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Several drugs are now available to treat multiple sclerosis. MS treatment has included immunomodulatory agents for 15 years; monoclonal antibody therapies have recently been added. IFN beta and Glatiramer acetate are effective in reducing relapses and lesions visible on magnetic resonance imaging (MRI) in patients with MS. Natalizumab, a monoclonal antibody, reduces the short-term risk of increasing disability and the rate of clinical relapse in patients with relapsing MS. Clinical trials are currently underway to assess the efficacy of other monoclonal antibodies and immunosuppressors. In the future, remyelinating and neuroprotective approach offers new perpectives., (Copyright (c) 2009 Elsevier Masson SAS. All rights reserved.)

Multiple sclerosis (MS) is the most common chronic inflammatory neurologic disorder diagnosed in young adults and, due to its chronic course, is responsible for a substantial economic burden. MS is considered to be a multifactorial disease in which both genetic and environmental factors intervene. The well-established human leukocyte antigen (HLA) association does not completely explain the genetic impact on disease susceptibility. However, identification and validation of non-HLA-genes conferring susceptibility to MS has proven to be difficult probably because of the small individual contribution of each of these genes. Recently, associations with two single nucleotide polymorphisms (SNPs) in the IL2RA gene (rs12722489, rs2104286) and one SNP in the IL7RA gene (rs6897932) have been reported by several groups. These three SNPs were genotyped in a French and a German population of MS patients using the hME assay by the matrix-assisted laser desorption/ionization time of flight technology (Sequenom, San Diego, CA, USA). We show that these SNPs do contribute to the risk of MS in these two unrelated European MS patient populations with odds ratios varying from 1.1 to 1.5. The discovery and validation of new genetic risk factors in independent populations may help toward the understanding of MS pathogenesis by providing valuable information on biological pathways to be investigated.

Interferons (IFNs) were considered for the treatment of patients with multiple sclerosis (MS) after the demonstration, based on small studies, of the efficacy of type IFN beta in decreasing the frequency of exacerbations in relapsing-remitting multiple sclerosis when administered intrathecally, subcutaneously, or intramuscularly. Three preparations of IFN beta are now approved in Europe and North America: chronologically IFN beta-1b (Berlex/Schering), IFN beta-1a given intramuscularly (Biogen), and IFN beta-1a given subcutaneously (Ares Serono). These treatments have now been in use for more than 10 years, and are supposed to decrease relapse rates. However a lot of questions remain unanswered: it is difficult to compare the various preparations; there remain controversies about the effects of different routes of administration and of different dosage preparations; the role of neutralizing antibodies remains partially understood; and the long term effect on disability has not yet been demonstrated.

We investigated the influence of age at disease onset on timing of the progressive phase in 957 patients with multiple sclerosis (MS). Age at onset powerfully predicts the probability of developing a primary progressive form of the disease. Moreover, age at onset strongly determines the time to conversion to secondary progression for patients presenting with a relapsing form. This suggests that age at onset strongly influences the neurodegenerative component of MS.

Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disorder. Despite substantial evidence for polygenic inheritance of the disease, the major histocompatibility complex is the only region that clearly and consistently demonstrates linkage and association in MS studies. The goal of this study was to identify additional chromosomal regions that harbor susceptibility genes for MS. With a panel of 390 microsatellite markers genotyped in 245 U.S. and French multiplex families (456 affected relative pairs), this is the largest genomic screen for MS conducted to date. Four regions met both of our primary criteria for further interest (heterogeneity LOD [HLOD] and Z scores >2.0): 1q (HLOD=2.17; Z=3.38), 6p (HLOD=4.21; Z=2.26), 9q (HLOD; Z=2.71), and 16p (HLOD=2.64; Z=2.05). Two additional regions met only the Z score criterion: 3q (Z=2.39) and 5q (Z=2.17). Further examination of the data by country (United States vs. France) identified one additional region demonstrating suggestive linkage in the U.S. subset (18p [HLOD=2.39]) and two additional regions generating suggestive linkage in the French subset (1p [HLOD=2.08] and 22q [HLOD=2.06]). Examination of the data by human leukocyte antigen (HLA)-DR2 stratification identified four additional regions demonstrating suggestive linkage: 2q (HLOD=3.09 in the U.S. DR2- families), 6q (HLOD=3.10 in the French DR2- families), 13q (HLOD=2.32 in all DR2+ families and HLOD=2.17 in the U.S. DR2+ families), and 16q (HLOD=2.32 in all DR2+ families and HLOD=2.13 in the U.S. DR2+ families). These data suggest several regions that warrant further investigation in the search for MS susceptibility genes.

Multiple sclerosis (MS) is a demyelinating autoimmune disease with a strong yet complex genetic component. To date only the HLA-DR locus, and specifically the HLA-DR15 allele, has been identified and confirmed as influencing the risk of developing MS. Genomic screens on several datasets have been performed and have identified several chromosomal regions with interesting results, but none have yet been confirmed. We tested seven of the most-promising regions (on chromosomes 1p, 2p, 3p, 3q, 5q, 19q, and Xp) identified from several genomic screens in a dataset of 98 multiplex MS families from the United States and 90 multiplex MS families from France. The results did not confirm linkage to 2p, 3q, 5q, or Xp in the overall dataset, or in subsets defined by geographic origin or HLA-DR15 status. Regions on 1p34, 3p14, and 19q13 produced lod scores >0.90 in at least one subset of the data, suggesting that these regions should be examined in more detail.

The diagnosis of inflammatory optic neuritis remains essentially clinical, and may be improved by complementary investigations. The prognosis is related to the evolution of visual acuity and the risk of development of multiple sclerosis. The treatment of acute episodes is better precised but remains a matter of debate. Long term treatment has benefited from the results of recent MRI studies.

GENERAL DATA: The clinical manifestations and neuropathological signs of multiple sclerosis have been recognized for more than one hundred years, but the cause remains unknown., Epidemiology: Multiple sclerosis is not evenly distributed throughout the world. There is an important north-south gradient in the northern hemisphere and inversely in the southern hemisphere; multiple sclerosis is more frequent in the higher altitudes. For a given latitude, there is a difference by ethnic origin. These observations indicate that multiple sclerosis is a multifactorial condition determined by both genetic and environmental factors., Strategies of Genetic Studies: Progress in our knowledge of the human genome and statistical analysis techniques have made it possible to search for genetic factors in multiple sclerosis using two complementary approaches. The first is by anonymous screening and the second is to search for a candidate gene. The HLA locus is the only one with an identified predisposing effect for multiple sclerosis. It only accounts for 10 to 20% of the genetic predisposition for multiple sclerosis and many factors remain to be discovered.

We have analyzed with localized proton magnetic resonance spectroscopy (MRS) 31 lesions in 28 patients with multiple sclerosis (MS). The course of the disease was either relapsing remitting, secondary progressive, or primary progressive. Four patients had an isolated neurological syndrome suggestive of MS. The decrease in the NAA/Cre ratio and the raise of the Cho/Cre ratio were more pronounced in patients with an acute isolated neurological syndrome, suggesting the predominance of an inflammatory process, and the presence of an axonal dysfunction in the initial course of the lesion. The NAA/Cre ratio was negatively correlated with clinical disability and thus could be used as an index of disease activity. Patients with a secondary progressive course exhibited a significant increase in the Myo/Cre ratio compared to those with a relapsing remitting course. Thus, there may be an association between the evolution towards a progressive disease and axonal loss or the development of gliosis. The isointense lesions to the cerebrospinal fluid on MRI T1 weighted sequences were characterized by a sharp raise in the Cho/Cre ratio suggesting demyelination and/or intense inflammation. Gadolinium enhanced lesions were not characterized by a specific neurochemical profile.

Magnetic resonance spectroscopy allows in vivo neurochemical exploration of multiple sclerosis (MS) lesions and normal appearing white matter on MRI. It gives insights into pathophysiology: inflammation (increase of choline), recent demyelination (increase in lipids and choline), axonal dysfunction (decrease of NAA), gliosis (increase of myoinositol). The spectroscopic profile of lesions is not specific to MS. Therefore MRI remains the first investigation to perform when MS is suspected. However, spectroscopy is a sensitive, reproducible, non invasive tool which may provide an index of activity. In the future, spectroscopy may contribute in homogenizing patient selection for clinical trials and might be used, in association with MRI, to evaluate therapeutic efficiency. Spectroscopy might also influence therapeutic choices by identifying the prevailing lesional mechanism: inflammation, demyelination, axonal destruction, or gliosis.

The immune system is involved in the pathophysiology of multiple sclerosis (MS) but the initiating antigen(s) is not yet identified. Since cytokines control both the intensity and the quality of the immune response they may be relevant candidates for the genetic susceptibility to MS. To analyze the contribution of type 1 and type 2 cytokine and cytokine receptor genes in the genetic susceptibility to MS, we have examined, in 116 French MS sibpairs, whether there is significant linkage between MS and 15 cytokine or cytokine receptor genes using 31 highly polymorphic genetic markers. The data were analyzed using the maximum likelihood score and the transmission disequilibrium approaches. None of the candidate genes tested was significantly linked to MS on the whole population. However, after stratification of the analysis on the basis of sharing (or not) of the HLA-DRB1*1501 allele, indication of linkage was found for the IL2-RB gene. These findings suggest that the IL2-RB locus contributes to the genetic susceptibility in a subgroup of MS patients.

Recently, genome-wide searches for multiple sclerosis (MS) susceptibility genes have suggested that the chromosome 17q22-q24 region might contain susceptibility genes in two sets of families of different ethnic backgrounds (Finnish and British). Therefore, we decided to test this region in two sets of families of different ethnic backgrounds (American and French), but collected according to the same diagnostic criteria. All lod-score values were non-significant. Moreover, we could exclude that the 17q22-24 region might contain a gene increasing the sibling recurrence risk of MS over 1.4, rendering the existence of such a gene very unlikely, at least in the group of tested families.

We investigated neurochemical abnormalities in the normal-appearing white matter (NAWM) on MRI of patients with optic neuritis (ON) and compared them to those of patients with multiple sclerosis (MS). Patients with ON (42) were classified into three groups according to abnormalities on brain MRI. Patients with MS (55) were divided in two groups: relapsing remitting MS (RRMS) and secondary progressive MS (SPMS). All patients underwent MRI of the brain and localised proton magnetic resonance spectroscopy (MRS) of NAWM. The results were compared to those of 15 controls. Patients with MS had significant abnormalities compared with controls and with patients with ON. Patients with RRMS and those with ON had comparable MRS parameters, while patients with SPMS had significant spectroscopic abnormalities in comparison with controls, but also with patients with RRMS. These changes consisted of a decrease in N -acetylaspartate, a neuronal marker, which may reflect axonal dysfunction and/or loss. MRS abnormalities were detected in 14 patients with ON (27 %). The main abnormalities consisted of a decrease in N -acetylaspartate, an increase in choline-containing compounds at long echo times, and the presence of free lipid peaks at short echo times. MRS of the NAWM on MRI may prove useful for detecting neurochemical brain abnormalities in ON not visible on MRI.

Objective: To determine the efficacy of MRS in discriminating between relapsing remitting (RR) and secondary progressive (SP) MS., Methods: MRS at long and short echo times was carried out in 104 patients with MS stratified for clinical course (RR or SP), and the results were compared with those of 15 control subjects. Normal-appearing white matter (NAWM) was studied in 55 patients, and a high-T2-signal area on MRI in 49 others., Results: At long echo times, there was a highly significant decrease in the ratios N-acetyl-aspartate/creatine (NAA/Cr) and NAA/ choline (Cho) in high-T2-signal areas and in the NAWM in patients with an SP course compared with control subjects and patients with an RR course. There was a significant negative correlation between these ratios and clinical disability measured by Expanded Disability Status Scale score, which was independent of disease duration. Discriminant values between patients with RR and SP courses were found in the NAWM (NAA/Cr = 1.75 and NAA/Cho = 1.5), but not in high-T2-signal areas. At short echo times, there was a significant increase in the ratio myoinositol/Cr in high-signal areas of patients with an SP course compared with control subjects, and the presence of abnormal resonances in the lesions and NAWM for free amino acids and lipids (in 30% and 8%, respectively) and GLX complex (glutamine, glutamate, gamma-aminobutyric acid; 16% and 20%, respectively)., Conclusions: Studying normal-appearing white matter on MRI with MRS allows discrimination between relapsing remitting and secondary progressive patients. In the NAWM of patients with MS and an SP course, severe axonal loss/dysfunction is negatively correlated to clinical disability and independent of the duration of the disease.

Objective: To describe clinical and MRI features of patients with a disease suggestive of CNS inflammation after hepatitis B vaccination., Methods: Eight patients with confirmed CNS inflammation occurring less than 10 weeks after hepatitis B vaccination are described. They received follow-up clinically and on MRI for a mean period of 18 months., Results: Clinical and MRI findings were compatible with acute disseminated encephalomyelitis. However, clinical follow-up, repeated MRI, or both showed the persistence of inflammatory activity, which makes this encephalitis more suggestive of MS than of acute disseminated encephalomyelitis., Conclusion: The persistent inflammatory activity observed clinically and on MRI in these patients is comparable with that usually observed in MS. Epidemiologic studies are currently testing the hypothesis of a triggering role of hepatitis B vaccination in CNS demyelination.

Background: Both genetic and environmental factors play a role in the pathophysiology of MS and may influence the clinical expression of the disease., Objective: To determine the contribution of familial factors to the clinical expression of MS., Methods: The French Multiple Sclerosis Genetics Group identified 87 sibling pairs. For each patient, sex, age at onset, duration of the disease, and disease course from onset were recorded. Disability was determined by the progression index (PI), defined as the ratio of the Expanded Disability Status Scale (EDSS) score disease duration when the latter exceeded 5 years. Statistical analyses were performed either with a group of patients (clinical features, relation between human leukocyte antigen and clinical features) or with a group of sibpairs (concordance for clinical features)., Results: The mean age at onset was 29.6 years, the ratio of women to men was 59:28, and the mean PI was 0.27. There was no correlation for disease course and age at onset between sibs with MS. In contrast, we observed a weak but significant correlation of the PI in MS sibpairs (r = 0.234, p = 0.03)., Conclusion: This study revealed a concordance in MS sibling pairs for the disease severity, supporting the hypothesis that the degree of disability might be partly influenced by familial factors (environmental or genetic).

Objective: To test 23 genes coding for growth factors and their receptors as candidates for MS genetic susceptibility in 84 multiplex families of French origin by linkage analysis., Background: Epidemiologic studies have indicated that genetic susceptibility in MS exists. To identify MS susceptibility genes, association and linkage studies were performed with candidate genes suggested by the pathology of MS. The most consistent result was genetic association and linkage of MS to human leukocyte antigen (HLA) DR15. Recent advances in the knowledge of MS pathology have suggested that the oligodendrocyte, the myelin-forming cell in the CNS, and its growth factors might play a crucial role in MS., Methods: Fifty-two polymorphic markers within or flanking 23 candidate genes were used. Data were analyzed with the maximum likelihood score (MLS) approach. We also searched for a genetic interaction with HLA., Results: Negative results were obtained for all candidate genes. The lower limits of the relative risk (Xs) possibly excluded for any candidate gene ranged from 1.3 to 2.8. Positive MLS values (up to 0.93) were observed for transforming growth factor beta 3 (TGFbeta3) in HLA DR15-associated families, suggesting a possible role for this growth factor in interaction with HLA., Conclusions: Oligodendrocyte growth factors do not play a significant role in MS genetic susceptibility, at least in the tested sample. TGFbeta3, the only gene highlighted by this study, deserves further analysis.

Apolipoprotein E (apo E) is postulated to be a major lipid carrier protein in the brain involved in brain development and repair. Multiple sclerosis (MS) is a major demyelinating disease characterized by destruction of myelin and marked alteration of myelin cholesterol and lipid metabolism. We have determined serum and cerebrospinal fluid (CSF) apo E concentrations using an original time-resolved immunofluorometric assay and calculated intrathecal apo E concentration. Apo E concentrations were determined in 13 control subjects and 129 neurological patients: 34 definite MS patients, 25 with Guillain-Barré syndrome (GBS), 32 with amyotrophic lateral sclerosis (ALS) and 38 with other neurological diseases. Seven clinical parameters (sex, age, age at MS onset, duration of the disease, course, clinical status and disability score) were considered in MS patients. Significant (P < 0.01) decrease in CSF apo E was observed in MS, linked to a decrease in intrathecal apo E. The decreased CSF apo E concentration in MS patients occur independent of the apo E genotype. Apo E is considered as a neurotrophic factor in the brain. Any decrease in intrathecal apo E synthesis would thus contribute to progression of neurological diseases, such as MS.

To better characterize the cellular immune response taking place in the MS central nervous system, we investigated the blood and CSF T cell receptor (TCR) V beta 5 and V beta 17 repertoire in HLA-typed patients with recently diagnosed MS or other neurological diseases (OND). Using a RT-PCR based technique, we analysed directly ex vivo the CDR3 size of TCR beta chains utilizing V beta 5 (eight patients with MS and one with OND) or V beta 17 (eight patients with MS and six with OND) gene segments on paired blood-CSF samples. Globally, the analysis of V beta 5-J beta and V beta 17-J beta repertoire showed a less diverse pattern in the CSF samples than in the corresponding peripheral blood lymphocytes both in MS and in OND patients. However, we did not detect any recurrent clonal expansion within the V beta 5+ T cells in MS patients, underlining the potential limits of V beta 5-based immunotherapy in MS. We found an expanded T cell population using the same V beta 17-J beta 1.6 combination with identical CDR3 length in the CSF of three MS patients and none of the control patients. These results suggest selective expansion of T cells expressing this segment gene in the MS central nervous system.

Objectives: To evaluate in patients with multiple sclerosis (MS) the occurrence of clinical systemic signs and biological autoimmune abnormalities, including positive titers of antinuclear antibodies and antiphospholipid antibodies, suggestive of autoimmune diseases that may affect the central nervous system. Also, to compare the clinical and magnetic resonance imaging features and evolution of MS in patients with and without autoimmune abnormalities., Design and Patients: Prospective study of 161 patients fulfilling the criteria of having probable or definite MS hospitalized in our institution between November 1990 and June 1992., Results: Among the 161 patients, 84 (52.1%) had at least 1 clinical and/or biological general sign suggestive of an autoimmune disease; 64 were followed up for 4 to 5 years. The diagnosis of MS was confirmed in 50 patients and is still pending in 14 of them. No significant difference was found between patients with MS who were free of autoimmune features and those with autoimmune abnormalities (MS plus) concerning the age of disease onset, the presenting symptoms and signs, symptoms found on neurologic examination, and the course of the disease. For all patients with confirmed MS, general signs were found in 13.3%, positive titers of antinuclear antibodies in 26%, and positive titers of antiphospholipid antibodies in 6.2%., Conclusions: Patients with MS with autoimmune features, including those with titers of antinuclear antibodies of 1:100 or less and/or antiphospholipid antibodies, are not different than others with MS, and therefore should not be excluded from clinical trials.

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.

In investigating a possible link between a novel retroviral agent (provisionally called MSRV), recently characterised in multiple sclerosis (MS), and the neuropathology of MS, it was found that there was a significant correlation between gliotoxicity and reverse transcriptase activity in monocyte/macrophage culture supernatants (MMCS) unique to MS patients. MMCS from healthy controls and patients with other neurological diseases did not display either gliotoxicity or reverse transcriptase activity. The observed gliotoxic effect was an initial, intermediate filament network disorganization and subsequent cell death which was specific to astrocytes and oligodendrocytes. The reverse transcriptase activity and MSRV-specific RNA were observed during the first 2 weeks of culture in MMCS from patients with active MS. The further elucidation of the molecular form(s) of this gliotoxic factor and its original source may be crucial in elucidating important etiopathogenic mechanisms in MS.

Objective: To evaluate the efficiency of mitoxantrone in multiple sclerosis., Methods: Forty two patients with confirmed multiple sclerosis, selected as having a very active disease on clinical and MRI criteria were randomised to receive either mitoxantrone (20 mg intravenously (IV) monthly) and methylprednisolone (1 g iv monthly) or methylprednisolone alone over six months. In the steroid alone group five patients dropped out due to severe exacerbation., Results: Blinded analysis of MRI data showed significantly more patients with no new enhancing lesions in the mitoxantrone group compared with the steroid alone group, (90% v 31%, P < 0.001). In the mitoxantrone group there was a month by month decrease almost to zero in the number of new enhancing lesions, and in the total number of enhancing lesions, whereas both remained high in the steroid alone group. The differences were significant for both indices at all months from 1-6. Unblinded clinical assessments showed a significant improvement in change in EDSS at months 2-6 in the mitoxantrone group, with a final mean improvement of more than one point (-1.1 v + 0.3; P < 0.001). There was a significant reduction in the number of relapses (7 v 31; P < 0.01), and an increase in the number of patients free of exacerbation (14 v 7; P < 0.05)., Conclusion: In this selected group of patients with multiple sclerosis with very active disease, mitoxantrone combined with methylprednisolone was effective in improving both clinical and MRI indices of disease activity over a period of six months whereas methylprednisolone alone was not. Further double blinded long term studies are needed to properly evaluate the effect of mitoxantrone on progression in disability.

We used a rapid long TE proton magnetic resonance spectroscopic (MRS) sequence in the normal appearing white matter of 11 patients with definite multiple sclerosis (MS) localizing the volume of interest in the centrum semi-ovale. The metabolic changes were compared to the same area in 11 normal brains. We found a significant decrease in NAA/Cr ratios and a borderline significance of increase in Cho/Cr ratios in patients with MS. A discriminant analysis was performed on these data. This allowed to obtain a simple ratio, NAA/(Cho+Myo), which discriminated MS patients from controls. Our results indicate that normal appearing white matter on MRI is biochemically abnormal in patients with MS. In addition MRS could be routinely used after a standard MRI examination in patients with MS for clinical correlations, total load of the disease assessment and monitoring clinical trials.

Multiple sclerosis in a disease of the central nervous system characterized by perivascular and periventricular lesions of the myelin and immune cell infiltrates and increased permeability of the blood-brain barrier. We have found a cytotoxic factor of the cerebrospinal fluid (CSF) specific for multiple sclerosis patients which has 2 main characteristic effects in vitro on primary or immortalized astrocyte cultures: (1) disruption of the gliofilament network of the cells; and (2) apoptotic cell death induction. Moreover, in vivo, intraventricular injections of minute amounts of partially purified gliotoxic factor in adult rats have striking effects on both the morphology and general organization of astrocytes in the entire brain and the permeability characteristics of the blood brain barrier, which becomes leaky to immunoglobulins. These pathological effects are strongly similar to some of the neuropathological findings reported during the course of MS--They suggest an entirely new hypothesis to explain the active stage of the disease: the presence of a new factor of unknown extrinsic (viral) or intrinsic (cellular) origin, able to disorganize the glial cytoskeleton and glial cell differentiation. This factor is then able to provoke glial cell death. Such glial cell death may result in both demyelination and increased blood brain barrier permeability. Both in vitro and in vivo studies strongly support the idea that this gliotoxic factor plays a central role in the pathogenesis of MS, making its full identification a critical theme for MS research.

During the past 10 years, considerable attention has been devoted to cognitive impairment in multiple sclerosis. Occasionally this impairment may be so severe that multiple sclerosis presents as a dementia associated with only minor neurological signs and symptoms. The cases of two women affected by multiple sclerosis who presented with a pure dementia are reported. In the first patient, a progressive apragmatic behavioural disturbance with reduced short term memory and learning abilities were the main clinical features. Neuropathological examination of the brain disclosed numerous plaques in the periventricular white matter, with severe atrophy of the corpus callosum. Plaques were also seen in the white matter of both hippocampus and in the columns of the fornix. The impairment of short term memory could be linked to these lesions. Behavioural changes were probably related to the bilateral lesions of the long associative bundles that disconnected the frontal lobes from other parts of the cerebral hemispheres. In the second patient, visual hallucinations were associated with cognitive dysfunction. MRI showed large plaques in the white matter of both left frontal and temporal lobes. Smaller plaques were also present in the periventricular white matter of the occipital lobes, the nature of which were confirmed by a stereotactic biopsy.

To investigate functional and anatomical features of callosal involvement in multiple sclerosis (MS), performances of 90 patients with definite MS and 25 matched normal control subjects were compared on three tasks exploring interhemispheric transfer of auditory, sensory, and motor information: a verbal dichotic listening task, a crossed tactile finger localization task, and an alternate finger tapping task. Each patient also underwent a magnetic resonance imaging (MRI) scan (1) to appreciate the extent of white-matter changes by a semiquantitative evaluation of hemispheric brain MRI hyperintensities and (2) to measure the degree of total and regional callosal atrophy using an automatized method of partition of the midsagittal callosal area. Interhemispheric transfer and/or integration was impaired in patients with MS for all modalities explored and proportional to both degree of callosal atrophy and diffusion of white-matter lesions. Moreover, in good agreement with data obtained from partial commissurotomy studies, performance on each functional task was predominantly associated with atrophy of one part of the callosum, namely left-ear dichotic suppression with the posterior callosal region, alternate finger tapping with the anterior region, and cross-localization with midanterior and posterior regions. Finally, a subgroup of patients without MRI white-matter hyperintensities also showed significant impairment of callosal function and relative atrophy of the callosum. These findings suggest the potential clinical value of callosal involvement in MS and the usefulness of MS as a model of interhemispheric disconnection.

Numerous immune abnormalities have been described in multiple sclerosis, including dysfunction of humoral, cellular and non specific immunity. The main abnormality probably concerns suppressive T cell function. The decrease of this function could explain the breakdown of immunological tolerance towards myelin antigens. The primary responsibility of these abnormalities in the triggering of the disease has still to be demonstrated. Moreover, the antigenic target of immune dysfunction has not yet been determined. A better understanding of T cell traffic into the central nervous system and of the mechanisms of interactions between the T cells and the antigen on one hand, the T cells and the cells presenting antigen on the other hand, offer encouraging therapeutic possibilities.

Signs of cerebral disconnection, especially left ear suppression to dichotically presented verbal stimuli, have been reported in multiple sclerosis patients and found to be correlated to morphological atrophy of the corpus callosum on magnetic resonance imaging. To reinvestigate this issue, 26 patients satisfying criteria for definite multiple sclerosis were proposed 3 tasks aimed at evaluating interhemispheric function: a dichotic listening task, a motor finger-tapping task and a sensory transfer task. Performance at these tasks suggested impaired callosal function in MS patients, compared to normal controls. Callosal morphology was assessed on midsagittal MRI sections using a digitalised method of partition of the callosal area into 6 subregions and automatized surface measurements. Results of correlations between task performance and callosal areas showed a significant correlation between total callosal atrophy and severity of interhemispheric impairment on each functional task. Moreover, impaired motor transfer was specifically related to atrophy of the anterior callosal regions. These results suggest that MS patients may constitute a suitable population to studying interhemispheric transfer of information through the callosal commissure and that this approach may be useful in the clinical management of MS patients.

Multiple sclerosis definition is anatomical. Its symptomatology is not specific and 4 main criteria are necessary in order to obtain a diagnosis of certitude or of presumption: 1) dissemination of signs and symptoms in space and time; 2) respect of age; 3) the symptomatology must be the expression of lesions affecting mainly the white matter; 4) elimination of other possible diagnosis. CSF examination, evoked potential and NMR study may help to the diagnosis, but no abnormality is specific of multiple sclerosis.

The polymerase chain reaction was used, in a blind study, to look for retroviral sequences in DNA extracted from the peripheral blood mononuclear cells of 11 patients with the spinal form of multiple sclerosis (MS). Control subjects consisted of 7 patients with other neurological diseases and 5 healthy blood donors. Three sets of oligonucleotides were used. They could detect all known human oncoretroviruses, lentiviruses, or spumaretroviruses. The primers recognized conserved sequences in the long terminal repeats of the proviral DNA. Control experiments showed that the primers crossreacted within the human immunodeficiency virus or human T-cell lymphotropic virus group and that they provided the expected level of sensitivity. Therefore the assay could have detected not only known human retroviruses but also new related members. In spite of this, no retroviral sequences were detected in either the MS or the control specimen.

The interobserver variability of the expanded disability status scale (EDSS) was studied in 59 patients with multiple sclerosis (MS). Interrater agreement was measured by the kappa coefficient. Agreement was low in patients with mild disability (EDSS less than 5); it was higher in patients with EDSS equal to or greater than 5. The difference between ratings of 2 independent examiners was equal to at least 1 point in 34% of the MS cases. This variability must be taken into consideration in designing clinical trials in MS.

Cognitive evaluation of 6 cases of adult adrenoleukodystrophy (ALD) included in a brain magnetic resonance (MR) study are reported: 2 males with adrenomyeloneuropathy and 4 women heterozygous for ALD. Cognition was normal in 4 and MR scan in 2 of them. In the 2 others, there were mild modifications of the white matter. One patient suffered of visual retention disturbances with abnormalities of the white matter in MR scan. In the last, cognitive decline was observed; MR scan showed atrophy of cortex and corpus callosum and periventricular high signal areas. Comparison with leukoaraiosis in healthy adults and with multiple sclerosis suggests that there is probably a relationship between cognition and extension of brain MR abnormalities. Time of appearance and frequency of cognitive dysfunction might be explained by the natural history of each of these diseases.

MR T2 Weighted sequences on the brain demonstrate disseminated "high signal zones" (HSZ) in patients with Multiple Sclerosis; these morphological alterations are corresponding to the plaques. From the very beginnings of MR in 1981, everybody recognizes the main importance of this fact. MR appears as the most sensible exploration in patients with M.S. But the signal alteration is not specific; the clinical considerations and the evolution are requested. The aim of this work is to give a reference tool for evolutive evaluation of the disease. A work station with a specially developed software are presented. The HSZ thresholding is partially automatic. The edition of a cerebral mapping is developed. These results are discussed.

Among 70 pathologically proven MS cases, we found 12 cases with onset before 25. Only females were affected. There was no positive familial history of MS. In every case the diagnosis was considered during life. Mean duration of the disease was 29.1 +/- 12.5 years. This was significantly longer (p less than 0.001) than in the control group (58 pathologically proven cases with onset after 25). There were no acute courses. Progressive courses (1 case) and remittent courses (5 cases) were less frequent than in the control group (p less than 0.001 and p less than 0.01, respectively). The frequency of remittent-progressive courses (6 cases) was similar in both groups. The length of remittent-progressive courses (30.2 +/- 16.2) and remittent courses (28.6 +/- 9.7) was longer than that of control group (p less than 0.001). The symptomatology of onset was similar in both groups and had no predictive value for prognosis. The overall frequency of signs and symptoms was not statistically different in both groups. For each sign, the percentage of affected patients, throughout the course of the disease, was always smaller in early onset MS than in control group, except for optic neuritis which was as frequent in both groups. However, this was statistically significant only for ocular motricity and nystagmus.

The myelinotoxicity of sera from multiple sclerosis (MS) patients was determined by the assessment of visible myelin damage in guinea-pig spinal cord-spinal ganglia and in rat cerebella cultivated on collagen-coated coverslips in Leighton tubes. No change was seen in 22 cases. These data show that serum myelinotoxicity is low in MS - as compared with that of Experimental Allergic Encephalomyelitis. It appears a little specific phenomenon, the mechanism of which remains unclear. It can be easily assessed only in very sensitive culture techniques and is best measured by biochemical methods. This does not preclude the pathophysiological significance of the serum myelinotoxicity in MS. Supernatants of cerebro-spinal fluid (CSF) cell cultures in 10 MS patients caused no demyelination. Pooled concentrated supernatants of CSF cell cultures from 13 to 20 MS patients--containing from 7.3 to 11.7 micrograms IgG/ml gave no patent in vitro demyelination in 3 different experiments. The released products of CSF cell cultures in MS are not very toxic for myelin. However these experiments have to be repeated with more sensitive culture techniques, biochemical assay of myelinotoxicity and more concentrated CSF cultures supernatants.

Multiple Sclerosis (MS) cases found at autopsy in patients who had died from other diseases and in whom no sign or symptom could be related to MS are called "asymptomatic". Three cases are reported. The first patient was a 62 year old man who presented with a slowly progressive disturbance of gait, incontinence and deterioration of intellectual function. A falx meningioma was surgically removed. The patient died 3 years later with an acute respiratory illness. Examination of the brain disclosed evidence of the operation and numerous old plaques disseminated through the cerebral hemispheres (centrum semi-ovale, periventricular regions, internal thalamus and junction between cortex and white matter) and in the brain stem. The second case, a 77 year old woman with diabetes mellitus and hypertension, presented with cortical blindness and disturbances of memory of acute onset. She died one year later. Examination of the brain showed multiple infarcts involving the territories of both posterior cerebral arteries and the left middle cerebral artery. Numerous old plaques were seen in the periventricular regions, in the corpus callosum and in the left middle cerebellar peduncle. The third case, a 60 year old woman with mitral and aortic stenosis, presented with cortical deafness and transient right hemiparesis. She died 5 years later. Brain examination showed infarcts involving both middle cerebral artery territories. There was also many old plaques in the periventricular areas, thalamus, internal capsule, centrum semi-ovale, brain stem and right nucleus dentatus. In the 3 cases, the optic tracts were normal. The spinal cord, examined only in the first case, was also normal. The asymptomatic character of these MS cases can be explained first by the location of the plaques and the lack of spinal cord and optic tract involvement. It could also be due to the small size of the plaques and to axonal preservation. Such features are rare since our 3 observations have been selected from a pathological collection of 125 MS cases and 9,300 general neuropathological records. Six other cases have been previously reported by other authors.

Multiple sclerosis (MS) affects nearly 40 000 patients in France. Many factors are mixed up in the development of MS. Epidemiologic studies demonstrate the importance of environmental factors and some possible epidemics of MS in Faroe Islands and Iceland. Recent investigations in Orkney Islands present the hypothesis of two periods of peculiar vulnerability. In Caucasians, genetic investigations show the overpresentation of antigens HLA A3, B7, DR2-DW2. It is possible that remittent MS is related to B7, DW2, DR2 and progressive MS to DR3, B8 DR3, A1 B8 DR3. This distinctions could be also applied to response to immunosuppressive treatment. However, studies of familial MS suggest that only one gene is not able to induce susceptibility to MS. Interpretation of virologic studies is difficult; recent advances in virologic research (isolation, hybridization) will perhaps demonstrate the importance of viral components in MS. Interpretation of presence of myelin basic protein, antimyelin antibodies, anti-oligodendrocytes antibodies, antigangliosides antibodies, antibrain antibodies is also difficult because identification methods are in constant progress and it is not possible to know whether these antibodies are cause or only consequence of pathologic process. Lymphocytic populations studies demonstrate that immunoregulation is probably defective in MS and that T lymphocytes subpopulations fluctuate, according to the state of the illness. Variations of NK activity are discussed. MS lymphocyte production of interferon is probably decreased. Recent advances in neuropathologic studies, central nervous system tissue cultures and in experimental demyelination are summarized. Cultures of precursors of oligodendrocytes and their maturation in vitro, selection and culture of mature oligodendrocytes, their applications to MS oligodendrocytes are emphasized. The recent models of chronic experimental allergic encephalomyelitis (EAE), the prevention of EAE by interferon, basic protein, copolymer I have already place and implication in the comprehension and treatment of MS. Virologic models are also in important progress. Interests of evoked potentials, C.T. Scan and of nuclear magnetic resonance are discussed. Main therapeutic trends are emphasized. The underlying ethic problem of the choice of a therapy is discussed.