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PubMed1987

Demyelination and neurological signs in experimental allergic encephalomyelitis.

Because of the reported absence of demyelination in some animals with neurological signs of experimental allergic encephalomyelitis (EAE), it has been suggested that these signs are not due to demyelination. The present study demonstrates that there is ample demyelination in the central nervous system (CNS) and peripheral nervous system (PNS) to account for the neurological signs in rats with myelin basic protein (MBP)-induced acute EAE as well as in rats and rabbits with whole-spinal-cord-induced acute EAE. The main reasons for failure to detect demyelination in animals with neurological signs of EAE appear to be inadequate histological techniques and incomplete examination of the nervous system, particularly the PNS and the lumbar, sacral and coccygeal segments of the spinal cord.

Animals↗
PubMed2005

Axon loss is responsible for chronic neurological deficit following inflammatory demyelination in the rat.

Axonal loss is now considered a consistent feature of MS pathology and evidence suggests that its accumulation may be the pathological correlate for the development of irreversible disability. In this study, we investigated the features of axonal loss in myelin autoimmunity and tested the hypothesis that loss of axons determines permanent neurological impairment in a model of inflammatory demyelination that closely mimics the pathology and course of MS. EAE was induced in DA rats by injection of recombinant mouse MOG with IFA. Animals that developed progressive EAE were killed at several time points after disease onset and animals that followed a chronic relapsing-remitting course of EAE were killed at approximately 4 months, exhibiting varying degrees of residual disability. Toluidine blue staining of semithin sections and immunohistochemistry for OX-42 were used to quantify demyelination, remyelination, inflammation and axonal loss in the spinal cord of MOG-EAE rats. In progressive EAE, the degree of axon loss, demyelination and inflammation all correlated significantly with clinical severity scores and a causative role for macrophages in the pathogenesis of axonal injury is suggested. However, in the chronic stage of relapsing-remitting EAE, in rats having suffered a variable number of relapses, only axonal loss correlated significantly with clinical severity scores. In addition, both axonal loss and clinical severity scores correlated with the number of relapses. These findings imply that secondary, or 'bystander', axonal loss is the main determinant of irreversible neurological disability in MOG-EAE and make the model a useful tool for the investigation of mechanisms of axonal loss and the evaluation of the benefits of neuroprotective therapies under conditions of antibody-mediated inflammatory demyelination.

Animals↗
PubMed2006

Etanercept and demyelinating disease in a patient with psoriasis.

The tumor necrosis factor-alpha antagonist (TNF-alpha) etanercept has been approved for the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and psoriasis. Earlier reports on the use of etanercept or infliximab in patients with rheumatoid arthritis, psoriatic arthritis, or juvenile rheumatoid arthritis suggested an increased risk of demyelinating disease. It is imperative that dermatologists have a keen awareness of this possible adverse event given the increased use of this class of drugs. We report a case of demyelinating disease occurring in a patient treated for psoriasis. The relation of TNF-alpha antagonist therapy to demyelinating disease/multiple sclerosis is explored. It is recommended that patients be diligently screened before starting TNF-alpha antagonist therapy and that vigilance for symptoms of demyelinating disease/multiple sclerosis be included in follow-up examinations during treatment with these drugs.

Adolescent↗
PubMed2000

Restricted immune responses lead to CNS demyelination and axonal damage.

Although autoreactive T-cells have a pivotal role in initiating the inflammatory process in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS), recent evidence suggests a relevant role for autoantibodies specific for myelin proteins as well. To examine the role of B-cells in the cerebrospinal fluid of patients with MS, we analyzed the V(H) gene usage in ten MS patients by PCR technologies. Analysis of HCDR3 length revealed an oligoclonal accumulation of B-cells. Sequence analysis of the V(H)3 and V(H)4 gamma transcripts of two MS individuals demonstrated that this accumulation was related to the expansion and somatic diversification of a limited groups of B-cell clones. These findings are indicative of a chronic and intense antigenic stimulation occurring in the CNS. Animal models, such as EAE, are of particular importance in order to elucidate the pathogenetic effector mechanisms in autoimmune demyelination. In a non-human primate model of EAE, we describe that the immunodominant T-cell epitope is presented exclusively by a monomorphic DRB1 allele, suggesting that susceptibility to EAE may be linked to this unique restriction and, therefore, providing a possible mechanism for MHC linkage to diseases. Moreover, we report on the presence of inflammation, sharp demyelination and axonal damage in EAE induced with whole myelin as well as with recombinant myelin oligodendrocyte glycoprotein (MOG), but not with myelin basic protein alone. The presence of axonal pathology was supported by immunohistochemistry with anti-amyloid precursor protein and anti-non phosphorilated neurofilaments monoclonal antibodies within early active demyelinated plaques. These findings suggest that axonal damage may be an early event in the pathogenesis of autoimmune demyelinating diseases of the CNS and highlights the importance of animal models in which therapies targeting repair and axonal survival may be exploited.

Animals↗
PubMed2000

Correlating magnetic resonance imaging markers of axonal injury and demyelination in motor impairment secondary to stroke and multiple sclerosis.

The primary pathological mechanisms in stroke and multiple sclerosis (MS) are very different but in both diseases, impairment may arise from a final common pathway of axonal damage. We aimed to examine the relationship between motor impairment, magnetisation transfer ratio (MTR) (an index of demyelination), and N-acetyl aspartate (NAA) loss (an index of axonal injury) localised to the descending motor pathways in stroke and MS. Twelve patients between 1 and 10 months after first ischaemic stroke causing a motor deficit and 12 patients with stable MS with asymmetric motor deficit were examined. T(2)-weighted imaging of the brain together with MTR and proton (voxel 1.5x2x2 cm(3)) MRS localised to the posterior limb of the internal capsule were performed and correlated to a composite motor deficit score. MTR and NAA in the internal capsule were reduced in both stroke and MS patients compared to controls. NAA loss correlated with motor deficit score in both stroke and MS (p<0.001 and p = 0.04, respectively). Correlations were seen between MTR and motor deficit (p<0.001) MTR and NAA loss (p <0.001) in stroke patients but not in MS patients. Axonal injury in the descending motor tracts would appear to be an important determinant of motor impairment in both stroke and MS. In stroke, MTR measures of demyelination are closely related to axonal damage and thus also correlate with motor deficit. However in MS, MTR measures of demyelination do not correlate with NAA loss or motor deficit suggesting that demyelination and gliosis may occur independently of axonal damage and are less closely linked with functional impairment.

Adult↗
PubMed2002

A critical role for the protein tyrosine phosphatase receptor type Z in functional recovery from demyelinating lesions.

Several lines of evidence suggest that tyrosine phosphorylation is a key element in myelin formation, differentiation of oligodendrocytes and Schwann cells, and recovery from demyelinating lesions. Multiple sclerosis is a demyelinating disease of the human central nervous system, and studies of experimental demyelination indicate that remyelination in vivo requires the local generation, migration or maturation of new oligodendrocytes, or some combination of these. Failure of remyelination in multiple sclerosis could result from the failure of any of these processes or from the death of oligodendrocytes. Ptprz encodes protein tyrosine phosphatase receptor type Z (Ptpz, also designated Rptpbeta), which is expressed primarily in the nervous system but also in oligodendrocytes, astrocytes and neurons. Here we examine the susceptibility of mice deficient in Ptprz to experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. We observe that mice deficient in Ptprz show impaired recovery from EAE induced by myelin oligodendrocyte glycoprotein (MOG) peptide. This sustained paralysis is associated with increased apoptosis of mature oligodendrocytes in the spinal cords of mutant mice at the peak of inflammation. We further demonstrate that expression of PTPRZ1, the human homolog of Ptprz, is induced in multiple sclerosis lesions and that the gene is specifically expressed in remyelinating oligodendrocytes in these lesions. These results support a role for Ptprz in oligodendrocyte survival and in recovery from demyelinating disease.

Animals↗
PubMed1998

TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by localized areas of demyelination. Although the etiology and pathogenesis of MS remain largely unknown, it is generally assumed that immune responses to myelin antigens contribute to the disease process. The exact sequence of events, as well as the molecular mediators that lead to myelin destruction, is yet to be defined. As a potent mediator of inflammation, the cytopathic cytokine, tumor necrosis factor (TNF) has been considered to be a strong candidate in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). However, its role in immune-mediated demyelination remains to be elucidated. To determine the contribution of TNF to the pathogenesis of the MS-like disease provoked by the myelin oligodendrocyte glycoprotein (MOG), we have tested mice with an homologous disruption of the gene encoding TNF. Here we report that upon immunization with MOG, mice lacking TNF develop severe neurological impairment with high mortality and extensive inflammation and demyelination. We show further that inactivation of the TNF gene converts MOG-resistant mice to a state of high susceptibility. Furthermore, treatment with TNF dramatically reduces disease severity in both TNF-/- mice and in other TNF+/+ mice highly susceptible to the MOG-induced disease. These findings indicate that TNF is not essential for the induction and expression of inflammatory and demyelinating lesions, and that it may limit the extent and duration of severe CNS pathology.

Animals↗
PubMed2000

Can antiglycolipid antibodies present in HIV-infected individuals induce immune demyelination?

Of the eight clinically defined neuropathies associated with HIV infection, there is compelling evidence that acute and chronic inflammatory demyelinating polyneuropathy (IDPN) have an autoimmune pathogenesis. Many non-HIV infected individuals who suffer from sensory-motor nerve dysfunction have autoimmune indicators. The immunopathogenesis of demyelination must involve neuritogenic components in myelin. The various antigens suspected to play a role in HIV-seronegative IDPN include (i) P2 protein; (ii) sulfatide (GalS); (iii) various gangliosides (especially GM1); (iv) galactocerebroside (GalC); and (v) glycoproteins or glycolipids with the carbohydrate epitope glucuronyl-3-sulfate. These glycoproteins or glycolipids may be individually targeted, or an immune attack may be raised against a combination of any of these epitopes. The glycolipids, however, especially GalS, have recently evoked much interest as mediators of immune events underlying both non-HIV and HIV-associated demyelinating neuropathies. The present review outlines the recent research findings of antiglycolipid antibodies present in HIV-infected patients with and without peripheral nerve dysfunction, in an attempt to arrive at some consensus as to whether these antibodies may play a role in the immunopathogenesis of HIV-associated inflammatory demyelinating polyneuropathy.

Animals↗
PubMed2001

Acute focal demyelinating disease simulating brain tumors: histopathologic guidelines for an accurate diagnosis.

The object of the present study was to determine the histopathological guidelines for accurate diagnosis of cases of acute focal demyelinating disease that simulates brain tumors. The surgical pathology of three such cases is assessed. Histopathological keys to the diagnosis of such cases are as follows. First, a pattern of sheets of atypical gemistocytic astrocytes in the white matter that show well-formed processes and that are adequately distanced from each other argues against a diagnosis of neoplasm. Second, uniform distribution of foamy macrophages aligned along axons, with occasional focal collections surrounding blood vessels and in the absence of any associated coagulative necrosis argues against the presence of a tumor. Third, perivascular chronic inflammatory infiltration, especially a mixture of lymphocytes and macrophages, favors the diagnosis of demyelination plaque. In such cases the lymphocytes will be predominantly T cells. Fourth, pleomorphic astrocytic proliferation with a lack of vascular endothelial proliferation should raise the suspicion that the lesion may not be a brain tumor. These diagnostic keys should be followed when diagnosing cases that are suspected to be demyelination processes rather than brain tumors. The presence of demyelination plaque should then be confirmed by imaging modalities such as staining with myelin-and axon-specific stains.

Adult↗
PubMed1999

Idiopathic inflammatory demyelinating diseases of the central nervous system: differentiating between acute disseminated encephalomyelitis and malignant multiple sclerosis.

Multiple sclerosis (MS) is the most frequent demyelinating disorder of the central nervous system (CNS). However, at presentation, it is frequently difficult to differentiate between malignant MS (MMS) and other fulminant CNS demyelinating diseases like acute disseminated encephalomyelitis (ADEM). The literature contains many case reports of ADEM but few series. We report on four representative cases of acute demyelinating diseases, together with evaluation of treatment, course and follow-up. We also present clinical, laboratory, neuropathologic, neuroimaging and data on therapeutic options, including follow-up, in order to establish distinguishing characteristics of MMS and ADEM. Good clinical outcome from a postinfectious, monophasic episode, correlating with regressive demyelinating lesions on MRI, after more than 2 years differentiate best. Therapeutic efficacy, prior infection and initial MRI lesions seem to be of limited value. Despite the advances of neuroimaging and laboratory techniques, objective parameters are still missing, but findings on basic immunologic mechanisms of humoral and cellular response might provide further insight. Copyright 1999 Harcourt Publishers Ltd.

Journal Article↗
PubMed2001

A case of acute inflammatory demyelinating polyradiculoneuropathy in early pregnancy.

Acute or chronic inflammatory demyelinating polyradiculoneuropathy is a rare disorder that presents with weakness, hyporeflexia, and sensory loss. Treatment consists of immunosuppression and/or plasma exchange. A woman in the first trimester of pregnancy presents with flaccid quadriplegia and numbness. Electromyography demonstrated a demyelinating polyneuropathy with active denervation. The diagnosis of acute inflammatory demyelinating polyradiculoneuropathy was made. She was treated with corticosteroids and plasmapheresis. Despite slow improvement, she decided to terminate the pregnancy at 18 weeks' gestation. At 1 year postpartum she is still in remission. Inflammatory demyelinating polyradiculoneuropathy should be considered in the differential diagnosis of every pregnant woman with new onset peripheral neuropathy. It is suggested that relapse occurs three times more common during pregnancy. Plasmapheresis is the recommended treatment.

Adult↗
PubMed2000

Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group.

BACKGROUND: Treatment with interferon beta has been shown to help patients with established multiple sclerosis, but it is not known whether initiating treatment at the time of a first clinical demyelinating event is of value. METHODS: We conducted a randomized, double-blind trial of 383 patients who had a first acute clinical demyelinating event (optic neuritis, incomplete transverse myelitis, or brain-stem or cerebellar syndrome) and evidence of prior subclinical demyelination on magnetic resonance imaging (MRI) of the brain. After initial treatment with corticosteroids, 193 patients were randomly assigned to receive weekly intramuscular injections of 30 microg of interferon beta-1a and 190 were assigned to receive weekly injections of placebo. The study end points were the development of clinically definite multiple sclerosis and changes in findings on MRI of the brain. The trial was stopped after a preplanned interim efficacy analysis. RESULTS: During three years of follow-up, the cumulative probability of the development of clinically definite multiple sclerosis was significantly lower in the interferon beta-1a group than in the placebo group (rate ratio, 0.56; 95 percent confidence interval, 0.38 to 0.81; P=0.002). As compared with the patients in the placebo group, patients in the interferon beta-1a group had a relative reduction in the volume of brain lesions (P<0.001), fewer new or enlarging lesions (P<0.001), and fewer gadolinium-enhancing lesions (P<0.001) at 18 months. CONCLUSIONS: Initiating treatment with interferon beta-1a at the time of a first demyelinating event is beneficial for patients with brain lesions on MRI that indicate a high risk of clinically definite multiple sclerosis.

Adult↗
PubMed1978

Degradation of basic protein in myelin by neutral proteases secreted by stimulated macrophages: a possible mechanism of inflammatory demyelination.

In inflammatory demyelinating diseases such as multiple sclerosis and experimental allergic encephalomyelitis, myelin destruction occurs in the vicinity of infiltrating mononuclear cells. The observations that myelin can be altered prior to phagocytosis and in areas not contiguous with inflammatory cells suggests a common mechanism for the initial stages of demyelination. Because stimulated macrophages secrete several neutral proteases, including plasminogen activator, we have investigated the possibility that myelinolysis could be mediated directly or indirectly by these enzymes. Isolated myelin was incubated with conditioned media from cultures of thioglycollate-stimulated mouse peritoneal macrophages in the presence and absence of plasminogen. Myelin appeared to be vulnerable to attack by at least two proteolytic activities secreted by the macrophages, a plasminogen-dependent and a plasminogen-independent activity; of the major proteins in myelin, the basic protein was most susceptible. The direct myelinolytic activity of macrophage-conditioned media was abolished by EDTA, and the plasminogen-dependent hydrolysis was abolished by p-nitrophenylguanidinobenzoate, an inhibitor of plasminogen activator and plasmin. These results suggest that the plasminogen activator released by the stimulated macrophages generated plasmin which hydrolyzed basic protein in intact myelin. This interpretation was confirmed by the observation that urokinase, a plasminogen activator, in the presence of plasminogen brought about marked degradation of basic protein in myelin. We propose that the release of neutral proteases by stimulated macrophages involved in cell-mediated reactions, and its amplification by the plasminogen-plasmin system, may play a significant role in the demyelination observed in several inflammatory demyelinating diseases.

Animals↗
PubMed1990

Changed distribution of sodium channels along demyelinated axons.

Voltage-gated sodium channels are largely localized to the nodes of Ranvier in myelinated axons, providing a physiological basis for saltatory conduction. What happens to these channels in demyelinated axons is not known with certainty. Experimentally demyelinated axons were examined by using a well-characterized, polyclonal antibody directed against sodium channels. Immunocytochemical and radioimmunoassay data were consistent with the distribution of an increased number of sodium channels along segments of previously internodal axon. These findings affirm the plasticity of sodium channels in demyelinated axolemma and may be relevant to understanding how axons recover conduction after demyelination.

Animals↗
PubMed1994

Early recruitment of oligodendrocyte precursors in CNS demyelination.

The source of the new population of oligodendrocytes which successfully remyelinates experimentally induced demyelination of the cat optic nerve was studied with a combination of techniques. These included correlative light microscopy, immunocytochemistry, electron microscopy and autoradiography in transverse and longitudinal sections. Extending the analysis from the newly generated oligodendrocyte back to the very early demyelinative phase of the lesion enabled the identification of a glial precursor cell (GPC) outside the lesion which appeared to be readily recruitable and motile. This cell is likely to be the product of the division of a putative resting progenitor cell residing in a central fascicular location of the normal optic nerve surrounding the lesion. On arriving at the fringe of the lesion, GPCs are transformed into vimentin-positive small glial cells (SGCs) possibly by signals from demyelinated axons to which the SGCs become closely apposed. Small glial cells, which together with GPCs share several features in common with O-2A perinatal progenitors of the rodent optic nerve, then differentiate into oligodendrocytes. Together these findings suggest that the events leading to remyelination of adult mammalian optic nerve commence soon after the demyelinating injury and might recapitulate the principal events of developmental myelinogenesis.

Animals↗
PubMed2006

Disruption of neurofascin localization reveals early changes preceding demyelination and remyelination in multiple sclerosis.

Saltatory conduction in the nervous system is enabled through the intimate association between the leading edge of the myelin sheath and the axonal membrane to demarcate the node of Ranvier. The 186 kDa neuron specific isoform of the adhesion molecule neurofascin (Nfasc186) is required for the clustering of voltage gated Na+ channels at the node, whilst the 155 kDa glial specific isoform (Nfasc155) is required for the assembly of correct paranodal junctions. In order to understand the relationship between these vital structures and how they are affected in multiple sclerosis we have examined the expression of Nfasc155 and Nfasc186 in areas of inflammation, demyelination and remyelination from post-mortem brains. Fourteen cases of neuropathologically confirmed multiple sclerosis (8 female and 6 male; post-mortem delay 7-24 h; age 37-77 years; and disease duration 15-40 years), comprising 20 tissue blocks with 32 demyelinating or remyelinating lesions, were used in this study. A significant early alteration in Nfasc155+ paranodal structures occurs within and adjacent to actively demyelinating white matter lesions that are associated with damaged axons. Shaker-type Kv1.2 channels, normally located distally to the paranode, overlapped with the disrupted Nfasc155+ structures. In the absence of Nfasc155, Kv1.2 channels abutted normally clustered Nfasc186+ nodes, indicating that complete disruption of the paranodal structure and movement of Kv1.2 channels precede alterations at the node itself. Within areas of partial remyelination, a number of atypical triple-Nfasc155+ structures were noted that may represent transient oligodendrocyte-axonal contacts during the process of myelin repair or aberrant interactions. Within shadow plaques discretely clustered Na+v, Nfasc186+ and Nfasc155+ domains indicated the restoration of normal nodal architecture. The alterations in oligodendrocyte Nfasc155 expression that accompany inflammation and demyelination suggest an ongoing disruption to the axonal-oligodendrocyte complex within newly forming as well as established lesions in multiple sclerosis, resulting in destruction of the Nfasc186+/Na+v nodal complex vital to successful fast neurotransmission in the CNS.

Adult↗
PubMed1999

Linkage analysis of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in the rat identifies a locus controlling demyelination on chromosome 18.

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) with a complex etiology comprising a genetically determined predisposition and a suspected auto- immune pathogenesis. Experimental autoimmune encephalomyelitis (EAE) is an animal model for MS, which can be used to define susceptibility loci for autoimmune neuroinflammation. We have recently established a chronic relapsing EAE model characterized by inflammation and focal demyelination in the CNS by immunizing a variety of rat strains with the CNS-specific myelin oligodendrocyte glycoprotein (MOG). This model is more MS-like than any other rodent EAE model described up to now. Here we present the first systematic genome search for chromosomal regions linked to phenotypes of MOG-induced EAE in a (DA x ACI) F(2)intercross. A genome-wide significant susceptibility locus linked to demyelination was identified on chromosome 18. This region has not been described in inflammatory diseases affecting other organs and the responsible gene or genes may thus be nervous system specific. Other chromosomal regions showing suggestive linkage to phenotypes of MOG-induced EAE were identified on chromosomes 10, 12 and 13. The chromosome 10 and 12 regions have previously been linked to arthritis in DA rats, suggesting that they harbour immunoregulatory genes controlling general susceptibility to autoimmune diseases. We conclude that identification of susceptibility genes for MOG-induced EAE on rat chromosomes 10, 12, 13 and 18 may disclose important disease pathways for chronic inflammatory demyelinating diseases of the CNS such as MS.

Animals↗
PubMed1982

Spinal cord and optic nerve demyelination in experimental herpes simplex virus type 2 infection.

To produce a model of central nervous system (CNS) demyelination, three strains of herpes simplex virus type 2 (HSV-2) were injected intracerebrally into Swiss-Webster outbred mice. Animals developed pupillary abnormalities and leg weakness and, by light and electron microscopy, had focal lesions of primary demyelination in optic nerves and spinal cords. Oligodendrocytes and astrocytes in these lesions contained herpesvirus. Both mouse age and virus dose were important determinants of the rate and severity of the infectious process, as judged by mortality and clinical signs of disease. A low virus dose in older mice favored survival of neurologically abnormal mice beyond the acute stage of infection. When the MS, G, and 186 strains of HSV-2 were compared, no evidence of a major effect of virus strain on the clinical course or type of pathology was seen. This study demonstrates that HSV-2 can produce multifocal demyelination in the CNS in mice. The intracerebral route appears to be important in producing a model of more generalized demyelination unrelated to the site of injection than has been previously reported in other experimental herpesvirus infections. The possible relationship of this model to optic neuritis, neuromyelitis optica, and multiple sclerosis is discussed.

Animals↗