Retrograde labeling correlates with motor unit number estimation in rapid-stretch nerve injury.

INTRODUCTION/AIMS: Rapid-stretch nerve injuries represent a substantial treatment challenge. No study has examined motor neuron connection after rapid-stretch injury. Our objective in this study was to characterize the electrophysiological properties of graded rapid-stretch nerve injury and assess motor neuron health using retrograde labeling and muscle adenosine triphosphatase (ATPase) histology. METHODS: Male C57BL/6 mice (n = 6 per group) were rapid-stretch injured at four levels of severity: sham injury, stretch within elastic modulus, inelastic deformation, and stretch rupture. Serial compound muscle action potential (CMAP) and motor unit number estimation (MUNE) measurements were made for 48 days, followed by retrograde labeling and muscle ATPase histology. RESULTS: Elastic injuries showed no durable abnormalities. Inelastic injury demonstrated profound initial reduction in CMAP and MUNE (P < .036) on day 2, with partial recovery by day 14 after injury (CMAP: 40% baseline, P = .003; MUNE: 55% baseline, P = .033). However, at the experimental endpoint, CMAP had recovered to baseline with only limited improvement in MUNE. Inelastic injury led to reduced retrograde-labeled neurons and grouped fiber type histology. Rupture injury had severe and nonrecovering electrophysiological impairment, dramatically reducing labeled neurons (P = .005), and atrophic or type 1 muscle fibers. There was an excellent correlation between MUNE and retrograde-labeled tibial motor neurons across injury severities (R2  = 0.96). DISCUSSION: There was no significant electrophysiological derangement in low-severity injuries but there was recoverable conduction block in inelastic injury with slow recovery, potentially due to collateral sprouting. Rupture injuries yielded permanent failure of injured axons to reinnervate. These results provide insight into the pathophysiology of clinical injuries and recovery.

Ultrasound of peripheral nerve injury.

Nerve injury in children is important to recognize early given the greater chance for recovery. Both children and adults have better outcomes the sooner nerve injuries are recognized and repaired. Children have even better functional results after surgical repair, thought to be related to their neural plasticity. Ultrasound is a powerful diagnostic tool for grading and mapping peripheral nerve injury and is complementary to electromyography and nerve conduction studies. Nerve injuries can be classified into low and high grade with ultrasound adding essential prognostic information and aiding in patient management. High-grade nerve injuries likely require surgical intervention. This article will review nerve anatomy and injury grading systems that radiologists can learn quickly in order to accurately communicate with their clinical partners. A practical approach to describe the sonographic appearance of nerve injury will be discussed. This article will show radiologists how the added value of ultrasound for peripheral nerve injury can directly affect clinical management.

A Case of Posterior Tibial Nerve Injury After Arthroscopic Calcaneoplasty.

We report the first case of distal posterior tibial nerve injury after arthroscopic calcaneoplasty. A 59-year-old male had undergone right arthroscopic calcaneoplasty to treat retrocalcaneal bursitis secondary to a Haglund's deformity. The patient complained of numbness in his right foot immediately after the procedure. Two years later and after numerous assessments and investigations, a lateral plantar nerve and medial calcaneal nerve lesion was diagnosed. In the operating room, the presence of an iatrogenic lesion to the distal right lateral plantar nerve (neuroma incontinuity involving 20% of the nerve) and the medial calcaneal nerve (complete avulsion) was confirmed. The tarsal tunnel was decompressed, and both the medial and the lateral plantar nerve were neurolyzed under magnification. To the best of our knowledge, our case report is the first to describe iatrogenic posterior tibial nerve injury after arthroscopic calcaneoplasty. It is significant because this complication can hopefully be avoided in the future with careful planning and creation of arthroscopic ports and treated appropriately with early referral to a nerve specialist if the patient's symptoms do not improve within 3 months.

MRI features of peripheral traumatic neuromas.

OBJECTIVES: To describe the MRI appearance of traumatic neuromas on non-contrast and contrast-enhanced MRI sequences. METHODS: This IRB-approved, HIPAA-compliant study retrospectively reviewed 13 subjects with 20 neuromas. Two observers reviewed pre-operative MRIs for imaging features of neuroma (size, margin, capsule, signal intensity, heterogeneity, enhancement, neurogenic features and denervation) and the nerve segment distal to the traumatic neuroma. Descriptive statistics were reported. Pearson's correlation was used to examine the relationship between size of neuroma and parent nerve. RESULTS: Of 20 neuromas, 13 were neuromas-in-continuity and seven were end-bulb neuromas. Neuromas had a mean size of 1.5 cm (range 0.6-4.8 cm), 100 % (20/20) had indistinct margins and 0 % (0/20) had a capsule. Eighty-eight percent (7/8) showed enhancement. All 100 % (20/20) had tail sign; 35 % (7/20) demonstrated discontinuity from the parent nerve. None showed a target sign. There was moderate positive correlation (r = 0.68, p = 0.001) with larger neuromas arising from larger parent nerves. MRI evaluation of the nerve segment distal to the neuroma showed increased size (mean size 0.5 cm ± 0.4 cm) compared to the parent nerve (mean size 0.3 cm ± 0.2 cm). CONCLUSION: Since MRI features of neuromas include enhancement, intravenous contrast medium cannot be used to distinguish neuromas from peripheral nerve sheath tumours. The clinical history of trauma with the lack of a target sign are likely the most useful clues. KEY POINTS: • MRI features of neuromas include enhancement and lack of a target sign. • Contrast material cannot be used to distinguish traumatic neuromas from PNSTs. • Traumatic neuromas can simulate peripheral nerve neoplasms on imaging.

Spectrum of superficial nerve-related tumor and tumor-like lesions: MRI features.

Superficial soft-tissue masses arising from skin appendages, metastasis, and inflammatory lesions have been widely reported. However, nerve-related superficial mass-like lesions other than peripheral nerve sheath tumors are less commonly described. High resolution magnetic resonance imaging (MRI) is an excellent non-invasive tool for the evaluation of such lesions. In this article, the authors discuss the entire spectrum of these lesions and also outline a systemic diagnostic approach.

Neuroma-in-continuity: a review of pathophysiology and approach to the affected patient.

A neuroma-in-continuity is a neuroma resulting from a nerve injury in which internal neuronal elements are partially disrupted (with a variable degree of disruption to the endoneurium and perineurium) while the epineurium typically remains intact. The portion of injured axons are misdirected and embedded in connective tissue, which may give rise to local neuroma pain and a distal nerve deficit. The lesion may result from a multitude of injury mechanisms, and clinical presentation is often variable depending on the nerve affected. Clinical, electrodiagnostic, and imaging examinations are helpful in assessing the extent and degree of the lesion. If no clear evidence of recovery is identified within 3-4 months post-injury, the patient may benefit from operative exploration. Surgical management options include neurolysis, neuroma resection, nerve grafting, and nerve transfer, or a combination of modalities. A primary consideration of surgery is the possibility of further downgrading nerve function in the pursuit of more, thereby highlighting the need to carefully weigh the advantages and disadvantages prior to surgical intervention. The objective of this review article is to describe the current understanding of the pathophysiology of neuroma-in-continuity lesions, and to review the approach to the affected patient including clinical evaluation, ancillary testing, and intraoperative assessment and treatment options.

A new insight on peripheral nerve repair: the technique of internal nerve splinting.

OBJECTIVE: Neuropathic pain produced by symptomatic neuromas is an important problem after peripheral nerve injury (PNI). End-to-end anastomosis of the nerve stump for PNI is well established but cannot efficiently prevent neuroma-in-continuity formation. METHODS: Sciatic nerve injury was used in the experimental model. Seventy-two rats were randomly divided into four groups: rats with nerve anastomosis sites supported with silicone tubes represented the internal nerve splinting (INS) group (n = 18); rats with end-to-end nerve anastomosis represented control group 1 (CON1) (n = 18); rats with INS and the nerve anastomosis site represented control group 2 (CON2) (n = 18); and rats that underwent the same surgical procedures for skin and muscle operations but without sciatic nerve injury represented the normal group (n = 18). RESULTS: Gross evaluations of the nerve anastomosis sites, gastrocnemius muscle atrophy, axonal regeneration and remyelination, neuropathic pain, and scar hyperplasia of the neuromas were performed, as well as motor function evaluations. Axonal regeneration, remyelination, and gastrocnemius muscle atrophy were similar between the INS group and CON1 (p > 0.05). However, neuropathic pain and scar hyperplasia-as evaluated according to the expression of anti-sigma-1 receptor antibody and anti-α-smooth muscle actin, respectively-and the weight ratios of the neuromas were reduced in the INS group compared with those of CON1 and CON2 (p < 0.05). CONCLUSIONS: Application of INS in nerve repair effectively prevented traumatic neuroma-in-continuity formation and inhibited neuropathic pain without influencing nerve regeneration in rats.

Functional Gait Assessment Using Manual, Semi-Automated and Deep Learning Approaches Following Standardized Models of Peripheral Nerve Injury in Mice.

Objective: To develop a standardized model of stretch−crush sciatic nerve injury in mice, and to compare outcomes of crush and novel stretch−crush injuries using standard manual gait and sensory assays, and compare them to both semi-automated as well as deep-learning gait analysis methods. Methods: Initial studies in C57/Bl6 mice were used to develop crush and stretch−crush injury models followed by histologic analysis. In total, 12 eight-week-old 129S6/SvEvTac mice were used in a six-week behavioural study. Behavioral assessments using the von Frey monofilament test and gait analysis recorded on a DigiGait platform and analyzed through both Visual Gait Lab (VGL) deep learning and standardized sciatic functional index (SFI) measurements were evaluated weekly. At the termination of the study, neurophysiological nerve conduction velocities were recorded, calf muscle weight ratios measured and histological analyses performed. Results: Histological evidence confirmed more severe histomorphological injury in the stretch−crush injured group compared to the crush-only injured group at one week post-injury. Von Frey monofilament paw withdrawal was significant for both groups at week one compared to baseline (p < 0.05), but not between groups with return to baseline at week five. SFI showed hindered gait at week one and two for both groups, compared to baseline (p < 0.0001), with return to baseline at week five. Hind stance width (HSW) showed similar trends as von Frey monofilament test as well as SFI measurements, yet hind paw angle (HPA) peaked at week two. Nerve conduction velocity (NCV), measured six weeks post-injury, at the termination of the study, did not show any significant difference between the two groups; yet, calf muscle weight measurements were significantly different between the two, with the stretch−crush group demonstrating a lower (poorer) weight ratio relative to uninjured contralateral legs (p < 0.05). Conclusion: Stretch−crush injury achieved a more reproducible and constant injury compared to crush-only injuries, with at least a Sunderland grade 3 injury (perineurial interruption) in histological samples one week post-injury in the former. However, serial behavioral outcomes were comparable between the two crush groups, with similar kinetics of recovery by von Frey testing, SFI and certain VGL parameters, the latter reported for the first time in rodent peripheral nerve injury. Semi-automated and deep learning-based approaches for gait analysis are promising, but require further validation for evaluation in murine hind-limb nerve injuries.

Rapid-stretch injury to peripheral nerves: comparison of injury models.

OBJECTIVE: Traditional animal models of nerve injury use controlled crush or transection injuries to investigate nerve regeneration; however, a more common and challenging clinical problem involves closed traction nerve injuries. The authors have produced a precise traction injury model and sought to examine how the pathophysiology of stretch injuries compares with that of crush and transection injuries. METHODS: Ninety-five late-adolescent (8-week-old) male mice underwent 1 of 7 injury grades or a sham injury (n > 10 per group): elastic stretch, inelastic stretch, stretch rupture, crush, primary coaptation, secondary coaptation, and critical gap. Animals underwent serial neurological assessment with sciatic function index, tapered beam, and von Frey monofilament testing for 48 days after injury, followed by trichrome and immunofluorescent nerve histology and muscle weight evaluation. RESULTS: The in-continuity injuries, crush and elastic stretch, demonstrated different recovery profiles, with more severe functional deficits after crush injury than after elastic stretch immediately following injury (p < 0.05). However, animals with either injury type returned to baseline performance in all neurological assessments, accompanied by minimal change in nerve histology. Inelastic stretch, a partial discontinuity injury, produced more severe neurological deficits, incomplete return of function, 47% ± 9.1% (mean ± SD) reduction of axon counts (p < 0.001), and partial neuroma formation within the nerve. Discontinuity injuries, including immediate and delayed nerve repair, stretch rupture, and critical gap, manifested severe, long-term neurological deficits and profound axonal loss, coupled with intraneural scar formation. Although repaired nerves demonstrated axon regeneration across the gap, rupture and critical gap injuries demonstrated negligible axon crossing, despite rupture injuries having healed into continuity. CONCLUSIONS: Stretch-injured nerves present unique pathology and functional deficits compared with traditional nerve injury models. Because of the profound neuroma formation, stretch injuries represent an opportunity to study the pathophysiology associated with clinical injury mechanisms. Further validation for comparison with human injuries will require evaluation in a large-animal model.

Testing the effectiveness and the contribution of experimental supercharge (reversed) end-to-side nerve transfer.

OBJECTIVE: Supercharge end-to-side (SETS) transfer, also referred to as reverse end-to-side transfer, distal to severe nerve compression neuropathy or in-continuity nerve injury is gaining clinical popularity despite questions about its effectiveness. Here, the authors examined SETS distal to experimental neuroma in-continuity (NIC) injuries for efficacy in enhancing neuronal regeneration and functional outcome, and, for the first time, they definitively evaluated the degree of contribution of the native and donor motor neuron pools. METHODS: This study was conducted in 2 phases. In phase I, rats (n = 35) were assigned to one of 5 groups for unilateral sciatic nerve surgeries: group 1, tibial NIC with distal peroneal-tibial SETS; group 2, tibial NIC without SETS; group 3, intact tibial and severed peroneal nerves; group 4, tibial transection with SETS; and group 5, severed tibial and peroneal nerves. Recovery was evaluated biweekly using electrophysiology and locomotion tasks. At the phase I end point, after retrograde labeling, the spinal cords were analyzed to assess the degree of neuronal regeneration. In phase II, 20 new animals underwent primary retrograde labeling of the tibial nerve, following which they were assigned to one of the following 3 groups: group 1, group 2, and group 4. Then, secondary retrograde labeling from the tibial nerve was performed at the study end point to quantify the native versus donor regenerated neuronal pool. RESULTS: In phase I studies, a significantly increased neuronal regeneration in group 1 (SETS) compared with all other groups was observed, but with modest (nonsignificant) improvement in electrophysiological and behavioral outcomes. In phase II experiments, the authors discovered that secondary labeling in group 1 was predominantly contributed from the donor (peroneal) pool. Double-labeling counts were dramatically higher in group 2 than in group 1, suggestive of hampered regeneration from the native tibial motor neuron pool across the NIC segment in the presence of SETS. CONCLUSIONS: SETS is indeed an effective strategy to enhance axonal regeneration, which is mainly contributed by the donor neuronal pool. Moreover, the presence of a distal SETS coaptation appears to negatively influence neuronal regeneration across the NIC segment. The clinical significance is that SETS should only employ synergistic donors, as the use of antagonistic donors can downgrade recovery.

A systematic review of animal models for experimental neuroma.

Peripheral neuromas can result in an unbearable neuropathic pain and functional impairment. Their treatment is still challenging, and their optimal management is to be defined. Experimental research still plays a major role, but - although numerous neuroma models have been proposed on different animals - there is still no single model recognised as being the reference. Several models show advantages over the others in specific aspects of neuroma physiopathology, prevention or treatment, making it unlikely that a single model could be of reference. A reproducible and standardised model of peripheral neuroma would allow better comparison of results from different studies. We present a systematic review of the literature on experimental in vivo models, analysing advantages and disadvantages, specific features and indications, with the goal of providing suggestions to help their standardisation. Published models greatly differ in the animal and the nerve employed, the mechanisms of nerve injury and the evaluation methods. Specific experimental models exist for terminal neuromas and neuromas in continuity (NIC). The rat is the most widely employed animal, the rabbit being the second most popular model. NIC models are more actively researched, but it is more difficult to generate such studies in a reproducible manner. Nerve transection is considered the best method to cause terminal neuromas, whereas partial transection is the best method to cause NIC. Traditional histomorphology is the historical gold-standard evaluation method, but immunolabelling, reverse transcriptase-polymerase chain reaction (RT-PCR) and proteomics are gaining increasing popularity. Computerised gait analysis is the gold standard for motor-recovery evaluation, whereas mechanical testing of allodynia and hyperalgesia reproducibly assesses sensory recovery. This review summarises current knowledge on experimental neuroma models, and it provides a useful tool for defining experimental protocols. Furthermore, it could help future research to define standard experimental model(s) of peripheral neuromas, allowing better comparison of results and improvement of our understanding of such a complex disease.

Peripheral nerve injury grading simplified on MR neurography: As referenced to Seddon and Sunderland classifications.

The Seddon and Sunderland classifications have been used by physicians for peripheral nerve injury grading and treatment. While Seddon classification is simpler to follow and more relevant to electrophysiologists, the Sunderland grading is more often used by surgeons to decide when and how to intervene. With increasing availability of high-resolution and high soft-tissue contrast imaging provided by MR neurography, the surgical treatment can be guided following the above-described grading systems. The article discusses peripheral nerve anatomy, pathophysiology of nerve injury, traditional grading systems for classifying the severity of nerve injury, and the role of MR neurography in this domain, with respective clinical and surgical correlations, as one follows the anatomic paths of various nerve injury grading systems.