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PubMed1997

Fulminating encephalopathy with perivenular demyelination and vacuolar myelopathy as the initial presentation of human immunodeficiency virus infection.

OBJECTIVE: To study the neuropathologic features in a case involving a 22-year-old woman in whom a fulminating encephalopathy developed as the initial manifestation of human immunodeficiency virus (HIV) infection. DESIGN: Case report. SETTING: Tertiary care hospital. PATIENT: The patient presented with rapidly progressive mental status, changes, cranial nerve abnormalities, and quadriplegia, which led to her death 5 months later. Serologic tests for HIV were initially indeterminate on Western blot analysis but were positive 1 week later. METHODS: A complete autopsy, including examination of the brain and spinal cord, was performed. Paraffin-embedded sections of the brain and spinal cord were examined using standard histologic staining procedures and immunohistochemical techniques. RESULTS: Neuropathologic examination revealed discrete foci of perivenular demyelination disseminated throughout the brain and spinal cord, as well as severe vacuolar myelopathy. Lesions typical of HIV encephalitis were not present. Human immunodeficiency virus-infected monocytes and microglia were observed in the vicinity of, but not restricted to, the perivenular demyelinating lesions. No other infectious agents were identified. CONCLUSIONS: The patient's acute encephalopathy was most likely the direct result of a widespread demyelinating process resembling acute disseminated encephalomyelitis. We suggest that the perivenular demyelination may represent an autoimmune reaction, possibly due to a nonspecific viral infection, occurring in the setting of chronic immunosuppression secondary to HIV. Although less likely, we cannot exclude the possibility that HIV could have directly triggered an autoimmune response that caused the acute disseminated encephalomyelitis-like lesions.

Adult↗
PubMed1998

Progressive central and peripheral demyelinating disease of adult onset in a Norwegian family.

OBJECTIVE: To describe the clinical features of a Norwegian family with a combined central and peripheral demyelinating disease. DESIGN: Multiple case report. SUBJECTS AND MATERIALS: Three generations of a Norwegian family. Medical records were available for all 9 members of the second generation and 5 affected members in the third generation. RESULTS: At least 5 members had clinical features, neuroimaging findings, and electrophysiologic signs indicating a chronic progressive disorder affecting both the central and peripheral nervous systems. The clinical symptoms developed between the ages of 30 and 70 years in affected family members, who gradually developed sensory loss, muscle deterioration, and distal weakness in all extremities, unsteady gait, and dysarthria. Five of 9 persons in the second generation had strokes and experienced mental deterioration. The initial stroke episodes were recognized between the ages of 54 and 68 years, and death occurred between the ages of 62 and 75 years. In 7 subjects, cerebrospinal fluid protein levels were increased, and in 5 agar gel electrophoresis indicated blood-brain barrier dysfunction. Seven family members had neuroimaging signs of a widespread white matter disorder. In 4 subjects, neurophysiological investigations indicated a polyneuropathy, and in 3 subjects, results from a sural nerve biopsy showed a demyelinating neuropathy. There was no evidence of co-inheritance with genetic markers of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (19p), PMP22 (17q), APP (21q), CMTX1 (Xq), or PLP (Xq). CONCLUSIONS: Progressive central and peripheral demyelinating disease seems to be a distinct type of hereditary adult-onset demyelinating disorder affecting both the peripheral and central nervous systems. Its exact nature remains unknown.

Adult↗
PubMed1996

Evidence for a mechanism of demyelination by human JC virus: negative transcriptional regulation of RNA and protein levels from myelin basic protein gene by large tumor antigen in human glioblastoma cells.

Human JC virus (JCV) is a neurotropic human polyomavirus that was found in the plaques and oligodendroglial cells of the brains of patients with the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). Transgenic mice expressing JCV large tumor (T)-antigen from integrated DNA showed dysmyelination in the central nervous system. However, the role of T-antigen from episomal DNA in the demyelination in PML remains unclear. In this report, we examined the effect of episomally expressed JCV T-antigen on the expression of myelin basic protein (MBP) in U-87 MG human glioblastoma cells to study the mechanism of demyelination. Expression assays of the MBP promoter in U-87 MG detected a 2.5-fold reduction in cells expressing intact T-antigen. Next, U-87 MG expressing T-antigen were examined by RNase protection assays for mRNA accumulation from the endogenous MBP promoter. Also, the expression of the MBP promoter plasmid was determined using in vitro transcription assays with extracts from T-antigen expressing cells. Both assays found a similar down-regulation of the MBP promoter by T-antigen, confirming that negative regulation occurred at the transcriptional level for the endogenous and exogenous MBP promoters. Furthermore, in situ immunofluorescence assays and quantitative Western blot analysis provided convincing evidence of a similar reduction in the level of MBP produced from the functional endogenous gene in U-87 MG glioblastoma cells expressing T-antigen. Thus, we provide evidence for the role of T-antigen in a transcriptional control mechanism for the demyelination that is caused by JCV in PML patients.

Antigens, Polyomavirus Transforming↗
PubMed2000

Schwann cell remyelination is restricted to astrocyte-deficient areas after transplantation into demyelinated adult rat brain.

The ability to generate large numbers of Schwann cells from a peripheral nerve biopsy makes them potential candidates for the clinical application of cell transplantation to enhance remyelination in human demyelinating disease. Transplant-derived Schwann cell remyelination has previously been demonstrated in the spinal cord but not for demyelinated axons in the brain, a more likely site for initial clinical intervention. We have transplanted Schwann cells from male neonatal rat sciatic nerves into ethidium bromide-induced areas of demyelination in the deep cerebellar white matter of adult female rats. The extent of Schwann cell remyelination 28 days after transplantation was significantly increased in lesions that received direct injections of Schwann cells compared with non-transplanted lesions. Using in situ hybridisation to identify the rat Y chromosome, transplanted male cells were found to co-localise with the P0 immunoreactive area of Schwann cell remyelination. Combined immunohistochemistry and in situ hybridisation confirmed that many remyelinating Schwann cells were transplant-derived. P0 immunoreactivity and transplanted male cells were found in GFAP-negative, astrocyte-free areas. Transplanted Schwann cells were not identified outside of transplanted lesions, nor did they did not contribute to remyelination of a lesion at a distance from the site of transplantation. Our findings indicate that demyelinated axons in the adult brain can be remyelinated by transplanted Schwann cells but that migration and remyelination are restricted to areas from which astrocytes are absent.

Animals↗
PubMed1998

Root stimulation improves the detection of acquired demyelinating polyneuropathies.

Thirty-one patients with a presentation compatible with an acquired demyelinating polyradiculoneuropathy were prospectively evaluated for proximal conduction block using root stimulation (RS) of cervical and/or lumbar roots. These same techniques were applied to 78 controls (40 pathological). Proximal conduction block was noted in 20/31 cases and none of the controls. Only 7 of 31 cases met published demyelinating criteria. Intravenous immune globulin therapy was completed by 21/31 patients and 20/21 responded. RS is superior to published electrophysiologic criteria for identifying demyelinating polyneuropathies and predicting who will respond to treatment. RS should be performed in all patients suspected of having an acquired demyelinating polyneuropathy when traditional nerve conduction studies criteria are nondiagnostic. RS reliably predicts those likely to respond to immunosuppressive therapy.

Adult↗
PubMed1999

Multifocal acquired demyelinating sensory and motor neuropathy: the Lewis-Sumner syndrome.

We report 11 patients with multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy, defined clinically by a multifocal pattern of motor and sensory loss, with nerve conduction studies showing conduction block and other features of demyelination. The clinical, laboratory, and histological features of these patients were contrasted with those of 16 patients with multifocal motor neuropathy (MMN). Eighty-two percent of MADSAM neuropathy patients had elevated protein concentrations in the cerebrospinal fluid, compared with 9% of the MMN patients (P < 0.001). No MADSAM neuropathy patient had elevated anti-GM1 antibody titers, compared with 56% of MMN patients (P < 0.01). In contrast to the subtle abnormalities described for MMN, MADSAM neuropathy patients had prominent demyelination on sensory nerve biopsies. Response to intravenous immunoglobulin treatment was similar in both groups (P = 1.0). Multifocal motor neuropathy patients typically do not respond to prednisone, but 3 of 6 MADSAM neuropathy patients improved with prednisone. MADSAM neuropathy more closely resembles chronic inflammatory demyelinating polyneuropathy and probably represents an asymmetrical variant. Given their different clinical patterns and responses to treatment, it is important to distinguish between MADSAM neuropathy and MMN.

Adult↗
PubMed1998

Connexin32-null mice develop demyelinating peripheral neuropathy.

Mutations in the gene encoding the gap junction protein connexin32 (Cx32) cause X-linked Charcot-Marie-Tooth disease (CMTX), a common form of inherited demyelinating peripheral neuropathy. To learn more about the pathogenesis of CMTX, we examined the PNS and CNS of cx32-null mice (cx32-/Y males and cx32-/-females) by light and electron microscopy. These mice develop a progressive demyelinating peripheral neuropathy beginning by 3 months of age, and at all ages, motor fibers are more affected than sensory fibers. Like other genes of the X chromosome, the cx32 gene appears to be randomly inactivated, since only some myelinating Schwann cells express Cx32 in heterozygous cx32 +/- females. Heterozygous cx32 +/- females have fewer demyelinated and remyelinated axons than age-matched homozygous cx32-/- females and cx32-/Y males. Although oligodendrocytes also express Cx32, no abnormalities in CNS myelin were found. These findings indicate that a null cx32 allele in myelinating Schwann cells is sufficient to cause an inherited demyelinating neuropathy, so that Cx32 has an essential role in myelinating Schwann cells both in mice and in humans.

Aging↗
PubMed1999

Demyelination and remyelination of the caudal cerebellar peduncle of adult rats following stereotaxic injections of lysolecithin, ethidium bromide, and complement/anti-galactocerebroside: a comparative study.

Experimentally induced demyelination due to the direct injection of gliotoxic agents has provided powerful models for studying the biology of remyelination. For the most part, these models have involved injection into white matter tracts of the spinal cord. However, the spinal cord has a number of limitations, such as the size of lesions that it is possible to make and its unsuitability for long-term direct cannulation for the delivery of putative remyelination-enhancing agents. In this study, we describe the natural history of three new models of demyelination/remyelination based on the stereotaxic injection of three gliotoxins: lysolecithin, ethidium bromide, and a combination of anti-galactocerebroside antibody and complement (GalC-ab/comp) into the caudal cerebellar peduncle of adult rats. All three agents produced large areas of demyelination with minimal axonal damage, which undergo extensive remyelination. Ethidium bromide- and GalC-ab/comp-induced lesions remyelinated more slowly than those induced by lysolecithin. The contribution to the remyelination of the lesion by Schwann cells reflects the degree of astrocyte damage incurred within the demyelinated area and is greatest for ethidium bromide-induced demyelination. These new models not only provide further insights into the mechanisms of CNS remyelination but also provide a valuable new resource for addressing a series of key issues relevant to current efforts to promote CNS remyelination either by the enhancement of intrinsic processes or by the transplantation of myelinogenic cells.

Animals↗
PubMed1999

Remyelination occurs as extensively but more slowly in old rats compared to young rats following gliotoxin-induced CNS demyelination.

Age is one of the many factors that influence remyelination following CNS demyelination, although it is not clear whether it is the extent or rate of remyelination that is affected. To resolve this issue we have compared remyelination in young and old adult rat CNS following gliotoxin-induced demyelination. Remyelination of areas of ethidium bromide-induced demyelination in the caudal cerebellar peduncle reached completion by 4 weeks in young adult rats (2 months) but was not complete until 9 weeks in old adult rats (9-12 months). We have also shown that remyelination of lysolecithin-induced demyelination in the spinal white matter of old adult rats (18 months) can be extensive, with longer survival times (8 weeks) than have previously been examined. Thus, it is the rate rather than the extent of remyelination that changes in the ageing CNS. These results have important implications for understanding the mechanisms of remyelination, indicating that remyelination need not occur rapidly for it to be extensive. The capacity for the process of remyelination to continue over many weeks must also be borne in mind when assessing remyelination-enhancement strategies either by transplantation or promotion of endogenous mechanisms.

Aging↗
PubMed2000

Tumour necrosis factor alpha mRNA expression in early multiple sclerosis lesions: correlation with demyelinating activity and oligodendrocyte pathology.

The precise role of tumour necrosis factor alpha (TNFalpha) in multiple sclerosis (MS) is still controversial. Most findings from the animal model experimental allergic encephalomyelitis have yet to be confirmed in multiple sclerosis. The aim of this study was to define the significance of TNFalpha with respect to the hallmark of MS, that is demyelination. Therefore, 78 lesion areas from diagnostic brain biopsies of 32 patients were analysed. Lesion demyelinating activity was classified by the presence of myelin degradation products in macrophages and macrophage activation markers. Non-radioactive in situ hybridisation was carried out to detect TNFalpha mRNA expressing cells. DNA fragmentation was visualised by TdT-mediated X-dUTP nick end labeling. A significantly higher number of cells expressed TNFalpha mRNA in active demyelinating lesions than in inactive or remyelinating lesions irrespective of the extent of the inflammatory infiltrate. TNFalpha mRNA expression correlated with the appearance of DNA fragmentation in T lymphocytes and oligodendrocytes within the lesions. In the periplaque white matter, expression of TNFalpha mRNA negatively correlated with oligodendrocyte numbers. These data support previous findings from animal models and in vitro experiments. Although not proving, the current study strongly suggests a pathogenic role of TNFalpha in demyelination in human multiple sclerosis and gives further support for TNFalpha-directed therapeutic strategies.

Adolescent↗
PubMed1990

Cisplatin-induced peripheral neuropathy. Frequent off-therapy deterioration, demyelinating syndromes, and muscle cramps.

Forty-five patients with cisplatin-induced peripheral neuropathy (PN) were evaluated retrospectively after treatment with cumulative doses of cisplatin ranging from 201 to 1952 mg/m2. The patients were followed for up to 23 months (median, 4.5 months), and 32 of them were evaluated more than once. Severity of symptoms was related to higher cumulative doses of cisplatin but with marked individual variability. Off-therapy deterioration of the PN continued in 14 patients (31%) for 2.5 to 5.5 months after withdrawal of cisplatin, and only four patients showed some improvement during the follow-up period. Symptomatic deterioration often was heralded by new onset of muscle cramps (with normal Ca2+/Mg2+ levels) and/or by manifestations of probable spinal dorsal column and/or nerve root demyelinating syndromes presenting as either Lhermitte's sign and/or as an electric-shock sensation along the upper extremities when outstretched in 90 degrees shoulder abduction. Cramps and demyelinating syndromes were each noted in 31% of the patients. Muscle cramps tended to resolve several months after withdrawal of therapy, and demyelinating syndromes were always transient (1.5 to 6.0 months) and did not progress despite ongoing therapy in five patients. Our study indicates that, after withdrawal of therapy, patients with cisplatin-induced PN may continue to deteriorate for several months. Manifestations of muscle cramps and demyelinating syndromes signify a worsening course of the PN but should not automatically indicate interruption of therapy.

Adult↗
PubMed2000

Electrophysiological features of inherited demyelinating neuropathies: A reappraisal in the era of molecular diagnosis.

The observation that inherited demyelinating neuropathies have uniform conduction slowing and that acquired disorders have nonuniform or multifocal slowing was made prior to the identification of mutations in myelin-specific genes which cause many of the inherited disorders involving peripheral nerve myelin. It is now clear that the electrophysiological aspects of these disorders are more complex than previously realized. Specifically, certain mutations appear to induce nonuniform slowing of conduction which resemble the findings in acquired demyelinating neuropathies. It is clinically important to recognize the different electrodiagnostic patterns of the various inherited demyelinating neuropathies. In addition, an understanding of the relationship between mutations of specific genes and their associated neurophysiological findings is likely to facilitate understanding of the role of these myelin proteins in peripheral nerve function and of how abnormalities in myelin proteins lead to neuropathy. We therefore review the current information on the electrophysiological features of the inherited demyelinating neuropathies in hopes of clarifying their electrodiagnostic features and to shed light on the physiological consequences of the different genetic mutations.

Electrophysiology↗
PubMed2003

Cytotoxic drugs and interferons for chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy is a disease causing progressive or relapsing and remitting weakness and numbness. It is probably due to an autoimmune inflammatory process. Immunosuppressive or immunomodulatory drugs would be expected to be beneficial. OBJECTIVES: We aimed to review systematically the evidence from randomised trials concerning cytotoxic drugs and interferons for chronic inflammatory demyelinating polyradiculoneuropathy. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (searched December 2001), MEDLINE (searched January 1977 to December 2001), EMBASE (January 1980 to December 2001), CINAHL (searched January 1982 to December 2001) and LILACS (searched January 1982 to December 2001). We contacted the authors of the trials identified and other disease experts seeking other published and unpublished trials. SELECTION CRITERIA: We sought randomised and quasi-randomised trials of all immunosuppressive agents such as azathioprine, cyclophosphamide, methotrexate, cyclosporin A, mycophenolate mofetil, and rituximab and all immunomodulatory agents such as alpha interferon and beta interferon in participants fulfilling standard diagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy. DATA COLLECTION AND ANALYSIS: Two of us independently selected the trials which met our criteria, judged their methodological quality and extracted the data onto specially designed forms. We wanted to measure the change in disability after one year as our primary outcome measure. MAIN RESULTS: We found one parallel group open trial of azathioprine for nine months involving 27 participants and another of interferon beta involving 10 participants in a double blind crossover trial with each treatment period lasting 12 weeks. Neither trial provided our primary outcome measure and neither showed a significant beneficial effect on any of the outcome measures selected by the authors or ourselves in the protocol for this review. REVIEWER'S CONCLUSIONS: The evidence is inadequate to decide whether azathioprine, interferon beta or any other immunosuppressive drug or interferon is beneficial in chronic inflammatory demyelinating polyradiculoneuropathy.

Anti-Inflammatory Agents↗
PubMed2004

Cytotoxic drugs and interferons for chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy is a disease causing progressive or relapsing and remitting weakness and numbness. It is probably due to an autoimmune inflammatory process. Immunosuppressive or immunomodulatory drugs would be expected to be beneficial. OBJECTIVES: We aimed to review systematically the evidence from randomised trials concerning cytotoxic drugs and interferons for chronic inflammatory demyelinating polyradiculoneuropathy. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (searched May 2004), MEDLINE (searched January 1977 to May 2004), EMBASE (January 1980 to May 2004), CINAHL (searched January 1982 to December 2001) and LILACS (searched January 1982 to December 2001). We contacted the authors of the trials identified and other disease experts seeking other published and unpublished trials. SELECTION CRITERIA: We sought randomised and quasi-randomised trials of all immunosuppressive agents such as azathioprine, cyclophosphamide, methotrexate, cyclosporin A, mycophenolate mofetil, and rituximab and all immunomodulatory agents such as alpha interferon and beta interferon in participants fulfilling standard diagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy. DATA COLLECTION AND ANALYSIS: Two of us independently selected the trials which met our criteria, judged their methodological quality and extracted the data onto specially designed forms. We wanted to measure the change in disability after one year as our primary outcome measure. MAIN RESULTS: We found one parallel group open trial of azathioprine for nine months involving 27 participants and another of interferon beta involving 10 participants in a double blind crossover trial with each treatment period lasting 12 weeks. Neither trial provided our primary outcome measure and neither showed a significant beneficial effect on any of the outcome measures selected by the authors or ourselves in the protocol for this review. REVIEWERS' CONCLUSIONS: The evidence is inadequate to decide whether azathioprine, interferon beta or any other immunosuppressive drug or interferon is beneficial in chronic inflammatory demyelinating polyradiculoneuropathy.

Anti-Inflammatory Agents↗
PubMed1999

A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease.

There are no established treatments for patients with acute, severe neurological deficits caused by multiple sclerosis or other inflammatory demyelinating diseases of the central nervous system who fail to recover after treatment with high-dose corticosteroids. We conducted a randomized, sham-controlled, double-masked study of plasma exchange without concomitant immunosuppressive treatment in patients with recently acquired, severe neurological deficits resulting from attacks of inflammatory demyelinating disease, who failed to recover after treatment with intravenous corticosteroids. Patients who did not achieve moderate or greater improvement after the first treatment phase crossed over to the opposite treatment. Moderate or greater improvement in neurological disability occurred during 8 of 19 (42.1%) courses of active treatment compared with 1 of 17 (5.9%) courses of sham treatment. The primary analysis was positive. Improvement occurred early in the course of treatment, and was sustained on follow-up. However, 4 of the patients who responded to the active treatment experienced new attacks of demyelinating disease during 6 months of follow-up. Moderate or greater improvement occurred during follow-up in only 2 of 13 patients who failed to improve during the treatment phase. Plasma exchange leads to functionally important neurological recovery in an important proportion of severely disabled patients with acute attacks of idiopathic inflammatory demyelinating disease.

Adult↗
PubMed2001

P0 protein is a target antigen in chronic inflammatory demyelinating polyradiculoneuropathy.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is widely regarded as an autoimmune disorder, although the autoantigen remains unknown. In this study, the sera of 21 CIDP patients were examined by immunofluorescence for antimyelin activity and by Western blotting for binding to myelin proteins. Six sera contained anti-P0 immunoglobulin G antibodies, and four of these caused conduction block and demyelination following intraneural injection in experimental animals. Absorption with P0 protein eliminated the demyelinating activity. These results show that P0 is an autoantigen in some patients with CIDP. Since P0 possesses powerful adhesion properties and is largely responsible for myelin compaction, the demonstration of demyelination by human anti-P0 antibodies provides new insight into this important and common immunopathological process.

Animals↗
PubMed1981

Evidence for a "dying-back" gliopathy in demyelinating disease.

Recurrent demyelination was produced in mice by Cuprizone administration. During the second course of Cuprizone, the animals showed greater resistance to the toxin and demyelination occurred slowly and was complete only after prolonged periods. The earliest changes in oligodendrocytes occurred in the most distal processes, the inner cytoplasmic tongues, which showed degenerative changes 3 to 4 weeks before degeneration of the oligodendrocyte cell bodies or demyelination occurred. The results show for the first time that in demyelinating disease, a "dying-back" process similar to that described in axonal disease can affect the oligodendrocyte.

Animals↗
PubMed1982

Ross River virus-induced demyelination: I. Pathogenesis and histopathology.

Ross River virus (strain T48) infection in mice causes an encephalomyelitis characterized by focal, primary demyelination in the cerebellum, brain stem, and spinal cord. Maximal serum and brain content of virus occurs on days 2 and 4, respectively. Virus is not detectable in serum after day 3 or in brain after day 9. Histopathological lesions are present by day 2 and consist of perivascular macrophage and polymorphonuclear leukocyte infiltration, focal necrosis in the internal granule cell layer, and myelin disruption. Mononuclear cell infiltrates are present by day 5. Foci of demyelination in the presence of preserved axons become more widespread by day 8, and early partial remyelination occurs by day 13. Immunosuppression reduces the mononuclear cell infiltration but does not alter the demyelination . Although the mechanism of Ross River virus-induced demyelination is not known, these findings suggest that it is not immune mediated.

Animals↗