CASE REPORT
Neurological Recovery Across a 12-cm-Long Ulnar
Nerve Gap Repaired 3.25 Years Post Trauma:
Case Report
Damien P. Kuffler, PhD*
Onix Reyes, MD‡
Ivan J. Sosa, MD§
Jose Santiago-Figueroa, MDk
*Institute of Neurobiology, University of
Puerto Rico, San Juan, Puerto Rico;
‡Doctor’s Center Hospital, Manati, Puerto
Rico; §Section of Neurosurgery, University of Puerto Rico, San Juan, Puerto Rico;
kDepartment of Orthopedic Surgery,
University of Puerto Rico, San Juan,
Puerto Rico
Correspondence:
Damien Kuffler, PhD,
Institute of Neurobiology,
201 Blvd. del Valle,
San Juan, Puerto Rico 00901.
E-mail: [email protected]
Received, July 6, 2010.
Accepted, March 10, 2011.
Published Online, June 24, 2011.
Copyright ª 2011 by the
Congress of Neurological Surgeons
BACKGROUND AND IMPORTANCE: The standard clinical technique for repairing
peripheral nerve gaps is the use of autologous sensory nerve grafts. The present study
tested whether a collagen tube filled with autologous platelet-rich fibrin could induce
sensory and motor recovery across a 12-cm nerve gap repaired 3.25 years post trauma,
and reduce or eliminate neuropathic pain.
CLINICAL PRESENTATION: Two years postrepair, good ring and small finger motor
function had developed that could generate 1 kg of force, and topographically correct
2-point discrimination and sensitivity to vibration in the small and ring finger and
proximal but not distal wrist had developed. The patient’s excruciating neuropathic pain
was reduced to tolerable, and he avoided the indicated extremity amputation. The
12-cm-long nerve gap was bridged with a collagen tube filled with autologous plateletrich fibrin.
CONCLUSION: We demonstrate that a conduit filled with platelet-rich fibrin can induce
limited, but appropriate, sensory and motor recovery across a 12-cm nerve gap repaired
3.25 years post trauma, without sacrificing a sensory nerve, can reduce existing
excruciating neuropathic pain to tolerable, and allow avoidance of an indicated upperextremity amputation. We believe the technique can be improved to induce more
extensive and reliable neurological recovery.
KEY WORDS: Nerve gaps, Nerve trauma, Neuropathic pain, Platelet-rich-fibrin
Neurosurgery 69:E1321–E1326, 2011
DOI: 10.1227/NEU.0b013e31822a9fd2
A
nnually, more than 50 000 peripheral
nerve repair procedures are performed in
the United States (National Center for
Health Statistics, 1995). Immediate neurorrhaphy of transected peripheral nerves leads to
almost perfect neurological recovery, neurorrhaphy #14 days postlesion leads to good
recovery in 49% of patients, and neurorrhaphy
14 days to 6 months leads to only reasonable
recovery in 28% of patients.1
One explanation for the reduced neurological
recovery with nerve repairs performed at increasing time post trauma is that long-term
axotomized neurons lose their ability to extend
axons,2 and that the denervated Schwann cells of
the distal nerve stump lose their ability to
ABBREVIATION:
Separation
NEUROSURGERY
GPS,
Gravitation
Platelet
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synthesize and release neurotrophic factors required to induce axon regeneration.3-6 However,
long-term transected axons can regenerate and
reinnervate newly denervated muscles even after
they have been transected for up to 22 years.7 In
addition, faster and more extensive generation
of long-term axotomized axons can be induced
if long-term axotomized neurons are electrically stimulated, or if neurotrophic factors are
administered to induce the denervated distal
nerve Schwann cells, causing them to release
neurotrophic factors that promote regeneration
of the axotomized neurons.8
The lack of reinnervation of long-term denervated targets is generally attributed to their
becoming irreversibly atrophied.9-12 However,
this belief is not well founded. Although longterm denervated intrinsic muscles undergo irreversible atrophy, extrinsic muscle fibers do not
and can be reinnervated. Therefore, following an
VOLUME 69 | NUMBER 6 | DECEMBER 2011 | E1321
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.
KUFFLER ET AL
ulnar nerve trauma, reinnervation must be established as soon as
possible before the intrinsic muscle targets become irreversibly
atrophied. This is most rapidly accomplished by performing
median to ulnar nerve or tendon transfers rather than the slower
nerve graft technique.13 For extrinsic muscles, which do not
become irreversibly atrophied, rapid reinnervation is not as
critical. Additional evidence supports the survival of long-term
denervated muscle fibers as follows: (1) denervated adult rat
muscles survive and can be reinnervated more than 1 year
postdenervation14; (2) human muscle denervated up to 3 years
contained atrophied, but intact muscle fibers among small immature myofibers.15-17 Thus, clinical evidence shows that human
muscle fibers do not irreversibly atrophy, which is probably
applicable to sensory targets.
When severed nerve ends cannot be coupled because of the
length of a nerve gap, the clinical standard for inducing neurological recovery across a nerve gap is to graft one or more lengths
of autologous sensory nerve between the nerve ends. However,
such grafts have limitations. One is that when sensory nerve grafts
are used to bridge extremity peripheral nerve gaps, good neurological recovery is generally limited to gaps of 5 to 8 cm
in length. However, it has recently been shown that 1 patient
recovered neurological function when an 11-cm nerve gap was
repaired by the use of a sural nerve graft.18-21 Another limitation
of sensory nerve grafts is that they are considered beneficial
generally when the nerve repair is performed ,9 months postlesion and in younger patients.22-27 Then, using sensory nerve
grafts has the negative impact of creating a permanent sensory
deficit. Therefore, it would be beneficial to have a nerve repair
technique that was effective in inducing neurological recovery
across long nerve gaps, for repairs performed at long times post
trauma and that did not require creating a sensory deficit.
One explanation for sensory nerve grafts inducing limited axon
regeneration and neurological recovery is that, although it is
generally accepted that pure sensory peripheral nerve graft
Schwann cells promote both sensory and motor axon regeneration,
evidence shows that they are more effective in promoting sensory
than motor axon regeneration.28 Thus, the observed motor axon
regeneration is due not as much to the sensory Schwann cells but to
their laminin-rich extracellular matrix.29 This is best explained by
sensory nerve Schwann cells not releasing the appropriate combinations of factors required to promote motor axon regeneration.29 Another explanation for limited axon regeneration is
that the cells within sensory nerve grafts become ischemic, which
creates a toxic environment that inhibits axon regeneration.30-32
Alternative techniques have been tested for bridging nerve gaps
to induce axon regeneration and neurological recovery. Among
these are acellular nerve grafts,33 empty collagen tubes,34,35 empty
fibrin tube,36 biocompatible noncollagen tubes,37 collagen tubes
filled with pure fibrin,38 nerve grafts plus fibrin,39 and arteries,
veins, and muscle tubes.40 These techniques are generally only as
effective as autologous sensory nerve grafts and therefore are
applied clinically. Despite their limitations, sensory nerve grafts
remain the standard clinical technique for repairing nerve gaps.
E1322 | VOLUME 69 | NUMBER 6 | DECEMBER 2011
METHODS
Patient Selection
A 48-year-old male patient presented at the University District Hospital
3.25 years following an ulnar nerve trauma at the elbow; he had no ulnar
nerve function and was experiencing excruciating neuropathic pain. The
patient had never undergone any previous nerve repair surgery and was
seeking complete upper extremity amputation to reduce or eliminate his
excruciating neuropathic pain, which was not being alleviated by morphine. The patient was offered the opportunity to participate in an institutional review board-approved nerve repair study with the guarantee of
an extremity amputation if his pain was not reduced to what he considered
a satisfactory level. The patient agreed to participate in the study.
Motor Recovery Analysis
Motor control was assessed by asking the patient to move, extend,
and flex his fingers and hand, while muscle strength was determined
with the use of a strain gauge. The extent of recovery of motor function
of the operated hand was analyzed using the British Medical Research
Council motor function scale,25,41 which involves a 6-point grading
scale: grade 5, muscle contracts normally against full resistance; grade 4,
muscle strength is reduced, but muscle contraction moves joint against
resistance; grade 3, muscle strength is further reduced to where a joint
can be moved only against gravity; grade 2, muscle can move only if
the resistance of gravity is removed; grade 1, only a trace of movement
is seen; grade 0, no movement is observed.
Sensory and Pain Analysis
The degree of the patient’s pain was evaluated by asking the patient
to classify his pain on a scale of 0 to 10, where 0 equaled no pain, and
10 equaled debilitating pain.
Sensitivity to touch was assessed by stroking the skin with a Q-tip, to
cold temperature by wiping the skin with an alcohol swab, to pressure by
pressing the skin with a fine stylus, to pain by pressing the skin with
a pin, and to vibration by applying a tuning fork to the skin.
Following the initial assessment that the patient had no ulnar nerve
motor or sensory function, exploratory surgery was performed to
examine the site of the apparent nerve trauma. The ulnar nerve was
found to be completely transected and to have a several centimeter gap,
with many centimeters of macerated nerve. Based on these observations,
it was decided that an electrophysiological assessment was not required.
However, before the nerve repair, a second motor and sensory nerve
function analysis was performed as described and no nerve motor or
sensory function was found.
Preparation of Platelet-Rich Fibrin
After administering general anesthesia, but before any surgical interventions, 50 mL of whole blood were collected from a peripheral vein. The
whole blood was put into an EBI Biomet Corp. (Warsaw, Indiana) disposable Gravitation Platelet Separation (GPS) centrifuge tube containing
citrate-based anticoagulant, and the tube was placed in a GPS centrifuge
where it was spun at 3200 rpm for 12 minutes leading to the separation of
about 8 mL of highly concentrated unactivated platelet-rich fibrin.
Collagen Bridging Tube
Two 2 3 8 cm sheets of collagen (Veritas, Synovis Life Technologies,
St. Paul, Minnesota), Food and Drug Administration-approved for soft
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REPAIRING LONG NERVE GAPS
tissue repair, were sewn end-to-end by using 3-0 polypropylene sutures
and then into a tube with the use of polypropylene sutures, and the
handle of a surgical tool with a diameter slightly larger than the nerve to
be repaired was used as a template.
Surgery
Under full anesthesia, the ulnar nerve injury site was exposed at the
elbow, showing nerve transection with massive maceration. The proximal nerve stump was refreshed to where, under visual inspection, it
looked anatomically normal, and the distal nerve stump was refreshed to
where no scarring was apparent under visual inspection. After the nerve
stumps were refreshed, the nerve had a 12-cm long gap.
The 16-cm-long collagen tube was cut 8 mm longer than the nerve
gap. This allowed both nerve ends to be secured 3 mm into the ends of
the collagen tube with polypropylene sutures around the tube’s entire
circumference through the tube and the nerve epineurium (Figure, A).
The additional 2 mm of tube length were to avoid placing the repaired
nerve under tension.
Autologous Platelet-Rich Fibrin
After securing the collagen tube in place, a fine cannula attached to
a syringe filled with saline solution was inserted into the distal end of the
tube, and the tube was flushed to wash out blood and any debris (Figure, B).
A 10-mL syringe containing 8 mL of autologous platelet-rich fibrin
and a 1-mL syringe containing thrombin plus calcium chloride were
attached to 2 in-ports of a ratio mixer (Micromedics, Inc, St. Paul,
Minnesota), and a fine flexible catheter was attached to the out-port. The
catheter was inserted from the distal to the central end of the collagen
tube, and was slowly withdrawn as the 2 syringe plungers were
FIGURE. Repair of a 12-cm ulnar nerve gap. A, 2 sheets of collagen sewn endto-end and then into a tube placed in the 12-cm-long nerve gap. B, the collagen
tube being filled with platelet-rich fibrin. C, the collagen tube filled with
autologous platelet-rich fibrin.
NEUROSURGERY
simultaneously pressed, causing the syringe contents to mix and be
ejected, thus entirely filling the collagen tube (Figure, C). The fibrin
polymerized in about 20 seconds, and the incision was closed.
RESULTS
Pain Reduction
Slightly less than 3 months post surgery, but before any signs of
neurological recovery, the patient’s excruciating neuropathic pain
began to decrease. By 1 year post surgery the patient’s pain had
decreased significantly and he had reduced his self-administered
analgesic from morphine to a mild analgesic. By 1.5 years post
surgery the patient stated that his neuropathic pain was so reduced that he no longer wanted an upper-extremity amputation.
By 2 years post surgery the patient’s neuropathic pain had decreased to a tolerable level, and he was no longer taking any
analgesics.
Although by 2 years post surgery the patient still had some
pain, it was no longer associated with the ulnar nerve injury site
and had shifted from his hand to a specific region of the medial
portion of his upper arm, where previously no pain had existed.
He also had slight Tinel pain in the lower arm and hand, secondary to the nerve regeneration process. That pain continued to
decrease, and the Tinel continued to extend further into the hand
and fingers over the following 6 months.
Development of Sensitivity and Motor Function
By 3 months post surgery, the operated hand of the patient
began to show signs of neurological recovery, starting with the
development of topographic sensitivity in his hand appropriate
for the ulnar nerve. By 1.5 years post surgery the patient had
developed appropriate topographic 2-point discrimination of
about 4 mm. Electromyelogram and evoked potential recordings
indicated that the repaired nerve conduction velocity was still
increasing.
By 1.5 years after nerve repair, muscles associated with the
repaired ulnar nerve began to twitch, indicating initiation of
motor innervation. By 2 years post surgery, the patient had full
flexion of superficial flexor muscles of his ring finger with motor
force of grade 5 using the British Medical Research Council
motor function scale. He also had extrinsic grade 4 motor
function of his small and ring fingers, and the ability to move
them and generate 1 kg of force. The intrinsic muscles had grade
0 function, with no movement observed. At that time, the patient
was able to return to his original profession as a farmer, although
doing lighter work than before the nerve trauma.
By 3 years after nerve repair, the patient had developed
vibration sensitivity in his small and ring fingers, and in the
proximal but not distal portion of his wrist.
DISCUSSION
Although autologous sensory nerve grafts are the standard
clinical technique for repairing peripheral nerve gaps, they have
VOLUME 69 | NUMBER 6 | DECEMBER 2011 | E1323
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KUFFLER ET AL
several limitations in inducing neurological recovery. Neurological recovery of extremity peripheral nerves (1) is generally good
for nerve gaps 5 to 8 cm in length, but decreases with increasing
gap length, and recovery has not been reported for gaps 12 cm or
longer42-45; (2) decreases with increasing time between trauma
and repair with no recovery for repairs performed .12 months
after nerve trauma2; (3) requires sacrificing a sensory nerve
function; and (4) has no influence in reducing existing neuropathic pain. Although many alternative techniques have been
tested, autologous sensory nerve grafts remain the standard for
clinical peripheral nerve repair.43,46,47
The present experiment was designed to determine whether
neurological recovery could be induced across a 12-cm-long nerve
gap bridged with a collagen tube filled with autologous plateletrich fibrin when the nerve repair was performed 3.25 years post
trauma. It was also designed to determine whether of the technique influenced the degree of existing neuropathic pain.
Bridging the 12-cm nerve gap 3.25 years after an ulnar nerve
trauma using only a collagen tube filled with autologous plateletrich fibrin led to recovery of both muscle and sensory function.
The limited sensory and motor recovery might have resulted from
applying the technique at the limits of its effectiveness, or that
additional factors or techniques are simultaneously required
to enhance the influence of the technique. However, even the
recovery that was achieved was an enormous quality-of-life
improvement for the patient, especially in reducing the excruciating neuropathic pain to tolerable, which allowed the patient to
return to work and avoid an upper extremity amputation.
Extensive data from adult rat muscle denervation, atrophy, and
reinnervation experiments show that rat muscles do not generally
become reinnervated more than 9 months after denervation.8
This is attributed to irreversible atrophy of the long-term denervated muscle fibers.9-12,14 But even among animal models,
denervation-triggered irreversible atrophy is not consistent. Oneyear denervated rat, but not rabbit tibialis anterior muscles show
a 50 to 60% reduction in muscle mass and cross-sectional area,
while rabbit, but not rat muscles can be reinnervated after 1 year
of denervation.48
The present study shows that adult human muscle fibers can be
reinnervated 3.25 years after denervation. This result is consistent
with data from a number of clinical studies showing that longterm denervated human muscles are resistant to atrophy,49
human muscles retain the ability to be reinnervated through
2 years of denervation,16 and that 3-year denervated human
muscles retain large-diameter denervated muscle fibers,17 and
small immature myofibers are associated with the intact atrophied
muscle fibers.15 Therefore, not all long-term human muscle fibers
atrophy irreversibly, and neurological function can be restored as
shown in the present case. An important issue raised by these data
is that caution is required when extrapolating from data from rat
studies to other animal models or humans
The neurological recovery in the present study shows that
long-term axotomized adult human sensory and motor neurons
can extend axons. Because this is generally not observed when
E1324 | VOLUME 69 | NUMBER 6 | DECEMBER 2011
sensory nerve grafts are used, this suggests that platelet-released
factors were responsible for inducing the axon regeneration. In
addition, some of the platelet-released factors could also have
interacted with denervated Schwann cells of the distal nerve to
induce them to synthesize and release the factors that could
contribute to promoting axon regeneration.10
The successful neurological recovery in the present study was
achieved with the use of the Biomet GPS Separation System.
Without further similar studies using platelet-rich fibrin separated
with the use of other techniques, we will not know whether the
present success resulted specifically from using the Biomet BPS
System or another aspect of the applied technique. Therefore, the
reviewer raises the excellent point as to why multiple studies, all
using platelet-rich fibrin, resulted in such different results, with
our study on a 12-cm-long nerve gap showing neurological recovery, while other studies working with relatively short nerve
gaps failed to find any neurological recovery.50,51 We hypothesize
that the differences resulted from the use of different techniques
to isolate the platelet-rich fibrin. To determine whether this is the
case requires further experimental studies. Such studies would
need to examine 3 parameters of the platelet-rich fibrin separation
techniques. Under identical experimental conditions, it should be
determined (1) what is the extent of axon regeneration and
neurological recovery achieved when platelet-rich fibrin is separated from whole blood using different techniques; (2) what are
the relative concentrations of separated platelets in the most
successful techniques; (3) what are the relative yields of separated
activated vs unactivated platelets in the successful techniques. A
final important study would be to determine the minimum
concentration of unactivated platelets required to induce sufficient axon regeneration to achieve neurological recovery and
whether increasing the concentration of platelets increases the
extent of axon regeneration and neurological recovery. Such
studies would indicate which of the existing platelet separation
techniques most reliably leads to sufficient axon regeneration and
neurological recovery, and this information could lead to the
development of a standardization of platelet separation techniques that are optimized for promoting axon regeneration and
neurological recovery.
Neuropathic pain can be reduced, if only for short periods, by
refreshing the central nerve stump or when transected axons
reinnervate their targets.52 Therefore, it is possible that the
observed reduction in neuropathic pain resulted from refreshing
the central nerve stump. However, the neuropathic pain began to
be reduced before any neurological recovery started to develop and
it was suppressed for more than 4 years. Both these observations
suggest that the reduced pain resulted from the direct action of
platelet-released factors on transected nociceptive axons.
CONCLUSION
The present data demonstrate that a human peripheral nerve
gap up to 12 cm in length repaired up to 3.25 years after nerve
trauma with a collagen tube filled with autologous platelet-rich
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REPAIRING LONG NERVE GAPS
fibrin can recover sensory and motor function. Simultaneously,
this technique can reduce existing neuropathic pain from excruciating to tolerable, and it can avoid sacrificing a sensory nerve.
Thus, this technique is more effective than the use of autologous
sensory nerve grafts for this function. These results should encourage the application of this or similar techniques to induce
enhanced axon regeneration and neurological recovery in patients
with long nerve gaps and for any nerve gap repair that must be
repaired at a long time post trauma. The significant reduction in
neuropathic pain induced by the single application of platelet-rich
fibrin to the refreshed central nerve stump suggests that this
approach may also reduce chronic neuropathic pain in cases of
painful peripheral neuropathies and for amputees experiencing
severed nerve chronic pain.
Disclosures
Except for limited personal financial contributions by several of the
authors, no external financial support was involved in performance of this
study. Biomet donated the GPS centrifuge and centrifuge tubes used to isolate
the platelet-rich fibrin, but this did not involve any financial or other
commitment to or from Biomet and/or the authors. None of the authors has
any financial or other interests in the materials used in this study. The authors
have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.
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Acknowledgments
We gratefully thank EBI Biomet for the GPS centrifuge and disposables used in
this surgery and Micromedics, Inc for the ratio mixer tips. This surgery was
performed under an institutional review board-approved clinical study proposal
and only after the patient provided informed consent.
COMMENT
A
s supported by prospective studies, tubular repair in humans has
emerged as an acceptable surgical technique for bridging nerve gaps.
The major limitation of tubulization grafting technique is the fact that it
E1326 | VOLUME 69 | NUMBER 6 | DECEMBER 2011
can be used only for short distances. Although previous experimental
studies have demonstrated effective regeneration after using conduits
filled with different constituents to bridge long gaps,1,2 there is a scarcity
of human literature on this subject with conflicting results regarding the
clinical outcome.3-5
This particular case here reported by Kuffler et al presents some
characteristics classically related to poor outcome after peripheral nerve
surgery including long nerve defect and late surgery. Contrary to what
one might expect, an appropriate recovery of both sensory and motor
function was observed even after surgery performed 3.25 years after ulnar
nerve injury. The platelet-rich fibrin used to fill the conduit might
explain this striking outcome, but contradictory results published in this
field do not support this technique. So, as pointed out by the authors,
further experimental investigation is needed to investigate the different
techniques used to prepare platelet-rich fibrin and its influence on axonal
regeneration. The authors should be encouraged to pursue their investigation in this field.
Roberto S. Martins
São Paulo, Brazil
1. Matsumoto K, Ohnishi K, Kiyotani T, Sekine T, Ueda H, Nakamura T, Endo K,
Shimizu. Peripheral nerve regeneration across an 80-mm gap bridged by a polyglycolic acid (PGA)-collagen tube filled with laminin-coated collagen fibers: a histological and electrophysiological evaluation of regenerated nerves. Brain Res. 2000;
23;868(2):315-328.
2. Mohanna PN, Young RC, Wiberg M, Terenghi G. A composite poly-hydroxybutyrate-glial growth factor conduit for long nerve gap repairs. J Anat.
2003;203(6):553-565.
3. Stanec S, Stanec Z. Ulnar nerve reconstruction with an expanded polytetrafluoroethylene conduit. Br J Plast Surg. 1998;51(8):637-639.
4. Weber RA, Breidenbach WC, Brown RE, et al. A randomized prospective study of
polyglycolic acid conduits for digital nerve reconstruction in humans. Plast Reconstr
Surg. 2000;106(5):1036-1045.
5. Moore AM, Kasukurthi R, Magill CK, Farhadi HF, Borschel GH, Mackinnon SE.
Limitations of conduits in peripheral nerve repairs. Hand. 2009;4(2):
180-186.
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