A novel animal model of symptomatic neuroma for assessing neuropathic pain.

INTRODUCTION: Following amputation, peripheral nerves lack distal targets for regeneration, often resulting in symptomatic neuromas and debilitating neuropathic pain. Animal models can establish a practical method for symptomatic neuroma formation for better understanding of neuropathic pain pathophysiology through behavioral and histological assessments. We created a clinically translatable animal model of symptomatic neuroma to mimic neuropathic pain in patients and assess sexual differences in pain behaviors. METHODS: Twenty-two male and female rats were randomly assigned to one of two experimental groups: (1) neuroma surgery, or (2) sham surgery. For the neuroma experimental group, the tibial nerve was transected in the thigh, and the proximal segment was placed under the skin for mechanical testing at the site of neuroma. For the sham surgery, rats underwent tibial nerve isolation without transection. Behavioral testing consisted of neuroma-site pain, mechanical allodynia, cold allodynia, and thermal hyperalgesia at baseline, and then weekly over 8 weeks. RESULTS: Male and female neuroma rats demonstrated significantly higher neuroma-site pain response compared to sham groups starting at weeks 3 and 4, indicating symptomatic neuroma formation. Weekly assessment of mechanical and cold allodynia among neuroma groups showed a significant difference in pain behavior compared to sham groups (p < 0.001). Overall, males and females did not display significant differences in their pain responses. Histology revealed a characteristic neuroma bulb at week 8, including disorganized axons, fibrotic tissue, Schwann cell displacement, and immune cell infiltration. CONCLUSION: This novel animal model is a useful tool to investigate underlying mechanisms of neuroma formation and neuropathic pain.

Tibial nerve compression due to osteochondroma of the fibular head: A case report.

RATIONALE: Osteochondroma is one of the most common primary benign bone tumors. In most cases, this disease is asymptomatic. However, it may become symptomatic owing to nerve and vascular compression when it affects the knee joint. Isolated tibial nerve palsy caused by proximal fibular osteochondroma is rare. PATIENTS CONCERNS: A 60-year-old male, was treated for degenerative arthritis of the right knee, referred to the right great toe flexion limitation that occurred 3 weeks prior. DIAGNOSES: Magnetic resonance imaging revealed compression of the tibial nerve and surrounding muscles due to an osseous lesion in the fibular head. A nerve conduction test confirmed tibial neuropathy in the right lower leg. INTERVENTIONS: Exploratory surgery was performed to decompress the tibial nerve and remove the bony lesion histopathologically diagnosed as an osteochondroma. OUTCOMES: Fifty-five months postoperatively, toe flexion recovered to normal. No recurrence of osteochondroma was observed. LESSONS: As in our case, if a bony lesion is diagnosed on radiographs with neurological symptoms, early decompression surgery is necessary. Moreover, since it can be misdiagnosed as a simple bony spur, magnetic resonance imaging and tissue biopsy are also indicated.

Tarsal tunnel ganglion cyst: intraneural or extraneural site?

Intraneural ganglion cysts are very uncommon lesions, whose diagnosis has increased since the articular theory and the description of the MRI findings were established. We present a case report of a 59-year-old man with symptoms of tarsal tunnel syndrome. Foot and ankle MRI demonstrated the presence of an intraneural cystic lesion in the posterior tibial neve and its connection with the subtalar joint through an articular branch. The identification of the specific radiological signs like the «signet ring sign¼ allowed establishing an adequate preoperative diagnosis, differentiating it from an extraneural lesion and facilitating the articular disconnection of the nerve branch during surgery.

Utility of the tibial nerve somatosensory evoked potentials in differentiating between neuromyelitis optica spectrum disorders and multiple sclerosis.

BACKGROUND: Somatosensory evoked potentials (SEPs) are widely used for the diagnosis and evaluation of neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). However, whether the parameters of tibial nerve SEPs can help to distinguish NMOSD from MS remains unclear. Thus, the aim of this study was to investigate the utility of tibial nerve SEP parameters in differentiating patients with NMOSD and MS. METHODS: The clinical data of patients with NMOSD or MS treated in our institution between 2005 and 2021 were retrospectively extracted from our electronic database. Additional inclusion criteria were presentation with sensory symptoms in the lower extremities with corresponding lesions in the magnetic resonance images as well as available data on anti-aquaporin-4 antibodies and tibial nerve SEPs. The Z-scores of the N21-P38 interval (central sensory conduction time), P38 latency, and P38 amplitude were compared between the patients with NMOSD and MS. The relationship of disease severity with the parameters of the tibial nerve SEPs was also evaluated. RESULTS: Twenty patients with NMOSD and 13 patients with MS were enrolled. The Z-scores of the N21-P38 interval and P38 latency were significantly higher in the MS group than in the NMOSD group (p < 0.05 and p < 0.01, respectively), whereas there was no difference in the Z-scores of the P38 amplitude between the two groups. In the MS group, only the N21-P38 interval and P38 latency were significantly correlated with disease severity (p < 0.05 and p < 0.01, respectively). In contrast, none of the tibial nerve SEP parameters were significantly correlated with disease severity in the NMOSD group. CONCLUSION: Evaluation of the N21-P38 interval and P38 latency in tibial nerve SEPs potentially helps in differentiating between NMOSD and MS.

Neuromucormycosis of Posterior Tibial Nerve: A Rare Presentation of Mucormycosis.

Opportunistic fungal infections are known to occur in immunocompromised patients. Mucormycosis is one of the most common opportunistic fungal infections with significant mortality rates. In this article, we present a case of an adult female, a known diabetic who presented with fever and pus discharge from the amputation site of toes in the left foot with blackening of the foot. Examination revealed gangrenous changes of the left foot with no distal pulses palpable. Computed tomography angiogram revealed no flow of blood in distal vessels of the left lower limb. Left below knee guillotine amputation was done. Intraoperative biopsy of the neurovascular bundle revealed invasive neuromucormycosis. She was started on liposomal amphotericin B. The wound started granulating after a few days with serial dressings and the patient was planned for split skin grafting.

Electrical stimulation or tacrolimus (FK506) alone enhances nerve regeneration and recovery after nerve surgery, while dual use reduces variance and combines strengths of each in promoting enhanced outcomes.

INTRODUCTION/AIMS: Repaired nerve injuries can fail to achieve functional recovery. Therapeutic options beyond surgery, such as systemic tacrolimus (FK506) and electrical stimulation (E-stim), can improve recovery. We tested whether dual administration of FK506 and E-stim enhances regeneration and recovery more than either therapeutic alone. METHODS: Rats were randomized to four groups: E-stim, FK506, FK506 + E-stim, and repair alone. All groups underwent tibial nerve transection and repair. Two sets of animals were created to measure outcomes of early nerve regeneration using nerve histology (n = 36) and functional recovery (n = 42) (21- and 42-day endpoints, respectively). Functional recovery was measured by behavioral analyses (walking track and grid walk) and, at the endpoint, muscle mass and force. RESULTS: Dual E-stim and FK506 administration produced histomorphometric measurements of nerve regeneration no different than either therapeutic alone. All treatments were superior to repair alone (FK506, P < .0001; E-stim, P < .05; FK506 + E-stim, P < .05). The E-stim and FK506 + E-stim groups had improved behavioral recovery compared with repair alone (at 6 weeks: E-stim, P < .05; FK506 + E-stim, P < .01). The FK506 group had improved recovery based on walking-track analysis (at 6 weeks: P < .001) and muscle force and mass (P < .05). The concurrent use of both therapies ensured earlier functional recovery and decreased variability in functional outcomes compared with either therapy alone, suggesting a moderate benefit. DISCUSSION: Dual administration of FK506 and E-stim showed minimal additive effects to further improve regeneration or recovery compared with either therapy alone. The data suggest the combination of FK506 and E-stim appears to combine the relative strengths of each therapeutic.

Anatomy of the tibial nerve in relation to the tarsal tunnel: A cadaveric study.

BACKGROUND: Tarsal tunnel syndrome (TTS) is typically caused by an anatomical variant or mechanical compression of the tibial nerve (TN) with variable success after surgical treatment. METHOD: 40 lower-leg specimens were obtained. Dissections were appropriately conducted. Extremities were prepared under formaldehyde solution. The tibial nerve and branches were dissected for measurements and various characteristics. RESULTS: The flexor retinaculum had a denser consistency in 22.5% of the cases and the average length was 51.9 mm. The flexor retinaculum as an independent structure was absent and 77.2% of cases as an undistinguished extension of the crural fascia. The lateral plantar nerve (LPN) and abductor digiti minimi (ADM) nerve shared same origin in 80% of cases, 34.5% bifurcated proximal to the DM (Dellon-McKinnon malleolar-calcaneal line) line 31.2% distally and 34.3% at the same level. CONCLUSION: Understanding the tibial nerve anatomy will allow us to adapt our surgical technique to improve the treatment of this recurrent pathology.

Preoperative Imaging of Intraneural Ganglion Cysts: A Critical Systematic Analysis of the World Literature.

BACKGROUND: Advancements in imaging and an understanding of the pathomechanism for intraneural ganglion cyst formation have led to increased awareness and recognition of this lesion. However, the precise role of imaging has been advocated for but not formally evaluated. METHODS: We performed a systematic review of the world literature to study the frequency of imaging used to diagnose intraneural ganglion cysts at different sites and compared trends in identifying joint connections. RESULTS: We identified 941 cases of intraneural ganglion cysts, of which 673 had published imaging. Magnetic resonance imaging (MRI, n = 527) and ultrasonography (US, n = 123) were the most commonly reported. They occurred most frequently in the common peroneal nerve (n = 570), followed by the ulnar nerve at the elbow (n = 88), and the tibial nerve at the ankle (n = 58). A joint connection was identified in 375 cases (48%), with 62% of MRIs showing a joint connection, followed by 16% on US, and 6% on computed tomography (CT). MRI was statistically more likely to identify a joint connection than was US (P < 0.01). In the last decade, joint connections have been identified with increasing frequency using preoperative imaging, with up to 75% of cases reporting joint connections. CONCLUSIONS: Preoperative imaging plays an important role in establishing the diagnosis of intraneural ganglion cyst as well as treatment planning. Imaging has proved superior to the sole reliance of operative exposure to identify a joint connection, which is necessary to treat the underlying disease. Failure to identify cyst connections on imaging can result in an inability to truly address the underlying pathoanatomy at the time of definitive surgery, leading to a risk for clinical recurrence. Therefore, management should be guided by an intersection between new knowledge presented in the literature, clinical expertise, and surgeon experience.

Predictive factors of effective tibial nerve release in tarsal tunnel syndrome.

BACKGROUND: Factors that may affect surgical decompression results in tarsal tunnel syndrome are not known. METHODS: A retrospective single-center study included patients who had undergone surgical tibial nerve release. The effectiveness of decompression was evaluated according to whether the patient would or would not be willing to undergo another surgical procedure in similar preoperative circumstances. RESULTS: The patients stated for 43 feet (51%) that they would agree to a further procedure in similar circumstances. Six feet with space-occupying lesions on imaging had improved results, but neurolysis failed in 9 feet with bone-nerve contact. Neurolysis was significantly less effective when marked hindfoot valgus (p = 0.034), varus (p = 0.014), or fasciitis (p = 0.019) were present. CONCLUSIONS: If imaging reveals a compressive space-occupying lesion, surgery has a good prognosis. In feet with static hindfoot disorders or plantar fasciitis, conservative treatment must be optimized. Bone-nerve contact should systematically be sought.

A Minimally Invasive Full Endoscopic Approach to Tibial Nerve Neurolysis in Diabetic Foot Neuropathy: An Alternative to Open Procedures.

BACKGROUND: Dellon et al. have reported that chronic nerve compression of the tibial nerve inside the tarsal tunnel, caused by diabetes mellitus, can be relieved following open decompression surgery. However, the large skin incision resulting from Dellon's procedure may cause wound healing problems. The authors report the possibility of a minimally invasive full endoscopic procedure. METHODS: Operations were performed under local anesthesia without a pneumatic tourniquet. An anesthetic agent was applied at the proximal part of the flexor retinaculum of the foot, and a hypodermic needle was advanced into the tarsal tunnel. Tarsal tunnel pressure and blood circulation of the tibial nerve using indocyanine green assessment were measured preoperatively. One 1-cm portal skin incision was made at the anesthetized area and the Universal Subcutaneous Endoscope system was inserted into the tarsal tunnel. The flexor retinaculum, tibial nerve, blood vessels, and abductor hallucis muscle fascia were identified under endoscopic observation. After decompression of the tarsal tunnel, the authors measured tarsal tunnel pressure and blood circulation of the tibial nerve for analysis of the effectiveness of the endoscopic decompression during the procedure. RESULTS: Fourteen operations were compiled and analyzed. Postoperative clinical status was improved based on the preoperative modified Toronto Clinical Neuropathy Score. The mean tarsal tunnel pressure dropped to 4.5 mmHg during surgery from the initial preoperative 49.4 mmHg in resting position. Endoscopic indocyanine green assessment showed more than 30 percent improvement of the vascularity surrounding the tibial nerve. CONCLUSION: The authors' minimally invasive full endoscopic procedure is a viable alternative approach for tarsal tunnel syndrome patients with diabetic foot neuropathy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Prohibitin 1 is essential to preserve mitochondria and myelin integrity in Schwann cells.

In peripheral nerves, Schwann cells form myelin and provide trophic support to axons. We previously showed that the mitochondrial protein prohibitin 2 can localize to the axon-Schwann-cell interface and is required for developmental myelination. Whether the homologous protein prohibitin 1 has a similar role, and whether prohibitins also play important roles in Schwann cell mitochondria is unknown. Here, we show that deletion of prohibitin 1 in Schwann cells minimally perturbs development, but later triggers a severe demyelinating peripheral neuropathy. Moreover, mitochondria are heavily affected by ablation of prohibitin 1 and demyelination occurs preferentially in cells with apparent mitochondrial loss. Furthermore, in response to mitochondrial damage, Schwann cells trigger the integrated stress response, but, contrary to what was previously suggested, this response is not detrimental in this context. These results identify a role for prohibitin 1 in myelin integrity and advance our understanding about the Schwann cell response to mitochondrial damage.

Innervation of Meissner's corpuscles and Merkel -cells by transplantation of embryonic dorsal root ganglion cells after peripheral nerve section in rats.

Transplantation of embryonic motor neurons has been shown to improve motor neuron survival and innervation of neuromuscular junctions in peripheral nerves. However, there have been no reports regarding transplantation of sensory neurons and innervation of sensory receptors. Therefore, we hypothesized that the transplantation of embryonic sensory neurons may improve sensory neurons in the skin and innervate Merkel cells and Meissner's corpuscles. We obtained sensory neurons from dorsal root ganglia of 14-day rat embryos. We generated a rat model of Wallerian-degeneration by performing sciatic nerve transection and waiting for one week after. Six months after cell transplantation, we performed histological and electrophysiological examinations in naïve control, surgical control, and cell transplantation groups. The number of nerve fibers in the papillary dermis and epidermal-dermal interface was significantly greater in the cell transplantation than in the surgical control group. The percent of Merkel cells with nerve terminals, as well as the average number of Meissner corpuscles with nerve terminals, were higher in the cell transplantation than in the surgical control group, but differences were not significant between the two groups. Moreover, the amplitude and latency of sensory conduction velocity were evoked in rats of the cell transplantation group. We demonstrated that the transplantation of embryonic dorsal root ganglion cells improved sensory nerve fiber number and innervation of Merkel cells and Meissner's corpuscles in peripheral nerves.

Chronic idiopathic axonal polyneuropathy: Electrophysiological progression and human leukocyte antigen associations.

BACKGROUND: We aimed to describe the electrophysiological progression rate of chronic idiopathic axonal polyneuropathy (CIAP) and look into the potential role of human leukocyte antigen (HLA) genetic susceptibility in its development. METHODS: We recruited 57 patients with CIAP (mean age at diagnosis 67, mean follow-up 7 years). The assessments included clinical and electrophysiological data and HLA-DQ genotyping. RESULTS: The DQA1*05 allele was found more frequently in patients than in healthy controls (odds ratio, 1.96, P = .011). In patients with length-dependent CIAP, a linear effect of time on the electrophysiological findings was found in the superficial radial (3.2% mean annual decrement, P < .001), sural (4.7% mean annual decrement, P = .002) and tibial nerve (6.1% mean annual decrement, P = .007) amplitudes, independently from age or gender. CONCLUSIONS: Patients with length-dependent CIAP, show a linear progression over time. Interesting associations of HLA-DQA1*05 allele with length-dependent CIAP and non-DQ2/DQ8 with idiopathic sensory ganglionopathy were found. These merit further investigation in larger cohorts and may suggest a role of the immune system in the pathogenesis of CIAP.

Outcome following neurectomy of the deep branch lateral plantar nerve and plantar fasciotomy for hindlimb proximal suspensory desmopathy in western performance horses: 21 cases.

OBJECTIVE: To report the outcome of horses used in western performance disciplines after deep branch lateral plantar neurectomy/fasciotomy surgery for hind limb proximal suspensory desmopathy (PSD). STUDY DESIGN: Retrospective analysis. SAMPLE POPULATION: Twenty-one client-owned horses. METHODS: Medical records were reviewed (2009-2019) for horses involved in western performance disciplines that had been treated with deep branch lateral plantar neurectomy and plantar fasciotomy for lameness due to hind limb PSD. Follow-up was obtained by reexamination and/or verbal interviews with owners >2 years postoperatively. RESULTS: Sixteen quarter horses and five paints were used for western pleasure (14/21), barrel racing (2/21), cutting (1/21), steer wrestling (1/21), working cow horse (1/21), team roping (1/21) and reining (1/21). A median duration of 8 months was required before horses were able to resume training or athletic work. Nine horses were able to return to a similar or higher level of athletic use, nine horses returned to a lower level of athletic performance, and three horses could not return to intended function. Owner satisfaction with outcome after the procedure was high (16/21), average (3/21), and low (2/21). CONCLUSION: Deep branch lateral plantar neurectomy and plantar fasciotomy allowed most horses to resume some athletic function as western performance horses. CLINICAL SIGNIFICANCE: These results provide evidence of potential outcomes when considering surgical treatment of hind limb PSD in western performance horses.

Unrecognized tibial nerve injury in total-ankle arthroplasty: Two case reports.

RATIONALE: Tibial nerve injury is a sustainable but rare complication during total-ankle arthroplasty (TAA). We outlined 2 previously unreported cases of tibial nerve injury in TAA, including the prognoses and possible causes. PATIENT CONCERNS: First, a 63-year-old woman complained of a 5-month history of persistent tingling sensation and numbness on the medial and plantar aspects of her foot after TAA. Second, a 50-year-old woman complained of a 6-month history of tingling sensation and numbness on the plantar surface of her forefoot after TAA. DIAGNOSIS: Explorations were performed on suspicion of tarsal tunnel syndrome; however, both patients exhibited complete laceration of tibial nerve with neuroma formation. INTERVENTIONS: In both patients, we excised the neuroma and performed end-to-end nerve repair. OUTCOMES: The sensory disturbance of the sole considerably improved at long-term follow-up over 8 years after the neurorrhaphy procedures. LESSONS: Tibial nerve injury is rare following TAA, and is sometimes unrecognized or misdiagnosed. If tibial nerve injury is suspected, prompt surgical exploration should be performed; great precaution must also be taken to prevent injury of the tibial nerve during TAA.

Development and persistence of neuropathic pain through microglial activation and KCC2 decreasing after mouse tibial nerve injury.

Gamma-amino butyric acid (GABA) is an inhibitory neurotransmitter in the mature brain, but is excitatory during development and after motor nerve injury. This difference in GABAergic action depends on the intracellular chloride ion concentration ([Cl-]i), primarily regulated by potassium chloride co-transporter 2 (KCC2). To reveal precise processes of the neuropathic pain through changes in GABAergic action, we prepared tibial nerve ligation and severance models using male mice, and examined temporal relationships amongst changes in (1) the mechanical withdrawal threshold in the sural nerve area, (2) localization of the molecules involved in GABAergic transmission and its upstream signaling in the dorsal horn, and (3) histology of the tibial nerve. In the ligation model, tibial nerve degeneration disappeared by day 56, but mechanical allodynia, reduced KCC2 localization, and increased microglia density remained until day 90. Microglia density was higher in the tibial zone than the sural zone before day 21, but this result was inverted after day 28. In contrast, in the severance model, all above changes were detected until day 28, but were simultaneously and significantly recovered by day 90. These results suggested that in male mice, allodynia may be caused by reduced GABAergic synaptic inhibition, resulting from elevated [Cl-]i after the reduction of KCC2 by activated microglia. Furthermore, our results suggested that factors from degenerating nerve terminals may diffuse into the sural zone, whereby they induced the development of allodynia in the sural nerve area, while other factors in the sural zone may mediate persistent allodynia through the same pathway.

Viral vector delivery of follistatin enhances recovery of reinnervated muscle.

INTRODUCTION: Poor recovery following nerve repair is due to progressive temporal loss of muscle function. Follistatin (FS), a glycoprotein with anabolic properties, may enhance muscle recovery following reinnervation. METHODS: Seventy-two male Sprague-Dawley rats underwent temporary (3 or 6 month) denervation or sham denervation. After reinnervation, rats were administered adeno-associated viral vectors expressing FS deoxyribonucleic acid (isoform FS-317) injected into the target muscle or sham treatment. Final assessment included muscle function testing, muscle histomorphology, nerve histomorphology, and FS protein quantification. RESULTS: FS improved muscle mass and type IIB muscle fiber size, and increased G-ratios and mean axon diameter in the 6-month temporary denervation group (P < .05). Elevated FS protein levels were detected in treated muscle (P < .05). FS increased satellite cell counts following temporary denervation and repair (P < .05). DISCUSSION: FS treatment had anabolic, neurotrophic, and satellite cell stimulatory effects when administered following prolonged (6-month) temporary denervation and repair.

Comparing electrical stimulation and tacrolimus (FK506) to enhance treating nerve injuries.

INTRODUCTION: Neuroenhancing therapies are desired because repair of nerve injuries can fail to achieve recovery. We compared two neuroenhancing therapies, electrical stimulation (ES) and systemic tacrolimus (FK506), for their capabilities to enhance regeneration in the context of a rat model. METHODS: Rats were randomized to four groups: ES 0.5 mA, ES 2.0 mA, FK506, and repair alone. All groups underwent tibial nerve transection and repair, and outcomes were assessed by using twice per week walking track analysis, cold allodynia response, relative muscle mass, and nerve histology. RESULTS: Electrical stimulation and FK506 groups demonstrated improved functional recovery and myelinated axon counts distal to the repair compared with repair alone. Electrical stimulation provided improvements in nerve regeneration that were not different from optimized FK506 systemic administration. DISCUSSION: Providing ES after nerve repair improved regeneration and recovery in rats, with minimal differences in therapeutic efficacy to FK506, further demonstrating its clinical potential to improve management of nerve injuries.

Injection of Fluoro-Gold into the tibial nerve leads to prolonged but reversible functional deficits in rats.

Tract tracing with neuronal tracers not only represents a straightforward approach to identify axonal projection connection between regions of the nervous system at distance but also provides compelling evidence for axonal regeneration. An ideal neuronal tracer meets certain criteria including high labeling efficacy, minimal neurotoxicity, rapid labeling, suitable stability in vivo, and compatibility to tissue processing for histological/immunohistochemical staining. Although labeling efficacy of commonly used fluorescent tracers has been studied extensively, neurotoxicity and their effect on neural functions remains poorly understood. In the present study, we comprehensively evaluated motor and sensory nerve function 2-24 weeks after injection of retrograde tracer Fluoro-Gold (FG), True Blue (TB) or Fluoro-Ruby (FR) in the tibial nerve in adult Spague-Dawley rats. We found that motor and sensory nerve functions were completely recovered by 24 weeks after tracer exposure, and that FG lead to a more prolonged delay in functional recovery than TB. These findings shed light on the long-term effect of tracers on nerve function and peripheral axonal regeneration, and therefore have implications in selection of appropriate tracers in relevant studies.