Abordaje Diagnostico

REVIEW ARTICLE

A Structured Approach
C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E to the Diagnosis of
Peripheral Nervous
ONLINE
System Disorders
By Zachary N. London, MD, FAAN
ABSTRACT
PURPOSE OF REVIEW:Neuroanatomic localization and pattern recognition can
be used to diagnose both focal lesions and generalized disorders of the
peripheral nervous system. This article describes the nature and pattern of
sensory and motor deficits associated with lesions of specific spinal nerve
roots, plexus, or peripheral nerves. It also describes the patterns of
sensory and motor deficits that suggest multifocal or generalized disorders
of the motor neurons, sensory neurons, and peripheral nerves.
RECENT FINDINGS: The pattern of sensory and motor deficits may be used to
distinguish lesions of the peripheral nervous system from those of the
CITE AS:
central nervous system. The spinal roots, nerve plexus, and peripheral
CONTINUUM (MINNEAP MINN) nerves supply specific muscles and receive sensory input from distinctive
2020;26(5, PERIPHERAL NERVE AND cutaneous regions. Focal lesions of these structures therefore produce
MOTOR NEURON DISORDERS):
1130–1160. characteristic patterns of sensory and motor deficits. Multifocal or
generalized disorders of the peripheral nervous system may be
Address correspondence to distinguished by categorizing their sensory and motor involvement,
Dr Zachary N. London, 1324
Taubman Center, 1500 E Medical
proximal and distal predominance, and degree of symmetry. Serum tests,
Center Dr, Ann Arbor, MI 48109, CSF analysis, electrodiagnostic studies, MRI, ultrasound, nerve biopsy, and
[email protected]. skin biopsy have unique roles in the diagnosis of suspected neuromuscular
RELATIONSHIP DISCLOSURE:
disorders.
Dr London has received personal
compensation for speaking SUMMARY: A structured approach to the diagnosis of nerve and motor
engagements from
the American Academy of neuron disorders can lead to hypothesis-driven diagnostic testing.
Neurology, the American Ancillary tests should be reserved for cases in which confirming or refuting
Association of Neuromuscular
a diagnosis will change patient management.
& Electrodiagnostic Medicine,
the American Clinical
Neurophysiology Society, the
University of Pennsylvania, and
T
the University of Rochester.
INTRODUCTION
UNLABELED USE OF he peripheral nervous system consists of the motor, sensory, and
PRODUCTS/INVESTIGATIONAL
autonomic neural elements that have extensions outside of the brain
USE DISCLOSURE:
Dr London reports no disclosure. and spinal cord. Motor neurons are located in the anterior gray matter
of the spinal cord and are often referred to as anterior horn cells. Their
© 2020 American Academy
axons traverse the nerve roots into the peripheral nerves and
of Neurology. communicate with the muscle at the neuromuscular junction. Sensory neurons
1130 OCTOBER 2020
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

are located in the dorsal root ganglia, which are located posteriorly just outside
the intervertebral foramina.
Dorsal and ventral roots travel through the intervertebral foramina and
fuse to form the spinal nerves. The anterior primary rami form the brachial
and lumbosacral plexus, which terminate in the peripheral nerves. Each of
these neuroanatomic structures is responsible for providing motor input to
specific muscles or receiving sensory input from specific areas in the
extremities or the afferent arcs of the deep tendon reflexes. When a patient
has right-sided focal weakness, the responsible lesion could be anywhere
along the motor pathway from the left motor cortex down through the
decussation at the medullary pyramids, in the corticospinal tracts, or in the
peripheral structures summarized above. For example, isolated weakness of
the right abductor pollicis brevis may be related to a central nervous system
(CNS) lesion or a peripheral lesion involving the C8 or T1 anterior horn cells,
corresponding ventral roots, lower trunk of the brachial plexus, medial cord of
the brachial plexus, median nerve, neuromuscular junction, or the muscle
itself. This list can be whittled down dramatically by adding a second clinical
abnormality, such as numbness over the palmar aspect of the right index
finger. The combination of those findings would make a right median
mononeuropathy significantly more likely than the other possible
localizations. This is the classic strategy of neuroanatomic localization; the
clinician uses the physical examination and a knowledge of functional
neuroanatomy to identify where the involved pathways overlap.
Disorders of the peripheral nervous system may be focal, multifocal, or
generalized, but the classic strategies of neuroanatomic localization work best
with focal lesions. In generalized disorders of the peripheral nervous system, the
innervations of individual muscles become less important than recognizing
patterns, such as whether the weakness and numbness are distal or proximal,
whether symptoms are symmetric between limbs, or whether cranial or
autonomic nerves are involved.
A rational approach to a patient with sensory or motor symptoms answers the
following questions about the clinical presentation:
u Does it localize to the CNS or to the peripheral nervous system?

u Can it localize to a single named peripheral nervous system structure?
u If it is multifocal or generalized:
◇ Does it involve sensory loss or weakness, or both?
◇ Is it primarily proximal or distal, or both?
◇ Is it symmetric or asymmetric?
u Is it acute or subacute in onset?
Often, the answers to these questions will narrow the differential diagnosis
enough so that the judicious use of ancillary testing can verify a specific
diagnosis.
CENTRAL OR PERIPHERAL NERVOUS SYSTEM

One of the first tasks of the clinician is to use the history and physical
examination to distinguish disorders of the peripheral nervous system from
CONTINUUMJOURNAL.COM 1131

APPROACH TO PERIPHERAL NERVOUS SYSTEM DISORDERS
disorders of the CNS. In addition to appreciation of upper motor neuron and

lower motor neuron signs on examination, a number of localization clues can be
useful in distinguishing central versus peripheral lesions (TABLE 1-1).
u Lesions in the brain and brainstem rarely cause pain. A notable exception is central
poststroke pain. This is a rare late effect of ischemic stroke, usually in the thalamus, and is
characterized by contralateral hyperalgesia and allodynia. The presence of pain with
neuropathic features (eg, burning, tingling, electric shock–like sensation) in the affected
limb(s) should prompt the examiner to consider a peripheral etiology.
u Hyporeflexia in a symptomatic limb suggests a peripheral lesion, whereas brisk reflexes in
a symptomatic limb suggest a central lesion.
u If all the signs and symptoms are in a single limb, both central and peripheral
localizations are possible. Hemibody symptoms suggest a central localization; no single
lesion in the peripheral nervous system can cause isolated symptoms affecting an
arm and leg on the same side of the body.
u If a patient has deficits in both strength and pain/temperature sensation in the same limb
and no other abnormalities, the lesion is either in the brain or the peripheral nervous
system, not in the spinal cord.
u Patients with ascending sensory loss in both lower extremities may have either a spinal
cord lesion or a polyneuropathy. Peripheral polyneuropathy causes length-dependent
symptoms and signs, so by the time the sensory loss spreads up above the knee, the
distal upper extremities are usually involved as well. Sensory loss that spreads up
from the feet to the groin or trunk without any upper extremity involvement is almost
always related to spinal cord pathology.
TABLE 1-1 Distinguishing Central From Peripheral Nervous System Lesions
Features Consistent With Any Central Nervous System Localization

◆ Brisk reflexes in an affected limb
◆ Increased tone in an affected limb
◆ Sensory or motor symptoms limited to two limbs on the same side of the body
◆ Weakness of extensors in the upper extremity
◆ Weakness of flexors in the lower extremity
Features Consistent With a Spinal Cord Localization
◆ Sensory loss in both legs with a sensory level on the trunk
◆ Decreased pinprick sensation on one side, weakness and diminished proprioception on the
other side
Features Consistent With a Peripheral Localization
◆ Axial or limb pain
◆ Diminished reflexes in an affected limb
◆ Weakness and diminished pain sensation in the same limb are not due to a spinal cord lesion
and are due to either a peripheral or brain/brainstem lesion
◆ Sensory loss that involves the hands and feet but not the trunk
1132 OCTOBER 2020

u Patients with upper extremity weakness due to a CNS lesion often have preferential KEY POINTS
involvement of the extensors, such as the triceps and wrist and finger extensor muscles.
Although rare, a proximal radial mononeuropathy could also affect these muscles. To rule ● The presence of
that out, it is useful to test the strength of the brachioradialis, which will be reduced in neuropathic pain in an
a proximal radial mononeuropathy but relatively spared (along with the other upper affected limb is more
extremity flexors) in a CNS lesion. suggestive of a peripheral
u Patients with leg weakness due to a CNS lesion often have preferential weakness of nervous system lesion than a
the flexors, such as the iliopsoas, hamstrings, and tibialis anterior. No single peripheral central nervous system
lesion could affect all of these muscles in isolation. lesion.
● Features that suggest a

central nervous system
FOCAL SYMPTOM PATTERN
lesion rather than a
The first question to ask is whether the sensory and motor signs and symptoms peripheral nervous system
can localize to a single named nervous system structure. The spinal nerve roots, lesion include a sensory
nerve plexus, and most peripheral nerves contain both afferent somatic sensory level on the trunk,
nerve fibers and efferent motor fibers. Lesions of these structures may cause hyperreflexia, hemibody
symptoms, weakness of
distinctive patterns of pain, sensory loss, and weakness. extensors in an arm, and
weakness of flexors in a leg.
Radiculopathy ● Neuralgic amyotrophy
A careful neurologic examination coupled with an understanding of the may appear to localize to
neuroanatomic functions of the spinal nerve roots may yield a very specific multiple nerves in the same
localization. TABLE 1-2 and TABLE 1-3 summarize the sensory and motor findings limb rather than a specific
part of the brachial plexus.
associated with lesions at each level.1 Sensory symptoms often precede motor
symptoms in cervical and lumbar radiculopathy. This should be considered in a
patient with axial and radicular pain who presents with a dermatomal pattern of
sensory loss.
The most common mechanisms of spinal nerve root compression are
intervertebral disk herniation and spondylosis.2 Less common causes include
synovial cysts, osteomyelitis and diskitis, vertebral fracture, bony malignant
disease, epidural hematoma, infectious radiculitis, or infiltrative disease of the
meninges. The presence of systemic symptoms may raise suspicion for some of
these less common mechanisms.
Plexopathy
The brachial and lumbosacral plexus are anatomically protected compared
to the spinal nerve roots but may be susceptible to trauma, structural
abnormalities, neoplastic infiltration, or inflammatory processes (TABLE 1-4
and TABLE 1-5).
Neuralgic amyotrophy (also known as idiopathic brachial plexitis or
Parsonage-Turner syndrome) is an uncommon disorder characterized by
subacute onset of pain, weakness, and sensory loss. Although it is usually referred
to as a plexopathy, neuralgic amyotrophy may present with multiple disparate
mononeuropathies in the same limb rather than dysfunction of a focal region of
the brachial plexus.3
Neurogenic thoracic outlet syndrome is a controversial and likely
overdiagnosed condition in which the lower trunk or C8 and T1 nerve roots are
injured or compressed by certain anatomic defects, such as an extra rib. It
presents with aching pain along the medial aspect of the upper extremity and
weakness of the intrinsic hand muscles.4
In patients with breast or lung cancer, the mechanisms of brachial plexopathy
include trauma during surgery, metastatic spread of tumor (which most

TABLE 1-2 Sensory, Motor, and Reflex Distributions of the Upper Extremity Rootsa
Principal Muscles Diminished

Structure Involved Sensory Distribution Reflexes
C5 root Rhomboidsb Lateral upper arm Biceps,
b brachioradialis
Supraspinatus
Infraspinatusb
Deltoidb
Brachioradialisb
Biceps
C6 root Supraspinatus Lateral forearm and hand, first Biceps,

two digits brachioradialis
Infraspinatus
Deltoid
Brachioradialisb
Triceps
Flexor carpi radialisb
Extensor carpi
radialisb
Pronator teresb
C7 root Tricepsb Centermost portion of the distal Triceps

b dorsal forearm and third digit
Flexor carpi radialis
Extensor carpi
radialisb
Pronator teresb
Extensor digitorumb
Flexor digitorumb
Flexor pollicis
longusb
C8 root Triceps Fourth and fifth digits and medial None

b hand
Extensor indicis
Flexor pollicis
longusb
Abductor pollicis
brevisb
Interosseib
T1 root Abductor pollicis Medial forearm None

brevisb
Interosseib
a
Modified with permission from London ZN.1 © 2019 American Academy of Neurology.
b
Muscle may be more prominently involved.
1134 OCTOBER 2020

commonly affects the lower trunk), and radiation injury. Tumor infiltration is
more likely to cause pain than radiation injury.5
Mononeuropathy
Most mononeuropathies occur at specific entrapment sites, regions where
specific nerves are relatively unprotected or susceptible to stretch or
compression due to day-to-day use or repetitive trauma. The most common
entrapment sites are the median nerve at the carpal tunnel, the ulnar nerve at
the elbow, the radial nerve at the spiral groove, and the fibular (peroneal)
nerve at the fibular head (TABLE 1-6 and TABLE 1-7).6 Most of these cause both
sensory and motor manifestations. Other causes of focal nerve injury include
acute trauma, ischemia, compression or invasion by tumor, infection, irradiation,
or injury due to cold.
Sensory, Motor, and Reflex Distributions of the Lower Extremity Rootsa TABLE 1-3

L2 root Iliopsoasb Anterior thigh None

b
Adductor longus
L3 root Iliopsoasb Medial thigh, knee Patellar

b
Quadriceps
Adductor longusb
L4 root Quadricepsb Medial lower leg Patellar

b
Adductor longus
Tibialis anterior
L5 root Gluteus mediusb Lateral lower leg, dorsal None

foot
Hamstrings
Tibialis anteriorb
Extensor digitorumb
Peroneus longusb
Tibialis posteriorb
S1 root Gluteus maximusb Posterior/lateral lower Ankle

b leg, plantar aspect of
Hamstrings
foot
Gastrocnemiusb
Peroneus longus
Extensor digitorum
Tibialis posterior
a
b

The most common mononeuropathies to cause a pure motor syndrome are

those that affect a nerve that does not have a sensory component. Examples
include the suprascapular nerve, the anterior interosseous nerve, or the posterior
interosseous nerve. Occasionally, entrapment of a mixed nerve, such as the ulnar
nerve or fibular (peroneal) nerve, may spare the fascicles involved in sensation.
In these cases, the distribution of the weakness is most helpful in localizing the
lesion. A pure motor syndrome that follows more of a myotomal pattern, with
denervation in the distribution of individual spinal roots, has been reported as a
complication of intrathecal chemotherapy or radiation therapy near the spinal
roots.7 In theory, injury or infiltration of the ventral spinal roots can cause a pure
motor radiculopathy, but this is rare.
TABLE 1-4 Sensory, Motor, and Reflex Distributions of the Upper Extremity Plexusa
Diminished
Structure Principal Muscles Involved Sensory Distribution Reflexes
Upper Supraspinatusb Lateral upper arm and forearm Biceps,

trunk b and first one to two digits brachioradialis
Infraspinatus
Deltoidb
Brachioradialisb
Bicepsb
Triceps
Pronator teres
Extensor carpi radialis
Lower Triceps Medial forearm and hand, None

trunk fourth and fifth digits
Extensor digitorumb
Extensor indicisa
Flexor digitorum
profundusb
Flexor pollicis longusb
Abductor pollicis brevisb
Interosseib
Middle Tricepsb Centermost portion of the Triceps

trunk b distal forearm and third digit
Extensor carpi radialisb
Pronator teresb
Extensor digitorumb
Flexor digitorumb
CONTINUED ON PAGE 1137
1136 OCTOBER 2020

Some peripheral nerves have no motor component. A focal lesion involving
one of these will result in isolated sensory loss in the distribution of that nerve.
Examples in the upper extremity include the superficial radial nerve and the
medial and lateral antebrachial cutaneous nerves. Examples in the lower
extremity include the lateral femoral cutaneous nerve, the saphenous nerve,
and the sural nerve. It is not uncommon for focal mononeuropathies of
mixed nerves to preferentially involve the sensory fascicles. A median
mononeuropathy caused by carpal tunnel syndrome, for example, commonly
presents with wrist pain and sensory loss in the palmar aspect of the first three
or four digits. Patients may not develop the characteristic thenar weakness
until late in the course of the disease.
CONTINUED FROM PAGE 1136
Diminished
Structure Principal Muscles Involved Sensory Distribution Reflexes
Lateral Bicepsb Lateral forearm, palmar hand Biceps
cord b and first three digits
Pronator teres
Flexor carpi radialisb
Flexor digitorumb
Medial Flexor digitorumb Medial forearm and hand, None

cord b fourth and fifth digits
Flexor pollicis longus
Abductor pollicis brevisb
Interosseib
Posterior Deltoidb Dorsal aspect of upper arm, Triceps,

cord b forearm, lateral hand, and the brachioradialis
Teres minor
first three digits
Brachioradialisb
Tricepsb
Extensor digitorumb
Extensor indicisb
a
b

MULTIFOCAL OR GENERALIZED SYMPTOM PATTERN

In patients with multifocal or generalized symptoms that appear to localize to the
peripheral nervous system, the next questions to ask are whether the symptoms
involve sensory loss or weakness, or both; whether they are proximal or distal, or
both; and whether they are symmetric or asymmetric (FIGURE 1-1).
MIXED SENSORY AND MOTOR SYMPTOM PATTERN

Most disorders of nerves, spinal roots, and plexus are characterized by both
sensory and motor involvement. The differential diagnosis can be narrowed
further by recognizing the pattern of signs and symptoms.
Proximal Asymmetric
Proximal asymmetric weakness and sensory loss are usually due to a
polyradiculopathy, polyradiculoneuropathy, or radiculoplexopathy. This pattern
is particularly suggestive of diabetic lumbosacral radiculoplexus neuropathy, also
known as diabetic amyotrophy, which presents with subacute progressive
asymmetric pain and weakness, most prominently affecting the proximal lower
extremity muscles. Most patients have superimposed weight loss and autonomic
dysfunction. The severity of the symptoms does not correlate with the severity of
the diabetes, and, in fact, glycemic dysregulation may be mild at the time of
diagnosis.8 For more information on diabetic lumbosacral radiculoplexus
neuropathy, refer to the article “Diabetes and Metabolic Disorders and the
Peripheral Nervous System” by Christopher H. Gibbons, MD, MMSc, FAAN,9 in
this issue of Continuum. Other causes of proximal asymmetric sensorimotor
symptoms include meningeal disorders, such as carcinoma, lymphoma,
sarcoidosis, or infections, which may infiltrate multiple nerves, roots, and
regions of the plexus.
TABLE 1-5 Sensory, Motor, and Reflex Distributions of the Lower Extremity Plexusa

Lumbar plexus Iliopsoas Anterior thigh, medial and Patellar

lateral thigh, medial lower leg
Quadriceps
Adductor longus
Lower Gluteus medius Posterior thigh, lateral lower Ankle

lumbosacral leg, all of foot
Gluteus maximus
plexus
Hamstrings
Tibialis anterior
Extensor digitorum
Peroneus longus
Tibialis posterior
Gastrocnemius
a
1138 OCTOBER 2020

Proximal and Distal Symmetric KEY POINTS
Peripheral nervous system disorders that involve proximal muscles are usually
● Injuries to nerve roots and
related to involvement of nerve roots (polyradiculopathy). Symmetric proximal mixed nerves, both of which
and distal involvement strongly suggests involvement of both nerve roots and contain both sensory and
the distal peripheral nerves (polyradiculoneuropathy). motor components, may
Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) presents present with pain or sensory
symptoms without
with acroparesthesia followed by symmetric ascending weakness and areflexia,
weakness.
usually developing over 1 to 2 weeks. The weakness usually affects proximal and
distal limb muscles symmetrically and may involve muscles involved in facial ● Chronic inflammatory
expression, speech, swallowing, neck flexion, breathing, and, occasionally, eye demyelinating
movements. Sensory loss is common but usually mild. Most patients report axial polyradiculoneuropathy
progresses for more than
and radicular pain. Patients often develop dysautonomia, characterized by sinus 8 weeks after symptom
tachycardia or labile blood pressure. Ninety percent of patients reach their nadir onset. Unlike acute
by 4 weeks.10 For more information on AIDP, refer to the article “Guillain-Barré inflammatory demyelinating
Syndrome” by Kazim A. Sheikh, MBBS,11 in this issue of Continuum. polyradiculoneuropathy, it is
generally not associated
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) causes with dysautonomia,
slowly progressive proximal and distal weakness, areflexia, and sensory loss. weakness of cranial
Progression continues for more than 8 weeks after symptom onset. Unlike AIDP, muscles, or dyspnea.
CIDP does not usually affect cranial nerves or muscles of respiration. For more
● Mononeuritis multiplex
information on CIDP, refer to the article “Chronic Inflammatory Demyelinating
affects named nerves but
Polyradiculoneuropathy and Its Variants” by Kelly Gwathmey, MD,12 in this not necessarily at the
issue of Continuum. common entrapment sites.
Proximal and Distal Asymmetric

The presence of significant asymmetry in a patient with prominent distal
weakness suggests a mononeuritis multiplex, which is defined by damage to at
least two named peripheral nerves, most often not at entrapment sites. The most
common mechanism is vasculitis, inflammatory destruction of the vasa
nervorum, and resultant ischemic nerve injury. The clinical course is usually
acute or stuttering, with significant pain and sensory and motor deficits in
discrete peripheral nerve distributions.13 Over time, mononeuritis multiplex may
affect so many nerves that the pattern becomes symmetric, a pattern referred to
as confluent mononeuritis multiplex.
Even when only one nerve is involved, the conditions that predispose patients
to mononeuritis multiplex should be considered if no evidence of trauma is
present, the involved nerve is not susceptible to entrapment, or the injury is not
at the common entrapment site (CASE 1-1).
Mononeuritis multiplex may occur in isolation (nonsystemic vasculitic
neuropathy) or may occur as a manifestation of eosinophilic granulomatosis
with polyangiitis, granulomatosis with polyangiitis, microscopic polyangiitis,
or polyarteritis nodosa. Other systemic inflammatory disorders, such as
rheumatoid arthritis, Sjögren syndrome, and systemic lupus erythematosus
(SLE) can predispose patients to mononeuritis multiplex.14 For more
information about vasculitic and other autoimmune axonal neuropathies,
refer to the article “Peripheral Neuropathies Associated with Vasculitis and
Autoimmune Connective Tissue Disease” by Chafic Karam, MD,15 in this issue
of Continuum.
Other causes of multiple mononeuropathies include lymphoma, diabetes,
hepatitis, or human immunodeficiency virus (HIV). Multifocal acquired
demyelinating sensory and motor neuropathy (MADSAM) is a rare variant of

CIDP that causes a chronic sensorimotor mononeuropathy multiplex with

involvement of individual nerves asymmetrically, distal more than proximal and
upper limbs more than lower limbs.16 Hereditary neuropathy with liability to
pressure palsies (HNPP) is an autosomal dominant disorder characterized by
recurrent painless mononeuropathies following compression or trivial trauma.17
Distal Symmetric
Distal symmetric involvement is consistent with a length-dependent
polyneuropathy. The differential diagnosis is based on the relative sensory and
motor involvement.
DISTAL SYMMETRIC POLYNEUROPATHY. The most common pattern of

generalized peripheral nerve dysfunction is aptly referred to as distal symmetric
polyneuropathy. This term is preferred over the less specific terms neuropathy,
peripheral neuropathy, and polyneuropathy, which are often used
interchangeably but fail to exclude focal or multifocal processes.
TABLE 1-6 Sensory, Motor, and Reflex Distributions of the Upper Extremity Nervesa

Dorsal scapular Rhomboidsb None None
b
Suprascapular Supraspinatus None None
b
Infraspinatus
Musculocutaneous Bicepsb Lateral forearm Biceps
Axillary Deltoid Lateral shoulder None
Radial
Superficial sensory nerve at None Dorsal hand and first three digits None
the wrist
Posterior interosseous Extensor digitorumb None None

b
Extensor indicis
At the spiral groove Brachioradialisb Dorsal hand and first three digits Brachioradialis
b
Extensor carpi radialis
Extensor digitorumb
Extensor indicisb
At the axilla Tricepsb Dorsal aspect of upper arm, forearm, lateral Brachioradialis,
b hand, and the first three digits triceps
Brachioradialis
Extensor digitorumb
Extensor indicisb
CONTINUED ON PAGE 1141
1140 OCTOBER 2020

Distal symmetric polyneuropathy is sensory predominant, with little or no
motor involvement until later in the course of the illness when patients may
have mild distal lower extremity weakness. Patients often experience
neuropathic pain, paresthesia, or sensory loss that starts in the toes and feet
because of length-dependent axonal injury. As the disease progresses, the
sensory symptoms move proximally. Around the time that sensory
abnormalities reach the knees, patients may also begin to experience
paresthesia, pain, or sensory loss in the fingertips. Sensory symptoms then
proceed proximally in the upper extremities. Loss of deep tendon reflexes
occurs in a length-dependent pattern. When present, motor involvement also
starts distally, with weakness of the toe flexor and extensor muscles. Atrophy
of the intrinsic foot muscles, such as the extensor digitorum brevis, may be
found before clinically significant weakness.
Patients with distal symmetric polyneuropathy may note mild sudomotor
dysfunction on directed questioning (reduced sweating in the feet or increased
sweating more proximally). However, more significant autonomic neuropathy,
CONTINUED FROM PAGE 1140

Median
Anterior interosseous Flexor pollicis longusb None None

Flexor digitorum
profundus 1–2b
At the carpal tunnel Abductor pollicis Palmar first through third digits None
brevisb
At the elbow Pronator teresb Palmar hand and first through third digits None
b
Flexor digitorum
profundus 1–2b
Abductor pollicis
brevisb
Ulnar
At the wrist Interosseib Palmar aspect of fourth and fifth digits None
b
Interossei
At the elbow Flexor digitorum Medial hand, fourth and fifth digits None
profundus 4–5b
a
b

including orthostatic hypotension, prominent sexual dysfunction, or gastroparesis,

is unusual and suggests specific disorders (eg, diabetes or amyloidosis).
Most distal symmetric polyneuropathies have a chronic time course with slow
progression. Most patients with this pattern have diabetes, prediabetes, or
idiopathic neuropathy. Although uncommon, vitamin B12 deficiency and
paraproteinemia (monoclonal gammopathy) should be excluded in all patients.18
Other common causes of distal symmetric polyneuropathy include toxicity due
to specific chemotherapeutic agents and chronic alcohol use.18
Distal symmetric polyneuropathy with motor greater than sensory
involvement suggests a distinct differential diagnosis. The most common cause
of this pattern is Charcot-Marie-Tooth disease (CMT), also known as hereditary
motor sensory neuropathy. Other diagnostic clues for CMT include a young
age of onset, a positive family history, and high arches and hammer toes related
to long-standing atrophy of intrinsic foot muscles. For more information on
Charcot-Marie-Tooth disease, refer to the article “Charcot-Marie-Tooth Disease
TABLE 1-7 Sensory, Motor, and Reflex Distributions of the Lower Extremity Nervesa
Structure Principal Muscles Involved Sensory Distribution Diminished Reflexes
Femoral
Above inguinal ligament Iliopsoas Medial thigh and lower leg Patellar
Quadriceps
Below inguinal ligament Quadriceps Medial thigh and lower leg Patellar
Obturator Adductor longus Medial thigh None
Sciatic Hamstrings Lateral lower leg, all of foot Ankle

Tibialis anterior
Extensor digitorum
Peroneus longus
Tibialis posterior
Gastrocnemius
Fibular (peroneal)
Deep Tibialis anterior First dorsal webspace None

Extensor digitorum
Superficial Peroneus longus Lateral lower leg, dorsal aspect of foot None
Common Tibialis anterior Lateral lower leg, dorsal aspect of foot None
Extensor digitorum
Peroneus longus
Tibial Tibialis posterior Plantar aspect of foot Ankle

Gastrocnemius
a
1142 OCTOBER 2020

KEY POINTS
● Mononeuritis multiplex is
usually an axonal process,
but multifocal acquired
demyelinating sensory and
motor neuropathy and
hereditary neuropathy with
liability to pressure palsies
are multifocal demyelinating
neuropathies.
● Distal symmetric
polyneuropathy usually
begins to involve the distal
upper extremities around
the time that the lower
extremity sensory
symptoms progress to the
level of the knees.
● Clinical features that

should raise suspicion for a
hereditary cause of
neuropathy include young
age of onset, family history,
and high arches and
FIGURE 1-1 hammer toes.
A pattern recognition approach for multifocal or generalized sensory and motor symptoms.
In each of the nine squares, diagnoses at the top tend to be symmetric, whereas diagnoses at
the bottom tend to be asymmetric.
AIDP = acute inflammatory demyelinating polyradiculoneuropathy; ALS = amyotrophic lateral sclerosis;
CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; CISP = chronic immune sensory
polyradiculoneuropathy; CMT = Charcot-Marie-Tooth disease; DADS = distal acquired demyelinating
symmetric neuropathy; DM1 = myotonic dystrophy type 1; FSHD = facioscapulohumeral dystrophy;
HNPP = hereditary neuropathy with liability to pressure palsies; IBM = inclusion body myositis; MADSAM =
multifocal acquired demyelinating sensory and motor neuropathy; MMN = multifocal motor neuropathy;
MND = motor neuron disease; NMJ = neuromuscular junction; PMA = progressive muscular atrophy; SMA =
spinal muscular atrophy.
and Other Hereditary Neuropathies” by Christopher J. Klein, MD, FAAN,19 in

this issue of Continuum.
Distal acquired demyelinating symmetric (DADS) neuropathy, a variant of CIDP,
is a rare cause of motor greater than sensory distal symmetric polyneuropathy.
DADS is a chronic inflammatory neuropathy characterized by symmetric distal
weakness and sensory loss, often with tremor.20 Many patients have an IgM
monoclonal gammopathy that binds to myelin-associated glycoprotein (MAG).
PURE MOTOR SYMPTOM PATTERN

Widespread weakness without significant sensory loss or pain localizes best to
disorders of the motor neurons, motor nerves, neuromuscular junctions, or the
muscles themselves. A summary of distinguishing features of pure motor
syndromes can be found in TABLE 1-8.
Proximal and Distal Symmetric

Proximal greater than distal symmetric weakness is usually due to a myopathy or,
less commonly, a disorder of neuromuscular junction transmission. Diagnostic

clues supporting a myopathy include myalgia, elevated serum creatine kinase,

and supportive EMG findings. Myasthenia gravis often causes ptosis, diplopia,
and dysarthria and dysphagia, although isolated limb weakness is rare.
Fatigability is a diagnostic clue, and electrodiagnostic studies and the presence of
anti–acetylcholine receptor antibodies confirm the diagnosis. Lambert-Eaton
myasthenic syndrome (LEMS) also causes proximal greater than distal weakness
with fatigue; other symptoms and signs of LEMS include reduced or absent
reflexes that augment following brief exercise and autonomic dysfunction
(particularly dry mouth). Cranial nerve involvement is uncommon. Although
transient improvement in strength is seen following brief exercise, most patients
subjectively report severe fatigue. Identification of antibodies reactive to
voltage-gated calcium channels and electrodiagnostic studies confirm the
diagnosis. Botulism is a syndrome in which the neurotoxin from the bacterium
Clostridium botulinum causes irreversible inhibition of acetylcholine release at the
presynaptic nerve terminals. Botulism presents with ocular and bulbar weakness
(usually with dilated poorly reactive pupils) that progresses to symmetric
descending flaccid paralysis throughout the trunk and extremities. Patients may
have blurry vision and paresthesia but rarely have true sensory loss. Symmetric
CASE 1-1 A 37-year-old woman with 6 months of fatigue, arthralgia, and chronic
cough presented to clinic 1 month after the sudden onset of right
footdrop and severe pain in her lower leg and foot. She had no history of
trauma to the leg or back.
On examination, she had severe weakness of right ankle dorsiflexion
but normal eversion and inversion strength. Sensation was diminished in a
patchy distribution in her feet, most prominently in a nummular area on
the dorsum of her right foot between the first and second toe. Nerve
conduction studies showed asymmetric sural sensory nerve action
amplitudes, lower on the left. The right fibular (peroneal) compound
muscle action potential (CMAP) amplitude was very low, without any
conduction slowing across the knee. Needle EMG showed active
denervation in the right tibialis anterior but was otherwise normal. Left
sural nerve biopsy showed endoneurial vessels with evidence of vessel
wall infarction and transmural infiltration by inflammatory cells.
COMMENT This patient had vasculitic mononeuritis multiplex. The initial clinical picture
was consistent with a focal mononeuropathy of the left deep fibular
(peroneal) nerve, which is not a common entrapment mononeuropathy.
The sudden onset, severe pain, bilateral sensory signs, and abnormal sural
nerve conduction studies further raised suspicion that this was the initial
presentation of mononeuritis multiplex, and the nerve biopsy confirmed
evidence of vasculitis. Additional serologic testing may have helped
determine if the patient’s weight loss, arthralgia, and cough were
manifestations of a systemic vasculitis, such as granulomatosis with
polyangiitis.
1144 OCTOBER 2020

motor neuronopathies also cause this pattern of weakness, although less
commonly than myopathies and neuromuscular junction disorders.
Rarely, CIDP may present with a pure motor syndrome characterized by
symmetric proximal and distal weakness without sensory loss or pain.
Spinal muscular atrophy (SMA) is an autosomal recessive motor neuronopathy
that usually presents in infancy or childhood. It is a pure lower motor neuron
Multifocal or Generalized Pure Motor Syndromes TABLE 1-8
Localization/Disease Pattern of Weakness Distinguishing Clinical Features
Myopathy Proximal predominant greater than Variable

distal predominant or multifocal
Neuromuscular junction
Myasthenia gravis Eyelids, eye movements, face, bulbar Fatigability

with or without limb involvement
Lambert-Eaton myasthenic syndrome Lower extremity predominant Hyporeflexia potentiated by exercise,

dysautonomia
Motor neuron
Amyotrophic lateral sclerosis Limb or bulbar onset Upper motor neuron signs,
pseudobulbar affect, weight loss,
frontotemporal dysfunction
Brachial amyotrophic diplegia Bilateral proximal arms No progression to other body

segments for >12–18 months
Leg amyotrophic diplegia One or both legs No progression to other body

segments for >12–24 months
Spinal muscular atrophy Limb, bulbar and respiratory Autosomal recessive inheritance
pattern, infant or childhood onset
Spinal bulbar muscular Bulbar and proximal Face and tongue fasciculations,
atrophy (Kennedy gynecomastia, X-linked recessive
disease) inheritance pattern
Hirayama disease Unilateral or bilateral hand and forearm Young men, progresses for years then
stabilizes, minipolymyoclonus, cold
paresis
Infectious Segmental or generalized Acute or subacute onset, encephalitis,

signs of systemic infection
Paraneoplastic Segmental or generalized Subacute onset, association with

nonmotor paraneoplastic syndromes
Nerve
Multifocal motor neuropathy Distal upper extremity, weakness in the Weakness more than atrophy early in
distribution of individual nerves; no the course
bulbar or respiratory involvement
Pure motor chronic inflammatory Symmetric proximal and distal Reduced or absent reflexes
demyelinating polyradiculoneuropathy weakness; no bulbar or respiratory
(CIDP) involvement

disease, presenting with progressive limb, bulbar, and respiratory weakness

without spasticity or hyperreflexia. It is classified as type 1, 2, 3, or 4, depending
on the age of onset and expected rate of progression. Type 1 has the earliest
onset and most severe course, whereas type 4 is diagnosed after age 18 and
is not necessarily fatal. It is important to distinguish SMA (a condition for
which effective molecular therapy now exists) from other causes of isolated
childhood weakness, such as congenital myopathies, muscular dystrophies,
and congenital myasthenic syndromes. For more information on SMA, refer to
the article “Spinal Muscular Atrophy” by Jessica Rose Nance, MD,21 in this
issue of Continuum.
In an adult with progressive proximal and distal weakness, progressive
muscular atrophy should be suspected. Progressive muscular atrophy is a
degenerative motor neuron disease only involving lower motor neurons. Most
patients with this pattern eventually develop upper motor neuron signs,
consistent with amyotrophic lateral sclerosis (ALS). Rarely, patients with ALS
will present with bilateral proximal arm weakness without prominent upper
motor neuron involvement (known as brachial amyotrophic diplegia).
Spinal bulbar muscular atrophy (also known as Kennedy disease) is an
X-linked recessive trinucleotide repeat disorder that affects men between the
fourth and seventh decades of life. Spinal bulbar muscular atrophy is a pure
lower motor neuron disorder that has a predilection for the lower cranial nerves.
Patients often present with dysarthria more than dysphagia and fasciculations of
the tongue and lower face. Proximal limb weakness typically follows, along with
atrophy and hyporeflexia in the upper arms and hip girdle. It is slowly
progressive, with disability accumulating over many years or decades. The
genetic defect is in the androgen receptor gene, so patients often have systemic
features such as gynecomastia, impaired sexual function, or infertility.22
Diabetes mellitus is also common. Unlike ALS, a substantial proportion of
patients with spinal bulbar muscular atrophy also have a sensory neuropathy,
which may be clinical or subclinical. For more information on spinal bulbar
muscular atrophy, refer to the article “Amyotrophic Lateral Sclerosis and Other
Motor Neuron Diseases” by Colin Quinn, MD, and Lauren Elman, MD,23 in this
issue of Continuum.

Proximal and distal weakness that is asymmetric is usually due to a neurogenic
disorder, with the exception of inclusion body myositis, which presents
with asymmetric weakness that preferentially involves deep finger flexors
and knee extensor muscles. The most common cause of this pattern of
weakness is ALS.
ALS most often presents with progressive asymmetric painless weakness
affecting both proximal and distal muscles, although distal muscles are affected
first. ALS has a variable presentation, especially early in the course, and no
sensitive biomarker is available to identify the majority of cases. The time course
of symptoms, presence or absence of coincident upper motor neuron signs,
and pattern of weakness are the most useful clinical features for differentiating
ALS from other motor neuron disorders or mimics.
ALS is a progressive, invariably fatal, neurodegenerative disease. It is usually
sporadic, but familial cases are well described and some sporadic cases appear to
be associated with genetic mutations. Apoptosis of the lower motor neurons
1146 OCTOBER 2020

causes degeneration of the motor axons and denervation of the muscles supplied KEY POINTS
by those axons. This leads to fasciculations, weakness, and atrophy in the
● Spinal bulbar muscular
affected muscles. ALS presents with limb onset in about two-thirds of cases atrophy may cause
and bulbar onset in about one-third of cases.24 Weakness may begin fasciculations in the face or
asymmetrically but characteristically spreads to other limbs or regions of tongue, signs of androgen
the brain over months. ALS does not cause pain, but intermittent muscle deficiency (including
gynecomastia), and slowly
cramps are common. Patients often lose a significant amount of body weight,
progressive bulbar and
in part because of muscle loss and dysphagia. Involvement of the lower cranial proximal weakness.
motor nerves is common, but the motor neurons supplying the extraocular
muscles are spared. ● The pseudobulbar affect
Among the degenerative diseases that affect the lower motor neurons, ALS is seen in patients with
amyotrophic lateral
unique in that it also causes dysfunction of the upper motor neurons that run sclerosis represents
from the motor cortex through the brainstem and into the spinal cord dysregulation of emotional
corticospinal tracts. Involvement of the corticobulbar tracts can cause emotional output rather than a mood
lability, characterized by crying or laughing with minimal stimulus. This is disorder.
known as pseudobulbar affect and represents a dysregulation of motor output of ● Overt dementia is not
emotion rather than a mood disorder.25 Patients may note increased yawning. common in amyotrophic
Upper motor neuron involvement causes spasticity, which may present as limb lateral sclerosis, but up to
stiffness causing gait dysfunction and impaired mobility out of proportion to the half of patients will have
some impaired cognition or
weakness. Upper motor neuron signs that may be found on examination include
behavioral problems.
spastic dysarthria, spasticity in the limbs, hyperreflexia, frontal release signs
(such as a palmomental reflex), and primitive reflexes (such as Babinski and ● Brachial amyotrophic
Hoffman signs.) diplegia and leg
Impaired cognition and behavioral problems are common in ALS, with as amyotrophic diplegia
present with painless flaccid
many of 50% of patients having some form of frontotemporal dysfunction and weakness starting in one
15% of patients meeting strict criteria for frontotemporal dementia.26 body segment, which may or
Although ALS typically spreads to involve all limbs, regional variants have may not eventually progress
been described. Brachial amyotrophic diplegia is a pure lower motor neuron to involve other body
segments or cause upper
disorder that leads to progressive weakness limited to the upper extremities for at motor neuron pathology.
least 12 to 18 months. It may start asymmetrically, but most cases progress to
being symmetric. Brachial amyotrophic diplegia is characterized by early
proximal arm involvement, as opposed to typical ALS, in which weakness of the
intrinsic hand muscles may be noted first. The flail leg variant of ALS, also
known as leg amyotrophic diplegia, presents with pure lower motor neuron
involvement limited to one or both lower extremities for at least 12 to 24 months.
Both brachial amyotrophic diplegia and leg amyotrophic diplegia are associated
with atrophy and diminished or absent reflexes in the affected limbs. Both may
eventually progress to involve other body segments or upper motor neurons, at
which point the clinical picture may resemble classic ALS. Life expectancy is
generally greater in brachial amyotrophic diplegia and leg amyotrophic diplegia
than in patients who presented with a more rapid progression between body
segments. A minority of patients never develop weakness beyond a single body
segment, in which case the disease is disabling but may not be fatal.27 For more
information on ALS, refer to the article “Amyotrophic Lateral Sclerosis and
Other Motor Neuron Diseases” by Colin Quinn, MD, and Lauren Elman, MD,23
in this issue of Continuum.
Infectious motor neuronopathies also present with asymmetric proximal and
distal weakness. Poliomyelitis is an infection of the spinal cord caused by the
poliovirus. The poliovirus has a predilection for motor neurons, leading to acute
asymmetric and patchy flaccid paralysis with or without bulbar and respiratory

CASE 1-2 A 35-year-old man presented

with 2 years of left thumb
weakness that had not
improved following carpal
tunnel release surgery.
Following surgery, he
developed progressive
weakness of both hands and
had to quit his job scooping
ice cream. He did not have
any pain or sensory loss. FIGURE 1-2
On examination, he had no Nerve conduction studies showing partial
facial or bulbar weakness. conduction block with proximal stimulation in a
patient with multifocal motor neuropathy.
He had mild atrophy and a APB = abductor pollicis brevis; L = left; NCS = nerve
few fasciculations in his left conduction study.
thenar eminence, but Reprinted with permission from Russell JW, Zilliox LA,
Continuum (Minneap Minn).33 © 2014 American Academy
otherwise bulk appeared
of Neurology.
normal. Strength was 4/5 for
left elbow flexion, wrist
flexion, finger flexion, and
thumb abduction. He could not fully extend the third and fourth fingers
on the right hand. Otherwise, strength was full. Sensation was intact
throughout, and reflexes were diminished but not absent throughout.
Nerve conduction studies were significant for conduction block in
several upper extremity motor nerves (FIGURE 1-233). Active denervation
was seen in some of the intrinsic hand muscles on the left, and decreased
recruitment was seen in the left biceps and right finger extensors. GM1
ganglioside antibody testing was negative.
COMMENT This case highlights many of the classic features of multifocal motor
neuropathy (MMN), and how it can be differentiated from amyotrophic
lateral sclerosis (ALS). The patient presented with slowly progressive focal
asymmetric arm weakness without sensory symptoms. The weakness was
in the distribution of named nerves (left median and right radial) but with
variable weakness of different finger extensors, suggesting differential
fascicular involvement. A motor neuron disease such as ALS would more
typically present with a myotomal pattern of weakness. MMN does not
affect bulbar and facial muscles, whereas ALS eventually does. Patients
with ALS usually have significant atrophy and fibrillations in the clinically
affected muscles; the relative absence of these features suggests that
some of his weakness was caused by demyelination rather than axonal
loss. GM1 ganglioside antibodies are not sensitive, and a positive test is not
necessary to make the diagnosis of MMN in the correct clinical and
electrodiagnostic setting.
1148 OCTOBER 2020

weakness. The polio vaccine became available in 1955, and the disease has been KEY POINTS
eradicated in the United States. The last case of wild-type poliomyelitis that
● Systemic infections with
originated in the United States was in 1979, and the last time a traveler with polio West Nile Virus and specific
was identified in the United States was in 1993.28 In 2019, there were 176 cases of enteroviruses may cause a
wild-type polio worldwide.29 poliolike illness
A poliolike illness has been associated with West Nile virus infection. A small characterized by flaccid
paralysis with or without
percentage of patients with West Nile viremia will develop encephalitis, with
encephalitis.
or without an acute regional flaccid paralysis. Sensory loss in the affected limbs
is common. ● The extensor digitorum
Enterovirus D68 infections have been increasing worldwide since an outbreak brevis muscle may atrophy
in 2014. Although most patients only develop a mild respiratory illness, the virus in sensorimotor distal
symmetric polyneuropathy
is associated with acute flaccid myelitis in a minority of patients.30 but is often relatively spared
Very rarely, patients may develop a motor neuron disease as part of a in distal myopathies.
paraneoplastic syndrome, presenting with subacute-onset asymmetric upper
limb weakness, with or without upper motor neuron involvement.31 This may ● The weakness in
amyotrophic lateral
co-occur with nonmotor manifestations such as sensory neuronopathy. It is a sclerosis tends to follow a
difficult diagnosis to make because the clinical features are nonspecific, and myotomal pattern, whereas
patients often have no known tumor history at the time of presentation. the weakness in multifocal
motor neuropathy may be in
the distribution of specific
Distal Symmetric
peripheral nerves.
Distal symmetric weakness is most commonly due to hereditary motor
neuropathies. Axonal forms of CMT and juvenile forms of ALS have significant ● Early in the course of
phenotypic and genotypic overlap with hereditary spastic paraplegia.32 multifocal motor
Some myopathies, such as myotonic dystrophy type 1, primarily affect the neuropathy, patients may
have significant weakness
distal muscles. A careful sensory examination can usually distinguish a distal with little or no atrophy,
myopathy from a distal symmetric polyneuropathy. The extensor digitorum suggesting that the motor
brevis muscle is often weak and atrophic in sensorimotor neuropathy but axons are still intact.
relatively spared in most distal myopathies.
Distal Asymmetric
Distal asymmetric weakness should raise concern for ALS, particularly if reflexes
are preserved or brisk. Several other disorders cause distal asymmetric weakness
and should be excluded.
Multifocal motor neuropathy (MMN) is an acquired disorder of the motor
nerves presenting with progressive asymmetric limb weakness and characterized
by multifocal conduction block on nerve conduction studies. The underlying
mechanism is an immune attack at the nodes of Ranvier. It can easily be mistaken
for ALS, but it is important to distinguish between the two conditions because
MMN is a treatable and nonlethal condition. In MMN, the lesions are at the
level of the peripheral nerve rather than the cell body in the anterior horn cell,
so weakness and atrophy are more likely to follow a pattern of multiple
mononeuropathies rather than a myotomal pattern as would be seen in ALS.
For example, a patient with ALS who has interosseous weakness will likely also
have ipsilateral weakness of thumb abduction because both are derived
from the C8 and T1 nerve roots and have motor neurons in the same level of the
spinal cord. Patients with MMN often have differential weakness of muscles that
share a myotome but are supplied by different nerves or even different nerve
fascicles (CASE 1-2). Because MMN causes conduction failure at the nodes of
Ranvier, it may cause weakness out of proportion to atrophy, especially early in
the course of the disease.34 Typically, patients with MMN will have diminished

deep tendon reflexes in affected muscles and should not have bulbar or
respiratory involvement. For more information on MMN, refer to the article
“Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Its
Variants” by Kelly Gwathmey, MD,12 in this issue of Continuum.
Hirayama disease, or monomelic amyotrophy, is not a neurodegenerative
disease of the motor neurons but an unusual form of cervical myelopathy that has
a predilection for the motor neurons. Patients are often young men of Asian
descent. Forward displacement of the posterior cervical dural sac with neck
flexion causes cord compression or venous congestion that preferentially
damages the C7, C8, and T1 anterior horn cells on one or both sides (CASE 1-3).
Patients usually present with progressive painless weakness in the hand and
forearm, with sparing of the brachioradialis. Distinctive clinical manifestations
include cold paresis and an irregular tremor (minipolymyoclonus) with finger
extension. Weakness is progressive at first, but the disease plateaus within 5 years
and does not spread to other body segments.35
CASE 1-3 A 19-year-old man presented for evaluation of weakness in his right hand
that had slowly progressed over the previous 2 years. He was a casual
bodybuilder and had been able to maintain excellent muscle bulk
everywhere in his body other than the right forearm and hand. Recently,
he had noticed fasciculations in some of the intrinsic hand muscles. He
did not report any sensory loss or pain, other than a propensity for the
hand to cramp at night.
On examination, he had mild atrophy of the right hand and weakness of
all intrinsic hand muscles on the right, including the interossei and thumb
abductors. Electrodiagnostic testing showed low-amplitude median and
ulnar compound muscle action potentials (CMAPs). On needle EMG,
evidence of active denervation in the right abductor pollicis brevis, flexor
pollicis longus, first dorsal interosseus, and extensor indicis was seen.
MRI of the cervical spine showed focal atrophy of the cord from C5
through C7 vertebral levels. Dynamic MRI with the neck in flexion showed
the posterior dura with anterior displacement and compression of the
cord. The flow voids in the posterior epidural space during neck flexion
were exaggerated, and a crescent-shaped enhancing epidural space
extending from C4 to T2 was seen.
COMMENT Slowly progressive hand weakness in one limb could, in theory, be caused
by a single lesion of the C8 nerve root or lower trunk of the brachial plexus.
However, the lack of pain or sensory loss would be unusual and should
raise suspicion for focal injury to the lower cervical motor neurons. The
dynamic MRI findings described in this case are classic findings in Hirayama
disease, a rare juvenile-onset myelopathy with a predilection for the lower
cervical anterior horn cells. Although it is often known as monomelic
amyotrophy, a significant minority of patients eventually develop
symptoms in the contralateral arm.
1150 OCTOBER 2020

PURE SENSORY SYMPTOM PATTERN KEY POINTS
Sensory dysfunction without significant weakness localizes best to the spinal
● Hirayama disease
cord sensory tracts, the dorsal root ganglia, the sensory nerves, or small (monomelic amyotrophy)
unmyelinated nerves. Most clinically significant lesions will cause static sensory presents in young men with
loss in a fixed distribution. When patients present with episodic migrating unilateral or bilateral hand
paresthesia, a neurologic etiology is rarely identified. weakness that progresses
for years and then plateaus.
Proximal and Distal Symmetric ● Proprioception is often

The central projections of the sensory neurons travel through the dorsal columns involved early in disorders
and the spinothalamic tracts. Disruption of these tracts from trauma, disk affecting the dorsal columns
disease, infection, or toxic-metabolic syndromes leads to sensory loss and pain and late in disorders
affecting the peripheral
below the level of the lesion. A focal injury to the dorsal columns in the lower nerves.
parts of the spinal cord may affect the lower extremities only, mimicking a distal
symmetric polyneuropathy. If the cervical dorsal columns are disrupted, patients ● Patients with sensory
may report generalized sensory loss. Patients with cervical cord involvement neuronopathy may initially
appear weak on
may also report electric shock–like sensations traveling down their spines with confrontational testing but
neck flexion (the Lhermitte phenomenon). are able to generate full
Isolated dorsal column dysfunction may lead to impaired position sense and power when they look at the
two-point discrimination with relatively preserved pain sensation. This is helpful limb being tested.
in differentiating this condition from polyneuropathy, in which proprioception is
● Sensory neuronopathy
usually spared relative to other primary sensory modalities. may be idiopathic or
The dorsal columns are often involved as part of a more extensive myelopathy. associated with Sjögren
A careful history and motor examination may reveal bowel and bladder syndrome, a paraneoplastic
retention, hyperreflexia, or spasticity. syndrome, human
immunodeficiency virus, or
pyridoxine overdose.
All peripheral sensory nerves are derived from neurons located within the dorsal
root ganglia. Certain infectious, inflammatory, and metabolic disorders are known
to preferentially damage these sensory neurons. Because these conditions may
affect any dorsal root ganglion, the sensory loss does not conform to the typical
length-dependent pattern seen in most distal symmetric polyneuropathies. Sensory
loss may be asymmetric and may affect proximal areas before distal areas, including
the upper extremities, face, and trunk. Special sensory modalities may be affected,
and pain is common. The sensory loss in the limbs is often profound, leading to gait
and limb ataxia. Patients may have pseudoathetosis, adventitious movements of
their distal extremities caused by markedly impaired proprioception. The examiner
may initially note weakness on confrontational testing, but strength may normalize
when the patient looks at the limb that is being tested, using visual cues to overcome
their lack of proprioception. Deep tendon reflexes are reduced or absent.
This clinical presentation is strongly suggestive of a sensory neuronopathy but
is nonspecific as to cause. About 20% of cases occur as part of a paraneoplastic
syndrome associated with small cell lung cancer, lymphoma, adenocarcinoma, or
neuroblastoma.36 Paraneoplastic sensory neuronopathy tends to be rapidly
progressive and may co-occur with other paraneoplastic disorders. Other
etiologies include Sjögren syndrome, toxicity related to cisplatin or other
chemotherapies, pyridoxine overdose, or HIV infection, although in many cases
it is idiopathic.
Wartenberg migratory sensory neuritis, a poorly understood multifocal
sensory neuropathy, presents with sudden-onset fixed numbness of one or more
cutaneous nerves with or without preceding pain in the distribution of the

affected nerve(s). The cause of Wartenberg migratory sensory neuritis is

unknown. An autoimmune etiology has been suggested, but immunomodulatory
therapy does not appear to be beneficial.37
A small percentage of patients with small fiber neuropathy present with a
non–length-dependent syndrome of asymmetric proximal and distal pain and
loss of sensation to small fiber modalities (pain and temperature). In this case,
nerve conduction studies are normal, but diagnosis can be confirmed with skin
biopsies from proximal and distal sites stained with protein gene product 9.5 (PGP 9.5).
Multifocal sensory loss may also be related to rare inflammatory diseases such
as a chronic immune sensory polyradiculoneuropathy (CISP); chronic ataxic
neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl
antibodies (CANOMAD); and chronic ataxic neuropathy with anti–disialosyl
IgM antibodies (CANDA).38
Distal Symmetric
As discussed above, distal symmetric polyneuropathy is often sensory predominant
with no motor involvement until later in the course of the illness. Small fiber
polyneuropathy is a subset of distal symmetric polyneuropathy in which only the
small unmyelinated nerve fibers are impaired. These fibers carry pain and
temperature sensation as well as the autonomic fibers destined for the sweat glands
and viscera, so, by definition, patients have no somatic motor involvement. The
most distal nerves tend to be affected most, so symptoms usually begin in the toes or
balls of the feet and gradually spread proximally up the legs and eventually into the
hands. Patients may report a general sense of numbness in these areas or specifically
note an inability to distinguish temperatures or recognize painful stimuli. Painless
injuries may occur. Most patients report paresthesia and neuropathic pain. On
examination, patients will have decreased pain and thermal sensation, with
preserved position sense. Strength and deep tendon reflexes are generally spared.
Autonomic nerve dysfunction may cause decreased sweating in the affected areas.
Loss of autonomic vasomotor control may result in skin color changes, leaving the
TABLE 1-9 Neuromuscular Disorders That Present Acutely or Subacutely
Localization Examples of Disorders

Motor neuron Acute flaccid paralysis, paraneoplastic
Spinal root Disk herniation, varicella-zoster virus
Sensory neuron Paraneoplastic, Sjögren syndrome, pyridoxine toxicity
Plexus Idiopathic neuralgic amyotrophy, diabetic lumbosacral

radiculoplexus neuropathy
Nerve Direct nerve trauma, toxic (eg, chemotherapy or heavy metal-

induced), vasculitic mononeuritis multiplex, acute inflammatory
demyelinating polyradiculoneuropathy (AIDP) and variants
Neuromuscular junction Botulism
Muscle Inflammatory myopathies, rhabdomyolysis due to a metabolic

myopathy, toxic myopathies
1152 OCTOBER 2020

skin looking shiny, dry, and atrophic. Other autonomic symptoms, such as KEY POINT
gastroparesis, erectile dysfunction, or constipation, may occur.39
● The most useful screening
The differential diagnosis for small fiber or sensory predominant polyneuropathy laboratory tests for the
is broad. Some of the more common etiologies include diabetes mellitus, chronic workup of distal symmetric
alcohol use disorder, drug toxicity, and associated with paraproteinemia. polyneuropathy are tests for
diabetes or prediabetes,
serum lipids and
ACUTE OR SUBACUTE ONSET
cholesterol, a vitamin B12
Although the distribution of signs and symptoms is of paramount importance in level, and serum protein
categorizing peripheral nervous system disorders, the time course can narrow electrophoresis and
the differential diagnosis even further, especially if symptoms develop rapidly. immunofixation.
The only truly acute neuromuscular disorders are those related to trauma, such as
a peripheral nerve injury. Infectious, inflammatory, and toxic processes may
present subacutely, developing over hours to days. TABLE 1-9 provides examples
of subacute disorders organized by neuroanatomic localization.
DIAGNOSTIC TESTING
Blood tests, CSF analysis, electrodiagnostic studies, imaging, and tissue biopsy
all serve a situational role in the workup for sensory and motor symptoms.
The history and physical examination are paramount in the diagnosis of
neuromuscular disorders and inform the yield of specific diagnostic tests.
Blood Testing
The purpose of blood testing is to identify evidence of a systemic disorder
that may cause or put the patient at risk for a neuromuscular syndrome.
Mononeuropathy and radiculopathy are usually caused by local trauma;
therefore, blood testing is generally not indicated.
Distal symmetric polyneuropathy, on the other hand, is presumed to be the result
of a systemic process, although it is not always possible to identify the culprit.
Dozens of tests could, in theory, suggest an underlying cause, but only a select few
have a high enough yield to merit testing in all patients with a distal symmetric
polyneuropathy phenotype.40 The most useful test is a measure of serum glucose.
This may include a hemoglobin A1c, fasting glucose, or 2-hour oral glucose tolerance
test. It is controversial whether hemoglobin A1c values in the range suggestive of
prediabetes, impaired fasting glucose, and impaired glucose tolerance should be
considered abnormal in the workup of neuropathy.41 Patients with distal symmetric
polyneuropathy have a very high risk of having metabolic syndrome, so a fasting
cholesterol panel and serum triglycerides should also be checked. Serum protein
electrophoresis and serum immunofixation should be obtained to screen for
paraproteinemia, also known as monoclonal gammopathy. The immunofixation is
important because it may help identify low-level paraproteins that may be
overlooked on serum protein electrophoresis alone. The level of the paraprotein
correlates with risk of malignancy, but even low-level paraproteinemia may be
associated with neuropathy. A serum vitamin B12 level should be obtained; if the
value is borderline (above the lower limit of normal but lower than 500 pg/mL), a
serum methylmalonic acid level should be checked as well. Elevated levels may
suggest a functional vitamin B12 deficiency, even when the vitamin B12 level is
borderline. Up to 50% or more of patients with distal symmetric polyneuropathy
have prediabetes or diabetes, and even more have metabolic syndrome.42 The
serum protein electrophoresis and immunofixation are abnormal in 9%, and
vitamin B12 is abnormal in 3.6%.40 Little evidence is available to support the

routine testing of thyroid-stimulating hormone (TSH), erythrocyte sedimentation

rate, folate, antinuclear antibodies, Venereal Disease Research Laboratory
(VDRL), or other commonly employed blood tests. However, if patients have
systemic symptoms, rapid onset of neuropathy, motor predominance, or a
non–length-dependent pattern, a more thorough evaluation may be indicated.
If hereditary neuropathy is suspected, the clinical phenotype and
electrodiagnostic features can help the physician estimate the likelihood of specific
genetic abnormalities. However, the widespread availability of next-generation
sequencing panels that include both common (PMP22, MPZ, GJB1, and MFN2) and
uncommon mutations may obviate the need to choose individual genes to
sequence.18 X-linked Fabry disease is a treatable cause of small fiber neuropathy,
cardiovascular dysfunction, renal failure, and skin lesions. Men with Fabry disease
will have deficient α-galactosidase A in plasma and leukocytes. Female carriers can
identified by confirming elevated plasma lyso-Gb3 levels.43 In the absence of clinical
features other than small fiber neuropathy, the yield of molecular testing is low.44
Hereditary transthyretin (TTR) amyloidosis is an autosomal dominant multisystem
disease that can present with sensorimotor polyneuropathy. Since it is treatable,
some authors advocate for genetic testing early in the workup of neuropathy,
especially when patients have a family history, evidence of cardiovascular disease,
carpal tunnel syndrome, and prominent dysautonomia.45 Routine genetic testing of
patients with uncomplicated distal symmetric polyneuropathy is not recommended.
Mononeuritis multiplex and nontraumatic plexopathies are often associated
with systemic disease, but little consensus exists on which blood tests have the
highest yield. Studies may include a complete blood cell count, basic metabolic
panel, hemoglobin A1c, HIV, hepatitis panel, and autoimmune testing, including
antinuclear antibodies, erythrocyte sedimentation rate, C-reactive protein,
antineutrophil cytoplasmic antibodies (ANCA), rheumatoid factor, complement
levels, and cryoglobulins.
If the history and examination suggest MMN, it is worthwhile to check for GM1
ganglioside antibodies. Anti-GM1 ganglioside antibodies are detected in at least 50%
of patients with MMN, and their presence is reasonably specific for this condition.34
Blood testing is usually nondiagnostic in demyelinating neuropathies. If the
time course and phenotype are suggestive of CIDP or DADS neuropathy, serum
protein electrophoresis and immunofixation should be obtained. If an IgM
paraprotein is identified, antibodies against MAG may verify the diagnosis of
DADS neuropathy. If an IgA or IgG paraprotein is identified, further workup
may be indicated to screen for POEMS (polyneuropathy, organomegaly,
endocrinopathy, monoclonal plasma cell disorder, and skin changes) syndrome.
In patients with a phenotype suggestive of a sensory neuronopathy, the workup
should include paraneoplastic autoantibodies (especially anti-Hu antibodies),
anti–Sjögren syndrome A (SSA) and anti–Sjögren syndrome B (SSB) antibodies
to screen for Sjögren syndrome, and HIV testing. Pyridoxine levels should be
obtained if a clinical suspicion for toxicity exists. Serum protein electrophoresis,
immunofixation electrophoresis, and Gd1b antibody testing may be helpful in
this population to screen for the rare disorders CANOMAD and CANDA.46
Blood tests are generally low yield in the workup of motor neuron diseases,
with a few exceptions. Genetic testing may be considered in patients with ALS
and affected family members. In cases in which the diagnosis is uncertain or the
patient has signs of frontotemporal dementia, obtaining C9orf72 hexanucleotide
repeat testing may be helpful, even in patients without a clear-cut family history.
1154 OCTOBER 2020

Spinal bulbar muscular atrophy should be considered in a male patient with KEY POINTS
bulbar-predominant pure lower motor neuron weakness and signs of androgen
● Paraproteinemia may be
insensitivity. The diagnosis can be verified by identifying a CAG repeat associated with chronic
expansion on the androgen receptor gene. inflammatory demyelinating
polyradiculoneuropathy, is
CSF Testing common in patients with
distal acquired
CSF albuminocytologic dissociation is defined as a CSF protein concentration of
demyelinating symmetric
greater than 45 mg/dL with white blood cell count of less than 50 cells/mm3. In neuropathy, and is present
the correct clinical context, this finding is supportive of the diagnosis of AIDP. in most patients with
A 2019 study found the sensitivity of this finding to be 73.2% when CSF was POEMS (polyneuropathy,
organomegaly,
obtained an average of 13 days after symptom onset.47 During the course of the
endocrinopathy,
disease, early protein levels may correlate with disease severity. Normal CSF monoclonal plasma cell
results must be interpreted with caution. Some studies suggest that more than disorder, and skin changes)
50% of patients will have normal CSF levels within 1 to 2 weeks of symptom syndrome.
onset, and 12% of patients never show abnormalities.48 A significant pleocytosis
● The overreliance on
in a patient with AIDP suggests associated HIV. The primary use of CSF analysis modest CSF protein
in a patient suspected of AIDP is to exclude infectious diseases and malignancies. elevations is a common
The role of CSF albuminocytologic dissociation in the diagnosis of CIDP is reason for the overdiagnosis
even less clear. One of the most common reasons for the overdiagnosis of CIDP is of chronic inflammatory
demyelinating
putting too much stock in mildly to moderately elevated CSF protein levels.49 polyradiculoneuropathy.
Rather than using the standard upper limit of normal of 45 mg/dL, evidence
indicates that higher age-matched upper limits of normal should be implemented
(50 mg/dL for patients younger than 50 years of age and 60 mg/dL for patients
older than 50 years of age).50 In the absence of both clinical and electrodiagnostic
criteria that support the diagnosis of CIDP, an elevated CSF protein should not be
used to justify immunomodulatory treatment.51
Electrodiagnostic Testing
Electrodiagnostic testing is used to identify a wide range of neuromuscular
disorders. A complete electrodiagnostic evaluation includes two complementary
tests, nerve conduction studies and needle EMG. Nerve conduction studies are
most commonly performed by placing surface electrodes approximating the
location of the nerves beneath the skin. The nerve is stimulated in one location,
and a recording electrode detects a remote response over the surface of the nerve
or an associated muscle. Needle EMG involves inserting a thin needle into
skeletal muscles and recording the electrical activity within the muscle.
Using a combination of these techniques, the electrodiagnostic consultant can
identify and localize neuromuscular lesions to any level of the peripheral nervous
system, including the motor neuron, spinal root, plexus, sensory and motor
peripheral nerves, neuromuscular junction, and the muscle itself.
Electrodiagnostic studies can provide information about whether a process is
focal or generalized, whether a neuropathy is primarily axonal or demyelinating,
and whether nerve dysfunction is subacute or chronic.
Practically speaking, electrodiagnostic testing is more useful for some
diagnoses than others. It should be considered foundational for the diagnosis of
mononeuropathies, mononeuritis multiplex, demyelinating neuropathies,
sensory neuronopathy, plexopathies, disorders of neuromuscular junction
transmission, and motor neuron disorders.
Electrodiagnostic testing has some value in the diagnosis of radiculopathy. It
can determine the function of nerve roots and the chronicity of lesions and rule

out mimics such as mononeuropathy or plexopathy. However, conventional

electrodiagnostic tests can only examine the function of the motor roots. They
are less sensitive in patients with isolated pain and sensory symptoms, a common
clinical scenario.
Electrodiagnostic testing is probably overused in the workup of distal
symmetric polyneuropathy. Nerve conduction studies can identify and determine
the severity of large fiber axonal polyneuropathy but should be normal in pure
small fiber neuropathy.52 Knowing whether large fibers are involved in a distal
symmetric polyneuropathy often has no meaningful impact on patient
management. Thus, the role of electrodiagnostic testing in patients with isolated
distal symmetric numbness is unclear. For more information on the role of
electrodiagnostic testing in the evaluation of peripheral neuropathies, refer to the
article “Test Utilization and Value in the Evaluation of Peripheral Neuropathies”
by Brian C. Callaghan, MD, MS, FAAN,53 in this issue of Continuum.
Imaging
MRI of the cervical, thoracic, or lumbar spine is the preferred imaging modality for
visualizing the soft tissues and bony structures that comprise the neuraxis. It can
identify the most common space-occupying lesions that compress the exiting
nerve roots and abnormalities within the roots themselves. MRI may also show
hypertrophic or enhancing nerve roots in patients with demyelinating
polyradiculoneuropathies such as AIDP, CIDP, and CISP. Dynamic MRI of the
cervical spine can be diagnostic of Hirayama disease. The major limitation of
MRI of the spine is that potentially pathogenic changes, such as intervertebral
disk bulges and neuroforaminal stenosis, are found in a high proportion of
asymptomatic individuals.
Focused MRI of the brachial or lumbosacral plexus may have a role in
identifying neoplastic or infectious infiltration or structural lesions such as
neurogenic thoracic outlet syndrome. The clinical utility of MRI in the diagnosis
of motor neuron disease is unclear. Hyperintense signal along the corticospinal
tracts has been noted in patients with upper motor neuron–predominant
disease.54
Ultrasound is not a new technology, but its role in the diagnosis of
neuromuscular disorders has been expanding with the application of high-
frequency transducers and improved image processing. Ultrasound imaging
enables real-time morphologic evaluation of nerves and muscles. In the correct
clinical context, the finding of an enlarged cross-sectional nerve diameter is
sensitive, but not specific, for the nerve swelling associated with compression
mononeuropathy.55 Other sonographic features can be used to identify traumatic
peripheral nerve injury and demyelinating neuropathies.56 Ultrasound has been
used as an adjunct to EMG to identify fasciculations, decreased muscle thickness,
and increased muscle echo intensity and echo variance in patients with motor
neuron disease.57 Ultrasound is painless and thus is better tolerated than EMG.
Ultrasound is operator dependent and is limited by inadequate penetration,
which is problematic with patients who are obese or when assessing deeper
structures.58
Tissue Biopsy
In the correct clinical context, a nerve or skin biopsy may aid in the diagnosis of
polyneuropathy.
1156 OCTOBER 2020

NERVE BIOPSY. Nerve biopsy is most useful in the evaluation of mononeuritis KEY POINTS
multiplex. Systemic vasculitides that involve small to medium-sized arteries may
● Electrodiagnostic
affect epineurial vessels, resulting in asymmetric painful neuropathy. Serologic testing is an important part
testing, urinalysis, and body imaging may identify the underlying condition, of the workup for
obviating the need for biopsy to support the initiation of immunomodulatory mononeuropathies,
treatment. mononeuritis multiplex,
demyelinating neuropathy,
If a patient with mononeuritis multiplex has no systemic symptoms or all the
sensory neuropathy, and
tests for systemic vasculitis or inflammatory disorders are negative, a nerve motor neuron disease, but it
biopsy may be necessary to diagnose nonsystemic vasculitic neuropathy. is not sensitive for small
Pathologic findings include inflammation around and necrosis of the vessel walls. fiber polyneuropathy or
pure sensory radiculopathy.
Biopsy of a nearby muscle increases diagnostic sensitivity for vasculitis.
Nerve biopsy has limited utility in the diagnosis of CIDP. Pathologic changes are ● MRI of the spine can
often more extensive in proximal portions of peripheral nerves and may affect identify common causes of
motor nerves more than sensory nerves. At the time of biopsy, disease-specific radiculopathy and aid in the
features may have already disappeared. However, signs of demyelination are still diagnosis of chronic
inflammatory demyelinating
considered a supportive feature in the European Federation of Neurological polyradiculoneuropathy and
Societies/Peripheral Nerve Society criteria for CIDP.59 Hirayama disease but may
Electrodiagnostic testing can be used to identify a functionally impaired show degenerative changes
cutaneous nerve for biopsy. The most commonly biopsied nerves are the sural, of questionable significance
in both symptomatic and
radial, or superficial fibular (peroneal) nerves. Complications of nerve biopsy asymptomatic individuals.
include sensory loss, chronic pain, and wound infection. These are usually mild, but,
nonetheless, nerve biopsy should be avoided if the diagnosis can be made with ● Ultrasound imaging is
noninvasive testing. useful in the workup of
entrapment neuropathies
and has emerging
SKIN BIOPSY. Skin biopsy to indications in the workup of
directly measure epidermal fiber other neuromuscular
density has become increasingly disorders.
used to diagnose small fiber
● A nerve biopsy is the
polyneuropathy and determine if it diagnostic test of choice for
is length dependent or diffuse. A suspected nonsystemic
biopsy is taken from a distal and a vasculitic neuropathy. In the
proximal site in a lower extremity setting of known systemic
vasculitis, nerve biopsy
and the tissue is stained with an should only be performed if
antibody to PGP 9.5, a panaxonal demonstrating peripheral
marker (FIGURE 1-3). The primary nerve involvement will lead
usefulness of this test is when the to a change in
immunomodulatory
diagnosis of neuropathy is
treatment.
uncertain or if a non–length-
dependent small fiber neuropathy
is suspected. The test may be
overused in patients whose clinical
manifestations are consistent with
distal symmetric small fiber FIGURE 1-3
Skin biopsies from the distal leg stained with
polyneuropathy because the protein gene product 9.5 (PGP 9.5), a panaxonal
results only rarely lead to a change marker, demonstrate normal intraepidermal
in management. nerve fiber density (A) in an asymptomatic
Immunoglobulin light chain patient and reduced density (B) in a patient with
distal symmetric polyneuropathy. Arrows
amyloidosis is a rare but serious
designate normal epidermal axons. The bar
cause of small fiber–predominant represents 50 microns.
polyneuropathy, often with Figure courtesy of A. Gordon Smith, MD, FAAN.

dramatic dysautonomia. Although nerve and skin biopsy with Congo red staining
may demonstrate amyloid deposits, these deposits can be found in bone marrow,
salivary gland, or subcutaneous fat in 85% of affected patients.60
CONCLUSION
Focal lesions of the peripheral nervous system cause deficits that may be unique
to the involved neuroanatomic structure. Multifocal or generalized peripheral
nervous system disorders can be identified by the characteristic patterns of
sensory and motor involvement. Clinicians should use the history and physical
examination to inform the judicious use of diagnostic testing. Electrodiagnostic
studies, CSF analysis, and tissue biopsy are particularly useful in many clinical
settings but may be overused in other settings. The focus of testing should be to
confirm or refute suspected diagnoses when doing so is likely to impact patient
management.
REFERENCES
1 London ZN. Resident basic science III: 10 Leonhard SE, Mandarakas MR, Gondim FAA, et al.
neuroanatomy: all the lesions. Course presented Diagnosis and management of Guillain-Barre
at American Academy of Neurology Annual syndrome in ten steps. Nat Rev Neurol 2019;15(11):
Meeting; May 6, 2019; Philadelphia, PA. 671–683. doi:10.1038/s41582-019-0250-9.
2 Kushchayev SV, Glushko T, Jarraya M, et al. ABCs 11 Sheikh KA. Guillain-Barré syndrome. Continuum
of the degenerative spine. Insights Imaging 2018; (Minneap Minn) 2020;26(5, Peripheral Nerve and
9(2):253–274. doi:10.1007/s13244-017-0584-z. Motor Neuron Disorders):1184–1204.
3 Shanina E, Liao B, Smith RG. Brachial 12 Gwathmey K. Chronic inflammatory demyelinating
plexopathies: update on treatment. Curr Treat polyradiculoneuropathy and its variants. Continuum
Options Neurol 2019;21(5):24. doi:10.1007/ (Minneap Minn) 2020;26(5, Peripheral Nerve and
s11940-019-0562-5. Motor Neuron Disorders):1205–1223.
4 Jones MR, Prabhakar A, Viswanath O, et al. 13 Gwathmey KG, Tracy JA, Dyck PJB. Peripheral
Thoracic outlet syndrome: a comprehensive nerve vasculitis: classification and disease
review of pathophysiology, diagnosis, and associations. Neurol Clin 2019;37(2):303–333.
treatment. Pain Ther 2019;8(1):5–18. doi:10.1007/ doi:10.1016/j.ncl.2019.01.013.
s40122-019-0124-2.
14 Collins MP, Hadden RD. The nonsystemic
5 Gwathmey KG. Plexus and peripheral nerve vasculitic neuropathies. Nat Rev Neurol 2017;
metastasis. Handb Clin Neurol 2018;149:257–279. 13(5):302–316. doi:10.1038/nrneurol.2017.42.
doi:10.1016/B978-0-12-811161-1.00017-7.
15 Karam C. Peripheral neuropathies associated
6 Hobson-Webb LD, Juel VC. Common entrapment with vasculitis and autoimmune connective
neuropathies. Continuum (Minneap Minn) 2017; tissue disease. Continuum (Minneap Minn) 2020;
23(2, Selected Topics in Outpatient Neurology): 26(5, Peripheral Nerve and Motor Neuron
487–511. doi:10.1212/CON.0000000000000452. Disorders):1257–1279.
7 Pradat PF, Delanian S. Late radiation injury to 16 Ikeda S, Koike H, Nishi R, et al. Clinicopathological
peripheral nerves. Handb Clin Neurol 2013;115: characteristics of subtypes of chronic inflammatory
743–758. doi:10.1016/B978-0-444-52902- demyelinating polyradiculoneuropathy. J Neurol
2.00043-6. Neurosurg Psychiatry 2019;90(9):988–996.
doi:10.1136/jnnp-2019-320741.
8 Llewelyn D, Llewelyn JG. Diabetic amyotrophy: a
painful radiculoplexus neuropathy. Pract Neurol 17 Attarian S, Fatehi F, Rajabally YA, Pareyson D.
2019;19(2):164–167. doi:10.1136/practneurol-2018- Hereditary neuropathy with liability to pressure
002105. palsies. J Neurol 2020;267(8):2198–2206.
doi:10.1007/s00415-019-09319-8.
9 Gibbons CH. Diabetes and metabolic disorders
and the peripheral nervous system. Continuum 18 Callaghan BC, Price RS, Feldman EL. Distal
(Minneap Minn) 2020;26(5, Peripheral Nerve and symmetric polyneuropathy: a review. JAMA 2015;
Motor Neuron Disorders):1161–1183. 314(20):2172–2181. doi:10.1001/jama.2015.13611.
1158 OCTOBER 2020

19 Klein CJ. Charcot-Marie-Tooth disease and 33 Russell JW, Zilliox LA. Diabetic neuropathies.
other hereditary neuropathies. Continuum Continuum (Minneap Minn) 2014;20(5, Peripheral
(Minneap Minn) 2020;26(5, Peripheral Nerve and Nervous System Disorders):1226–1240.
Motor Neuron Disorders):1224–1256. doi:10.1212/01.CON.0000455884.29545.d2.
20 Nobile-Orazio E. Chronic inflammatory 34 Beadon K, Guimarães-Costa R, Léger JM.
demyelinating polyradiculoneuropathy and Multifocal motor neuropathy. Curr Opin Neurol
variants: where we are and where we should go. 2018;31(5):559–564. doi:10.1097/WCO.
J Peripher Nerv Syst 2014;19(1):2–13. doi:10.1111/ 0000000000000605.
jns5.12053.
35 Preethish-Kumar V, Polavarapu K, Nashi S, et al.
21 Nance JR. Spinal muscular atrophy. Continuum Hirayama disease/cervical flexion-induced
(Minneap Minn) 2020;26(5, Peripheral Nerve and myelopathy progressing to spastic paraparesis: a
Motor Neuron Disorders):1348–1368. report on three cases with literature review.
Neurol India 2018;66(4):1094–1099. doi:10.4103/
22 Breza M, Koutsis G. Kennedy's disease (spinal
0028-3886.236966.
and bulbar muscular atrophy): a clinically
oriented review of a rare disease. J Neurol 2019; 36 Sharp L, Vernino S. Paraneoplastic neuromuscular
266(3):565–573. doi:10.1007/s00415-018-8968-7. disorders. Muscle Nerve 2012;46(6):841–850.
doi:10.1002/mus.23502.
23 Quinn C, Elman L. Amyotrophic lateral sclerosis
and other motor neuron diseases. Continuum 37 Herraets IJT, Goedee HS, Telleman JA, et al.
(Minneap Minn) 2020;26(5, Peripheral Nerve and High-resolution ultrasound in patients with
Motor Neuron Disorders):1323–1347. Wartenberg's migrant sensory neuritis, a
case-control study. Clin Neurophysiol 2018;129(1):
24 Talbott EO, Malek AM, Lacomis D. The epidemiology
232–237. doi:10.1016/j.clinph.2017.10.040.
of amyotrophic lateral sclerosis. Handb Clin
Neurol 2016;138:225–238. doi:10.1016/B978-0-12- 38 Crowell A, Gwathmey KG. Sensory
802973-2.00013-6. neuronopathies. Curr Neurol Neurosci Rep 2017;
17(10):79. doi:10.1007/s11910-017-0784-4.
25 Benbrika S, Desgranges B, Eustache F, Viader F.
Cognitive, emotional and psychological 39 Basantsova NY, Starshinova AA, Dori A, et al.
manifestations in amyotrophic lateral sclerosis at Small-fiber neuropathy definition, diagnosis, and
baseline and overtime: a review. Front Neurosci treatment. Neurol Sci 2019;40(7):1343–1350.
2019;13:951. doi:10.3389/fnins.2019.00951. doi:10.1007/s10072-019-03871-x.
26 Giordana MT, Ferrero P, Grifoni S, et al. Dementia 40 England JD, Gronseth GS, Franklin G, et al.
and cognitive impairment in amyotrophic lateral Practice parameter: the evaluation of distal
sclerosis: a review. Neurol Sci 2011;32(1):9–16. symmetric polyneuropathy: the role of laboratory
doi:10.1007/s10072-010-0439-6. and genetic testing (an evidence-based review).
Report of the American Academy of Neurology,
27 Pinto WBVR, Debona R, Nunes PP, et al. Atypical
the American Association of Neuromuscular and
motor neuron disease variants: still a diagnostic
Electrodiagnostic Medicine, and the American
challenge in neurology. Rev Neurol (Paris) 2019;
Academy of Physical Medicine and Rehabilitation.
175(4):221–232. doi:10.1016/j.neurol.2018.04.016.
PM R 2009;1(1):5–13. doi:10.1016/j.pmrj.2008.11.010.
28 Centers for Disease Control and Prevention.
41 Thaisetthawatkul P, Lyden E, Americo Fernandes J Jr,
Polio elimination in the United States. cdc.gov/
Herrmann DN. Prediabetes, diabetes, metabolic
polio/what-is-polio/polio-us.html?CDC_AA_
syndrome, and small fiber neuropathy. Muscle
refVal=https%3A%2F%2Ffanyv88.com%3A443%2Fhttps%2Fwww.cdc.gov%2Fpolio%
Nerve 2020;61(4):475–479. doi:10.1002/mus.26825.
2Fus%2Findex.html. Updated October 25, 2019.
Accessed July 30, 2020. 42 Stino AM, Smith AG. Peripheral neuropathy in
prediabetes and the metabolic syndrome.
29 Global Polio Eradication Initiative. Polio this week
J Diabetes Investig 2017;8(5):646–655.
as of 29 July 2020. polioeradication.org/polio-
doi:10.1111/jdi.12650.
today/polio-now/this-week/. Accessed July 30,
2020. 43 Balendran S, Oliva P, Sansen S, et al. Diagnostic
strategy for females suspected of Fabry disease.
30 Hixon AM, Clarke P, Tyler KL. Contemporary
Clin Genet 2019. doi:10.1111/cge.13694.
circulating enterovirus D68 strains infect and
undergo retrograde axonal transport in spinal 44 de Greef BT, Hoeijmakers JG, Wolters EE, et al.
motor neurons independent of sialic acid. J Virol No Fabry disease in patients presenting with
2019;93(16):e00578–19. doi:10.1128/JVI.00578-19. isolated small fiber neuropathy. PLoS One 2016;
11(2):e0148316. doi:10.1371/journal.pone.0148316.
31 Mélé N, Berzero G, Maisonobe T, et al. Motor
neuron disease of paraneoplastic origin: a rare 45 Kaku M, Berk JL. Neuropathy associated with
but treatable condition. J Neurol 2018;265(7): systemic amyloidosis. Semin Neurol 2019;39(5):
1590–1599. doi:10.1007/s00415-018-8881-0. 578–588. doi:10.1055/s-0039-1688994.
32 Rossor AM, Kalmar B, Greensmith L, Reilly MM. 46 Garcia-Santibanez R, Zaidman CM, Sommerville
The distal hereditary motor neuropathies. RB, et al. CANOMAD and other chronic ataxic
J Neurol Neurosurg Psychiatry 2012;83(1):6–14. neuropathies with disialosyl antibodies (CANDA).
doi:10.1136/jnnp-2011-300952. J Neurol 2018;265(6):1402–1409. doi:10.1007/
s00415-018-8853-4.

47 Zeng Y, Liu Y, Xie Y, et al. Clinical features and the 54 Rajagopalan V, Pioro EP. Unbiased MRI analyses
validation of the Brighton criteria in Guillain-Barré identify micropathologic differences between
syndrome: retrospective analysis of 72 hospitalized upper motor neuron-predominant ALS phenotypes.
patients in three years. Eur Neurol 2019;81(5–6): Front Neurosci 2019;13:704. doi:10.3389/fnins.
231–238. doi:10.1159/000503101. 2019.00704.
48 Nishimoto Y, Odaka M, Hirata K, Yuki N. Usefulness 55 Katzberg HD, Bril V, Breiner A. Ultrasound in
of anti-GQ1b IgG antibody testing in Fisher neuromuscular disorders. J Clin Neurophysiol
syndrome compared with cerebrospinal fluid 2016;33(2):80–85. doi:10.1097/WNP.
examination. J Neuroimmunol 2004;148(1–2): 0000000000000234.
200–205. doi:10.1016/j.jneuroim.2003.11.017.
56 Wee TC, Simon NG. Ultrasound elastography for
49 Cornblath DR, Gorson KC, Hughes RA, Merkies IS. the evaluation of peripheral nerves: a systematic
Observations on chronic inflammatory review. Muscle Nerve 2019;60(5):501–512.
demyelinating polyneuropathy: a plea for a doi:10.1002/mus.26624.
rigorous approach to diagnosis and treatment.
57 Hobson-Webb LD, Simmons Z. Ultrasound in the
J Neurol Sci 2013;330(1–2):2–3. doi:10.1016/j.
diagnosis and monitoring of amyotrophic lateral
jns.2013.04.015.
sclerosis: a review. Muscle Nerve 2019;60(2):
50 Breiner A, Moher D, Brooks J, et al. Adult CSF total 114–123. doi:10.1002/mus.26487.
protein upper reference limits should be
58 Boon AJ, Smith J, Harper CM. Ultrasound applications
age-partitioned and significantly higher than
in electrodiagnosis. PM R 2012;4(1):37–49.
0.45 g/L: a systematic review. J Neurol 2019;
doi:10.1016/j.pmrj.2011.07.004.
266(3):616–624. doi:10.1007/s00415-018-09174-z.
59 Joint Task Force of the EFNS and the PNS.
51 London ZN, Nowacek DG. Does cerebrospinal
European Federation of Neurological Societies/
fluid analysis have a meaningful role in the
Peripheral Nerve Society Guideline on
diagnosis of chronic inflammatory demyelinating
management of chronic inflammatory
polyradiculoneuropathy? Muscle Nerve 2019;
demyelinating polyradiculoneuropathy: report of
60(2):111–113. doi:10.1002/mus.26513.
a joint task force of the European Federation of
52 AANEM policy statement on electrodiagnosis for Neurological Societies and the Peripheral Nerve
distal symmetric polyneuropathy. Muscle Nerve Society–First Revision. J Peripher Nerv Syst 2010;
2018;57(2):337–339. doi:10.1002/mus.26003. 15(1):1–9. doi:10.1111/j.1529-8027.2010.00245.x.
53 Callaghan BC. Test utilization and value in 60 Gertz MA. Immunoglobulin light chain amyloidosis:
peripheral neuropathies. Continuum (Minneap 2018 Update on diagnosis, prognosis, and
Minn) 2020;26(5, Peripheral Nerve and Motor treatment. Am J Hematol 2018;93(9):1169–1180.
Neuron Disorders):1384–1391. doi:10.1002/ajh.25149.
1160 OCTOBER 2020

Abordaje Diagnostico

Uploaded by

Copyright:

Available Formats

Abordaje Diagnostico

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

Abordaje Diagnostico

Uploaded by

Copyright:

Available Formats

REVIEW ARTICLE

1130 OCTOBER 2020

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

u Does it localize to the CNS or to the peripheral nervous system?

CENTRAL OR PERIPHERAL NERVOUS SYSTEM

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

disorders of the CNS. In addition to appreciation of upper motor neuron and

TABLE 1-1 Distinguishing Central From Peripheral Nervous System Lesions

Features Consistent With Any Central Nervous System Localization

1132 OCTOBER 2020

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

● Features that suggest a

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Principal Muscles Diminished

C6 root Supraspinatus Lateral forearm and hand, first Biceps,

C7 root Tricepsb Centermost portion of the distal Triceps

C8 root Triceps Fourth and fifth digits and medial None

T1 root Abductor pollicis Medial forearm None

1134 OCTOBER 2020

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Principal Muscles Diminished

L2 root Iliopsoasb Anterior thigh None

L3 root Iliopsoasb Medial thigh, knee Patellar

L4 root Quadricepsb Medial lower leg Patellar

L5 root Gluteus mediusb Lateral lower leg, dorsal None

S1 root Gluteus maximusb Posterior/lateral lower Ankle

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

The most common mononeuropathies to cause a pure motor syndrome are

Upper Supraspinatusb Lateral upper arm and forearm Biceps,

Lower Triceps Medial forearm and hand, None

Middle Tricepsb Centermost portion of the Triceps

CONTINUED ON PAGE 1137

1136 OCTOBER 2020

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

CONTINUED FROM PAGE 1136

Medial Flexor digitorumb Medial forearm and hand, None

Posterior Deltoidb Dorsal aspect of upper arm, Triceps,

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MULTIFOCAL OR GENERALIZED SYMPTOM PATTERN

MIXED SENSORY AND MOTOR SYMPTOM PATTERN

Principal Muscles Diminished

Lumbar plexus Iliopsoas Anterior thigh, medial and Patellar

Lower Gluteus medius Posterior thigh, lateral lower Ankle

1138 OCTOBER 2020

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Proximal and Distal Asymmetric

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

CIDP that causes a chronic sensorimotor mononeuropathy multiplex with

DISTAL SYMMETRIC POLYNEUROPATHY. The most common pattern of

Principal Muscles Diminished

Musculocutaneous Bicepsb Lateral forearm Biceps

Axillary Deltoid Lateral shoulder None

Posterior interosseous Extensor digitorumb None None

CONTINUED ON PAGE 1141

1140 OCTOBER 2020

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

CONTINUED FROM PAGE 1140

Principal Muscles Diminished

Anterior interosseous Flexor pollicis longusb None None