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PubMed2002

Creutzfeldt-Jakob disease with amyotrophy and demyelinating polyneuropathy.

OBJECTIVE: To report the clinical and neuropathological features in a patient with Creutzfeldt-Jakob disease with amyotrophy and demyelinating polyneuropathy. DESIGN: Case report. PATIENT AND RESULTS: A 62-year-old man had progressive numbness of the left foot, unsteady gait, diminished deep reflexes, fasciculations, and tactile hypesthesia on the feet. Cerebrospinal fluid, electroneurography, and electromyography were suggestive of chronic inflammatory demyelinating polyneuropathy. He was treated with plasmapheresis, corticosteroids, and immunglobulins, with minimal improvement. After 2 months, severe amyotrophy, polyneuropathy, cerebellar signs, and dementia developed, and he died 8 months after onset of the disease. Autopsy and prion protein immunohistochemistry proved typical Creutzfeldt-Jakob disease. No mutation was found in the prion protein gene, and the codon 129 polymorphism was methionine-valine. In the ventral horn, the loss of the motoneurons was accompanied by prion protein immunoreactivity. The peripheral nerves were segmentally demyelinated but free of prion protein deposition. CONCLUSIONS: The view that peripheral neuropathy and amyotrophy may occasionally be an integral part of Creutzfeldt-Jakob disease is supported by our case, which showed these abnormalities simultaneously. These symptoms, when prominent, may cause problems in differential diagnosis.

Brachial Plexus Neuritis↗
PubMed1998

Demyelination in the central nervous system mediated by an anti-oligodendrocyte antibody.

The factors responsible for the major demyelinating disease of the central nervous system (CNS), multiple sclerosis, are poorly defined. Although T-cell-mediated immune responses play a pivotal role in establishing the inflammatory response, humoral factors also may be critical in disease progress. We have isolated a mouse monoclonal antibody (mAb 2B10) that recognizes a cell-surface molecule expressed exclusively by rat oligodendrocytes, the cells responsible for the formation and maintenance of CNS myelin. In cultures of neonatal rat spinal cord, mAb 2B10 specifically mediated oligodendrocyte cell death in the absence of complement. In the current study, mAb 2B10-producing hybridoma cells were implanted into adult rat brain ventricles, and the effect of mAb 2B10 on CNS cytoarchitecture was examined. In the optic nerves of mAb 2B10-treated animals, there was significant focal myelin degeneration near the optic chiasm. Axons in the myelin degenerate regions were largely healthy. There was no significant infiltration of hematopoietic-derived cells into the affected regions, but microglia were activated focally and phagocytosed the collapsed myelin. This study demonstrates that an antibody directed against myelin-forming cells induces CNS demyelination and supports the hypothesis that autoantibodies may play a role in CNS demyelinating diseases.

Animals↗
PubMed1997

Magnetic nerve root stimulation in two types of brachial plexus injury: segmental demyelination and axonal degeneration.

Magnetic cervical nerve root stimulation was performed in 9 patients with plexopathies secondary to suspension (SP) and in 12 cases with neurogenic thoracic outlet syndrome (NTOS). The findings were compared with those of the previously reported case groups: n-hexane polyneuropathy (HPNP), inflammatory demyelinating polyneuropathy (IDP), and motor neuron disease (MND). Muscle responses elicited by magnetic stimulation had very high rates of amplitude and area loss in the neck-axilla segments of the 6 SP patients. This, along with the other electrophysiological findings, suggested the presence of segmentally demyelinating plexus lesions. In NTOS patients, magnetic stimulation findings were not significantly different from those of the controls. Neck-axilla segment amplitude and are reduction rates in SP and IDP patients were significantly higher than those found in NTOS, HPNP, and MND groups, implying that magnetic nerve root stimulation may have a role in the demonstration of segmentally demyelinating lesions involving proximal nerve segments.

Adolescent↗
PubMed1999

Steroid-responsive multifocal demyelinating neuropathy with central involvement.

We describe 2 patients with associated central and peripheral demyelination. Electrophysiological studies revealed a demyelinating polyneuropathy with sensory and motor conduction blocks. Visual evoked potentials were abnormal. Motor evoked potentials showed abnormal central conduction time in 1 patient. Magnetic resonance imaging revealed regions of abnormal high signal in the spinal cord and brain; sural nerve biopsy disclosed a demyelinating neuropathy. Both patients showed clinical and electrophysiological improvement after steroid therapy.

Adult↗
PubMed1999

Conduction block and continuous motor unit activity in chronic acquired demyelinating polyneuropathy.

The term continuous motor unit activity (CMUA) may be used to refer to the involuntary, sustained activity of motor units caused by hyperactivity of peripheral motor nerves. CMUA has been reported in association with acquired neuropathies such as chronic inflammatory demyelinating polyneuropathy. The precise mechanism responsible for the excess muscle activity is not defined, but the activity is believed to originate in the peripheral nerves, perhaps at sites of focal demyelination. We describe a case of an acquired, demyelinating neuropathy associated with distal motor conduction block in which CMUA was observed in muscles innervated by blocked axons. Despite the prolonged disease duration of nearly 40 years, marked clinical and electrophysiological improvement as well as resolution of the CMUA were observed following immunosuppressive therapy. A relationship between the chronic motor conduction block and the excess muscle activity is postulated.

Chronic Disease↗
PubMed1999

Activity-dependent excitability changes in chronic inflammatory demyelinating polyneuropathy: A microneurographic study.

The purpose of this study was to investigate activity-dependent excitability changes in polyneuropathy and their correlation with symptomatology. First, we recorded sensory nerve action potentials (SNAPs) with an intraneural microelectrode during impulse trains in 11 patients with chronic inflammatory demyelinating polyneuropathy. When the stimulus frequency was increased to >/=20 Hz, all patients showed marked decreases in the amplitudes of averaged SNAPs (128 responses) associated with latency increases. The amplitude decreases were much greater than those in patients with axonal neuropathies. In single-unit recordings, responses showed latency increases, which were small but sufficient to cause decreases in the averaged responses. Clinical sensory impairment was correlated with the degree of preexisting conduction block or axonal loss, but not with the degree of rate-dependent amplitude decreases. Activity-dependent changes occur preferentially in demyelinating neuropathy and are a sensitive measure of demyelination. The mechanism responsible for the amplitude decreases could be conduction slowing or block caused by activity-dependent hyperpolarization.

Action Potentials↗
PubMed2000

Diagnostic criteria for demyelinating polyneuropathy associated with monoclonal gammopathy.

In order to define diagnostic criteria for the demyelinating polyneuropathy associated with monoclonal gammopathy of undetermined significance (MGUS), we compared 30 patients with idiopathic chronic inflammatory demyelinating polyneuropathy (CIDP) without a monoclonal gammopathy, with 29 patients with polyneuropathy associated with MGUS. All 59 patients fulfilled research criteria for CIDP. In the patients with MGUS, sensory symptoms and signs predominated, there was usually no cranial nerve involvement, and the neuropathy was symmetrical with a slowly progressive course. On electrophysiological examination, an abnormal median nerve sensory action potential in combination with a normal sural nerve action potential (AMNS) was not found. In idiopathic CIDP patients, a preceding infection was frequent, motor features predominated, there was often cranial nerve involvement, the neuropathy could be asymmetrical, and AMNS was frequently found. Diagnostic criteria for demyelinating polyneuropathy associated with MGUS are presented.

Action Potentials↗
PubMed1999

A tumor necrosis factor-induced model of human primary demyelinating diseases develops in immunodeficient mice.

We have reported previously that in the central nervous system (CNS) local expression of tumor necrosis factor (TNF) transgenes can trigger the development of oligodendrocyte apoptosis, primary inflammatory demyelination and neurological dysfunction, accompanied by lymphocyte and macrophage infiltration into the CNS. To distinguish between the local effects of transgene-encoded TNF and the potential encephalitogenic effects of immune infiltrates upon CNS disease pathogenesis, we have backcrossed Tg6074 TNF-transgenic mice to mice deficient in CD4, beta2-microglobulin (beta2m), immunoglobulin mu chain (Igmu) or recombination activation gene-1 (Rag-1). TNF was capable of triggering undiminished primary demyelination in all of the immunodeficient mice, in the presence of activated cells of the macrophage/microglial lineage. We conclude that TNF is sufficient to induce primary inflammatory demyelination and neurological deficits even in the absence of adaptive immunity.

Animals↗
PubMed2000

Remyelinating the demyelinated CNS.

The CNS has an inherent capacity to generate remyelinating cells following episodes of myelin loss. However, persistent demyelination is the major pathology of multiple sclerosis and the leucodystrophies, and is also a feature of spinal cord trauma. There are potentially two approaches for achieving remyelination in situations where it fails; enhancement of the inherent remyelinating capacity of the CNS, or transplantation of an exogenous source of myelin forming cells. In experimental animals it is possible to remyelinate demyelinated CNS axons by transplanting cultures containing central or peripheral myelinogenic cells. Glial cell transplantation may thus provide a therapeutic strategy for remyelinating areas of chronic demyelination as well as for stimulating axon regeneration. This presentation will review four issues that have to be addressed before glial transplantation can be undertaken in humans: is the procedure safe, what cells would be used, where would the cells come from and can we predict how much remyelination will be achieved? It concludes that the most promising approach will be to use multipotent neural precursor cells that have been committed to oligodendrocyte lineage differentiation prior to implantation. However, even with such preparations, which have considerable myelinating potential, the extent of remyelination that would be achieved can not yet be predicted with any degree of certainty.

Animals↗
PubMed2002

Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy is an immune mediated disorder characterised by progressive or relapsing symmetrical motor or sensory symptoms and signs in more than one limb, developing over at least two months. It may cause prolonged periods of disability and even death. Several uncontrolled studies have suggested a beneficial effect of intravenous immunoglobulin. OBJECTIVES: To review systematically the evidence from randomised controlled trials concerning the efficacy and safety of intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy. SEARCH STRATEGY: We used the Search Strategy of the Cochrane Neuromuscular Disease Review Group to search the Disease Group register and other databases for randomised controlled trials from 1985 onwards. SELECTION CRITERIA: Randomised controlled studies examining the effects of any dose of intravenous immunoglobulin versus placebo, plasma exchange or corticosteroids in patients with definite or probable chronic inflammatory demyelinating polyradiculoneuropathy. Outcome measures had to include one of the following: a disability score, the Medical Research Council sum score, electrophysiological data or walking distance. Studies which reported the frequency of adverse effects were used to assess the safety of treatment. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed literature searches to identify potentially relevant trials, scored their quality and extracted data independently. For dichotomous data, we calculated relative risks, and for continuous data, effect sizes (for definition see statistical analysis section) and weighted pooled effect sizes. Statistical uncertainty was expressed in 95% confidence intervals. Sensitivity analysis excluding studies with quality scores below A 0.50 and below B 0.75 was planned but not performed as all studies had quality scores above 0.75. MAIN RESULTS: Six randomised controlled trials were considered eligible including 170 patients. Four studies on 113 patients compared intravenous immunoglobulin against placebo. One trial with 17 patients compared intravenous immunoglobulin with plasma exchange in a cross-over design and one trial compared intravenous immunoglobulin with prednisolone in 32 patients. A significantly higher proportion of patients improved in disability within one month after the onset of intravenous immunoglobulin treatment as compared with placebo (relative risk 3.17, 95% confidence interval 1.74 to 5.75). Whether all these improvements are equally clinically relevant cannot be deduced from this analysis because each trial used a different disability scale with a unique definition of a significant improvement. To overcome this problem an attempt was made to transform the various disability scales to the modified Rankin score. In three trials including 87 patients this transformation could be carried out. A significantly higher proportion of patients improved one point after intravenous immunoglobulin treatment compared to placebo (relative risk 2.47, 95% confidence interval 1.02 to 6.01). The effect size for change of mean disability score at six weeks comparing intravenous immunoglobulin with plasma exchange revealed no difference between the two therapies (effect size -0.07, 95% confidence interval -0.76 to 0.63.) The proportion of patients with a significant improvement did not differ significantly between prednisolone and intravenous immunoglobulin (relative risk of 0.91 (95% CI 0.50 to 1.68). Also, no difference in mean improvement on the disability scale was found at two weeks (effect size -0.12, 95% confidence interval -0.68 to 0.45) or six weeks (effect size -0.07, 95% confidence interval -0.63 to 0.50) between prednisolone and intravenous immunoglobulin. There were no statistically significant differences in frequencies of side effects between the three types of treatment. REVIEWER'S CONCLUSIONS: The evidence from randomised controlled trials shows that intravenous immunoglobulin improves disability for at least two to six weeks compared with placebo, with a number needed to treat of three. During this period it has similar efficacy to plasma exchange and oral prednisolone. Since intravenous immunoglobulin, plasma exchange and prednisolone seem to be equally effective, it is currently uncertain which of these treatments should be the first choice. Cost, side effects, duration of treatment, dependency on regular hospital visits and ease of administration all have to be considered before such a decision can be made.

Humans↗
PubMed2004

Plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy is an uncommon progressive or relapsing paralysing disease caused by inflammation of the peripheral nerves. If the hypothesis that it is due to autoimmunity is correct, removal of autoantibodies in the blood by plasma exchange should be beneficial. OBJECTIVES: To evaluate the efficacy of plasma exchange in chronic inflammatory demyelinating polyradiculoneuropathy. SEARCH STRATEGY: We searched the Neuromuscular Disease Group Register (December 2003), and MEDLINE (January 1966 to January 2003), EMBASE (January 1980 to January 2003), CINAHL (January 1982 to December 2002) and LILACS (January 1982 to January 2003). We also scrutinised the bibliographies of the trials, and contacted the trial authors and other disease experts. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials in participants of any age comparing plasma exchange with sham treatment or no treatment. A trial showing no significant difference in the benefit from plasma exchange with intravenous immunoglobulin has been included in a separate Cochrane review. DATA COLLECTION AND ANALYSIS: Two authors selected the trials, extracted the data and assessed methodological quality independently. Where possible data were combined according to the methods of the Cochrane Neuromuscular Disease Review Group. MAIN RESULTS PRIMARY OUTCOME MEASURE: one crossover trial including 18 participants showed 2 (95% confidence interval (CI) 0.8 to 3.0) points more improvement after four weeks in an 11-point disability scale with plasma exchange (10 exchanges over four weeks) than with sham exchange. Rapid deterioration after plasma exchange occurred in eight of 12 who had improved. SECONDARY OUTCOME MEASURES: when the results of this trial and another with 29 participants treated in a parallel group design trial were combined, there were 31 points (95% CI 16 to 45) more improvement in an impairment scale after plasma exchange (six exchanges over three weeks) than after sham exchange. There were significant improvements in both trials in an electrophysiological measure, the proximally evoked compound muscle action potential, after three or four weeks. Non-randomised evidence indicates that plasma exchange induces adverse events in 3% to 17% of procedures. These are sometimes serious. REVIEWERS' CONCLUSIONS: Evidence from two small trials showed that plasma exchange provides significant short-term benefit in about two-thirds of patients with chronic inflammatory demyelinating polyradiculoneuropathy but rapid deterioration may occur afterwards. Adverse events related to difficulty with venous access, use of citrate and haemodynamic changes are not uncommon. More research is needed to identify agents which will prolong the beneficial action of plasma exchange.

Humans↗
PubMed2002

Cellular sources and targets of IFN-gamma-mediated protection against viral demyelination and neurological deficits.

IFN-gamma is an anti-viral and immunomodulatory cytokine critical for resistance to multiple pathogens. Using mice with targeted disruption of the gene for IFN-gamma, we previously demonstrated that this cytokine is critical for resistance to viral persistence and demyelination in the Theiler's virus model of multiple sclerosis. During viral infections, IFN-gamma is produced by natural killer (NK) cells, CD4(+) and CD8(+) T cells; however, the proportions of lymphocyte subsets responding to virus infection influences the contributions to IFN-gamma-mediated protection. To determine the lymphocyte subsets that produce IFN-gamma to maintain resistance, we used adoptive transfer strategies to generate mice with lymphocyte-specific deficiencies in IFN-gamma-production. We demonstrate that IFN-gamma production by both CD4(+) and CD8(+) T cell subsets is critical for resistance to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelination and neurological disease, and that CD4(+) T cells make a greater contribution to IFN-gamma-mediated protection. To determine the cellular targets of IFN-gamma-mediated responses, we used adoptive transfer studies and bone marrow chimerism to generate mice in which either hematopoietic or somatic cells lacked the ability to express IFN-gamma receptor. We demonstrate that IFN-gamma receptor must be present on central nervous system glia, but not bone marrow-derived lymphocytes, in order to maintain resistance to TMEV-induced demyelination.

Animals↗
PubMed2002

Periaxin mutations cause a broad spectrum of demyelinating neuropathies.

Previous studies have demonstrated that apparent loss-of-function mutations in the periaxin gene cause autosomal recessive Dejerine-Sottas neuropathy or severe demyelinating Charcot-Marie-Tooth disease. In this report, we extend the associated phenotypes with the identification of two additional families with novel periaxin gene mutations (C715X and R82fsX96) and provide detailed neuropathology. Each patient had marked sensory involvement; two siblings with a homozygous C715X mutation had much worse sensory impairment than motor impairment. Despite early disease onset, these siblings with the C715X mutation had relatively slow disease progression and adult motor impairment typical of classic demyelinating Charcot-Marie-Tooth neuropathy. In contrast, a patient with the homozygous R82fsX96 mutation had a disease course consistent with Dejerine-Sottas neuropathy. The neuropathology of patients in both families was remarkable for demyelination, onion bulb and occasional tomacula formation with focal myelin thickening, abnormalities of the paranodal myelin loops, and focal absence of paranodal septate-like junctions between the terminal loops and axon. Our study indicates a prominent sensory neuropathy resulting from periaxin gene mutations and suggests a role for the carboxyl terminal domain of the periaxin protein.

Adult↗
PubMed1982

Experimental models of virus-induced demyelination of the central nervous system.

One of the arguments in favor of a viral pathogenesis for multiple sclerosis is the existence of several experimental and natural animal models of virus-induced primary demyelination. This review deals comprehensively with such models. Well-known examples of demyelinating viral infections in their natural host are JHM, Theiler, visna, and canine distemper encephalomyelitides. Recent reports of experimental murine infections with pathogens such as vesicular stomatitis, Chandipura, herpes simplex, Venezuelan equine encephalomyelitis, and Semliki Forest viruses are also discussed. The thrust of the review is to include viral models suspected of producing primary demyelination on an immunopathological basis.

Animals↗
PubMed1984

Demyelination induced by serum from patients with Guillain-Barré syndrome.

Sera from 16 patients with acute Guillain-Barré syndrome (GBS) and 14 healthy control subjects were injected into rat sciatic nerve and assessed for demyelinating activity by electrophysiological and histological techniques. Only fresh GBS serum, and not GBS serum stored at -20 degrees C or -70 degrees C, blocked conduction to a significantly greater extent than did fresh control serum. Conduction block developed gradually, starting within 24 hours of injection and reaching a maximum between days 3 and 6. Recovery of conduction commenced thereafter, and conduction returned to normal by day 33. Quantitative histological studies on day 6 showed that fresh GBS serum produced significantly more widespread demyelination than did stored GBS serum (p less than 0.01). Stored GBS serum showed residual demyelinating activity when compared with fresh control serum (p less than 0.01). Fresh serum obtained from 4 patients after recovery from GBS did not produce conduction block, despite it having done so during the acute phase of the disease.

Animals↗
PubMed1986

Chronic demyelinating peripheral neuropathy in cerebrotendinous xanthomatosis.

Three siblings with chemically proved cerebrotendinous xanthomatosis presented with typical neurological manifestations of dementia and spinocerebellar disorder. Electrodiagnostic tests revealed demyelinating neuropathy in all three. Sural nerve biopsies showed loss of myelinated large fibers, marked Schwann cell proliferation, and onion bulb formation. Teased-fiber preparations confirmed the occurrence of segmental demyelination and remyelination. We suggest that demyelinating neuropathy is part of the neurological spectrum of cerebrotendinous xanthomatosis and should be considered in the differential diagnosis of a recessively inherited motor and sensory neuropathy.

Adolescent↗
PubMed1987

Acute ischemia causes axonal stasis, swelling, attenuation, and secondary demyelination.

Microsphere embolization of rat sciatic nerve capillaries results in a central fascicular ischemic core. Twenty-four hours after microembolization, the pathological alterations along the length of 55 myelinated fibers were reconstructed by computer imaging of 2,000 serial semi-thin epoxy sections of a tissue block that extended from just above and into an ischemic core. From proximal to distal, the typical sequence of pathological alterations was: normal----swollen dark axons + thin myelin or demyelination----attenuated axons----axon cytolysis (46 fibers) or normal axons (9 fibers). Because organelle accumulation and axonal swelling were the earliest and most proximal pathological lesions, we infer that regional hypoxia causes axonal stasis as a primary event. Demyelination was found in fibers showing swollen dark and attenuated axons. These findings suggest that axons are selectively vulnerable to acute ischemia and that, depending on severity, the fibers either undergo axonal degeneration or transitory structural alterations without axonal degeneration, the latter consisting of axonal changes and secondary demyelination.

Animals↗
PubMed1991

Serum interleukin-2 concentrations in Guillain-Barré syndrome and chronic idiopathic demyelinating polyradiculoneuropathy: comparison with other neurological diseases of presumed immunopathogenesis.

Serum concentrations of the cytokine interleukin-2 (IL-2) were quantitated by enzyme-linked immunosorbent assay in 42 patients with Guillain-Barré syndrome, 15 patients with chronic idiopathic demyelinating polyradiculoneuropathy, 37 patients with other neuropathies, 54 patients with other noninflammatory, nondemyelinating neurological disorders, and 26 healthy control subjects. We found markedly increased serum levels of IL-2 in patients with Guillain-Barré syndrome and to a much lesser extent, in patients with chronic idiopathic demyelinating polyradiculoneuropathy. Increased serum concentrations of IL-2 in patients with Guillain-Barré syndrome returned to normal in parallel with recovery from the disease. These findings suggest ongoing T-cell proliferation in patients with Guillain-Barré syndrome and some patients with chronic idiopathic demyelinating polyradiculoneuropathy. IL-2 levels were also raised in patients with active multiple sclerosis, myasthenia gravis, and herpes simplex encephalitis, and some patients with polymyositis, invoking T cells in the pathogenesis of these diseases.

Autoimmune Diseases↗