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Abstract
Peripheral nerve injuries are common, and there is no easily available formula for successful treatment.
Incomplete injuries are most frequent. Seddon classified nerve injuries into three categories:
neurapraxia, axonotmesis, and neurotmesis. After complete axonal transection, the neuron undergoes a
number of degenerative processes, followed by attempts at regeneration. A distal growth cone seeks out
connections with the degenerated distal fiber. The current surgical standard is epineurial repair with
nylon suture. To span gaps that primary repair cannot bridge without excessive tension, nerve-cable
interfascicular auto- grafts are employed. Unfortunately, results of nerve repair to date have been no
better than fair, with only 50% of patients regaining useful function. There is much ongoing research
regarding pharmacologic agents, immune system modulators, enhancing factors, and entubulation
chambers.Clinically applicable developments from these investigations will continue to improve the
results of treatment of nerve injuries
Introduction
Peripheral nerves were first distinguished from
tendons by Herophilus in 300 BC. By meticulous
dissection, he traced nerves to the spinal cord,
demonstrating the continuity of the nervous
system. In 900 AD, Rhazes made the first clear
reference to nerve repair. However, not until
1795 did Cruikshank demonstrate nerve healing
and recovery of distal extremity function after
repair. In the early 1900s, Cajal pioneered the
concept that axons regenerate from neurons and
are guided by chemotrophic substances. In 1945,
Sunderland promoted microsurgical techniques to
improve nerve repair outcomes. Since that time,
there have been a number of advances and new
concepts in peripheral nerve reconstruction.
Research regarding the molecular biology of
nerve injury has expanded the available strategies
for improving results. Some of these strategies
involve the use of pharmacologic agents, immune
system modulators, enhancing factors, and
entubulation chambers. A thorough
understanding of the basic concepts of nerve
injury and repair is necessary to evaluate the
controversies surrounding these innovative new
modalities.
Anatomy
The epineurium is the connective tissue layer of
the peripheral nerve, which both encircles and
runs between fascicles. Its main function is to
nourish and protect the fascicles. The outer layers
of the epineurium are condensed into a sheath.
Within and through the epineurium lie several
fascicles, each surrounded by a perineurial
sheath. The perineurial layer is the major
contributor to nerve tensile strength. The
endoneurium is the innermost loose collagenous
matrix within the fascicles. Axons run through
the endoneurium and are protected and nourished
by this layer.


Sunderland has demonstrated that fascicles
within major peripheral nerves repeatedly divide
and unite to form fascicular plexuses. This leads
to frequent changes in the cross-sectional
topography of fascicles in the peripheral nerves.
In general, the greatest degree of fascicular cross-
branching occurs in the lumbar and brachial
plexus regions. Several studies have
demonstrated greater uniformity of fascicular
arrangement in the major nerves of the
extremities; in fact, the palmar cutaneous and
motor branches of the median nerve may be
dissected proximally for several centimeters
without significant cross-branching. In nerve
repair, fascicular matching is critical to outcome,
and strategies for achieving this will be discussed.
The blood supply of peripheral nerves is a
complex anastomotic network of blood vessels. There are two major arterial systems and one
minor longitudinal system linked by anastomoses.
The first major system lies superficially on the
nerve, and the second lies within the
interfascicular epineurium.
The minor longitudinal system is located within
the endoneurium and perineurium. The major
superficial longitudinal vessels maintain a
relatively constant position on the surface of the
nerve. The segmental vascular supply consists of
a number of nutrient arteries that vary in size and
number and enter the nerve at irregular intervals.
They repeatedly branch and anastomose with the
internal longitudinal system to create an
interconnected system. Injection studies have
revealed the relative tortuosity of the blood
vessels, which accommodates strain and gliding
of the nerve during motion.

Endoneurial capillaries have the structural and
functional features of the capillaries of the central
nervous system and function as an extension of
the blood-brain barrier. The endothelial cells
within the capillaries of the endoneurium are
interconnected by tight junctions, creating a
system that is impermeable to a wide range of
macromolecules, including proteins. This barrier
is impaired by ischemia, trauma, and toxins, as
well as by the mast-cell products histamine and
serotonin.
Injury Classification
Seddon2 classified nerve injuries into three major
groups: neurapraxia, axonotmesis, and
neurotmesis.Neurapraxia is characterized by local
myelin damage, usually secondary to
compression. Axon continuity is preserved, and
the nerve does not undergo distal degeneration.
Axonotmesis is defined as a loss of continuity of
axons, with variable preservation of the
connective tissue elements of the nerve.
Neurotmesis is the most severe injury, equivalent
to physiologic disruption of the entire nerve; it
may or may not include actual nerve transection.
After injury (short of transection), function fails
sequentially in the following order: motor,
proprioception, touch, temperature, pain, and
sympathetic. Recovery occurs sequentially in the
reverse order.
Sunderland1 further refined this classification on
the basis of the realization that axonotmetic
injuries had widely variable prognoses. He
divided Seddon.s axonotmesis grade into three
types, depending on the degree of connective
tissue involvement. Neurapraxia is equivalent to a
Sunderland type 1 injury. Complete recovery
follows this injury, which may take weeks to
months.
Physiology of Nerve
Degeneration
Following axonal transection, a sequence of
pathologic events occurs in the cell body and
axon. The cell body swells and undergoes
chromatolysis, a process in which theNissl
granules (i.e., the basophilic neurotransmitter
synthetic machinery) disperse, and the cell body
becomes relatively eosinophilic. The cell nucleus
is displaced peripherally. This reflects a change in
metabolic priority from production of
neurotransmitters to production of structural
materials needed for axon repair and growth, such
as messenger RNA, lipids, actin, tubulin, and
growth-associated proteins.
Shortly after axonal transection, the
proximal axon undergoes traumatic degeneration
within the zone of injury. In most instances, the
zone of injury extends proximally from the injury
site to the next node of Ranvier, but death of the
cell body itself may occur, depending on the
mechanism and energy of injury.
Wallerian degeneration (i.e., breakdown
of the axon distal to the site of injury) is initiated
48 to 96 hours after transection. Deterioration of
myelin begins, and the axon becomes
disorganized. Schwann cells. proliferate and
phagocytose myelin and axonal debris
Nerve injury may disrupt the nerve-
blood barrier. Incompletely injured nerves may
then be exposed to unfamiliar proteins, which
may act as antigens in an autoimmune reaction.
This mechanism may propagate the cycle of
nerve degeneration.

Physiology of Nerve
Regeneration
After wallerian degeneration, the Schwann cell
basal lamina persists. The Schwann cells align
themselves longitudinally, creating columns of
cells called Büngner bands, which provide a
supportive and growthpromoting
microenvironment for regenerating axons.
Endoneurial tubes shrink as well, and Schwann
cells and macrophages fill the tubes.At the tip of the regenerating axon is the growth
cone, a specialized motile exploring apparatus.
The growth cone is composed of a structure of
flattened sheets of cellular matrix, called
lamellipodia, from which multiple fingerlike
projections, called filopodia, extrude and explore
their microenvironment. The filopodia are
electrophilic and attach to cationic regions of the
basal lamina. Within the filopodia are actin
polypeptides, which are capable of contraction to
produce axonal elongation. The cone releases
protease, which dissolves matrix in its path to
clear a way to its target organ.
The growth cone responds to four classes of
factors: (1) neurotrophic factors, (2) neurite-
promoting factors, (3) matrix-forming precursors,
and (4) metabolic and other factors. Neurotrophic
factors are macromolecular proteins present in
denervated motor and sensory receptors. They are
also found within the Schwann cells along the
regeneration path. These factors aid in neurite
survival, extension, andmaturation. The original
neurotrophic factor is nerve growth factor.This
protein was seen to be released by a murine
sarcoma and, when transplanted into chick
embryos, caused sensory and sympathetic axons
to grow toward the tumor. In addition to being
trophic (i.e., promotes survival and growth),
nerve growth factor is chemotropic (i.e., guides
the axon) and also affects growth-cone
morphology. Other neurotrophic factors include
ciliary neurotrophic factor3 and motor nerve
growth factor,4 which also have an important role
in the survival and regeneration of damaged
neurons.
Unlike the neurotrophic factors,the neurite-
promoting factors are substrate-bound
glycoproteins that promote neurite (axonal)
growth. Laminin, a major component of the
Schwann cell basal lamina, is bound to type IV
collagen, proteoglycan, and entactin, and has
been shown to accelerate axonal regeneration
across a gap.5 Fibronectin is another neurite-
promoting factor that has been shown to promote
neuritegrowth,6 as have neural cell adhesion
molecule and N-cadherin.7 Fibrinogen, a matrix-
forming precursor, polymerizes with fibronectin
to form a fibrin matrix, which is an important
substrate for cell migration in nerve
regeneration.8

The fourth class comprises a variety of factors
that enhance nerve regeneration but cannot
appropriately be placed in any of the first three
classes. Among them are acidic and basic
fibroblast growth factors,9 insulin and insulinlike
growth factor, eupeptin, glia-derived protease
inhibitor, electrical stimulation, and hormones
such as thyroid hormone, corticotropin, estrogen,
and testosterone
Nerve Grafting
Autografts
When primary repair cannot be performed
without undue tension, nerve grafting is required.
Autografts remain the standard for nervegrafting
material. Allografts have not shown recovery
equivalent to that obtained with autogenous nerve
and are still considered experimental.

The three major types of autograft are cable,
trunk, and vascularized nerve grafts. Cable grafts
are multiple small-caliber nerve grafts aligned in
parallel to span a gap between fascicular groups.
Trunk grafts are mixed motor-sensory whole-
nerve grafts (e.g., an ulnar nerve in the case of an
irreparable brachial plexus injury). Trunk grafts
have been associated with poor functional results,
in large part due to the thickness of the graft and
consequent diminished ability to revascularize
after implantation. Vascularizednerve grafts have
been used in thepast, but with conflictingresults.
They may be consideredif a long graft is needed
in a poorly vascularized bed. Because donor-site
morbidity is an issue, vascularized grafts have
been most widely utilized in irreversible brachial
plexus injuries.

The most common source of autograft is the sural
nerve, which is easily obtainable, the appropriate
diameter for most cable grafting needs, and
relatively dispensable. Other graft sources include
the anterior branch of the medial antebrachial
cutaneous nerve, the lateral femoral cutaneous
nerve, and the superficial radial sensory nerve.1
The technique of nerve grafting involves sharply
transecting the injured nerve ends to excise the
zone of injury. The nerve ends should display a
good fascicular pattern. The defect is measured,
and the appropriate length of graft is harvested to
allow reconstruction without tension. If the
injured nerve has a large diameter relative to the
nerve graft, several cable grafts are placed in
parallel to reconstruct the nerve. The grafts are
matched to corresponding fascicles and sutured to
the injured nerve with epineurial sutures, as in the
primary neurorrhaphy technique. Fibrin glue
maybe used to connect the cable grafts,thus
decreasing the number of sutures and minimizing
additional
trauma to the nerve grafts. The surgeon can make
fibrin glue intraoperatively by mixing thrombin
and fibrinogen in equal parts, as originally
described by Narakas.

Although nerve grafts have not generally been
considered polarized, it is recommended that the
graft be placed in a reversed orientation in the
repair site. Reversal of the nerve graft decreases
the chance of axonal dispersion through distal nerve branches. A well-vascularized bed is
critical for nerve grafting. The graft should be
approximately 10% to 20% longer than the gap
to be filled, as the graft inevitably shortens with
connective tissue fibrosis. The graft repair site
and the graft itself have been demonstrated to
regain the same tensile strength as the native
nerve by 4 weeks; therefore, the limb is usually
immobilized during this initial period to protect
the graft
Allografts
Allografts have several potential clinical
advantages: (1) grafts can be banked; (2) there is
no need for sacrifice of a donor nerve; and (3)
surgical procedures are quicker without the need
to harvest a graft. However, allografts are not as
effective as
autografts, mainly due to the immunogenic host
response. Ansselin and Pollard17 studied rat
allograft nerves and found an increase in helper T
cells and cytotoxic/suppressor T cells, implying
immunogenic rejection. The cellular component
of allografts.and with it, their
immunogenicity.can be destroyed by freeze-
thawing. This leads to the production of cell
debris, which in turn impairs neurite outgrowth.
Dumont and Hentz18 reported on a biologic
detergent technique that removes the
immunogenic cellular components without
forming cell debris. Their experiments in rats
have shown that allografts processed with this
detergent had equivalent postrepair results
compared with autografts.
Rehabilitation of Nerve
Injuries
The preoperative goals in a denervated extremity
are to protect it and to maintain range of
motion,so that it will be functional when
reinnervated. Splinting is useful to prevent
contractures and deformity. Range-of-motion
exercises are imperative while awaiting axonal
regeneration, so as to maintain blood and
lymphatic flow and prevent tendon adherence.
The extremity must be kept warm, as cold
exposure damages muscle and leads to fibrosis.
Judicious bandaging protects and limits venous
congestion and edema. Direct galvanic
stimulation reduces muscle atrophy and may be
of psychological benefit to the patient during the
prolonged recovery phase, but has not been
unequivocally demonstrated to enhance or
accelerate nerve recovery or functional outcome.
During reinnervation of the limb,
continued motor and sensory rehabilitation are
critical. Pool therapy can be helpful to improve
joint contractures and eliminate the effects of
gravity during initial motor recovery, thereby
enhancing muscular performance. Biofeedback
may provide sensory input to facilitate motor
reeducation. Early-phase sensory reeducation
decreases mislocalization and hypersensitivity
and reorganizes tactile submodalities, such as
pressure and vibration. Later goals include
recovery of tactile
gnosis.
Evaluation of Recovery
The most widely used grading
system for nerve recovery is that developed by
the Medical Research Council for the evaluation
of both motor and sensory return (Table 2).
Motor recovery is graded M0 through M5, and
sensory recovery is graded S0 through S4 on the
basis of the physical examination. An excellent
result is described as M5,S4; a very good result,
M4,S3+; good, M3,S3; fair, M2,S2-2+; poor,
M0-1,S0-1. Objective measurement of sensory
recovery includes density testing by use of
moving and static two-point discrimination and
threshold testing by use of Frey or Semmes-
Weinstein filaments. Measurement of grip and
pinch strength is of limited use because of
inability to discriminate among early levels of
recovery and the fact that both the median and the
ulnar nerve contribute to pinch and grip function.
Results
The first large series of results of nerve repairs
came from Woodhall and Beebe in 1956; they
reported on 3,656 injuries sustained during World
War II, with an average 5- year follow-up.19 The
results were relatively poor, tainting the concept
of nerve repair in the minds of surgeons for years.
It must be remembered that these injuries were
pre.antibiotic era war injuries with large areas of
soft-tissue destruction and wound contamination.
Repairs were performed without the benefit of
modern microsurgical technique
. The results from subsequent studies
in which modern surgical techniques were used
have been more encouraging. In a large
compilation of data from a 40-year period,
Mackinnon and Dellon19 reported that very good
results (M4,S3+) were obtained in approximately
20% to 40% of cases. Very few injuries
recovered fully, and war injuries generally did
worse.
A more recent series of primary
repairs and fascicular grafts in 132 patients with
median nerve injuries showed good to excellent
results in 47 of 98 patients (48%) treated with
grafting and in 17 of 34 patients (50%) treated
with secondary neurorrhaphy. 20 Overall, 65 of
132 patients (49%) had good to excellent results, 14 (11%) had fair results, and 53 (40%) had poor
results. Results were poor in four situations:
(1) the patient was more than 54 years old; (2) the
level of injury was proximal to the elbow; (3) the
graft length was greater than 7 cm; or (4) the
surgery was delayed more than 23 months.

In a separate series of 33 radial nerve repairs
treated with grafting or secondary neurorrhaphy,
Kallio et al21 demonstrated useful (good to
excellent) results in 21 patients. Grafting was
done in 21 cases and resulted in useful recovery
in 8. Vastamäki et al22 reviewed the data on 110
patients after ulnar nerve repair and demonstrated
useful recovery in 57 patients (52%).
In a study by Wood23 of 11 peroneal nerve
reconstructions, 9 were treated with nerve
grafting and 2 with direct neurorrhaphy. In the 9
patients treated with grafting, the results were
excellent in 2, good in 2, fair in 3, and poor in 2.
The only statistically significant prognostic factor
was nerve graft length. All 4 patients with nerve
grafts measuring 6 cm or less had good or
excellent results; in contrast, all 5 patients with
grafts longer than 6 cm or less had good or
excellent results; in contrast, all 5 patients with
grafts longer than 6 cm had fair or poor results.
Of the 2 patients treated with direct neurorrhaphy,
1 had an excellent result, and 1 had a good result.
On the basis of 40 years. Experience with nerve
repairs, Sunderland1 made a number of
generalizations regarding nerve reconstruction
results. He found that (1) young patients
generally do better than old patients; (2) early
repairs do better than late repairs; (3) repairs of
singlefunction nerves do better than mixednerve
repairs; (4) distal repairs do better than proximal
repairs; and (5) short nerve grafts do better than
long nerve grafts.
Strategies to Improve
Results
Because of the relatively large number of fair to
poor results still being obtained in civilian
injuries with modern microsurgical technique,
much research is being done to alter regeneration
mechanisms and improve results of nerve repair.
The strategies to improve results fall into four
major categories: pharmacologic agents, immune
system modulators, enhancing factors, and
entubulation chambers. Pharmacologic agents
work on the molecular level to alter nerve
regeneration. Horowitz24 has shown the positive
effects of gangliosides on rat sciatic nerve
regeneration. Gangliosides are neurotrophic (i.e.,
they aid in the survival and maintenance of
neurons) and neuritogenic (i.e., they aid in
increasing the number and size of branching
neural processes). Klein et al25 have shown
forskolin to be an activator of adenylate cyclase
that increases neurite outgrowth in vivo. Wong
and Mattox26 have shown that polyamines work
on the molecular level to increase the functional
recovery of rat
sciatic nerve.
Immune system modulators work by decreasing
fibrosis and/or histiocytic response. In a murine
model, ganglioside-specific autoantibodies have
been demonstrated after nerve injury. In that
gangliosides are neurotrophic and neuritogenic, it
is evident that antibodies to them would be
deleterious to nerve regeneration.27 Azathioprine
and hydrocortisone decrease the levels of these
autoantibodies, thereby imparting a protective
effect on gangliosides after nerve-blood barrier
disruption. Regarding other modulators, Sebille
and Bondoux- Jahan28 have shown that
cyclophosphamides increase motor recovery in
rat sciatic nerve. Bain et al29 have shown that
cyclosporin A increases nerve recovery in
primate and rat models.
The numerous enhancing factors include nerve
growth factor, ciliary neurotrophic factor, motor
nerve growth factor, laminin, fibronectin, neural
cell adhesion molecule, Ncadherin, acidic and
basic fibroblast growth factor, insulinlike growth
factor, and leupeptin. Nerve growth factor is
chemotrophic to regenerating neurons, as
demonstrated by the classic experiments first
done by Cajal in the early 1900s. Recent studies
lend support to these original theories. In animal
studies simi- lar to those of Cajal, a transected
nerve is allowed to regenerate toward appropriate
and inappropriate receptor nerve segments on
either end of a Y-shaped tubing. Axons have been
demonstrated to grow preferentially in a ratio of
2:1 to the appropriate nerve end.30 Other studies
have used Y chambers to show that nerves
preferentially grow toward their distal stump,
rather than toward tendon.31 Proximal motor
axons have been shown to grow preferentially
toward their distal motor axons instead of their
sensory axons.32 Although trophic factors
undoubtedly play a role in nerve regeneration
specificity, proper end-organ reinnervation is
essential to ultimate function. A considerable
pruning effect has been demonstrated to occur
after axonal mismatch and
initial reinnervation.

Entubulation chambers are an intriguing concept,
and extensive research is under way to better our
understanding of their effects. These chambers
are hollow cylindrical tubes that serve as the
conduit for loosely approximated nerve ends.
They allow decreased surgical handling of nerve
ends and thus decreased scarring. Use of
entubulation chambers leaves a small intentional
gap between nerve ends, which allows fascicular
rerouting. Entubulation chambers may also allow
local introduction of some of the previously mentioned pharmacologic agents, immune system
modulators, and enhancing factors.33

Entubulation chambers can be made
from a variety of materials. Some that are
currently being investigated include silicone,
Gore-Tex, autogenous vein or dura, and
polyglycolic
acid.34 Hentz et al33 have stated that
tubularization offers no advantage over epineurial
repair. Lundborg et al12 reported on the treatment
of 18 patients with silicone tubes and a 3- to 4-
mm repair gap. They stressed the importance of
using slightly larger tubes to prevent nerve
compression. Sensory and motor testing after 1
year showed improvement of tactile sensation
with tubularization; other variables were not
statistically different. Research is under way to
find a material that will allow diffusion of
nutrients, blood, and locally introduced factors;
will prevent aberrant sprouting; and will resorb
with time
Summary
Despite more than 100 years of intense laboratory
and clinical investigations, results of nerve
repairs are somewhat discouraging, with only
50% of patients regaining useful function. The
current standard of treatment is immediate
epineurial repair with nylon suture. If primary
repair would place more than modest tension on
the anastomosis, nerve-cable autografts are
employed to bridge the gap. At this time, there is
much research under way, and pharmacologic
agents, immune system modulators, enhancing
factors, and entubulation chambers offer promise
for future improvement innerve repair outcomes.
References
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2. Seddon HJ: Surgical Disorders of the
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3. Manthorpe M, Skaper SD, Williams LR, Varon
S: Purification of adult rat sciatic nerve ciliary
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4. Slack JR, Hopkins WG, Pockett S: Evidence
for a motor nerve growth factor. Muscle Nerve
1983.
5. Madison R, da Silva CF, Dikkes P, Chiu TH,
Sidman RL: Increased rate of peripheral nerve
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containing gel. Exp Neurol 1985.
6. Gundersen RW: Response of sensory neurites
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7. Dodd J, Jessell TM: Axon guidance and the
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9. Cordeiro PG, Seckel BR, Lipton SA, D.Amore
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