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PubMed2005

Cortical demyelination and diffuse white matter injury in multiple sclerosis.

Focal demyelinated plaques in white matter, which are the hallmark of multiple sclerosis pathology, only partially explain the patient's clinical deficits. We thus analysed global brain pathology in multiple sclerosis, focusing on the normal-appearing white matter (NAWM) and the cortex. Autopsy tissue from 52 multiple sclerosis patients (acute, relapsing-remitting, primary and secondary progressive multiple sclerosis) and from 30 controls was analysed using quantitative morphological techniques. New and active focal inflammatory demyelinating lesions in the white matter were mainly present in patients with acute and relapsing multiple sclerosis, while diffuse injury of the NAWM and cortical demyelination were characteristic hallmarks of primary and secondary progressive multiple sclerosis. Cortical demyelination and injury of the NAWM, reflected by diffuse axonal injury with profound microglia activation, occurred on the background of a global inflammatory response in the whole brain and meninges. There was only a marginal correlation between focal lesion load in the white matter and diffuse white matter injury, or cortical pathology, respectively. Our data suggest that multiple sclerosis starts as a focal inflammatory disease of the CNS, which gives rise to circumscribed demyelinated plaques in the white matter. With chronicity, diffuse inflammation accumulates throughout the whole brain, and is associated with slowly progressive axonal injury in the NAWM and cortical demyelination.

Acute Disease↗
PubMed1994

Proteolipid protein gene expression in demyelination and remyelination of the central nervous system: a model for multiple sclerosis.

We asked whether nonlethal injury to the oligodendrocyte as manifested by altered myelin gene expression is an early event in the pathogenesis of demyelinating disease and subsequent remyelination. Using simultaneous in situ hybridization and immunocytochemistry, we studied expression of proteolipid protein (PLP) antigen and mRNA in spinal cords of normal adult mice and of mice infected with Theiler's virus which provides an excellent model for multiple sclerosis. Downregulation of PLP mRNA was observed within 3 days and persisted for as long as 367 days following intracerebral virus infection of SJL/J mice which are susceptible to chronic demyelination. Downregulation of myelin gene products preceded the development of prominent inflammation and demyelination observed following virus infection. In contrast, no change from control uninfected mice was observed in the expression of PLP mRNA following infection of C57BL/10SNJ mice which are resistant to demyelination. Treatment of chronically infected susceptible SJL/J mice with a regimen which promotes CNS-type (oligodendroglial) remyelination resulted in a 3- to 4-fold increase in PLP mRNA expression in oligodendrocytes. Actin mRNA expression in PLP antigen-positive cells was unchanged following TMEV-induced demyelination or remyelination indicating up- or downregulation of myelin gene products as compared to constitutively expressed actin gene. These experiments support the hypothesis that early regulation of myelin gene expression may be an important determinant in demyelination and in remyelination following nonlethal injury to oligodendrocytes.

Animals↗
PubMed1999

Study on the gene and phenotypic characterisation of autosomal recessive demyelinating motor and sensory neuropathy (Charcot-Marie-Tooth disease) with a gene locus on chromosome 5q23-q33.

OBJECTIVES: To report the occurrence of the autosomal recessive form of demyelinating Charcot-Marie-Tooth disease (CMT) with a locus on chromosome 5q23-33 in six non-related European families, to refine gene mapping, and to define the disease phenotype. METHODS: In an Algerian patient with autosomal recessive demyelinating CMT mapped to chromosome 5q23-q33 the same unique nerve pathology was established as previously described in families with a special form of autosomal recessive demyelinating CMT. Subsequently, the DNA of patients with this phenotype was tested from five Dutch families and one Turkish family for the 5q23-q33 locus. RESULTS: These patients and the Algerian families showed a similar and highly typical combination of clinical and morphological features, suggesting a common genetic defect. A complete cosegregation for markers D5S413, D5S434, D5S636, and D5S410 was found in the families. Haplotype construction located the gene to a 7 cM region between D5S643 and D5S670. In the present Dutch families linkage disequilibrium could be shown for various risk alleles and haplotypes indicating that most of these families may have inherited the underlying genetic defect form a common distant ancestor. CONCLUSIONS: This study refines the gene localisation of autosomal recessive demyelinating CMT, mapping to chromosome 5q23-33 and defines the phenotype characterised by a precocious and rapidly progressive scoliosis in combination with a relatively mild neuropathy and a unique pathology. Morphological alterations in Schwann cells of the myelinated and unmyelinated type suggest the involvement of a protein present in both Schwann cell types or an extracellular matrix protein rather than a myelin protein. The combination of pathological features possibly discerns autosomal recessive demyelinating CMT with a gene locus on chromosome 5q23-33 from other demyelinating forms of CMT disease.

Adolescent↗
PubMed2001

Neutralization of the chemokine CXCL10 reduces inflammatory cell invasion and demyelination and improves neurological function in a viral model of multiple sclerosis.

Intracerebral infection of mice with mouse hepatitis virus (MHV) results in an acute encephalomyelitis followed by a chronic demyelinating disease with clinical and histological similarities with the human demyelinating disease multiple sclerosis (MS). Following MHV infection, chemokines including CXC chemokine ligand (CXCL)10 (IFN inducible protein 10 kDa), CXCL9 (monokine induced by IFN-gamma), and CC chemokine ligand 5 (RANTES) are expressed during both acute and chronic stages of disease suggesting a role for these molecules in disease exacerbation. Previous studies have shown that during the acute phase of infection, T lymphocytes are recruited into the CNS by the chemokines CXCL10 and CXCL9. In the present study, MHV-infected mice with established demyelination were treated with antisera against these two chemokines, and disease severity was assessed. Treatment with anti-CXCL10 reduced CD4+ T lymphocyte and macrophage invasion, diminished expression of IFN-gamma and CC chemokine ligand 5, inhibited progression of demyelination, and increased remyelination. Anti-CXCL10 treatment also resulted in an impediment of clinical disease progression that was characterized by a dramatic improvement in neurological function. Treatment with antisera against CXCL9 was without effect, demonstrating a critical role for CXCL10 in inflammatory demyelination in this model. These findings document a novel therapeutic strategy using Ab-mediated neutralization of a key chemokine as a possible treatment for chronic human inflammatory demyelinating diseases such as MS.

Animals↗
PubMed2000

[Remyelination by Schwann cell transplantation for CNS demyelinated axons: functional comparison with developmental myelination].

Transplantation of Schwann cells(SCs) induced remyelination of demyelinated rat dorsal column(DC) axons and improved conduction. To investigate the difference between developmental oligodendrocytic myelination and SC myelination in conductive functions of axons, we compared normally developmental DCs(10 days old, 22-23 days old, and adult rat), demyelinated DCs, and remyelinated DCs by SC transplantation. DCs of adult rats were demyelinated at T 11 by X-ray irradiation and ethidium bromide, and transplanted with SCs(3 x 10(4)) of adult rats. Three weeks later, the spinal cord was removed and pinned in a recording chamber and compound action potentials (CAPs) were recorded, to investigate conduction properties(conduction velocity, amplitude of CAP and response after high frequency stimulation). Normal DCs were recorded in same manner. Following transplantation of SCs, histological examination revealed SC-like patterns of remyelination of demyelinated axons. The conduction velocities of 10 days old DCs(1.7 +/- 3.4 m/s, n = 4) increased early to 8.1 +/- 3.3 m/s(22-23 days old, n = 7) and 12.2 +/- 1.5 m/s (adult, n = 5). After SC transplantation the velocity significantly improved 7.7 +/- 1.5 m/s(n = 5) compared to demyelinated axons(1.2 +/- 0.4 m/s, n = 7), but less than adult. A 600 Hz 0.5 sec stimulus train led to an amplitude decrement of 7.1 +/- 7.5%(n = 7) in demyelinated axons. Following transplantation, amplitude decreased in 66.2 +/- 11.9%(SC, n = 5), same as 22-23 days(71.7 +/- 11.7%, n = 7) old or adult(76.6 +/- 15.6%, n = 6). The recovery properties after high frequency stimulation developed earlier than conduction velocity. Following SC transplantation, the recovery properties improved to that of normal adult, but not conduction velocity. Lower conduction velocity may be due to shorter internode distance of remyelination after transplantation, same as 22-23 days old pups, than normal adult rats. Though anatomical difference and/or time after transplantation influenced the conduction, these result suggested SC remyelination might result in insufficient for conduction velocity.

Animals↗
PubMed1984

Experimental autoimmune encephalomyelitis. Augmentation of demyelination by different myelin lipids.

Alterations in the effect of a known encephalitogenic dose of myelin basic protein (MBP) when inoculated in combination with various myelin lipids have been examined in guinea pigs. A previous study demonstrated that, when MBP was given with galactocerebroside, it produced an acute autoimmune encephalomyelitis similar to that induced by whole white matter in which both inflammation and demyelination were features of the central nervous system lesions. MBP alone, on the other hand, resulted in inflammation only, without demyelination. The present study examined combinations of MBP with the myelin lipids galactocerebroside, sulfatide, ethanolamine phosphoglycerides, and serine phosphoglycerides. The lipids were given with or without MBP, in the same ratio as in intact central nervous system myelin, and were emulsified with complete Freund's adjuvant. An additional group received galactocerebroside and bovine serum albumin in complete Freund's adjuvant. These groups were compared with animals receiving either bovine white matter or MBP in complete Freund's adjuvant. Clinical autoimmune encephalomyelitis was observed in animals receiving bovine white matter, MBP, and all lipid-MBP emulsions; the bovine white matter, galactocerebroside/MBP, sulfatide/MBP, and ethanolamine phosphoglycerides/MBP groups demonstrated central nervous system lesions with a similar picture consisting of inflammation with demyelination, whereas inflammation without demyelination was seen in the MBP and serine phosphoglycerides/MBP groups. Thus, the addition of myelin lipids to MBP leads to the augmentation of demyelination in autoimmune encephalomyelitis lesions in the guinea pig. This might suggest that the immune response against MBP is enhanced by other myelin components. The relevance of these findings to human demyelinating disorders is discussed.

Animals↗
PubMed2003

Demyelinating neuropathies.

PURPOSE OF REVIEW: To review recent advances in heritable demyelinating neuropathies and their genotype-phenotype correlations. RECENT FINDINGS: Two themes dominated the literature on demyelinating neuropathies in the past 2 years: (1) the dissection of the localization and roles of new molecules in the axon-Schwann cell unit, including periaxin and connexin32, which are mutated in specific heritable neuropathies; (2) the recognition of the range of phenotypes associated with individual genetic abnormalities, so that the same defects can even produce both demyelinating and axonal forms of heritable neuropathies. The axonal injury associated with demyelination reflects elaborate interactions between axons and Schwann cells. SUMMARY: Demyelinating neuropathies, even those due to abnormalities in intrinsic Schwann cell or myelin proteins, can have clinical manifestations due to distally predominant axonal degeneration.

Axons↗
PubMed2000

Multifocal inflammatory demyelinating neuropathy: a distinct clinical entity?

BACKGROUND: Several patients have been reported with an asymmetric sensory or sensorimotor demyelinating neuropathy not fulfilling the diagnostic criteria for chronic inflammatory demyelinating polyneuropathy or multifocal motor neuropathy. OBJECTIVE: To present the clinical, electrophysiologic, radiologic, and pathologic features of six patients with an asymmetric sensory or sensorimotor demyelinating neuropathy. RESULTS: All six patients were initially affected in only one limb; in four patients the neuropathy progressed to other limbs in an asymmetric fashion during several years. On electrophysiologic examination, evidence of multifocal demyelination and conduction block in motor and sensory nerves was found in all patients. MRI of the brachial plexus revealed swollen nerves and an increased signal intensity on T2-weighted imaging in four patients. A biopsy sample taken from the brachial plexus of one patient revealed evidence of inflammation. All patients showed a beneficial response to IV immunoglobulin treatment. Thirty-four similar patients have been reported previously, many of whom were initially diagnosed as having various other (nontreatable) diseases. CONCLUSIONS: The authors propose calling this neuropathy "multifocal inflammatory demyelinating neuropathy" and considering it as a distinct clinical entity to facilitate early diagnosis of this treatable disorder.

Adult↗
PubMed2005

[Human herpesvirus-8 DNA in patients with certain demyelinating disorders].

Infectious etiology of the demyelinating diseases is an intensive matter of research. Among the suspected pathogens, herpesviruses had attracted particular attention because of their capacity to remain latent in nervous tissues, axonal transportation of some members within neurons, relapsing-remitting characteristic of the infections, and capability of inducing demyelination both in human host and animal models. Human herpesvirus-8 (HHV-8) is the least studied of this group even some of the HHV-8 related disorders such as HIV associated Castleman's disease, some lymphomas, monoclonal gammopathy of uncertain significance (MGUS), may be seen in patients with demyelinating conditions. The aim of this study was the investigation of a probable relationship between HHV-8 infection and certain demyelinating diseases. For this purpose, the presence of HHV-8 DNA has been investigated by polymerase chain reaction in the blood samples of 14 multiple sclerosis (MS), six chronic inflammatory demyelinizing polyneuropathy (CIDP), three Guillain-Barre syndrome (GBS), and one Miller-Fisher syndrome patients, together with 24 age- and sex-matched healthy subjects as control. As a result, one of MS, two of CIDP and all of the GBS patients were found HHV-8 DNA positive, whereas all the subjects in control group were negative. Although the interpretation of the results of this study does not seem to be possible owing to the limited number of patients, it emphasizes the need for larger scale, detailed studies on this subject since no other report dealing with this matter has been encountered in the literature.

Adolescent↗
PubMed1977

Conduction in myelinated, unmyelinated, and demyelinated fibers.

Conduction in demyelinated axons is characterized by decreased conduction velocity, temporal dispersion of impulses, and conduction failure. It is not possible to infer the electrical properties of the bared internodal axon membrane in demyelinated fibers from observations of decreased conduction velocity or conduction failure. Cytochemical evidence indicates that there are, in fact, distinct structural differences between nodal and internodal regions of the normal axon membrane. This conclusion is confirmed by freeze-fracture and pharmacological studies. A number of approaches to the development of effective symptomatic therapy in the demyelinating diseases are suggested by recent experimental findings: determination of the membrane properties necessary for conduction across focally demyelinated regions and the identification of agents that would encourage the development of these properties; alterations in the external milieu of demyelinated fibers; and the development of agents that might promote remyelination.

Animals↗
PubMed1980

In vivo and in vitro models of demyelinating diseases. III. JHM virus infection of rats.

Suckling rats of three inbred and three outbred strains were inoculated intraperitoneally (P) or intracerebrally (IC) with the JHM strain of mouse hepatitis virus (JHMV) and were monitored for evidence of neurologic diseases. Consequences of varying age at inoculation, route of injection, and virus dose were ascertained. No disease was evident after IP injection but IC inoculation with at least 10(4) plaque-forming units at 2 days of age resulted in either a rapidly fatal encephalitis or a chronic, progressive, fatal neurologic disease in most rats, regardless of strain. Inoculation at 5 or 10 days of age predominantly caused the chronic neurologic disease, characterized by demyelinating lesions in the brain, spinal cord, or optic nerve, which sometimes were evident as late as several months postinoculation. Demyelination in the optic nerve proved to be concurrent with demyelinating lesions elsewhere in the CNS. Occasionally, clinical remissions were observed in rats in which posterior paralysis developed, suggesting that remyelination in the rat can occur. Demonstration of virus replication, by infectivity, in rats exhibiting neurologic disease and in rats without clinical symptoms was substantiated by electron microscopic observations of virus development and assembly in oligodendroglia of the optic nerve and spinal cord. In view of the protracted course of the disease in some rats, presence of demyelinating lesions confirmed by light and electron microscopy, and remissions of clinical symptoms, the JHMV-infected rat seems to be an appropriate animal model to study virus-mediated progressive demyelinating disease.

Animals↗
PubMed1992

Subacute idiopathic demyelinating polyradiculoneuropathy.

Seven cases of subacute idiopathic demyelinating polyradiculoneuropathy had a monophasic illness characterized by progressive weakness of all four limbs that evolved during 4 to 8 weeks. Neurophysiological investigations implied demyelination in all seven cases. In two patients, sural nerve biopsy specimens that were taken showed macrophage-associated demyelination. All patients made substantial or complete recoveries with oral prednisolone (four cases) or without treatment (three cases). None of the patients required ventilation or had autonomic complications. These cases provide a link between the acute idiopathic demyelinating form of Guillain-Barré syndrome and chronic idiopathic demyelinating polyradiculoneuropathy.

Adult↗
PubMed1999

Quantitation of spinal cord demyelination, remyelination, atrophy, and axonal loss in a model of progressive neurologic injury.

Spinal cord pathology, such as demyelination and axonal loss, is a common feature in multiple models of central nervous system (CNS) injury and disease. Development of methods to quantify spinal cord pathology objectively would aid studies designed to establish mechanisms of damage, correlate pathology with neurologic function, and assess therapeutic interventions. In this study, we describe sensitive methods to objectively quantify spinal cord demyelination, remyelination, atrophy, and axonal loss following the initiation of a progressive inflammatory demyelinating disease with Theiler's murine encephalomyelitis virus (TMEV). Spinal cord demyelination, remyelination, and atrophy were quantified from representative 1-microm-thick cross sections embedded in Araldite plastic using interactive image analysis. In addition, this study demonstrates novel, automated methodology to quantify axonal loss from areas of normal-appearing white matter, as a measure of secondary axonal injury following demyelination. These morphologic methods, which are applicable to various models of CNS injury, provide an innovative way to assess the benefits of therapeutic agents, to determine mechanisms of spinal cord damage, or to establish a correlation with sensitive measures of neurologic function. J. Neurosci Res 58:492-504.

Animals↗
PubMed1997

Patterns of oligodendrocyte pathology in coronavirus-induced subacute demyelinating encephalomyelitis in the Lewis rat.

Intracerebral infection of rats with JHM coronavirus induces a chronic inflammatory demyelinating disease, which in many respects mimicks the pathology of multiple sclerosis. We investigated the patterns of demyelination and oligodendrocyte pathology in this model. In early stages of the disease infection of oligodendrocytes was associated with a downregulation of expression of mRNA for proteolipid protein in the absence of myelin destruction. When demyelinating lesions were formed infected oligodendrocytes were destroyed by necrosis, whereas oligodendrocytes that did not contain detectable virus antigen or RNA were in part dying by apoptosis. At this stage of the disease remyelination of the lesions was pronounced. At later stages after infection virus antigen was nearly completely cleared from the lesions. In spite of the lack of detectable virus, ongoing demyelination and unspecific tissue destruction occurred, and oligodendrocytes were mainly destroyed by apoptosis. These late lesions revealed only minimal central remyelination, but they were frequently repaired by Schwann cells. Our studies suggest that the mechanisms of myelin destruction in this model of virus-induced demyelination are complex and that the patterns of tissue damage may change during the course of the disease.

Animals↗
PubMed2001

Clinical spectrum of chronic acquired demyelinating polyneuropathies.

A number of presentations of chronic demyelinating polyneuropathy have been identified, each distinguished by its phenotypic pattern. In addition to classic chronic inflammatory demyelinating polyneuropathy (CIDP), which is characterized clinically by symmetric proximal and distal weakness and sensory loss, several regional variants can be recognized: multifocal motor neuropathy (MMN: asymmetric and pure motor), multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy (asymmetric, sensory, and motor), and distal acquired demyelinating symmetric (DADS) neuropathy (symmetric, distal, sensory, and motor). There are also temporal, pathological, and disease-associated variants. This review describes a clinical scheme for approaching the chronic acquired demyelinating polyneuropathies that leads to a rational use of supportive laboratory studies and treatment options. In addition, we propose new diagnostic criteria for CIDP that more accurately reflect current clinical practice.

Humans↗
PubMed1977

Tissue culture studies of demyelinating disease: a critical review.

Tissue culture studies of human and experimental demyelinating diseases have demonstrated that sera from patients with multiple sclerosis reversibly demyelinate central nervous system cultures. Similar changes are evoked by sera from animals with experimental allergic encephalomyelitis induced by inoculation with whole central nervous system tissue but not by encephalitogenic myelin basic protein. Sera and buffy coat or lymph node cells from humans with idiopathic polyneuritis and animals with experimental allergic neuritis demyelinate cultures of peripheral nervous system tissue. While these studies have contributed to speculations about pathogenetic mechanisms of demyelinating diseases, including the role of both circulating antibodies and delayed hypersensitivity factors, a number of important questions remain unanswered. Among these are the identity of the antigens that evoke antimyelin antibodies and the precise relationship of serum or cellular antimyelin factors to the pathogenesis or clinical course of the demyelinating diseases. Further studies with this technique may provide more complete information about the role of immunological events in induction of disease.

Animals↗
PubMed1993

Large focal tumor-like demyelinating lesions of the brain: intermediate entity between multiple sclerosis and acute disseminated encephalomyelitis? A study of 31 patients.

Thirty-one patients with large, focal cerebral demyelinating lesions are reported. Twenty-four patients had solitary lesions and 7 had multiple foci, the latter apparently of identical age. The lesions presented clinically and radiologically as brain tumors (gliomas or metastases) or as multiple cysts. Six patients were older than 57 years (2 in their 70s) at the onset of their symptoms. The demyelinating nature of the lesions was established through biopsy in each patient and all improved significantly after corticosteroid therapy. Three patients developed additional lesions during the follow-up periods ranging from 9 months to 12 years consistent with the course of multiple sclerosis. Twenty-eight patients did not develop additional lesions. These included 6 patients with multiple lesions at the onset. In 1 of the patients, the first symptoms developed 10 days after receiving vaccination against influenza. Two patients had concomitant malignancy (chronic monomyelogenous leukemia and retroperitoneal seminoma respectively) and 1 patient developed immunoblastic sarcoma in the opposite hemisphere after biopsy diagnosis and steroid treatment of her demyelinating lesion. Tumor-like masses of demyelination may occupy an intermediate position between multiple sclerosis and postinfectious/postvaccination encephalitis. The clinical course (history of vaccination in one instance, acute onset, good response to corticosteroids, no clinical or radiological evidence of new lesions in the great majority of patients) favored postinfectious/postvaccination encephalitis. Lesion size however greatly exceeded that of the small foci of perivenous demyelination seen in typical postinfectious/postvaccination encephalitis and tended to present as space-occupying masses.

Adolescent↗
PubMed1997

Inflammatory central nervous system demyelination: correlation of magnetic resonance imaging findings with lesion pathology.

Magnetic resonance imaging (MRI) is widely used to evaluate and monitor disease activity in inflammatory demyelinating central nervous system (CNS) diseases such as multiple sclerosis. The present study aimed at correlating MRI findings with histological parameters in 6 cases of biopsy-proven inflammatory demyelination of the CNS. The earliest stages of demyelinating activity manifested as almost isointense lesions with a massive gadolinium-DTPA (Gd-DTPA) enhancement in T1-weighted scans. In T2-weighted scans, early active lesions formed a border of decreased intensity compared with the lesion center and the perifocal edema. The morphological correlate of this pattern in our patients was activated macrophages in the zone of myelin destruction at the plaque border. Late active lesions were hypointense in T1 and hyperintense in T2 scans. Inactive demyelinated and remyelinating lesions were hyperintense in T2 scans and enhanced inhomogenously after Gd-DTPA application. T1 scans revealed major differences in the degree of hypointensity that correlated with the extent of axonal damage, extracellular edema, and the degree of demyelination or remyelination.

Adult↗