Gummatous syphilis, 150 neuromuscular weakness syndrome associated with, Kaposi’s sarcoma, 159, 159f
Guyon’s canal syndrome, 301–302 341 Kawasaki disease, 36
opportunistic infections in, 342 Keratoderma blennorrhagicum, 45
peripheral neuropathies associated with, 332b, 332–342 Ketonuria, 150
H progressive polyradiculopathy in, 342 Kf. See Capillary filtration coefficient
Habits, 156 HLA-B27, 44–45 Kidney
Hamstring strains, 190 HMG CoA reductase inhibitors. See Statins acid-base balance by, 116
Hansen’s disease, 100, 101f Hobbies, 155t arterial blood pressure maintenance by, 116
2560_Index_0365-0372.indd 368 3/17/2015 4:21:10 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Index 369
functions of, 115–116, 116b Low-intensity pulsed ultrasound (LIPUS), 200 chemotherapeutic agents, 126t, 126–127, 177
physiology of, 116–117 Low-level laser therapy (LLLT), 200–202, 202f, 306 drugs associated with, 125, 126t, 155t, 177
Kiloh-Nevin syndrome, 289 Lumbar nerves, 3f–4f highly active antiretroviral therapy, 126t, 128
Kinesio Taping, 304–305, 305f Lumbar radiculitis, 186 leflunomide, 126t, 127–128
Kinetic chain, 178 Lumbar radiculopathy mechanisms of, 125–129
degenerative lateral canal stenosis with, 187 platinum drugs, 126, 126t
description of, 72 risk factors for, 129
L diagnosis of, 187 statins, 128
Laboratory testing etiology of, 186 suramin, 126t, 127
basic metabolic panel, 146t, 146–147 extension-oriented exercise treatment for, 187 synergistic considerations, 129
cardiac enzymes, 148 fall risk associated with, 322t taxanes, 126t, 126–127
complete blood count, 145t, 145–146 lumbar thrust for, 187–188, 188f thalidomide, 126t, 127
culture, 150 manipulation for, 187 vinca alkaloids, 126t, 127
diagnostic uses of, 147–150 manual therapy for, 186–189, 187f–189f Mees lines
hemoglobin A1c, 150, 150t mechanical diagnosis and therapy for, 187 from arsenic poisoning, 61, 159f
hemostasis, 147 microdiscectomy for, 187 from thallium poisoning, 59, 60f, 159f
Hypothesis-Oriented Algorithm for Clinicians, 143, physical therapy for, 187 MEFV gene, 40
144f slump stretch for, 189, 189f Meralgia paresthetica, 190
immunological tests, 148–149 straight leg-raise test for, 187 Mercuric chloride, 62
inflammation, 147–148 Lumbar thrust, 187–188, 188f Mercury poisoning, 61–62
limitations to, 145 “Lupus fog,” 41 Mesoneurium, 6, 17
liver enzymes, 148, 149t “Lupus headaches,” 41 Metacarpophalangeal joint flexion, 210, 210f, 215f, 216
overview of, 143–145 Lyme borreliosis, 90–91 Methotrexate, 39
rapid plasma reagin, 150 Lyme disease, 90f, 90–91 Methyl mercury, 62
urinalysis, 149t, 149–150 Methylmalonyl CoA, 110
Laboratory values, 145 Metronidazole, 335
Lacertus fibrosus, 295 M Microdiscectomy, for lumbar radiculopathy, 187
Lactic acid dehydrogenase (LDH), 148 Macronutrients, 106, 108 Microvascular theory, of diabetic neuropathy, 80
Lambert-Eaton myasthenic syndrome (LEMS), 138 Macrosomia, 76, 76f Middle scalene, 277
Large-fiber neuropathies, 162t Magnesium, 111 Migraine headaches, 274
Large-fiber sensory testing, 161, 162t Magnetic resonance imaging, 144 Mikulicz disease. See Sjögren’s syndrome
Large-vessel injury, 7 Malnutrition, 106, 106t, 108 Mindfulness-based stress reduction, 340
Laser therapy, low-level, 200–202, 202f, 306 Manual testing Minerals, 106
Lateral epicondylalgia, 184–185 for carpal tunnel syndrome, 297–298 Mini-Mental State Examination (MMSE), 164
Lateral epicondylitis, 276 muscle, 160, 160f, 232 Monochromatic infrared energy (MIRE), 203–204, 339
Lateral femoral cutaneous nerve entrapment, 190 for radial tunnel syndrome, 293 Mononeuropathies
Lateral plantar nerve, 317 Manual therapy cranial, 81–82
“Laughing gas.” See Nitrous oxide ankle neuropathies treated with, 190–191 definition of, 122
Lead carpal tunnel syndrome treated with, 185–186 in HIV-positive patients, 342
Environmental Protection Agency allowable levels cervical radiculopathy treated with, 182–184, 183f multiple, 43
for, 58 clinicians who perform, 181 somatic, 82
half-life of, 56–57 cubital tunnel syndrome treated with, 185 Mononeuropathy multiplex, 122
in house paint, 56, 56f, 58 definition of, 181 Motion, 16
industrial uses of, 55–56 entrapment neuropathies treated with, 303 Motor cortex, 29–30
occupational exposure to, 56, 56b foot neuropathies treated with, 190–191 Motor nerve conduction studies, 136–137, 198
tissue storage of, 56–57 hamstring strains treated with, 190 Motor unit potentials, 140–141
Lead encephalopathy, 58 inflammation managed through, 178 Mulder click, 318
Lead poisoning lateral epicondylalgia treated with, 184–185 Multi-Directional Reach Test (MDRT), 326
in adults, 57 lumbar radiculopathy treated with, 186–189, Multiple mononeuropathies, 43
axonal abnormalities caused by, 58 187f–189f Multiple sclerosis, 41
blood lead levels associated with, 56–57, 57t meralgia paresthetica treated with, 190 Muscle wasting, 159f
in children, 57 neurodynamic tests, 182 Muscle weakness
chronic, 57 overview of, 181–182 fall risks associated with, 323
detection of, 57–58 pain modulation using, 182 in Guillain-Barré syndrome, 229–232
electroneuromyography studies for, 58 piriformis syndrome treated with, 189–190 Musculocutaneous nerve palsy, 243
laboratory testing for, 58 research of, 181 Musculoskeletal examination, 160, 160f
neuropathies caused by, 53, 55–59 thoracic outlet syndrome treated with, 184 Myasthenia gravis, 138
physiological effects of, 55 Marie-Strümpell spondylitis. See Ankylosing spondylitis Mycobacterium leprae, 100
in pregnancy, 57 (AS) Mycobacterium tuberculosis, 94–95
prevention of, 58 Massage, 340 Myelin, 5
renal system effects of, 58 Mechanical diagnosis and therapy, for lumbar Myelin sheath, 16–17, 17f
routes of exposure, 56 radiculopathy, 187 Myelinated nerve, 5
screening for, 58 Medial plantar nerve, 317 Myofascial release, for entrapment neuropathies,
signs and symptoms of, 57 Median nerve. See also Carpal tunnel syndrome (CTS) 303f–304f, 303–304
treatment of, 58–59 anatomy of Myoglobinuria, 149
Leflunomide, 126t, 127–128 in carpal tunnel syndrome, 298–299
Leprosy, 100–101, 101f, 101t in pronator syndrome, 295–296, 296f
Lipofuscin, 111 anterior interosseous nerve syndrome of, 296–297 N
Liver enzymes, 148, 149t compression of Naffziger’s syndrome, 270
Long thoracic nerve injury, 243, 244b in carpal tunnel syndrome, 216, 299 Nageotte nodules, 334
Low back pain, in golfers, 249 pronator syndrome as cause of, 294–296 Na+/K+-activated ATPase, 121
Lower extremity deep motor branch of, 299 National Patient Safety Goals, 179
anatomy of, 311–312 demyelination of, 27 Neck distraction test, 183
entrapment neuropathies of entrapment neuropathies of, 294–299 Nerve biopsy, 145
deep peroneal nerve, 315f, 315–316 focal axonal swelling of, 27 Nerve compression, 31
examination of, 313–314 innervation by, 215 Nerve conduction studies
gait analysis in, 313 neuropathy of, 25 Guillain-Barré syndrome diagnosis using, 229
intervention for, 314 plantar cutaneous branch of, 295 motor, 136–137, 198
lateral plantar nerve, 317 pronator syndrome of, 294–296 sensory, 137–138, 138t
medial plantar nerve, 317 splinting of, 215f–216f, 215–216 Nerve growth factor binding, 127
pathology of, 312–313 Medical history, 325 Nerve regeneration, physical agents for, 196–197
posterior tibial nerve, 316f, 316–317 Medication history, 325 Nervous system
superficial peroneal nerve, 315, 315f Medication-induced neuropathy complexity of, 2
sural nerve, 314, 314f additive considerations, 129 description of, 2
neuromotor dysfunction in, fall risk associated with, amiodarone, 126t, 128–129 Neural mobilization
323–324 anti-tumor necrosis factor alpha drugs, 128 for carpal tunnel syndrome, 186
Lower motor neuron injury, 16 bortezomib, 126t, 127 for entrapment neuropathies, 304–305
2560_Index_0365-0372.indd 369 3/17/2015 4:21:10 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
370 Index
for foot neuropathies, 191 vitamin B6, 109 Peripheral edema, 159
sliding technique of, 304–305 vitamin B7, 109 Peripheral myeloneuropathy, 55, 55t
surgical, 304 vitamin B9, 109 Peripheral nerve injuries
terminology associated with, 304 vitamin B12, 109 biomechanical, 19–21
Neurapraxia vitamin B15, 110 chemotoxic, 19–21
characteristics of, 9t, 11, 312 vitamin D, 111 ischemic, 20
definition of, 9, 18, 137, 281, 312b Nutritional status, 106 overuse as cause of. See Overuse/overuse injuries
etiology of, 18 Nutritional supplements, 340 physical agents for. See Physical agents
illustration of, 11f physiological basis for, 19–21
Neurocysticercosis, 97 rehabilitation intervention for. See Rehabilitation
Neurodynamic tests, 182 O intervention
Neurofilaments, 3 Occipital pain, 274 response to, 18–19
Neurogenic thoracic outlet syndrome, 184 Occupational history, 154–156, 155t Seddon classification of, 9t, 9–11, 312b
Neurokinin 1, 28–29 Oculomotor nerve testing, 164t space-occupying lesions and, 20
Neurolemma, 12 Olfactory nerve testing, 164t Sunderland classification of, 10t, 11, 19, 312b
Neurolemmocyte, 5 Oligoarthritis, 40b Peripheral nerves
Neurological examination, 160 Olney’s lesions, 55 biomechanics of, 7–9
Neuroma, 318, 318f Operant therapy, 220–221 chronic compression of, 20
Neuromuscular rehabilitation, 178 Opportunistic infections, 342 circulatory system in, 7
Neuromuscular weakness syndrome, HIV-associated, Optic nerve testing, 164t cross-sectional representation of, 16f–17f
341 Optic neuritis, 163 definition of, 2
Neurons Optic neuropathy, 107 description of, 15
anatomy of, 16 Orthostatic hypotension, 162, 231, 260 elongation of, 8
conductivity of, 3 Orthotics inflammation of, spinal cord neuroplastic changes
definition of, 3 fabrication of, 209 induced by, 28–29
dendrites of, 3–4 splints/splinting. See Splints/splinting sensitization of, 30–31
directional transport of, 7 Osteoporosis structure of, 16–18
dorsal root ganglia, 126 in ankylosing spondylitis, 44 tensile strength of, 8, 19
efferent, 7 in celiac disease, 48 Peripheral nervous system lupus, 41
excitability of, 3 Otoliths, 255 Peripheral nervous system (PNS)
myelinated, 17f Overuse/overuse injuries alcohol effects on, 65
spinal cord, 125 animal model of, 26–29, 27f–29f, 31–32 blood supply of, 7, 7f, 18
spinal motor, 16 in athletes, 239 components of, 2
types of, 5t carpal tunnel syndrome, 25–26 conduction structures of, 2
Neuropathic pain. See also Pain effects of, 26 functional anatomy of, 2–7, 3f
description of, 176 rat model of, 26–29, 27f–29f, 31–32 nutrition for, 107
distal symmetrical polyneuropathy as cause of, 333 Oxalic acid, 63 oxygen requirements of, 6
modulation of, 197f–198f, 197–198 Oxaliplatin, 126t support structures of, 2
transcutaneous electrical nerve stimulation for, Peripheral neuropathy
197f–198f, 197–199 alcohol-related, 53, 63–65
Neuropathies. See also Peripheral neuropathy; specific P behaviors predisposing to, 156t
neuropathy Paclitaxel, 126t, 127 in celiac disease, 48
causes of, 25 Paget-Schroetter syndrome, 247, 270, 272 chronic kidney disease as cause of, 119–122
connective tissue disorders and, 38 Pain. See also Neuropathic pain connective tissue disorders associated with, 21
diabetic. See Diabetic neuropathies acupuncture for, 340 definition of, 2
entrapment. See Entrapment neuropathies behavior therapy for, 220t–221t, 220–222 diabetes mellitus as cause of, 20, 78–79. See also
nutritional deficiency-related. See Nutritional chronic. See Chronic pain Diabetic neuropathies
deficiency-related neuropathies complementary and alternative medicine therapies ethylene glycol as cause of, 63
vasculitic, 37 for, 340–341 fall risks, 259–261
Neurosyphilis, 150 complex regional pain syndrome, 269, 281b, 281–282 functional impairments caused by, 165
Neurotmesis definition of, 222 habits predisposing to, 156t
axonotmesis versus, 137 Fordyce’s model of, 220 HIV-related, 92t, 92–94
characteristics of, 9t in HIV-related distal symmetrical polyneuropathy, hobbies predisposing to, 155t
definition of, 10, 19, 137, 312b 333, 336–337, 340–341 homeostasis affected by, 2
description of, 312 responses to, 220, 220t–221t infections that cause. See Infections
illustration of, 11f stress management used to reduce, 340 nitrous oxide, 53–55, 55t
types of, 19 suffering versus, 222 occupations predisposing to, 155t
Neurotoxic neuropathy, 334–335 Pain behaviors, 222 risk factors for, 25
Neurotubules, 3 Pain modulation Seddon classification of, 9t, 9–11, 312b
Niacin, 109 low-level laser therapy for, 202 signs and symptoms of, 291t
Nicotinamide, 109 physical agents for, 197f–198f, 197–198 Sunderland classification of, 10t, 11, 19, 312b
Night blindness, 108 Pain scales, 336 system impairment associated with, 157t
Nitrous oxide, 53–55 Palmaris profundus, 299 Peripheral polyneuropathy, 64
N-methyl-D-aspartate (NMDA) receptor, 54 Pancoast tumors, 20 Peripheral sensitization, 334
NmmAT2, 12 Pantothenic acid, 110 Peritoneal dialysis, for chronic kidney disease, 118–119
N2O. See Nitrous oxide Paragonimus, 97 Peritonitis, 119
Nodes of Ranvier, 5, 17 Paralytic polio, 91–92 Pernicious anemia, 322t
Nonenzymatic glycosylation theory, of diabetic Parasitic infections, 97f–98f, 97–99 Peroneal nerve injury, in football athletes, 243–244
neuropathy, 80–81 Paresthesia, 127 Peroneal neuropathy, 244
Nonnecrotizing myopathy, 70 Paroxysmal pain, 21 Phalen’s test, 298
Non–patient-identified problems (PIP), 173 Parsonage-Turner syndrome, 100, 275 Phoenix wrist extension outrigger, 212f–213f
Nucleoside reverse transcriptase inhibitors, 93, 128, 332, Partial pressure of oxygen, 7 Phosphoinositides, 80
334–335 Passive cable theory, 3–4 Photobiomodulation, 201
Nutrients, 105–107 Passive range of motion, 160 Phrenic nerve injury, from transaxillary first rib
Nutritional deficiency-related neuropathies Past medical history, 154 resection, 285
clinical presentation of, 107–108 Past surgical history, 154 Physical Activity Scale for the Elderly, 326
copper, 111–112 Patient education, 174, 178–179 Physical agents
electrolytes, 111 Patient self-management, 179 classes of, 196t
macronutrients, 108 Patient-identified problems (PIP), 173 definition of, 196
nutrients, 105–107 Patient-therapist collaboration, 174 denervated muscle preservation using, 199
overview of, 105 “Pencil-in-cup” deformity, 47, 47f description of, 195
α-tocopherol, 110–111 Penicillamine, for arsenic poisoning, 61 electrical stimulation, 195–196
trace elements, 111–112 Perikaryon, 3 frequency rhythmic electrical modulation system,
vitamin A, 108 Perineurial membrane, 8 198–199
vitamin B1, 108–109 Perineurium low-level laser therapy, 200–202, 202f
vitamin B2, 109 anatomy of, 18 monochromatic infrared energy, 203–204
vitamin B3, 109 functions of, 6, 18 nerve regeneration using, 196–197
2560_Index_0365-0372.indd 370 3/17/2015 4:21:10 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
Index 371
pain modulation uses of, 197f–198f, 197–198 Potassium chloride, for thallium poisoning, 60 S
pulsed electromagnetic field, 202–203 Prediabetes, 76 Sacral nerves, 3f–4f
role of, 195–196 Pregnancy, lead exposure during, 57 Salivary gland inflammation, in Sjögren’s syndrome,
transcutaneous electrical nerve stimulation, Pressure ulcers, 72b 42
197f–198f, 197–198 Presynaptic sympathetic nerve fibers, 16 Saphenous nerve
ultrasound, 199–201 Problem list, 173 anatomy of, 312
Physical examination Progressive polyradiculopathy, 342 entrapment of, 317–318
Babinski test, 163 Proinflammatory cytokines, 27, 30f, 30–31, 177 Scalene muscles
balance assessment, 163–164 Prolonged immobilization, 177 anterior, 277, 278f–279f
clonus test, 163 Promyelocytic leukemia, 60 middle, 277
cognitive examination, 164–165 Pronator syndrome, 294–296 Scalenectomy, 283
cranial nerves, 163, 164t Proprioception, 161, 162t Scalenotomy, 271, 283
functional examination, 165 Proprioceptive testing, 325 Scalenus anticus syndrome, 270
integument, 158–160, 159f Proprioceptors, 18 Scalenus minimus, 278, 279f, 284
musculoskeletal system, 160, 160f Protease inhibitors, 335 Scalenus pleuralis, 278, 279f
neurological system, 160 Protection, 177 Schistosoma haematobium, 98
overview of, 156–157 Proteins, 106, 149t Schistosoma japonicum, 98
postural assessment, 157, 158f–159f Prothrombin time (PT), 147 Schistosoma mansoni, 98
sensory system, 160–163, 162b Protozoans, 97–99 Schistosomiasis, 98
vital signs, 157 Proximal interphalangeal joint contractures, 214f Schwann cells, 5, 6f, 11–12, 17, 126
Physical therapy, for HIV-related distal symmetrical Psoriatic arthritis, 39, 40b, 46b, 46–47, 47f Seddon classification, 9t, 9–11, 312b
polyneuropathy, 338–339, 339t Pulsed electromagnetic field (PEF), 202–203 Selective serotonin reuptake inhibitors, 337
Pica, 56 Punishment, 221 Self-management, 179
Piriformis syndrome, 189–190 Pyridoxine, 109 Semmes Weinstein filaments, 78f, 84, 203–204,
Pitchers, injuries in, 246 325
Plasmapheresis, for Guillain-Barré syndrome, 230 Senile dementia of Alzheimer type, 3
Platelet count, 145t, 146 R Sensitization, 30–31
Platelets, 146 Radial nerve Sensory nerve action potential (SNAP), 137–138
Platinum drugs, 126, 126t entrapment neuropathies of, 292–294 Sensory nerve conduction studies, 137–138, 138t
Pneumothorax, 285 posterior interosseous nerve syndrome, 292–294 Sensory reweighting, 255–257, 256f
POEMS, 159 splinting of, 212f–215f, 212–215 Sensory systems
Poisonings superficial branch of, entrapment of, 294 description of, 15
arsenic, 53, 60–61, 61b Wartenberg’s syndrome, 294 examination of, 160–163, 162b
ethylene glycol, 62–63, 63t Radial tunnel syndrome, 184, 292–293 Serial casting, 217
lead. See Lead poisoning Radiation fibrosis, 279 Seronegative spondyloarthropathies
mercury, 61–62 Radiographic studies, 144 ankylosing spondylitis, 44, 44f, 45b
thallium, 53, 59t, 59–60, 60f RANTES, 333 enteropathic arthritis, 47–48
Poliomyelitis, 91–92 Rapid plasma reagin (RPR), 150 manifestations of, 44
Polyarthritis, 40b Raynaud’s phenomenon, 42f, 272 overview of, 43–44
Polyneuropathy Reactive arthritis, 44–46, 45t, 46f psoriatic arthritis, 46b, 46–47, 47f
critical illness. See Critical illness polyneuropathy Receptors, 18 reactive arthritis, 44–46, 45t, 46f
definition of, 259 Red blood cell count, 145t, 146 Sharpened Romberg test, 161
diabetes, 20 Reflex sympathetic dystrophy (RSD), 281–282 Shoes
distal symmetrical. See Distal symmetrical Refsum disease, 163 for fall prevention, 326
polyneuropathy Rehabilitation intervention rocker, 261–262
peripheral, 64 coordination, communication, and documentation of, Short Form-41, 234
uremic, 121–122 174–176 Short Form Health Survey-36, 164–165, 326
Polyol pathway, in diabetic neuropathy, 80 definition of, 174 Short Physical Performance Battery (SPPB), 325
Polyradiculoneuropathy direct intervention, 176–179 Sibson’s fascia, 277
chronic inflammatory demyelinating, 93–94 emotional response to injury or illness, 176 Sicca syndrome. See Sjögren’s syndrome
in Sjögren’s syndrome, 42 Guillain-Barré syndrome, 228, 234 Sinusitis–infertility syndrome, 62
Positive psychology, 223 Hypothesis-Oriented Algorithm for Clinicians guide Sjögren’s syndrome, 41–43, 160
Posterior interosseous nerve syndrome, 292–294 for, 143, 144f, 173 Skin
Posterior interosseus neuropathy (PIN), 246–247 International Classification of Functioning, Disability assessment of, 325
Posterior tibial nerve, 316f, 316–317 and Health use in, 172–173, 173t care of, in diabetes mellitus, 77–78, 78b, 78f
Postganglionic fibers, 16 overview of, 172 examination of, 158–160, 159f
Postherpetic neuralgia (PHN), 95–96, 342 patient education, 174, 178–179 Sleeping sickness, 99
Postpolio syndrome, 322t, 324 patient-therapist collaboration, 174 “Sliders,” 182, 186
Postural control. See also Balance principles of, 177b Slump stretch, for lumbar radiculopathy, 189, 189f
physiology of, 253–254, 254f Reiter’s syndrome. See Reactive arthritis Small-fiber neuropathy, 81, 83–84
somatosensory signals involved in, 254 Relaxation training, 224 Smoking, 156
vestibular signals involved in, 254–255 Religiosity, 220 Social history, 154, 156
visual signals involved in, 255 Renal blood flow, 117 Sodium, 146
Postural instability Repetitive nerve stimulation (RNS), 138–139 Soft tissue mobilization, for entrapment neuropathies,
description of, 255, 259 Repetitive strain injury, 29–30 303–304
exacerbation of, 262 Rest, 177 Soma, 3
lateral motion limitation as treatment for, 262 Restless legs syndrome (RLS), 120, 122 Somatic mononeuropathies, 82
rocker shoes for, 261–262 Retinol, 108 Somatosensation, 323
treatments and interventions for, 261–262 Retrograde conduction, 4 Somatosensory system, in postural control, 254
vibrating insoles for, 261 Review of systems, 156, 156t–157t Sorbitol, 80
whole body vibration for, 261 Rheumatoid arthritis (RA), 38–39, 39f Space-occupying lesions, 20
Postural orientation, 258 juvenile, 39–40 Sparganosis, 97
Postural sway, 255, 257, 259, 261 Rheumatoid factor (RF), 38, 148 Spasticity, 161
Postural tone, 161 Rheumatoid nodules, 38–39, 39f Spatial summation, 3
Posture Rheumatoid spondylitis. See Ankylosing spondylitis (AS) Specific gravity, 149
adaptation of, to sensory pathway loss, 255–258 Rheumatoid vasculitis (RV), 38 Speech, 233
anticipatory compensation of, 259 Riboflavin, 109 Spinal cord
assessment of, 157, 158f–159f Ridley-Jopling scale, 100–101 central sensitization of, 31
automatic reactions, 258–259 Rifampin, 101 length of, 2
correction of, 178 Rigidity, 161 neurons of, 125
intramodal dependencies, 257–258 Rocker shoes, 261–262 neuroplastic changes of, peripheral nerve
loss of individual inputs effect on, 257 Rod and Frame test, 256 inflammation as cause of, 28–29
“retraining” of, 178 Romaña’s sign, 99 Spinal motor neuron, 16
sensory reweighting hypothesis of, 255–257, 256f Romberg test, 55, 111, 161 Spinal nerves, 2, 4f
thoracic outlet syndrome caused by abnormalities of, Ronnskar disease, 60 Spinal thrust manipulation with microdiscectomy,
280–281 Rotator cuff tear, 275 188
Potassium, 122, 146–147 Rule-of-nine test, 292, 292f Spirometra, 97
2560_Index_0365-0372.indd 371 3/17/2015 4:21:10 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black
372 Index
Splints/splinting historical background of, 270–271 U
brachial plexus, 211f, 211–212 lower, 273–274 Ubiquinone, 128
combined peripheral nerve injuries treated with, 217, mixed, 274–275 Ulcerative colitis, 43, 47
217f “motor type” neurogenic, 273 Ulnar claw, 302f
dynamic, 211, 214f musculoskeletal problems associated with, 275–276 Ulnar claw splint, 216f
ideal characteristics of, 209 neurological, 272–275 Ulnar groove, 301
mechanics of, 210–211 occipital pain in, 274 Ulnar nerve
median nerve, 215f–216f, 215–216 pathophysiology of anatomy of, 301
minimalistic design of, 217 anterior scalene anomalies, 277, 278f–279f cubital tunnel syndrome of. See Cubital tunnel
overview of, 209 axillary arch muscles, 278–279 syndrome
radial nerve, 212f–215f, 212–215 C7/8 fixation, 279 entrapment neuropathies of, 299–302
static, 210 cervical rib anomalies, 279–280, 280f Guyon’s canal syndrome, 301–302
terminology associated with, 210–211 clavicle abnormalities, 279 Ulnar nerve splinting, 216f, 216–217
three-point pressure splint, 210, 210f congenital fibromuscular bands, 277 Ulnar tunnel syndrome. See Guyon’s canal syndrome
ulnar nerve, 216f, 216–217 elongated C7 transverse process, 280 Ultrasound
wrist, 210, 210f first rib anomalies, 280 carpal tunnel syndrome treated with, 200, 306
Spondylitis middle scalene anomalies, 277 description of, 199–201
ankylosing, 39, 44, 44f, 45b overview of, 276–277 entrapment neuropathies treated with, 305–306
psoriatic arthritis and, 46b postural abnormalities, 280–281 Unmyelinated nerve, 5
Spurling’s test, 161 radiation fibrosis, 279 Upper extremity
St. John’s wort, 341 scalene muscles, 276–277 deep vein thrombosis of, 247
Stance test, 326 scalenus minimus, 278, 279f, 284 dermatomes of, 291f–292f
Static splint, 210 scalenus pleuralis, 278, 279f Upper thoracic outlet syndrome, 274
Statins, 128 traction plexopathy, 281 Uremic neuropathy, 119, 121, 121t
Stavudine, 334 rotator cuff tear associated with, 275 Uremic polyneuropathy, 121–122
Still’s disease, 40b surgery for Urinalysis, 149t, 149–150
“Stinger syndrome,” 241–243, 242f overview of, 282–283 Urine, 116, 149t, 149–150
Straight leg-raising test, 161, 187 results of, 286 Urochrome, 149
Stress management, 340 transaxillary first rib resection, 283–286
Subacute combined degeneration, 110 transaxillary first rib resection for, 271 V
Subclavian artery trapezius spasm in, 275 Varicella-zoster virus, 95–97, 96f
compression of, 271 “true neurogenic,” 272–273 Vasa nervorum, 7, 7f, 18, 20
occlusion of, 271 upper, 274 Vasculitic diseases, 36–37, 37t
Substance P, 28–29, 31, 334 variability in presentation of, 270 Vasculitic neuropathy, 37
Subtalar joint, 191 vascular manifestations of, 271, 272 Vasculitis, 36, 128
Suffering versus pain, 222 venous, 272 Venous thrombectomy, 272
Sullivan’s sign, 318 Three-point pressure splint, 210, 210f Ventral rami, 3
Summation, 3 Thrombin, 147 Vestibular screening, 325
Sunderland classification, 10t, 11, 19, 312b Thrombocytopenia, 146 Vestibular system, in postural control, 254–255
Superficial branch of radial nerve, 294 Thumb abduction splint, 216f Vestibulocochlear nerve testing, 164t
Superficial peroneal nerve Tibial nerve, 312 Vibrating insoles, 261
description of, 191, 312 Tight cells, 7 Vinblastine, 126t
entrapment of, 315, 315f Timed Up and Go test, 325 Vinca alkaloids, 126t, 127
Support groups, 223, 234 Tinel’s sign, 163, 313 Vincristine, 126t
Suprascapular nerve injuries, in tennis players, 249 Tinel’s test, 297–298 Vinflunine, 127
Sural nerve α-Tocopherol, 110–111 Viscoelasticity, 8
anatomy of, 312, 314f Total brachial plexus decompression, 283–285 Vision acuity, 325
entrapment of, 314, 314f Trace elements, 111–112 Visual analog scales, 157
Suramin, 126t, 127 Traction plexopathy, 281 Visual field dependence testing, 256
Swallowing, 233 Trampoline-related injuries, 244–245, 245t Visual system, in postural control, 255
Symmetric psoriatic arthritis, 46b Transaxillary first rib resection, 283–286 Vital signs, 157
Sympathectomy, 284 Transcutaneous electrical nerve stimulation (TENS), Vitamin A, 108
Synapse, 5 197f–198f, 197–199 Vitamin B1, 108–109
Synaptic boutons, 5 Transmembrane ion channels, 3 Vitamin B2, 109
Syphilis, 150 Transtheoretical model, 326 Vitamin B3, 109
Systemic arthritis, 40b Trapezius spasm, 275 Vitamin B6, 109, 335
Systemic lupus erythematosus (SLE), 40–41 Trematodes, 97–98 Vitamin B7, 109
Treponema pallidum, 150 Vitamin B9, 109
T Triatoma infestans, 99 Vitamin B12, 109
Tabes dorsalis, 150 Triceps brachii, 160 Vitamin B15, 110
Taenia solium, 97, 97f Tricyclic antidepressants (TCA) Vitamin D, 111, 116
Taeniasis, 97f for chronic kidney disease-related neuropathy, 122 Vitamin E, 110–111
Tai chi chuan, 340 for diabetic neuropathies, 83 Volleyball injuries, 248
Tapeworms, 97 for HIV-related distal symmetrical polyneuropathy, 337 Voltage-gated ion channels, 3
Tarsal tunnel syndrome, 191, 315, 317 Trigeminal nerve testing, 164t
Taxanes, 126t, 126–127 Trigeminal sensory neuropathy, 42
Teleceptors, 18 Trigger points, 276
W
Wallerian degeneration, 11–12, 18, 137
Temporal arteritis, 36 Trochlear nerve testing, 164t
Warfarin, 272
Temporal summation, 3 “True neurogenic” thoracic outlet syndrome, 272–273
Wartenberg’s sign, 215f, 300, 301f
Tennis injuries, 248–249 Trypanosoma cruzi, 99
Wartenberg’s syndrome, 294
“Tensioners,” 186, 189 Tsetse fly, 99
Weakness, in Guillain-Barré syndrome, 229–232
Thalidomide, 126t, 127 Tuberculosis, 94–95
Web space splint, 215f
Thallium, 53, 59t, 59–60, 60f Tumor necrosis factor-α
Wegener’s granulomatosis, 36–37
Therapeutic taping, for entrapment neuropathies, anti-TNFα drugs, 128
Wernicke–Korsakoff syndrome, 109
304f–305f, 305 pain sensitivity affected by, 30
White blood cell count, 145t, 145–146
Thiamine, 108–109 thalidomide effects on, 127
Whole body vibration, 261
Thimerosal, 62 Tunnel syndromes
Wrist extension immobilization splint, 210, 210f
Thoracic nerves, 3f–4f carpal. See Carpal tunnel syndrome (CTS)
Thoracic outlet syndrome (TOS) definition of, 291
arterial, 271–272 description of, 289 Y
biceps tendonitis in, 275–276 diagnosis of, 291–292 Young syndrome, 62
classic, 273 pathogenesis of, 290–291
complex regional pain syndrome, 269, 281b, 281–282 radial, 184, 292–293 Z
definition of, 269 risk factors for, 291, 291t Zalcitabine, 126t
description of, 159, 184 Seldon classification of, 291, 291t Zidovudine, 334
elements of, 269 signs and symptoms of, 291–292 Zinc, 107
embryology of, 276–277 tarsal, 191, 315, 317 Zoster sine herpete (ZSH), 96–97
2560_Index_0365-0372.indd 372 3/17/2015 4:21:10 PM

Process CyanProcess
CyanProcess Magenta
MagentaProcess
YellowProcess Black

Peripheral Nerve Injury Anatomical PDF

Uploaded by

Copyright:

Available Formats

Peripheral Nerve Injury Anatomical PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Peripheral Nerve Injury Anatomical PDF

Uploaded by

Copyright:

Available Formats

What is the book about?

What is the book about?

What conditions are discussed in relation to peripheral nerve injuries?

What conditions are discussed in relation to peripheral nerve injuries?

Peripheral Nerve Injury

An Anatomical and Physiological Approach

Stephen J. Carp, PT, PhD, GCS

2560_FM_i-xii.indd i 3/17/2015 4:21:06 PM

2560_FM_i-xii.indd ii 3/17/2015 4:21:07 PM

I wish to thank all my teachers and mentors—

2560_FM_i-xii.indd iii 3/17/2015 4:21:07 PM

2560_FM_i-xii.indd iv 3/17/2015 7:02:52 PM

2560_FM_i-xii.indd v 3/17/2015 4:21:07 PM

2560_FM_i-xii.indd vi 3/17/2015 4:21:07 PM

2560_FM_i-xii.indd vii 3/17/2015 4:21:07 PM

Kevin Ball, PhD Jennifer A. Mai, PT, DPT, MHS, NCS

2560_FM_i-xii.indd viii 3/17/2015 7:02:52 PM

Section One: Anatomy, Physiology, Section Two: Etiology of Peripheral Nerve

2560_FM_i-xii.indd ix 3/17/2015 4:21:07 PM

2560_FM_i-xii.indd x 3/17/2015 4:21:07 PM

2560_FM_i-xii.indd xi 3/17/2015 4:21:07 PM

2560_FM_i-xii.indd xii 3/17/2015 4:21:08 PM

Anatomy, Physiology, Biomechanics,

2560_Chapter 1_0001-0014.indd 1 3/16/2015 4:13:12 PM

Introduction The PNS is often simplistically likened to an electri-

2560_Chapter 1_0001-0014.indd 2 3/16/2015 4:13:13 PM

2560_Chapter 1_0001-0014.indd 3 3/16/2015 4:13:13 PM

L5 Figure 1-2 Spinal nerves of the peripheral nervous

2560_Chapter 1_0001-0014.indd 4 3/16/2015 4:13:13 PM

2560_Chapter 1_0001-0014.indd 5 3/16/2015 4:13:13 PM

2560_Chapter 1_0001-0014.indd 6 3/16/2015 4:13:13 PM

Epineurium Biomechanics of Peripheral Nerves

2560_Chapter 1_0001-0014.indd 7 3/16/2015 4:13:14 PM

2560_Chapter 1_0001-0014.indd 8 3/16/2015 4:13:14 PM

Table 1-2 Seddon Classification of Peripheral Neuropathy

2560_Chapter 1_0001-0014.indd 9 3/16/2015 4:13:14 PM

Table 1-3 Sunderland Classification System of Peripheral Neuropathy

2560_Chapter 1_0001-0014.indd 10 3/16/2015 4:13:14 PM

dual myotomal or dermatomal innervation through an Wallerian Degeneration

2560_Chapter 1_0001-0014.indd 11 3/16/2015 4:13:14 PM

2560_Chapter 1_0001-0014.indd 12 3/16/2015 4:13:14 PM

2560_Chapter 1_0001-0014.indd 13 3/16/2015 4:13:14 PM

2560_Chapter 1_0001-0014.indd 14 3/16/2015 4:13:14 PM

Introduction Efferent, Afferent, and

2560_Chapter 2_0015-0024.indd 15 3/16/2015 4:13:56 PM

2560_Chapter 2_0015-0024.indd 16 3/16/2015 4:13:57 PM

2560_Chapter 2_0015-0024.indd 17 3/16/2015 4:13:57 PM

2560_Chapter 2_0015-0024.indd 18 3/16/2015 4:13:57 PM

2560_Chapter 2_0015-0024.indd 19 3/16/2015 4:13:57 PM

2560_Chapter 2_0015-0024.indd 20 3/16/2015 4:13:57 PM

2560_Chapter 2_0015-0024.indd 21 3/16/2015 4:13:57 PM

2560_Chapter 2_0015-0024.indd 22 3/16/2015 4:13:57 PM

2560_Chapter 2_0015-0024.indd 23 3/16/2015 4:13:57 PM

Introduction Peripheral Nerve Damage and

2560_Chapter 3_0025-0034.indd 25 3/16/2015 4:14:34 PM

2560_Chapter 3_0025-0034.indd 26 3/16/2015 4:14:35 PM

2560_Chapter 3_0025-0034.indd 27 3/16/2015 4:14:35 PM

Withdrawal threshold (g)

2560_Chapter 3_0025-0034.indd 28 3/16/2015 4:14:35 PM