Normal Peripheral Nerve Research Articles

Hydrogen sulfide controls peripheral nerve degeneration and regeneration: a novel therapeutic strategy for peripheral demyelinating disorders or nerve degenerative diseases.

After peripheral nerve injury, the process of Wallerian degeneration is initiated in the distal stump of injured nerves. Wallerian degeneration in peripheral nerves involves axonal degeneration and degradation of the myelin sheath in Schwann cells. This provides the necessary conditions for axonal regeneration and remyelination. After nerve injury, macrophages are also recruited to the distal nerve stump and, together with Schwann cells, play a role in the clearance of myelin debris. Thus, a series of processes help to promote peripheral nerve regeneration, which includes axonal regeneration and remyelination. This is in contrast to injuries within the adult central nervous system, in which successful regeneration encounters several significant barriers: myelin-associated inhibition (Neuman et al., 2002), diminished axonal growth capacity (Ruff et al., 2008) and glial scarring (Yiu and He, 2006). Because the successful regeneration of injured peripheral nerves relies on a harmonious degenerating process, it is essential to identify a molecular mechanism that regulates axonal degeneration or myelin fragmentation during Wallerian degeneration to foster the conditions allowing efficient peripheral nerve regeneration. We have recently shown that hydrogen sulfide (H2S) is important for axonal degradation and demyelination. We focus here on the effects of H2S on axonal degradation and on understanding the underlying mechanisms of H2S-associated demyelination, dedifferentiation and proliferation in Schwann cells during Wallerian degeneration. In addition, we discuss a novel strategy for nerve regeneration in the injured perip heral nerve or peripheral neuropathy.

Novel presentation of lepromatous leprosy in an erythema gyratum repens‐like pattern

Leprosy can have diverse cutaneous and occasionally perplexing presentations. We report an unusual case of lepromatous leprosy (LL) with annular lesions resembling erythema gyratum repens. A 55-year-old man presented with a symmetrical, hypopigmented, and erythematous rash of bizarre appearance over the lateral aspect of the upper arm, and anterior and posterior aspects of the trunk of two months' duration. He gave a history of self-resolving episodes of bilateral pedal edema, and numbness and pricking sensations in both the hands and feet, which had occurred intermittently over the previous six years. An ulcer measuring 2 cm in size was present over the adjacent surface of the right first and second toes. The bilateral ulnar and radial cutaneous nerves were symmetrically thickened. Slit-skin smears revealed numerous acid-fast bacilli. Skin biopsy from the trunk showed collections of histiocytes, lymphocytes, and plasma cells in the dermis and around the blood vessels. The patient was diagnosed with LL and started on multibacillary multi-drug therapy. Lepromatous leprosy can have varied clinical manifestations and is often a great imitator. However, the skin smear positivity, even in normal skin, symmetrical cutaneous and peripheral nerve involvement, and histopathology in the present patient were indicative of LL. This report highlights a rare presentation of leprosy. Clinicians should be aware of these rare manifestations as lepromatous cases still occur in certain regions.

Electron microscopy of human peripheral nerves of clinical relevance to the practice of nerve blocks. A structural and ultrastructural review based on original experimental and laboratory data

AimThe goal is to describe the ultrastructure of normal human peripheral nerves, and to highlight key aspects that are relevant to the practice of peripheral nerve block anaesthesia. MethodUsing samples of sciatic nerve obtained from patients, and dural sac, nerve root cuff and brachial plexus dissected from fresh human cadavers, an analysis of the structure of peripheral nerve axons and distribution of fascicles and topographic composition of the layers that cover the nerve is presented. Myelinated and unmyelinated axons, fascicles, epineurium, perineurium and endoneurium obtained from patients and fresh cadavers were studied by light microscopy using immunohistochemical techniques, and transmission and scanning electron microscopy. Structure of perineurium and intrafascicular capillaries, and its implications in blood–nerve barrier were revised. ResultsEach of the anatomical elements is analyzed individually with regard to its relevance to clinical practice to regional anaesthesia. ConclusionsRoutine practice of regional anaesthetic techniques and ultrasound identification of nerve structures has led to conceptions, which repercussions may be relevant in future applications of these techniques. In this regard, the ultrastructural and histological perspective accomplished through findings of this study aims at enlightening arising questions within the field of regional anaesthesia.

Computer aided diagnostic problem solving: Identification of peripheral nerve disorders

AimThe aim was to design and develop a decision support system with a graphical user interface for the prediction of the case of peripheral nerve disorder and to build a classifier using artificial neural networks that can distinguish between carpal tunnel syndrome, neuropathy and normal peripheral nerve conduction. Materials and methodsThe data used were the Nerve Conduction Study data obtained from Kannur Medical College, India. A recurrent neural network and a two-layer feed forward network trained with scaled conjugate gradient back-propagation algorithm were implemented and results were compared. ResultsBoth the networks provided fast convergence and good performance, accuracy being 98.6% and 97.4% for the recurrent neural network and the feed forward networks respectively, the confusion matrix in each case indicated only a few misclassifications. The developed decision support system also gave accurate results in agreement with the specialist's diagnosis and was also useful in storing and viewing the results. DiscussionsIn the field of medicine, programs are being developed that aids in diagnostic decision making by emulating human intelligence such as logical thinking, decision making, learning, etc. The system developed proves useful in combination with other systems in providing diagnostic and predictive medical opinions. It was not meant to replace the specialist, yet it can be used to assist a general practitioner or specialist in diagnosing and predicting patient's condition. ConclusionsThe study proves that artificial neural networks are indeed of value in combination with other systems in providing diagnostic and predictive medical opinions. But the major drawback of these studies, which makes use of the nerve conduction study data are the inherent shortcomings of the interpretation of the results, which include lack of standardization and absence of population-based reference intervals.

Expression of c‐Jun and Sox‐2 in human schwannomas and traumatic neuromas

Schwann cells myelinate axons of the peripheral nervous system. This process of myelination is regulated by various transcription factors. c-Jun and Sox-2 are negative regulators of myelination and control Schwann cell differentiation and plasticity. Schwannoma cells within tumours no longer express myelin markers, and show increased proliferation and decreased apoptosis. We have shown previously that several signalling pathways are activated in schwannoma cells in situ, in particular the c-Jun N-terminal kinase (JNK) pathway. Both in vitro and in vivo we have demonstrated that c-Jun and Sox-2 are co-regulated in Schwann cells and evidence shows that both these proteins regulate myelination negatively. In this study, we aimed to characterize the expression of c-Jun and Sox-2 in schwannoma and traumatic neuroma. Immunohistochemistry using antibodies to c-Jun and Sox-2 was applied to six schwannomas, and the results were compared with those seen in traumatic neuroma and normal nerve. Increased expression of c-Jun and Sox-2 was seen in schwannoma. We have demonstrated increased expression of c-Jun and Sox-2 in schwannoma compared to traumatic neuroma. There was no expression of c-Jun and Sox-2 in a histologically normal peripheral nerve.

Immunohistochemical Evaluation of Heat Shock Protein Expression in Normal Canine Nerve and Peripheral Nerve Sheath Tumours

Abnormal expression of heat shock proteins (HSPs) has been observed in many human neoplasms and such expression has prognostic, predictive and therapeutic implications. The aim of this study was to evaluate immunohistochemically the expression of HSP 27, HSP 32 and HSP 90 in normal canine peripheral nerves and in four benign and 15 malignant canine peripheral nerve sheath tumours (PNSTs). In normal nerve, all of the HSPs were detected in axons, epineurial fibroblasts and scattered Schwann cell bodies. Cytoplasmic expression of HSP 27 was more widespread and intense in benign PNSTs compared with malignant PNSTs (P <0.05). Widespread and intense nuclear expression of HSP 32 was also associated with benign tumours (P <0.01), while high HSP 90 immunoreactivity was detected in all tumours, suggesting that HSP 90 might represent a new therapeutic target.

DIAGNOSTIC YIELD OF SURAL NERVE BIOPSY, A RETROSPECTIVE ANALYSIS OF 10 YEARS DATA

MethodReports of sural nerve biopsies, done between period of January 2000 and March 2010 at Neuropathology Department of Frenchay Hospital were analysed retrospectively.ResultsThe total number of biopsies was 194. 111...

Spinal charcot‐marie‐tooth disease: A reappraisal

Distal hereditary motor neuropathy (dHMN) is characterized by isolated distal muscle atrophy without sensory deficit. Nevertheless, clinical sensory loss has been reported despite preserved sensory nerve conduction in a few patients, thus differentiating these cases from the classical type 2 Charcot-Marie-Tooth disease (CMT2). We report 4 patients who presented with clinical sensory and motor neuropathy and normal peripheral sensory nerve conduction studies and were investigated with complete electrophysiological studies, including somatosensory evoked potentials (SEP). These patients had a clinical presentation of classical CMT with isolated axonal motor neuropathy suggestive of dHMN. Interestingly, tibial nerve SEPs showed abnormalities suggestive of proximal involvement of dorsal roots that may explain the clinical somatosensory disturbances. These cases support the concept of spinal CMT that should be recognized as an intermediate form between dHMN and CMT2. SEP recording was helpful in defining a more precise phenotype of spinal CMT.

Normal and sonographic anatomy of selected peripheral nerves. Part III: Peripheral nerves of the lower limb.

The ultrasonographic examination is currently increasingly used in imaging peripheral nerves, serving to supplement the physical examination, electromyography and magnetic resonance imaging. As in the case of other USG imaging studies, the examination of peripheral nerves is non-invasive and well-tolerated by patients. The typical ultrasonographic picture of peripheral nerves as well as the examination technique have been discussed in part I of this article series, following the example of the median nerve. Part II of the series presented the normal anatomy and the technique for examining the peripheral nerves of the upper limb. This part of the article series focuses on the anatomy and technique for examining twelve normal peripheral nerves of the lower extremity: the iliohypogastric and ilioinguinal nerves, the lateral cutaneous nerve of the thigh, the pudendal, sciatic, tibial, sural, medial plantar, lateral plantar, common peroneal, deep peroneal and superficial peroneal nerves. It includes diagrams showing the proper positioning of the sonographic probe, plus USG images of the successively discussed nerves and their surrounding structures. The ultrasonographic appearance of the peripheral nerves in the lower limb is identical to the nerves in the upper limb. However, when imaging the lower extremity, convex probes are more often utilized, to capture deeply-seated nerves. The examination technique, similarly to that used in visualizing the nerves of upper extremity, consists of locating the nerve at a characteristic anatomic reference point and tracking it using the “elevator technique”. All 3 parts of the article series should serve as an introduction to a discussion of peripheral nerve pathologies, which will be presented in subsequent issues of the “Journal of Ultrasonography”.

Bers-ERK Schwann Cells Coordinate Nerve Regeneration

In this issue of Neuron, Napoli et al. (2012) demonstrate that elevated ERK/MAPK signaling in Schwann cells is a crucial trigger for Schwann cell dedifferentiation in vivo. Moreover, the authors show that dedifferentiated Schwann cells have the potential to coordinate much of the peripheral nerve response to injury.

Vav deficiency impedes peripheral nerve regeneration in mice

The regeneration of adult peripheral nerves is a complex, multi-step process that is often incomplete, resulting in pain and/or loss of muscle innervation. Success is based on a fine-tuned interplay of neurons, Schwann cells, fibrocytes and macrophages realizing Wallerian degeneration, fiber regrowth and revascularization. Following trauma, the nerves distal to the injury site undergo Wallerian degeneration, an event that includes the phagocytosis of debris and the formation of Schwann cell scaffolds that guide the sprouting nerve fibers. The actin cytoskeleton is critical to all of these processes; therefore, activators of the cytoskeleton such as Rho GTPases and RhoGEFS such as Vav2 and Vav3 represent attractive targets for therapeutic intervention. Sciatic nerve segments were surgically resected and reconstructed, and the degenerative/regenerative outcomes were compared in wild-type and Vav2/3 double knockout mice. Vav2/3 knockout nerves showed delayed Wallerian degeneration and revascularization, a broadly control-like morphometry of the regenerated nerves including remyelination, and contradictory motor function recovery, whereby impaired toe spreading was accompanied by enhanced muscle weight recreation. The data suggest that Vav2 and Vav3 are required for normal peripheral nerve degeneration/regeneration, revascularization and functional recovery. Functional redundancy, compensatory mechanisms, and muscle (pseudo)hypertrophy, however, impede the understanding of and intervention in Vav-mediated processes.

Chronic immune sensory polyradiculopathy with cranial and peripheral nerve involvement

Chronic immune sensory polyradiculopathy (CISP) is a recently described restricted form of chronic inflammatory demyelinating polyradiculopathy (CIDP) [1]. It preferentially affects large myelinated fibres of the posterior roots, is associated with normal peripheral nerve conduction studies, and may respond to immunomodulatory treatment. We describe a patient with clinical features of CISP and additional cranial nerve involvement. A 61 year old woman presented with a 10 year relapsing-remitting neurological disorder. She initially presented with nausea, headache and photophobia followed by diplopia and unilateral ptosis consistent with an oculomotor nerve palsy. Intracranial CT, MRI, MRA, catheter angiography and CSF were all normal. Symptoms resolved over 18 months but an inflammatory cause was suspected after a relapse and treatment with 2 g/kg intravenous immunoglobulin (IVIg) was effective. Further relapses with additional poor balance, facial numbness and distal sensory symptoms responded promptly to IVIg. Intravenous methylprednisolone worsened her symptoms. Neurological examination revealed a partial right oculomotor nerve palsy. Pin prick sensation was reduced in a right trigeminal nerve distribution. Limb power was normal but reflexes were reduced in the upper limbs and absent in the lower limbs with flexor plantars. Romberg’s test was positive. Pin prick was reduced on the ulnar aspect of the right forearm and up to the mid-shins bilaterally. Vibration sense was reduced up to both ankles and proprioception impaired up to the right ankle. Examination after IVIg revealed that ophthalmoplegia, ptosis and a timed Romberg’s test had all improved. Systemic inflammatory/autoimmune blood tests were unremarkable and these included full blood count, ESR, CRP, ANA, ANCA, complement, rheumatoid factor, ENA, protein electrophoresis, immunofixation, acetylcholine receptor antibodies, immunoglobulins, ganglioside serology, lyme serology, treponemal serology and anti-neuronal antibodies. CSF was acellular with normal glucose and a raised protein level of 0.71 g/L (normal 0.15–0.65 g/L). Oligoclonal bands were absent. Neurophysiological data are presented in the appendix. In summary, the absolute values of all neurophysiological investigations listed were normal. However, the ulnar nerve SNAPs were significantly asymmetrical and the motor F-waves prolonged. Thermal thresholds were abnormal in the feet and right hand. Somatosensory evoked potentials were poorly formed in the right lower limb. Asymmetry of motor evoked potential latencies following cervical spine stimulation was consistent with a lesion distal to the intervertebral foramina. Electronic supplementary material The online version of this article (doi:10.1007/s00415-011-6326-0) contains supplementary material, which is available to authorized users.

Schwann Cell Mitochondrial Metabolism Supports Long-Term Axonal Survival and Peripheral Nerve Function

Mitochondrial dysfunction is a common cause of peripheral neuropathies. While the role of neuron and axonal mitochondria in peripheral nerve disease is well appreciated, whether Schwann cell (SC) mitochondrial deficits contribute to peripheral neuropathies is unclear. Here, we examine how SC mitochondrial dysfunction affects axonal survival and contributes to the decline of peripheral nerve function by generating mice with SC-specific mitochondrial deficits. These mice (Tfam-SCKOs) were produced through the tissue-specific deletion of the mitochondrial transcription factor A gene (Tfam), which is essential for mitochondrial DNA (mtDNA) transcription and maintenance. Tfam-SCKOs were viable, but as they aged, they developed a progressive peripheral neuropathy characterized by nerve conduction abnormalities as well as extensive muscle denervation. Morphological examination of Tfam-SCKO nerves revealed early preferential loss of small unmyelinated fibers followed by prominent demyelination and degeneration of larger-caliber axons. Tfam-SCKOs displayed sensory and motor deficits consistent with this pathology. Remarkably, the severe mtDNA depletion and respiratory chain abnormalities in Tfam-SCKO mice did not affect SC proliferation or survival. Mitochondrial function in SCs is therefore essential for maintenance of axonal survival and normal peripheral nerve function, suggesting that SC mitochondrial dysfunction contributes to human peripheral neuropathies.

N-WASp is required for Schwann cell cytoskeletal dynamics, normal myelin gene expression and peripheral nerve myelination

Schwann cells elaborate myelin sheaths around axons by spirally wrapping and compacting their plasma membranes. Although actin remodeling plays a crucial role in this process, the effectors that modulate the Schwann cell cytoskeleton are poorly defined. Here, we show that the actin cytoskeletal regulator, neural Wiskott-Aldrich syndrome protein (N-WASp), is upregulated in myelinating Schwann cells coincident with myelin elaboration. When N-WASp is conditionally deleted in Schwann cells at the onset of myelination, the cells continue to ensheath axons but fail to extend processes circumferentially to elaborate myelin. Myelin-related gene expression is also severely reduced in the N-WASp-deficient cells and in vitro process and lamellipodia formation are disrupted. Although affected mice demonstrate obvious motor deficits these do not appear to progress, the mutant animals achieving normal body weights and living to advanced age. Our observations demonstrate that N-WASp plays an essential role in Schwann cell maturation and myelin formation.

WT1 expression in normal and neoplastic cranial and peripheral nerves is independent of grade of malignancy

Wilms' tumor protein (WT1) expression is usually absent in normal glial cells of the CNS but is highly upregulated in brain tumor cells and its expression correlates with tumor grade. However, knowledge on WT1 expression in tumors of the peripheral nerve system (PNS) is limited. As WT1 antibodies not only serve as biomarker for cancerous tissue but also are considered for cancer immunotherapy, knowledge of WT1 expression in tumorous and normal peripheral nerve tissue is important for therapeutical purposes. We analyze the immunohistochemical expression of WT1 in 101 samples consisting of 13 normal nerves, 10 neurofibromas, 69 schwannomas and 9 malignant peripheral nerve sheath tumors (MPNST). Tumor samples included 14 specimen from patients with a proven neurocutaneous disorder (neurofibromatosis type 1 and 2) and 3 cases of schwannomatosis. In 50 vestibular schwannomas tumor growth extension was correlated to WT1 expression. WT1 expression is present in Schwann cells of the majority of normal human nerves (11/13). In peripheral nerve sheath tumors, cytoplasmic WT1 protein is expressed in the cytoplasm of the neoplastic cells in all tumors, including MPNST, neurofibromas and schwannomas. The WT1 expression is independent of tumor malignancy or tumor growth extension and is not associated with a neurocutaneous disorder. WT1 expression in normal and neoplastic tissue differs in the peripheral and the central nervous system. These findings may point to a different functional role of WT1 in the PNS and the CNS.

Reply to letter to the editor: hybrid peripheral nerve sheath tumor

We would like to thank Dr. Teresa Pusiol and her colleagues for their interest in our paper and for their valuable comments. We agree with their comments that hybrid peripheral nerve sheath tumor has been previously reported in extradigital sites. The normal peripheral nerve sheath consists of Schwann cells, fi broblasts, and perineurial cells, and benign peripheral nerve sheath tumor including schwannoma, neurofi broma, and perineurioma is generally composed of these cells. Previous ultrastructural studies have elucidated that peripheral nerve sheath tumors contain these cells in various proportions. Recently, peripheral nerve sheath tumors with discrete areas of more than one histological type have been described, and these tumors have been designated as hybrid peripheral nerve sheath tumor (HPNST). HPNST consisting of two components is pathologically subdivided into schwannoma-neurofi broma, schwannoma-perineurioma, and neurofi broma-perineurioma. Furthermore, we believe that HPNST consisting of all three components with a discrete area, namely schwannoma-neurofi broma-perineurioma, actually exists, although this tumor may be extremely rare.

Polymorphism of CAG motif of SK3 gene is associated with acute oxaliplatin neurotoxicity

There is no agreement on which channel is involved in oxaliplatin neurotoxicity, most investigators favouring voltage-gated sodium channels. However, the small conductance Ca(++) activated K(+) channels, encoded by the SK1-3 genes, are also involved in membrane excitability, playing a role in after-hyperpolarization at the motor nerve terminal. As the SK3 gene is characterized in Caucasians by a highly polymorphic CAG motif within the exon 1, we hypothesize that SK3 gene polymorphism may influence the development of acute nerve hyperexcitability in oxaliplatin-treated patients. Patients eligible for an oxaliplatin-containing regimen were enrolled. Detailed neurological examination, nerve conduction studies and needle electromyography were performed before and after oxaliplatin administration. DNA was extracted by polymerase chain reaction, and each allele was isolated and sequenced. We evaluated 40 patients. After oxaliplatin administration, 28 patients developed symptoms of neurotoxicity, which were severe in 11. Patients were divided into three groups according to neurophysiological data: G0 (normal peripheral nerve excitability [PNE]), 16 patients; G1 (mild PNE), 15 patients; G2 (severe PNE), 9 patients. Genetic analysis showed different alleles ranging from 13 to 23 CAG repeats. Patients carrying alleles containing 13-15 CAG repeats experienced a significantly higher incidence of severe nerve hyperexcitability (chi-square 48.6; df 16; P=0.0001). The results suggest that OXA-neurotoxicity may be related to distribution of the polymorphic CAG motif of the SK3 gene, which might modulate nerve after-hyperpolarization. The 13-14 CAG repeat allele could mark patients susceptible to acute OXA neurotoxicity.

Expression of ErbB-1 and ErbB-2 in meningioma

Meningiomas are benign intracranial tumours treated by neurosurgical resection. Residual or recurrent tumour may be treated with radiotherapy. Effective molecular therapy for residual and recurrent meningiomas is currently unavailable. We tested meningiomas for In-ErbB-1 and ErbB-2, and the levels were compared to normal brain, peripheral nerve, glioblastoma multiforme and vestibular schwannoma. Our findings with immunohistochemistry and western blot analysis indicate a level of ErbB-1 similar to normal peripheral nerve, but a high expression of ErbB-2 similar to the vestibular schwannoma and glioblastoma multiforme. These preliminary results implicate a potential role for ErbB-2 in the benign tumourigenesis of meningioma consistent with the theoretical hierarchical interactions of homodimers of ErbB-2 that may be associated with low signal transduction.

CNS-Resident Glial Progenitor/Stem Cells Produce Schwann Cells as well as Oligodendrocytes during Repair of CNS Demyelination

After central nervous system (CNS) demyelination-such as occurs during multiple sclerosis-there is often spontaneous regeneration of myelin sheaths, mainly by oligodendrocytes but also by Schwann cells. The origins of the remyelinating cells have not previously been established. We have used Cre-lox fate mapping in transgenic mice to show that PDGFRA/NG2-expressing glia, a distributed population of stem/progenitor cells in the adult CNS, produce the remyelinating oligodendrocytes and almost all of the Schwann cells in chemically induced demyelinated lesions. In contrast, the great majority of reactive astrocytes in the vicinity of the lesions are derived from preexisting FGFR3-expressing cells, likely to be astrocytes. These data resolve a long-running debate about the origins of the main players in CNS remyelination and reveal a surprising capacity of CNS precursors to generate Schwann cells, which normally develop from the embryonic neural crest and are restricted to the peripheral nervous system.

Dorsal caudal tail and sciatic motor nerve conduction studies in adult mice: Technical aspects and normative data

Mice provide an important tool to investigate human neuromuscular disorders. The variability of electrophysiological techniques limits direct comparison between studies. The purpose of this study was to establish normative motor nerve conduction data in adult mice. The dorsal caudal tail nerve and sciatic nerve motor conduction studies were performed bilaterally on restrained anesthetized adult mice. The means and standard deviations for each electrophysiological parameter were determined in normal mice. Data were compared with inflammatory demyelinating polyneuropathy mice to determine whether these parameters discriminate between normal and abnormal peripheral nerves. Normal adult mice had a distal latency of 0.89 (+/-0.17) ms and 0.75 (+/-0.09) ms, distal compound motor unit action potential amplitude of 13.2 (+/-5.9) mV and 28.1 (+/-8.3) mV, and conduction velocity of 74.6 (+/-9.0) m/s and 76.5 (+/-8.3) m/s, respectively. These data were validated by the finding of statistically significant differences in several electrophysiological parameters that compared normal and polyneuropathy-affected mice. A standardized method for motor nerve conduction studies and associated normative data in mice should facilitate comparisons of disease severity and response to treatment between studies that use similar models. This would assist in the process of translational therapeutic drug design in neuromuscular disorders.