Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple sclerosis (MS) is a central nervous system demyelinating disease of implicated autoimmune aetiology. The effect was evaluated of intravenous gammaglobulin (IVIg), a successful therapy in various autoimmune diseases, in relapsing-remitting MS patients treated for three years. IVIg treatment significantly reduced the number and severity of acute exacerbations and resulted in a lesser neurological disability. There were no significant short or long-term adverse effects to IVIg treatment. To clarify the putative therapeutic effects of IVIg, this treatment was examined in the animal model of experimental autoimmune encephalomyelitis (EAE) in the rat. IVIg suppressed active EAE in relation to disease severity and duration, despite the presence of T-cell reactivity to specific antigens, while the treatment had no effect on passive EAE induced by adoptive transfer of myelin basic protein specific CD4 + T-cells. It is concluded that IVIg treatment may be a promising treatment in relapsing-remitting MS as it can alter the natural course of the disease.
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PMID:Intravenous gammaglobulin treatment in multiple sclerosis and experimental autoimmune encephalomyelitis: delineation of usage and mode of action. 796 56

We reviewed 200 patients with paraneoplastic encephalomyelitis (PEM) and anti-Hu antibodies to show possible clinical differences with respect to previous series, and to identify patient, tumour and treatment-related characteristics associated with neurological disability and survival. The median age of the 200 patients was 63 years (range 28-82 years) and 75% were men. The predominant neurological syndromes were sensory neuropathy (54%), cerebellar ataxia (10%), limbic encephalitis (9%) and multifocal involvement (11%). Sensorimotor neuropathies with predominant motor involvement were observed in only 4% of the patients. Pathological or X-ray evidence of a tumour was obtained in 167 patients (83%) and was a small-cell lung cancer (SCLC) in 74% of those with histological diagnosis. Coexistence of extrathoracic tumours with SCLC was rare (0.5%). Positive Hu immunoreactivity was observed in the extrathoracic tumours of six out of seven patients in whom autopsy or long-term follow-up ruled out a coexisting SCLC. PEM preceded the diagnosis of the tumour in 71% of patients (mean delay +/- SD 6.5 +/- 7.0 months; range 0.1-47 months). In the 24 patients in whom the tumour diagnosis was the initial event, PEM predicted the progression or relapse of the tumour in 87% of them. No tumour was found in 33 patients, including four who had a post-mortem study and four with >5 years of follow-up. In a logistic regression analysis, treatment of the tumour, associated or not with immunotherapy, was an independent predictor of improvement/stabilization of PEM [odds ratio 4.56; 95% confidence interval (CI) 1.62-12.86]. Cox multivariate analysis indicated that the variables independently associated with mortality were: age >60 years [relative risk (RR) 1.49; 95% CI 1.05-2.12], Rankin score at diagnosis >3 (RR 1.60; 95% CI 1.12-2.28), more than one area of the nervous system affected (RR 1.61; 95% CI 1.08-2.40), and absence of treatment (RR 2.56; 95% CI 1.76-3.71). We conclude that, unlike previous series, the majority of our patients were male, and there was a low occurrence of predominantly motor neuropathies and extrathoracic tumours coexisting with SCLC. When the diagnosed extrathoracic tumour expresses Hu antigens, further tests to rule out a coexisting SCLC are probably unnecessary. Finally, the predictors of mortality and PEM evolution found in the study may be important in the design of future therapeutic protocols, and emphasize the importance of early diagnosis and treatment of the underlying tumour.
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PMID:Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. 1135 30

Recent models of experimental autoimmune encephalomyelitis (EAE) have indicated that antigens co-expressed in the retina and uvea might be of pathogenetic relevance in Multiple Sclerosis (MS). We investigated the clinical spectrum and magnetic resonance imaging of 11 MS patients with concomitant uveitis, and determined the frequency of clinically silent intraocular inflammation in a prospective series of 50 patients. Two of the 11 patients had panuveitis, seven had anterior, and the remaining two had intermediate uveitis. The onset of uveitis preceded that of neurological symptoms by a mean of 8.5 years (range 1-20). None of the 50 MS patients studied prospectively by using slit lamp examinations and dilated funduscopy showed any evidence of uveitis but six patients had signs of retinal inflammation ("periphlebitis retinae"). Cranial MRI did not reveal "atypical" lesional distribution in MS patients with uveitis or periphlebitis retinae. No correlation between the type of MS and uveitis, or between the degree of neurological disability and the type of uveitis was found.
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PMID:Patients with Multiple Sclerosis and concomitant uveitis/periphlebitis retinae are not distinct from those without intraocular inflammation. 1144 Jul 44

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Most patients undergo an initial relapsing-remitting (RR-MS) course that transforms into a relentless neurodegenerative disorder, termed secondary progressive (SP)-MS. Reversible inflammation and demyelination account readily for the pattern of RR-MS but provide an unsatisfactory explanation for irrevocable decline in SP-MS. Axon loss is thought to be responsible for progressive, non-remitting neurological disability during SP-MS. There is considerable potential for neuroprotective therapies in MS, but their application awaits animal models in which axonal loss correlates with permanent neurological disability. In this report, we describe quantitative immunohistochemical methods that correlate inflammation and axonal loss with neurological disability in chronic-relapsing experimental autoimmune encephalomyelitis (EAE). At first attack, CNS inflammation, but not axon loss, correlated with the degree of neurological disability. In contrast, fixed neurological impairment in chronic EAE correlated with axon loss that, in turn, correlated with the number of symptomatic attacks. As proposed for MS, these observations imply a causal relationship between inflammation, axon loss, and irreversible neurological disability. This chronic-relapsing EAE model provides an excellent platform for 2 critical objectives: investigating mechanisms of axon loss and evaluating efficacy of neuroprotective therapies.
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PMID:Axon loss in the spinal cord determines permanent neurological disability in an animal model of multiple sclerosis. 1182 41

Specific chemokines and chemokine receptors have been implicated in inflammatory demyelinating diseases of the central nervous system (CNS), including multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Amino-terminal modifications of chemokines can alter receptor interactions, converting agonists to specific antagonists. To examine the function in EAE of murine types 1 and 5 CC chemokine receptors (CCR1 and CCR5), we used Met-RANTES, a peptide that blocks both receptors; controls received heat-inactivated peptide. There was no effect of active treatment on acute-monophasic EAE, regardless whether compound was given at onset or in a pre-treatment regimen. Administered at disease onset, Met-RANTES modestly but significantly ameliorated fixed neurological disability at the endpoint of chronic-relapsing EAE. Met-RANTES treatment did not reduce CNS cellular infiltrates or up-regulation of CCR1 and CCR5 in affected CNS tissues. Analysis of a subset of mice suggested a trend towards reduced axonal pathology in those receiving active treatment. These data indicate that chemokine receptor blockade with Met-RANTES does not affect leukocyte trafficking in chronic-relapsing EAE. Further analysis of the effects of chemokine receptor blockade may need to focus on leukocyte activation within the affected CNS as well as trafficking events.
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PMID:Treatment of experimental autoimmune encephalomyelitis with the chemokine receptor antagonist Met-RANTES. 1209 6

Multiple sclerosis (MS) is an important cause of progressive neurological disability, typically commencing in early adulthood. There is a need for safe and effective therapy to prevent the progressive central nervous system (CNS) damage and resultant disability that characterize the disease course. Increasing evidence supports a chronic autoimmune basis for CNS damage in MS. In the present study, we review current concepts of autoimmune pathogenesis in MS, assess current therapies aimed at countering autoimmune attack and discuss potential therapeutic strategies. Among currently available therapies, beta-interferon and glatiramer acetate have a modest effect on reducing relapses and slowing the accumulation of disability in relapsing-remitting MS. Beta-interferon is of doubtful efficacy in secondary progressive MS and appears to aggravate primary progressive MS, possibly by increasing antibody-mediated CNS damage through inhibition of B-cell apoptosis. Mitoxantrone may reduce relapses and slow disability progression in relapsing-remitting and secondary progressive MS, but its use is limited by the risk of cardiomyopathy. There are currently no effective treatments for primary progressive MS. Many therapies that are effective in the animal model, experimental autoimmune encephalomyelitis (EAE), are either ineffective in MS or--in the case of gamma-interferon, lenercept and altered peptide ligands--actually make MS worse. This discrepancy may be explained by the occurrence in MS of defects in immunoregulatory mechanisms, the integrity of which is essential for the efficacy of these treatments in EAE. It is likely that the development of safe, effective therapy for MS will depend on a better understanding of immunoregulatory defects in MS.
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PMID:Prevention of autoimmune attack and disease progression in multiple sclerosis: current therapies and future prospects. 1241 39

Axonal degeneration has been identified as the major determinant of irreversible neurological disability in patients with multiple sclerosis (MS). Axonal injury begins at disease onset and correlates with the degree of inflammation within lesions, indicating that inflammatory demyelination influences axon pathology during relapsing-remitting MS (RR-MS). This axonal loss remains clinically silent for many years, and irreversible neurological disability develops when a threshold of axonal loss is reached and compensatory CNS resources are exhausted. Experimental support for this view-the axonal hypothesis-is provided by data from various animal models with primary myelin or axonal pathology, and from pathological or magnetic resonance studies on MS patients. In mice with experimental autoimmune encephalomyelitis (EAE), 15-30% of spinal cord axons can be lost before permanent ambulatory impairment occurs. During secondary progressive MS (SP-MS), chronically demyelinated axons may degenerate due to lack of myelin-derived trophic support. In addition, we hypothesize that reduced trophic support from damaged targets or degeneration of efferent fibers may trigger preprogrammed neurodegenerative mechanisms. The concept of MS as an inflammatory neurodegenerative disease has important clinical implications regarding therapeutic approaches, monitoring of patients, and the development of neuroprotective treatment strategies.
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PMID:Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. 1255 5

Axonal pathology has been highlighted as a cause of neurological disability in multiple sclerosis. The Daniels (DA) strain of Theiler's murine encephalomyelitis virus infects the gray matter of the central nervous system of mice during the acute phase and persistently infects the white matter of the spinal cord during the chronic phase, leading to demyelination. This experimental infection has been used as an animal model for multiple sclerosis. The GDVII strain causes an acute fatal polioencephalomyelitis without demyelination. Injured axons were detected in normal appearing white matter at 1 week after infection with DA virus by immunohistochemistry using antibodies specific for neurofilament protein. The number of damaged axons increased throughout time. By 2 and 3 weeks after infection, injured axons were accompanied by parenchymal infiltration of Ricinus communis agglutinin I(+) microglia/macrophages, but never associated with perivascular T-cell infiltration or obvious demyelination until the chronic phase. GDVII virus infection resulted in severe axonal injury in normal appearing white matter at 1 week after infection, without the presence of macrophages, T cells, or viral antigen-positive cells. The distribution of axonal injury observed during the early phase corresponded to regions where subsequent demyelination occurs during the chronic phase. The results suggest that axonal injury might herald or trigger demyelination.
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PMID:Axonal injury heralds virus-induced demyelination. 1265 18

Axonal degeneration within the spinal cord contributes substantially to neurological disability in multiple sclerosis (MS). Thus neuroprotective therapies that preserve axons, so that they maintain their integrity and continue to function, might be expected to result in improved neurological outcome. Sodium channels are known to provide a route for sodium influx that can drive calcium influx, via reverse operation of the Na+/Ca2+ exchanger, after injury to axons within the CNS, and sodium channel blockers have been shown to protect CNS axons from degeneration after experimental anoxic, traumatic, and nitric oxide (NO)-induced injury. In this study, we asked whether phenytoin, which is known to block sodium channels, can protect spinal cord axons from degeneration in mice with experimental allergic encephalomyelitis (EAE), which display substantial axonal degeneration and clinical paralysis. We demonstrate that the loss of dorsal corticospinal tract (63%) and dorsal column (cuneate fasciculus; 43%) axons in EAE is significantly ameliorated (corticospinal tract: 28%; cuneate fasciculus: 17%) by treatment with phenytoin. Spinal cord compound action potentials (CAP) were significantly attenuated in untreated EAE, whereas spinal cords from phenytoin-treated EAE had robust CAPs, similar to those from phenytoin-treated control mice. Clinical scores in phenytoin-treated EAE at 28 days were significantly improved (1.5, i.e., minor righting reflex abnormalities) compared with untreated EAE (3.8, i.e., near-complete hindlimb paralysis). Our results demonstrate that phenytoin has a protective effect in vivo on spinal cord axons, preventing their degeneration, maintaining their ability to conduct action potentials, and improving clinical status in a model of neuroinflammation.
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PMID:Phenytoin protects spinal cord axons and preserves axonal conduction and neurological function in a model of neuroinflammation in vivo. 1290 34

T cells that are autoreactive against myelin antigens play a pivotal role in the pathogenesis of multiple sclerosis (MS). The concept of T cell vaccination (TCV) has been developed to generate an immune response against these autoreactive pathogenic T cells. Immunologic data accumulated so far demonstrates depletion of T cells reactive against immunodominant myelin peptides after immunization in the animal model of experimental autoimmune encephalomyelitis, as well as in vaccinated MS patients. Clinical trials have confirmed the safety and efficacy of TCV in a small number of immunized MS patients. TCV resulted in reduced relapse rates and slowed the progression of neurological disability and MRI brain lesion load. Recently, there have been several double-blind, placebo-controlled studies initiated to evaluate the role of TCV in MS. Specifically, it is important to examine the effect of early TCV, given after the first episode suggestive of the disease, in order to prevent the process of epitope spreading.
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PMID:T-cell vaccination in multiple sclerosis. 1487 46


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