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The International Panel on MS Diagnosis presents revised diagnostic criteria for multiple sclerosis (MS). The focus remains on the objective demonstration of dissemination of lesions in both time and space. Magnetic resonance imaging is integrated with dinical and other paraclinical diagnostic methods. The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations, including "monosymptomatic" disease suggestive of MS, disease with a typical relapsing-remitting course, and disease with insidious progression, without clear attacks and remissions. Previously used terms such as "clinically definite" and "probable MS" are no longer recommended. The outcome of a diagnostic evaluation is either MS, "possible MS" (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or "not MS."

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A 21-year-old woman presented with a 5-month history of meningeal signs and evidence of intracranial hypertension and, as shown by magnetic resonance imaging (MRI), progressively more extensive meningeal enhancement, particularly within the spinal canal. Autopsy disclosed the presence of primary diffuse leptomeningeal gliomatosis with spinal cord predominance, possibly arising within heterotopic leptomeningeal glial tissue in the cervical region. No parenchymal primary lesion was identified. MRI with gadolinium appears to be the imaging modality of choice for the early detection of primary diffuse leptomeningeal neoplasia.

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OBJECTIVE: To assess the effectiveness of diphenhydramine hydrochloride (Benadryl) in the treatment of patients with idiopathic truncal dystonia. DESIGN: Before-and-after trial. SETTING: University referral center. PATIENTS: Five consecutive patients with idiopathic truncal dystonia who were poorly treated with conventional pharmacotherapies. No patients were withdrawn from the trial for adverse side effects. INTERVENTIONS: Treatments with diphenhydramine hydrochloride (50 mg intravenously or up to 500 mg/kg orally). Follow-up for up to 20 months. MAIN OUTCOME MEASURE: Dystonia evaluation. RESULTS: Diphenhydramine therapy was associated with minimal side effects, and it was most effective in treating patients with dystonia who experienced lightning jerks. Treatment with intravenous diphenhydramine may have a predictive value on a future response to oral therapy. CONCLUSION: Diphenhydramine should be considered a therapeutic option for idiopathic truncal dystonia with lightning jerks.

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Myelin basic protein (MBP)-specific T-cell lines from patients with multiple sclerosis (MS) and healthy controls were analyzed for the expression of CD45 isoforms and adhesion molecules. In the multiple sclerosis group, 22 of 24 MBP-specific T-cell lines were CD4+. Two distinct patterns were observed with regard to CD45 isoform expression. Pattern I showed dual expression of CD45 isoforms (CD4+CD45RA+CD45RO+CD29+) and Pattern II included cells with a single CD45 isoform (CD4+CD45RA-CD45RO+CD29+). All 10 cell lines from healthy controls were CD4+ and displayed Pattern II (CD4+CD45RA-CD45RO+CD29+). The dual expression of CD45 isoform in T-cell lines from MS was stable, did not represent a transition stage from CD45RA to CD45RO, and was cell-cycle independent. All cell lines from MS and controls expressed increased levels of LFA-1 (CD11a), LFA-2 (CD2), LFA-3 (CD58), ICAM-1 (CD54), and VLA-4 (CDw49d). These data show the presence of unique MBP-specific T cells (CD4+CD45RA+CD45RO+CD29+) that might play a role in the pathogenesis of MS.

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In this study, 13 clinically and pathologically diagnosed cases of Alzheimer's disease were analyzed for the presence of intercellular adhesion molecule 1 (ICAM-1), ICAM-2, lymphocyte function associated antigen-1 (LFA-1), HLA-DR, LN-1, and LN-2. ICAM-1 was observed primarily on neuritic plaques and cerebrovascular endothelium. ICAM-1 was also shown to be present in brain tissue derived from 14 normal cases; however, the degree of immunoreactivity was quantitatively less compared to Alzheimer cases and was largely restricted to cerebrovascular endothelium. LFA-1 was shown to be present on microglial cells and leukocytes. Consistent with the findings of previous reports, HLA-DR was found to be expressed on microglial cells. In this study we failed to demonstrate dual immunolocalization for ICAM-1 and LFA-1, ICAM-1 and HLA-DR, or ICAM-1 and LN-2. As microglial cells express both HLA-DR and LFA-1, they may serve to mediate antigen presentation functions by interacting with lymphocyte ICAM-1. Alternately, the expression of these immune-associated glycoproteins on glial cells may be epiphenomenal occurring secondary to some aspect of the disease process. Finally, the presence of ICAM-1 within neuritic plaques raises the question as to whether adhesion may play some role in the process of neurite outgrowth and neurodegeneration.

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Astrocytes play an important role in antigen presentation to T lymphocytes by their ability to express major histocompatibility class II (Ia) antigen upon exposure to a number of agents, including interferon-gamma (IFN-gamma). Astrocytes have been shown to express a variety of voltage-sensitive ion channels including voltage-sensitive K+ channels. The function(s) of these channels in astrocyte functions is not clearly understood. In this investigation, we examined: (1) the comparative effects of mouse, rat, and human recombinant IFN-gamma (rIFN-gamma) on the induction of Ia antigen and DNA synthesis in rat astrocytes; (2) the effect of tetraethylammonium (TEA), a K+ channel blocker, on rat IFN-gamma-induced Ia expression and DNA synthesis in rat astrocytes. Our data show that all INF-gamma induce DNA synthesis in rat astrocytes but only rat and mouse and not the human IFN-gamma will induce Ia expression. TEA in a dose-dependent manner inhibited both Ia expression and DNA synthesis in rat astrocytes. The concentration kinetics of TEA with regard to maximum inhibition of Ia and DNA synthesis were different. Furthermore, these inhibitory effects were not a result of toxic or nonspecific effect of TEA on astrocytes as demonstrated by viability data and lack of any effect of tetramethylammonium, an analogue of TEA, that does not block K+ ion channels. These data suggest a role of K+ channels in Ia expression and DNA synthesis, therefore in immunological functions of astrocytes.

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Antigen presentation reactions are dependent upon the expression of the class II major histocompatibility antigens (MHC), the T-cell receptor, and the presented antigen. Recent studies demonstrate that such processes also require the presence of adhesion molecules such as lymphocyte functional antigen 1 (LFA-1) and its cell surface ligand, intercellular adhesion molecule 1 (ICAM-1). It has been suggested that the brain astrocyte can function as a facultative antigen presenting cell (APC). This hypothesis is based upon the ability to induce the expression of the class II MHC antigens on astrocytes, and on their ability to present myelin basic protein to encephalitogenic T-cells in vitro. The best in vivo data showing that astrocytes serve as intracerebral APCs is the finding that astrocytes in multiple sclerosis plaques are DR+ (class II MHC in human). However, it still remains to be resolved whether the in vivo expression of the MHC antigens in disease states is instrumental to antigen presentation mechanisms or whether these cell surface glycoproteins are expressed secondary to brain immune responses. If astrocytes function as immunocompetent APCs within the brain, it would seem that they would also be able to express molecules important for intercellular adhesion. Here, we present the first data that indicates that human astrocytes are capable of expressing ICAM-1 in response to cytokines that either induce or upregulate the expression of DR. In essence, cytokines derived from different cell types seem to exert similar pleiotropic effects on the modulation of MHC and ICAM-1 expression on astrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

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The astrocyte is the most abundant cell within the central nervous system (CNS). This cell subserves a multiplicity of important functions that contribute to the process of neural development as well as to the integrity of normal brain function. Adding to the already exhaustive list of capabilities, the astrocyte has now been demonstrated to function as an intracerebral antigen presenting cell. These findings are serving to revise our view of the brain as an immunoprivileged site and perhaps will shed some light on the pathogenetic mechanisms involved in a number of CNS disorders of immune dysregulation. In this review we provide some perspective on the regulatory mechanisms that influence astrocyte immune functions. Specifically, we address the role played by the major histocompatibility complex (MHC) antigens as well as adhesion molecules in the initiation of brain immune responses.

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The brain has been traditionally viewed as an immunologically privileged site. However, recent findings suggest that the brain is in fact equipped with its own immune circuitry. Astrocytes and microglia have been considered the most likely candidates to assume the role of intracerebral antigen presenting cells (APC). Using the techniques of immunofluorescence cytochemistry and flow cytometric analysis, we observed that vasoactive intestinal polypeptide (VIP) can significantly inhibit gamma-interferon (IFN-gamma)-induced Ia expression on astrocytes derived from newborn Lewis rats. Further, we analyzed a number of neuropeptides and transmitters for their ability to exert a similar inhibitory modulation on IFN-gamma induced Ia expression or for the ability to induce or augment Ia expression on rat astrocytes. Our results showed that only norepinephrine (NE), a major brain neurotransmitter, and VIP, a ubiquitous brain peptide, have the ability to inhibit Ia expression on Lewis rat astrocyte cultures. Alternately, we report that cholecystokinin (CCK), a brain/gut peptide, has the ability to induce Ia on about 5-10% of the cells analyzed. These findings suggest that endogenous brain substances have the ability to modulate intracerebral immune responses by regulating the expression of Ia on astrocytes.

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One of the characteristics of Alzheimer's disease is the early loss of neurons in pathways involved in processing olfactory information. Olfactory function was assessed in subjects with Alzheimer's disease using a conventional Smell Identification Test and a simple three odor match-to-sample problem. The patients exhibited a diminished capacity to identify common odors but were severely impaired in their ability to use novel odors in a match-to-sample task. Subjects with Parkinson's disease had a severe deficit for identifying common odors with the majority scoring as anosmic. Multiple sclerosis was not accompanied by detectable changes in olfactory functioning. The results of the Alzheimer's group are similar to recent animal studies that have shown lesions of the piriform-entorhinal cortex produce a variety of memory deficits that are particularly acute in tasks involving novel odors.

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The astrocyte is now recognized as a facultative immunocompetent antigen-presenting cell that can initiate intracerebral immune responses. However, despite the presence of activated T lymphocytes and their associated lymphokines within the central nervous system, there is a paucity in the expression of the major histocompatibility (MHC) antigens on normal neural tissue. These membrane-localized glycoproteins are required for the process of antigen presentation and, therefore, for the initiation of immune responses. To date, little is understood regarding the nature of inhibitory mechanisms that might be responsible for maintaining the brain as an immunoprivileged site. In this study we found that norepinephrine, a major brain transmitter, significantly inhibited gamma interferon-induced MHC class II antigen expression on astrocytes derived from neonatal Lewis rats. We show that this inhibition can be attenuated by the addition of a beta-adrenergic antagonist, propranolol, but not by the addition of a beta 1-selective antagonist, atenolol, or by an alpha-adrenergic antagonist, phentolamine. Furthermore, it was found that a similar inhibition could be achieved by the addition of either dibutyryl-cAMP or dipyridimole, a phosphodiesterase inhibitor. Therefore, it seems that norepinephrine-mediated inhibition of MHC class II antigen expression on astrocytes works through beta 2-adrenergic signal transduction pathways. Taken together, these in vitro results suggest that the brain contains inhibitory factors that may play a pivotal role in the regulation of intracerebral immune responses by modulating the expression of MHC antigens on astrocytes.

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Recent evidence that astrocytes can be induced to express the class II major histocompatability (MHC) antigens suggests that these cells may be involved in the development of intracerebral immune responses. The principal inducer of MHC class II antigen (Ia) expression is a soluble lymphokine, gamma-interferon (gamma-IFN). Normally astrocytes do not express significant levels of Ia antigens despite the fact that agents such as gamma-IFN may be present in the central nervous system (CNS). Here we report that a major neurotransmitter, norepinephrine (NE), inhibits, in a dose-response fashion, the ability of gamma-IFN to induce Ia antigen expression on cultured astrocytes derived from newborn BALB/c mice. This finding may indicate that the brain contains inhibitory modulators that serve to prevent the up-regulation of intracerebral immune responsiveness.

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A humoral factor having many of the physical properties of a glycoprotein and lacking many of the characteristics of other immunosuppressants has been detected in the serum and plasma of patients with active multiple sclerosis. Kinetic studies indicate that the earliest biochemical event inhibited by LTIF is the incorporation of labeled nucleotides into acid insoluble ribonucleic acid. This material, designated lymphocyte transformation inhibition factor (LTIF), inhibits blast transformation in mitogen-stimulated T lymphocytes. The serum factor is usually associated with active multiple sclerosis but is also detected in some lymphoproliferative disorders. Partial purification has separated this material from serum immunoglobulins, but these procedures led to an accelerated loss of biological activity.

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