Myelin Sheath Of Peripheral Nerves Research Articles

Intrascrotal extratesticular schwannoma: A clinical case and a review of literature

Schwannoma is a benign tumor that grows from the Schwann cells forming the myelin sheath of peripheral nerves. The clinical manifestations are nonspecific and generally due to compression of the adjacent structures of a growing tumor. The location of the tumor in the scrotum is rare; its primary diagnosis is difficult and only immunohistochemical examination allows the final diagnosis to be established. The authors present a clinical case of a patient operated on at the Urology Department, Moscow Clinical Research Center, for intrascrotal schwannoma causing impaired microcirculation in the scrotal skin to form purulent scrotal ulcers. In terms of the benign pattern and extratesticular localization of the tumor, its removal without orchifuniculectomy can yield a good clinical result.

Schwannoma of the left superior eyelid in a 10-year-old child

Schwannoma is a rare benign neurogenic tumor. It arises from Schwann cells located at the myelin sheath of peripheral nerves. Its incidence is frequently associated with the orbit. Ocular tissues in general and eyelids in particular are rarely affected. Very few reports can be found in the literature describing eyelid schwannomas. Amongst these, we have found only two describing it affecting children. To our knowledge, this is the first case report about eyelid schwanomma in Brazil - and it involves a child.

Permanent Anosmia in a Patient Treated with Pegylated Interferon Alfa

Introduction: Interferon Alfa has antiviral and antiproliferative immunomodulatory effects. It is known to cause diabetes, hypothyroidism and certain dermatologic conditions. There have been 6 case reports demonstrating temporary anosmia due to use of this drug and one case report showing permanent anosmia. This is a case report of Interferon Alfa causing permanent anosmia. Case Report: A 57-year-old male with known hepatitis C infection was treated with Pegylated Interferon Alfa (IFN- alfa). Patient developed anosmia and cacosmia within few weeks of starting treatment. He was however continued on the medication to treat hepatitis C for 48 weeks but failed treatment. Interferon Alfa was discontinued but patient continued to have anosmia even 12 months after completing treatment. There was no history of recurrent allergies or sinusitis. Neurology had evaluated the patient and there was no cranial nerve abnormality. MRI of the brain ruled out any organic cause. He did not show any signs of Alzheimer's dementia or Parkinson's disease. He was extensively evaluated by ENT (otorhinolaryngiologist) as well. He had no evidence of nasal obstruction, polyps, mass, fractures, infection or atrophy of mucosa. His anosmia was thought to be permanent due to use of Pegylated Interferon Alfa. Discussion: Anosmia is a rare side effect of IFN-alfa and can develop with 2 weeks of starting treatment. It has been known to persist up to 13 months after discontinuing the medication. The exact mechanism of action by which this medication causes anosmia is not well understood. It is proposed that it is due to changes in neuroendocrine hormonal effects due to immunoregulatory effects of IFN-alfa. Alternatively, it may stimulate autoantibodies which can destroy the myelin sheath of peripheral nerves and cause permanent nerve damage. It is important to know this rare side effects of IFN-alfa so that patients may be informed about it. It will be unethical to start this medication without informing patients about this side effect especially if it can cause permanent anosmia since there is a chance that he may fail treatment as well.Table: Drugs causing anosmia

NDRG4 Protein-deficient Mice Exhibit Spatial Learning Deficits and Vulnerabilities to Cerebral Ischemia

The N-myc downstream-regulated gene (NDRG) family consists of four related proteins, NDRG1-NDRG4, in mammals. We previously generated NDRG1-deficient mice that were unable to maintain myelin sheaths in peripheral nerves. This condition was consistent with human hereditary motor and sensory neuropathy, Charcot-Marie-Tooth disease type 4D, caused by a nonsense mutation of NDRG1. In contrast, the effects of genetic defects of the other NDRG members remain unknown. In this study, we focused on NDRG4, which is specifically expressed in the brain and heart. In situ mRNA hybridization on the brain revealed that NDRG4 was expressed in neurons of various areas. We generated NDRG4-deficient mice that were born normally with the expected Mendelian frequency. Immunochemical analysis demonstrated that the cortex of the NDRG4-deficient mice contained decreased levels of brain-derived neurotrophic factor (BDNF) and normal levels of glial cell line-derived neurotrophic factor, NGF, neurotrophin-3, and TGF-β1. Consistent with BDNF reduction, NDRG4-deficient mice had impaired spatial learning and memory but normal motor function in the Morris water maze test. When temporary focal ischemia of the brain was induced, the sizes of the infarct lesions were larger, and the neurological deficits were more severe in NDRG4-deficient mice compared with the control mice. These findings indicate that NDRG4 contributes to the maintenance of intracerebral BDNF levels within the normal range, which is necessary for the preservation of spatial learning and the resistance to neuronal cell death caused by ischemic stress.

Biomarkers of CIDP in patients with diabetes or CMT1

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease that targets the myelin sheaths in peripheral nerves. Primary demyelination can be detected by electrodiagnostic studies or nerve biopsy, but these do not distinguish between demyelination resulting from CIDP or from non-inflammatory causes such as diabetes or Charcot-Marie-Tooth type I. Consequently, the diagnosis of CIDP in such patients is often missed. Studies are needed to establish electrodiagnostic criteria for CIDP in patients with diabetes, and to identify biomarkers that distinguish between inflammatory and non-inflammatory causes of demyelinating neuropathy.

Intralabyrinthäre Schwannome

Schwannomas are benign neurogenic tumors arising from Schwann cells that usually form the myelin sheath of peripheral nerves. The typical localization of vestibular schwannomas is the internal auditory canal or the cerebellopontine angle. Intralabyrinthine lesions are extremely rare. Here we describe a series of four consecutive cases of intralabyrinthine schwannomas that were treated in the Department of Otorhinolaryngology, Head and Neck Surgery, Klinikum Bielefeld in Bielefeld, Germany. Therapeutic options are discussed and the literature is reviewed.

Pals1 Is a Major Regulator of the Epithelial-Like Polarization and the Extension of the Myelin Sheath in Peripheral Nerves

Diameter, organization, and length of the myelin sheath are important determinants of the nerve conduction velocity, but the basic molecular mechanisms that control these parameters are only partially understood. Cell polarization is an essential feature of differentiated cells, and relies on a set of evolutionarily conserved cell polarity proteins. We investigated the molecular nature of myelin sheath polarization in connection with the functional role of the cell polarity protein pals1 (Protein Associated with Lin Seven 1) during peripheral nerve myelin sheath extension. We found that, in regard to epithelial polarity, the Schwann cell outer abaxonal domain represents a basolateral-like domain, while the inner adaxonal domain and Schmidt-Lanterman incisures form an apical-like domain. Silencing of pals1 in myelinating Schwann cells in vivo resulted in a severe reduction of myelin sheath thickness and length. Except for some infoldings, the structure of compact myelin was not fundamentally affected, but cells produced less myelin turns. In addition, pals1 is required for the normal polarized localization of the vesicular markers sec8 and syntaxin4, and for the distribution of E-cadherin and myelin proteins PMP22 and MAG at the plasma membrane. Our data show that the polarity protein pals1 plays an essential role in the radial and longitudinal extension of the myelin sheath, likely involving a functional role in membrane protein trafficking. We conclude that regulation of epithelial-like polarization is a critical determinant of myelin sheath structure and function.

Treatment of Chronic Inflammatory Demyelinating Polyneuropathy

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired, immune-mediated, non-length-dependent polyradiculoneuropathy that is progressive or relapsing over a period of at least 8weeks, often evolving over time to a relatively symmetric pattern. Although the exact pathogenesis is unclear, it is thought to be mediated by both cellular and humoral reaction to the peripheral nerve myelin sheath involving nerve roots and proximal and distal nerves. Early medical treatment of CIDP is important to prevent axonal loss occurring as a secondary effect of progressive demyelination. Only three treatments for CIDP have demonstrated benefit in randomized controlled studies: corticosteroids, plasma exchange, and intravenous immunoglobulin. About 25% of patients fail to respond to these treatments or respond inadequately. These treatments have similar efficacy but differ significantly in cost and adverse effects. These factors are considered in treatment selection.

Does direction of induced electric field or current provide a test of mechanism involved in nerve regeneration?

We suggest an experimental comparison of two directions for applying the time-varying magnetic fields which have been found to speed spontaneous regeneration of injured peripheral nerves and in attempts to repair spinal cord injuries. Time-varying magnetic fields induce currents in a plane perpendicular to the magnetic field direction. The lower conductivity of the spinal cord's sheath (dura matter) or of the myelin sheath of peripheral nerves would seem to confine the induced electric fields and currents to the spinal cord or nerve itself. The proposed comparison could allow choosing between two possible modes of action of the fields: (1) Magnetically-induced electric fields or currents may be encouraging ion flow or otherwise helping enzyme, channel or other interactions at the cell membrane, as is thought to be the case in field stimulation of healing in bone. This mechanism should be independent of field direction. (2) Work in developing organisms and with fields applied to nerve cells in vitro has shown that neurite growth is guided parallel to both endogenous and external electric fields. This mechanism would be effective when induced electric fields are parallel, but not when they are perpendicular to the nerve. Any experimental test should seek to produce as close as possible to the same induced current intensity with both field directions. Possible confounding factors, as well as breakdowns in the assumptions of the simple model presented here, would have to be considered. This proposal was motivated by a recent report in which the authors listed a changed field direction as one of several possible reasons for an unsuccessful experiment.

N-Myc Down-regulated Gene 1 Modulates the Response of Term Human Trophoblasts to Hypoxic Injury

The placenta is susceptible to diverse insults during human pregnancy. The expression of the protein N-myc down-regulated gene 1 (NDRG1) is regulated during cell proliferation, differentiation, and in response to stress. Nevertheless, the function of this protein in humans remains unknown. We tested the hypothesis that NDRG1 is up-regulated in hypoxic primary human trophoblasts and that NDRG1 modulates trophoblast response to hypoxia. We initially demonstrated that the expression of NDRG1 is enhanced in primary human trophoblasts exposed to hypoxia. Importantly, we found a similar increase in NDRG1 expression in placental samples derived from either singleton gestations complicated by intrauterine growth restriction or from dizygotic twin gestation where one twin exhibited growth restriction. Having established efficient lentivirus-mediated transfection of primary human trophoblasts, we overexpressed NDRG1 in trophoblasts, which resulted in enhanced trophoblast differentiation. In contrast, lentivirus-driven short interfering RNA-mediated silencing of NDRG1 diminished trophoblast viability and differentiation. Consistent with these results, NDRG1 reduced the expression level of p53 in trophoblasts cultured in standard or hypoxic conditions. Furthermore, NDRG1 expression was regulated by the activity of SIRT1 (Sir2-like protein 1), which promotes cell survival. Together, our data indicate that NDRG1 interacts with SIRT1/p53 signaling to attenuate hypoxic injury in human trophoblasts.

Cell-specific deletion of glucosylceramide synthase in brain leads to severe neural defects after birth

Sialic acid-containing glycosphingolipids, i.e., gangliosides, constitute a major component of neuronal cells and are thought to be essential for brain function. UDP-glucose:ceramide glucosyltransferase (Ugcg) catalyzes the initial step of glycosphingolipid (GSL) biosynthesis. To gain insight into the role of GSLs in brain development and function, a cell-specific disruption of Ugcg was performed as indicated by the absence of virtually all glucosylceramide-based GSLs. Shortly after birth, mice showed dysfunction of cerebellum and peripheral nerves, associated with structural defects. Axon branching of Purkinje cells was significantly reduced. In primary cultures of neurons, dendritic complexity was clearly diminished, and pruning occurred early. Myelin sheaths of peripheral nerves were broadened and focally severely disorganized. GSL deficiency also led to a down-regulation of gene expression sets involved in brain development and homeostasis. Mice died approximately 3 weeks after birth. These results imply that GSLs are essential for brain maturation.

Intravenous Immunoglobulin in the Treatment of Childhood Guillain-Barré Syndrome: A Randomized Trial

Guillain-Barre syndrome (GBS) is an acute inflammatory demyelinating polyradiculoneuropathy manifested by progressive flaccid paralysis.1,2 With the eradication of poliomyelitis, GBS has become the most common cause of acute motor paralysis in children. The etiology and pathophysiology of GBS has a postulated immune-mediated mechanism.3,4 In classical GBS there is destruction of peripheral nerve myelin sheath, which results in the hallmark symptomatology. There are also less frequently encountered axonal variants, those with and without sensory involvement and an ataxia-ophthalmologic syndrome with no weakness (Miller-Fisher syndrome). These other axonal variants have a more clearly understood immunologic basis that involves antibody attack on a variety of target glycolipid antigens on nerve terminals and axons.4 Classic demyelinating GBS syndrome has a less well-defined pathogenesis. The disorder typically begins after recovery from a preceding illness or vaccination. Distal paresthesias evolve into a symmetrically progressive ascending distal and proximal weakness of the limbs. There are diminished or absent tendon stretch reflexes, often in association with facial weakness and limb and back pain.1,2 After several days the cerebrospinal fluid (CSF) demonstrates an elevation in protein without significant pleocytosis (albuminocytological dissociation). Weakness may continue to progress rapidly with need of ventilatory support, often with associated autonomic dysfunction. It has generally been perceived that the clinical course in children may be somewhat milder, with greater likelihood of recovery in comparison to adults.1 Immune-mediated mechanisms involving both cellular and humoral responses in GBS have been postulated. Microscopic studies have demonstrated both lymphocyte and macrophage infiltration into nerve fibers.3,4 Experimental allergic neuritis can mimic the symptoms of GBS in rodents and rabbits after immunization with peripheral nerve extracts.5,6 Despite failure to exacerbate mild experimental allergic neuritis in rodents with the transfer of sera from patients … Reprint requests to (F.J.D.), Department of Pediatrics, Connecticut Children’s Medical Center, 282 Washington St, Suite 2A, Hartford, CT 06106. E-mail: fdimari{at}ccmckids.org

Ndrg1-deficient mice exhibit a progressive demyelinating disorder of peripheral nerves.

NDRG1 is an intracellular protein that is induced under a number of stress and pathological conditions, and it is thought to be associated with cell growth and differentiation. Recently, human NDRG1 was identified as a gene responsible for hereditary motor and sensory neuropathy-Lom (classified as Charcot-Marie-Tooth disease type 4D), which is characterized by early-onset peripheral neuropathy, leading to severe disability in adulthood. In this study, we generated mice lacking Ndrg1 to analyze its function and elucidate the pathogenesis of Charcot-Marie-Tooth disease type 4D. Histological analysis showed that the sciatic nerve of Ndrg1-deficient mice degenerated with demyelination at about 5 weeks of age. However, myelination of Schwann cells in the sciatic nerve was normal for 2 weeks after birth. Ndrg1-deficient mice showed muscle weakness, especially in the hind limbs, but complicated motor skills were retained. In wild-type mice, NDRG1 was abundantly expressed in the cytoplasm of Schwann cells rather than the myelin sheath. These results indicate that NDRG1 deficiency leads to Schwann cell dysfunction, suggesting that NDRG1 is essential for maintenance of the myelin sheaths in peripheral nerves. These mice will be used for future analyses of the mechanisms of myelin maintenance.

Insertion of mutant proteolipid protein results in missorting of myelin proteins.

Two brothers with a leukodystrophy, progressive spastic diplegia, and peripheral neuropathy were found to have proteinaceous aggregates in the peripheral nerve myelin sheath. The patients' mother had only subclinical peripheral neuropathy, but the maternal grandmother had adult-onset leukodystrophy. Sequencing of the proteolipid protein (PLP) gene showed a point mutation IVS4 + 1 G-->A within the donor splice site of intron 4. We identified one transcript with a deletion of exon 4 (Deltaex4, 169bp) encoding for PLP and DM20 proteins and lacking two transmembrane domains, and a second transcript with exon 4 + 10bp encoding three transmembrane domains. Immunohistochemistry showed abnormal aggregation in the myelin sheath of MBP and P0. Myelin-associated glycoprotein was present in the Schmidt-Lanterman clefts but significantly reduced in the periaxonal region. Using immunogold electron microscopy, we demonstrated the presence of mutated PLP/DM20 and the absence of the intact protein in the patient peripheral myelin sheath. We conclude that insertion of mutant PLP/DM20 with resulting aberrant distribution of other myelin proteins in peripheral nerve may constitute an important mechanism of dysmyelination in disorders associated with PLP mutations.

Diagnosis of CIDP.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease that targets the myelin sheaths of peripheral nerves. In clinical practice the diagnosis is often difficult to make because of the clinical heterogeneity of the disease, its multifocality and predilection for proximal nerve segments, and the limitations of our electrophysiologic and pathologic techniques. Although there are rather stringent research criteria for selecting patients to clinical trials, there are no generally agreed-on clinical diagnostic criteria for CIDP, and application of the research criteria to routine clinical practice would miss the diagnosis in a majority of patients. Because of this uncertainty, the prevalence of CIDP is greatly underestimated, and patients are often left untreated despite progression of their disease. However, given what is known about the clinical presentation and pathophysiology of CIDP, patients with neuropathy of otherwise unknown etiology are more likely to have CIDP than idiopathic axonal neuropathy, and warrant a trial of therapy if they have nerve conduction velocities below the lower limits of normal, prolongation of F-waves beyond the normal range, or presence of conduction block or temporal dispersion. A favorable response to therapy, consisting of stabilization or improvement of the neuropathy, would confirm the diagnosis.

Measurement of the repeat period of myelin sheath using ultrathin frozen sections.

The myelin sheath of peripheral nerves was observed by transmission electron microscopy (TEM) using plastic-embedded sections and ultrathin frozen sections. Repeat distances of myelin sheaths were measured in high-powered electron micrographs. The ultrathin frozen sections showed a longer repeat distance than the plastic-embedded sections. The ultrathin frozen sections were thought to contain fewer artefacts, as they had not been subject to dehydration and embedding. It is known that broken myelin sheaths are often observed under conventional TEM. It is thought that these procedures cause contraction and partial destruction of the myelin sheath.

Evidence that antisulfatide autoantibodies from rats experimentally infected with Trypanosoma cruzi bind to homologous neural tissue.

Earlier studies in Trypanosoma cruzi-infected rats revealed an increased antibody activity against sulfatide, a specific constituent of both myelin sheaths of peripheral nerves and T. cruzi epimastigotes. To investigate further the characteristics of such anti-sulfatide antibodies, we analyzed their IgG isotypes as well as their ability to bind to homologous neural host structures. Antisulfatide IgG-enriched fractions were obtained from rats acutely infected with T. cruzi. Immunoglobulin isotypes were determined by an enzyme-linked immunosorbent assay (ELISA) method to show that IgG2a and, more significantly, IgG2b were the predominant isotypes of antisulfatide autoantibodies. Further immunofluorescence studies carried out in coronal sections of the rat forebrain revealed, in turn, that antisulfatide antibodies were capable of reacting with homologous neural tissues. Specific binding of these rat autoantibodies to sulfocerebroside on cell surfaces in vivo may in theory play some detrimental role, given the reported ability of rat IgG2b to fix complement or to mediate antibody-dependent cell-mediated cytotoxicity reactions.

An adhesion test system based on Schneider cells to determine genotype–phenotype correlations for mutated P0 proteins

Myelin protein zero (MPZ, P0) is well known as the adhesion molecule responsible for the compaction of the myelin sheath of peripheral nerves. Mutations are linked to Charcot-Marie-Tooth syndrome type 1B (CMT1B) and the more severe Dejerine–Sottas syndrome (DSS). Three mutations leading to phenotypes of increasing severity (Ser34del/CMT1B, Ser34Cys/DSS, INS663GC/DSS) were expressed in S2 insect cells and resulted in a decreased adhesion capability in correlation with their respective phenotypes.

Experimental polyneuropathy produced in guinea-pigs immunized against sulfatide.

Antibodies to sulfatide are associated with polyneuropathy. To investigate the role of anti-sulfatide antibodies in this neurological disorder, guinea-pigs were immunized with sulfatide, and their behavior, serology and pathology were compared with animals injected with simple Freund's adjuvant. Eleven of 13 guinea-pigs that developed raised serum anti-sulfatide antibodies after five injections of sulfatide showed definite motor weakness. Demyelination of peripheral nerves and immunoglobulin deposits at peripheral nerve myelin sheath were found in symptomatic animals only. Functional impairment of the animals was significantly correlated with serum anti-sulfatide IgG levels and pathological findings in nerve fiber studies. Control animals and animals that received 1-3 injections of sulfatide were behaviorally and pathologically normal.

Immunocytochemical studies of human peripheral nerve with serum from patients with polyneuropathy and paraproteinemia.

Immunohistochemical binding of IgM paraproteins to nerve was studied using the immunoperoxidase technique with serum from 10 patients with benign plasma cell dyscrasia and neuropathy. We stained the myelin sheaths of peripheral nerves and roots fo five patients who had myelin-absorbable IgM paraproteins. Two patients with IgM paraproteins that did not react with myelin showed predominant staining of axons, while three were completely negative. Serum specimens from normal volunteers and patients with paraproteinemias or ALS were also unreactive. Immunocytochemical methods can detect IgM paraproteins with an affinity for nerve antigens and may assist in the diagnosis and classification of plasma cell dyscrasia associated neuropathy.