Peripheral Demyelination Research Articles

A nationwide survey of combined central and peripheral demyelination in Japan

ObjectivesTo clarify the clinical features of combined central and peripheral demyelination (CCPD) via a nationwide survey.MethodsThe following characteristics were used to define CCPD: T2 high-signal intensity lesions in the brain,...

A novel and robust conditioning lesion induced by ethidium bromide

Molecular and cellular mechanisms underlying the peripheral conditioning lesion remain unsolved. We show here that injection of a chemical demyelinating agent, ethidium bromide, into the sciatic nerve induces a similar set of regeneration-associated genes and promotes a 2.7-fold greater extent of sensory axon regeneration in the spinal cord than sciatic nerve crush. We found that more severe peripheral demyelination correlates with more severe functional and electrophysiological deficits, but more robust central regeneration. Ethidium bromide injection does not activate macrophages at the demyelinated sciatic nerve site, as observed after nerve crush, but briefly activates macrophages in the dorsal root ganglion. This study provides a new method for investigating the underlying mechanisms of the conditioning response and suggests that loss of the peripheral myelin may be a major signal to change the intrinsic growth state of adult sensory neurons and promote regeneration.

Central and Peripheral Nervous System Demyelination Following Mycoplasma Pneumonia Infection With Review of Literature

Central and Peripheral Nervous System Demyelination Following Mycoplasma Pneumonia Infection With Review of Literature

Ranolazine attenuates mechanical allodynia associated with demyelination injury.

The aim of this study was to determine whether ranolazine, a new medication that targets sodium channels to improve cardiac ischemia and angina, could be an effective analgesic agent for pain associated with demyelination injury. Many agents have been used to treat neuropathic pain but not all neuropathic conditions respond similarly to treatment. We have demonstrated that ranolazine, an agent that blocks voltage-gated sodium channels Nav 1.4, 1.5, 1.7, and 1.8, is effective in attenuating mechanical hyperalgesia in both complete Freund's adjuvant and spared nerve injury preclinical models of inflammatory and neuropathic pain, respectively. Here we test the efficacy of this drug in a newly validated model of demyelination injury that responds uniquely to a number of treatment options. After determination of baseline nerve conduction velocities (NCVs) and withdrawal responses from heat and mechanical stimulation in male Sprague-Dawley rats (300-350 g), 1 μg/30 μL of doxorubicin was injected into one sciatic nerve. The contralateral nerve provided a sham-injected control. Two weeks after doxorubicin injection, NCV and sensitivity to heat and mechanical stimulation were reassessed before and after treatment with ranolazine (10, 30, 50 mg/kg) administered intraperitoneally using an experimenter-blinded, randomized design. Doxorubicin injection produced a significant hyperalgesic effect in response to mechanical but not heat stimulation. Conduction velocities in the injected limbs were reduced when compared with controls. Ranolazine reduced mechanical allodynia with peak efficacy at 30 mg/kg. Fifty milligram/kilogram ranolazine restored NCVs by approximately 50%, but had no effect in the uninjected limb. Ranolazine exerts broad-spectrum actions to reduce mechanical allodynia that is associated with peripheral demyelination injury.

Unusual presentation of hereditary neuropathy with liability to pressure palsies

BackgroundHereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal-dominant painless peripheral neuropathy characterized by episodes of repeated focal pressure neuropathies at sites of entrapment/compression, with a considerable variability in the clinical course. Electrodiagnostic and genetic testing are important in the diagnostic evaluation of these patients.Case presentationWe report an unusual HNPP phenotype, five compression neuropathies in four nerves in a patient with bilateral hand numbness. A 42-year-old female, presented with acute bilateral paresthesias and weakness in her hands after starting yoga exercises requiring hyperextension of her hands at the wrists. Her presentation was complicated by: a) a remote history of acute onset foot drop and subsequent improvement, b) previous diagnoses of demyelinating peripheral neuropathy, possibly Charcot-Marie-Tooth disease, and c) exposure to leprosy. Electrodiagnostic testing showed 5 separate compression neuropathies in 4 nerves including: severe left and right ulnar neuropathies at the wrist, left and right median neuropathies at the wrist and left ulnar neuropathy at the elbow. There was a mild generalized, primarily demyelinating, peripheral polyneuropathy. Based on the clinical suspicion and electrodiagnostic findings, consistent with profound demyelination in areas of compression, genetic analysis was done which identified a deletion of the PMP-22 gene consistent with HNPP.ConclusionHNPP can present with unusual phenotypes, such as 5 separate mononeuropathies, bilateral ulnar and median neuropathies at the wrists and ulnar neuropathy at the elbow with mild peripheral demyelinating polyneuropathy associated with the PMP-22 gene deletion.

Increased proinflammatory cytokines in sera of patients with multifocal motor neuropathy

BackgroundMultifocal motor neuropathy (MMN) is characterized by clinical improvement with intravenous immunoglobulin and the frequent detection of anti-ganglioside antibodies. However, the immunological background of the neuronal damage in MMN is still unclear. ObjectiveThe aim of this study is to investigate abnormalities in the cytokine and chemokine profiles of MMN patients. MethodsSera from 16 patients with MMN, 16 patients with sporadic amyotrophic lateral sclerosis (ALS), and 15 patients with other non-inflammatory neurological diseases (ONDs) were analyzed for 27 cytokines and chemokines using a multiplex bead array. We also checked whether the altered cytokine/chemokine profile in the MMN group differed significantly in the presence or absence of abnormal electrophysiological findings. ResultsSerum IL-1Ra, IL-2, G-CSF, TNF-α, and TNFR1 levels were significantly higher in the MMN group than in the ONDs group. Of these, G-CSF and TNF-α also showed significant increases compared to the ALS group. Serum G-CSF and TNF-α levels were significantly higher in MMN patients presenting with focal demyelination including conduction block than in patients without any focal demyelination. ConclusionsProinflammatory cytokines may contribute to peripheral nerve demyelination in MMN.

A Case of Acute Combined Central and Peripheral Demyelination

Demyelinating disease can acutely affect the central or peripheral nervous system in the forms of acute disseminated encephalomyelitis, acute inflammatory demyelinating polyradiculoneuropathy, and related disorders. Rarely, demyelination can affect the central and peripheral nervous system simultaneously in a disorder that has been described as acute severe combined demyelination. We describe a 54-year-old woman who presented with rapidly progressive ascending paralysis and areflexia with abnormalities in cerebrospinal fluid, electrodiagnostic studies, and magnetic resonance imaging of the brain and cervical spine. She had antibodies to GD1a and responded to treatment with intravenous immunoglobulin and corticosteroids. Our case illustrates that, even in severe form, acute combined central and peripheral demyelination may be considered a treatment responsive and potentially reversible disease.

12. Co-existence of primary progressive MS and CMT1A

A 48-year old man presented with a 20-year history of neurological symptoms. He reported slowly progressive changes in gait, mild right leg weakness and subtle short-term memory problems. There was no history of discrete relapses and no family history of neurological disease. The neurological examination revealed upper and lower limb weakness, marked lower limb spasticity, globally brisk reflexes and extensor plantar responses. MRI of the brain demonstrated white matter T2/FLAIR hyperintensities with extensive pericallosal involvement and MRI of the spinal cord revealed lesions in the thoracic cord suggestive of demyelination. Somatosensory and visual evoked potentials were markedly delayed and oligoclonal bands were detected in cerebrospinal fluid, consistent with multiple sclerosis. Nerve conduction studies demonstrated electrophysiological evidence of a generalised demyelinating, sensorimotor neuropathy, without temporal dispersion or conduction block, suggestive of an inherited cause. Genetic testing revealed PMP22 duplication, confirming Charcot-Marie-Tooth disease type 1A. This case highlights the rare co-existence of acquired central demyelination (i.e. primary progressive MS) in conjunction with inherited peripheral demyelination (CMT 1A).

Combined central and peripheral demyelination

Acquired central and peripheral demyelination in the same patient is a very rare feature. We report a 52-year-male patient with the chronic autoimmune hepatitis (CAH) presenting with pure motor areflexic quadriparesis from 4 months and recent onset of drowsiness of 4 days duration. Studies of imaging and electrophysiology suggested central pontine myelinolysis and chronic inflammatory demyelinating polyradiculoneuropathy. Patient was effectively treated with high dose steroids. To the best of our knowledge, this is the first case of central and peripheral demyelination in a patient with CAH.

Central and peripheral demyelination

Several conditions cause damage to the inherently normal myelin of central nervous system, perepheral nervous system or both central and perepheral nervous system and hence termed as central demyelinating diseases, perepheral demyelinating diseases and combined central and perepheral demyelinating diseases respectively. Here we analysed and foccused on the etiology, prevalance, incidence and age of these demyelinating disorders. Clinical attention and various diagnostic tests are needed to adequately assess all these possibilities.

Neurofascin: a novel target for combined central and peripheral demyelination

Combined central and peripheral demyelination (CCPD) is a rare clinical entity characterized by inflammatory demyelination in both the central and peripheral nervous system. A recently conducted nation-wide survey revealed that clinical features of CCPD are atypical for multiple sclerosis, including an absence of oligoclonal immunoglobulin G bands in most CCPD cases. We found that autoantibody responses of CCPD target the nodes and paranodes of Ranvier in the brain and peripheral nerve tissues. We identified anti-neurofascin antibody in the serum from these CCPD patients. CCPD patients showed a significantly higher positive rate of anti-neurofascin antibody than the other limited form of inflammatory demyelinating diseases. Autoantibody responses targeting neurofascins, which are common proteins to the central and peripheral nervous system may play a pivotal role in combined demyelination in CCPD.

Two faces of Schwann cell dedifferentiation in peripheral neurodegenerative diseases: pro-demyelinating and axon-preservative functions.

In vertebrates, Schwann cells are glial cells that form a myelin sheath, which produces the saltatory conduction of neural impulses in the peripheral nervous system (Sherman and Brophy, 2005). In the case of abnormal myelin sheath generation due to genetic mutations or myelin sheath destruction by acquired nerve damage induced by inflammation or drugs, problems arise in the peripheral nervous system, leading to muscle atrophy or sensory disorders (Sherman and Brophy, 2005; Jessen and Mirsky, 2008). During the embryonic period, the neural crest cells migrate along with growing peripheral axons. A Schwann cell precursor that has finished migrating and has attached to a growing nerve may wrap around a few or as many as dozens of axons, but ultimately only target a single axon that requires a myelin sheath in response to a certain stimulus (Sherman and Brophy, 2005; Jessen and Mirsky, 2008). In the period of Schwann cell generation, the cell is called Schwann cell progenitor or immature Schwann cell. Subsequently, the Schwann cell begins the process of myelin-related gene expression and wraps the axon with the elongated Schwann cell membrane, which continues throughout the postnatal period to complete the myelin sheath formation (Sherman and Brophy, 2005; Jessen and Mirsky, 2008). The mature myelin sheath will last a lifetime, except when damage, such as nerve injury, occurs. Acute and chronic demyelinating peripheral neuropathies are primary diseases that cause myelin destruction in adults (Jessen and Mirsky, 2008). When a peripheral nerve is physically severed, distal axons are completely degenerated, and the Schwann cells wrapped around the axons directly participate in the degeneration of the myelin sheath, which leads to demyelination (Jessen and Mirsky, 2008). Afterwards, macrophages that migrate from the blood assist in completely removing the degenerated axon and the myelin sheath (Martini et al., 2008). Meanwhile, in inflammatory demyelinating diseases, acute or chronic form of demyelination may occur regardless of axonal damage, and it is considered that demyelination occurs due to local inflammation caused by autoimmune mechanisms, which may attack components of the myelin sheath or junctional regions (Pollard and Armati, 2011).

Anti‐neurofascin antibodies in patients with combined central and peripheral demyelination

Anti‐neurofascin antibodies in patients with combined central and peripheral demyelination

Clinical features of patients with Guillain‐Barré syndrome at seven hospitals on the East Coast of Australia

To document the clinical features of Guillain-Barré syndrome (GBS) in Australia, we performed a retrospective analysis of all patients admitted to several hospitals along the East Coast of Australia from 2000 to 2012. Using hospital records, we reviewed all patients with a diagnosis of GBS admitted to seven hospitals. From these, we report information of subjects who fulfilled standard diagnostic criteria. We excluded patients where inadequate information was available or who were under the age of 18. We report the features of 335 patients, in 228 of whom neurophysiological data were available. There were 168 cases of acute inflammatory demyelinating polyneuropathy (AIDP), 17 of acute motor axonal neuropathy (AMAN), 4 of acute motor and sensory axonal neuropathy (AMSAN), and 35 of Miller-Fisher syndrome (MFS). The median age at onset was 52.5 years (18-89 years) with a male : female ratio of 1.61 : 1. Upper respiratory tract infections were the most frequently identified trigger (151 subjects, 44.5%). Most patients were severely affected, with 42.7% of subjects bedbound, and an additional 24% requiring ventilatory support. GBS affects adults of all ages and usually follows a severe clinical course. In contrast to other autoimmune diseases, males are more frequently affected. A wide variety of triggering factors leads to a relatively stereotypical clinical syndrome. The most common variant of GBS in Australia is AIDP. This study shows that the clinical features of GBS in Australia are similar to that previously reported and confirms the male predominance, increased incidence with age, and frequent evidence of peripheral nerve demyelination as features of GBS.

Anti‐neurofascin antibody in combined central and peripheral demyelination

AbstractNeurofascin (NF), a cell adhesion molecule expressed in both the central nervous system (CNS) and the peripheral nervous system (PNS), plays important roles in developing and maintaining neural structures. There are several subtypes of NF resulting from post‐translational modifications: NF155, 166, 180 and 186. Among them, NF155 and NF186 are expressed in the mature CNS/PNS. NF155 is present on the oligodendroglial cell surface in the CNS and on the Schwann cell surface in the PNS at paranodes, where it tightly connects with contactin and caspr on the axonal surface of the paranode, and acts as a stabilizer of the nodes of Ranvier. NF186 exists on the axonal surface at the nodes of Ranvier. NF186 is associated with voltage‐gated Na channels (Nav), whereas both NF186 and Nav are anchored by ankyrin G. NF186 contributes to the clustering of Nav at the node. Combined central and peripheral demyelination (CCPD) is an inflammatory demyelinating disorder affecting both the CNS and PNS tissues. Distinct mechanisms including multiple sclerosis and chronic inflammatory demyelinating polyradiculoneuropathy have been hypothesized to play a role in this condition on the basis of distinctive clinical and laboratory findings. We detected anti‐NF155 antibody by cell‐based assay, enzyme‐linked immunosorbent assay, and western blot in both the sera and cerebrospinal fluids of CCPD patients at high frequencies, but did not detect it in patients with other neurological disease or healthy controls. Herein, basic aspects and the clinical significance of NF as indispensable regulators and autoimmune target molecules are summarized.

Clinical and imaging features and genetic analysis of a case with adult-onset Krabbe disease

To investigate clinical and imaging features of a patient with adult-onset Krabbe disease and to detect the underlying genetic mutations. Clinical and cranial MRI features of the patient were analyzed. Pathogenesis, clinical manifestation, cranial MRI features and diagnostic criteria for the disease were discussed. The patient had presented asymmetric limb weakness and difficulty in walking. Electromyography suggested peripheral nerve demyelination. Cranial MRI showed increased signal intensity in white matter with involvement of the corticospinal tracts. Screening of GALC gene mutation has found the patient to be heterozygous for T1685C (Ile562Thr) and homozygous for A1921G (Thr641Ala), both of which were considered to be polymorphisms. In addition, he was heterozygous for G136T (Asp46Tyr), which had not been described previously. Clinical manifestations of adult-onset Krabbe disease may be atypical. Cranial MRI and galactocerebroside activity assay should be carried out for patients featuring chronic progressive corticospinal tract injury. An Asp46Tyr mutation probably underlies the disease in the current case.

Anti-neurofascin antibody in patients with combined central and peripheral demyelination

We aimed to identify the target antigens for combined central and peripheral demyelination (CCPD). We screened target antigens by immunohistochemistry and immunoblotting using peripheral nerve tissues to identify target antigens recognized by serum antibodies from selected CCPD and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cases. We then measured the level of antibody to the relevant antigen in 7 patients with CCPD, 16 patients with CIDP, 20 patients with multiple sclerosis, 20 patients with Guillain-Barré syndrome, 21 patients with other neuropathies, and 23 healthy controls (HC) by ELISA and cell-based assays using HEK293 cells. At the initial screening, sera from 2 patients with CCPD showed cross-like binding to sciatic nerve sections at fixed intervals, with nearly perfect colocalization with neurofascin immunostaining at the node and paranode. ELISA with recombinant neurofascin revealed significantly higher mean optical density values in the CCPD group than in other disease groups and HC. Anti-neurofascin antibody positivity rates were 86% in patients with CCPD, 10% in patients with multiple sclerosis, 25% in patients with CIDP, 15% in patients with Guillain-Barré syndrome, and 0% in patients with other neuropathies and HC. The cell-based assay detected serum anti-neurofascin antibody in 5 of 7 patients with CCPD; all others were negative. CSF samples examined from 2 patients with CCPD were both positive. In anti-neurofascin antibody-positive CCPD patients, including those with a limited response to corticosteroids, IV immunoglobulin or plasma exchange alleviated the symptoms. Anti-neurofascin antibody is frequently present in patients with CCPD. Recognition of this antibody may be important, because patients with CCPD who are antibody positive respond well to IV immunoglobulin or plasma exchange.

Bipolar I Disorder Presaging X-Linked Adrenoleukodystrophy

Bipolar I Disorder Presaging X-Linked Adrenoleukodystrophy

POEMS syndrome and interleukin‐12: Missing piece in the pathogenesis of peripheral nerve demyelination

POEMS syndrome and interleukin‐12: <scp>M</scp>issing piece in the pathogenesis of peripheral nerve demyelination

Dietary restriction supports peripheral nerve health by enhancing endogenous protein quality control mechanisms

The peripheral nervous system (PNS) comprises of an extensive network of connections that convey information between the central nervous system (CNS) and peripheral organs. Long myelinated nerve fibers are particularly susceptible to age-related changes, as maintenance of the insulating glial membrane requires extensive synthesis and processing of many proteins. In rodent models, peripheral demyelination caused by genetic risk factors or by normal aging are attenuated by intermittent fasting (IF) or calorie restriction (CR) supporting a role for dietary intervention in preserving neural function. This review will summarize recent studies examining mechanisms by which life-long CR or extended IF supports peripheral nerve health.