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PubMed1983

Immunological treatment of multiple sclerosis.

Immunosuppressive treatment of multiple sclerosis (MS) is based on the autoimmune hypothesis for which the main evidence is the close histological similarity between the human disease and chronic relapsing EAE. Although controlled trials indicate that ACTH is effective in accelerating recovery from relapses, long term ACTH or oral steroids are ineffective. Two controlled trials have suggested a beneficial effect of azathioprine, but neither was conducted "blind" and neither was sufficiently convincing to cause the widespread adoption of azathioprine by neurologists. One controlled trial, also not blind, reported a beneficial effect of an intensive course of cyclophosphamide, but this hazardous treatment will not be widely adopted unless other trials confirm this result. The converse hypothesis that MS is due to a deficient immune response to a virus has led to trials of immunostimulation. Interferon and levamisole have proven ineffective so far, but transfer factor slowed disease progression in one well conducted trial.

Adrenocorticotropic Hormone↗

PubMed2002

Epitope spreading and molecular mimicry as triggers of autoimmunity in the Theiler's virus-induced demyelinating disease model of multiple sclerosis.

The pathogenesis of multiple sclerosis (MS), a human demyelinating disease of the central nervous system (CNS), is currently unknown. It is widely thought that MS is an autoimmune disease which is supported by animal studies showing that myelin-specific CD4+ T cells can induce similar clinical disease in mice as observed in MS. However, the mechanism(s) of activation of these autoreactive CD4+ T cells are unknown. Although genetic susceptibility is important, other factors may be involved. Viral infections have long thought to be involved in the pathogenesis of MS although there exists little or no direct evidence implicating a role for a specific virus in MS pathogenesis. This review will discuss two models of virus-induced CNS autoimmunity, molecular mimicry and epitope spreading. These two mechanisms of activation of autoreactive T cells are presented in the context of MS.

Animals↗

PubMed2006

Visual spatial neglect in multiple sclerosis.

Neuropsychological dysfunction in multiple sclerosis (MS) patients is now a well-established clinical finding. We examined the entity of visual spatial neglect in demyelinating disease and its correlation to the functional and neuroradiological parameters. The phenomenon of visual spatial neglect was examined in 20 (5 male and 15 female) MS patients. Two different examination methods were used--the line bisection test and the random shape cancellation test. The results were compared with 20 aged matched control individuals. The correlation of the visual spatial neglects to neurological deficits and handicaps, using Kurtzke's Expanded Disability Status Scale (EDSS), as well as with the MRI's neuroradiological findings, was analyzed. A highly significant different result on the line bisection test for three various line lengths (p = .006, p < .0001, p < .001) with displacement towards the right side was found. In all the cancellation subtests, a significant difference in error rate was found in comparing patients to controls toward a higher one on the left side of the MS patients (p = .005, p < .002, p < .0001 and p = .02 in the left side subtest, and p = n.s. in the right side subtest). There was no significant correlation between the cancellation tests and bisection results and the EDSS scale data, as well as with the neuroradiological findings. The present results demonstrate the presence of visual spatial neglect among MS patients, even without the demonstration of a characteristic neuroanatomical lesion. The hypotheses for this finding are discussed with a stress on the possibility of disruption of multiple intrahemispheric connections, especially under the condition of asymmetry of dominance regarding spatial attention.

Adult↗

PubMed2001

Linking structural, metabolic and functional changes in multiple sclerosis.

In patients with multiple sclerosis (MS), conventional magnetic resonance imaging (MRI) has markedly improved our ability to detect the macroscopic abnormalities of the brain and spinal cord. New quantitative magnetic resonance (MR) approaches with increased sensitivity to subtle normal-appearing white matter (NAWM) and grey matter changes and increased specificity to the heterogeneous pathological substrates of MS may give information complementary to conventional MRI. Magnetization transfer imaging (MTI) and diffusion-weighted imaging (DWI) have the potential to provide important information on the structural changes occurring within and outside T2-visible lesions. Magnetic resonance spectroscopy (MRS) adds information on the biochemical nature of such changes. Functional MRI might quantify the efficiency of brain plasticity in response to MS injury and improve our understanding of the link between structural damage and clinical manifestations. The present review summarizes how the application of these MR techniques to the study of MS is dramatically changing our understanding of how MS causes irreversible neurological deficits.

Central Nervous System↗

PubMed1991

[Changes in the responses of motor units to transcranial magnetic stimulation in patients with multiple sclerosis and stroke].

In multiple sclerosis and stroke the muscle responses to transcranial magnetic stimulation are frequently delayed, reduced in amplitude or absent. To investigate the underlying pathophysiological mechanisms, responses of single motor units to transcranial magnetic stimulation were analysed using peri-stimulus time histograms. The following response patterns were detected: 1. prolongation of latency and duration of the primary peak which occurs in healthy controls 17 to 30 ms after the stimulus and has a duration of 2 to 8 ms, 2. lack of an excitatory response, 3. prolongation of the interval between sub-peaks within the primary peak and 4. multimodal responses. Possible mechanisms for these changes are: reduction and dispersion of conduction velocities in corticospinal axons associated with impaired summation of excitatory post-synaptic potentials at the spinal motoneurone, frequency-dependent or complete conduction block in corticospinal neurones and compensatory activation of other descending motor pathways.

Adult↗

PubMed1992

On the immunopathology of multiple sclerosis lesions.

Active chronic multiple sclerosis (MS) lesions contain numerous T-200 and leukocyte function associated antigen (LFA)-1-positive infiltrating cells. Macrophages at the lesion edge are stained for immunoglobulins (Ig), Class I and Class II major histocompatibility complex (MHC) antigens, for interferon (IFN)-alpha and for the beta-2 integrin adhesion molecule gp 150/95. In the periplaque area, numerous CD2, CD4, and CD8 positive T cells and cells reactive for the CD45RO phenotype of memory cells and for gamma/delta T cell receptors are located between MHC-positive glial cells. White matter at the edge is diffusely stained for intercellular adhesion molecule (ICAM)-1 and LFA-3. Remote from lesions, labeling for Class II MHC, ICAM-1 and LFA-3 was enhanced on some endothelial and glial cells. These findings indicate that adhesion molecules are involved in the formation and possibly also in the reactivation of MS lesions.

Antigens, CD↗

PubMed1990

Preliminary trial of 3,4-diaminopyridine in patients with multiple sclerosis.

Ten patients with multiple sclerosis (MS) were enrolled in a preliminary trial of the potassium channel blocker, 3,4-diaminopyridine, to evaluate drug toxicity and pharmacokinetics. The patients were treated with oral 3,4-diaminopyridine, first with increasing single doses up to 100 mg and then with divided dosage for up to 3 weeks. Paresthesias were reported by all patients and abdominal pain was dose limiting in 6 patients. 3,4-Diaminopyridine levels and half-life varied widely from patient to patient. Cerebrospinal fluid levels of 3,4-diaminopyridine were about 10% of those in serum. Neither seizures nor epileptiform changes on electroencephalographic examination occurred. Small reversible improvements in specific neurological deficits were seen on examination in all patients and reversible improvement in visual evoked response latencies were found in 2 patients. These results suggest that further study of 3,4-diaminopyridine in patients with MS is warranted.

4-Aminopyridine↗

PubMed2001

Subjective complaints, verbal fluency, and working memory in mild multiple sclerosis.

Patients with mild multiple sclerosis (MS) regularly report subjective complaints characterized by generalized cognitive inefficiency. A feature of these complaints is reduced verbal fluency, for example, losing the thread of conversation. Mild MS patients and controls were compared on subjective complaints, verbal fluency, and working memory, and the possible role of working memory was investigated. As predicted, subjective difficulties and verbalfluency each correlated with working memory. Subjective difficulties and verbal fluency were also related. Within the control group, the subjective difficulties were associated only with depression. On the other hand, in the MS group, subjective difficulties were unrelated to affective state but were correlated with working memory. For the patients, partialing out depression and anxiety did not influence any of the correlations involving subjective difficulties, verbal fluency, or working memory. These findings support the proposal that working memory impairment underlies subjective complaints of mild MS patients and that verbal dysfluency is part and parcel of this phenomenon.

Adult↗

PubMed2005

Association of multiple sclerosis with ILT6 deficiency.

Multiple sclerosis (MS) is an autoimmune disorder of multifactorial etiology. Family studies have shown strong genetic contributions. Linkage analyses have revealed several regions harboring risk genes including chromosome region 19q13. ILT6 is one of the most interesting candidate genes, since ILTs are involved in the generation of immunological tolerance. There is an absence/presence of variability of the ILT6 gene comprising several exons, thus incapacitating the gene function. In the present study, we examined the association of ILT6 deletion with MS. Using PCR typing, deficiency of ILT6 was examined in 607 blood donors and in 751 Caucasian German, as well as 89 French MS patients. Homozygous ILT6 deficiencies were significantly more prevalent in MS patients (7.1%) than in blood donors (3.8%; P=0.009). ILT6 deficiency is associated with MS in the German population and hence a likely risk factor for autoimmune disorders.

Chromosomes, Human, Pair 19↗

PubMed1992

Primary Sjögren's syndrome in patients with multiple sclerosis.

The relationship between multiple sclerosis (MS) and primary Sjögren's syndrome (PSS) is ambiguous; it was suggested that some patients diagnosed with MS may instead have PSS. In a recent epidemiologic study, the prevalence of PSS was 2.7% in southern Sweden. We randomly selected 30 patients with definite MS from our patient population and investigated them for evidence of PSS according to the Copenhagen criteria. One patient had clinical symptoms compatible with PSS and also fulfilled the Copenhagen criteria. In addition, five patients had keratoconjunctivitis sicca, one had xerostomia, and three had histopathologic evidence of sialadenitis in the lower lip salivary glands. However, one of these findings alone is not sufficient to support the diagnosis of PSS. We conclude that MS and PSS may coexist in the same individual, but PSS is not more common among MS patients than expected in the general population.

Antibodies, Antinuclear↗

PubMed1992

T cell vaccination in multiple sclerosis: a preliminary report.

Multiple sclerosis (MS) is a presumed autoimmune disease of the central nervous system. Inoculation of attenuated T cell clones recognizing immunodominant regions of myelin autoantigens can protect animals from the induction of experimental autoimmune diseases. In this phase one trial, we investigated whether inoculations with attenuated T cell clones are feasible in humans for eventual trials with autoreactive clones and whether there are any associated immunologic effects. A total of seven inoculations with attenuated, autologous T cell clones isolated from the cerebrospinal fluid in four subjects with progressive MS was performed. No untoward side effects were observed. Immunologic studies suggested that the inoculation of autologous activated T cell clones followed by partial, short-term, immunosuppression as evidenced by a decrease of subsequent responses to stimulation via the CD2 pathway and increases in the autologous mixed lymphocyte response. We conclude that the use of attenuated autoreactive T cell clones appears feasible for further clinical trials in humans with autoimmune diseases.

Clone Cells↗

PubMed2001

Herpesvirus and multiple sclerosis.

Evidence suggests that multiple sclerosis (MS) is caused by host genetic factors in association with one or more environmental agents. The clinical and pathological features of MS implicate viral infections as either cofactors in its aetiology or triggers of relapses, although no specific environmental factors have been identified. In particular, several herpesviruses have attracted interest because their ability to cause latent infections that periodically reactivate has some familiarity with the relapsing-remitting course of MS. Further, most human herpesviruses can be readily found within the central nervous system and several are known to be capable of inducing demyelination, both in humans and in experimentally infected animals. This brief review takes a systematic look at reported associations between herpesviruses and MS and suggests some criteria that must be met in further studies. One of the greatest challenges in confirming or refuting a role for herpesviruses in chronic diseases is their ubiquitous nature. It is stated from the outset that the associations described here remain controversial.

Antiviral Agents↗

PubMed1984

Imbalance in recruitment of IgG (Gm) allotype-producing B-cell subsets from blood to brain in multiple sclerosis.

In Gm3/Gm3 homozygous multiple sclerosis (MS) patients, in vitro production of the G1m(3) allotype of IgG1 induced by the T-independent polyclonal B-cell activator Salmonella paratyphi B (SPB) was lower than that of normal individuals of the same Gm phenotype. In contrast, lymphocytes from Gm1/Gm3 heterozygous MS patients responded to the same stimulus with a significantly increased G1m(3) allotype synthesis not observed in normal individuals of the same phenotype. The high level of intrathecal IgG1 production observed in MS patients might be achieved by a selection at the blood-brain barrier of some peripheral T-independent B-cell clones which in Gm3/Gm3 homozygous would bear the G1m(3) allotype, hence a peripheral depletion of this subset, whereas in Gm1/Gm3 heterozygous a preferential admission of the G1m(1)-producing B-cells would lead to a preferential synthesis of this allotype in the central nervous system and to a relative increase of G1m(3) production by the remaining peripheral B cells.

B-Lymphocytes↗

PubMed1992

[11th International Histocompatibility Workshop 1991: Personal data for the Multiple Sclerosis Study].

In our multiple sclerosis (MS) study as a part of the 11th IHWS we HLA-typed 6 MS families with 9 patients and defined the complement polymorphisms (BF, C2, C4) of these families. The aims of the study were the definition of the MS susceptibility gene and the investigation of the involvement of other factors in the etiopathogenesis of MS. The MS study of the IHWS demonstrated a strong association with HLA-DRw15 and -DWw6 in a Caucasian population. The heterozygous C2 deficiency in our family PD1 linked with the haplotype A25 B18 DR2 BFS C4A4 C4B2 confirmed by complement titration may express the participation of complement factors in the etiopathogenesis of MS resulting in immunogenetic heterogeneity of MS. Analysis of the 3 MS pairs of sisters shows the linkage of HLA with the assumed MS susceptibility gene. This could not be confirmed in the whole MS family study of the 11th IHWS.

Chromosome Mapping↗

PubMed1981

Nuclear magnetic resonance imaging of the brain in multiple sclerosis.

Ten patients with multiple sclerosis (MS) were scanned by means of cranial X-ray computed tomography (CT) with and without intravenous contrast enhancement, and by nuclear magnetic resonance (NMR) using an inversion-recovery sequence. Altogether 19 lesions varying in size between about 7 mm X 5 mm and 13 mm X 8 mm were demonstrated by CT. They were all situated in the periventricular region. Two patients also showed moderate ventricular enlargement. In addition to these abnormalities 112 further lesions were demonstrated on the NMR scans. These lesions varied in size from 4 mm X 3 mm to 12 mm X 7 mm and were particularly well seen in the periventricular region and brainstem. Care is required in the assessment of NMR scans to exclude artefacts, background noise, and mottle as well as normally situated grey matter and partial volume effects from cerebral sulci. NMR nevertheless demonstrates abnormalities in MS on a scale not previously seen except at necropsy.

Adolescent↗

PubMed1994

The HLA-Dw2 haplotype segregates closely with multiple sclerosis in multiplex families.

Multiple sclerosis (MS) is associated with the HLA class II specificity Dw2, but the importance of its influence has been questioned, since sib-pair analysis has failed to show linkage with this haplotype. However, the use of 'identity by descent' (IBD) analysis may not be ideal, since it does not make use of the facts that (i) the Dw2-haplotype is the only haplotype with a confirmed role in MS, and (ii) it performs its influence in a dominant manner. We have investigated nine Swedish multiplex MS families. In eight of the families, the Dw2 haplotype occurred in MS patients. Within these families, Dw2 was shared by all 17 individuals with MS. In a compilation of 48 published multiplex MS families in which at least one patient carried Dw2, only three of 107 individuals with MS did not carry the Dw2 haplotype. This indicates that the Dw2 haplotype, when present in familial MS, may confer a stronger influence in MS susceptibility than generally recognized.

Genes, MHC Class II↗

PubMedDate not supplied

Nociceptive R3 reflex in relapsing-remitting multiple sclerosis patients.

Pain in multiple sclerosis (MS) patients has only recently been recognised as a genuine symptom of this disease. It is important to determine whether this pain is the consequence of another symptom of MS or whether it is due to a demyelinating lesion affecting pain pathways. A close relationship has been found between the R3 component of the blink reflex and the pain threshold. The aim of this work was to carry out an objective evaluation of the nociceptive system in MS patients by means of the R3 component of the blink reflex. The study was performed on 20 healthy volunteers and on 20 clinically defined relapsing-remitting MS patients with EDSS not > 3.5, normal R1 and R2 components of the blink-reflex, personal and family anamnesis negative for migraine and trigeminal neuralgia; the patients were not taking drugs at the time of the test. A significant difference was found, between healthy volunteers and patients, for R3 threshold, pain threshold and R3 latency.

Adult↗

PubMed1998

A gliotoxic factor and multiple sclerosis.

The pathogenesis of multiple sclerosis (MS) is unknown. Searching for possible toxic factors, it was found that 3-day exposure to heat-treated cerebrospinal fluid (CSF) from MS patients caused apoptotic death of astrocytes and oligodendrocytes, but not fibroblasts, myoblasts, Schwann cells, endothelial cells and neurons, in vitro. CSFs from other inflammatory or non-inflammatory neurological diseases showed no toxicity. Exposure of these glial cells to partially purified MS CSF produced DNA fragmentation, apoptotic bodies, chromatin condensation, cell shrinkage, and changes in the levels of known cytokines. A cytotoxic factor, called gliotoxin, was characterized chromatographically as a stable 17-kDa glycoprotein. Since this protein is highly cytotoxic for astrocytes and oligodendrocytes, it may represent an initial pathogenic factor, leading to the neuropathological features of MS, such as blood-brain barrier involvement and demyelination.

Animals↗