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.

Traumatic neuroma of the posterior tibial nerve due to previous surgery presenting as a massive tumor in the midfoot: A case report.

A case report of traumatic neuroma, a benign non-neoplastic tumor of the posterior tibial nerve is presented. The soft tissue mass in the midfoot region was likely a sequela of previous nerve decompression surgery that the patient underwent five years previously in the same region and on the same nerve. Physical examination and history taking, along with an MRI, were important steps in reaching a definitive diagnosis of traumatic neuroma based on the findings of an interventional radiologist and histopathological evaluation of the biopsy by a pathologist. The lesion was subsequently surgically removed utilizing a multidisciplinary management approach. The patient recovered uneventfully and no symptom recurrence was noted at the 30-month follow-up. The tumor was the largest reported in the literature at the time. This case was also unique in that the patient was relieved of pronation and regained tactile sensation in the midfoot.

Schwannoma of the plantarmedial aspect of the foot: A case report.

Schwannomas of the common medial plantar nerve branch are rare solitary nerve sheath tumors. Fewer than a dozen cases have since been described in the literature, most of which were initially misdiagnosed as ganglion cysts. The case of a 56-year-old male who developed a painful mass on the plantar medial hallux, misdiagnosed as a ganglion cyst, is presented. After surgical intervention and pathological analysis the patient was diagnosed as having a schwannoma. A schwannoma is a slowly growing neoplasm of Schwann cell origin. It is very rare for a schwannoma to transform into a malignant lesion and usually occurs in individuals between the ages for 20-50. Schwannomas usually have a predilection for the head and upper extremities and is very rare in the foot and ankle. The principal treatment of a schwannoma is surgical excision, which eliminates symptoms and can correctly diagnose the mass. Even though schwannomas of the foot have been reported in literature, this case demonstrates an abnormal location on a branch of the medial plantar nerve. Level of Clinical Evidence: Level 4 of Evidence.

A3 adenosine receptor agonist attenuates neuropathic pain by suppressing activation of microglia and convergence of nociceptive inputs in the spinal dorsal horn.

Peripheral nerve injuries cause glial activation and neuronal hyperactivity in the spinal dorsal horn. These changes have been considered to be involved in the underlying mechanisms for the development and maintenance of neuropathic pain. Using double immunofluorescence labeling, we previously demonstrated that spinal microglial activation induced by nerve injury enhanced convergence of nociceptive inputs in the spinal dorsal horn from uninjured afferents. The adenosine A3 receptor (A3AR) agonists have been shown to have antinociceptive activities in several experimental neuropathic pain models. However, the mechanisms underlying these antinociceptive actions of the A3AR agonist are still not fully explored. In this study, the effects of the A3AR agonist (i.e., IB-MECA) on microglial activation, enhancement of convergent nociceptive inputs, and nocifensive behaviors were examined after tibial nerve injury. Injury to the tibial nerve initially caused hyposensitivity to touch stimulus at 3 days, and then resulted in tactile allodynia at 14-day post-injury. The daily systemic administration of IB-MECA (0.1 mg/kg/day) for 8 days in a row starting on the day of nerve injury or 7 days after nerve injury prevented the development of behaviorally assessed hypersensitivities, and spinal microglial activation induced by nerve injury. These treatments also suppressed anomalous convergence of nociceptive primary inputs in the spinal dorsal horn. The present findings indicate that the A3AR agonist attenuates neuropathic pain states by suppressing enhanced microglial activation, and anomalous convergence of nociceptive inputs in the spinal dorsal horn from uninjured afferents after injury to the peripheral nerve.

Selective expression of Narp in primary nociceptive neurons: role in microglia/macrophage activation following nerve injury.

Neuronal activity regulated pentraxin (Narp) is a secreted protein implicated in regulating synaptic plasticity via its association with the extracellular surface of AMPA receptors. We found robust Narp immunostaining in dorsal root ganglia (DRG) that is largely restricted to small diameter neurons, and in the superficial layers of the dorsal horn of the spinal cord. In double staining studies of DRG, we found that Narp is expressed in both IB4- and CGRP-positive neurons, markers of distinct populations of nociceptive neurons. Although a panel of standard pain behavioral assays were unaffected by Narp deletion, we found that Narp knockout mice displayed an exaggerated microglia/macrophage response in the dorsal horn of the spinal cord to sciatic nerve transection 3days after surgery compared with wild type mice. As other members of the pentraxin family have been implicated in regulating innate immunity, these findings suggest that Narp, and perhaps other neuronal pentraxins, also regulate inflammation in the nervous system.

Effect of adenosine A1 receptor agonist on the enhanced excitability of spinal dorsal horn neurons after peripheral nerve injury.

Neuronal hyperactivity has been implicated in abnormal pain sensation following peripheral nerve injuries. Previous studies have indicated that the activation of adenosine A1 receptors (A1R) in the central and peripheral nervous systems produces an antinociceptive effect. However, the mechanisms involved in the peripheral effect are still not fully understood. The effects of the local application of the selective A1R agonist, 2-chloro-N(6)-cyclopentyladenosine (CCPA) on neuronal hyperactivity were examined in this study using a neuropathic pain model induced by a tibial nerve injury. We utilized Fos protein-like immunoreactivity induced by noxious heat stimulation to examine changes in the number of Fos protein like immunoreactive (Fos-LI) neuron profiles in the spinal dorsal horn, and behavioral analysis for mechanical and thermal sensitivities. The nerve injury induced an exaggerated Fos response to noxious heat stimulation. The number of Fos-LI neuron profiles was significantly decreased and their distribution was restricted to the central terminal field of the spared peroneal nerve 3 days after the injury. The number of Fos-LI neuron profiles returned to control levels and a large number of these profiles were observed in the central terminal field of the injured tibial nerve 14 days after the injury. These enhanced Fos responses were attenuated by the local application of CCPA. The nerve injury also resulted in mechanical allodynia and thermal hyperalgesia. The local application of CCPA inhibited thermal hyperalgesia, but was less effective against mechanical allodynia. These results indicated that activation of peripheral A1R plays a role in the regulation of nerve injury-induced hyperalgesia.

MRI findings in patients with tibial nerve compression near the knee.

The soleus sling has been recently identified as a site of compression of the tibial nerve resulting in tibial neuropathy. Diagnosis of soleal sling syndrome is difficult, and has been based mainly on clinical examination. Advances in MR imaging with high-resolution 3-Tesla scanners have made direct visualization of nerve pathology possible. With the use of high-resolution imaging and fat-suppression protocols, tibial nerve compression at the soleal fascial arch can be demonstrated in a subset of patients presenting with idiopathic tibial neuropathy. The purpose of this paper is to confirm the ability of MR imaging to demonstrate pathologic changes in the tibial nerve in patients presenting with soleal sling syndrome. Additionally, patients presenting with tibial neuropathy and ganglion cysts, both extra- and intraneural, were examined to determine if the site of compression corresponded to the region of the soleus sling. Nine patients were included in the study, two with idiopathic soleus sling syndrome, four with extraneural, and three with intraneural ganglion cysts. In the patients presenting with idiopathic soleus sling syndrome, MR imaging demonstrated a thickened soleus sling with T2 hyperintensity of the tibial nerve at the level of the sling and denervation changes in muscles of the posterior compartment of the leg. In patients with extraneural ganglion cysts, MR imaging demonstrated a "sandwich"-like compression of the tibial nerve between the cyst and the soleus sling with corresponding tibial nerve T2 hyperintensity and denervation change in posterior compartment muscles. No compression of the tibial nerve at the soleus sling was found in the intraneural ganglion population. We conclude that MR imaging is effective in demonstrating pathologic changes in the tibial nerve at the soleus sling. Based on the MRI findings, we also believe that the soleus sling is a component of the compression when patients present with extraneural ganglion cysts and tibial neuropathy near the knee; in these patients, we recommend release of the soleus sling as part of the definitive management.

3T magnetic resonance neurography of tibial nerve pathologies.

Diagnosis of tibial neuropathy has been traditionally based on clinical examination and electrodiagnostic studies; however, cross-sectional imaging modalities have been used to increase the diagnostic accuracy and provide anatomic mapping of the abnormalities. In this context, magnetic resonance neurography (MRN) offers high-resolution imaging of the tibial nerve (TN), its branches and the adjacent soft tissues, and provides an objective assessment of the neuromuscular anatomy, abnormality, and the surrounding pathology. This review describes the pathologies affecting the TN and illustrates their respective 3 Tesla (T) MRN appearances with relevant case examples.

Inhibition of transmitter release and attenuation of anti-retroviral-associated and tibial nerve injury-related painful peripheral neuropathy by novel synthetic Ca2+ channel peptides.

N-type Ca(2+) channels (CaV2.2) are a nidus for neurotransmitter release and nociceptive transmission. However, the use of CaV2.2 blockers in pain therapeutics is limited by side effects resulting from inhibition of the physiological functions of CaV2.2 within the CNS. We identified an anti-nociceptive peptide (Brittain, J. M., Duarte, D. B., Wilson, S. M., Zhu, W., Ballard, C., Johnson, P. L., Liu, N., Xiong, W., Ripsch, M. S., Wang, Y., Fehrenbacher, J. C., Fitz, S. D., Khanna, M., Park, C. K., Schmutzler, B. S., Cheon, B. M., Due, M. R., Brustovetsky, T., Ashpole, N. M., Hudmon, A., Meroueh, S. O., Hingtgen, C. M., Brustovetsky, N., Ji, R. R., Hurley, J. H., Jin, X., Shekhar, A., Xu, X. M., Oxford, G. S., Vasko, M. R., White, F. A., and Khanna, R. (2011) Suppression of inflammatory and neuropathic pain by uncoupling CRMP2 from the presynaptic Ca(2+) channel complex. Nat. Med. 17, 822-829) derived from the axonal collapsin response mediator protein 2 (CRMP2), a protein known to bind and enhance CaV2.2 activity. Using a peptide tiling array, we identified novel peptides within the first intracellular loop (CaV2.2(388-402), "L1") and the distal C terminus (CaV1.2(2014-2028) "Ct-dis") that bound CRMP2. Microscale thermophoresis demonstrated micromolar and nanomolar binding affinities between recombinant CRMP2 and synthetic L1 and Ct-dis peptides, respectively. Co-immunoprecipitation experiments showed that CRMP2 association with CaV2.2 was inhibited by L1 and Ct-dis peptides. L1 and Ct-dis, rendered cell-penetrant by fusion with the protein transduction domain of the human immunodeficiency virus TAT protein, were tested in in vitro and in vivo experiments. Depolarization-induced calcium influx in dorsal root ganglion (DRG) neurons was inhibited by both peptides. Ct-dis, but not L1, peptide inhibited depolarization-stimulated release of the neuropeptide transmitter calcitonin gene-related peptide in mouse DRG neurons. Similar results were obtained in DRGs from mice with a heterozygous mutation of Nf1 linked to neurofibromatosis type 1. Ct-dis peptide, administered intraperitoneally, exhibited antinociception in a zalcitabine (2'-3'-dideoxycytidine) model of AIDS therapy-induced and tibial nerve injury-related peripheral neuropathy. This study suggests that CaV peptides, by perturbing interactions with the neuromodulator CRMP2, contribute to suppression of neuronal hypersensitivity and nociception.

Further insights into the antinociceptive potential of a peptide disrupting the N-type calcium channel-CRMP-2 signaling complex.

The N-type voltage-gated calcium channel (Cav 2.2) has gained immense prominence in the treatment of chronic pain. While decreased channel function is ultimately anti-nociceptive, directly targeting the channel can lead to multiple adverse side effects. Targeting modulators of channel activity may facilitate improved analgesic properties associated with channel block and a broader therapeutic window. A novel interaction between Cav 2.2 and collapsin response mediator protein 2 (CRMP-2) positively regulates channel function by increasing surface trafficking. We recently identified a CRMP-2 peptide (TAT-CBD3), which effectively blocks this interaction, reduces or completely reverses pain behavior in a number of inflammatory and neuropathic models. Importantly, TAT-CBD3 did not produce many of the typical side effects often observed with Cav 2.2 inhibitors. Notably chronic pain mechanisms offer unique challenges as they often encompass a mix of both neuropathic and inflammatory elements, whereby inflammation likely causes damage to the neuron leading to neuropathic pain, and neuronal injury may produce inflammatory reactions. To this end, we sought to further disseminate the ability of TAT-CBD3 to alter behavioral outcomes in two additional rodent pain models. While we observed that TAT-CBD3 reversed mechanical hypersensitivity associated with a model of chronic inflammatory pain due to lysophosphotidylcholine-induced sciatic nerve focal demyelination (LPC), injury to the tibial nerve (TNI) failed to respond to drug treatment. Moreover, a single amino acid mutation within the CBD3 sequence demonstrated amplified Cav 2.2 binding and dramatically increased efficacy in an animal model of migraine. Taken together, TAT-CBD3 potentially represents a novel class of therapeutics targeting channel regulation as opposed to the channel itself.

Diffusion tensor imaging of peripheral nerve in patients with chronic inflammatory demyelinating polyradiculoneuropathy: a feasibility study.

INTRODUCTION: The purpose of this study was to assess the clinical feasibility of diffusion tensor imaging (DTI) for the evaluation of peripheral nerves in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: Using a 3-T magnetic resonance imaging scanner, we obtained DTI scans of the tibial nerves of 10 CIDP patients and 10 sex- and age-matched healthy volunteers. We prepared fractional anisotropy (FA) maps, measured the FA values of tibial nerves, and compared these values in the two study groups. In nine patients, we also performed tibial nerve conduction studies and analyzed the correlation between the FA values and parameters of the nerve conduction study. RESULTS: The tibial nerve FA values in CIDP patients (median 0.401, range 0.312-0.510) were significantly lower than those in healthy volunteers (median 0.530, range 0.469-0.647) (Mann-Whitney test, p < 0.01). They were significantly correlated with the amplitude of action potential (Spearman correlation coefficient, p = 0.04, r = 0.86) but not with nerve conduction velocity (p = 0.79, r = 0.11). CONCLUSION: Our preliminary data suggest that the noninvasive DTI assessment of peripheral nerves may provide useful information in patients with CIDP.

Nerve repair by end-to-side nerve coaptation: histologic and morphometric evaluation of axonal origin in a rat sciatic nerve model.

OBJECTIVE: We compared the origin and quality of regenerating myelinated axons after end-to-side neurorrhaphy or end-to-end neurorrhaphy. METHODS: Transected adult rat tibial nerves were either end-to-end coapted or the distal stump was sutured to a perineurial window of the fibular nerve. Electromyographic recordings from the gastrocnemius muscle 8 weeks later revealed reinnervation by tibial nerve axons. Retrograde tracing of neurons projecting across the coaptation sites was performed with Dil for the tibial nerve and FluoroGold for the fibular nerve to reveal the origin of regenerating axons. Orientation of regenerating axons was demonstrated by immunohistochemical staining of the coaptation sites. Nerve cross-sections proximal and distal to the coaptation sites were evaluated regarding quality and quantity of myelinated axons inside the donor and acceptor nerves in comparison to nonoperated nerve samples. RESULTS: Compound muscle action potential responses were not different 8 weeks after end-to-side as compared with end-to-end coaptation. Double fluorescence of spinal motoneurons (L4-L6) and dorsal root ganglion neurons (L4-L6) elucidated events of collateral sprouting of sensory and motor donor axons. Morphometric analysis demonstrated significantly higher numbers of regenerated myelinated axons distal to end-to-end as distal to end-to-side repair. Furthermore, events of axonal sprouting in the donor nerve proximal to the end-to-side coaptation site were discovered. However, with quantitative parameters such as fiber density and g-ratio, no impairment of the donor nerve was evident. CONCLUSION: The current study supports the hypothesis that end-to-side neurorrhaphy represents an opportunity for peripheral nerve repair when a proximal nerve stump is not available.

Preparation and application of rat myostatin antiserum.

OBJECTIVE: To prepare and identify a polyclonal antibody against rat myostatin and investigate myostatin expression in the rat atrophic gastrocnemius muscle after tibial nerve crush. METHODS: The purified fusion protein was used as antigen to immunize rabbits for the preparation of polyclonal antibody. The polyclonal antibody of the protein was measured by enzyme linked immunosorbent assay (ELISA), western-blot and immunochemistry. Myostatin protein expression levels in normal and atrophic gastrocnemius muscle were detected by western-blot and immunochemistry assays. RESULTS: The GST-myostatin had a purity of 96% and possessed high titer and specificity. The level of myostatin in gastrocnemius muscle significantly increased one week after tibial nerve crush, reached the peak on day 14, and then returned to normal level on day 28. CONCLUSION: We have successfully made antiserum of rat myostatin and found that the expression level of myostatin protein in the gastrocnemius after tibial nerve crush-induced atrophy was time-dependent. This study provides an experimental basis to clarify the possible role of myostatin during skeletal muscle atrophy.

Sciatic cross-over in patients with peroneal and tibial intraneural ganglia confirmed by knee MR arthrography.

BACKGROUND: A predictable mechanism and stereotypic patterns of peroneal intraneural ganglia are being defined based on careful analysis of MRIs. Peroneal and tibial intraneural ganglia extending from the superior tibiofibular joint which extend to the level of the sciatic nerve have been observed leading to the hypothesis that sciatic cross-over could exist. Such a cross-over phenomenon would allow intraneural cyst from the peroneal nerve by means of its shared epineurial sheath within the sciatic nerve to cross over to involve the tibial nerve, or vice versa from a tibial intraneural cyst to the peroneal nerve. METHOD AND FINDINGS: One patient with a peroneal intraneural ganglion and another with a tibial intraneural ganglion each underwent a knee MR arthrogram. These studies were not only definitive in demonstrating the communication of the cyst to the superior tibiofibular joint connection but also in confirming sciatic cross-over. Contrast injected into the knee could be demonstrated tracking to the superior tibiofibular joint and then proximally into the common peroneal or tibial nerve respectively, crossing over at the sciatic nerve, and then descending down the tibial and peroneal nerves. The arthrographic findings mirrored MR images upon their retrospective review. CONCLUSIONS: This study provides direct in vivo proof of the nature of sciatic cross-over theorized by critical review of MRIs and/or experimental dye injections done in cadavers. This study is important in clarifying the potential paths of propagation of intraneural cysts at points of major bifurcation.

Effects of distal nerve injuries on dorsal-horn neurons and glia: relationships between lesion size and mechanical hyperalgesia.

Penetrating limb injuries are common and usually heal without long-lasting effects, even when nerves are cut. However, rare nerve-injury patients develop prolonged and disabling chronic pain (neuralgia). When pain severity is disproportionate to severity of the inciting injury, physicians and insurers may suspect exaggeration and limit care or benefits, although the nature of the relationship between lesion-size and the development and persistence of neuralgia remains largely unknown. We compared cellular changes in the spinal dorsal-horn (the initial CNS pain-processing area) after partial or total tibial-nerve axotomies in male Sprague-Dawley rats to determine if these changes are proportional to the numbers of peripheral axons cut. Unoperated rats provided controls. Plantar hind-paw responses to touch, pin, and cold were quantitated bilaterally to identify hyperalgesic rats. We also compared data from nerve-injured rats with or without hyperalgesic responses to mechanical hind-paw stimulation to evaluate concordance between pain behaviors and dorsal-horn cellular changes. Hyperalgesia was no less prevalent or severe after partial than after total axotomy. L(5) spinal-cord sections from rats killed 7 days postoperatively were labeled for markers of primary afferents (substance P calcitonin gene-related peptide isolectin B4, gamma aminobutyric acid, and glial fibrillary acidic protein), then labeled cells were stereologically quantitated in somatotopically defined dorsal-horn regions. Total axotomy reduced markers of primary afferents more than partial axotomy. In contrast, GABA-immunoreactive profiles were similarly reduced after both lesions, and in rats with sensory loss versus hyperalgesia. Numbers of GFAP-immunoreactive astrocytes increased independently of lesion size and pain status. Small nerve injuries can thus have magnified and disproportionate effects on dorsal-horn neurons and glia, perhaps providing a biological correlate for the disproportionate pain of post-traumatic neuralgias (including complex regional pain syndrome-I) that follow seemingly minor nerve injuries. However, the presence of similar dorsal-horn changes in rats without pain behaviors suggests that not all transcellular responses to axotomy are pain-specific.