Modern Concepts of Peripheral Nerve Repair

Modern Concepts
of Peripheral Nerve
Repair
Kirsten Haastert-Talini
Hans Assmus
Gregor Antoniadis
Editors
123
Modern Concepts of Peripheral
Nerve Repair
Kirsten Haastert-Talini • Hans Assmus
Gregor Antoniadis
Editors
Modern Concepts of
Peripheral Nerve Repair
Editors
Kirsten Haastert-Talini Gregor Antoniadis
Hannover Medical School Peripheral Nerve Surgery Unit
Institute of Neuroanatomy and Cell Biology Department of Neurosurgery
Hannover University of Ulm
Germany Günzburg
Bayern
Hans Assmus Germany
Schriesheim
Germany
ISBN 978-3-319-52318-7 ISBN 978-3-319-52319-4 (eBook)

DOI 10.1007/978-3-319-52319-4
Library of Congress Control Number: 2017944161
© Springer International Publishing AG 2017

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Preface
We, the editors of this book, join active membership of the German interdisciplinary
study group named “NervClub” and we recognized that a concise book (comprisal)
on modern concepts of peripheral nerve repair is currently not available for interna-
tional readers. Therefore, we edited this book with a focus on very common and
frequently occurring traumatic peripheral nerve injuries, their diagnostic with
decision-making, and their reconstruction and long-term post-surgery patient care.
This book should provide a compendium for graduated medical doctors interested
in neurosurgery, hand surgery, or traumatology and final-year medical students with
an upcoming interest in peripheral nerve surgery.
The topics have been carefully selected and the authors have treated them in a
compact and illustrative way. The group of authors is comprised of internationally
recognized experts in the field of peripheral nerve injury and repair from both the
clinical and scientific points of view.
Our biggest thanks go to the authors for their enthusiasm to contribute to this
project and to all those who helped us in editing this book.
We would like to thank further Ms. Lena Freund for her professional redrawing
of our figures in Chaps. 1 and 10.
We thank Dr. Sylvana Freyberg, who, as the editor of Springer Heidelberg
Medicine Books Continental Europe & UK, did accept our proposal and supported
us through the project.
We also thank our project coordinator Ms. Rajeswari Balachandran and our proj-
ect manager Ms. Govindan Meena, both from Springer Nature SPi Global, for their
kind assistance.
Hannover, Germany Kirsten Haastert-Talini

Schriesheim, Germany Hans Assmus
Günzburg, Germany Gregor Antoniadis
May 2017
v
Contents
1 The Peripheral Nerve: Neuroanatomical Principles Before

and After Injury �� 1
Gregor Antoniadis
2 State-of-the-Art Diagnosis of Peripheral Nerve Trauma:
Clinical Examination, Electrodiagnostic, and Imaging�� 11
Christian Bischoff, Jennifer Kollmer, and Wilhelm Schulte-Mattler
3 Timing and Decision-Making in Peripheral Nerve Trauma�� 27
Hans Assmus
4 Conventional Strategies for Nerve Repair �� 41
Mario G. Siqueira and Roberto S. Martins
5 Surgical Techniques in the Lesions of Peripheral Nerves�� 53
Kartik G. Krishnan
6 Specific Challenges in Brachial Plexus Surgery�� 65
Thomas J. Wilson and Lynda J.-S. Yang
7 Alternative Strategies for Nerve Reconstruction�� 79
F. Siemers and K.S. Houschyar
8 Clinical Follow-Up �� 97
Gilda Di Masi, Gonzalo Bonilla, and Mariano Socolovsky
9 Rehabilitation Following Peripheral Nerve Injury �� 109
Sarah G. Ewald and Vera Beckmann-Fries
10 Peripheral Nerve Tissue Engineering: An Outlook
on Experimental Concepts�� 127
Index�� 139
vii
The Peripheral Nerve: Neuroanatomical
Principles Before and After Injury 1
Gregor Antoniadis
Contents
1.1 Anatomy of the Peripheral Nerve 1
1.2 Classification of the Nerve Injuries 4
1.3 Neuroanatomical Situation After Injury: Nerve Degeneration 6
1.4 Nerve Regeneration 8
References 9
1.1 Anatomy of the Peripheral Nerve
Peripheral nerves arise from the spinal cord, and they contain axons from different
types of neurons serving various effector organs or sensory endings.
The cell bodies of motor neurons that innervate skeletal muscle fibres are situ-
ated in the anterior horns of the grey matter of the spinal cord. Enlargements of the
cord in the cervical and lumbar segments mark the major regions supplying the
upper and lower limbs (Fig. 1.1).
The first sensory neurons are situated in the dorsal root ganglia, which are located
in the intervertebral foramina, just proximal to the fusion of the anterior and poste-
rior roots.
The peripheral nerve is composed of motor, sensory and sympathetic nerve
fibres. A nerve fibre is the conducting unit of the nerve and contains the following
elements: a central core, the axon and Schwann cells. Some nerve fibres are sur-
rounded by a myelin component (myelinated nerve fibres), and others are free of
such myelin sheath (unmyelinated nerve fibres) [2, 9, 17, 20].
G. Antoniadis, MD, PhD

Peripheral Nerve Surgery Unit, Department of Neurosurgery, University of Ulm,
Ludwig-Heilmeyer-Str. 2, 89312 Günzburg, Germany
e-mail: gregor.antoniadis@uni-ulm.de, pnc.antoniadis@gmail.com
© Springer International Publishing AG 2017 1

K. Haastert-Talini et al. (eds.), Modern Concepts of Peripheral Nerve Repair,
DOI 10.1007/978-3-319-52319-4_1
2 G. Antoniadis
The axons contain organelles including mitochondria, neurofilaments, endoplas-

mic reticulum, microtubules and dense particles. Axons originate from their corre-
sponding neuronal cell bodies which are located in the spinal cord, dorsal root
ganglia or autonomic ganglia, respectively.
The Schwann cells are the glial cells of the peripheral nervous system and located
along the longitudinal extent of the axon.
In healthy peripheral nerves, nerve fibres of different diameter exist, large and small
fibres. Only large fibres (>1.5 μm in diameter) are surrounded by segmental lipoprotein
coating or covering of myelin. In this case the membranes of neighbouring Schwann
cells wrap concentrically around a segment of the axon. The small area between the
neighbouring Schwann cells is known as the “node of Ranvier”. The node of Ranvier
permits ionic exchanges between the axoplasm of a nerve fibre and the intercellular
space and permits saltatory conduction of a nerve action potential impulse, which
jumps from one node to the next and is the basis for fast signal conduction. There is a
basal lamina around each Schwann cell and its contents (Fig. 1.1 and 1.2).
The small and less myelinated fibres (<1.5 μm in diameter) are often grouped and
enveloped by the membrane of a Schwann cell, which does not wrap a lipoprotein
sheath around them (Remak bundles). These fibres do not have the structural capac-
ity for saltatory conduction, and nerve impulses transmit slowly along the axon.
A Schwann cell not only provides myelins and a basal membrane as guidance for
axons but, as a source of trophic and growth factors, it supports also the mainte-
nance of its neighbouring axon.
The connective tissue which forms the supporting framework for the nerve fibres
is the interfascicular endoneurium. A thin sheath of specialized perineurial cells,
called perineurium, covers a bundle of nerve fibres (fascicle).
The nerve fascicles vary in number as well as in size, depending on a given nerve
as well as the level of the nerve examination.
The endoneurium is a matrix of small-diameter collagen fibrils which are pre-
dominantly longitudinally oriented. Microvessels with tight junctions are found at
this structure, and the tissue adjacent to these capillaries probably serves as a blood-
nerve barrier additional to the endoneurial tissue itself [2, 7].
The perineurium consists of oblique, circular and longitudinal collagen fibrils
dispersed amongst perineurial cells [23]. The outer lamellae of the perineurium
have a high density of endocytotic vesicles which may play a role in molecular
transport, e.g. of glucose. The inner lamellae have tight junctions between contigu-
ous perineurial cells, which may block the intercellular transport of macromolecules
and crucially contribute to a blood-nerve barrier [10]. The interruption of the peri-
neurium can affect the function of the axons, which it encloses. The perineurium is
the major source of tensile strength for nerve and is transversed by vessels which
carry a perineurial sleeve of connective tissue.
The epineurium represents the connective tissue that covers the entire nerve
trunk. The epineurium can extend internally to separate the fascicles (interfascicu-
lar epineurium). The layer between the epineurium and the surrounding tissue is
called paraneurium.
The axoplasm contains proteins and cytoskeletal elements including microtu-
bules and neurofilaments. The axoplasm is continuously built and sustained by axo-
nal transport mechanisms.
1 The Peripheral Nerve: Neuroanatomical Principles Before and After Injury 3
Fig. 1.1 Schematic diagram of a normal nerve (Illustration by Lena Julie Freund, Aachen,
Germany)
Stucture of peripheral nerve:

External epineurium
Intraneural epineurium
Fascicle
Perineurium Fascicle pattern of

Endoneurium peripheral nerves:
Monofascicular
Nerve fiber
Oligofascicular
Ungrouped Grouped Polyfascicular
Fig. 1.2 Morphology of the peripheral nerve (From Kretschmer et al. [9])
The relationship between the fascicles within the peripheral nerve is constantly
changing along a longitudinal course. Sunderland noted that the maximum length of
nerve with a constant pattern was 15 mm [22].
Three types of nerves concerning their fascicular pattern can be distinguished [12, 13]:
1 . Nerves with a monofascicular pattern.

2. Nerves with an oligofascicular pattern (2–10 fascicles).
3. Nerves with a polyfascicular pattern. For this nerve type, there are two subtypes that
can be distinguished: the polyfascicular nerve with diffuse arrangement of fascicles
and the polyfascicular nerve with group arrangement of fascicles.
Peripheral nerves receive the blood supply from small vessels leading to the
e pineurium (intrinsic), perineurium and endoneurium. The normal nerve is criti-
cally dependent upon the intrinsic blood supply and the perineurial and endoneurial
4 G. Antoniadis
vessels. The intrinsic vessels are similar to other vessels with the exception of hav-
ing endothelial cells that contain tight junctions to aid in diffusion and extrusion of
compounds. The intrinsic blood supply is crucial during regeneration, as the blood-
nerve barrier breaks down uniformly along the nerve within days of injury, allowing
large molecules, such as growth factors and immune cells, to cross and enter the
endoneurial space [16].
The extrinsic blood supply system is composed of segmentally arranged vessels
which vary in size and generally originate from neighbouring large arteries and
veins. As these nutrient vessels reach the epineurium, they ramify within the epineu-
rium and supply the intraneural plexus through ascending and descending branches
[11, 12].
1.2 Classification of the Nerve Injuries
More than 70 years ago, nerve lesions were characterized as compression, contu-
sion, laceration or division lesions. Seddon introduced in 1943 a classification sys-
tem based on nerve fibre and nerve trunk pathology in three categories: neurapraxia,
axonotmesis and neurotmesis [21].
The new classification according to Sunderland is based on histological features
of the nerve trunk in 5° [18, 22] (Figs. 1.3 and 1.4):
Grade I By this type of lesion, there is an interruption of conduction at the site of

injury. Therefore, this lesion grade corresponds to neurapraxia of Seddon classifica-
tion. It is characterized by a focal demyelination. The rearrangement of the myelin
sheath takes 3–4 weeks. After this period the nerve can almost regain its normal
function.
Grade II This lesion corresponds to Seddon axonotmesis. The axon is severed, but
the endoneurial sheath of nerve fibre and the basal lamina are preserved. The axons
undergo Wallerian degeneration. The regeneration process lasts some months,
depending on the distance between lesion and target muscle. The regeneration pro-
cess may result nearly in a restitutio ad integrum.
Sunderland
1˚
2˚
3˚
4˚
5˚
Fig. 1.3 Correlation of
Neurotmesis Axonotmesis Neutotmesis
classifications according to
Seddon and to Sunderland Seddon
Epineurium
Perineurium
Endoneurium
Basal lamina
1
Axon
Fig. 1.4 Classification according to Sunderland (With permission from Terzis and Smith [25])
Grade III The essential features of these injuries are destructions of endoneurial
structures of the nerve fibres. A disintegration of axons and Wallerian degeneration
and loss of the endoneurial tube continuity occur. The perineurium is kept intact.
This situation leads to a certain degree of misdirection of regenerating axons, fol-
lowed by extensive unrecoverable functional deficits.
Grade IV In grade IV injuries, the fasciculi and the perineurium are ruptured,
while the epineurium is still preserved. Compressing forces are even able to block
the outgrowth of regeneration axon sprouts, resulting in a neuroma in continuity.
6 G. Antoniadis
The lesion grades IV and V present a very poor prognosis concerning spontaneous
recovery.
Grade V In this lesion there is a complete loss of continuity of the nerve trunk and
no chance for a spontaneous recovery. Regenerative attempts produce neuroma for-
mation on the separated nerve stumps.
Millesi established a further classification system of reactive nerve fibrosis types.

The connective tissue reaction upon lesion surrounding the nerve fibre, fascicles and
fascicle groups is designated in these cases as fibrosis [13–15].
Millesi classified the fibrosis in three types:
Type A: Fibrosis of the epineurium.

The thickened epineurium leads to a strangulation of nerve structures. This type
of fibrosis can occur in all cases of grades I, II or III lesions, according to Sunderland’s
classification. Chances of spontaneous recovery remain decreased as usually a long-
lasting nerve compression occurred. An opening of the epineurium (epineurotomy)
is the treatment of choice.
Type B: Fibrosis of the epifascicular and interfascicular epineurium.
The connective tissue between the fascicles is involved. Each fascicle group is
affected. There is a compression within the nerve. An internal neurolysis to decom-
press all fascicle groups is indicated. This procedure must be done meticulously and
using the microscope.
Type C: Fibrosis of the endoneurium.
This type of fibrosis takes place in grades III and IV lesions according to
Sunderland’s classification. This fibrosis involves all fascicles and presents with the
danger for the development of a neuroma in continuity. Type C fibrosis has a very
poor prognosis, and there are no chances for a spontaneous recovery. A reconstruc-
tion of the nerve after the resection of damaged parts must be done.
1.3 euroanatomical Situation After Injury: Nerve

N
Degeneration
Axons, Schwann cells, macrophages, fibroblasts and other cell types demonstrate
significant changes in response to nerve injury.
An injury of the neuronal soma, in very proximal lesions, is a very severe nerve
injury without potential for recovery. It occurs in injuries with direct mechanical or
vascular insult to the neuronal soma [8].
In peripheral axonal injuries, neuronal cell death does not occur, in contrast to an
avulsion of the nerve roots, which results in neuronal cell death and loss of the
soma. Therefore, peripheral nerves have a regenerative potential after injury.
Waller described in 1850 an antegrade nerve degeneration (Wallerian degenera-
tion), which is characterized by a loss of cellular integrity and trafficking of intracel-
lular components along the distal nerve end. We know today that a degeneration of
the neuromuscular synapses can precede the process for several hours and that this
is independent from the Wallerian degeneration [5].
The process of Wallerian degeneration is completed after several weeks, and it

includes the gradual dissolution of axoplasm and myelin distal to an injury and their
gradual phagocytosis or their debris (Fig. 1.5).
Fig. 1.5 Degeneration and regeneration after nerve injury (With permission from Terzis and
Smith [25]) (1) Normal, healthy neuron with myelinated axon. (2) After transection injury, the
proximal axon has undergone retrograde reaction with somal chromatolysis, nuclear migra-
tion and nuclear enlargement. The distal axon has undergone Wallerian degeneration. (3) The
proximal axon has begun to sprout filopodia from the growth cone to begin axonal regenera-
tion. (4) Upon successfully re-establishing connectivity of one axonal sprout, redundant
sprouts undergo the dying-back process. (5) A terminal bulb is created by damming up axonal
contents if an insurmountable obstruction is encountered. (6) If scar produces an annular con-
striction around a regenerating axon (arrows), the resulting axonal calibre will never return to
normal [26]
8 G. Antoniadis
Observations of Wallerian degeneration have revealed that the initial degradation

of axonal components rapidly leads to recruitment and activation of non-neuronal
cells that crucially contribute to the regeneration process. This process includes the
dedifferentiation, proliferation and migration of Schwann cells, with the activation
of macrophages within the endoneurium and the recruitment of complementary
immune cells from the periphery. These cells prepare the distal nerve for regenera-
tion by clearing myelin debris and other inhibitors to axonal regeneration during the
neural wound-healing response.
The recruitment of Schwann cells and macrophages is linked to the secretion of
several other specific pro-inflammatory cytokines and chemokines. The secretion of
these pro-inflammatory agents similarly stimulates the recruitment of macrophages
and immune-competent cells from the periphery [19].
1.4 Nerve Regeneration
As a consequence of any severe injury to a peripheral nerve, there is a predictable

sequence of distal and proximal axonal degeneration. Whenever the injury does not
lead to neuronal death, a sequence of regeneration proceeds, which may be abortive
or may result in effective functional restoration.
Proximal to the axonal disruption, the axon undergoes limited degeneration up to
the last preserved internode (node of Ranvier). This axonal degeneration is similar
to that observed in the distal stump. The neuron exhibits central chromatolysis, and
this represents the metabolic preparation for a shift from maintenance of nerve con-
duction to a regenerative mode reprogrammed to generate structural proteins.
Ramon-y-Cajal started the modern era in nerve regeneration research by proving
that nerve regeneration occurs by axonal outgrowth from the proximal stump and
not by autoregeneration of the degenerated distal nerve [3].
During 24 h after transection injury, the proximal axon bulges into a growth
cone. By the end of the first 24 h, a few sprouts have reached the areas of injury, and
the penetration of the developing scar at the site of injury proceeds from the second
to third day. The axonal sprouts originating from the proximal nerve stump are
accompanied by Schwann cells derived from the reciprocation of the terminal satel-
lite cells. The growth cone is rich of endoplasmic reticulum, microtubules, micro-
filaments, large mitochondria, lysosomes and other vacuolar and vesicular structures
of unknown significance.
During Wallerian degeneration of the distal nerve end, Schwann cells assume the
dual role of phagocytosis of myelin and axonal debris, and they proliferate within
the basal lamina of remaining endoneurial connective tissue sheaths. As they prolif-
erate, Schwann cells become densely packed in longitudinal rows histologically
recognized as the bands of Bungner [6].
After a peripheral nerve injury, three types of intrinsic and extrinsic processes
affect the neuron, on molecular level:
1. Positive signals, derived from retrograde transport of kinases, such as mitogen-

activated protein kinases (MAPKs), are transported from the injury site to the
cell body [1].
2. Axonal injury leads to the disruption of action potential conduction and a large
influx of calcium and a depolarizing wave. This initial calcium influx leads to
protein kinase C (PKC) activation within the cell body and the nuclear export of
a regeneration-associated gene repressor [4].
3. Interruption of retrograde transport of trophic factors and negative regulators of
axonal growth from the end organ leads to the upregulation of regeneration-
associated genes [1].
Current research on the intrinsic regeneration capacity of neurons focuses on the

interplay between cytoskeletal assembly and blocking of the inhibitory effects of
myelin.
A regenerating axon grows through a scar with an average rate of about 0.25 mm
per day, and once the axonal sprouts reach the distal endoneurial tube, axonal
growth continues at an average 1.0–8.5 mm per day, depending upon multiple fac-
tors. The speed of nerve regeneration is inversely proportional to the distance of the
nerve injury from the cell body as observable by the progressing Tinel’s sign. In
each instance the nerve will be regenerating under ideal conditions. When the
underlying bed is well vascularized, nerve regeneration proceeds through non-
vascularized nerve grafts at 2–3 mm per day, and axonal elongation is even faster
through vascularized nerve grafts, approaching 3–4 mm per day [24, 25].
It is recognized that the quality and speed of regeneration of a nerve are improved
when there is a minimum amount of scar tissue filling the gap. Also, a better prog-
nosis for return of function exists when regenerating axons enter their native endo-
neurial tubes and become guided back towards the appropriate target organ. Beside
pure mechanical factors, the amount of time, which is allowed to elapse between
injury and repair, is very important for the prognosis of functional recovery. Other
factors such as the age of the patient, the type of nerve, the level of nerve injury, the
cause of the injury and the associated injuries all influence the functional outcome
after nerve reconstruction, but cannot yet be manipulated.
References
1. Abe N, Cavalli V. Nerve injury signaling. Curr Opin Neurobiol. 2008;18:276–83.
2. Birch R. Surgical disorders of the peripheral nerves. 2nd ed. London: Springer; 2011.
3. Cayal RY. Degeneration and regeneration of the nervous system, vol. 1. London: Oxford
University Press; 1978.
4. Cho Y, Sloutsky R, Naegle KM, Cavalli V. Injury-induced HDAAC5 nuclear export is essential
for axon regeneration. Cell. 2013;155:894–908.
5. Gillingwater TH, Ribschester RR. The relationship of neuromuscular synapse elimination to
synaptic degeneration and pathology: insights from WldS and other mutant mice. J Neurocytol.
2003;32:863–81.
6. Jessen KR, Mirsky R. The repair Schwann cell and its function in regenerating nerves.
J Physiol. 2016;594:3521–31.
7. Kim DH, Midha R, Murovic JA, Spinner RJ. Kline and Hudson’s nerve injuries. Philadelphia:
Saunders Elsevier; 2014.
8. Koliatsos VE, Price WL, Pardo CA, Price DL. Ventral root avulsion: an experimental model of
death of adult motor neurons. J Comp Neurol. 1994;342:35–44.
9. Kretschmner T, Antoniadis G, Assmus H. Nervenchirurgie. Heidelberg: Springer Verlag; 2014.
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10. Lundborg G, Rydevick B. Effects of stretching the tibial nerve of the rabbit. A preliminary
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Surg Br. 1973;55B:390–401.
11. Lundborg GA. A 25-year perspective of peripheral nerve surgery: evolving neuroscientific
concepts and clinical significance. J Hand Surg Am. 2000;25:391–414.
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13. Millesi H. Chirurgie der peripheren Nerven. München: Urban & Schwarzenberg Verlag; 1992.
14. Millesi H. Reappraisal of nerve repair. Surg Clin North Am. 1981;61:321–40.
15. Millesi H, Rath TH, Reihsner R, Zoch G. Microsurgical neurolysis: its anatomical and physi-
ological basis and its classification. Microsurgery. 1993;14:430–9.
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1966;7:1–15.
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19. Perrin FE, Lacroix S, Avilés-Trigueros M, David S. Involvement of monocyte chemoattractant
protein-1, macrophage inflammatory protein-1alpha and interleukin-1beta in Wallerian degen-
eration. Brain. 2005;128:854–66.
20. Rea P. Essential clinically applied anatomy of the peripheral nervous system in the limbs.
Amsterdam: Elsevier; 2015.
21. Seddon HJ. Three types of nerve injury. Brain. 1943;66:237–88.
22. Sunderland S. Nerve injuries and their repair. A critical appraisal. Edinburgh/London/

Melbourne/New York: Churchill Livingstone; 1991.
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demyelination and remyelination. Brain Res. 1975;965:923–9.
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State-of-the-Art Diagnosis of Peripheral
Nerve Trauma: Clinical Examination, 2
Electrodiagnostic, and Imaging
Christian Bischoff, Jennifer Kollmer,
and Wilhelm Schulte-Mattler
Contents
2.1 Introduction 11
2.2 History Taking and Physical Examination 12
2.3 Electrodiagnostic Procedures 13
2.4 Imaging 17
2.4.1 High-Resolution Ultrasound 17
2.4.2 MRI 19
eferences
R 24
2.1 Introduction
Peripheral nerve trauma is no exception from the rule that appropriate treatment
requires a clear diagnosis. Specific clinical diagnostic tests, such as Hoffmann and
Tinel’s sign, and technologies, such as electrodiagnostic and imaging procedures,
C. Bischoff (*)
Neurologische Gemeinschaftspraxis, Burgstraße 7, D-80331 Munich, Germany
e-mail: bischoff@profbischoff.de
J. Kollmer (*)
Department of Neuroradiology, University of Heidelberg,
Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany
e-mail: jennifer.kollmer@med.uni-heidelberg.de
W. Schulte-Mattler (*)
Department of Neurology, University Hospital Regensburg/Bezirksklinikum Regensburg,
Universitätsstraße 84, D-93053 Regensburg, Germany
e-mail: wilhelm.schulte-mattler@klinik.uni-regensburg.de

DOI 10.1007/978-3-319-52319-4_2
12 C. Bischoff et al.
were developed to improve diagnostic accuracy [19]. The development has not yet
come to an end. In the recent years, major accomplishments were achieved in
neuroimaging methods of peripheral nerves [22, 29]. The more classical electrodi-
agnostic methods benefitted from a better understanding of the timing of the patho-
logical findings after an injury [11, 17].
2.2 History Taking and Physical Examination
In a traumatized patient, careful history taking and physical examination are manda-
tory, as they provide the key information to answer the following questions:
• Is patient’s pain nociceptive, or neuropathic, or both?

• Are there neurological deficits that can be attributed to one or to multiple lesions
of peripheral nerves?
• Where are the lesions?
• How severe and of what type (neurapraxia, axonotmesis, neurotmesis, see Chap. 1)
are the lesions?
• Are there neurological deficits that cannot necessarily be explained by a periph-
eral nerve lesion but, for instance, by a spinal or by a cerebral lesion?
• Are there pre-existing pathological conditions, such as peripheral neuropathy,
that contribute to the patient’s actual signs and symptoms?
Only in rare cases, all of these questions can sufficiently be answered on history
and clinical examination alone. In the other cases, history and clinical examination
constitute the basis for rational decisions about necessity and timing of additional
diagnostic testing, especially electrodiagnostic and imaging studies, which are of
established high value.
The answers to the questions listed above provide the information to sensibly
make therapeutic decisions (see also Chap. 3).
During follow-up after a nerve trauma, the key question is whether reinnerva-
tion takes place in time or not. This can be assessed clinically, as it is nicely
illustrated by the original descriptions of what nowadays is known as Hoffmann-
Tinel’s sign. Paul Hoffmann and Jules Tinel independently from each other
described the occurrence of tingling by pressure applied to an injured nerve.
Hoffmann shortly later reported that the paresthesia could also be elicited by
percussion of the nerve.
They used their observation to monitor nerve regeneration after its surgical repair
[15, 36]. Nonetheless, in many clinical situations, electrodiagnostic and imaging
studies may be necessary to provide additional relevant information.
Finally, the functional outcome is judged mainly clinically. Again, electrodiag-
nostic and imaging studies may provide necessary informations, which not infre-
quently are relevant for forensic purposes.
2 State-of-the-Art Diagnosis of Peripheral Nerve Trauma 13
2.3 Electrodiagnostic Procedures
The most relevant electrodiagnostic methods to assess peripheral nerve lesions are
needle electromyography (EMG) and nerve conduction studies (NCS) [6, 8, 19].
For an EMG study, a needle electrode is inserted into the target muscle, and its elec-
trical activity at rest and at various degrees of voluntary contraction is recorded
from multiple positions within that muscle. The idea behind EMG is that axonal
damage causes functional and structural changes of the motor units of the inner-
vated muscle, which consequently result in changes of the electrical properties of
the affected motor units.
For an NCS a peripheral nerve is stimulated electrically, and the resulting
action potentials are recorded. The idea behind NCS is that a loss of functional
axons causes a loss of amplitude of the recorded action potentials. Recordings can
be made from the nerve itself (sensory or mixed NCS) or from a muscle inner-
vated by that nerve (motor NCS). The diagnostic yield of a motor NCS is much
higher if the stimulation is done not only at one but at two or more sites along that
nerve and if the action potentials of different stimulation sites are compared with
each other. Tables 2.1 and 2.2 list pathological findings and their diagnostic
meaning.
The tables indicate that the electrodiagnostic findings and their time course may
provide valuable information about both the site and the type of a suspected nerve
lesion. Table 2.3 is intended to help the reader plan a sensible timing for the diag-
nostic tests and to “decode” their results.
Some time intervals after the trauma are noteworthy [8].
Table 2.1 EMG findings in a weak muscle and their diagnostic meaning
EMG finding Occurrence/cause Timing
Normal Central nervous system Always
lesion (e.g., intracranial
hemorrhage)
Not a severe nerve lesion Until the occurrence of pathological
spontaneous activity
Pathologic spontaneous Axonotmesis, neurotmesis, Begins 10–14 days after a lesion,
activity myopathy ends after full recovery, may persist
for decades if recovery is incomplete
Polyphasic motor unit Partial axonotmesis, Begins 6 weeks after an incomplete
action potentials myopathy lesion, ends after recovery, some may
(MUAPs) persist
Large MUAPs (may be Partial axonotmesis Begins 6–12 months after an
polyphasic) incomplete lesion, persists after
recovery
Increased (>20/s) Neurapraxia, partial Begins immediately after the lesion,
discharge rate of single axonotmesis accompanies weakness
motor units
Table 2.2 NCS findings in a nerve supplying a weak muscle and their diagnostic meaning
NCS finding Occurrence/cause Timing
Normal compound muscle Central nervous system lesion Always
action potentials (CMAPs) (e.g., intracranial
hemorrhage),not a severe nerve
lesion, myopathy
Normal (CMAPs) Stimulation distal to the lesion Ends 4–7 days after the
only lesion (due to Wallerian
degeneration of axons)
Normal CMAPs upon nerve Neurapraxia (also called Begins with the lesion, ends
stimulation distal to the “conduction block”) with recovery
lesion, low CMAPs upon Axonotmesis Ends 4–7 days after the
proximal stimulationa lesion (due to Wallerian
degeneration of axons)
Innervation anomaly Always
Low CMAPs at all Axonotmesis Begins 4–7 days after the
stimulation sites, lesion (due to Wallerian
low sensory nerve action degeneration of axons), ends
potentials (SNAPs) with full recovery
Mildly reduced nerve Axonotmesis Parallels low CMAPs
conduction velocity (NCV) Pre-existing polyneuropathy No relationship to the nerve
(leg, 30–40 m/s; arm, trauma
40–50 m/s)
Severely reduced NCV (leg, Demyelinating neuropathy, not No relationship to the nerve
<30 m/s; arm, <40 m/s) caused by nerve trauma trauma
a
Note that this finding is often labeled “conduction block,” although conduction block is only one
of its potential causes
Immediately after a severe lesion an EMG may be valuable: If motor unit action
potentials (MUAPs) are recorded, the lesion is incomplete, and thus neurotmesis is
ruled out. If pathologic spontaneous activity (PSA) is recorded within the first
10 days or if abnormally polyphasic or enlarged MUAPs are found within the first
4 weeks, a pre-existing neuropathy (or, rarely, a myopathy) is documented. It should
also be noted that PSA may persist for years. Thus, the occurrence of PSA not nec-
essarily indicates a recent lesion. The recency of a lesion can be inferred from PSA
only if the PSA was not found in an early recording but does appear later on.
If increased discharge rates of motor units are found at any time, a central ner-
vous system lesion is ruled out.
An NCS may make particular sense within the first 4 days, namely, before
Wallerian degeneration (see Chap. 1) becomes apparent [11]. Only during this time,
the distal part of the lesioned nerve can be stimulated electrically. This results in a
Table 2.3 Electrodiagnostic findings after a nerve trauma over time

Type of lesion
Total axonotmesis,
Time after trauma Neurapraxia Partial axonotmesis neurotmesis
Immediately EMG No PSA, DR ↑ No PSA, DR ↑, No PSA, no MUAPs
MUAPs n MUAPs n
NCS ∆CMAP ∆CMAP ∆CMAP
4–7 days EMG No PSA, DR ↑, No PSA, no MUAPs
MUAPs n
NCS CMAPs ↓ No CMAPs
10–20 days EMG PSA, DR ↑, PSA, no MUAPs
MUAPs n
NCS CMAPs ↓ No CMAPs
>6 weeks EMG n PSA, DR ↑, PSA, small polyphasic
polyphasic MUAPs (“nascent”) MUAPs
NCS n CMAPs ↓ No CMAPs
Years EMG n MUAPs ↑ (PSA), MUAPs ↑
NCS n CMAPs (↓) CMAPs ↓
DR discharge rate (of motor units!), MUAP motor unit action potential, PSA pathologic spontane-
ous activity, CMAP compound muscle action potential, ∆CMAP normal CMAPs upon nerve stim-
ulation distal to the lesion, low CMAPs upon proximal stimulation (see Table 2.2), n normal, ↑
pathologically increased, ↓ pathologically decreased
normal compound muscle action potential (CMAP) following stimulation distal to

the lesion and a low CMAP following stimulation proximal to the lesion, a finding
that reliably localizes the nerve lesion. After the completion of the Wallerian degen-
eration, namely, after 11 days [11], all CMAPs are low or have disappeared, irre-
spective to where the lesion is located. If a low CMAP upon distal stimulation is
found within the first 4 days, a pre-existing lesion is documented. Conversely, a
normal CMAP during that time documents the integrity of that nerve before the
trauma. This finding, as well as the absence of PSA early on EMG, can be particu-
larly helpful in the evaluation of potentially iatrogenic nerve lesions.
A major shortcoming of the established electrodiagnostic methods is that they do
not help to make the important distinction between neurotmesis and total axonotme-
sis; the latter denominates a condition of a nerve characterized by all of its axons
suffering from axonotmesis.
Figure 2.1 illustrates a common clinical situation and how a good knowledge
about the benefit of electrodiagnostic procedures and the meaning of the respective
findings are important for appropriate treatment decisions.
a d
2mV 2mV
5ms 5ms
b e
100µV
100ms 100ms
c f
1mV
Fig. 2.1 A 74-year-old man experienced plegia of his left foot extensors immediately after sur-
gery on his lumbar spine. As a complication of the surgery was suspected, the patient underwent a
second operation 1 day after the first one, which did not resolve the problem. First electrodiagnos-
tic examination was done 2 days after the first surgery: (a) motor nerve conduction study (NCS)
recordings from his left extensor digitorum brevis muscle, stimulation of the peroneal nerve at the
dorsum of the foot (upper trace), and below and above the fibular head (lower traces). Compound
muscle action potentials (CMAPs) upon distal stimulation are low, indicating a pre-existing lesion,
and CMAPs upon proximal stimulation are absent, which shows that there is an additional lesion
that can be localized at the fibular head (Table 2.3, “immediately”). (b) The electromyogram
(EMG) of the anterior tibial muscle shows pathologic spontaneous activity (PSA), which also
demonstrates a pre-existing lesion. (c) Increased (>20/s) discharge rates of motor units show that
at least 80% of the motor units of the muscle are not functional [31]. These results point to the site
of the actual lesion and show the pre-existing one. The type of the lesion cannot be inferred. A
subsequent electrodiagnostic examination was done 20 days after surgery: (d) NCS as in (a) all
CMAPs are absent, showing that the type of the lesion is axonotmesis (or neurotmesis) (Table 2.3,
“10–20 days”). (e) The electromyogram (EMG) of the anterior tibial muscle shows pathologic
spontaneous activity (PSA), showing that the type of the lesion is axonotmesis that took place at
least 10–14 days before this recording was made. (f) Discharge rates of motor units are normal,
showing a functional recovery of many motor units of this muscle since the recording (c) was
made. These results do not permit to localize the lesion but show that the lesion type is partial
axonotmesis, more pronounced in the extensor digitorum brevis than in the anterior tibial muscle.
It should be noted that the second operation could have been avoided if the first electrodiagnostic
examination had taken place immediately
2.4 Imaging
2.4.1 High-Resolution Ultrasound
Ultrasound imaging of peripheral nerves is done since a quarter of a century [13].

Initially, this was done virtually exclusively by radiologists and orthopedic sur-
geons. Neurological studies on this subject were published from the beginning of
this millennium [2]. Since then technology had made extreme progress, especially
the spatial resolution of ultrasound was dramatically improved. However, the pen-
etration depth of ultrasound is still limited. This is the main shortcoming of ultra-
sound, especially if compared with magnetic resonance imaging (MRI) [29]. As a
consequence of the methodological improvements, the number of publications on
“ultrasound” and “peripheral nerve” increased from less than one per year before
2000 to 60 PubMed entries in 2015.
To date, the clinical significance of ultrasound imaging of peripheral nerves in
general is not without controversial discussion [5], while its role in the diagnosis of
traumatic nerve lesions is yet better defined [7, 20, 27, 37]. This is because the
major diagnostic issue in traumatic lesions is to determine both the type and the
morphology of the lesion and not so much to localize the lesion. As a major point,
the important distinction between neurotmesis and total axonotmesis, which cannot
be made with electrodiagnostic methods, can readily be made with ultrasound.
When the diagnostic value of ultrasound was studied prospectively in 65 patients
with nerve trauma, the use of ultrasound strongly modified the diagnosis and the
therapy in 58 % of cases. It specifically contributed to the following:
• Distinction between neurotmesis and axonotmesis

• Identification of etiology
• Demonstration of multiple sites of nerve damage
The contribution of ultrasound was clearly the highest in cases with neurophysi-
ological evidence of complete axonal damage [27]. Figure 2.2 illustrates a typical
clinical situation in which ultrasound imaging clearly demonstrates a peripheral
nerve’s neurotmesis.
Ultrasound can be used to study the development of neuromas, both before and
after nerve surgery. Unfortunately, the information that can be drawn from such
imaging is of limited value so far, as there is no relation between enlargement of
neuroma and nerve function unless the size of the neuroma exceeds a cutoff beyond
which prognosis is negative [9].
Before nerve surgery, ultrasound can be used to detect the location of proximal
and distal nerve stumps. They can be marked on the skin preoperatively to help the
surgeon better tailor the procedure to the damaged nerve’s needs and save time that
otherwise would be needed for the search for the stumps [20].
During nerve surgery, ultrasound imaging can time efficiently and reliably be
used to assess the severity of the underlying nerve injury and the type (intraneural/
perineural) and grade of nerve fibrosis [21].
Fig. 2.2 A 64-year-old woman got a lipoma removed from her cubital fossa. Immediately after
surgery she experienced plegia of her finger extensors. Four weeks after, there still was plegia of
all muscles innervated by her radial nerve distal to the extensor carpi radialis brevis muscle. Upon
EMG examination of the plegic muscles, there was abundant spontaneous activity but no MUAPs.
High-resolution ultrasound imaging (upper, provided by Peter Pöschl, Regensburg) clearly shows
a transected nerve, with (A, B) and (C, D) marking the nerve stumps. This finding is confirmed by
visual inspection during subsequent surgery (lower)
If carried out monthly after nerve surgery, ultrasound examinations could earlier
pick up signs of failed neuroregeneration than electrodiagnostic procedures and
thus ascertain the need of surgical revision (see also Chap. 3) [24].
2.4.2 MRI
2.4.2.1 Background and Overview

Traditionally, MRI has been included in the diagnostic assessment of peripheral
neuropathies only to rule out any suspicion of a causative mass lesion that might
lead to a compression injury of the adjacent nerve. In the early 1990s, the group of
Filler and colleagues started to develop MRI sequences for imaging of the periph-
eral nervous system in experimental studies which required a higher structural reso-
lution and an increased nerve lesion contrast [12]. They were also the first who
termed this optimized MRI technique as magnetic resonance neurography (MRN)
[12]. Very early it became clear that heavily T2-weighted (T2w) sequences with fat
saturation are most suitable to distinguish between healthy and impaired nerve tis-
sue [3, 22]. While normal nerves appear isointense or slightly hyperintense to mus-
cle tissue in these sequences, the MRN correlate of a nerve lesion is a markedly
increased T2w signal or rather an increase in the T2 relaxation time of the corre-
sponding nerve, a marker with high sensitivity but low specificity; for instance, it
cannot differentiate between mechanical and immune-mediated, metabolic, or
hereditary nerve injury [22]. The spatial extension of the signal change has been
first described in experimental animal studies in neurotmetic and axonotmetic nerve
injuries. A significant increase of the intraneural T2w signal has been observed in
animals to occur within 24–48 h after traumatic axonal damage, not just at the lesion
site but also along the distal course of the nerve due to Wallerian degeneration.
Nerve regeneration after successful neurosurgical restoration was accompanied by
a normalization of the formerly increased T2w signal with a proximo-to-distal
course over several weeks [4]. These MRN findings correlated well with both elec-
trophysiological and histological data. In contrast to traumatic nerve injuries with
complete or partial nerve discontinuity, the T2w signal increase in demyelinating
neuropathies has been found to be restricted to the lesion site without any distal or
proximal extension [4].
These first experimental studies provided the basis for the implementation of
MRN in the diagnostic workup of peripheral nerve disorders in human patients.
Nowadays, it is an accepted technique that allows the direct and precise visualiza-
tion of nerve injury even on a fascicular microstructural level (fascicular imaging)
[28, 34]. That means that MRN can clearly differentiate between nerve lesions
affecting the complete cross section of a nerve and partial and therewith fascicular
lesions containing often somatotopic information [28]. In traumatic nerve injury, it
can visualize the affected individual fascicles, the proximal lesion border, potential
distal discontinuity, or nerve compressing masses such as hematoma or bone frag-
ments [34].
2.4.2.2 Technical Requirements

The term MRN implies the application of certain MR pulse sequences that can visu-
alize peripheral nerves and distinguish them from surrounding soft tissue and ves-
sels [12]. The basic requirements to achieve a structural resolution sufficient for
imaging of nerve tissue, or rather visualization of nerve fascicular structure, are a
high magnetic field strength of 3 Tesla and heavily T2w, fat-saturated sequences
with an in-plane resolution of 0.1–0.4 × 0.1–0.4 mm, and a slice thickness of not
more than 2–3.5 mm [29]. Fat saturation is crucial to reliably differentiate between
bright nerve signal and surrounding fat tissue and can be achieved by either
frequency-selective saturation of the fat signal in T2w fast spin echo (SE) sequences
or with nulling of the fat signal as it is done in short inversion recovery (STIR) or
turbo inversion recovery magnitude (TIRM) sequences [3]. Unenhanced T1w
sequences can be beneficial in regions of difficult anatomical orientation, e.g.,
peripheral nerves emerging from the lumbosacral plexus. Additional application of
a contrast agent and subsequent acquisition of T1w sequences with fat saturation are
needed in cases of mass lesions like nerve or nerve sheath tumors, but also in
remaining or recurring neuropathy after surgical interventions to rule out an over-
production of potentially nerve compromising scar tissue [22].
2.4.2.3 MRN Findings in Nerve Injury

In patients with traumatic brachial plexus injuries, it is of utmost importance to
early differentiate between a nerve root avulsion from the spinal cord, also referred
to as a preganglionic lesion, and a postganglionic nerve lesion, involving the supra-
or infraclavicular parts of the brachial plexus (trunks, divisions, cords, branches)
[32]. A total nerve root avulsion can be easily diagnosed with conventional imaging
methods, such as CT myelography or spinal MRI, which will show an unencapsu-
lated pouch of fluid due to the extravasation of cerebrospinal fluid (CSF), com-
monly termed pseudomeningocele (Fig. 2.3). Most complete tears or avulsions of
nerve roots or ganglia cannot be grafted due to the retraction of proximal nerve
a b c
Fig. 2.3 MRN: 3D constructive interference in steady state (CISS) sequence in sagittal (a), coro-
nal (b), and transversal (c) reformations. Arrows point to pseudomeningoceles of the C6, C8, and
Th 1 nerve root, representing complete traumatic nerve root avulsions
tissue. In case of postganglionic brachial plexus lesions, a further differentiation

between a complete separation of proximal and distal nerve ends (neurotmesis)
without any chance of spontaneous recovery (Fig. 2.4) and an incomplete or partial
nerve discontinuity or stretching injury (neuropraxia or axonotmesis), which might
recover without surgical treatment, is essential for an adequate surgical planning
and also for a prognostic estimation. Besides direct visualization of nerve disconti-
nuity (Fig. 2.4), the most obvious MRN sign of a complete nerve transsection is an
end-bulb neuroma (EBN; Fig. 2.5a), while an incomplete nerve lesion might show
Fig. 2.4 MRN: 3D

T2-weighted inversion
recovery sampling
perfection with application
optimized contrasts using
different flip angle
evolution (SPACE)
sequence. Coronal
reconstruction.
Postganglionic brachial
plexus lesions showing
neurotmesis. Arrowhead
points to the proximal, and
arrow points to the distal
nerve ends. Note the
remarkable distance
between proximal and
distal nerve ends caused by
retraction
a b
Fig. 2.5 MRN: axial T2-weighted sequence with spectral fat saturation (a) and axial contrast-
enhanced T1-weighted sequence with spectral fat saturation (b). Note the markedly increased
cross-sectional diameter and intraneural T2w signal (arrows) of the sciatic nerve at mid-thigh level
representing an end-bulb neuroma after traumatic amputation of the right leg at knee level. After
the application of a contrast agent, the end-bulb neuroma shows the typical increased, slightly
inhomogeneous enhancement (arrowheads)
a neuroma-in-continuity (NIC) [14, 23]. A neuroma consists of fibroneural tissue

that develops as a result of failed nerve regeneration with a multidirectional prolif-
eration of cells as well as distortion of normal nerve architecture. Both EBN and
NIC show continuity with the proximal parent nerve, but only NIC shows continuity
with the distal parent nerve as well [1]. Typically, traumatic neuromas present not
only with an increased, often heterogeneous, T2w signal but also with a marked
increase of the cross-sectional diameter and an oval or nodular form on coronal or
sagittal images (Fig. 2.5) [33]. After the application of a contrast agent, it will show
an increase and also a heterogeneous enhancement (Fig. 2.5b) [1, 32]. Even in the
absence of a defined neuroma, an increase of the nerve diameter might be visible,
which is another, this time morphometric and therewith signal independent, MRN
sign of nerve damage. It is not just related to neuromas but is an unspecific MRN
sign of nerve impairment in general.
The average speed of nerve regrowth is around 1 mm per day, so that a complete
recovery can take months or even years. During that time, it might be difficult to
monitor proper nerve regeneration and failure of axonal regrowth, e.g., due to dislo-
cation of the proximal and distal nerve ends or fascicles, which would require early
surgical therapy (see also Chap. 3). MRN with its direct visualization of nerve
lesions can help to monitor the physiological regrowing in that it shows the disap-
pearance of the formerly bright T2w signal with a proximo-to-distal gradient [10].
Any interpretation of an increased nerve T2w signal has to be made carefully and
with the knowledge that the T2w signal might be artificially increased related to
certain specific MRI artifacts like the magic angle effect. In the majority of cases, it
can be avoided easily by positioning the examined extremity with an alignment of
less than 30° relative to the B0 field direction [18]. However, in examinations of the
cervical and lumbar plexus, this alignment is not always realistic due to the normal
anatomical course of the emerging nerves, and it is important that these angulation-
induced signal changes are not mistaken for true pathologic nerve lesions [3].
Determining the existence or absence of physiological nerve repair is crucial and
might be diagnostically challenging even when changes in the proximo-to-distal
extend of nerve T2w signal all together with clinical and electrophysiological exam-
inations are performed (see also Chap. 3). Current studies discuss the validity and
diagnostic advantage of new techniques, such as diffusion tensor tractography
(DTT), a method based on direction-dependent diffusion in anisotropic structures or
rather anisotropic movement of water molecules, to monitor early nerve regenera-
tion in vivo. First results of animal studies showed that tracked fibers terminate at
the point of axonal discontinuity within hours after traumatic nerve injury, while
fibers may extend distal to the located injury and show an increase in the fractional
anisotropy (FA) in case of nerve regeneration [25, 35]. However, further investiga-
tions and correlation with clinical and electrophysiological measurements are
needed to estimate the diagnostic benefit and outcome.
The most frequent traumatic injuries of the sciatic nerve are iatrogenic and
are either induced by gluteal injection injury or periprocedural in hip replace-
ment surgery. In case of iatrogenic trauma related to hip replacement surgery,
direct imaging identification of the exact lesion site and determination of injury
severity are often challenging, due to metal artifacts that are related to metal
implants in the direct vicinity of the nerve. However, new techniques of artifact
reduction make it still possible to achieve a nerve lesion contrast that is suffi-
cient for precise lesion localization [39]. Besides complex adjustments of
sequence parameters whose description would exceed the purpose of this book,
the following aspects should be kept in mind: spin echo (SE) or turbo spin echo
(TSE) sequences are more beneficial than gradient echo (GRE) sequences, as
the 180° refocusing pulse used in SE sequences corrects for large magnetic field
inhomogeneities and therewith reduces dephasing artifacts. Additionally, STIR
sequences should be used for the necessary fat suppression in T2w sequences,
as they are less dependent on a homogenous magnetic field than spectral fat
saturation techniques [39]. Furthermore, the acquisition of T1w sequences
might be beneficial as they are less vulnerable to susceptibility artifacts while
providing sufficient anatomical resolution for the detection of nerve discontinu-
ity or compromising material [39].
Clinical and electrophysiological measurement at proximal sites of the lower
extremities often lacks to precisely localize the nerve lesion as well as to give an
estimation of the regenerative potential without surgical therapy. MRN has been
proven to be able to directly visualize the exact lesion site with high sensitivity by
evaluating the typical MRN pattern as described before, but can also give a
detailed pathomorphological description of the injury, like overproduction of epi-
or intraneural scar tissue, development of neuroma, or extent of fascicular involve-
ment [30].
2.4.2.4 MRN Findings in Denervated Muscle

Not only the nerves but also the muscle tissue is visualized through MRN. Normal
muscle tissue presents with an intermediate signal on T1w and T2w sequences. In
acute nerve injury and subsequent denervation of dependent muscles, a marked
increase of the T2 relaxation time can be observed as early as 5 days after an axo-
notmesis or neurotmesis [38]. MRI findings well correlate with the amount of spon-
taneous activity on EMG [16, 26] and with the size of the MUAPs [16]. Its main
advantages, namely, its painlessness and its ability to visualize the whole cross sec-
tion of an extremity (Fig. 2.6), must be balanced against its lower sensitivity to
axonotmesis and its blindness to neurapraxia [26]. Overall, in certain clinical situa-
tions, it may be particularly helpful to complement electrodiagnostic procedures
and MRN.
a b
Fig. 2.6 MRN: axial T2-weighted sequence with spectral fat saturation (a, b). A lesion of the
common peroneal nerve (a) leads to an increased T2w signal of depending muscles (arrowheads
point to the anterior tibial, extensor longus, and long peroneal muscles) which is the MRN corre-
late of muscle denervation. In contrast to that, the pattern of an L5 radiculopathy (b) shows an
additional denervation signal nerve in the posterior tibial and popliteus muscle (arrows in b;
arrows in a show the normal signal intensity of the same muscles)
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Timing and Decision-Making
in Peripheral Nerve Trauma 3
Hans Assmus
Contents
3.1 Introduction 27
3.2 The Decision Process 28
3.3 Preoperative Decisions and Therapeutic Options (Indication) 30
3.4 Intraoperative Decisions 33
3.5 Indication in Case of Partial Lesions and Neuroma Formation 35
3.6 Decisions in or Concerning Combined Lesions 35
3.7 Perioperative Techniques: Choice of Anesthesia and Application of Tourniquet 36
3.8 Postoperative Decisions and Revision Surgery 36
3.9 Prevention of Nerve Injuries and Future Aspects 38
References 39
3.1 Introduction
The decision processes during diagnosis and treatment of an injury of the peripheral
nerve are much more complex than, for example, those for injuries of bones or ten-
dons. The nature and cause of the injury, its localization, and its depth/severity
require very distinct decisions with regard to timing and technique for intervention.
Timing of the nerve repair is important.
Basically, a sharply and neatly transected nerve is to be judged different than a
nerve that has been bluntly transected or violently torn. While the first is usually
caused by a cut, the latter two occur during injuries with bony fractures, gunshots,
or electrical and other physical traumata.
H. Assmus
Abtweg 13, D-69198 Schriesheim, Germany
e-mail: hans-assmus@t-online.de

DOI 10.1007/978-3-319-52319-4_3
28 H. Assmus
A sharp transection injury within a clean (not contaminated) wound requires

immediate repair, while in the majority of cases, a wait-and-see attitude and an
(early) secondary nerve reconstruction is advisable. For appropriate decision-
making, a good knowledge of the pathophysiological conditions in the peripheral
nervous system and of related processes, which occur at the same time in the
central nervous system, is helpful. The crucial role of the time factor in nerve
reconstruction relates to the early induction of the regeneration processes by intra-
cellular signaling of the axotomized neurons and their neighboring nonneural
cells [9].
There is no debate that nerve reconstruction performed as early as possible
strongly increases the prognosis and condition for optimized functional recov-
ery. The quality of motor recovery is continuously decreasing 6 months after
injury [5, 6, 15]. This limitation is less strong for sensory recovery. It has to be
avoided, however, to disrupt a possibly ongoing spontaneous recovery after a
completely reversible nerve block (neurapraxia, see Chap. 1). Overhasty, but
also too broad resection of a neuroma in continuity after gunshot, contusion, or
stretching or of a neuroma after partial transection could result in poorer out-
come than an observant approach. Modern techniques like electrodiagnostical
nerve stimulation or neurosonography considerably facilitate the diagnostic
classification of peripheral nerve injuries and result into early nerve reconstruc-
tion where indicated.
3.2 The Decision Process
A general outline of the complex decision process for nerve reconstruction surgery
and its timing is illustrated in Fig. 3.1. Depending on whether an open or closed
injury exists, it has to be decided for a primary or secondary reconstruction surgery.
During the decision process, the wound condition, the depth of the injury, and even-
tually also results of an exploratory exposure of the nerve or from imaging or elec-
trophysiological evaluations have to be considered. During primary or early
secondary reconstruction, additional decision has to be taken with regard to the
appropriate reconstruction technique. During a regular postoperative monitoring,
the regeneration process has to be documented, and eventually new diagnostic and
surgical decisions have to be taken. A mean monitoring and treatment period covers
approximately 2 years and more.
The complex challenge of nerve repair and reconstruction, including additional
steps that may become necessary, is exemplarily outlined by the practical case
example below. Subject is a typical and frequent lower arm injury with disconnec-
tion of the ulnar nerve.
3 Timing and Decision-Making in Peripheral Nerve Trauma 29
Open injury Contusion/Traction
Sharp? No No Spontaneus
complete/
improvement?
partial?
Yes
Nerve Regen. Yes

Repair in electrophysiol Yes
time verified
In by EMG
possible? continuity? etc.?
No No
No
Yes
Exposure/decompression/
Primary repair Secondary repair
neurolysis
No
Nerve
Coaptation
structure
possible?
Yes No intact?
Donor
End-to-end coaptation, split
nerve
repair No
available? Yes
Yes
Nerve transplantation Neurotization end-to- Heterolog.

nerve tansfer side technique transplantation
Muscle/tendon transfer Improvement?

etc. No
Conservative therapy
Yes
rehabilitation
Fig. 3.1 Algorithm of the diagnostic and therapeutic steps and treatment strategies for nerve
injury
Case Example
A younger patient sustained a laceration of the left volar proximal forearm 1
month ago with transection of the ulnar nerve. During primary wound care,
the nerve ends had been loosely approximated.
30 H. Assmus
The nerve surgeon, to whom the patient had been referred for further
anagement, faces the following options depending on the assessment of the
m
pattern of injury:
• Attempt of an end-to-end coaptation of the ulnar nerve. Therefore, the

nerve would be mobilized over a long distance followed by its transposi-
tion to the palmar side of the elbow. This approach is favorable when only
a small defect resulted from a sharp transection of the nerve.
• If a tension-free end-to-end coaptation is not possible, decision for an
autologous nerve transplantation has to be considered. As donor nerve
preferably the dorsal cutaneous branch of the ulnar nerve, alternatively the
sural nerve could be used. Artificial nerve conduits (see Chap. 8) cannot
yet be considered as general alternatives to autologous nerve transplants.
• Discussable is an additional opening of the Loge de Guyon to prevent sec-
ondary nerve compression by tissue swelling. It is indispensable, however,
when the technique mentioned below is performed.
• Not generally accepted is the option to increase the motor function of the
intrinsic hand muscles by an additional end-to-side coaptation (see Chap.
4) between the final motor branch of the anterior interosseous nerve and
the deep branch of the ulnar nerve. The end-to-side technique is, however,
more often used in repair of very proximal ulnar nerve lesions, especially
in brachial plexus reconstruction.
3.3 reoperative Decisions and Therapeutic Options

P
(Indication)
The schematic overview in Fig. 3.2 illustrates the lining up of diagnostic decision-

making processes.
After a trauma with assumed lesion of a peripheral nerve, it applies first to prove
or to exclude the same. In the case of a proven nerve injury, its depth has to be docu-
mented. Careful anamnesis could often point on a nerve injury, e.g., a report of
violent shooting in electrifying pain in the context of a surgical intervention. In the
case of a traumatic accident, its course and primary clinical status are to be exactly
documented, not only for insurance-legal reasons but also to answer the question
whether the lesion has developed by the accident mechanism (e.g., avulsion injury)
or the supply of a fracture (e.g., with a humerus fracture).
The severity level of the nerve lesion has to be classified as this is indispensable
for the statement of the injury depth and the prognosis (see Chap. 1) but serves
equally for the decision-making regarding the treatment strategy, in particular the
indication for the operation. The Medical Research Council (MRC) scale
(http://www.mrc.ac.uk/research/facilities-and-resources-for-researchers/mrc-scales/
mrc-muscle-scale/) and the Seddon and Sunderland classifications (with the
Nerve without function

diagnostic procedures
Electrodiagnostic MR-
Sonography
studies Neurography
Path. Alteration
Structural
spont. of nerve
discontinuity?
activity? signal?
Yes Alteration
No muscle Alteration of
response? nerve signal? of muscle
signal?
No Yes
No Axonotmesis Axonotmesis No
neurotmesis neurotmesis
Neurapraxia
Fig. 3.2 Primary diagnostic procedures (see also Chap. 2)
additions of Millesi) are still commonly used (see Chap. 1). Especially in early
stages after nerve lesion, it can be difficult or impossible to differentiate between
neurapraxia, axonotmesis, and neurotmesis just on the basis of clinical symptoms
and physical findings. Therefore, additional electrophysiological investigations are
essential [17]. In early stages after a nerve injury, compound muscle action p otentials
(CMAPs) and motor units (MU) can be examined, which are, however, of only
limited evidence. Recently, nerve sonography showed its superiority over the
electrophysiological assessments [7]. But also nerve sonography has its limitations,
as it is very much restricted to the examination of rather superficial nerves.
Deep-running nerves can be judged, however, with the magnetic resonance neurog-
raphy (MRN) (see Chap. 2). Already today, this modern method substantially affects
diagnostic and therapeutic decision-making processes and in particular also the
planning of the surgical intervention [8]. Ultrasound or standard MRN are unable to
fully discriminate between neurotmesis and axonotmesis, in particular when the
nerve remains in continuity. Diffusion tensor tractography (DTT) represents a recent
development in MR imaging that may revolutionize this aspect of the diagnosis and
monitoring of peripheral nerve trauma [19].
Sunderland Grade III lesions may often regenerate spontaneously (incomplete
regeneration) and then result in better functional recovery than after nerve recon-
struction. Both will result in incomplete regeneration, but the degree may vary
32 H. Assmus
considerably. Especially in this scenario, the decision for the correct procedure is
very important for the further process. On the basis of novel diagnostic techniques,
in particular related to the advances in peripheral nerve imaging, patients may be
more correctly selected to receive prompt surgical intervention when indicated, and
invasive procedures may be more correctly avoided when spontaneous regeneration
is likely. Simon et al. [20] suggest that “further exploration of non-invasive strate-
gies to augment nerve regeneration processes, such as modulation of central and
axonal plasticity through repetitive stimulation and functional retraining paradigms,
may provide further benefit for patients with moderate and severe nerve injury,
including those patients in whom surgical intervention is not needed” [20].
In general, an indication for a surgical procedure results from the following
reasons [4]:
• To confirm or establish diagnosis

• To restore continuity to a severed or ruptured nerve
• To release a nerve of an agent that is compressing, distorting, or occupying it
Contraindications for a surgical intervention include bad general condition of the

patient and risk of general or local sepsis, as well as uncertainty over the kind and
extent of the injury (e.g., bullet or saw injury). A nerve reconstruction is not reason-
able whenever no appropriate instrumental, machine-aided, or spatial conditions are
present and whenever no experienced operation team is available. In certain cases
also a primary muscle or tendon transfer can be the better choice, e.g., in the case of
irreparable lesions of predominantly motor nerves (such as of the radial and com-
mon peroneal nerves).
In fact, the ideal case of a primary treatment of a nerve injury, i.e., the smooth
uncomplicated disconnection of a nerve, is rather the exception. For the far more
frequent secondary treatment, temporal limits have been specified, which vary
depending upon the examiner (Fig. 3.3).
Acute peripheral nerve lesions require a differentiated proceeding. The strategic
decision for an immediate reconstruction or a wait-and-see attitude depends on the
type and the depths of the lesion. Generally a complete/total nerve transection injury
can be assumed whenever an open cut or stab injury exists along the nerve trajectory
and the loss of the nerve function has been proven clinically. During wound
treatment the discontinuity of the nerve will be confirmed, and under optimal condi-
tions, primary nerve reconstruction will be performed. This is not only the simplest
decision to be taken by the nerve surgeon but also the ideal scenario for the patient
with the best prognosis. Under ideal conditions the prerequisites are as follows:
(1) smooth sharp transection and clean wound properties, (2) experienced nerve
surgeon, and (3) appropriate technical equipment and surgery room. Certain types
of nerve injury and their extent together with the extent of accompanying injuries
and other concomitant factors, however, do often prohibit primary nerve repair.
Most examiners do not define a strict time limit for the primary coaptation. The
transition to an early secondary treatment runs smooth, although an intervention
within the first week (≤ 10 days) after injury is generally referred to as the optimum.
Time from injury
8–24 hrs.
Less than 2–45 Less than
(max. 10
8 hrs. days 6 weeks
days)
Tension Tension
free free
suture? No suture?
Yes Yes
Early Late
Primary Secondary
secondary secondary
coaptation coaptation
coaptation coaptation
Nerve transplantation etc.
Fig. 3.3 Timing and temporal limits of primary and secondary peripheral nerve repair
A maximum time window of 6 weeks is accepted for secondary nerve repair. Such
secondary nerve repair may not always have an inferior prognosis, because a highly
experienced nerve surgeon performing a meticulous and conservative approach may
compensate the disadvantages of the delayed treatment.
The decision to accomplish a reconstruction after more than 6 months must be
discussed with the patient and depends on many factors like the age of the patient,
the kind of nerve injured (motor or sensory), the proximo-distal height of the injury,
concomitant lesions, etc.
3.4 Intraoperative Decisions
The main principle is to perform tension-free and optimal adaptation of the nerve
ends and fascicles. Contused nerve stumps have to be trimmed back to the healthy
epineurium and a visible fascicular structure. During an immediate repair approach,
34 H. Assmus
it may be difficult to estimate exactly the length of necessary resection, especially

in the case of more blunt dissection injuries. This specific condition may be better
evaluated in a secondary approach or delayed repair procedure. The delay, h owever,
should be kept as short as possible since nerve ends retract with time and this will
consequently impair the coaptation of the nerve ends without significant tension.
For combined lesions (cut and crush), decision-taking for immediate or delayed
treatment is particularly difficult and responsible. The latter is also true for gunshot
injuries in which typically a massive, diffuse destruction of tissue is present. Once,
in these cases, a neuroma in continuity is found during the secondary care, the
intraoperative recording of the compound nerve action potential (cNAP) can
deliver reliable evidence whether nerve conduction at the lesion site is preserved or
not. Such evidence facilitates very much the decision whether to remove the
neuroma or not [13].
After the decision for nerve reconstruction has been taken, the appropriate recon-
struction approach has to be considered. The intraoperative decision-taking process
is illustrated in Fig. 3.4. In addition further important intraoperative determinations
have to be made, like the length of the resection of the nerve stumps (how much to
resect) and the anatomical allocation of the nerve bundle groups. The use of intra-
operative motor and sensory nerve differentiation methods can diminish the risk of
fascicular mismatch when grafting an autologous nerve. Available intraoperative
methods for the differentiation between sensory and motor fascicles are the ana-
tomic method, based on separate identification of groups of fascicles, the electro-
physiological method, using stimulation of nerve fascicle in the awakened patient,
and histochemical method, which is based on staining for enzymes specific to motor
or sensory nerves. Both the latter methods are difficult to use, because the patient
has to be highly compliant for the electrodiagnostic evaluation and because of the
time gap that develops before sample tissue has been analyzed histochemically.
Nerve defect > 3 mm (after mobilization and/or transposition)
Donor No
No distal
nerve proximal
stump?
available? stump?
Yes No Yes Yes
Autologous Nerve transfer

Muscle
transplantation Allograft/tube end-to-side-
neurotization
(nerve transfer) technique
Fig. 3.4 Decision-taking depending on the length of the nerve defect

Finally, the appropriate donor nerve has to be identified. Most of the time, the sural
nerve is selected, but the cutaneous antebrachial and the saphenous nerve comprise
good alternatives.
Special techniques alternative to autologous nerve grafting and their limitations
are described and discussed in the Chaps. 4 and 7.
Harvesting the donor nerve can be done by different methods: for the sural nerve,
several small incisions will be made along the nerve course, or a nerve stripper will
be used [3], which reduces the operation time significantly and gives the best cos-
metic results. The decision depends on personal preferences of the nerve surgeon.
An additional consideration is needed with regard to the degree of justifiable ten-
sion at the coaptation site. An epineural coaptation with little tension is the method of
choice [21]. This is usually achieved by sufficient mobilization of the nerve as well as
by transposition of the nerve (e.g., transposition of the ulnar nerve into the cubital
fossa) or through slight joint bending. A rough indication for what degree of tension
is barely acceptable at the coaptation site can give the application of 10-0 sutures.
Whether fibrin glue is an alternative or additive to suture is discussed in Chap. 4.
Techniques like end-to-side coaptation and the direct muscular neurotization
(only a treatment at ultima ratio) are not commonly accepted as alternative
approaches for nerve reconstruction (see Chap. 4). The latter techniques may be
considered in reconstruction of extensive proximal lesions or extended brachial
plexus lesions (see Chap. 6).
3.5 I ndication in Case of Partial Lesions and Neuroma

Formation
Treatment of neuroma is generally challenging and often results in disappointing

results. The decision for or against neuroma resection may be difficult to take and
deserves in-depth discussion with the patient. This is also true for neuroma in con-
tinuity, e.g., those of the median nerve at the wrist resulting from superficial cut
injuries. Such neuroma can only be treated with the so-called split-repair by remov-
ing only neuromatous parts and preservation of those nerve fascicles that are still
functional. In these cases intraoperative sonography and cNAP studies could be
helpful to evaluate intact nerve fascicles (see Chaps. 2 and 5). The performance of a
split-repair is challenging, can only be done using a surgery microscope or magnify-
ing glasses, and requires specific expertise from the responsible nerve surgeon.
3.6 Decisions in or Concerning Combined Lesions
Due to the fact that traffic accidents represent the most frequent cause of peripheral
nerve injuries, examiners are frequently confronted with combined lesions.
Combined lesions significantly impact the timing of nerve repair, because the pri-
mary attempt is the treatment of bony injuries, e.g., the primary stabilization of one
or more fractures. Treatment of a vascular lesion is additionally prior ranking and
36 H. Assmus
could represent the first brick of the treatment chain in case of life-threatening blood
loss. It has further to be considered that a tendon suture should not be performed
together with a nerve reconstruction because the aftercare of both is different,
immobilization versus mobilization, respectively. A radial nerve palsy resulting
from a fracture of the humerus bone, again, is confronting the nerve surgeon with
the need for decision between early exploration and wait-and-see attitude. What the
best strategy can be is still controversially discussed. Since it is generally accepted
that the radial nerve palsy spontaneously recovers with a rate of more than 70%, the
wait-and-see concept is favored in closed humerus shaft fractures [10].
3.7 erioperative Techniques: Choice of Anesthesia

P
and Application of Tourniquet
With the decision taken for a nerve reconstruction, the question for the appropriate
anesthesia arises. General anesthesia is not required for all approaches. Basically,
small nerves travelling superficially can also be treated in local anesthesia. For
larger nerves of the extremities, regional anesthesia may be sufficient in some cases;
mostly general anesthesia is preferred by the surgeon because surgery under regional
anesthesia requests a very high compliance from the patient.
The need of bloodless conditions is controversially discussed as they are obliga-
tory among hand and plastic surgeons, but less common among neurosurgeons. The
reason for this is that the procedure was thought to be linked to complications and
possible damages. Distal to the tourniquet, the nerve line expires within 15–45 min;
however, it very rapidly recovers after opening of the cuff, e.g., within a few min-
utes [14]. The technique can be used without any risks whenever properly performed
(broad, well-padded cuff, a pressure of 50–75 mm Hg below systolic pressure, for a
maximum of 1.5–2 h). In case bloodless conditions are needed for an extended time
period, renewed application of the cuff is possible after transient opening. During
the nerve transplantation procedure, however, the tourniquet is opened. A sterile
cuff should be used whenever it needs to be placed close to the operating field. The
advantage of the bloodless conditions is enabling of a rapid and careful preparation
under very good overview of the operation field. Furthermore, small nerve branches
can more easily be preserved and small vessels punctually coagulated.
3.8 Postoperative Decisions and Revision Surgery
The proper timing of nerve repair approaches plays an important role not only at the
beginning of the treatment but also after nerve reconstruction has been performed.
Right after the intervention, it remains uncertain whether it will result in successful
functional recovery or not. The regeneration process is to be traced carefully and by
means of follow-up examinations in 6-week intervals. While protection sensitivity
usually returns spontaneously, tactile discrimination ability returns spontaneously
in only a limited number of cases. To support recovery of the latter, it requires
purposeful sensory reintegration programs [18]. Therefore, the stimulation of the

relearning process must begin immediately after the nerve reconstruction has been
performed [9]. Two promising adjunct procedures exist that have been evaluated
intensively in animal studies and are about to be translated into clinical application.
This is 1 h low-frequency electrical stimulation of the proximal nerve end at the
time of reconstruction and daily rehabilitation exercise [12]. A general suggestion
to apply the procedures, however, does not yet exist.
Whenever recovery of sensitivity and motor function is missing after reasonable
time from primary or secondary nerve reconstruction, the puzzling question of a
surgical revision arises. In average a 6-month follow-up period should be consid-
ered, and not only the condition of the nerve itself but also the patient’s individual
conditions (age of the injury and the patient, height/localization of the lesion, even-
tual concomitant lesions) are of concern. As illustrated in Fig. 3.5, while evaluating
the nerve condition, the nerve surgeon does not exclusively depend on a clinical
process observation performed with the utmost care, but needs to additionally con-
sider results from electrodiagnostic and imaging assessments. In early stages of
reinnervation, it is not possible to record a sensory (or motor) nerve/muscle action
potential. Sensory nerve function, however, can be evaluated also in early reinnerva-
tion stages by recording of somatosensory evoked potentials (SSEPs) [2]. Weak
peripheral volleys within the SSEP may emerge, and a central magnification can
enable detection of a cerebral response also in cases where no peripheral NAP can
be recorded.
With regard to modern imaging techniques, diffusion tensor tractography (DTT),
a special technique of MR neurography, is described to be promising in visualizing
Closed injury with nerve lesion Nerve rapair accomplished
Inact or
regenerated
axons?
Electrodiagnostic MR-Neurography Neurosono-

Clinical assessment
study DTT? graphy
Op. exploration
Nerve in
SEP? continuity?
Sensory
Reinn Pot.? Axon-
function?
CNAP? sprouting?
Yes No Yes
No Yes
No
Regeneration questionable Regeneration verified
Fig. 3.5 Diagnostic procedures during follow-up

38 H. Assmus
sprouting axons [20]. On the other hand, neurographic examinations and

psychometric tests (e.g., Weinstein Enhanced Sensory Test, Semmes-Weinstein
Monofilament Test, Shape-Texture Identification Test) are helpful for the documen-
tation of the extent and degree of recovered sensitivity [18].
The techniques used within the revision surgery depend on the intraoperative
findings and are basically not different from those used for the primary care
(see Chap. 4). Whenever it is obvious to the surgeon that the nerve is irreversibly
damaged without the chance of regeneration, he/she usually has to decide for one of
the following options. In case the proximal nerve end is lacking, bypassing the
defect using nerve fiber transfer from another nerve is an option. Direct muscle
neurotization may be reasonable in case the distal stump is lacking. But also end-to-side
coaptation or tendon transfers represent methods of choice. Especially in radial and
peroneal nerve palsy, proper early tendon transfer – performed in parallel to the
nerve reconstruction – could be considered because it is suitable to enhance wrist
extension and grip function, i.e., foot lifting, while awaiting the return of nerve and
muscle function.
3.9 Prevention of Nerve Injuries and Future Aspects
Although innovations in nerve reconstruction procedures have reached an excel-

lent level, complete functional recovery is still rarely seen – except in children
[16]. Therefore, it cannot be emphasized enough that it is of outmost importance to
avoid injuries of peripheral nerves during any kind of surgical intervention [1].
Iatrogenic peripheral nerve injuries originate from disregardful approaches during
skin incision and surgical access. An essential prerequisite to prevent such injuries
is a good overview over the operation field for which to achieve; magnifying
glasses and bloodless conditions could be helpful. Also the (so-called mini-) inci-
sions, e.g., during carpal tunnel release surgery, often result in new peripheral
nerve lesions. Another typical example is the lesion of the accessory nerve during
disregardful extirpation of neighboring lymph nodes [7]. Whenever peripheral
nerve lesions occur even though adequate diligence has been taken, the harm for
the patient must be reduced to the absolute minimum. Therefore, diagnostic clari-
fication has to be immediately performed, and prolonged delay of nerve recon-
struction has to be avoided. Iatrogenic injuries should be managed with exactly the
same timing considerations as non-iatrogenic injuries, depending on the presumed
injury mechanism [15].
Taking the indication and decision for peripheral nerve repair is progressively
facilitated through improved diagnostic techniques, especially related to modern
imaging methods. How precise the DTT technique could, for example, predict the
degree of an expectable regeneration keeps, however, to be demonstrated in the
future. Once, in the future, it is possible to delay the degenerative processes related
to peripheral nerve injury and to simultaneously accelerate the nerve regeneration
processes, the timing of nerve repair will become less meaningful – the time period
for successful surgical intervention would be significantly prolonged [11].
Furthermore, the decision processes related to nerve repair would be facilitated.
Despite the fact that current treatment strategies demonstrate some success, further
efforts need to be done with the goal, to simultaneously potentiate axonal regenera-
tion, increase neuronal survival, modulate central reorganization, and inhibit or
reduce target organ atrophy [22].
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Int Rev Neurobiol. 2013;109:165–92.
Conventional Strategies
for Nerve Repair 4
Mario G. Siqueira and Roberto S. Martins
Contents
4.1 Neurolysis 42
4.1.1 External Neurolysis 42
4.1.2 Internal Neurolysis 42
4.2 End-to-End Neurorrhaphy 43
4.3 End-to-Side Neurorrhaphy 45
4.4 Graft Repair 46
4.5 Direct Muscular Neurotization 47
4.6 Fibrin Glue Versus Suture 48
4.7 Factors Influencing the Results of Surgical Repair 49
References 49
The central objective of nerve repair is to assist regenerating axons to re-establish useful
functional connections with the periphery. Sir Sydney Sunderland
During the last decades, significant changes in the surgical management of nerve
injuries have occurred, based on an improved knowledge of basic nerve biology
and on the advance of surgical technologies like the use of magnification, bipolar
coagulator, microinstruments, and fine suture material and the introduction of elec-
trophysiologic methods for intraoperative assessment of nerve injuries. These
advances led to improved functional results, increasing the number of surgical
explorations and the attempts to repair lesions that previously were considered
irrepairable.
M.G. Siqueira, MD, PhD (*) • R.S. Martins, MD, PhD

Peripheral Nerve Surgery Unit, Department of Neurosurgery,
University of São Paulo Medical School, Rua Virgilio de Carvalho Pinto,
381/apt.42, 05415-030 São Paulo, SP, Brazil
e-mail: mgsiqueira@uol.com.br

DOI 10.1007/978-3-319-52319-4_4
42 M.G. Siqueira and R.S. Martins
In this chapter we describe the common surgical techniques in current use for
nerve repair, external and internal neurolysis, end-to-end suture, and nerve grafting
and two less used techniques, end-to-side suture and muscular neurotization.
4.1 Neurolysis
Neurolysis has been defined by Seddon [26] as an operation in which an injured

nerve is freed from scar tissue or other neighboring tissue to facilitate regeneration.
In this procedure whenever possible the tissue dissection should occur along ana-
tomical planes. Attention should be devoted to hemostasis and minimal tissue dam-
age, since bleeding and tissue debris will promote excessive scarring, which will
attenuate the results of the surgical procedure.
There are two types of neurolysis, external and internal.
4.1.1 External Neurolysis
The external neurolysis consists of freeing the nerve from a constricting or distort-
ing agent by dissection outside the epineurium, usually including the mesoneurium,
an adventitious tissue that contains collateral blood vessels, and sometimes includ-
ing the most external epineurium as well. The inner layers of the nerve remain
intact. Nerve segments are freed circumferentially using a number 15 scalpel or
Metzenbaum scissors. Seldom used as the treatment itself, the external neurolysis
should be performed in all lesioned nerve segments before surgical reconstruction.
It is usually begun by working from normal to abnormal nerve sections beginning
well distal as well as proximal to the lesion site. Thickened or scarred portion of the
external epineurium will then be resected. If carefully done, long lengths of nerves
can be mobilized without serious interference with their blood supply. However,
extensive manipulation may, in rare cases, promote neurological deterioration. A
good deal of argument about the value of external neurolysis for the improvement
of function in a direct fashion still exists. Apparently this technique could be valu-
able when the nerve is intact but tethered or immobilized by scar tissue and the
patient complains of severe neuritic pain. In spite of this limited indication, external
neurolysis is performed as the first step of almost all types of nerve repair. Figure 4.1
demonstrates the situation of a scarred sciatic nerve (Fig. 4.1a) and its appearance
after external neurolysis (Fig. 4.1b).
4.1.2 Internal Neurolysis
Internal neurolysis is the exposure of nerve fascicles after epineurotomy and their
separation by interfascicular dissection or by removal of interfascicular scar tissue.
It is an essential part of some procedures [2] as follows: (1) separation of intact from
damaged fascicles in partially damaged nerves, (2) separation of a fascicle during a
4 Conventional Strategies for Nerve Repair 43
a b
Fig. 4.1 Intraoperative view of a gunshot injury to the sciatic nerve. (a) Scar tissue involving the
nerve. (b) After external neurolysis the main trunk of the nerve as well as its peroneal and tibial
divisions can be identified. D distal, M medial, PN peroneal nerve, SN sciatic nerve, TN tibial nerve
nerve transfer, and (3) separation of intact fascicles during removal of a benign
nerve tumor. Another indication for this procedure is given when there is an incom-
plete nerve tissue loss distal to the lesion, but the patient has pain of neuritic nature
which does not respond to conservative management. When performing this tech-
nique, the surgeon should keep in mind that the removal of abundant fibrous tissue
between the fascicles may impair the blood supply to this structure [18] with the
potential risk of some loss of function.
4.2 End-to-End Neurorrhaphy
Since Hueter in 1873 [6] described an end-to-end coaptation of nerve ends by plac-
ing sutures in the epineurium, the end-to-end suture became the procedure of choice
for nerve lesions where opposition of stumps can be gained without excessive ten-
sion. Excessive tension across a nerve repair site is known to impair the local blood
circulation, to increase the scarring at the coaptation site, and finally to impair
regeneration. The opposition of the nerve ends is facilitated by mobilization of the
stumps, transposition of the nerve, and, in selected cases, mild flexion of the extrem-
ity. Every nerve repair should be performed with optical magnification (surgical
loupes or microscope) and adequate lighting. The end-to-end neurorrhaphy should
be done only when the nerve gap is small (usually less than 2 cm). A test to evaluate
the possibility of direct suture without prohibitive tension involves passing an epi-
neurial suture of 7-0 nylon. If the suture keep the stumps together without tearing
the epineurium, the end-to-end neurorrhaphy is possible.
There are three types of end-to-end neurorrhaphy: epineurial, perineurial, and
group fascicular. All three procedures always initiate with the preparation of the
nerve ends. Transverse cuts, distant 1 mm from each other, are progressively made
with a sharp instrument (micro scissors or surgical blade) until an area of healthy
appearing fascicles without fibrotic tissue is reached. Following resection of the
devitalized tissue hemostasis is imperative because bleeding could lead to excessive
fibrosis and distortion of the nerve architecture. A small tipped bipolar coagulator or
sponges dipped in a solution of 1:100,000 epinephrine in 10 ml of saline should be

used for this purpose. The prepared nerve ends are then gently mobilized and
approximated to be coapted, without excessive tension. In the epineurial technique
the entire nerve trunk is sutured as a unit. Finely spaced interrupted nylon sutures
inserted into the epineurium are used to approximate the stumps, first laterally and
then along volar and dorsal epineurial surfaces. Suture material should be passed
through the epineurium only, as the incorporation of neural elements results in scar
tissue formation. The sutures should be placed approximately 0.5–1.0 mm from the
incised edge, with the needle piercing the surface of the nerve and emerging just
subepineurially. In the opposing nerve stump, the second passage of the needle
begins subepineurially and emerges on the surface. The size, the depth, and the
number of sutures should be minimized to decrease iatrogenic trauma and the for-
mation of foreign body granuloma. The number of sutures required for adequate
alignment of the stumps varies depending upon the nerve diameter. Having in mind
that an adequate alignment is paramount for the success of the surgical procedure,
it is desirable to perform the smallest number of sutures possible because all suture
materials evoke an inflammatory reaction, which can result in production of excess
granulation tissue. To maintain alignment of the nerve stumps, the first two sutures
are placed in the nerve trunk 180° apart. Additional sutures are then placed in the
upper portion of the nerve. Grasping carefully the ends of the two first sutures, the
nerve trunk is rotated to expose the underside of the nerve where additional sutures
are placed, completing the apposition of the nerve stumps. All sutures should be tied
with equal tension. The tension applied should be just enough for alignment and
contact of the neural bundles. Excessive tension may result in crushing and malalign-
ment of the nerve bundles. Identification of the longitudinal epineurial blood ves-
sels, which are not always present, helps to avoid rotation of the nerve ends and
consequent malalignment of the fascicles. The visualization of fascicular patterns
on the cut nerve surfaces can also be effective to help the correct realignment of
peripheral nerve stumps in areas of consistent topography (e.g., distal ulnar and
median nerves). The fascicular topography changes after 1–2 cm of neural trim-
ming, but groups of fascicles can usually be opposed as closely as possible even
though the repair is done at epineurial level. The epineurial technique is the most
performed end-to-end neurorrhaphy in clinical practice and illustrated in Fig. 4.2.
a b
Fig. 4.2 Intraoperative view after resection of a neuroma in continuity of the ulnar nerve at the
elbow. (a) Distance between the two stumps of the nerve after resection of the lesioned tissue and
normal retraction (nerve gap). (b) End-to-end epineurial repair
As expertise and technical development in microsurgery have progressed, suture

repair of peripheral nerve subunits, like the perineurial or fascicular repair, has
increased in popularity. The technique involves resection of the outer epineurium, fol-
lowed by intraneural dissection of fascicles in both nerve stumps and perineurial sutur-
ing of individual fascicles with one or two sutures of 10-0 suture material. The
perineurial repair represents the best possibility of nerve alignment by the surgeon.
However, this advantage may be offset by the amount of neural trauma the technique
demands. In clinical practice this procedure is seldom performed. Grouped fascicular
repair is a less aggressive method of nerve alignment done by the identification of
grouped fascicular patterns in both nerve ends and suturing through the thickened inner
epineurium. This technique is used mainly in areas of well-defined nerve topography
such as the distal median and ulnar nerves and the radial nerve around the elbow.
Superiority of one end-to-end neurorrhaphy over another has never been clearly
demonstrated [8]. In practice, the accurate alignment of the fascicles or grouping of
fascicles is often difficult because of trauma, edema, and scarring that can distort the
normal topography.
4.3 End-to-Side Neurorrhaphy
End-to-side neurorrhaphy was first described by Letievant in 1873 [30], but the idea
was abandoned due to poor results. More than a century later, Viterbo et al. [32]
reintroduced the technique with apparently promising results. The end-to-side neu-
rorrhaphy involves coaptation of the distal stump of a transected nerve to the trunk
of an adjacent healthy donor nerve. It has been proposed as an alternative technique
when the proximal stump of an injured nerve is unavailable or when the nerve gap
is too long to be bridged by a nerve graft. Collateral sprouting is the accepted mech-
anism of nerve regeneration following end-to-side neurorrhaphy, where regenerat-
ing axons originated from the most proximal Ranvier’s node of the donor nerve
grow toward the coaptation site [29, 37]. Whether the receptor nerve should be
coapted to the donor nerve through an epineurotomy or a perineurotomy is still
controversial. Although some experimental papers revealed no difference if a nerve
window at the coaptation site was made or not [32, 33], other investigators claim
that the greater degree of axonal damage to the donor nerve after a perineurotomy
enhances axonal regeneration with better histological results [35, 36]. The clinical
experience with this technique has been published in the form of case reports and
small clinical series, and no randomized clinical trials have been performed in order
to compare end-to-side coaptation to other reconstructive techniques. The clinical
outcomes of end-to-side repair are often disappointing. In a recent published review
of the clinical applications of the technique, Tos et al. [30] demonstrated that a dis-
crepancy between experimental and clinical results still exists, and the authors con-
cluded that at present the end-to-side repair could not substitute standard techniques
in most situations. In the majority of cases, it will provide only limited sensory
recovery [23, 28, 34]. It can be considered a valid therapeutic option only in cases
of failure of other attempts of nerve repair or whenever other approaches are not
feasible, especially when protective sensibility is a reasonable goal.
4.4 Graft Repair
Nerve grafting dates back to Philippeaux and Vulpian in 1817 [9]. In extensive
injuries, especially those due to blunt mechanisms, loss of nerve tissue may produce
lengthy lesions which, when resected, result in a large nerve gap. A nerve gap is
defined as the distance between two ends of a severed nerve and consists not only of
an amount of nerve tissue lost in the injury or debridement but also of the distance
that the nerve has retracted due to its elastic properties [15]. Small nerve gaps
(<2 cm) can be overcome by stretching the nerve stumps to a limited extent to attain
apposition, making possible a primary repair. But when a significant amount of
stretching and mobilization is necessary, the consequent increase in the suture line
tension endangers the extrinsic vascular supply to the nerve leading to connective
tissue proliferation and formation of scar tissue [13]. In this situation of an irreduc-
ible nerve gap, the gold standard management continues to be autologous nerve
grafting. The nerve grafts serve as a guide for the axons of the proximal stump as it
regrows toward the distal stump.
Small-caliber grafts seem to serve better than longer whole nerve grafts [14].
For a nerve graft to survive, it must be revascularized, and when the nerve is too
thick, the central part of the nerve graft will not become revascularized, and the
outcome of the repair will be poor. The sural nerve, by far the most commonly
used donor nerve, is harvested from the ankle until near the knee, and 30–40 cm
of the nerve is usually obtained in adults from each leg for grafting. Other sen-
sory nerves like the medial antebrachial cutaneous or the sensory branch of the
radial nerve are used as well. The grafts should be harvested after the injured
nerves have been exposed, the extent of lesion defined, and the gap between the
prepared nerve stumps measured. Then the number of grafts required is calcu-
lated. To release tension on suture lines, the length of the grafts should be about
15–20% greater than the measured gap because they always present some
shrinkage owing to a relative initial hypovascularization. The nerve grafts are
initially similar to other devascularized tissue implants. The regeneration of the
blood supply must be provided by the nerve stumps and surrounding tissues and
takes some time. In the beginning the graft relies on the imbibition from the sur-
rounding for nutrition. Consequently, long grafts and a poorly vascularized tis-
sue bed could be responsible for ischemic necrosis of the central graft core, with
destruction of Schwann cell tubules and failure of axonal regeneration through
the graft.
The most popular as a graft technique is an interfascicular grouped fascicular
approach described by Millesi in the early 1970s [16, 17]. The principles and surgi-
cal technique of nerve grafting are similar to direct repair. The proximal and distal
ends of the nerve are transversely sectioned until viable fascicles are visualized, and
groups of fascicles are then isolated both proximally and distally. Usually oriented
in a reverse fashion to minimize the diversion of regenerating fibers from the distal
neurorrhaphy, a number of small-caliber nerve grafts are attached between the nerve
ends, connecting corresponding groups of fascicles. The coaptation is maintained
by one or two fine sutures often supplemented by fibrin glue. As much of the
a b
Fig. 4.3 Intraoperative view of a penetrating stab wound to the right supraclavicular region.
(a) An injury of the upper trunk of the brachial plexus was identified. (b) Reconstruction was
performed with nerve grafts. AD anterior division of the upper trunk, C5 fifth spinal nerve, C6 sixth
spinal nerve, D distal, M medial, PD posterior division of the upper trunk, SM sternocleidomastoid
muscle, UT upper trunk, * suprascapular nerve, ** supraclavicular nerves
f ascicular structure of each stump as possible is covered in this fashion. Individual

grafts should be positioned loosely, not too close to each other, to permit maximal
contact with a viable recipient bed. Figure 4.3 illustrates a brachial plexus injury
that has been repaired by an interfascicular grouped fascicular approach.
Graft length might influence regeneration as longer grafts may be harder to
revascularize, but in clinical practice no agreement exists on the maximal length
that may be bridged by a nerve graft. Although good results are eventually reported
with longer grafts, most nerve surgeons agree that the outcome is worse with grafts
greater than 10 cm.
4.5 Direct Muscular Neurotization
Described in the beginning of the twentieth century, the surgical insertion of

peripheral nerves directly into denervated muscles is called direct muscular
neurotization. This procedure is indicated when no distal nerve stump is a vailable
for neural coaptation or when the lesion involves the neuromuscular junction
[24]. Experimentally it was observed that the implantation of a normal nerve near
denervated motor end plates reinnervates this site and that axons that do not have
contact with those persistent motor end plates will induce new ones in previously
denervated areas [22]. However, clinically the neurotization restores significantly
less function, when compared with direct repair or grafting, leaving areas of the
target muscle denervated [12]. In most published reports, an entire nerve was
implanted into the target muscle, probably leaving denervated areas outside the
reach of the regenerating axons. To overcome this problem, Brunelli [4] suggested
that the donor nerve should be splitted into multiple fascicles and distributed
widely across the muscle. Direct muscular neurotization is a potentially effective
technique when the normal nerve-muscle interface has been destroyed [1], but
until now there are only a few reports of clinically successful reinnervation in the
literature, and this technique has no stablished role in reconstructive nerve
surgery.
4.6 Fibrin Glue Versus Suture
Epineurial suture repair is generally considered as the gold standard for peripheral
nerve repair, but when nerve trauma is extensive, the suture method can be difficult
and time-consuming. Specific training is necessary for nerve repair by suture which
requires the placement of stitches that persist as foreign bodies producing inflam-
mation and different degrees of scarring. The number of stitches (the less the better
[11]) and the surgical skill certainly play a role in the improvement of outcomes.
Fibrin glue is one of the alternatives to suture [10]. Concentrated fibrinogen and
thrombin are common ingredients in the mostly used fibrin glues, which are differ-
ing in the antifibrinolytic agent contained or the application procedure. Currently,
the use of fibrin sealants as nerve glue still has not been approved and their use on
nerve surgery is considered off-label.
The fibrin sealants simulate the last stages of the clotting cascade forming a sub-
stance resembling a physiologic blood clot that holds the nerve ends together [7].
The artificial “clot” protects the repair from scar tissue and allows healing to occur.
Its structural integrity is preserved for about 3 weeks by the antifibrinolytic compo-
nent of the sealant [5].
The potential advantages of fibrin glue for nerve repair include ease of use,
reduced operative time, less tissue manipulation/trauma with consequent less
inflammation/fibrosis, and maintenance of nerve architecture with better fascicular
alignment [3, 19, 20, 27].
The amount of publications concerning the use of fibrin sealants as nerve glue is
small. A recently published systematic review [25] found 14 animal studies, one
cadaver study, and only one clinical study that fit the study criteria. Although some
of the results were conflicting, most found fibrin glue repair to be efficient (and
sometimes even superior) to suture repair.
The following are some practical remarks: (1) Nerve repair with fibrin glue has
an initial low tensile strength, and its use should be limited to situations without
tension in the coaptation (grafts and nerve transfers) and in cases with difficult
exposures or exceptionally small-caliber nerves; (2) Before the use of the glue, a
meticulous hemostasis should be done, and the nerve surfaces should be dry of
excess fluids to ensure optimal adherence [31]; (3) After nerve repair, the nerve
glue should be left to polymerize and cross-link for several minutes before irriga-
tion; (4)The inevitable small amount of glue that stays between the nerve ends
should not be a concern as fibrin glue is nontoxic and does not block axon regen-
eration [21]; (5) Like in the repair by suture, at the end of the surgery, the upper
extremity should be immobilized for 3 weeks to ensure an ideal environment for
axon regeneration.
Despite the apparent advantages of fibrin glue, its low tensile strength should
always be kept in mind. To overcome this potential disadvantage, two combined
strategies were created: to add fibrin glue to a standard suture repair and to reduce
the number of stitches by using fibrin glue to reinforce the repair. There is no advan-
tage with the first strategy, but the reduced number of stitches may ultimately lead
to better outcomes. In practice the use of a few stitches complemented by the fibrin
glue to enhance the coaptation has been adopted by many nerve surgeons.
4.7 Factors Influencing the Results of Surgical Repair
Besides the surgical techniques, the results of repair of peripheral nerves are cer-
tainly influenced by some biological aspects:
1. Younger patients recover more completely and in a shorter period of time. This
is probably related to shorter limb length, faster rate of regeneration, and greater
adaptability and compensatory sensory and motor reeducation.
2. The level of the injury. Too proximal injuries require greater metabolic biosyn-
thesis for functional return, and this may exceed the capabilities of the nerve cell
body and result in cell death.
3. The result of the repair of pure motor or pure sensory nerves is usually better. In
mixed-function nerves, the potential for transposition of axons during regenera-
tion with improper end-organ reinnervation exists.
4. The extent of the injury. Lesions in continuity or those with focal neuroma for-
mation or small gaps will present better results than injuries with irreducible
gaps or long length of defect owing to segmental vascular supply, suture line
tension, and biologic considerations in nerve grafting.
5. Associated injury may add further difficulty to nerve regeneration. Polysystemic
trauma, massive deep wounds, sepsis, scar formation, and contraction wound
healing may interfere with the management of the patient.
6. The merits and indications for immediate versus early secondary repair have
been discussed in Chap. 3. However, it is important to emphasize that as the
interval between the time of injury and surgical intervention increases, irrevers-
ible changes occur in the nerve trunk, particularly in the distal segment. In addi-
tion, neurogenic atrophy and fibrosis of denervated muscle segments complicate
the potential for functional recovery. Therefore, early repair is advocated, when-
ever possible.
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Surgical Techniques in the Lesions
of Peripheral Nerves 5
Kartik G. Krishnan
Contents
5.1 I ntroduction 53
5.2 T echnology of Illumination and Optics 54
5.2.1 The Operating Microscope 54
5.2.2 The Retractor-Integrated Endoscope 55
5.2.3 The Video Telescope Operating Microscopy (ViTOM) or the Exoscope 56
5.3 Techniques in Nerve Coaptation 59
5.4 Techniques in Intraoperative Diagnostics 62
References 63
5.1 Introduction
Some basic prerequisites for the successful performance of any surgical operation
are the following: (a) profound knowledge [of the structures being manipulated—
anatomy, physiology, biochemistry, pathophysiology, eventual anomalies, and the
course of abnormalities with passage of time], (b) adequate exposure of the struc-
tures being manipulated [clear illumination, optical magnification, and the variety
of surgical approaches to the target structures], (c) familiarity and dexterity with the
tools of surgery and intraoperative diagnostics, and (d) a sound understanding of the
goals to be achieved, the means to achieve them, the merit the procedure might
bring forth, and implementation of this knowledge to the situation at hand. The
aforementioned concepts do not stand alone as separate entities; they rather inter-
twine in the most appropriate fashion as the surgeon delivers his service to achieve
a particular goal he has in mind.
K.G. Krishnan, MD, PhD

Division of Reconstructive Neurosurgery, Justus Liebig University,
Klinikstrasse 33, D-35929 Giessen, Germany
e-mail: Kartik.Krishnan@neuro.med.uni-giessen.de

DOI 10.1007/978-3-319-52319-4_5
54 K.G. Krishnan
In the given context, let us consider the example of a peripheral nerve lesion at its
early stage requiring a surgical procedure. One is confronted with specific tasks of (a)
understanding the intrinsic nature of the lesion itself and the functional derangement
it has brought forth; (b) decision-making about the choice of the method of surgical
treatment, viz., release the nerve or reconstruct it with grafts or other means; (c) decid-
ing the choice of technique and surgical approach to the lesion; and (d) implementing
intraoperative diagnostics to deepen the understanding of the lesion.
This chapter will narrate the technical aspects of surgery for peripheral nerve lesions.
5.2 Technology of Illumination and Optics
Like in any other discipline, the surgical approach to peripheral nerve lesions requires
adequate exposure of the anatomical structures, excellent illumination of the operat-
ing field, and magnification [14, 15]. There are various ways to achieve this.
5.2.1 The Operating Microscope
The modern operating microscope had a widely rotatable head equipped with a cold
light and an optical beam splitter. The microscope head is held by a delicately
balanced holding system, which is either stationary (ceiling mounted) or mobile
(wheel mounted). The modern operating microscope (Fig. 5.1) comes with
Fig. 5.1 The modern operating microscope with the optical beam splitter
5 Surgical Techniques in the Lesions of Peripheral Nerves 55
integrated changeable optic filters for fluorescence microscopy and navigation

match possibilities that aid in additional intraoperative diagnostics and tracking,
respectively. In modern times, the operating microscope is an integral part of any
surgical procedure. Microminiature sutures of nerves and vessels are best done
under microscopic magnification (as opposed to magnification using binocular
loupes). Perfusion of blood vessels and patency of anastomoses are best studied
using indocyanine green video angiography integrated to the operating microscope.
The one major disadvantage of the operating microscope today is its physical bulk.
It simply takes away much valuable space in the operating setting.
5.2.2 The Retractor-Integrated Endoscope
Minimally invasive surgical methods are becoming increasingly popular. Post-

traumatic nerve lesions are frequently, if not always, associated with severe scar-
ring; it is advisable to widely expose such scarred post-traumatic nerve lesions.
However, compression neuropathies and other pathological changes not accompa-
nied by scarring may and can be explored through minimal skin incisions using the
endoscope [9, 12, 13]. Formerly endoscopic surgery was limited to predefined body
spaces such as paranasal sinuses, thoracic cavity, abdominal cavity, joint spaces, etc.
The one exception of the use of endoscopy in nerve surgery was the carpal tunnel
syndrome, where the tight canal was blindly dilated using blunt bougies in order to
introduce the endoscope. This method is available both as monoportal and as bipor-
tal techniques, however limited to the decompression of the carpal tunnel [5].
Beginning of this century, we designed the retractor-integrated endoscope named
after the author, in cooperation with the Karl Storz Company of Tuttlingen, Germany
(Fig. 5.2), which is a universal tool for use on any nerve on the body [12, 13].
Fixation for table mount

Suction canal
Suction regulator
Clear vision
de irrigation port
lade bla
rb tor
to rac
rac et
ret wr
oa
d rro
Br Na
aft
c sh
Opti
Fig. 5.2 The retractor-integrated Krishnan endoscope in two variations. The narrow one is used
for releasing the median nerve at the carpal tunnel and the tibial nerve at the tarsal tunnel. For all
other purposes, the broader blade is used
56 K.G. Krishnan
The principle is to create a space along the topographical course of the nerve [or
any other structure of surgical interest] by means of soft-tissue retraction and
manipulate the nerve [or the structure of interest]. This technique has found a wide
range of indications and routine application in simple decompression and transposi-
tion of peripheral nerves irrespective of their anatomical location, extensive explo-
ration of nerves for occult pathology, simple nerve suturing, and even harvesting
nerves for grafting. The one main disadvantage of the retractor-integrated endo-
scope is its limitation for use only in non-scarred regions. Furthermore, the use of
the retractor endoscope for the exploration of nerves in patients with a rich layer of
subcutaneous adipose tissue requires extraordinary skills. Clinical trials have shown
the feasibility of application of the retractor endoscope for the exploration of almost
any nerve of the extremities [9, 12]. Figure 5.3 exemplarily depicts the decompres-
sion of the median nerve in carpal tunnel syndrome using the retractor endoscope.
Trials comparing the open nerve release with the endoscopic release have shown
that the long-term results of both methods are just the same; however, the short-term
results of the retractor endoscopic nerve decompression are superior to the open
technique [4].
One issue of endoscopic exploration of peripheral nerves worthy of mention here
is the use of tourniquets on extremities. Application of exsanguinating or non-
exsanguinating tourniquets at the proximal part of the extremity highly facilitates
recognition and visualization of anatomical structures. However, improper applica-
tion of very high pressures for prolonged periods might result in secondary iatro-
genic compression neuropathies and might prove counterproductive. It is to be
borne in mind that there is no single empirical pressure level for upper and lower
extremities. My preferred method is to add 80–110 mm Hg to the present systolic
pressure and pump up the tourniquet to that value. For example, I will apply 180 mm
Hg tourniquet pressure (in a person with a thin arm) when the present systolic pres-
sure is 100 mm Hg. In a person with abundant subcutaneous fat tissue with a sys-
tolic pressure of 100 mm Hg, I will recommend a tourniquet pressure of no more
than 220 mm Hg. Blindly pumping up to 300 mm Hg for arms and 400 mm Hg for
legs should be strongly discouraged. Tourniquets nullify the possibility of any and
all electrophysiological measurements. Thus tourniquets should not be used, when
one contemplates intraoperative monitoring or diagnostics.
5.2.3 T
he Video Telescope Operating Microscopy (ViTOM)
or the Exoscope
The ViTOM telescope is an exoscope that was designed as an additional observation

tool complementing the microscope in open surgical procedures [17, 20]. Being a
derivative of the endoscope, the exoscope optic is held in place at a distance of
25–75 cm from the object of interest using a simple mechanical holding arm, the
endoscope camera and the light cable are connected to the exoscope at the provided
a b
c d
Fig. 5.3 The retractor endoscopic decompression of the carpal tunnel. (a–d) The steps of the
surgery until the transverse carpal ligament (tcl) is transected, and the median nerve (m) is deroofed
along its course within the carpal tunnel, atm accessory thenar muscle
slots, and the high-definition image is projected to an external monitor (Fig. 5.4).

The camera offers an optical magnification of 1–2×. The effective magnification
achieved with the exoscope depends on the working distance and the size and reso-
lution of the monitor used. For example, with a minimal working distance of 25 cm,
the object field of approximately 3.5 cm is achieved with a 2× zoom of the camera;
58 K.G. Krishnan
Locking screw
Mechanical holding arm

mounted on the operating table
HD-Camera
90º Exoscope
Li
gh
tc
ab
le
0º Exoscope
Fig. 5.4 The setting of the exoscope. The mechanical arm is shown to hold the 90° exoscope,
whereas the 0° exoscope is shown as an inset
a 26″ monitor will offer a maximal effective magnification of 16×, whereas a 52″
monitor is capable of offering a 34× magnification. Encouraged by the sleekness of
the system, several groups, including ours, studied the application of the exoscope,
where usually one would use an operating microscope. In this feasibility study, we
successfully performed lumbar spinal discectomies, anterior cervical discectomies
and fusion, evacuation of intracerebral hematomas, removal of schwannomas from
peripheral nerves, and even microvascular anastomoses and microneural sutures
[8]. A possible surgical setup for exoscopic surgery is shown in Fig. 5.5.
The major disadvantage of the exoscope is its mechanical holding arm and the
cumbersome refocusing and variation of magnification. This disadvantage has more
to do with the holding system, rather than the optics and illumination offered by the
exoscope. Various alternative holding arm systems are available, Endocrane,
UniArm, Point Setter, and Versacrane, to name a few. Important features that are yet
to be integrated with the exoscope are fluorescence microscopy and navigation
Fig. 5.5 A surgical procedure performed under HD-exoscopic illumination and magnification
match, whereas endoscopes already offer these prospects. In the recent years, aug-
mented reality and image superimposition technology have shown rapid evolution
and are put to use in the automobile industry. The magnifying high-definition exo-
scope, especially when integrated with such powerful tools, is capable of evolving
into yet another advanced gadget for performing surgical operations.
Irrespective of the technology used for achieving illumination, magnification,
and exposure, these appliances should be seen as tools in the armamentarium of the
contemporary surgeon. Routine use of such technology will make the surgeon aptly
recognize the indications for their application whenever and wherever found
appropriate.
5.3 Techniques in Nerve Coaptation
Allegedly, the first reported nerve coaptation was performed by the celebrated
Persian physician Avicenna. Before his times peripheral nerves belonged to the cat-
egory of “noli me tangere” or “touch me not,” due to a false conception that touch-
ing severed nerves produced epileptic seizures. Avicenna himself advocated not
touching the nerve, rather bring its severed ends together by adapting the surround-
ing connective tissue [15]. The results of axonal growth depend directly on the
amount of foreign [suture] material implanted to perform the nerve coaptation.
Consequently, meticulous microsurgical techniques were employed, and neurorrha-
phies came to be performed using microminiature suture material (Fig. 5.6). In
order to achieve precision in coaptation of the individual proximal fascicles to their
distal counterparts, the interfascicular nerve suturing technique became popular.
However, this was quickly discarded, owing to the amount of tissue scarring the
interfascicular suture technique had caused within the repaired nerve. The contem-
porary nerve repair technique involves the epineural adaptation of the nerve as a
whole using a few microsutures, having provided the correct orientation of the prox-
imal and distal stumps, and buttressing the suture with the application of fibrin glue
60 K.G. Krishnan
Fig. 5.6 Tension-free and torque-free microminiature suture of the median nerve with grafts. The
inset shows the surgeon’s hand holding a needle driver bearing the suture material
[which is absorbed quickly and replaced by a fine film of autologous fibrous sheath]
(also see Chap. 4). Some experimental works have tested suture-free methods such
as laser welding of nerve ends, which have somehow failed to enter the main stream
of clinical practice [2, 18]. A detailed description of microsurgical techniques and
placement of microminiature suture of nerves are out of the scope of this chapter,
and the reader is referred to Krishnan [10].
One other important issue to prevent [or minimize] intraneural scarring is to
attain a tension-free coaptation of the nerve ends. Consequently, the higher the ten-
sion at the suture line, the poorer is the axonal sprouting and growth across that
suture line. Thus, it is agreed that injury of nerves with tissue deficiency are better
grafted than sutured under tension. Peripheral nerve grafts are taken from superfi-
cial sensory nerves, some of them being sural nerves, saphenous nerves, and medial
and lateral antebrachial cutaneous nerves. It is to be borne in mind that while graft-
ing a “nerve,” the surgeon does not graft axons, rather Schwann cells that serve as a
scaffolding for the sprouting and growing axons from the proximal nerve stump in
order to reach its target structure located distally. There has been a profound and
lasting search for equipotential alternatives to autologous nerve grafts—however so
far in vain. Chapter 7 in this book deals with this issue. Further developments are
awaited along these lines (Chap. 10).
The technical aspects of harvesting nerves for grafting deserve some mention in
this chapter dedicated to surgical technique. The classical approach to harvesting a
nerve is to make the skin incision along the entire course of the graft, carefully dis-
sect and transect the nerve, and prepare it for autologous transplantation. However,
this approach makes the nerve harvest a cumbersome major operation in its own
right. In order to minimize the trauma of nerve harvest, endoscopic techniques were
Fig. 5.7 An intraoperative photograph of harvesting the entire sural nerve through a 1 inch skin
incision behind the lateral malleolus using the Assmus nerve stripper
introduced [21]. Albeit being minimally invasive, the endoscopic nerve harvest is
quite time consuming. A much simpler and minimally invasive option was described
by one of the editors of this book (HA): the use of a nerve stripper [1]. This is the
preferred technique of the author of this chapter [11]. The technique is as follows
[referring to the sural nerve—the most harvested nerve for reconstruction]: the sural
nerve is exposed at the level of the lateral malleolus and transected here. With the
use of the Assmus nerve stripper, the entire length of the nerve up to its origin from
the popliteal fossa is dissected and stripped off (Fig. 5.7). The entire procedure takes
approximately 10–20 min depending on the proficiency of the surgeon. One techni-
cal disadvantage of this method is the harvest of only a part of the sural nerve,
especially in the eventuality of the anatomical variation that the nerve bi- or trifur-
cates quite proximally. In this case, a resistance is felt by the surgeon at the point of
bifurcation (usually half way up the dorsal aspect of the calf), and a second skin
incision there might become necessary.
The one main critique the stripping technique has brought forth is the shearing
forces acting on the graft as the nerve is being manipulated. However, it has been
elegantly demonstrated by a microscopic study that the stripped nerves are no more
damaged than those that had been harvested in the open manner [7]. Furthermore,
as already mentioned, as we graft a nerve, we do not transplant the nerve fascicles
or axons; essentially we transplant the Schwann cell scaffolding, which can impos-
sibly be damaged by manipulations no graver than severe homogenization.
62 K.G. Krishnan
5.4 Techniques in Intraoperative Diagnostics
There are two kinds of intraoperative diagnostic tools in peripheral nerve lesions,
viz., that of form and that of function. In former times, the fibrotic nerve was pal-
pated so that the surgeon could “feel” its consistency. When found necessary, the
nerve sheath was opened, and the fascicles were explored under the magnification
of the operating microscope. The latter manipulation does run the risk of additional
iatrogenic fibrosis. In modern times, intraoperative ultrasonographic imaging is
able to offer much information about the continuity and condition of the nerve fas-
cicles without having to open the nerve sheath. Neurosonography has become a
standard diagnostic tool for not only judging the grade of fibrosis but also to detect
occult lesions along the course of the explored nerve that otherwise would go unde-
tected. Intraoperative neurosonography is also an important tool to control the
extent of resection in some types of tumors affecting or encompassing peripheral
nerves [6, 19].
A nerve lesion that shows structural integrity does not necessarily mean that the
conduction across the lesion is intact. Intraoperative electrophysiological studies
have come to play a significant role in modern peripheral nerve surgery [3, 16].
Intraoperative electrophysiology can be subdivided into two categories: (a) “moni-
toring” an intact nerve function during a manipulation inside the nerve, e.g., whilst
removing an intraneural tumor, and (b) “diagnosing” the functional integrity of the
lesioned fascicles of a peripheral nerve. For monitoring, somatosensory evoked
potential (SSEP) and motor evoked potential (MEP) tests are the two salient meth-
ods. In addition to this, my preferred technique is to record SSEP from the head
leads and electromyographic potentials (EMG) from the target muscle supplied by
the motor nerve while directly stimulating the nerve fascicles during tumor removal.
Specifically designed stimulation-integrated microdissectors aid in performing the
microsurgical steps of tumor resection and simultaneously stimulate the fascicles.
As opposed to monitoring and preserving the integrity of conducting nerve fascicles
during an intraneural manipulation, the method of choice for intraoperative diagno-
sis is to measure the nerve conduction velocity by means of recording the com-
pound nerve action potential (cNAP) across a nerve lesion. In this method, the nerve
is exposed both proximal and distal to the lesion it lodges; the electrical stimulation
is applied to the nerve proximal to the lesion with a tripolar stimulation electrode in
the shape of a trident hook, and the cNAP is recorded using a bipolar hook electrode
lead placed distal to the nerve lesion (Fig. 5.8). Sometimes it is possible to recog-
nize partial lesions of nerves and replace only those fascicles that do not show con-
duction—effectuating the so-called split repair.
Surgical techniques in peripheral nerve lesions have evolved rapidly with the
availability of technological advancement. The technological breakthrough in many
areas of surgery notwithstanding the basic principles of peripheral nerve surgery
will continue to remain the same. These are as follows: (a) expose the nerve
adequately proximal and distal to the area of lesion; (b) inspect, examine, and study
the lesion meticulously from both the morphological and functional points of view;
(c) constantly endeavor to preserve any available function of the nerve fascicles
Fig. 5.8 Intraoperative recording of compound nerve action potential. Inset shows the nerve being
stimulated using a tripolar trident hook electrode proximal to the lesion and the potentials captured
using a bipolar hook electrode. The technologist is seen in the background
while treating a nerve lesion; and lastly (d) treat only those fascicles that are non-
functional with a hope to render them functional.
The means to achieve the abovementioned goals will obviously vary with two
basic qualities of the future nerve surgeon, viz., his open-mindedness to apply new
techniques and his familiarity with evolving technology in every walk of our fasci-
nating times.
References
1. Assmus H. Sural nerve removal using a nerve stripper. Neurochirurgia (Stuttg). 1983;26:51–2.
2. Barton MJ, Morley JW, Stoodley MA, Lauto A, Mahns DA. Nerve repair: toward a sutureless
approach. Neurosurg Rev. 2014;37(4):585–95.
3. Campbell WW. Evaluation and management of peripheral nerve injury. Clin Neurophysiol.
2008;119(9):1951–65.
4. Dützmann S, Martin KD, Sobottka S, Marquardt G, Schackert G, Seifert V, Krishnan KG. Open
vs retractor-endoscopic in situ decompression of the ulnar nerve in cubital tunnel syndrome: a
retrospective cohort study. Neurosurgery. 2013;72(4):605–16.
5. Hansen TB, Majeed HG. Endoscopic carpal tunnel release. Hand Clin. 2014;30(1):47–53.
6. Koenig RW, Schmidt TE, Heinen CP, Wirtz CR, Kretschmer T, Antoniadis G, Pedro
MT. Intraoperative high-resolution ultrasound: a new technique in the management of periph-
eral nerve disorders. J Neurosurg. 2011;114(2):514–21.
7. Koller R, Frey M, Rab M, Deutinger M, Freilinger G. Which changes occur in nerve grafts
harvested with a nerve stripper? Morphological studies. Handchir Mikrochir Plast Chir.
1995;27(2):98–101. German.
8. Krishnan KG, Schoeller K, Uhl E. The application of a compact HD-exoscope for illumination
and magnification in high-precision surgical procedures. World J Neurosurg. Accepted 2016.
9. Krishnan KG. Endoscopic decompression of the tarsal tunnel. Tech Foot Ankle Surg.
2010;9(2):52–7.
64 K.G. Krishnan
10. Krishnan KG. Part 4: appendices. In: Krishnan KG, editor. A handbook of flap raising tech-
niques. Stuttgart/New York: Georg Thieme Verlag; 2008. p. 93–106.
11. Krishnan KG. Harvesting of the sural nerve using a stripper. Neurosurgery. 2007;60(1):E208.
12. Krishnan KG, Pinzer T, Schackert G. A novel endoscopic technique in treating single nerve
entrapment syndromes with special attention to ulnar nerve transposition and tarsal tunnel
release – clinical application. Neurosurgery. 2006;59(1):ONS 89–100.
13. Krishnan KG, Pinzer T, Reber F, Schackert G. The endoscopic exploration of the brachial
plexus: technique and topographical anatomy. Neurosurgery. 2004;54(2):401–9.
14. Kriss TC, Kriss VM. History of the operating microscope: from magnifying glass to microneu-
rosurgery. Neurosurgery. 1998;42(4):899–908.
15. Litynski GS. Endoscopic surgery: the history, the pioneers. World J Surg. 1999;23(8):

745–53.
16. Malessy MJ, Pondaag W, van Dijk JG. Electromyography, nerve action potential, and com-
pound motor action potentials in obstetric brachial plexus lesions: validation in the absence of
a “gold standard”. Neurosurgery. 2009;65(4 Suppl):A153–9.
17. Mamelak AN, Danielpour M, Black KL, Hagike M, Berci G. A high-definition exoscope sys-
tem for neurosurgery and other microsurgical disciplines: preliminary report. Surg Innov.
2008;15(1):38–46.
18. Menovsky T, Beek JF. Laser, fibrin glue, or suture repair of peripheral nerves: a comparative
functional, histological, and morphometric study in the rat sciatic nerve. J Neurosurg.
2001;95(4):694–9.
19. Pedro MT, Antoniadis G, Scheuerle A, Pham M, Wirtz CR, Koenig RW. Intraoperative high-
resolution ultrasound and contrast-enhanced ultrasound of peripheral nerve tumors and tumor-
like lesions. Neurosurg Focus. 2015;39(3):E5.
20. Shirzadi A, Mukherjee D, Drazin DG, et al. Use of the Video Telescope Operating Monitor
(VITOM) as an alternative to the operating microscope in spine surgery. Spine (Phila Pa 1976).
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21. Spinks TJ, Adelson PD. Pediatric sural nerve harvest: a fully endoscopic technique.

Neurosurgery. 2009;64(5):360–3; discussion 363–4.
Specific Challenges in Brachial
Plexus Surgery 6
Thomas J. Wilson and Lynda J.-S. Yang
Contents
6.1 Introduction 65
6.2 Challenges in the Preoperative Evaluation 66
6.3 Challenges in Intraoperative Decision-Making 71
6.4 Challenges in Postoperative Evaluation 73
Conclusion 75
References 76
6.1 Introduction
Brachial plexus injuries are devastating, resulting in loss of function of the upper
extremity, which carries significant morbidity. In adults, trauma is the most com-
mon etiology of brachial plexus injury. In neonates, the exact pathophysiology of
brachial plexus injuries is unclear but occurs before or during labor and parturition
[1]. Neonatal brachial plexus palsy (NBPP) occurs in approximately 1 in 1000 live
births [5]. A significant proportion of these patients will demonstrate spontaneous
recovery with therapy alone and no operative intervention. However, there remains
a subset of these patients that will not recover without operative intervention.
Until only recently, adult and neonatal brachial plexus palsies were thought of as
nonsurgical pathologies. Little was available in the way of surgical treatment. Early
efforts had poor results which discouraged continuing surgical treatment [32]. World
T.J. Wilson
Department of Neurosurgery, Stanford University, Palo Alto, CA, USA
e-mail: thowil@med.umich.edu
L.J.-S. Yang, MD, PhD (*)
Department of Neurosurgery, University of Michigan, Ann Arbor, MI, USA
e-mail: ljsyang@med.umich.edu

DOI 10.1007/978-3-319-52319-4_6
66 T.J. Wilson and L.J.-S. Yang
War II ultimately revived the interest in repair of adult brachial plexus injuries, and
during this time, Seddon pursued repair with improved outcomes, sparking a renewed
interest. Neonatal brachial plexus palsy, however, remained a nonsurgical condition
until the work of Gilbert revived interest when he reported improved outcomes and,
in particular, improved safety of operative intervention [27, 29]. As surgery has
increasingly become an option and new innovative techniques have been employed,
a number of challenges have arisen that span the gamut from preoperative evaluation
and decision-making to intraoperative decisions regarding the optimal nerve recon-
struction strategy to be performed to evaluating outcomes in these patients postop-
eratively. In this chapter, we highlight specific challenges facing the peripheral nerve
surgeon in each phase of care and highlight the areas needing further research. While
the majority of these specific challenges pertain to the NBPP population, decisions
regarding whether to perform nerve graft repair or nerve transfer pertain to both the
NBPP population and adult population, and both will be highlighted. As research
continues and new innovative techniques for evaluation and treatment are developed,
these specific challenges are likely to be overcome, but with progress, new chal-
lenges and new questions are likely to be raised.
6.2 Challenges in the Preoperative Evaluation
Preoperatively, the main challenges facing the peripheral nerve surgeon when evalu-
ating a patient with NBPP are (1) determining whether or not to operate and (2) the
optimal timing of operative intervention. This begs the question, what is the optimal
method of evaluation to guide this decision-making? While a significant proportion
of patients with NBPP will recover spontaneously if given time, data also have
shown that earlier operative intervention is associated with improved outcomes fol-
lowing graft repair or nerve transfer [8, 36]. Thus, early dichotomization of patients
into those likely to spontaneously recover and those unlikely to spontaneously
recover has great importance. The most fundamental question to be addressed by all
methods of evaluation that informs the likelihood of recovery is: what is the nature
of the injury? Lesions likely to recover include neurapraxic injuries and axonot-
metic injuries. Those lesions with no hope of spontaneous recovery include nerve
root avulsions (preganglionic) and postganglionic, neurotmetic lesions (ruptures).
The mainstay of evaluation of these patients remains the physical examination.
While documenting a baseline examination shortly after birth is extremely impor-
tant, little is gleaned with regard to prognostication from this initial examination.
The exception may be the presence of Horner’s syndrome in the context of a pan-
plexopathy. The presence of Horner’s syndrome is indicative of a preganglionic,
non-recoverable lesion and an indication for surgery [3]. Aside from this finding,
there are no reliable indicators of non-recoverable lesions. Hence, time must be
allowed to observe for spontaneous recovery. Though the optimal time period is not
universally agreed upon, the most commonly used time period is 3 months. Gilbert
demonstrated that motor outcomes at 5 years of age were poor in those children who
failed to spontaneously recover biceps function by 3 months of age [23, 27, 28].
6 Specific Challenges in Brachial Plexus Surgery 67
Thus, this is the rationale for evaluation at 3 months, with those children not
demonstrating spontaneous recovery of biceps function being unlikely to recover
and thus likely to benefit from operative intervention.
However, further detailed analysis revealed flaws in this system. Michelow and
colleagues demonstrated that if absent biceps function at 3 months is utilized as the
sole criterion for prediction of recovery, the prediction is incorrect in 12% of
patients. When multiple movements were assessed at 3 months and combined into
an overall score, the percentage of incorrect predictions dropped to only 5% [7].
One of the issues with assessment at 3 months of age is that some patients will go
on to develop biceps contraction at 6 months, though the significance of this finding
is uncertain [39, 44]. Waters has shown that patients developing biceps function
after 5 months of age have improved outcomes with operative management com-
pared to nonoperative management [8, 18]. Thus, the significance of delayed recov-
ery of biceps function is unclear. Other tests such as the towel test and cookie test
have been suggested to be helpful in predicting those patients likely to benefit from
surgery [9, 13, 38]. In the towel test, a towel is placed over the infant’s face and the
infant is observed for the ability to remove the towel with the affected arm [9]. In
the cookie test, a small cookie is placed in the infant’s hand and the humerus is held
at the infant’s side. The infant is then observed for the ability to generate enough
elbow flexion to bring the cookie into his/her mouth [13]. This remains a specific
challenge to the peripheral nerve surgeon as there is no consensus as to what method
of evaluation should be used. The ideal evaluation would be highly specific and
sensitive and able to be predictive at a young age.
In adults, one of the mainstays of evaluation of the peripheral nervous system is
the electrodiagnostic study including nerve conduction studies and electromyogra-
phy (EMG), but these studies are fraught with difficulties in neonates. EMG studies
are often difficult to interpret and are often discordant with clinical findings. When
a paralyzed biceps is encountered clinically, one would expect an EMG to show a
loss of motor unit potentials (MUPs) and the presence of denervation activity.
However, frequently, in the setting of a paralyzed biceps in infants, motor unit
potentials are present and denervation activity is absent [36]. A number of reasons
have been suggested for these confusing findings. Malessy and colleagues have sug-
gested five reasons that there may be the presence of motor unit potentials despite
no observed biceps activity: (1) inadequacy of the clinical examination, (2) overes-
timation of the number of motor unit potentials, (3) luxury innervation, (4) central
motor disorders, and (5) abnormal nerve branching [11]. Examining an infant is
limited by the inability of the infant to voluntarily participate in the examination.
For this reason, it may be that Medical Research Council (MRC) grade 1 or 2 move-
ment may be missed. The estimate of the number of motor unit potentials (MUPs)
may be overestimated due to the difference in the size of motor fibers in infants
versus adults. Because fibers are smaller in infants, a significantly larger number of
fibers are recorded for the same EMG needle uptake area compared to adults.
Luxury innervation refers to the idea that muscles have more than one neuromuscu-
lar synapse early in development. During normal development, pruning occurs so
that only one neuromuscular synapse remains. However, there is disagreement
about when this pruning occurs. If this pruning occurs after birth, it may be that the
presence of a brachial plexus lesion affects this pruning process. It has previously
been shown that in infants with NBPP, intraoperative stimulation of C7 yields elbow
flexion and shoulder abduction, suggesting luxury innervation of the biceps by C7
[10, 40]. This luxury innervation is not pruned due to the lack of competition from
C5 and C6 as a result of the brachial plexus injury. This may result in identifying
MUPs in the biceps from C7 rather than C5 or C6. Many motor pathways depend
on afferent input for normal formation. However, in NBPP, not only is the motor
pathway lost but the afferent sensory pathway is also lost. This may result in abnor-
mal formation of central motor pathways such that even if axonal regeneration
occurs to the biceps, the motor pathways may not form correctly to allow movement
[30, 51]. Finally, abnormal branching of regenerating axons may occur. Because of
abnormal branching and misdirection, axonal regeneration can terminate in other
muscles resulting in co-contraction of various muscles. This co-contraction due to
abnormal branching may result in detection of MUPs despite lack of activation of
the biceps.
With all of the incumbent challenges of EMG and nerve conduction studies in
neonates, we are left to ask whether or not there is any value to obtaining such stud-
ies. There does still appear to be some value to obtaining these studies, and we still
do routinely obtain them. Electrodiagnostic studies can be poor at detecting nerve
root avulsions. We have previously shown that the sensitivity for nerve root avul-
sions is only 27.8%. However, electrodiagnostic studies do appear to be useful in
detecting ruptures. The sensitivity of electrodiagnostic studies for intraoperatively
confirmed ruptures was 92.8%. This pattern is the opposite pattern compared to
computed tomographic (CT) myelography which showed increased sensitivity for
avulsions and lower sensitivity for ruptures. Thus, the two studies complement each
other [24]. Electrodiagnostic studies do potentially provide useful information,
though their interpretation and optimal timing remain challenges in the evaluation
of NBPP.
In addition to the clinical examination and electrodiagnostic studies, a variety of
imaging modalities are available to aid in the evaluation of the patient with
NBPP. However, each modality comes with its own set of challenges, and no
consensus exists for the appropriate set of diagnostic imaging for these patients.
Historically, CT myelography is likely the most commonly employed imaging
modality in these patients. We have shown previously that CT myelography has
only a 58.3% sensitivity for nerve ruptures but a 72.2% sensitivity for avulsions
[24]. While this adds valuable information, CT myelography is certainly not highly
sensitive. Debate also exists as to what criteria should be used to diagnose an avul-
sion. The two most debated criteria are pseudomeningocele alone versus pseudo-
meningocele with absent rootlets. Studies vary in the reported value of each of these
diagnostic criteria. Tse et al. reported a sensitivity of 73% when pseudomeningocele
alone was used versus 68% when pseudomeningocele with absent rootlets was
used. While not highly sensitive, CT myelography is highly specific with reported
specificity of 96% whether pseudomeningocele alone or with absent rootlets was
used [21]. A previous report from Chow and colleagues had shown that utilizing
pseudomeningocele with absent rootlets for diagnosis improved the specificity from
85% to 98% [12]. One possible explanation for why Tse and colleagues did not find
a similar increase is that their cohort of patients had a high proportion of Narakas
grade 3 and 4 injuries and thus included more injuries to C8 and T1 where avulsions
are more likely to occur. In their study, 18 of 19 pseudomeningoceles identified
contained absent rootlets. If they had had a more mixed population relative to injury
severity and level, they may have observed a similar increase in specificity as Chow
observed [21]. Regardless, the optimal diagnostic criteria remain debated and sen-
sitivity remains a challenge. Additionally, CT myelography brings with it chal-
lenges inherent to the procedure including the invasive nature of the procedure,
instillation of intrathecal contrast and associated risks, and exposure to ionizing
radiation.
More recently, high-resolution magnetic resonance (MR) imaging and MR
myelography have been used in place of and compared to CT myelography. MR
myelography has been shown to have a similar sensitivity and specificity for nerve
root avulsions compared to CT myelography, 68% and 96%, respectively [21]. In
another study of high-resolution MR imaging, the sensitivity and specificity for
nerve root avulsions were 75% and 82%, respectively [48]. Some of the same issues
are present as with CT myelography, however, including defining the diagnostic
criteria to be used for avulsions and imaging of the more distal nerves for evidence
of rupture. High-resolution MR imaging/MR myelography does offer some advan-
tages, including the noninvasive nature of the study, the lack of intrathecal contrast
administration, and the lack of exposure to ionizing radiation. With a similar sensi-
tivity and specificity compared to CT myelography and the several aforementioned
advantages, we have replaced CT myelography with high-resolution MR imaging in
the evaluation of patients with NBPP.
One challenge of both CT and MR myelography is visualization of the extra-
foraminal nerve roots and trunks in order to evaluate for evidence of rupture.
Ultrasound can help overcome this challenge. Ultrasound is particularly useful in
evaluating the upper and middle trunks and less so the lower trunk. The sensitiv-
ity in identification of neuromas in our study was 84% for both the upper and
middle trunks and 68% for the lower trunk. Ultrasound can also be used to pro-
vide some information about how proximal the injury is based on evaluation of
the serratus anterior and rhomboid muscles. Atrophy in these muscles detected
on ultrasound suggests a proximal injury, making the presence of a viable proxi-
mal stump for nerve grafting less likely and making us favor nerve transfer
instead [25]. Ultrasound has little ability to evaluate the preganglionic segments
of nerve roots, making evaluation for avulsion difficult with this imaging
modality.
One of the main challenges in preoperative decision-making is identification of
appropriate candidates for nerve surgery as early as possible. To that end, we
attempted to identify peripartum and neonatal factors that were associated with
persistent NBPP. We identified cephalic presentation, induction or augmentation of
labor, birth weight > 9 lbs., and the presence of Horner’s syndrome as increasing
the likelihood of persistence. Cesarean delivery and Narakas grade 1 and 2 injuries
reduced the odds of persistence. Horner’s syndrome is a constellation of clinical

findings including ptosis, anhidrosis, and miosis due to injury to the sympathetic
trunk. The Narakas scale is an injury grading scale where Narakas grade 1 is injury
to the upper trunk only (C5, C6), grade 2 is injury to the upper and middle trunks
(C5, C6, C7), grade 3 is pan-plexus injury without Horner’s syndrome, and grade
4 is a pan-plexus injury with Horner’s syndrome. The study was performed on a
biased sample, however, due to the fact that the population of patients was that
already referred for evaluation by a nerve surgeon [37]. Nonetheless, the design of
this study was such that it was intended to address the main challenge in the preop-
erative evaluation of patients with NBPP which is early identification of those
patients that will not recover who should undergo nerve surgery. While the physi-
cal examination, electrodiagnostic studies, imaging studies, and peripartum/neona-
tal history all have a role in the evaluation, we are still in need of a predictive
algorithm that incorporates all of these methods of evaluation that can dichotomize
these patients with high sensitivity and specificity. Future research should continue
to address this challenge. Until such research addresses this challenge, we have
developed our own algorithm for evaluation at the University of Michigan
(Fig. 6.1).
University of Michigan
NBPP treatment pathway 0 Months
(New patient)
History and physical

physiotherapy
1 Month
History and physical
physiotherapy
electrodiagnostics
Yes biceps function 3 Months *No biceps function

Yes biceps MUAPs No biceps MUAPs
Physiotherapy Clinical examination
US for shoulder integrity MRI/US
Physiotherapy
6 Months
Yes No
Hand-to-mouth 6 Months
Hand-to-mouth
Continue physiotherapy Nerve surgery

expectant management *For flail arm, surgery
at 3 months
Fig. 6.1 Flowchart of the University of Michigan Neonatal Brachial Plexus Palsy (NBPP) path-
way of presurgery decision-making. US Ultrasound, MRI Magnet Resonance Imaging, MUAP
Motor Unit Action Potential
6.3 Challenges in Intraoperative Decision-Making
Once a decision is made to operate on a patient for persistent NBPP, a number of

intraoperative challenges face the nerve surgeon. The main decision is what inter-
vention to perform: neurolysis alone, nerve graft repair, or nerve transfer. For a
number of reasons, this decision remains challenging. One main reason is the lack
of comprehensive postoperative data that allow head-to-head comparison of inter-
ventions. This will be discussed in the next section. With the available data, how
does the nerve surgeon make this decision?
In adults, recoding nerve action potentials (NAPs) across a lesion in continuity
can be helpful. When nerve action potentials are recorded across a lesion, it is often
best to perform neurolysis alone, as nerve action potentials traveling across a lesion
in continuity suggest a recovering nerve [43]. However, in neonates, nerve action
potentials are not similarly useful. Intraoperative nerve action potentials in neo-
nates are thought to provide overly optimistic data. One study included ten lesions
in continuity and found positive NAPs across the lesion in five patients. Neurolysis
alone was performed in these patients and none had a good recovery [33]. In an
additional study, Pondaag and colleagues found that the specificity for a severe
lesion of absent NAPs and compound muscle action potentials (CMAPs) across a
lesion in continuity was high (>90%). However, the sensitivity was very low
(<30%) [41]. Taken together, the available data suggest that intraoperative NAPs
and CMAPs in neonates are not useful in guiding decisions. Thus, the surgeon is
challenged with relying on preoperative assessment to determine who should
undergo nerve reconstruction and that is fraught with the challenges previously
described.
Thus, once a decision for surgery is made, the real decision is whether to graft or
to transfer. There are very little data and very few studies directly comparing nerve
grafts to nerve transfers for NBPP. Thus, determining the optimal intervention
remains challenging. There are currently disagreements about the role of nerve
transfers in the treatment of NBPP. The International Federation of Societies for
Surgery of the Hand suggests that the role of nerve transfers in NBPP is unclear but
that nerve transfers are a viable option for Erb’s palsy but should not be first-line
treatment for more severe injuries. The committee suggests that there should not be
an overreliance on nerve transfers and there should remain an inclination toward
brachial plexus exploration and nerve graft repair [52]. Further data, however, are
needed to determine the optimal roles of both nerve transfer and nerve graft repair.
Erb’s palsy with C5 and C6 injury is the most common pattern of injury in
NBPP. While nerve graft repair is the traditional intervention, nerve transfers have
been shown to be a viable option. Recovery of elbow flexion has been shown to be
good following ulnar or median nerve fascicle transfer to the biceps or brachialis
branch of the musculocutaneous nerve. In one study, 87% of patients undergoing
these transfers obtained functional elbow flexion recovery. Outcomes were worse
for supination recovery with only 21% recovering functional supination [34]. While
there was no direct comparison to nerve graft repair, these outcomes suggest nerve
transfer is a viable option.
Reinnervation of the suprascapular nerve is important for restoration of external

rotation of the shoulder following C5/C6 injury in NBPP. Early experience reinner-
vating the suprascapular nerve was poor regardless of whether nerve graft repair or
nerve transfer was used [35]. More recently, however, outcomes have been better.
There have been mixed data comparing spinal accessory nerve transfer with C5
nerve graft repair. Spinal accessory nerve transfer is at least equivalent to C5 nerve
graft repair, but some data suggest it may have better outcomes [47, 53]. Seruya and
colleagues found that C5 nerve graft repair led to poorer shoulder function and also
increased secondary shoulder surgery compared to spinal accessory to suprascapu-
lar nerve transfer [47]. The major challenge remains making a decision to graft or to
transfer in the setting of a lack of data comparing the two interventions. Future stud-
ies will need to focus on comparing outcomes. Additionally, as we discuss in the
next section, it will be important to compare outcomes more in depth than simply
motor outcome.
A similar dilemma exists in the adult population of brachial plexus injury
patients. What is the optimal repair strategy to maximize outcomes? For upper
trunk injuries with loss of shoulder abduction, external rotation, and elbow flexion,
there is little in the way of direct comparisons between nerve graft repair and nerve
transfer. However, two recent meta-analyses help compare the two strategies, and
both concluded that nerve transfer strategies are superior to nerve graft repair.
These studies utilized the Medical Research Council (MRC) grading scale where
M5 is normal strength, M4 is movement against active resistance, M3 is movement
against gravity but no active resistance, M2 is movement with gravity eliminated,
and M1 is flicker movement or contraction only. Garg and colleagues found that
83% of patients with nerve transfers achieved M4 or greater elbow flexion strength
and 96% achieved M3 or greater. Comparatively, only 56% of patients with nerve
graft repair achieved M4 or greater strength and 82% achieved M3 or greater.
Shoulder outcomes were similarly better with nerve transfers. Seventy-four per-
cent of dual nerve transfer patients achieved M4 or greater shoulder abduction
strength versus 46% with nerve graft repair. Both shoulder abduction and external
rotation were better in the nerve transfer group [26]. Ali and colleagues recently
supported these findings. They found that nerve transfer techniques were superior
to nerve graft repair for the restoration of elbow flexion and shoulder abduction.
Specifically, with regard to elbow flexion, the Oberlin procedure (transfer of an
ulnar fascicle to the biceps branch of the musculocutaneous nerve) was superior to
all other strategies [4]. Thus, for upper trunk brachial plexus injuries, nerve trans-
fer seems to be superior to nerve graft repair, but no direct comparative data are
available. This data is not conclusive, however, and there certainly remains contro-
versy. In fact, in a systematic review, we previously found that the data did not
support the sole use of nerve transfers for upper brachial plexus injury. We recom-
mended at that time that the standard should still include brachial plexus explora-
tion with nerve graft repair when feasible [55]. Additional comparative studies are
needed to better elucidate the optimal strategy.
Restoration of hand function following lower trunk injuries is similarly challeng-
ing. In addition to nerve graft and nerve transfer techniques, an additional
consideration is the Doi procedure (double free muscle transfer) [20]. Ray and
colleagues initially described a series of four patients with isolated lower trunk
injuries in whom they performed transfer of the nerve to the brachialis to the anterior
interosseous nerve, with good clinical outcomes [42]. Isolated lower trunk injuries,
however, are relatively uncommon. With concomitant involvement of the upper
brachial plexus, nerve transfer options become more limited. Dodakundi and

colleagues initially reported success of the double free muscle transfer in total
brachial plexus injury [19]. As an adjunctive intervention, wrist arthrodesis has been
shown to improve both finger range of motion and overall hand function in patients
with double free muscle transfer for pan-plexus injury [2]. Recently, Satbhai and
colleagues reported an improvement in overall functional outcome and quality of
life using the double free muscle transfer versus single free muscle transfer or nerve
transfer for patients with pan-plexus injury [46]. However, it is not clear that hand
function was significantly better. In addition, this study pertains to patients with
pan-plexus injury and focuses on the overall function of the limb. In cases of iso-
lated lower trunk injury, it is not clear what strategy, whether nerve graft, nerve
transfer, free muscle transfer, or tendon transfer, yields the best results. Thus, deter-
mining the optimal reconstructive strategy remains challenging.
6.4 Challenges in Postoperative Evaluation
Postoperatively or, in the case of those neonates who are managed nonoperatively,
throughout the natural history of the condition, we are tasked with evaluating these
children in some way. This is particularly important in order to collect data to
determine if operative intervention is helpful and in order to compare different types
of intervention head to head. To this point, most evaluations have focused on motor
outcomes and grading individual motor movements on scales such as the Medical
Research Council (MRC), Active Movement Scale (AMS), and Louisiana State
University motor grading scales. While a variety of outcome measures have been
used, the five most common in the published literature include range of motion of
the shoulder, range of motion of the elbow, the Mallet scale, MR imaging findings,
and the MRC grading scale [45]. Very few evaluation instruments/metrics are
specifically validated for use in the NBPP population. Validated evaluation instru-
ments/metrics include the Active Movement Scale, Toronto Scale Score, Mallet
Score, Assisting Hand Assessment, and Pediatric Outcomes Data Collection
Instrument [16]. While gross motor function and evaluation of body structure and
function are important, this may not capture the complete picture, as simply grading
motor strength ignores other important factors such as sensation, arm preference,
proprioception, functional use of the extremity, cognitive development, pain, quality
of life, and language development [22]. Thus, it remains a specific challenge to
determine how best to evaluate patients with NBPP. While a number of these
domains of evaluation are specifically to the NBPP population, a similar problem
exists when evaluating adults with brachial plexus injury following intervention.
In this population, it also remains a specific challenge to go beyond purely
evaluating motor recovery and rather to also evaluate quality of life, functional use
of the affected limb, and pain [22].
One challenge of the postoperative evaluation is determining the optimal dura-
tion of time to follow these patients. From age 5 onward, these patients generally
have stable to improved hand and shoulder function. However, over the same time
course, elbow function tends to slightly deteriorate. This is true whether or not nerve
reconstruction was performed. Children who have poor shoulder external rotation
benefit from shoulder surgery with significant improvement postoperatively [50].
Because of the continued decrease in elbow function and the significant benefit to
shoulder external rotation following surgery for those patients in whom external
rotation limitation is recognized, it is important to follow these patients throughout
childhood and adolescence and into adulthood.
In the general population, approximately 90% of people have a right arm prefer-
ence/dominance. In children with left upper extremity brachial plexus palsy, that
percentage remains roughly the same, 93% in our previous study. However, when
the right upper extremity is the affected limb, only 17% preferred the right limb.
This is a significant deviation away from the population average [54]. This suggests
neural plasticity is at work early in the development of these children. However,
what is not clear is how dominant the unaffected extremity becomes. Is the affected
extremity essentially a useless limb, or is there only a slight preference for the unaf-
fected extremity? More importantly, do surgical interventions improve the func-
tional use of the extremity and reduce the preference for the unaffected extremity?
Finally, do nerve transfers that offer earlier, though some would argue less com-
plete, recovery offer advantages over nerve graft repair due to the fact that recovery
occurs when motor patterns are being established? These are the challenges in eval-
uation that remain to be answered.
It may not simply be weakness that leads to altered limb preference and reduced
functionality. Proprioception plays a large role in the functional use of extremities.
However, to this point, little focus has been given to evaluating proprioception fol-
lowing brachial plexus injury. We have previously assessed elbow position sense in
adolescents with a history of NBPP. We found that position sense is impaired in the
affected limb following NBPP [14]. Similarly, tactile spatial perception is reduced
in the hand of the affected limb following NBPP [15]. It is unclear how much this
affects daily use of the limb and overall limb preference. However, it may be an
important component not assessed by purely focusing on gross motor function.
Further assessments of proprioception and advanced sensory modalities are needed
in future studies to determine their importance in daily activities and which inter-
ventions improve these modalities that contribute to complex functional use.
Delayed or altered use of the affected limb may also affect development in a
more global fashion. Motor impairments in children have previously been reported
to delay language [31]. The nature of the relationship between motor function and
language is unclear. Decreased motor function may impair the ability of the child to
explore the world around them, thus delaying language. We have previously shown
a high rate of language delay in toddlers with a history of NBPP [17]. This finding
has several important implications. First, it suggests that treating children with
NBPP is more complex than simply focusing on motor rehab. Recognizing the
association of language delay and NBPP means that rehabilitation focused on
language development should be part of the overall rehabilitation program.

Furthermore, it suggests that assessment of language is an important component of
the global assessment of these patients. A further understanding of exactly how
language development and motor deficits, and more specifically NBPP, are linked
may lead to a better understanding of interventions that may address this issue. For
example, if delays in language development result from a decreased ability to
explore the surroundings at a very young age, those interventions that favor early
recovery, i.e., nerve transfers as opposed to nerve graft repair, may favor improved
language development. This remains hypothetical, however, but points to the chal-
lenge of needing more complex evaluations to determine optimal interventions.
With language development being affected, one might hypothesize that behav-
ioral issues may arise in children with a history of NBPP. This hypothesis turns out
to be correct. Children with a history of NBPP show global developmental delays,
difficulty with hand-eye coordination, and a higher incidence of emotional and
behavioral problems. This was closely associated with the severity of initial injury
[6]. One might assume that earlier or more complete recovery may be associated
with a reduction in behavioral problems, but this has never been demonstrated.
Thus, it remains a challenge to evaluate behavioral outcomes and to determine what
factors are associated with reduced behavioral issues, including which interventions
may help reduce these issues.
All of these challenges point to need for more global and comprehensive evalua-
tion of patients with NBPP, both managed operatively and nonoperatively.
Ultimately, what is important to these patients is having the highest quality of life
possible. A number of factors have been identified as affecting the quality of life in
these patients including social impact and peer acceptance, emotional adjustment,
aesthetics and body image, functional limitations, finances, pain, and family dynam-
ics [49]. The diversity of these factors points to the fact that assessment necessarily
involves more than simply assessing motor function. It remains the challenge of the
nerve surgeon taking care of patients with NBPP to develop the optimal assessment
metrics and intervals and to compare interventions head to head using optimized
global metrics, ultimately moving beyond simply the World Health Organization
International Classification of Functioning, Disability, and Health Body Function
and Structure domain and moving into evaluations in the Activity and Participation
domain (http://www.who.int/classifications/icf/en/).
Conclusion
Neonatal brachial plexus palsy is a relatively common pathology. While most
children will recover without surgical intervention, a number of challenges face
the nerve surgeon throughout the preoperative, intraoperative, and postoperative
care of these patients. Similar dilemmas regarding nerve graft repair versus nerve
transfer face both the nerve surgeon treating NBPP and adult brachial plexus
injury. Surgery for NBPP is in its relative infancy, which is the origin of most of
these challenges. Further data are needed to help overcome these obstacles and
guide decision-making for these patients. While these challenges remain, it is an

exciting field that holds promise for helping to improve function and quality of
life for these patients through progressively improved decision-making algo-
rithms and surgical intervention. With progress, however, new questions are
likely to arise that will continue to challenge the nerve surgeon in optimizing
care of these patients.
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Alternative Strategies for Nerve
Reconstruction 7
F. Siemers and K.S. Houschyar
Contents
7.1 Introduction 80
7.2 Peripheral Nerve Grafts 81
7.3 Allogeneic Decellularized Nerve Transplantation 83
7.4 Nerve Conduits 85
7.4.1 Biological Nerve Conduits 85
7.4.2 Synthetic Nerve Conduits 86
7.4.3 Technique of Tubulization 88
7.5 Polyesters for Nerve Conduit Fabrication 89
7.5.1 PGA 89
7.5.2 PLA 89
7.5.3 PLLA 90
7.5.4 PLGA 90
7.5.5 PCL 91
7.5.6 Poly(D,L-lactide-co-ε-caprolactone) 91
7.6 Proteins with Synthetic Biomaterials 91
7.6.1 Nondegradable Nerve Conduits: Silicone, Plastic, and
Polytetrafluoroethylene Tubes 92
7.6.2 Degradable Nerve Conduits 93
7.7 Conclusions and Recommendations 94
References 94
F. Siemers (*) • K.S. Houschyar

Plastic and Reconstructive Surgery, BG Clinic Bergmannstrost Halle,
Merseburger Str. 165, 06112 Halle, Germany
e-mail: frank.siemers@bergmannstrost.de; Khosrow-Houschyar@gmx.de

DOI 10.1007/978-3-319-52319-4_7
80 F. Siemers and K.S. Houschyar
7.1 Introduction
A peripheral nerve injury results whenever a nerve is crushed, compressed, or cut and in
consequence the proper communication between the peripheral and central nervous
system is lost [1]. Peripheral nerves possess the capacity of self-regeneration after trau-
matic injury. The quality of functional regeneration depends on a number of factors
including location of the injury, size, and the age of the individual [2]. The classification
of injury type is useful to understand the likelihood of complete recovery and the prog-
nosis. The longitudinal nature of crushing injuries and different levels of nerve injury
can be seen at various locations along the nerve. This is the most challenging nerve
injury for the surgeon as some fascicles will need to be protected and not “downgraded,”
whereas others will require surgical reconstruction [3] (Table 7.1). Microsurgical recon-
struction is required for reconnecting nerve ends, and if substance loss occurs, the two
stumps must be bridged. Autologous nerve grafts have been the most widely used strat-
egy for bridging nerve gaps; nonetheless, this technique has disadvantages (Table 7.2)
[4]. During the last years, significant developments in materials sciences have
Table 7.1 Neurosensory recovery based upon Sunderland classification

Neurosensory recovery based upon Sunderland classification
Sunderland Recovery pattern Rate of recovery Need for surgery
I Complete Fast (days–weeks) None
II Complete Slow (weeks) None
III Variable Slow (weeks–months) Maybe
IV Poor Little/None Yes
V None None Yes
Table 7.2 Advantages and disadvantages of nerve grafts for the repair of peripheral nerve injury
Nerve transplant Advantages Disadvantages
Nerve autograft Provides a suitable environment Limited amount of tissue
for nerve regeneration
No risk of immunological Limited number of grafts
rejection
Simple and safe to obtain Donor site morbidity and potential loss
of function
Easy to suture to the injured
tissue
Nerve allograft Unlimited source tissue Lack of appropriate animal donor
tissue
No donor site trauma for the Uncertain histocompatibility
recipient
Ethical and legal concerns
Tissue- Fabricated from polymers or Degradable biomaterials are expensive
engineered biomacromolecules
material Unlimited source materials Antigenicity
Easy to produce Exhibit poor tenacity, making them
difficult to suture to the injured nerve
No donor site trauma
7 Alternative Strategies for Nerve Reconstruction 81
represented lively research in the area of alternative (nonnervous) conduits. There was
an increasing a vailability of a number of new innovative manufacturing procedures and
biomaterials [4]. Translation to the patient of artificial synthetic nerve grafts is still lim-
ited in spite of the large body of preclinical research. Today, the most popular approach
is still biological tubulization with nonnervous autologous tissues, creating a scaffold
that can bridge a nerve gap [4]. In fact, this approach avoids complications due to any
possible graft-versus-host reaction and is less expensive.
7.2 Peripheral Nerve Grafts
Autografts In patients with larger nerve gaps where the injury must be bridged, use
of an autograft remains the most reliable repair technique [3, 5]. Nerve autografts
have been studied extensively, and their superiority over epineurial suturing under
tension has been reported [6]. By using nerve autografts, the surgeons prepare a
structural guidance of the natural material for axonal progression from the proximal
to the distal nerve stumps. Donor sites for autograft nerve tissue are represented by
functionally less important nerves like superficial cutaneous nerve, posterior interos-
seous nerve, sural nerves, or medial and lateral antebrachial cutaneous nerves [6, 7].
The three major types of autografts are trunk grafts, cable grafts, and vascular-
ized nerve grafts [3]. Trunk grafts are mixed motor and sensory grafts. Trunk grafts
have poor functional results due to their instability and large diameters which inhib-
its its ability to properly revascularize the center of the graft. Cable grafts are several
sections of small nerve grafts aligned in parallel to connect fascicular groups.
Vascularized nerve grafts have the advantage that there is no period of ischemia
compared to nonvascularized grafts and the necessity for revascularization is
avoided [3]. Sensory donor nerves are most often used, with the sural nerve being
the most commonly harvested (Fig. 7.1a, b). The choice of autograft is dependent
on several factors, that is, the size of the nerve gap, location of proposed nerve
repair, and associated donor-site morbidity [8]. Use of autografts is currently
restricted to critical nerve gaps of nearly 5 cm length [6].
The main limitations in the use of nerve autografts are considered to be mis-
match of donor nerve size and fascicular inconsistency between the autograft and
the distal/proximal stumps of the recipient nerve. Because a mismatch in axonal
size and alignment further limits the regeneration capacity of the autografts, the
type of nerve autografts chosen, like motor nerves, sensory nerves, or mixed nerves,
is also decisive for a successful outcome [6]. A prolonged surgical time together
with the potential risk of infection and formation of painful neuroma represents
other important drawbacks of nerve autografting [6]. Altogether, the recovery time
for the patient can be prolonged, owing to the need for a second surgery. The limita-
tions of autografts forced researchers to develop alternative manufacturing
approaches for novel nerve conduits for peripheral nerve repair [6].
Allografts Nerve allografts have a history that exceeds that of autografts. In 1885,
Eduard Albert reported the use of a nerve allograft from an amputated limb to bridge a
3 cm median nerve gap arising from resection of a sarcoma [9]. The use of donor-related
Fig. 7.1 (a, b) Sensory donor nerves are most often used, with the sural nerve being the most
commonly harvested. (a, b) A minimally invasive technique of sural nerve harvesting is begun
through a small incision at the level of the lateral malleolus, thereby identifying the nerve and
inserting the nerve-harvesting device. An additional small incision, if needed, is placed at the junc-
tion of the middle and distal thirds of the lower leg, a landmark at which an anastomosis occurs
between the medial and lateral sural cutaneous nerves
or cadaveric nerve allografts is reserved for devastating or segmental nerve injuries. Like
all tissue allotransplantation, nerve allografts require systemic immunosuppression; the
associated morbidity of immunomodulatory therapy limits the widespread application
of nerve allografting. Several techniques (e.g., irradiation, cold preservation, lyophiliza-
tion) to reduce nerve allograft antigenicity have been published [10].
Nerve allografts have demonstrated clinical utility in repairing extensive periph-

eral nerve injuries where there is a paucity of donor nerve material. Allografts used
in peripheral nerve injuries are commercially processed to be cell- and protein-free
[3]. This allows the nerve allograft to serve as a scaffold that is repopulated by
Schwann cells and host axons over time [3]. The use of allografts presents limita-
tions including especially risk of cross contamination, immune rejection, secondary
infection, and limited supply [6]. Therefore, the use of allografts requires systemic
immunosuppressive therapy, but long-term immune suppression is not a desirable
treatment due to increased risk of infection and decrease of healing rate, and it occa-
sionally results in tumor formation and other systemic effects [6]. In order to over-
come some of these limitations, nerve allografts can be processed by repeated
irradiation, freeze–thaw cycles, and decellularization with detergents [11].
7.3 Allogeneic Decellularized Nerve Transplantation
Since 2007, decellularized nerve grafts are in clinical use. Since 2013, this alterna-
tive is also available in German-speaking countries; however, only a few clinics in
Germany gathered experience in this field (Fig. 7.2).
The allogeneic transplants, which are generated from human donor nerve, com-
bine many advantages due to its macrostructure and the three-dimensional micro-
structure. First clinical observations indicated in broken sensitive nerves good
results to a defect distance of 3 cm. In the ten cases described, the 2-point discrimi-
nation (2PD) was 6 mm or better.
Fig. 7.2 Allogeneic decellularized nerve transplantation. (a) Surgical preparation of the median
nerve. (b) Bridging the nerve gap with a decellularized allogeneic nerve. (c) Suturing the decellu-
larized qallogeneic nerve with the median nerve
Fig. 7.2 (continued)
The largest prospective study on the use of allogeneic nerve grafts was published
in 2011 by Brooks et al. under the name “RANGER study.” The RANGER study
registry was initiated in 2007 to study the use of processed nerve allografts (AxoGen®
nerve allograft (AxoGen Inc., Alachua, FL)) in contemporary clinical practice [12].
Twelve sites with 25 surgeons contributed data from 132 individual nerve injuries.
Data was analyzed to determine the safety and efficacy of the nerve allograft. Sufficient
data for efficacy analysis were reported in 76 injuries (49 sensory, 18 mixed, and 9
motor nerves). The mean age was 41 ± 17 (18–86) years. The mean graft length was
22 ± 11 (5–50) mm. Subgroup analysis was performed to determine the relationship
to factors known to influence outcomes of nerve repair such as nerve type, gap length,
patient age, time to repair, age of injury, and mechanism of injury. Meaningful recov-
ery was reported in 87% of the repairs reporting quantitative data. No graft-related
adverse experiences were reported, and a 5% revision rate was observed. Processed
nerve allografts performed well and were found to be safe and effective in sensory,
mixed, and motor nerve defects between 5 and 50 mm. The outcomes for safety and
meaningful recovery observed in this study compare favorably to those reported in the
literature for nerve autograft and are higher than those reported for nerve conduits.
Xenografts A nerve xenograft is obtained from a member of a species other than

that of the recipient. A research group developed an experimental animal model to
study the potential transplantation of nerve xenografts using the newer immunosup-
pressive agents RS-61443 and FK-506. They transplanted 2 cm sciatic nerve xeno-
grafts obtained from golden Syrian hamsters into a 0.5 cm gap in the sciatic nerve
of Lewis rats. The functional recovery in the test animals was found to be not as
good as those in the control autografts [13].
Another research team used acellular nerve xenografts and seeded them with
bone marrow stromal cells [14]. When the allograft and the xenograft were com-
pared with electrophysiological studies, it was observed that the xenografts were as
effective as the allografts in regenerating the nerves. Allograft and xenografts have
certain disadvantages such as disease transmission and immunogenicity.
7.4 Nerve Conduits
7.4.1 Biological Nerve Conduits
The use of a conduit as a vehicle for moderation and modulation of the cellular and
molecular ambience for nerve regeneration has been widely investigated [15].
A combination of physical, biological, and chemical factors has made the study
of nerve tubes a complex process, rising tremendous interest in the fields of medi-
cine. The ideal tubular material has not yet been established. Several materials,
either of biologic origin or synthetically fabricated, have been applied for these
purposes. The ideal conduit would be made of a low-cost, biologically inert material
that is biocompatible; flexible; thin; transparent; inhibitor of inflammatory pro-
cesses such fibrosis, neuromas, gliomas, swelling, ischemia, and adhesions; and
facilitator of the processes that contribute to regeneration, accumulating factors that
promote nerve growth [15]. Biological conduits such as autologous veins, arteries,
muscle, and heterogeneous collagen tubes denatured skeletal muscle or muscle
basal lamina, veins, and polyglycolic acid (PGA)–collagen tubes [16]. Biomaterials
such as artery, vein, and muscle have been widely used to repair relatively short
nerve defects. These materials can provide support for the nerve in the short term
and degrade to innocuous products after complete nerve regeneration.
Table 7.3 Design criteria for nerve guidance conduits

Ideal properties Description
Biocompatibility Material should not harm the surrounding tissues
Protein modification/release Laminin/fibronectin coating for increased cellular adhesion;
controlled/sustained growth factor release
Degradation/porosity Degradation rate should complement nerve regeneration rate;
conduit should allow nutrient diffusion and limit scar tissue
infiltration
Anisotropy An internal scaffold or film should provide directional
guidance
Physical fit Conduit should have a large enough internal diameter to not
“squeeze” the regenerating nerve; wall thickness limited
Electrically conducting Capable of propagating electrical signals
Support cells Schwann cells/stem cells capable of delivering neurotrophic
factors to the site of regeneration
Table 7.3 summarizes the types and the performance of a variety of conduit
materials.
In the 1980s, preclinical research by Glasby and colleagues demonstrated that
autografts of skeletal muscle which had been deeply frozen in liquid nitrogen and
subsequently thawed can provide a valuable matrix for the regenerating nerve, when
oriented coaxially with respect to the nerve tissue. In eight patients, this type of
grafts was used to repair injured digital nerves. Assessment from 3 to 11 months
after operation showed recovery to MRC (Medical Research Council) sensory cat-
egory S3+ in all patients [17]. Lundborg reported about different methods of frozen
muscle grafts and other conduits bridging nerve gaps [18].
There are several advantages, however, in using vein conduits for nerve recon-
struction [19]. The tissue composition of veins is similar to that of nerve tissue.
Furthermore, muscle–vein-combined graft conduits have been broadly devised and
effectively employed for repair of segmental nerve injuries [20]. Manoli et al. con-
ducted a retrospective clinical trial in order to compare regeneration results after
digital nerve reconstruction with muscle-in-vein conduits, nerve autografts, or
direct suture [21]. In a total of 46 patients with 53 digital nerve injuries with a seg-
mental nerve injury ranging between 1 and 6 cm, no statistically significant differ-
ences between all three groups could be found. The authors also emphasized that
after harvesting a nerve graft, reduction of sensibility at the donor site occurred in
10 of 14 cases but only in one case after harvesting a muscle-in-vein conduit.
7.4.2 Synthetic Nerve Conduits
They include nondegradable and degradable nerve conduits (Fig. 7.3). Synthetic

polymers, though often less biocompatible relative to biopolymers, offer opportuni-
ties for tailored degradation and control of mechanical strength, porosity, and
microstructure properties [22].
Fig. 7.3 Examples for nerve conduit designs. (a) Acellular nerve repair material and its applica-
tion for the repair of 2 cm ulnar nerve defect in the fourth finger. (b) Acellular nerve repair material
and its application for the repair of 2 cm radial nerve defect in the thumb
In the meantime, the material choice for nerve conduits shifted toward the use of
more biocompatible synthetic polymers. Biodegradable polyesters, such as polygly-
colic acid (PGA), polylactic acid (PLA), poly(ε-caprolactone) (PCL), poly(lactic
acid-co-glycolic acid) (PLGA), polyurethanes (PUs), and nonbiodegradable poly-
mers such as methacrylate-based hydrogels, silicone, polystyrene, and polytetra-
fluoroethylene), were used as nerve conduit materials and intensively studied in
preclinical models [6].
7.4.3 Technique of Tubulization (Fig. 7.4)
Surgery on the peripheral nerve requires microsurgical techniques. Following

debridement and neurolysis if applicable, the nerve stumps are located with one or
two u-sutures of 8/0 to 10/0 nylon and inserted into the moistened tube with an
overlap of 2–3 mm (Fig. 7.4a, c).
In addition to the defect length, the nerve diameter must be detected in the prepa-
ration. Of this, the choice of the size of the nerve conduit depends. All operational
steps have to be carried out using a magnifying optics and microsurgical instru-
ments and sutures. A microsurgical expertise is a prerequisite for a successful place-
ment of a nerve tube [23].
Fig. 7.4 Schematic
representation of the
tubulization technique.
(a–c) Nerve stumps are
located with one or two
u-sutures of nylon and c
inserted into the moistened
tube with an overlap of
2–3 mm. (b, d) After
finishing each coaptation,
the lumen has to be rinsed
with normal saline or
electrolyte solution using a
small cannula to remove
d
any remaining blood clots
Tubulization has to be performed after release of the tourniquet to prevent bleed-

ing into the conduit. After finishing each coaptation, the lumen has to be rinsed with
normal saline or electrolyte solution using a small cannula to remove any remaining
blood clots (Fig. 7.4b, d). Immobilization of the adjacent joints is advisable for at
least 10 days. Massaging the scar should be avoided due to the risk of dislocation of
the tube in the first weeks following the operation. Tubulization seems equally
appropriate for primary and secondary nerve reconstructions as well as for recon-
struction after neuroma resection [24].
7.5 Polyesters for Nerve Conduit Fabrication
Most of current resorbable synthetic polymer membranes on the market are based
on aliphatic polyesters. PGA, PLA, PLLA, PLGA, and PCL are polyesters most
commonly used in the fabrication of nerve conduits.
7.5.1 PGA
The PGA conduit, also known as the GEM Neurotube, has been the most extensively
studied synthetic biodegradable conduit both experimentally and clinically [20]. First
descriptions go back to Mackinnon and Dellon who published in 1990 a report of 15
digital nerve lesions being reconstructed with hollow polyglactin (PGA) conduits
[25]. It is a porous synthetic aliphatic polyester made of polyglycolic acid, which
exhibits a high tensile modulus with very low solubility in organic solvents [26]. In an
earlier study, PGA-based crimped tube device (Neurotube®; Synovis Micro Companies
Alliance, Birmingham, AL, USA) was described for the repair of peripheral nerve
injuries [6]. In a more recent experimental study, bone marrow-derived stem cells
(BMSCs) were combined with PGA tube (PGAt) (Neurotube®) in autografted rat
facial nerves [27]. After cutting of the mandibular branch of the rat facial nerve, surgi-
cal repair consisted of autologous graft in a PGA filled with basement membrane
matrix with undifferentiated bone marrow-derived stem cells (BMSCs) or Schwann-
like cells that had been differentiated from BMSCs. After 6 weeks of surgery, animals
from either cell-containing group had compound muscle action potential amplitudes
significantly higher than the control groups. PGA is also often combined with natural
polymers such as collagen [28]. Weber et al. reported the results of the first random-
ized, prospective, multicenter evaluation comparing autografts and PGA conduits for
the repair of digital nerve gaps [29]. PGA tubes produced good to excellent functional
sensation in 100% of patients with nerve gaps <4 mm, 83% of patients with nerve
gaps 5–7 mm, and 71% of patients with nerve gaps >8 mm.
7.5.2 PLA
PLA (polylactic acid) is one of the most common and important polymers because
of its suitable mechanical properties and biocompatibility [30]. Biocompatible
PLA can be derived from lactic acid obtained from corn, sugar beet, or wheat. PLA
has been used commercially as membranes, such as Resolut Adapt®, Vicryl®, Epi-
Guide®, and Vivosorb®, and each of these membranes may have its own properties.
PLA was used as a nerve conduit material in a number of studies [31]. In one study,
a multilayer PLA nerve conduit was fabricated by microbraiding to obtain ade-
quate mechanical strength at the injury site [32]. In the experimental applications
on rats, successful regeneration through a 10 mm gap was observed at 8 weeks
after operation. In another study, a PLA nerve conduit was made by immersion
precipitation to bridge a 20 mm long gap in an animal nerve transection model
[33]. The researchers reported that the functional recovery after 18 months was
about 80%, based on electrophysiology and behavior analysis. PLA conduits
grafted with FGF1 (fibroblast growth factor 1) and chitosan–nano-Au (gold) after
plasma activation showed the greatest regeneration capacity and functional recov-
ery when they were tested for their ability to bridge a 15 mm critical gap defect in
a rat sciatic nerve injury model.
7.5.3 PLLA
PLLA is a highly crystalline and stereoregular form of PLA. Researchers reported

that PLLA nerve conduits modified with laminin-derived AG73 peptides and a
PEG (polyethylene glycol) containing an outer layer are effective for preventing
the adhesion of surrounding tissue [34]. In one experimental study, a PLLA nerve
conduit was fabricated by extrusion and was used in a 10 mm sciatic nerve defect
model in rats [35]. As a result at 16 weeks, the nerve fiber density in the distal
sciatic nerve repaired with the PLLA conduits was similar to that repaired with
control isografts. The research group found also an increased axon number and
nerve fiber density in the PLLA mid-conduit compared with control isograft at
16 weeks.
7.5.4 PLGA
PLGA (poly(lactic-co-glycolic acid)) has been the most frequently used biodegrad-
able polymer in tissue engineering for fabricating porous foams for biomedical
applications. PLGA is a co-polyester that has been evaluated extensively as a nerve
guide material due to its ease of fabrication, approval by the FDA, and low inflam-
matory response it created [7]. In an earlier experimental study, PLGA conduits
with longitudinally aligned channels were produced by using a combined thermally
induced phase transition technique and injection molding [36]. Macropores were
organized into bundles of channels up to 20 μm wide in the PLGA matrix, which
then was used as a nerve conduit.
7.5.5 PCL
PCL (poly (ε-caprolactone)), another polyester, has high solubility in organic sol-
vents and low melting temperature (55–60 °C) and glass transition temperatures
(−60 °C) [26]. Oliveira et al. fabricated PCL conduits for regeneration of transected
mouse median nerves and investigated the effect of transplanted MSCs (mesenchy-
mal stem cells) on nerve regeneration by seeding MSCs on the PCL nerve conduits
before grafting [37]. The animals treated with MSCs had a significantly larger num-
ber of regenerated unmyelinated and myelinated nerve fibers and blood vessels
compared to the control group, indicating the possibility of improving regeneration
and function of median nerve after a traumatic lesion.
7.5.6 Poly(D,L-lactide-co-ε-caprolactone)
Poly(D,L-lactide-co-ε-caprolactone) is a copolymer of caprolactone monomers and

lactic acid. Cylindrical poly(D,L-lactide-co-ε-caprolactone) 80/20 copolymer nerve
conduits were fabricated by using an ink-jet system in an experimental study [6].
Radulescu et al. found that hNGF-EcR-293 cells could be genetically modified to
deliver NGF (nerve growth factor) in vitro and in vivo to support the local neurore-
parative factor delivery via a tightly controlled system [38]. They demonstrated that
these cells could attach and survive for more than 8 weeks when cultured on the
80/20 PLA-PCL copolymer but failed to attach and died on 25/75 and 40/60 PLA–
PCL copolymer used. In another study by Chiriac et al., the Neurolac™ nerve con-
duit was tested in a clinical setting on 28 nerve lesions on various sites: arm, elbow,
forearm, wrist, palm, and fingers with an average defect length of 11 mm [39]. After
an average of 21.9 months of follow-up (3–45 months), subjective criteria (cold
intolerance and pain) and objective criteria (strength) were compared with the con-
tralateral side. Grip strength averaged 64.62% of the contralateral side. The research-
ers observed eight complications, the most serious being two fistulizations of the
Neurolac™ device close to a joint and one neuroma formation. All in all, it was
concluded that the use of Neurolac™ in repairing hand nerve defects cannot be
considered very effective.
7.6 Proteins with Synthetic Biomaterials
Proteins such as collagen are natural polymers. The blends of natural polymers with
synthetic polymers are considered as hybrid structures. Schmauss et al. analyzed the
nerve regeneration of their patients after reconstruction with collagen nerve conduits
terminated after 12 months [40]. The researchers examined 20 reconstructed nerves
in 16 patients with a mean follow-up of 58.1 months (range, 29.3–93.3 months).
They found an improved sensibility at current follow-up compared with the 12-month
follow-up in 13 cases. Three cases had the same values, whereas four cases had wors-
ened sensibility. Improvement of sensibility was associated with a significantly
shorter nerve gap length with significantly better results if the gap length was
<10 mm. In another prospective cohort study, the clinical use of artificial nerve con-
duits for digital nerve repair was presented [41]. The researchers presented their
clinical experiences based on a review of the outcome and techniques in the current
literature. Fifteen digital nerve lesions in 14 patients have been overcome by interpo-
sitional grafting of a hollow collagen I conduit. A follow-up of 12 months could be
guaranteed in 12 cases. The mean nerve gap was 12.5 ± 3.7 mm. Four out of 12
patients, assessed 12 months postoperatively, showed excellent sensibility (S4). Five
patients achieved good sensibility, one poor, and two no sensibility. Lohmeyer et al.
presented a prospective two-center cohort study on digital nerve reconstruction with
collagen nerve conduits [42]. The data were put into the context of a comprehensive
review of existing literature. Over a period of 3 years, all consecutive digital nerve
lesions that could not be repaired by tensionless coaptation with a gap length of less
than 26 mm were reconstructed with nerve conduits made from bovine collagen
I. Sensibility was assessed 1 week and 3, 6, and 12 months postoperatively by static
and moving 2-point-discrimination (2PD) and monofilament testing. Forty-nine digi-
tal nerve lesions in 40 patients met the inclusion criteria. The mean nerve gap was
12.3 ± 2.3 mm (span 5–25 mm). Forty nerve reconstructions could be included in the
12-month follow-up. Three cases, assessed 12 months postoperatively, showed
excellent sensibility (static 2PD < 6 mm). Seventeen achieved good (2PD 6–10 mm),
5 fair (2PD 11–15 mm), 6 poor (2PD > 15 mm, but protective sensibility), and 9
achieved no sensibility. Monofilament test results were significantly better if gap
length was shorter than 12 mm. Boeckstyns et al. demonstrated in a prospective ran-
domized trial with 43 patients the reparation of the ulnar or the median nerve with a
collagen nerve conduit or with conventional microsurgical techniques [43]. As a
result, use of a collagen conduit produced recovery of motor and sensory functions
that were equivalent to direct suture 24 months after repair when the nerve gap inside
the tube was 6 mm or less.
7.6.1 N
ondegradable Nerve Conduits: Silicone, Plastic,
and Polytetrafluoroethylene Tubes
The silica gel canal was the earliest artificial conduit described in 1982 [44].
Nondegradable nerve conduits generally eliminate the need to harvest autologous
nerves. But nondegradable nerve conduits always cause compression of the regen-
erating nerve that could negatively affect axonal regeneration, and they often cause
inflammation of the surrounding tissues. Furthermore, these types of conduits
require a second surgery for their removal, which could cause more injury to the
patient and pain.
7.6.2 Degradable Nerve Conduits
The commonly used degradable materials include chitosan, collagen, polyglycolic

acid conduit, glycolide trimethylene carbonate conduit, polylactic acid conduit,
polycarbolacton conduit, natural collagen, and hydrogel conduit [45].
Researchers are enthusiastically investigating new biodegradable materials with
excellent chemical and physical properties. Biodegradable collagen and chitosan
collagen tubes were proved to promote the growth of axons. During the last 25 years,
studies on chitosan as a biomaterial for nerve tissue engineering applications have
been intensified [46].
Chitosan, a polysaccharide, which is industrially produced (hydrolyzed) from
chitin, due to its high biocompatibility and stimulating influence on natural healing
processes is of particular interest for use as nerve conduit. So far, conducted animal
studies showed that the chitosan due to the bioactive properties supports nerve regen-
eration [45, 46]. The positively charged biopolymer interacts with negatively charged
biomolecules and cellular components, thus promoting the restoration of the nerve
continuity. Chitosan – thanks to its anti-adhesive and antibacterial properties – also
ensures for a reduced formation of scar tissue and reduces the risk of infection.
Clinical trial results, however, for new product chitosan nerve conduits (Reaxon®
nerve guides) are still lacking. The researcher group of Haastert-Talini reported an
analysis of chitosan nerve guides (CNGs) enhanced by introduction of a longitudinal
chitosan film to reconstruct critical length 15 mm sciatic nerve defects in rats [47].
The investigations demonstrated that the CNGs (chitosan nerve guides) enhanced by
the guiding structure of the introduced chitosan film significantly improved morpho-
logical and functional results of nerve regeneration in comparison with simple hol-
low CNGs. In another study, Haastert-Talini et al. showed an analysis of chitosan
tubes used to reconstruct 10 mm nerve defects in rats [48]. Investigations were per-
formed demonstrating that the chitosan tubes allowed morphological and functional
nerve regeneration similar to autologous nerve grafts. Hollow biodegradable materi-
als can be used to repair only relatively short nerve defects, and the functional recov-
ery is still not satisfying. Neubrech et al. recently initiated a randomized double-blind
controlled multicenter trial in Germany including 100 patients with traumatic sen-
sory nerve lesions of the hand without a gap [49]. Patients will be randomized to
primary microsurgical repair of the injured nerve with the additional use of a chito-
san nerve tube or direct tension-free microsurgical repair of the injured nerve alone.
Furthermore, currently at three hospitals (BG hospitals) in Germany, again, a
prospective randomized study has been initiated in which the results of the applica-
tion of Reaxon® nerve guides will be examined. As participating clinic, we can
report here as a preliminary result that our short-term investigation after 6 months
demonstrates that the chitosan tubes allowed functional and morphological nerve
regeneration similar to autologous nerve grafts with a nerve gaps of 6–10 mm. This
suggests that similar to animal studies, chitosan nerve conduits support nerve cell
adhesion and neurite outgrowth in human patients.
7.7 Conclusions and Recommendations
It can be seen that the development of nerve conduits for peripheral nerve repair is
a highly sophisticated and active process. Both conduits and acellular allografts are
useful tools for dealing with short nerve gaps. The convenience of either one should
facilitate adequate nerve debridement and the avoidance of over tensioned repairs.
Though with time and mounting experience the recommended maximum repair
length of conduits seems to be decreasing while that of the acellular allograft seems
to be increasing, the critical gap sizes for either tool are not known. Autograft is still
the gold standard, but in the right situations, either conduits or acellular allograft
can achieve equivalent or at least similar results making them excellent options for
nonessential nerve repairs and something that should be at least considered for more
important nerves. Though autograft donor deficits or complications are typically
minimal or rare, significant problems can occur. The exact roles of both tools in the
nerve repair algorithm continue to be defined.
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Clinical Follow-Up
8
Gilda Di Masi, Gonzalo Bonilla, and Mariano Socolovsky
Contents
8.1 Sensorimotor Evaluations 99
8.2 Pain Evaluation 101
8.3 Global Scales 102
8.4 Post-operative Complications 102
8.4.1 Nerve Damage 102
8.4.2 Vascular Injury 103
8.4.3 Postoperative Bleeding 103
8.4.4 Wound Complications 104
8.4.5 Pain 104
Conclusion 105
References 106
Analysing the results of nerve repair is very important to compare the effectiveness
of different strategies and, thus, develop standardized guidelines for the manage-
ment and treatment of nerve injuries.
This analysis process can be extremely complex, since many different factors
influence functional recovery after peripheral nerve repair. Two of the most impor-
tant variables are the time between the injury and the surgery, and the level of repair.
The deleterious effect of time is widely reflected in the literature [6, 10, 22], no
matter which technique is employed during nerve reconstruction. Within 3 weeks of
denervation, muscle atrophy begins, and over the next 2 years, the muscle is almost
totally replaced by fibrous tissue. If the period to reinnervation of the main effectors
G. Di Masi (*) • G. Bonilla • M. Socolovsky (*)

Peripheral Nerve and Plexus Surgery Unit, University of Buenos Aires School of Medicine,
Hospital de Clínicas, Buenos Aires, Argentina
e-mail: gildadimasi@gmail.com; bonilla_gonzalo@hotmail.com;
marianosocolovsky@gmail.com

DOI 10.1007/978-3-319-52319-4_8
98 G. Di Masi et al.
exceeds 24 months, motor recovery will not be achieved due to irreversible muscle
fibrosis. This limitation does not exist for sensory recovery, however, which can be
expected even after delayed and high-level nerve repairs [19].
Patient age is another important factor that we must take into account. The results of
nerve repairs in children are better, because of their higher potential for axonal growing
and the shorter distances between the repair site and target muscle. The latency period
between the lesion and the onset of reinnervation is also less. However, there is no
distinct age threshold after which results suddenly become less favourable.
The mechanism of injury and severity of trauma also influence the outcome.
Nerve injuries caused by traction have a worse prognosis than other injuries like
stab wounds, because they affect large segments of the nerve. Associated bone frac-
tures, vascular injuries and soft tissue defects, all indicators of trauma severity, gen-
erate ischemia, perineural scarring and/or defects in effectors, all of which negatively
influence outcomes.
Certainly, the use of an appropriate surgical technique is essential to recovery. It
is well known that the best results are obtained with end-to-end anastomoses;
however, in most cases, using a nerve graft is necessary.
Graft length is another prognostic factor after the repair of large nerves (median,
ulnar, sciatic, etc.). However, during repair of the brachial plexus, in an analysis
conducted by the current authors, no differences were identified between using
nerve transfers with long grafts (>10 cm) and the reconstruction of primary trunks
with short grafts [24].
The importance of systematic rehabilitation is also well known. However, it is
not easy to quantify adherence to rehabilitation when the results of nerve repair are
analysed. The current authors have developed a scale for this purpose (Table 8.1).
Using this scale to analyse results in a series of patients with brachial plexus injuries
treated with long-graft nerve transfers, the fundamental role played by rehabilita-
tion in determining outcomes was evident [24].
Furthermore, functional outcomes repairing different nerves in comparable cir-
cumstances are not always the same. Numerous studies have been published describ-
ing better results after the repair of the radial nerve than the median or ulnar nerves;
there also is a better prognosis repairing the tibial versus peroneal nerve [11, 14].
To put treatment results in proper perspective, it is important to document these
aforementioned factors. This is especially important for interpreting and evaluating
the results of a specific treatment and, thereby, optimizing treatment strategies.
Table 8.1 The rehabilitation scale [24]

Score Description
1 No rehabilitation at all or less than once per week
2 Rehabilitation more than once weekly, but not at a specialized centre
3 Good progress with a comprehensive rehabilitation programme, but not in a specialized
centre; periodically supervised by a specialized neurorehabilitation centre
4 Patient adheres perfectly to the whole rehabilitation programme at a specialized
neurorehabilitation centre
8 Clinical Follow-Up 99
The degree of sensory and motor recovery is the criterion most commonly used
to evaluate the results of nerve repair. Sensory recovery is not a reliable sign of
regeneration, however, mainly because of its late appearance and difficulties with its
objective evaluation. However, it is important after the repair of particular nerves
like the median, ulnar and tibial nerve, as these provide protective sensation. It is
less important as an outcome following the repair of nerves like the radial, axillary,
musculocutaneous, femoral and fibular nerve.
On the other hand, although motor recovery is also late, it is a reliable sign of
successful regeneration. It takes between 2 and 3 years to achieve maximum motor
recovery, versus 5–7 years for maximum sensory restoration.
In general terms, the follow-up of any patient submitted to a peripheral nerve
reconstructive surgery should be every 2 or 3 months. Clinical evaluation – includ-
ing progression of Tinel’s sign – and serial neurophysiological studies can help
determine early recoveries. The regular endpoint of follow-up is around 3 years for
motor results and around five for sensory recovery. At that time, it is presumed that
the maximum recovery point will be reached. Of course it is not possible to general-
ize these time spans for every patient: depending on the time from trauma to sur-
gery, the distance from the injury site to the target muscles/skin, the type of
reconstruction and so on, the end of follow-up variates from patient to patient.
One important concept to keep in mind when analysing the results of nerve repair
is that of ‘useful recovery’, which entails the functional impact of recovery. The
definition of ‘useful’ is variable and depends on the nerve involved. For example,
useful sensory recovery for the tibial nerve means recovery of superficial pain and
some tactile sensation (≥S2). However, for the median or ulnar nerve, it is also
imperative to recover some two-point discrimination.
Similarly, useful motor recovery (≥M3) after peroneal nerve repair involves plantar
dorsiflexion to 90°, since this is enough for the patient to stop using a foot brace [19].
A variety of scales and questionnaires have been developed and published to
objectify these results. They may be categorized according to the function they eval-
uate: motor, sensory, pain or global.
8.1 Sensorimotor Evaluations
The scale most commonly used to assess sensorimotor reinnervation is the British
Medical Research Council (BMRC) scale [15] (Tables 8.2 and 8.3). This scale was
promoted and standardized after the Second World War in order to eliminate or
Table 8.2 British Medical M0 No contractions

Research Council motor
M1 Visible or palpable contractions
scale [12]
M2 Active movement, with gravity eliminated
M3 Active movement against gravity
M4 Active movement against resistance
M5 Normal power
Table 8.3 British Medical Research Council sensory scale [12]

S0 Absence of sensation
S1 Recovery of deep cutaneous pain sensation
S2 Recovery of superficial pain and some tactile sensation
S2+ Same as S2, with overresponse
S3 Recovery of pain and tactile sensation, with disappearance of overresponse
S3+ Same as S3, with some two-point discrimination
S4 Complete recovery
reduce interobserver variability. The motor and sensory components are not inte-
grated, actually operating as two separate scales. The widely used motor scale can
be used to evaluate either bulky muscles or muscle groups or small muscles like the
intrinsic muscles of the hand. On the other hand, the sensory scale has been criti-
cized [20] as being based on subjective parameters.
Tools exist to help us to quantify these results. The goniometer is used to evaluate
active range of motion, and the dynamometer to measure muscle strength. The
tested limb should always be compared with the contralateral limb (if normal).
The grip strength test (using a Jamar dynamometer) is the method most often
used to communicate motor strength results.
Similarly, there are tools to quantify sensory results. The Semmes-Weinstein
monofilament test can be employed to assess cutaneous pressure threshold.
Compared to using a classical tuning fork, this test provides quantitative data that
can be used to monitor nerve regeneration.
The two-point discrimination (2PD) test is a tool for evaluating tactile gno-
sis. Tactile gnosis is the hand’s ability to recognize the characteristics of differ-
ent objects, like their shape and texture. It is an important marker of functional
recovery. One major flaw this test has is that the results can be variable, since
there is no standardization of the technique, and different examiners perform
the test differently. For this reason, it is important to provide a detailed descrip-
tion of the protocol used, especially the pressure applied. It also is not recom-
mended that this test be used as the sole instrument to measure sensory
function.
The shape/texture identification (STI) is a test developed by Rosen and Lundborg
that consist of identifying three forms and three textures, with the index finger in
median nerve injuries and the little finger if the ulnar nerve is affected. In patients
with injury to both nerves, the index finger is assessed.
The Sollerman hand function test consists of 20 activities that replicate the main
handgrips utilized in daily life, such as taking coins from a purse or undoing but-
tons. Each subtest has a score depending on the quality of handgrip and the diffi-
culty the patient has performing the task. This test reflects the integration of sensory
and motor functions.
8.2 Pain Evaluation
The numerical rating scale (NRS) for pain and the pain visual analogue scale
(PVAS) are often used to determine pain intensity. Both are easy to apply but have
flaws. First, they treat pain as a linear and continuous phenomenon, which is not so
in most cases. On the other hand, not all patients respond to these scales the same
way, since the experience of pain is very variable.
The McGill Pain Questionnaire [16] is a multidimensional scale that provides
information not only on the intensity of pain but on other characteristics like sensa-
tion quality (e.g. sharp, pins and needles) and the patient’s emotional response to
pain. However, it is too long a questionnaire to readily integrate into daily clinical
practice.
The Integrated Pain Score scale [2] (Table 8.4) allows us to record, over time,
the characteristics and intensity of pain. Since it is simple and quick, it allows
Table 8.4 Integrated pain score [2]

Parameter Description PTS Sum
Intensity (VAS) 0–10 ✓
Incapacity 0–10 ✓
Frequency of pain Never 0 ✓
Rarely 1
Once a day 2
More than once a day 3
Continuous 4
Use of pain medication Never 0 ✓
Occasionally 1
Once a day 2
More than once a day 3
All the time 4
No alleviation 1 ✓
Zones affected by pain Distal 1 ✓
Medial 1 ✓
Proximal 1 ✓
Sleep Normal 0 ✓
Awakens only some nights 1
Awakens once every night 2
Awakens more than once 3
every night
Insomnia 4
Use of hypnotics 1 ✓
Total ✓
patients to be monitored successively before and after surgery. It separately

analyses pain intensity and frequency, degree of disability, the use of analgesics,
number of territories involved (proximal, middle or distal) and the effects of pain
on sleep.
8.3 Global Scales
The Rosen scale was developed to allow for the documentation and quantification
of functional outcomes after nerve repair at the wrist or distal forearm [21].
It includes three domains: sensory, motor and pain/discomfort. Motor function is
assessed using the MRC scale and grip strength test (with a Jamar dynamometer).
The evaluation of sensory function employs Semmes-Weinstein monofilaments, the
2PD to evaluate tactile gnosis, and the STI test. Pain/discomfort is evaluated using
a scale with four grades (0–3) to categorize hyperesthesia and intolerance to cold.
The disability of arm, shoulder and hand (DASH) outcome questionnaire is an
instrument developed specifically to assess results in the upper limb. It was intro-
duced by the American Academy of Orthopaedic Surgeons in collaboration with
other organizations. It is mostly a measure of disability. One of the objectives behind
its development was to facilitate comparisons between different disorders affecting
the upper limb. It is currently available in several different languages, including
English, German, Italian, Spanish, Swedish, French and Dutch. It consists of a
30-item questionnaire addressing the patient’s health status over the preceding week.
Individual items ask about the patient’s difficulty performing various physical activi-
ties due to problems in their shoulder, arm or hand (20 items); the severity of symp-
toms like pain, pain related to activity, tingling, weakness and stiffness (five items);
and the impact these symptoms exert on social activity, work, sleep and self-image
(four items). Each item has five possible answers. The final score ranges from 0 (no
disability) to 100 (severe disability). According to a study by Gummesson et al. [9],
this questionnaire can detect both small and large changes in disability over time
post-operatively in patients with musculoskeletal disorders of the upper limb.
The Michigan Hand Outcomes Questionnaire (MHQ) consists of 37 items that
evaluate disability across six domains: function, activities of daily living, pain, hand
appearance, patient satisfaction and disability at work.
8.4 Post-operative Complications
8.4.1 Nerve Damage
Nerve damage during surgery on peripheral nerves is uncommon. The main cause
of this type of unintentional injury is the surgeon’s unfamiliarity with the regional
anatomy accessed. There is also the possibility of so-called anatomic variants,
which must be taken into account during any procedure, since failure to recognize
such deviations from ‘normal’ can lead to the injury of such structures.
The anatomy of the lower limb has a lower percentage of anatomical variants
than the upper limb. One example of an anatomical variant in the upper limb is the
recurrent branch of the median nerve, which, though always present, can vary in its
location and occasionally be damaged if not recognized.
The nerves most often injured are the median nerve, the ulnar nerve, the digital
nerves and communicating branch between the median and ulnar nerve (Berretini’s
branch or anastomosis). Many nerves are susceptible to damage, like the palmar cuta-
neous branch and the motor branch of the median nerve, the external digital nerve to
the fourth finger and the common digital nerve for the third and fourth finger [8].
Fibrosis of the median nerve, both intra- and perineural, can result from chronic
compression and be secondary to surgery [29]. Fibrosis of this nerve frequently
causes highly annoying dysaesthesias, intense local pain and local skin hypersensi-
tivity. In these cases, neither internal nor external neurolysis is indicated, since it has
not been demonstrated that good results are obtained with these techniques.
8.4.2 Vascular Injury
During virtually every surgery, an anatomical region with blood vessels is

approached. The location of these vessels, as with major nerves, tends to be ana-
tomically constant; however, collateral branches can vary significantly. Obviously,
the severity of the vascular insult and resulting bleeding and ischemia depends upon
the size and status of the vessel involved: injury to a major arterial branch is of much
greater concern than injury to a fourth-order branch or distal vessel.
During surgery to peripheral nerves, we sometimes elect to ‘forget’ distal vessels
that cross our surgical field, thereby rendering the nerve dissection more difficult.
We can sometimes afford to do so thanks to collateral circulation that permits us to
section such vessels without significant consequences. Before doing this, however,
we have several things to determine, like whether or not collateral circulation actu-
ally exists; whether the vessel might be used in some other reconstruction procedure
like a free vascularized graft; and whether the calibre and flow of the vessel are too
great to allow for adequate spontaneous coagulation, so that it becomes necessary to
use vascular clips to prevent post-operative bleeding [18].
Vascular injury may occur even during seemingly simple nerve surgeries, like
carpal tunnel decompression. For example, if we extend the opening of the carpal
ligament distally, we can injure the superficial and/or deep palmar arches that pro-
vide circulation to the fingers [25].
8.4.3 Postoperative Bleeding
Bleeding is a common complication of all types of surgery. In the case of nerve

surgery, it is rare if all haemostatic measures are taken in each plane of dissection.
Compressive haematoma formation is highly unusual but can result from
increased blood pressure post-operatively. Both blood pressure and the presence of
haemorrhage must therefore be monitored closely; and if a local haematoma

increases in volume to a point at which there is a risk of ischaemia with further
enlargement (e.g. compartment syndrome), immediate intervention is necessary to
stop the bleeding [27].
With mild bleeding, there is some risk of adhesion formation or flanges that can,
in the long term, cause nerve compression associated with different symptoms like
paraesthesia, hypoesthesia and pain.
8.4.4 Wound Complications
8.4.4.1 Wound Dehiscence

When planning any surgery, it is important to consider which skin incision to use,
because it not only has an aesthetic but legal connotations, sometimes leading to
legal claims.
It also should be considered during planning that previous scars might alter skin
circulation. The patient’s metabolic state is important too, since diabetes may alter
normal healing, and patients with hypoproteinaemia take longer to heal their
wounds. Another important issue is the presence of skin folds; for example, with
carpal tunnel surgery, the skin incision should not cross the transverse folds of the
wrist, as this can lead to the formation of a hypertrophic scar or keloid [7]. Six
months after surgery, only 2% of patients still have tender scars. When a post-
operative patient presents with a painful hypertrophic scar, surgical revision may
become necessary, even performing a Z-plasty to avoid new hypertrophic scarring
and associated discomfort.
8.4.4.2 Wound Infection

As with bleeding, wound infections are common to all types of surgery. The inci-
dence of superficial skin infections reported in the literature is between 0.5% and
6% for carpal tunnel surgery. Deep infections have also been reported after surgery
for carpal tunnel syndrome. Risks for deep infections include the use of drains,
prolonged surgery and performing a synovectomy of carpal tunnel tendons [23].
8.4.5 Pain
The patient who presents with a traumatic peripheral nerve injury associated with
pain must report certain features for the pain to actually be ascribed to the injury. In
the first place, discomfort should be felt in the distribution of the affected nerve
[26]. Additionally, the area should experience anaesthesia or sensory loss, as it is
rather unlikely for someone to feel pain originating from an injured nerve without
some tactile alterations, regardless of whether the anaesthesia is complete or partial.
In general, pain is described as a burning sensation, as an electric shock or as a very
annoying tingling. Quite often, pain is triggered by stimuli that would otherwise be
non-painful, such as gentle touch (allodynia) [3, 4]. On clinical examination, there
may be autonomic changes in the distribution of the nerve, albeit slight and unlike
those of the reflex sympathetic dystrophy mentioned below. As well, the patient
may have a positive Tinel’s sign, which the examiner can elicit by percussing
directly over the proximal end of the nerve. In doubtful cases, it may be useful to
perform a nerve block with local anaesthetics to confirm the diagnosis [28].
The most important differential diagnoses for neuropathic pain are the com-
plex regional pain syndromes (formerly known as reflex sympathetic dystrophy)
[17, 30]. In these patients, pain initially is acute and dysaesthetic, often felt as a
burning sensation, distributed distally, and associated with exaggerated responses
of the sympathetic nervous system (e.g. sudden flushing and increased sweating
immediately followed by pallor and limb coldness). Sympathetic blockade helps
to confirm the diagnosis and initially provides a certain degree of therapeutic
relief. Long-term control is difficult, however, because the pain tends to be
chronic.
After it has been determined that the pain is due to an injured nerve, medical
treatment should be administered. One of the most commonly used drugs (and pre-
ferred by the current authors) is gabapentin, starting at a daily dose of 600 mg, usu-
ally plateauing at about 1800 mg, but with a maximum allowable dose of 3600 mg
daily. Amitriptyline, carbamazepine, and ultimately pregabalin are other drugs that
are commonly used to treat neuropathic pain. Other alternatives, like non-steroidal
anti-inflammatory drugs and electrostimulation [13], have proven useful in some
cases.
With patients for whom medical treatment is insufficient to alleviate symptoms,
there are two initial surgical options. First, if the nerve is small, superficial and pre-
dominantly sensory, as is the case with the sensory branch of the radial or sural
nerve, it can be directly resected proximal to the injury. With sectioning of the nerve,
the pain disappears at the price of cutaneous anaesthesia in the area supplied by the
peripheral nerve sectioned; almost always, this is well tolerated. This section should
be done, if possible, 15–20 cm proximal to the affected area [1]. On the other hand,
if the nerve cannot be sacrificed, as with the greater sciatic nerve, then neurolysis or
reconstruction with a graft, depending on the severity of the injury, is the treatment
of choice [5]. The right time to perform any of these procedures depends on the
pain’s response to drugs. However, it is generally agreed that a traumatized nerve
that generates pain should be surgically explored if it does not respond to pharma-
cological treatment within a reasonable time frame, not to exceed 45 days [12].
Conclusion
Clinical follow-up in peripheral nerve surgery greatly varies depending on the
time and site of the primary injury, among many other factors that influence the
outcome. Several scales exist, designed to measure the final outcome of a nerve
reconstruction, which is of paramount importance when comparing different
techniques. At present, there is not consensus towards this point, and different
departments use a different way to determine their results. Hopefully, this prob-
lem will be solved in the future if a unique method to evaluate results is
employed.
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Rehabilitation Following Peripheral
Nerve Injury 9
Sarah G. Ewald and Vera Beckmann-Fries
Contents
9.1 Introduction 109
9.1.1 Site/Level of Injury 110
9.2 Rehabilitation 110
9.2.1 Evaluation Methods 111
9.2.2 Rehabilitation: Considerations and Methods 113
Conclusion 123
References 124
9.1 Introduction
The impact of a peripheral nerve injury (PNI) on an individual’s function ranges

from moderate and temporary to significant and life changing, depending upon the
severity and location of the injury and patient-specific factors. The functional loss
that results from a PNI can be sensory, motor or sensory, and motor in nature. The
quality of life (QoL) for these patients is substantially reduced with approximately
25% of patients still out of the workforce 1.5 years after surgery (as cited by Davis
et al. [5]). Not only do patients lose function, unfortunately they may also gain
S.G. Ewald, OTR, MA Ed (*)

City Handtherapie, Stampfenbachstrasse 42,
CH-8006 Zurich, Switzerland
e-mail: sgewald@city-handtherapie.ch
V. Beckmann-Fries, PT, MME
UniversitätsSpital Zürich, Physiotherapie Ergotherapie/Handtherapie,
Gloriastrasse 25, CH-8091 Zurich, Switzerland
e-mail: vera.beckmann-fries@usz.ch

DOI 10.1007/978-3-319-52319-4_9
110 S.G. Ewald and V. Beckmann-Fries
function in the form of persistent pain, hyperesthesia, hyperalgesia, or allodynia.

Rehabilitation following injury to a peripheral nerve is essential to optimize func-
tion and outcomes. Clinical studies have demonstrated that patients that receive
hand therapy tailored to their needs have better outcomes, for example, for sensory
function, than patients that do not receive treatment [3, 17]. Rehabilitation of PNI in
the upper extremity is performed by occupational and physical therapists; many of
these therapists have the additional qualification of “hand therapist,” which indi-
cates additional training in this specialty practice area of both professions.
Worldwide, there are about 8500 therapists that practice “hand therapy” [9]. The
hand therapist tailors the treatment in response to the functional loss that the patient
presents with. Not only functional loss will be addressed in therapy. The so-called
gain in function, mainly in sensory input as hyperesthesia, hyperalgesia, or allo-
dynia, will be addressed in therapy as well. Thus, the course of therapy may be
highly variable between patients: some need functional therapy and intense sensory
rehabilitation, and for others afflicted with intense pain, pain treatment and educa-
tion about pain management will be given a greater priority in therapy.
9.1.1 Site/Level of Injury
In general, the more proximal the injury, the greater the impact is on function. A
brachial plexus injury is a severe and devastating injury requiring in most cases
multiple surgeries and a prolonged course of rehabilitation. A more distal injury at
the level of the wrist still impacts function significantly and may have life-changing
implications. For example, an injury resulting in a laceration of the median and
ulnar nerves at the level of the wrist results in loss of sensation and partial loss of
motor function in the hand. Loss of sensation in the hand significantly impacts hand
dexterity and overall hand function and can result in further injury to the hand due
to the lack of protective sensation. In comparison, laceration of the radial nerve at
the level of the wrist results in the lack of sensation on the dorsum of the hand, and
motor function remains intact. As the dorsum of the hand is less directly involved in
tasks that require dexterity, the loss of this sensation, while surely an irritant, has
less impact on overall function. However, laceration of the sensory branch of the
radial nerve can develop as possible source of persistent pain [8].
This chapter will focus on the rehabilitation process for peripheral nerve injuries
that occur distal to the brachial plexus/mid-humerus in the upper extremity.
9.2 Rehabilitation
Following PNI, it is recommended that a patient be referred as early as possible for

therapy [17, 26]. The rehabilitation program is designed and implemented by the
therapist after careful evaluation of the patient and his/her condition and functional
9 Rehabilitation Following Peripheral Nerve Injury 111
level. As the patient progresses, evaluation is ongoing, and treatment is continu-

ously adapted and modified in response to evaluation results; this occurs in all
phases of rehabilitation.
9.2.1 Evaluation Methods
The therapist’s assessment of the patient is comprised of a variety of evaluation

methods and tools. The multifactorial evaluation helps the therapist gain a clear
picture of the functional impact of the injury and the patient’s needs. It also provides
a baseline against which progress or lack thereof can be measured. An overview of
evaluation tools frequently utilized by hand therapists when assessing patients with
PNI can be found in Table 9.1. The results of the evaluation guide the development
of the therapy program and often motivate the patient to continue with exercises.
The therapist evaluates not only motor and sensory function as components of body
function but also the patient’s activity and participation levels. Incorporating the
International Classification of Functioning, Disability and Health (ICF) with its bio-
psychosocial model and classification system into the evaluation process is advanta-
geous as it offers all members of the health-care team a common framework when
viewing the patient and his or her individual situation.
For example, evaluation of range of motion, strength, and sensory function cer-
tainly help to determine levels of biomechanical function and impairments, but this
does not translate into an assessment of overall functional status in multiple life
domains of the patient. It is important to consider the psychosocial factors such as
coping, depression, and anxiety as well. The rehabilitation process should also
focus on improvements in quality of life (QoL) and function in daily living. There
is a “need for increased screening and assessment of factors that reach beyond the
biomedical model” [28]. Figure 9.1 illustrates the multiple factors that can impact
the outcome for a patient with a PNI. While many of the factors are a given such as
age and cognitive capacity, some of them can be influenced during the rehabilita-
tion process.
A multicentered prospective study in the Netherlands [11] found that sensibil-
ity of the hand, grip strength, and the disabilities of arm, hand, and shoulder
(DASH) questionnaire score were the best prognostic factors for functional recov-
ery after peripheral nerve injury (median and/or ulnar nerve) at the level of the
forearm. The Rosén Score, developed for median and ulnar nerve injuries at the
level of the forearm, is a helpful prognostic tool for surgeons, therapists, and
patients [20, 21, 25, 27].
The therapist’s evaluation is ongoing and essential for her clinical reasoning pro-
cesses and planning therapy. Once the initial evaluation has been completed, treat-
ment is implemented. The treatment plan is customized to the needs of the patient,
and the therapist will make use of many tools, methods, and approaches in an effort
to treat the patient at a very individual level.
Table 9.1 Evaluation tools used by therapists

Evaluation tools
Objective measure Subjective measure
Rating
To be evaluated Test Prognostic tool scales Questionnaires
Pain and cold Rosén Score – a Visual McGill Pain
sensitivity tool to assess analog Questionnaire
functioning and scale
pain of patients (VAS)
suffering from Numeric Cold Sensitivity
median and/or rating Severity (CSS)
ulnar nerve scale Cold Intolerance
laceration at wrist (NRS) Symptom Severity
or distal forearm (CISS)
level
Motor Reflexes
function Manual muscle
testing
Grip and pinch
strength testing
with dynamometer
and pinch gauge
Sensory Two-point Ten test
function discrimination
(2PD)
Semmes-Weinstein
monofilament
testing (SWM)
Modified Moberg
pickup test
Shape/texture
identification (STI)
test
Grating domes
Localization of
touch (as
locognosia test)
Functional use Activities of daily Disabilities of arm,
of hand living (ADL) hand, and shoulder
requires motor checklist (DASH) or
and sensory 9-Hole Peg Test QuickDASH
function Functional Canadian
Dexterity Test Occupational
(FDT) Performance
Purdue Pegboard Measure (COPM)
Test Michigan Hand
Jebsen Taylor Test Questionnaire
of Hand Function (MHQ)
Sollerman hand
function test
Quality of life Short Form 36
(SF-36)
Sense of Antonovsky’s short
coherence 13-item scale
Biological Factors
- Age
- Extent of Injury (additional structures involved)
- Cognitive Capacity and Function, etc.
Individual Factors
- Personality Environmental Factors
- Motivation - Therapy
- Sense of Coherence - Life Situation
- Goal Orientation - Family and social support, etc.
- Adherence to Therapy, etc.
Fig. 9.1 Influences on outcome after PNI
9.2.2 Rehabilitation: Considerations and Methods
The therapeutic approach is multimodal and may include treatment to decrease pain
and edema, the use of custom-made or prefabricated splints, instruction in adaptive
methods to improve function in day-to-day life, and facilitation of motor relearning
and sensory reeducation. Nerves recover slowly after laceration and repair, notably
at the rate of 1–3 mm per day after a 2–3-week latency period [6], and a prolonged
course of therapy is usually required. The frequency of therapy may vary consider-
ably depending on the nerve that is injured and the subsequent impact on the
patients’ function and the phase of recovery. The focus of therapy in the initial
phase, defined as the early postoperative phase, is on protecting the injured struc-
tures, reduction of postoperative swelling, pain management, maintaining function
in adjacent noninjured structures, preserving cortical representation, and improving
the level of function in daily activities.
As the patient progresses to the innervation phase, therapy focuses on regaining
motor and sensory function and reintegrating this function into the overall function
of daily living. Pain management or addressing sensory gain of function as hyper-
esthesia may still be a treatment aim. The patient may require splints that balance or
support muscle function in the hand. At each step of the recovery process, it is
important that patients are given tools and instructions that allow them to participate
fully in the process and facilitate their recovery. A well-designed home program is
essential at every step of the rehabilitation process. The program should be reevalu-
ated and adjusted at regular intervals. Effective rehabilitation makes use of the
patients’ resources and abilities during each of the recovery phases. It is beneficial
for a patient to attend therapy at regular intervals to monitor progress and adapt the
home program. For some patients, once the home program is established, it may be
sufficient for therapy visits to take place on a weekly or even monthly basis.
Recovery may be prolonged, and periods of intensive therapy are required when
treatment is initiated and periodically in response to changes or additional surgery.
In this section, we will describe some of the tools and methods used in therapy to
achieve these aims.
9.2.2.1 Postoperative Swelling and Protection of the Sutured Nerve

Postoperative swelling is to be expected and is treated much the same as for any
other injury, that is, with positioning, elevation, manual edema mobilization, and
compression. An initial period of protection following the operative repair of the
nerve is recommended [6, 22]. In the initial phase of therapy, therapists protect
the repaired nerve with splinting or bandaging. The surgeon in charge defines the
period of protection; it depends on the location of the injury and how much ten-
sion there is on the repair site. While it is important to protect the repair, to limit
the expected side effects on non-involved tissue and joints, it is advisable to
immobilize the fewest joints and soft tissues possible without compromising the
repair [14].
9.2.2.2 Pain Management

“Pain has been defined as a multidimensional experience consisting of sensory-
discriminative, affective–motivational, and cognitive–evaluative components” [24].
After peripheral nerve injury, pain is to be expected, and it is a priority to address all
aspects of pain as early as possible in the course of treatment. Strategies for pain
management are manifold, as shown in Table 9.2.
Some patients develop neuropathic pain after peripheral nerve injury. Pain
management for these patients is of utmost importance and includes the previ-
ously mentioned strategies; additional psychological support must be consid-
ered. It is recognized that neuropathic pain is associated with a poor outcome
and high levels of disability [16]. Patient outcomes, such as level of pain, dis-
ability, and patient satisfaction, are influenced by psychosocial factors, such as
depression, coping, and anxiety [28]. It is therefore paramount that the thera-
pists assess and address these psychosocial factors as part of the rehabilitation
process.
Table 9.2 Overview of pain management methods used in hand therapy following peripheral
nerve injury
Management used Aim
Positioning the affected body part Prevention of secondary harm through mal
positioning
Sensory input Providing positive, comfortable sensations
Thermal modalities Decrease of muscle tone proximal to the injured
side and/or positive comfortable sensations
Transcutaneous electrical nerve Triggers the gate and opiate systems for pain
stimulation (TENS) modulation
Graded motor imagery (which includes Maintain and/or reawaken cortical representation
mirror therapy)
Providing information about injury, pain Improve patient’s ability to cope with and
mechanism, coping strategies self-manage pain
9.2.2.3 Scar Optimization

As with any other type of injury, it is important that the scar be as mobile, flexible,
and esthetically appealing as possible. To this end, the therapist may employ scar
massage, taping, electrophysical modalities, and in some cases the use of silicone
with compression dressings [2]. Patients can be instructed to perform daily scar
massage as part of their home program. The use of silicone dressings for scar treat-
ment is to be avoided if there is a problem with gain of function: hyperesthesia,
hyperalgesia, or allodynia. In our experience, the silicone dressing is often so com-
fortable for the patient that as sensation returns, which is often quite uncomfortable,
the patient may refuse to discontinue the use of the dressing and the hypersensitive
area thus becomes even more uncomfortable.
9.2.2.4 Improving Function and Activities of Daily Living

Gaining functional use of the extremity and overall function in day-to-day life is
ongoing. It is important that the extremity be integrated into any activity as much as
possible. This may mean the injured extremity can only be used initially to stabilize
objects, while the uninjured hand performs the majority of the task. Maintaining
cortical representation for the injured extremity is essential, the brain is plastic and
remodels rapidly, and nonuse of the extremity will result in a cortical reorganization
[15], which may be challenging to remodel as recovery of the nerve and function
progresses. Not only cortical representation is very important, therapist must also
consider the mobility of torso and shoulder; if the upper extremity is not incorpo-
rated into daily tasks, the flexibility of the thoracic spine diminishes rapidly, result-
ing in unwanted side effects.
During therapy, the patient will be instructed in adaptive methods, and adaptive
equipment will be provided as needed to accomplish activities of daily living. As
patients’ needs vary depending on their living, work, and family situations as well
as their coping mechanisms, this process is highly individualized. The use of ADL
checklists and questionnaires such as the DASH can be very helpful in identifying
areas of function that can be improved upon with therapy.
9.2.2.5 Sensory Function and Reeducation

Initially, a nerve laceration results in an absence of sensation. When there is no
sensation present, it is easy to burn or cut the hand in the area that lacks sensation.
Patients must be taught to inspect the body area that lacks sensation on a daily basis
and to care for any injuries to this area carefully. It is important to use the hand to
maintain integration in body schema. The use of a body part that has no sensation is
quite challenging, it requires close visual control on the part of the patient, and this
is a skill that must be learned.
As the nerve recovers and sensory function resumes, in some cases, the patient
may experience an excess of sensation, so-called hyperesthesia, in the area where
sensation is recovering. This can be quite uncomfortable and result in protective
behavior and nonuse of the hand. In this situation, the therapist will instruct the
patient in a desensitization program. Desensitization uses materials, contact parti-

cles, and vibration to reduce the hyperesthesia of the affected body part [4, 29].
Frequent and regular application of stimulus, beginning with material that is just
tolerable to touch and progressing toward materials that are perceived to be more
noxious, is required to achieve the desired effect. Significant improvement in the
level of discomfort resulting from the hyperesthesia has been observed with a
6-week course of desensitization treatment [4, 10, 29]. Patients are instructed in a
home program that is monitored closely and adjusted regularly. Most patients see an
improvement within 1–2 weeks, although it may take several weeks of treatment
with the home program until feelings of hyperesthesia are sufficiently resolved to
allow the hand to be used freely.
It is critical to distinguish between hyperesthesia and allodynia. In the case of
allodynia, stimulation of the affected area must be avoided; classical desensitization
will exacerbate the perceived pain, not reduce it. Allodynia is part of neuropathic
pain; a different approach such as “somatosensory rehabilitation” as described by
Spicher [23] should be utilized.
Sensory reeducation following nerve injury must start as early as possible. In
patients for whom sensory reeducation was initiated early, discriminative sensation
was significantly better at 6 months than in patients for whom sensory training was
initiated when some sensory function had recovered [17, 19]. In the early phase
when no sensation is present, sensory reeducation may take the form of mirror ther-
apy. Mirror therapy utilizes a mirror, and the patient placed with the mirror perpen-
dicular at midline so that the injured hand is hidden from view behind the mirror and
the uninjured hand is viewed in the mirror and reflected as if it were the uninjured
hand. Rosén et al. [17] describe the following exercises for early sensory reeduca-
tion: initially the patient is instructed to view the uninjured hand in the mirror, then
to name the fingers on the hand while viewing the hand in the mirror, then to slowly
move the uninjured hand, and then to move both hands symmetrically. A partner can
be involved and asked to symmetrically gently touch both hands while the patient
observes in the mirror. It is thought that mirror therapy helps to maintain cortical
representation of the affected body area (Fig. 9.2).
Early sensory reeducation includes the use of the sensible hand for activity.
Patients should be encouraged to use their visual and auditory capabilities to pro-
cess information that is encountered by the hand. Two-handed activities, such as
shoe tying, peeling an orange, and opening a packet, should be encouraged when
motor function is present. When no motor function is present, the hand can assist
when positioned to stabilize objects during activity. These methods help maintain
cortical representation and integration of the affected area.
The perception of moving touch recovers earlier than static touch. As moving
touch begins to recover, the patient can be instructed in a simple home program that
can be done with a partner. The partner is instructed to use the tip of a pen to “draw”
different types of lines along the affected area. The patient is asked to identify the
type of line.
The next step in the course of sensory reeducation is made when the patient is
able to discern Semmes-Weinstein monofilament 4.31 or 4.56 [17]. With this level
Fig. 9.2 Mirror Therapy:

The patient is asked to
focus his attention on the
image in the mirror. The
mirror reflects the
uninjured hand as the
contralateral hand. The use
of a mirror in this manner
can be helpful for pain
reduction and is used in
early sensory reeducation
Figs. 9.3, 9.4, and 9.5 Image 3 Sensory Roll: Patient discriminates between four different sur-
faces of equal width. Image 4 identifying different types of materials. Image 5 discriminating
among different raised shapes on a sensory block
of sensation present, it is possible to begin more formal sensory retraining that

focuses on the identification and discrimination of different surfaces and forms.
Examples of these types of exercises are visible in Figs. 9.3, 9.4, and 9.5. In this
phase, it is essential to start with a small number of items and surfaces that can be
identified by the patient. These items and surfaces should be significantly different
from one another so that the patient has success. As the patient’s speed and accuracy
with identification improves, the difference in the surfaces and objects should
lessen. The objects and surfaces that are part of the sensory reeducation program are
refined continuously to challenge but also at a pace that allows the patient to suc-
ceed in completing the task. Sensory reeducation is challenging and requires intense
concentration on the part of the patient. It is recommended that a patient has a home
program and the training take place several times a day for short periods of time
(5–10 min). Recent innovations in sensory reeducation of the hand include the use
of selective temporary anesthesia at level of the forearm to enhance sensation in the
injured hand [13, 18].
9.2.2.6 Motor Function

After major peripheral nerve injuries, muscles innervated by the involved nerves
atrophy (Fig. 9.6) and undergo interstitial fibrosis, with initial weight loss of 30% in
the first month and 50–60% by 2 months. Approximately 4 months after laceration
and surgery, the muscle atrophy reaches a relatively stable state at 60–80% weight
loss. The likelihood of functional reinnervation of the affected muscles diminishes
within about 12 months. This is a consequent of the progressing fibrosis [12]. The
initial phase of treatment focuses on instructing the patient in passive range of
motion exercises to be performed daily to preserve joint mobility and prevent con-
tractures. As nerve function recovers and the muscle is reinnervated, active
Fig. 9.6 Intrinsic muscle

atrophy and contracture of
fourth and fifth finger
following ulnar nerve
injury
Fig. 9.7 Electrical
stimulation of denervated
muscles (post laceration of
N. ulnaris at wrist level)
exercises to encourage muscle function should be instructed, progressing from

gravity eliminated planes to resistive exercises that facilitate the development of
muscle strength and control. In some clinics, functional electrical stimulation
(Fig. 9.7) is used to maintain motor function in the absence of nerve function.
The electrical stimulation may prevent or delay some degree of muscle atrophy
[1]. However, the level of evidence in clinical studies for electrical stimulation of
denervated muscle is limited and based on small case series reports [16]. In our
experience, patients like this type of treatment, and the visual aspect of this therapy
should not be underestimated. The patient observes the muscles contracting and
actively experiences these movements. Maintaining or restoring normal motor pat-
terns is an important treatment goal. During the interval from of time from injury to
reinnervation, many patients develop compensatory movement patterns [16]. It is
sometimes quite a challenge to restore normal movement patterns once the compen-
satory movement has been established. Motor function is easier to implement in
everyday purposeful activity – but this requires functional sensibility. If the patient
has no sensation in his affected fingers, it is unlikely that he will use the affected
body part and integrate the reinnervated muscle functions. Motor functions underlie
the same principles of cortical reorganization as sensory functions. Elbert and
Rockstroh [7] coined the following phrases that we find useful when educating
patients about motor recovery: “practice makes perfect; use it or lose it; fire together,
wire together; you have to dream to achieve it.”
Recovering motor function is often supported with the use of custom-made or
prefabricated splints.
9.2.2.7 Splinting
Splints are used to protect a structure, prevent contractures, correct deformities,
enhance movement, and/or facilitate function. As splints to protect a structure can
be easily imagined, we will focus here on splints that enhance movement, facilitate
function, and prevent or correct deformities. Therapists are often challenged to
Fig. 9.8 Low profile splint for radial nerve injury
Fig. 9.9 Radial nerve splint with removal dynamic outrigger for finger extension
create a splinting solution that enhances function and is comfortable and acceptable
to the patient.
Splinting for Radial Nerve Injuries

Injury to the radial nerve above the elbow results in paralysis of the extensors of the
wrist and fingers, and as a result the flexors are unopposed. Finger flexion is possi-
ble but is now accompanied by wrist flexion as the wrist extensors are not working.
Grasping an object is possible but releasing the object with the lack of finger exten-
sor function becomes difficult. For smaller objects, it may suffice to relax the flexors
to release an object, but for larger objects, the lack of finger extensor muscle func-
tion will prevent release of the object. The function of the extensor muscles can be
replicated with splints. Both custom-made and prefabricated splints can be used to
replicate extensor function and simultaneously prevent the flexor muscles from
shortening and the extensor muscles from overlengthening during the recovery
period. Some examples of splints used for radial nerve injuries can be seen in
Figs. 9.8 and 9.9.
Splinting for Ulnar Nerve Injuries

In the case of an ulnar nerve injury, the intrinsic muscles of the hand are affected.
When intrinsic muscle function is absent, the extensor muscles have no antagonist,
and this results in hyperextension of metacarpal phalangeal (MCP) joints and flex-
ion of the interphalangeal (IP) joints of fourth and fifth fingers. To balance the pull
of the extrinsic extensor muscles on the MCP joints, a simple splint can be con-
structed that guides the MCP joints of the fourth and fifth finger into flexion and
provides resistance to the extensors. The hand becomes much more functional with
the use of such a splint, and flexion contractures of the interphalangeal joints are
Fig. 9.10 Soft splint for ulnar nerve injury
Fig. 9.11 Thermoplastic
splint for ulnar nerve
injury
prevented. In our experience, patient acceptance of such splints is very good, par-
ticularly when they are permitted some choice as to color and materials and are
fabricated to be as unobtrusive as possible. Example of splints used for ulnar nerve
injuries can be seen in Figs. 9.10 and 9.11.
Splinting for Median Nerve Injuries

When the median nerve is injured, for example, at the level of the wrist, the intrinsic
muscles of the thumb and to some extent the index and long fingers (lumbrical
muscles) are impacted. This results in decreased thumb function as opposition is
lost, as some of the intrinsic muscles (adductor pollicis and one head of the flexor
pollicis brevis) of the thumb are innervated by the ulnar nerve and long flexor func-
tion remains; it is primarily the loss of opposition that poses a problem. A splint that
places the thumb in opposition and applied during activity and removed at will, will
often suffice to improve function (Figs. 9.12, 9.13, and 9.14).
Figs. 9.12, 9.13, and 9.14 Splints to support thumb opposition
Fig. 9.15 Tenodesis splint for high-level median and ulnar nerve injuries
Splinting for Combined Median and Ulnar Nerve Injuries

When both median and ulnar nerves are injured, a more complex splint is required.
The type of splint required depends on the level of the injury; when the level of the
injury is in the upper arm and the long flexors are paralyzed, the patient will be able
to extend but not flex the fingers; when only extension is possible, custom-made
tenodesis splint can provide function (Fig. 9.15)
Fig. 9.16 Dynamic splint

for combined ulnar and
median nerve injury
Fig. 9.17 Static splint for

combined ulnar and
median nerve injury
When the injury occurs in the distal forearm or at the wrist level, a hand-based
splint that places the thumb in opposition and prevents hyperextension of the MCP
joints can improve function (Figs. 9.16 and 9.17).
Conclusion
Following a peripheral nerve injury, the intensity, quantity, and focus of therapy is
highly variable. The nerve that is injured and the resulting impact upon the patient’s
ability to function play a determining role in the amount and type of therapy that is
needed. “Rehabilitation after any nerve repair is slow and may require extensive
hand therapy input for up to two years” [26]. The recovery process following a
nerve injury can be quite prolonged, and therapeutic treatment must be adjusted
regularly; it is important that patients with nerve injuries are reevaluated and treated
at regular intervals by a skilled therapist. Treatment may include pain manage-
ment, treatment of the resultant scar and edema, protective training, interventions
to enhance function in activities of daily living, splints to enhance function and
minimize contractures, as well as motor and sensory relearning programs. Equally
important is the provision of comprehensive home program that educates the
patient and allows him or her to participate in their own recovery process. During
this process, it is imperative that the patient be supported by the health-care team,
and realistic expectations with regard to outcomes are communicated. Although
the patient would surely like to hear that he or she can expect a full recovery, in the
case of median and ulnar nerve injuries, Vordemvenne et al. [25] found on average
that about 70% of hand function could be expected. The health-care team must
communicate not only with the patient but with one another with regard to the
patient’s situation, progress, and further planning.
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Peripheral Nerve Tissue Engineering:
An Outlook on Experimental Concepts 10
Contents
10.1 T he Leading Thought 127
10.2 The Characteristics of Peripheral Nerve Regeneration Through
Bioartificial Nerve Guides 128
10.3 The Concept of Functionalization of Bioartificial Nerve Guides 130
10.4 The Limitations for Translation of Experimental Work into Clinical Application 131
10.4.1 The Perniciousness of Multidisciplinary Approaches 131
10.4.2 The Perils of Preclinical Work 133
10.4.3 The Regulatory Constraints 136
References................................................................................................................................. 136
10.1 The Leading Thought
Experimental work on the tissue engineering of peripheral nerves is undertaken

with the aim to develop a substitute for the gold standard autologous nerve trans-
plantation to reconstruct longer defects [22] or the alternative approach of suturing
a so-called muscle-in-vein graft [49] between the separated ends of a transected
nerve. As described in Chap. 5, bioartificial nerve implants, mainly with a single
hollow lumen (nerve guidance channels, NGCs), are already available for short
defect repair (< 3 cm) but are currently not approved for clinical use in bridging
longer nerve defects.
Illustrations: Lena Julie Freund, MSc Animal Biology and Biomedical Science, Aachen, Germany
K. Haastert-Talini, Dr. med. vet.

Adjunct Professor, Institute of Neuroanatomy and Cell Biology, Hannover Medical School,
Carl-Neuberg-Str. 1, D-30519 Hannover, Germany
Center for Systems Neuroscience (ZSN) Hannover, Hannover, Germany
e-mail: Haastert-talini.kirsten@mh-hannover.de

DOI 10.1007/978-3-319-52319-4_10
128 K. Haastert-Talini
Today, it is obvious that additional modification of hollow NGCs is needed in

order to make their properties comparative or even surpassing to those of autolo-
gous nerve grafts [14, 22]. Chapter 5 in this book provides an overview of currently
available nerve conduits for clinical use. The outer shell of a complex tissue-engi-
neered nerve graft should shield the regenerating nerve tissue from the invasion of
scar tissue-forming cells, mainly fibroblasts, and besides of being biocompatible it
should allow optimal diffusion of nutrients and metabolites [10, 13]. Biomaterials
used for the fabrication of nerve guides are often naturally derived polymers like the
extracellular matrix molecules collagen or fibrin, polysaccharides like chitosan, or
proteins like silk fibroin [22]. It is highly important that any type of nerve guide
provides continuous collapse stability during its degradation in vivo to prevent a
secondary compression of the regenerated nerve tissue [10]. Tissue engineering
approaches further focus on the resembling of the biological structure of autologous
nerve grafts as they contain nerve regeneration support cells such as Schwann cells
of the repair phenotype [29] that secrete neurotrophic factors and extracellular
matrix components. The incorporation of most as possible beneficial properties of
an autologous nerve graft into tissue-engineered constructs is warranted [11]. This
includes, for most of the experimental approaches, the creation of a three-dimen-
sional endoneurial structure (resembling the bands of Büngner) but also the poten-
tial incorporation of other regeneration supporting cells and molecules and provision
or induction of an adequate vascularization [14].
10.2 T
he Characteristics of Peripheral Nerve Regeneration
Through Bioartificial Nerve Guides
The properties of a tissue-engineered nerve implant can only be optimized in consid-

eration of the process that naturally occurs when a nerve gap is bridged by a hollow
NGC. This process has been evaluated initially using a silicone NGC bridging a
10 mm sciatic nerve gap in the rat [57], and more detailed information has been added
over the years [2, 10]. As illustrated in Fig. 10.1, the regeneration process through a
hollow NGC with a single lumen includes two main phases. The first period from day
1 to day 14 is characterized by the molecular and cellular phase [2], which is subdi-
vided into the fluid phase, the matrix phase, and the cellular phase [10]. While previ-
ous reports mainly focused on the role of migrating perineurial, endothelial, and, most
importantly, Schwann cells during this phase [10], there is recently increasing evi-
dence for an important role of the biomaterials potential immunomodulatory proper-
ties. The crucial involvement of different phenotypes polarized from invading
macrophages during Wallerian degeneration and peripheral nerve regeneration (see
also Chap. 1) has been well characterized [8]. The population of the NGC with pro-
healing M2 phenotype macrophages has a supportive effect on Schwann cell migra-
tion and the following axonal regeneration [41]. Results of our own work indicate, for
example, that the nerve guide material chitosan has an immunomodulatory effect and
drives the early polarization of invading macrophages especially toward the pro-heal-
ing M2c phenotype [52]. The second period, from day 14 onward [2], is characterized
10 Peripheral Nerve Tissue Engineering: An Outlook on Experimental Concepts 129
Distal
Proximal nerve end
nerve end
Extracellular matrix Perineural cell

molecules
M2 macrophage
Neutrophic
factor Repair Schwann cell
Distal
Proximal nerve end
nerve end
Regrowing axon Regenerated axon

with myelianting Schwann cells
Repair Schwann cell
Fig. 10.1 The regeneration process occurring when a peripheral nerve gap has been bridged with
a hollow nerve guidance channel can be divided into two main phases (a, b). (a) The molecular and
cellular phase: When the nerve guide is initially filled with plasma exudate, extracellular matrix
molecules and neurotrophic factors accumulate within its lumen (also referred to as the fluid sub-
phase [10]). This is followed by the formation of a loose fibrin bridge between the separated nerve
ends (also referred to as the matrix subphase [10]). The regenerative matrix is then populated by
migrating and proliferating Schwann cells, perineurial cells (mainly fibroblasts), and endothelial
cells (also referred to as the cellular subphase [10]) and, under optimized conditions, by pro-
healing macrophages of the M2a and M2c phenotype [41]. (b) The axonal and myelination phase:
Axonal sprouts travel along the regenerative matrix and the basal laminae provided by the Schwann
cells (also referred to as the axonal subphase [10]). Once axonal sprouts have reached their appro-
priate targets distal to the nerve lesion, they mature and gain in diameter, which induces their
myelination by neighboring Schwann cells (also referred to as the myelination subphase [10])
by the ingrowth of axonal sprouts that follow the migrating Schwann cell front into
the NGC and later by the myelination of those axons that mature and increase in diam-
eter upon making contact to their appropriate target tissue [10]. Once the nerve defect
is healed and the regrown axons have reinnervated their targets, the repair Schwann
cells will undergo another reprogramming and adopt the phenotypes of nonmyelinat-
ing Remak cells or myelinating Schwann cells [29] again.
10.3 T
he Concept of Functionalization of Bioartificial
Nerve Guides
The functionalization of nerve guides with regeneration-promoting substances,

mainly neurotrophins or neurotrophic factors [23, 30], has been proven to increase
the axonal regeneration [11, 22]. On the other hand, the optimal mixture of these
proteins, as well as their optimal temporal-spatial distribution along a nerve guide,
is still subject of experimental work [33]. Furthermore, it has been repeatedly
discussed that neurotrophins and other neurotrophic proteins have a limited

stability (short half-life time in vivo) and that the high dosages, which need to be
delivered, can negatively interfere with the regeneration process [10]. Timely and
accurate reinnervation of the target tissue could especially be impaired by exag-
gerating axonal sprouting or entrapment of regenerating axons at sites of high pro-
tein concentration [35]. Furthermore, support of the regeneration process may be
achieved by supplementing an appropriate cytokine mixture [40] and/or using a
biomaterial for nerve guide fabrication with immunomodulatory properties to
induce invasion of pro-healing macrophages [36]. Recently, it has been postulated
that the microenvironment created after peripheral nerve lesion is uniquely affect-
ing macrophages plasticity [53]. Future studies on the interaction of Schwann cells
and invading macrophages, besides those needed for myelin removal, will proba-
bly elucidate new aspects to be considered in peripheral nerve tissue engineering
approaches.
Over the years, diverse fabrication techniques for preparing structured nerve
implants were evaluated including computer-assisted manufacturing, laser-based
tissue blotting, and advanced electrospinning or self-assembly of engineered poly-
mers [22]. Furthermore, various surface modifications such as uniform or graduated
coating or change of topography ranging from creating an uneven surface up to
formation of longitudinal grooves have been evaluated [10, 46].
At first, structural modifications should provide an optimal surface for
migrating host cells (so far Schwann cells are mainly considered) and support the
remodeling of the bands of Büngner for an optimized axon guidance [11, 27, 39].
This type of modification with physical or topographical guidance cues is also
considered to increase the speed and quality of peripheral nerve regeneration [22,
35]. In order to at best resemble the native nerve graft architecture with its axon
guiding, elongated, fascicular bands of Büngner, researchers have included fibers
(of micro- or nanoscale), filaments, (hydro-)gels, or sponges into the lumen of
nerve guides [21, 22, 35].
Secondly, certain modifications should also increase the surface-volume rela-
tionship and as such the concentration of regeneration-promoting proteins
released from the separated nerve ends and the surrounding into the graft [10].
Other types of modifications can also change the type of nerve implants from
being a more or less complex guidance structure or surface for Schwann cell
migration into a guiding drug delivery system with pharmacotherapeutic activity
[14, 22]. The latter would be of special interest for delayed reconstruction
approaches when the initial and physiological upregulation of the repair program
and the reprogrammed phenotype of repair Schwann cells [29] have disappeared
over time [55]. Pharmacotherapeutic attempts should aim into the incorporation
and timely and spatially balanced liberation of neurotrophic molecules, cyto-
kines, or other substances that could modify the phenotype of Schwann cells
toward a prolonged support of the regeneration program. It has been demon-
strated, for example, that the pharmaceutical substance FTY720P (fingolimod)
promotes the phenotype of the repair Schwann cells in vitro [26], and it needs
future studies to identify if this could be an appropriate pharmacological tool to
be incorporated into drug delivering NGCs.
A highly active research field in the last decades has been the potential use of
cell therapy in peripheral nerve regeneration. Primary autologous Schwann cells
have been representing the first choice of a cellular supplement to tissue-engi-
neered nerve grafts. But although multiple protocols have been developed (e.g., [7,
25, 31, 48]), the harvest of autologous Schwann cells still has almost the same limi-
tation as the harvest of a complete autologous nerve graft. Therefore, the use of
autologous Schwann cells as cellular substitute in a clinical setting is still only an
option for the most devastating cases [34]. This is the reason why in the recent
years, different types of mesenchymal stem cells (derived from bone marrow,
Wharton’s jelly, adipose tissue, or skin) have been explored as potential substitutes
for Schwann cells within tissue-engineered nerve grafts [15, 32, 45, 47]. In this
context, the term “tissue engineering” is not limited to the combination of innova-
tive biomaterials with regeneration-promoting cells, extracellular matrix compo-
nents, or neurotrophic proteins but refers also to the supplementation of these
additives to acellular nerve guides to improve also the performance of those in
long-distance repair [54]. Figure 10.2 summarizes the main concepts for NGC
modification toward the development of an optimized substitute for autologous
nerve grafts.
10.4 T
he Limitations for Translation of Experimental Work
into Clinical Application
Although so many innovations arose and so diverse material science approaches

have been undertaken, only a very limited number of new products have been trans-
lated “from bench to bedside” into a clinical use in the last years. The reasons for
this may be as manifold as the engineering ideas.
10.4.1 The Perniciousness of Multidisciplinary Approaches
At first, material scientists may not always be appropriately introduced by their col-
laboration partners to the specific needs of the biological system they are asked to
develop biomaterials for. This can lead to discrepancies, and although the most
modern fabrication techniques are used, the developed material compositions may
become inappropriate. One example we have experienced in our own group is the
Distal
Nerve
Proximal nerve end
guidance
nerve end
channel
b
Longitudinal film
Grooved inner surface
Material bound
or Neurotrophic factors
encapsulated
Material bound
or Cytokines
c encapsulated
Material bound
or Pharmaceutical
encapsulated
Transplanted stem cell

producing neurotrophic factors and cytokines
Transplanted Schwann cell

producing neurotrophic factors and cytokines
Fig. 10.2 The remodeling of the peripheral nerve regeneration-supporting properties provided
by an autologous nerve graft includes three main concepts: (a) Providing a three-dimensional
guidance structure within the lumen of hollow nerve guidance channels, e.g., by placing a scaf-
fold providing a channel like porosity or another longitudinal guidance structure. This could be
achieved, for example, by the use of hydrogels, micro- or nanotubules (left), and micro- or
nanofibers (center) or by the introduction of longitudinal films or grooves (right). (b) The inte-
gration of neurotrophic molecules, cytokines, or pharmaceutical substances that are either bound
to the biomaterial or encapsulated for coordinated release should result in the induction of an
optimized and prolonged support of the regeneration process. (c) The incorporation of support
cells aims to provide additional guidance for regrowing axons and to deliver a regeneration-
promoting milieu
properties of an electrospun polycaprolactone nerve guide that, although the quali-

fication of this synthetic polymer has been proven before [23], did in our hands
induce a massive and deleterious foreign body reaction upon suture between sepa-
rated nerve ends [12]. Another example is the natural polysaccharide chitosan,
which was already in the 1990s used as biomaterial for nerve guide fabrication but
demonstrated insufficient stability to be further processed into a clinical product
[16]. Anyhow chitosan was further investigated for its use as a biomaterial for neu-
ral repair [20], and finally, about 20 years later, an optimized nerve guide was devel-
oped [24] and registered for clinical use (nerve gap repair <3 cm) in Europe and the
USA (see Chap. 5). A third example, again from our own laboratory, is the use of a
hyaluronic acid-based laminin containing hydrogel, originally developed to support
regeneration of vascular and neural tissue and with favorable properties for organo-
typic in vitro cultures of sensory dorsal root ganglia [43, 58]. Surprisingly, this
specific hydrogel did, instead of supporting the regeneration process, impair periph-
eral nerve regeneration [38]. In general, hydrogels are used to provide a matrix in
which invading or transplanted cells feel as confident as in their physiological des-
tinations. In the context of peripheral nerve regeneration, the hydrogel should sup-
port the migration of Schwann cells and other support cells, like, e.g., the
pro-regenerative macrophages mentioned before. But when it comes to the ques-
tions of how cell-friendly the hydrogel filler and how porous the wall of the NGC
should be, specific interactions have to be considered. A recent study demonstrated
that when the porous properties of the NGC wall allow uncontrolled infiltration of
the cell-friendly hydrogel filler with fibroblasts, this will negatively interfere with
the nerve regeneration process [13]. Interestingly, a much simpler modification of a
hollow single lumen chitosan nerve guide, namely, the longitudinal introduction of
a central chitosan film, was much more successful in increasing the regeneration
outcome across a critical defect length of 15 mm in the rat sciatic nerve after imme-
diate [37] and after delayed nerve reconstruction [52]. It can be expected that trans-
lation of this two-chambered chitosan nerve guide design into a medical product
will be done in a reasonable period. As another example for fruitful collaboration
between material scientists and clinical scientists, a more complex, microstructured
collagen nerve guide has been developed recently. This specific nerve implant
allowed successful nerve repair across a 20 mm sciatic nerve gap in the rat [4] and
can also be filled with mesenchymal stem cells for cellular regeneration support [3].
For the latter nerve guide, first results from a clinical study are expected in not later
than 1–2 years’ time.
10.4.2 The Perils of Preclinical Work
Another obstacle for the translation of all the recent innovations into a promising
new medical product, likely, is the fact that many attempts are not adequately evalu-
ated. Simple biocompatibility studies may convince material scientists in the first
step, but the novel biomaterials may reveal non-appropriate properties when tested
in a more comprehensive way in challenging preclinical models. The highest poten-
tial for a propagation of a novel nerve guide into a medical product for clinical use
have those approaches that have proven their regeneration-supporting properties in
comprehensive in vitro and in vivo studies. Reports that conclude only from bio-
compatibility studies with glial cell lines, for example, that a biomaterial is very
promising for the fabrication of a NGC, are of minimal value for clinical scientists.
In vitro studies utilizing cell lines can indeed reveal important information, but the
cell lines need to be appropriate for the specific field of neural regeneration
addressed. And for a more substantial indication of the biomaterial properties, those
studies need regularly to be followed by evaluation of the behavior of primary nerve
cells [19]. Also from an ethical point of view, in vitro studies are warranted to
reduce the number of animals devoted to in vivo experiments, but a final compre-
hensive preclinical in vivo evaluation, probably also in different animal models, is
unavoidable [19]. A meaningful result from in vivo studies, again, will only be
obtainable when the different levels of peripheral nerve regeneration that range
from proven regeneration of axons across a substantial distance over evidenced
reinnervation of distal targets (including indicated specificity of this reinnervation)
to, most important, functional recovery [6, 44] are appropriately evaluated. Qualified
preclinical animal models should recapitulate the specific nerve regeneration pro-
cesses, which also take place during peripheral nerve regeneration in human
patients. The rat sciatic nerve transection and reconstruction model is the far most
used in vivo system [1, 18]. Therefore, studies using this model have a higher value
with regard to comparability among each other. The rat sciatic nerve model allows
evaluation of the reconstruction of defect lengths up to 15–20 mm in a large variety
of functional assessments [6, 44]. Although already accepted as a critical defect
length model, the critical defect length in human patients is considerably longer
(> 10 cm), but the rat sciatic nerve model is still the most appropriate and at best
standardized model [1]. The rat median nerve model is considered to be appropriate
for extrapolation toward human upper limb or digital nerve injuries and provides
from an ethical point of view the high advantage of only minimal impairment for the
animal well-being [28]. Rat models have further been developed to additionally
address different health conditions and their impact on peripheral nerve regenera-
tion. Studies performed in the Goto-Kakizaki rat that presents with moderately
increased and clinically relevant blood glucose levels, thus resembling diabetes type
2 conditions [50, 51], deliver information important for an increasing amount of
patients. The mean life expectancy of the laboratory rat additionally allows consid-
eration of delayed nerve reconstruction approaches, a condition that is also highly
relevant for a significant number of patients in which primary nerve reconstruction
cannot be performed due to a seriously affected general health condition [9]. Finally,
after comprehensive preclinical investigation, first inhuman experiences are eventu-
ally achievable by repairing the sural nerve after its harvest as an autologous nerve
graft with the novel nerve guide that is about to be established for clinical use [5].
For the clinical scientists and clinicians interested into the latest developments
and novel medical products that may become available in the nearer future, it is of
outmost importance to know about the predictability of the results published from
experimental work. Only with this knowledge, the curious reader will be able to
conclude that an experimental approach to develop a novel nerve guide is indeed
promising and deserves the enterprise to be processed toward a clinical product.
In vitro studies demonstrating the biocompatibility with primary peripheral
nerve cells, primary neurons, or organotypic cultures from dorsal root ganglia or
spinal cord preparations and also providing evidence for a stimulated neurite
outgrowth from primary sensory or motor neurons by the tested biomaterial provide
a legitimization for in vivo studies [19]. For this legitimation, it is not obligatory to
demonstrate optimal biomaterial properties by complex peripheral nerve regenera-
tion in vitro models, which evaluate neurite outgrowth from spinal cord slices to
peripheral nerve segments or nerve guide material [17, 56]. The latter in vitro
systems are the most refined and sophisticated ones, but on the opposite, they are
difficult to establish and to propagate.
Preclinical in vivo models should then be chosen in consideration of ethical as
well as assessment concerns [18, 44]. When used as a stand-alone readout, histo-
morphometrical evaluation of axonal regeneration across a certain distance does not
predict the final functional outcome [6]. Such evaluation needs to be combined with
at least one predictive assessment of functional recovery, which can be the histo-
logical proof of target tissue reinnervation by retrograde labeling or the recording of
evoked compound muscle action potentials upon stimulation of the repaired nerve
[6]. Diverse readouts exist to determine the recovery of complex voluntary motor
functions (e.g., video gait analysis in sciatic nerve models or grasping test in median
nerve model) as well as sensory recovery (e.g., von Frey mechanical pain threshold
test) [6, 44]. Such complex evaluations are of course of highest value for the transla-
tion of study results into the propagation of a novel approach toward a medical
product for clinical use.
There is one examination technique, which should receive specific consider-
ation in this context: the calculation of the Sciatic Functional Index (SFI) from
measured distances between the spread toes of the hind paws. The index indicates
complete sciatic nerve dysfunction (no spreading of toes possible anymore) when
calculation of its mathematical formula equates to −100, and it indicates full sci-
atic nerve function when the formula equates to zero [44]. Alternative calculation
of sciatic nerve trunk specific indices, like for the tibial nerve or peroneal nerve
(TFI, PFI), is also performed related to the fact that regenerating axons could be
misdirected from the common sciatic nerve stem into the non-appropriate trunk
[6]. Although results for the calculation of the different functional indices are still
often presented, the assessment of the same has considerable drawbacks when used
to determine the degree of functional motor recovery after nerve gap reconstruc-
tion procedures. While demonstrating enough reliability and values returning to
approximately pre-injury values after nerve crush injuries of different severity
[42], obtainable values after repair of nerve transection, especially with any type of
gap bridging implant, are often not valid to discriminate between treatments as
they do not reach values indicating substantial recovery [44]. This is due to the
already mentioned innervation of alternative motor targets by misdirected regener-
ating axons leading to contractures, joint stiffness, and abnormal paw posture in
general [6, 44]. Therefore, conclusions about the quality of novel NGCs, which are
drawn on the basis of SFI or alternative calculations and histomorphometrical anal-

ysis of regenerated axons close to the implant, should not be considered as strong
and predictive for a clinical translatability.
10.4.3 The Regulatory Constraints
Finally, before a novel medical product is made available for clinical use, there are
regulatory aspects that have to be considered and which represent a considerably
high burden especially for cell-supplemented tissue-engineered products that are
not supplemented with the patient’s autologous cells, the so-called advanced ther-
apy medicinal products (regulation on advanced therapies (Regulation (EC)
1394/2007)). Furthermore, regulatory work including toxicity and biocompatibility
tests as well as phase I and II clinical studies are expensive to perform already for
novel nerve implants that are probably cell-free but composed of completely novel
biomaterials. Consideration of the last two points underscores the preceding para-
graphs from this chapter and the need to design experimental studies with high
predictability of a potential clinical value of novel tissue-engineered nerve implants.
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Index
A nerve damage during surgery, 102

Allodynia, 104, 110, 115, 116 postoperative, 103
Axon scar, 104
axonal injury, 9 swelling, 85, 113, 114
axonal outgrowth, 8 vascular injury, 103
axonal regeneration/regenerating axon, 5, wound dehiscence, 104
7–9, 39, 45–47, 68, 92, 128, 130, Connective tissue
135 endoneurium, 2, 3, 8
axonal sprouts, 8, 9, 129 interfascicular, 2
myelinated, 1, 2, 7, 91 epineurium
unmyelinated/non-myelinated, 1 epineurotomy, 6
external, 42
internal/interfascicular, 2, 6
B gliding, 2
Bandaging, 114 mesoneurium, 42
Bands of Bungner/Bands of Büngner, 8, 128, perineurium, 2
130 Contracture, 118–120, 123, 135
Biomaterial, 81, 85, 93, 128, 130–136 Cortical representation, 113, 115, 116
Brachial plexus injury Cytokine
neonatal brachial plexus palsy (NBPP) cytokine mixture/liberation of cytokines,
cookie test, 67 130, 131
postoperative evaluation, 73–75 cytokine pro-inflammatory, 8
preoperative evaluation, 66–70
towel test, 67
(nerve) root avulsion D
postganglionic, 20, 21, 66 Decompression, 56
preganglionic, 20, 66 decompression of the carpal tunnel, 55–57
rupture, 66, 68, 69 Desensitization, 116
Disability of arm, shoulder and hand (DASH),
102, 111, 115
C Dressing, 115
Clinical diagnosis, 11, 22
Clinical follow-up
International Classification of Functioning, E
Disability and Health, 75, 111 Edema, 45, 113, 114, 123
multifactorial evalution, 111 Electrodiagnostic techniques
Complications compound muscle action potential (CMAP)
bleeding, 103–104 low, 15, 16
infection, 104 normal, 15

DOI 10.1007/978-3-319-52319-4
140 Index
Electrodiagnostic techniques (cont.) I

compound nerve action potential (cNAP), Imaging techniques
34, 62, 63 computed tomographic (CT) myelography,
(needle) electromyography/EMG, 13 68
electrophysiological measurements/ diffusion tensor tractography (DTT), 22,
electrodiagnostical nerve 31, 37, 38
stimulation, 22, 23, 28, 56 imaging techniques magnetic resonance
motor unit action potential (MUAP), 14, neurography (MRN,
15, 18, 23 MR-neurography)
motor unit potential (MUP), 67, 68 short inversion recovery sequences
nerve action potentials/NAP, 63, 71 (STIR), 20, 23
nerve conduction studies/NCS turbo inversion recovery magnitude
mixed NCS, 13 sequences (TIRM), 20
motor NCS, 13 T1-weighted sequences (T1w), 20, 21,
sensory NCS, 13 23
nerve conduction velocity/NCV T2-weighted sequences (T2w), 19–24
large, 14 T2w fast spin-echo sequences (SE), 20,
polyphasic, 14 23
pathologic sponatenous activity (PSA), magnetic resonance imaging (MRI), 17,
14–16 19–24, 70
sensory nerve action potential myelography, 69
(SNAP), 14 nerve sonography/(high resolution)
somato-sensory evoked potential (SSEP), ultrasound/neurosonography,
37, 62 17–18, 28, 31, 62
Endoscope, 56, 59 spinal, 20
retractor integrated Krishnan Immunosuppression, 82
endoscope, 55 FK-506, 85
Erb’s palsy/Erb palsy, 71 Intraoperative diagnostics/decisions
Exoscope, video telescope operating assessment, 31, 37, 41
microscopy, 56–59 decision-making, 71–73
decision-taking, 34
electrophysiological studies, 62
F motor evoked potentials, 62
Fascicle neurosonography/nerve sonography,
fascicular imaging, 19 28, 31, 35, 37, 62
fascicular lesion/fascicular injury, 19 somato-sensory evoked potential (SSEP), 62
Fibroblast, 6, 128, 129, 133
Fibrosis
(nerve) fibrosis type A, 6 M
(nerve) fibrosis type B, 5 Macrophage
(nerve) fibrosis type C, 6 M2 phenotype, 128
iatrogenic, 62 pro-healing, 128–130
interstitial, 118 Matrix, 2, 86, 89, 90, 128, 129, 131, 133
Medical Research Council (MRC)
motor scale, 99, 100
G sensory scale, 100
Guidance cues, 130 Mesenchymal stem cells, 91, 131, 133
Motor function, 30, 37, 73–75, 100, 102, 110,
116, 118–119, 135
H Motor imagery, 114
Horner’s syndrome, 66, 69, 70 mirror therapy, 116, 117
Index 141
Motor impairment, 74 endoscopic surgery

language development, 74, 75 biportal technique, 55
Muscle transfer, 73 monoportal technique, 55
Myelin, 1, 2, 4, 7–9, 130 end-to-end/end-to-end-coaptation/
Myopathy, 14 end-to-end suture/end-to-end
Doi procedure, 73 neurorrhaphy
epineurial (repair), 43, 44
group fascicular (repair), 43, 45
N perineurial (repair), 43, 45
Neonatal brachial plexus palsy (NBPP). See end-to-side/end-to-side-coaptation/
Brachial plexus injury end-to-side neurorrhaphy
Nerve conduit/nerve guide epineurotomy, 45
bioartificial, 128–131 perineurotomy, 45
chitosan, 93, 128, 133 fibrin-glue, 35, 46, 48–49, 59–60
collagen, 91, 92, 133 (clinical) follow-up, 97–105
polycaprolactone (PCL), 91, 133 muscle-in-vein transplant, 86, 127
polyglycolic acid (PGA), 88, 89, 93 nerve allograft, 81–85
polylactic acid (PLA), 88–90, 93 nerve conduits, 85–94, 128
polylactic-co-glycolic acid nerve transfer, 43, 48, 66, 69, 71–75, 98
(PLGA), 90, 93 Oberlin procedure, 72
Nerve damage/nerve injury/nerve trauma/ primary reconstruction, 28, 32, 37,
nerve laceration 89, 134
axonotmesis results of surgical repair, 49
complete, 17, 19 revision surgery, 36–38
partial, 16, 19 secondary reconstruction, 28, 33, 37, 89
combined lesion, 35 suture, 43–46, 48–49, 59–60
intraneural, 17 suture-free, 60
nerve block, 28 timing, 27–39
neurapraxia, 4, 31 xenograft, 85
neurotmesis, 4, 17, 21 Nerve stripper/Assmus nerve stripper, 35, 61
partial lesion, 62 Nerve tumor, 43
perineurial, 2, 3, 45 schwannoma, 58
sharp transection, 28, 30, 32 Neurolysis
Nerve fiber external, 42, 103
monofascicular, 3 internal, 6, 42–43
myelinated, 1, 91 Neuroma
oligofascicular, 3 in continuity/neuroma-in-continuity, 5, 6,
polyfascicular, 3 22, 28, 34, 35, 44
unmyelinated/non-myelinated, 1, 91 end-bulb neuroma, 21, 22
Nerve reconstruction/nerve repair Neuron
anesthesia, 36 motor neuron/motoneuron, 1, 135
autologous nerve transplant sensory neuron/dorsal root ganglion
graft length, 47 neuron, 1, 2, 133, 135
harvesting, 35, 60 Neuropathy, 14, 20, 55, 56
interfascicular grouped fascicular peripheral, 12, 19
approach, 46–47 Neurotization, 47
nerve stripping, 35 muscular neurotization, 35, 38, 42,
small caliber graft, 46 47–48
decellularized nerve graft, 83–85 Neurotrophic factor/neurotrophic protein,
decision-making, 27–39 128–131
decision-making algorithm, 76 Node of Ranvier/Ranvier’s node, 2, 8, 45
142 Index
O shape/texture identification (STI),

Operating microscope, 54–55, 58, 62 38, 100, 102
Weinstein Enhanced Sensory, 38
Rosen scale, 102
P sensory
Pain proprioception, 73, 74
allodynia, 104, 110, 115, 116 protective sensibility, 45, 92
burning, 104 shape/texture identification (STI),
electric shock, 104 100, 102
evaluation tactile sensation, 99
Integrated Pain Score scale, 101–102 two point discrimination (2PD), 83, 92,
McGill Pain Questionaire, 101 99, 100, 102
numerical rating scale (NRS), 101 Sollerman hand function test, 100
pain visual analogue scale (PVAS), 101 Regeneration
hyperalgesia, 110, 115 functional recovery, 9, 16, 28, 31, 36,
hyperesthesia, 102, 110, 113, 115, 116 38, 49, 85, 90, 93, 97, 100,
management, 110, 113, 114, 123 111, 134, 135
medical treatment, 105 proximal nerve end/stump, 8, 37,
neuropathic, 12, 105, 114, 116 38, 60
nociceptive, 12 speed, 9, 22, 117–118, 130
tingling, 12, 102, 104 Regulatory constraints, 136
treatment, 110 Rehabilitation
Pan-plexopathy, 66 hand therapy, 110, 114, 123
Perception reeducation, 113, 115–118
moving touch, 116 rehabilitation scale, 98
static touch, 116 re-learning, 113, 123
Polyneuropathy sensory therapy, 37, 98, 99, 110, 117
demyelinating, 19 Rosen Score/Rosén Score, 111
pre-existing, 14
Postoperative monitoring, 28
Pre-clinical (work/investigation) S
rat sciatic nerve, 134 Schwann cell
readout, 135 autologous, 128, 131
Psychometric tests. See Recovery, basal lamina/basal laminae, 2, 8, 129
psychometric tests Remak cell, 129
Repair Schwann cell, 129, 131
Seddon classification, 4
Q Sensibility/sensation
Quality of life (QoL), 73–76, 109, 111 proprioception, 73, 74
protective sensibility/protective sensation,
45, 92, 99, 110
R tactile sensation, 99
RANGER study, 84 two point discrimination (2PD), 83, 92, 99,
Rat. See Pre-clinical (work/investigation) 100, 102
Recovery Sensory function, 92, 100, 102, 110, 111, 113,
Michigan Hand Outcomes Questionnaire 115–119
(MHQ), 102 Splint
motor dynamic, 120, 123
dynamometer, 100 nerve, 120
goniometer, 100 soft, 121
plantar dorsiflection, 99 static, 123
psychometric tests tenodesis, 122
Semmes-Weinstein Monofilament, thermoplastic, 121
38, 100, 102, 116 Splinting, 114, 119–123
Index 143
Sunderland classification, 30, 80 exsanguinating, 56

Surgical techniques non-exanguinating, 56
exposure, 53, 59 Transcutaneous electrical nerve stimulation
graft repair, 46–47 (TENS), 114
illumination, 54–59 Translation, 81, 131–136
magnification, 41, 43, 53, 59
split repair, 62
tubulization, 88–89 V
Sympathetic blockade, 105 Vascularization
Sympathetic dystrophy, 105 blood supply, 46
extrinsic blood vessels, 4
intrinsic blood vessels, 4
T micro vessels, 2
Tinel’s sign/Hoffmann and Tinel’s sign/
Hoffmann-Tinel’s sign, 9, 11, 12,
99, 105 W
Tissue engineering, 90, 93, 127–136 Wallerian degeneration, 4–8, 14, 15, 19, 128
Tourniquet distal nerve end/stump, 6, 8, 38

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Printed on acid-free paper

This Springer imprint is published by Springer Nature

Hannover, Germany Kirsten Haastert-Talini

1 The Peripheral Nerve: Neuroanatomical Principles Before

1.1 Anatomy of the Peripheral Nerve

G. Antoniadis, MD, PhD

© Springer International Publishing AG 2017 1

The axons contain organelles including mitochondria, neurofilaments, endoplas-

Stucture of peripheral nerve:

Perineurium Fascicle pattern of

1 . Nerves with a monofascicular pattern.

1.2 Classification of the Nerve Injuries

Grade I By this type of lesion, there is an interruption of conduction at the site of

Millesi established a further classification system of reactive nerve fibrosis types.

Type A: Fibrosis of the epineurium.

1.3  euroanatomical Situation After Injury: Nerve

The process of Wallerian degeneration is completed after several weeks, and it

Observations of Wallerian degeneration have revealed that the initial degradation

1.4 Nerve Regeneration

As a consequence of any severe injury to a peripheral nerve, there is a predictable

1. Positive signals, derived from retrograde transport of kinases, such as mitogen-­

Current research on the intrinsic regeneration capacity of neurons focuses on the

© Springer International Publishing AG 2017 11

2.2 History Taking and Physical Examination

• Is patient’s pain nociceptive, or neuropathic, or both?

2.3 Electrodiagnostic Procedures

Table 2.3 Electrodiagnostic findings after a nerve trauma over time

normal compound muscle action potential (CMAP) following stimulation distal to

2.4.1 High-Resolution Ultrasound

Ultrasound imaging of peripheral nerves is done since a quarter of a century [13].

• Distinction between neurotmesis and axonotmesis

2.4.2.1 Background and Overview

2.4.2.2 Technical Requirements

2.4.2.3 MRN Findings in Nerve Injury

tissue. In case of postganglionic brachial plexus lesions, a further differentiation

Fig. 2.4 MRN: 3D

a neuroma-in-continuity (NIC) [14, 23]. A neuroma consists of fibroneural tissue

2.4.2.4 MRN Findings in Denervated Muscle

© Springer International Publishing AG 2017 27

A sharp transection injury within a clean (not contaminated) wound requires

3.2 The Decision Process

Open injury Contusion/Traction

Nerve Regen. Yes

Nerve transplantation Neurotization end-to- Heterolog.

Muscle/tendon transfer Improvement?

• Attempt of an end-to-end coaptation of the ulnar nerve. Therefore, the

3.3  reoperative Decisions and Therapeutic Options

The schematic overview in Fig. 3.2 illustrates the lining up of diagnostic decision-­

Nerve without function

Fig. 3.2 Primary diagnostic procedures (see also Chap. 2)

• To confirm or establish diagnosis

Contraindications for a surgical intervention include bad general condition of the

Time from injury

Nerve transplantation etc.

Hannover, Germany Kirsten Haastert-Talini

1 The Peripheral Nerve: Neuroanatomical Principles Before

1.1 Anatomy of the Peripheral Nerve

1.2 Classification of the Nerve Injuries

1.3 euroanatomical Situation After Injury: Nerve

1.4 Nerve Regeneration

1. Positive signals, derived from retrograde transport of kinases, such as mitogen-

2.2 History Taking and Physical Examination

2.3 Electrodiagnostic Procedures

2.4.1 High-Resolution Ultrasound

2.4.2.1 Background and Overview

2.4.2.2 Technical Requirements

2.4.2.3 MRN Findings in Nerve Injury

2.4.2.4 MRN Findings in Denervated Muscle

3.2 The Decision Process

3.3 reoperative Decisions and Therapeutic Options

The schematic overview in Fig. 3.2 illustrates the lining up of diagnostic decision-

3.4 Intraoperative Decisions

3.5 I ndication in Case of Partial Lesions and Neuroma

3.6 Decisions in or Concerning Combined Lesions

3.7 erioperative Techniques: Choice of Anesthesia

3.8 Postoperative Decisions and Revision Surgery

3.9 Prevention of Nerve Injuries and Future Aspects

4.1.1 External Neurolysis

4.1.2 Internal Neurolysis

4.2 End-to-End Neurorrhaphy

4.3 End-to-Side Neurorrhaphy

4.4 Graft Repair

f ascicular structure of each stump as possible is covered in this fashion. Individual

4.5 Direct Muscular Neurotization

4.6 Fibrin Glue Versus Suture

4.7 Factors Influencing the Results of Surgical Repair

5.2 Technology of Illumination and Optics

5.2.1 The Operating Microscope

5.2.2 The Retractor-Integrated Endoscope

Minimally invasive surgical methods are becoming increasingly popular. Post-

5.3 Techniques in Nerve Coaptation

5.4 Techniques in Intraoperative Diagnostics

6.2 Challenges in the Preoperative Evaluation

6.3 Challenges in Intraoperative Decision-Making

6.4 Challenges in Postoperative Evaluation

guide decision-making for these patients. While these challenges remain, it is an

7.2 Peripheral Nerve Grafts

7.3 Allogeneic Decellularized Nerve Transplantation

7.4 Nerve Conduits

7.4.1 Biological Nerve Conduits

7.4.2 Synthetic Nerve Conduits