A full genome search in multiple sclerosis.

The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold over the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of lambda>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (non-significant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 chi2 = 10.8, adjusted P < 0.01)(DS2 and DS3 chi2 = 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.

Dirty-appearing white matter in multiple sclerosis: preliminary observations of myelin phospholipid and axonal loss.

"Dirty-appearing white matter" (DAWM) in multiple sclerosis (MS) is defined as a region(s) with ill-defined borders of intermediate signal intensity between that of normal-appearing white matter (NAWM) and that of plaque on T(2)-weighted and proton density imaging. To delineate the histopathology of DAWM, four formalin-fixed cerebral hemisphere slices of three MS patients with DAWM were scanned with T(2)- weighted and proton density sequences. The myelin water fraction (MWF) was obtained by expressing the short T(2) component as a fraction of the total T(2) distribution. Hemispheric sections were then stained with Luxol fast blue (LFB) for myelin phospholipids, for myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP) for myelin; Bielschowsky silver impregnation for axons; and for glial fibrillary acidic protein (GFAP) for astrocytes. Compared to NAWM, DAWM showed reduction in MWF, corresponding to a reduction of LFB staining. DAWM also showed reduced Bielschowsky staining. Quantitatively, the change in MWF in DAWM most consistently correlated with the change in LFB staining. The findings of this preliminary study suggest that DAWM is characterized by loss of myelin phospholipids, detected by the short T(2) component, and axonal reduction.

Field testing of a minimal record of disability in multiple sclerosis: the United States and Canada.

The IFMSS Minimal Record of Disability (MRD) in Multiple Sclerosis was field tested at eight medical centers in the U.S. and Canada. The goals were to conduct a qualitative and quantitative evaluation of the MRD. Assessment were completed on 249 patients with definite MS by neurologists and allied health professionals. Effective administration required some study and practice. Refinement of some unclear wording and awkward format will improve ease of administration. The MRD fit well into clinic routines and was accepted by staff and patients. Scoring presented few problems and these were related to overlap among the MRD scales, poor wording, and content not appropriate to MS. Quantitative evaluation of the MRD indicated that Incapacity Status primarily reflects disability in mobility and self-care when used as a composite score. Heterogeneity of content in Incapacity Status suggests that summed scores be used cautiously. Both Incapacity and Environmental Status had high levels of reliability and high correlations with established measures of impairment in MS. Inter-rater agreement of the ISS and ESS were also high. Once some necessary revisions are made, the MRD should be well on its way to achieving the IFMSS goal of developing a brief, reliable, valid, and appropriate instrument acceptable to a wide variety of workers in MS.

Empirical support for psychological profiles observed in multiple sclerosis.

Though increasing attention is being paid to psychological aspects of multiple sclerosis, much research continues to examine patients as differing in quantity rather than quality of psychological abnormality or response. Cluster analysis was used to identify distinctive psychological profiles in a large sample of patients with multiple sclerosis. It employed three measures, carefully chosen to capture the main responses historically observed in multiple sclerosis. These measures were (1) the patient's physical disability-impairment, assessed by a neurologist; (2) physical disability-impairment as perceived and reported by the patient; and (3) self-reported psychological well-being (or distress) independent of physical signs and symptoms. The optimal solution from the cluster analysis separated the 99 patients into 10 clusters, which were collapsed into four profiles, consistent with the labels "depression," "denial," "exaggerated somatic," and "severity-related." These data give strong empirical support to the existence of discrete and distinctive coping styles in multiple sclerosis.

Temporal lobe involvement in multiple sclerosis patients with psychiatric disorders.

Patients with multiple sclerosis (MS) frequently develop psychiatric disturbances. The clinical histories and magnetic resonance imaging results from eight patients with MS and psychiatric disorders were compared with those from eight control MS patients matched for age, sex, duration and severity of illness, and clinical course. Both groups had widespread lesions on the magnetic resonance imaging scans; however, the psychiatric group had more clinically defined sites of MS involvement, possibly indicating a difference in the biologic activity of the lesions in this group. The total lesion area was not different between the groups. However, the distribution of lesions did differ; the psychiatric group had significantly more temporal lobe involvement than the control group. These results indicate a role for the cerebral lesions themselves, particularly those in the temporal lobes, in the genesis of psychiatric disorders in MS.

Pregnancy and multiple sclerosis. A prospective study.

OBJECTIVE: To conduct a prospective assessment of pregnancy on women with multiple sclerosis (MS), focusing on pregnancy outcome and relapses during gestation and up to 6 months after delivery. DESIGN: Expected numbers of relapses were based on data for (1) "self-controls": the mothers ("cases") themselves prior to becoming pregnant and (2) "matched controls": female patients with MS "matched" to the mothers for year of birth, age of MS onset, MS type, MS course, and initial MS symptom(s). SETTING: Cases and controls were identified from an ambulatory care MS clinic that serves the province of British Columbia, Canada. PATIENTS OR OTHER PARTICIPANTS: Women with a diagnosis of MS who attended the MS clinic during 1982 through 1986 and subsequently became pregnant during 1982 through 1989 inclusive were included in this study as cases. Matched controls were women with MS who attended the MS clinic during the same period but did not become pregnant. RESULTS: No significant increase in relapse rate was found for cases during the first two trimesters of gestation. The number of relapses was significantly less than expected during the third trimester compared with matched controls (chi 2 = 6.80, df = 1, P < .02), but not compared with self-controls (chi 2 = 3.39, df = 1, P > .05). The observed number of relapses for the 6 months after delivery did not differ significantly from expected (self-controls: chi 2 = 2.84, df = 2, P > .05; matched controls: chi 2 = 1.76, df = 2, P > .05). CONCLUSION: These data suggest that neither pregnancy nor the 6-month period after delivery is a risk factor for relapse in MS. They are consistent with previous observations that, in the long term, pregnancy does not influence subsequent MS disability.

Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group.

We performed yearly MRI analyses on 327 of the total 372 patients in a multicenter, randomized, double-blind, placebo-controlled trial of interferon beta-1b (IFNB). Clinical results are presented in the preceding companion paper. Baseline MRI characteristics were the same in all treatment groups. Fifty-two patients at one center formed a cohort for frequent MRIs (one every 6 weeks) for analysis of disease activity. The MRI results support the clinical results in showing a significant reduction in disease activity as measured by numbers of active scans (median 80% reduction, p = 0.0082) and appearance of new lesions. In addition, there was an equally significant reduction in MRI-detected burden of disease in the treatment as compared with placebo groups (mean group difference of 23%, p = 0.001). These results demonstrate that IFNB has made a significant impact on the natural history of MS in these patients.

Scales for rating impairment in multiple sclerosis: a critique.

We reviewed scales proposed over the past 35 years for the rating of neurologic impairment in MS. We focused on the Expanded Disability Status Scale (EDSS) which has been recommended as the most useful scale for rating impairment by the International Federation of Multiple Sclerosis Societies in its Minimal Record of Disability for Multiple Sclerosis. We consider that the EDSS has important flaws that seriously limit its usefulness. In light of the widely accepted three-tier classification of dysfunction developed by the World Health Organization, the title is inappropriate. More substantial problems include inadequate precision in defining the degree of impairment in some functional categories of the scale, and the use of a mixture of neurologic signs elicited on examination and subjective information obtained from the patient in defining the overall scale. We suggest guidelines for developing a "Neurologic Impairment Scale" to rate impairment in MS.

Differential effects of beta and gamma interferons on expression of major histocompatibility complex antigens and intercellular adhesion molecule-1 in cultured fetal human astrocytes.

We investigated the modulatory effects of human interferon beta (IFN-beta) and gamma (IFN-gamma) on expression of class I and II major histocompatibility complex (MHC) antigens and intercellular adhesion molecule-1 (ICAM-1) in fetal human astrocytes in culture using flow cytometry and immunocytochemistry. Under the baseline condition, class I MHC antigen and ICAM-1 were expressed in a moderate number (23 to 76%) of astrocytes, whereas class II MHC antigen was expressed in only a small number (0.3 to 8%) of astrocytes. Following a 72-hour treatment with IFN-gamma (10 to 100 U/ml), expression of all three antigens increased greatly. Expression of class I MHC antigen was also elevated by exposure to IFN-beta (10 and 100 IU/ml). However, IFN-beta did not significantly induce expression of class II MHC antigen or ICAM-1. Furthermore, IFN-beta significantly reduced IFN-gamma-induced expression of class II MHC antigen but not of class I MHC antigen or of ICAM-1. The differential effects of IFN-beta and IFN-gamma on expression of class I and II MHC antigens and ICAM-1 in fetal human astrocytes suggest that interferons serve as modulators of astrocyte function at sites of inflammation in the human CNS.

Cause of death in patients attending multiple sclerosis clinics.

Between 1972 and 1988, 145 deaths occurred among 3,126 patients attending the Multiple Sclerosis (MS) Clinics in Vancouver, British Columbia (N = 1,583), and London, Ontario (N = 1,543). We could determine the exact cause of death in 82.1% of cases (119 of 145). Of the 119 patients for whom the cause of death was known, 56 deaths (47.1%) were directly attributed to complications of MS. Of the remaining 63 deaths, 18 (28.6%) were suicides, 19 (30.2%) were due to malignancy, 13 (20.6%) to an acute myocardial infarction, seven (11.1%) to stroke, and the remainder (9.5%) to miscellaneous causes, of which two may have been suicides. The proportion of suicides among MS deaths was 7.5 times that for the age-matched general population, and the proportion of MS deaths from malignancy was 0.67 times that for the age-matched general population. The proportion of deaths due to malignancy and stroke was the same for the MS patients and the age-matched general population.

Multiple sclerosis: in relapsing patients, immune functions vary with disease activity as assessed by MRI.

We have serially studied immunoglobulin G secretion in vitro, natural killer cell function, and concanavalin A-induced suppression in a group of seven patients with relapsing-remitting multiple sclerosis. In two patients, the development of a large clinically asymptomatic MRI lesion was accompanied by reductions in natural killer cell function, immunoglobulin G secretion in vitro (after pokeweed mitogen stimulation), and concanavalin A-induced suppression without parallel change in lymphocyte markers. We did not see this type of change in matched controls nor in stable multiple sclerosis studied serially. When clinical attacks appeared, there was no significant change in immune function. We conclude that changes in immune function correlate well with the activity of the disease as recognized by MRI. We suspect that decreased natural killer cell function, immunoglobulin G secretion in vitro, and concanavalin A-induced suppression are secondary to the large lesions recognized by MRI.

Randomized controlled trial of interferon-beta-1a in secondary progressive MS: MRI results.

OBJECTIVE: To examine MRI changes resulting from treatment of secondary progressive MS (SPMS) with two doses of interferon-beta-1a (Rebif). BACKGROUND: Interferon-beta (IFN-beta) reduces relapses and delays progression in relapsing-remitting MS, but there are conflicting results on its clinical benefit in SPMS. METHODS: In a double-blind, randomized, multicenter, placebo-controlled study (SPECTRIMS), 618 patients received IFN-beta-1a 22 microg, 44 microg, or placebo subcutaneously three times weekly for 3 years. T2 activity and burden of disease (BOD) were measured in 617 patients by using semiannual proton density/T2-weighted (PD/T2) MRI scans. A cohort of 283 patients also had 11 monthly PD/T2 and T1-weighted gadolinium-enhanced (T1-Gd) scans at study start. RESULTS: Treatment reduced median numbers of active lesions per patient per scan (semiannual T2 activity: 0.17, 0.20 and 0.67 for the high dose, low dose, and placebo, p < 0.0001; monthly combined unique activity [T1+T2]: 0.11, 0.22, and 1.00, p < 0.0001) and accumulation of BOD (percent change from baseline to month 36: -1.3, -0.5, and 10.0 for the high dose, low dose, and placebo, respectively; p = 0.0001). MRI benefit was most evident in the subgroup of patients who reported relapses in the 2 years before the study. Neutralizing antibody development was associated with reduction in treatment effect: antibody-positive patients did not show significant differences from placebo at either dose. CONCLUSIONS: Interferon-beta-1a used in SPMS showed significant effects on all MRI measures, particularly in patients with relapses in the 2 years before the study.

Linoleic acid and multiple sclerosis: a reanalysis of three double-blind trials.

Data from three double-blind trials of linoleic acid in the treatment of multiple sclerosis (MS) were reanalyzed to examine whether inconsistency in the results was due to a relationship between patient characteristics and treatment response. The combined data consisted of neurologic assessments over 2 1/2-year trials for 87 treated patients and 85 control patients. Treated patients with minimal or no disability at entry had a smaller increase in disability than did controls (p less than 0.05). In addition, treatment reduced the severity and duration of relapses at all levels of disability and duration of illness at entry to the trials.

Life expectancy in patients attending multiple sclerosis clinics.

One multiple sclerosis (MS) is diagnosed, important considerations often include life expectancy and the availability of life insurance. We designed a study specifically to examine life expectancy among MS clinic patients and analyzed the data using standard actuarial methods, both including and excluding suicides. The data show that severe MS disability, as measured by an Expanded Disability Status Score (EDSS) of greater than or equal to 7.5, is a major risk factor for death with case fatality ratios for this group of patients approaching 4 times the rate for controls. Conversely, excluding deaths by suicide, case fatality ratios for those with mild and moderate disability (EDSS less than or equal to 7.0) approach 1.4 times and 1.6 times for age- and sex-matched comparison groups. Life tables indicate that the overall life expectancy for MS is only about 6 to 7 years less than that for the "insured" population without MS.

The lesion of multiple sclerosis: imaging of acute and chronic stages.

Increased blood-brain barrier (BBB) permeability, important in the pathogenesis of MS, may be demonstrated as lesion enhancement with high-volume delayed CT (HVDCT). We studied 40 MS patients with history, neurologic examination, HVDCT, and MRI. In addition, 7 of the patients with enhancing CT lesions were followed with serial MRI for up to 3 years and 7 months. In 3 of these patients we repeated the HVDCT. Patients with enhancing lesions on CT were younger, had shorter duration of disease, and had more frequent clinical relapses than did patients without enhancement. More than half (56%) of the enhancing CT lesions were in the deep white matter, 23% were periventricular, and 21% were at the gray/white matter junction. Half the CT enhancing lesions, when followed by serial MRI, showed significant changes in lesion size. Although the majority (59%) of these lesions faded, some remained actively changing (25%) or became confluent with adjacent lesions (16%). In 48% of the MRI examinations that showed activity, some lesions were increasing in size while others were simultaneously decreasing in size. This study confirms that MS is a dynamic process in which recurrent episodes of BBB disruption and inflammation play a major role. Recurrent episodes of inflammation may well be a prelude to the largely irreversible changes of demyelination and gliosis.

Effect of interferon beta-1b in MS: assessment of annual accumulation of PD/T2 activity on MRI. UBC MS/MRI Analysis Group and the MS Study Group.

OBJECTIVE: To determine whether the efficacy of interferon beta-1b (IFNbeta-1b) on lesion activity could be shown with annual analysis of MRI. BACKGROUND: Clinical outcomes and MRI burden of disease changes in MS patients in a multicenter double-blind placebo-controlled 5-year trial of IFNbeta-1b have been reported, together with an analysis of 6-weekly MRI activity in a small subgroup during 2 years. MRI activity measurements based on annual scans have not been documented. METHODS: Patients were randomized into three treatment arms: placebo, 1.6 mIU, and 8 mIU IFNbeta-1b self-administered subcutaneously every other day. Active lesions were identified as new, enlarging, or recurrent on proton density and T2-weighted MRI scans. Gadolinium was not used. An annual accumulation activity index was developed as an additional analysis of lesion activity. RESULTS: During the 5 years, both high- and low-dose IFNbeta-1b groups showed a striking reduction in lesion annual accumulation activity on the activity index versus placebo (p = 0.001). Thirty-five percent of the high-dose patients and 29% of the low-dose patients were MRI inactive by this method of analysis, whereas only 16% of placebo patients were inactive (p = 0.001, placebo versus 8 mIU). CONCLUSIONS: This analysis of the annual accumulation of lesion activity shows that the previously reported treatment effect seen on MRI scanning once every 6 weeks in a subcohort of the patients can also be seen on yearly scans. This annual accumulation activity analysis provides an independent MRI confirmation of a treatment and dose effect for IFNbeta-1b.

Measles antibodies as related to HL-A types in multiple sclerosis.

One hundred thirty-six patients with multiple sclerosis and several control groups were studied for measles antibodies using several different antigens. Measles antibodies were higher in the multiple sclerosis population, but siblings also had higher titers than matched and random controls. The elevation in antibody titers (complement fixation) was found in female multiple sclerosis patients and male patients with HL-A types 3, 7, and W-18. Male patients not carrying these HL-A antigens had, as a group, relatively normal antibody levels. These data confirm a familial factor in elevated measles antibody titers. We suggest that HL-A antigens are linked to one of the factors that determines measles antibody titers in multiple sclerosis patients.

Magnetic resonance imaging of the head in the diagnosis of multiple sclerosis: a prospective 2-year follow-up with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT.

We previously compared the diagnostic capabilities of MRI of the head with CT, evoked potentials, and CSF oligoclonal banding (OB) analysis in a prospective evaluation of 200 patients with suspected multiple sclerosis (MS). To examine the ability of MRI and other paraclinical tests to predict the diagnosis of clinically definite MS (CDMS), we did a systematic clinical follow-up of 200 patients who were previously reported. In that study, 85 of 200 could be diagnosed as having laboratory-supported definite MS (LSDMS). In follow-up, we excluded one patient diagnosed as LSDMS who in retrospect was considered to have had CDMS at entry and 15 patients who were eventually diagnosed as having other diseases. After a mean follow-up of 2.1 years, 55 of the remaining 184 patients (30%) had developed CDMS. Thirty-eight of 84 patients with an original diagnosis of LSDMS (45%) and 17 of the remaining 100 patients with suspected MS (17%) had become CDMS. Forty-six of the 55 patients who developed CDMS in follow-up (84%) had an initial MRI that was strongly suggestive of MS. Fifty-two of those 55 CDMS patients (95%) had at least one MS-like abnormality on MRI when originally studied. In contrast, 38 of 55 (69%) had CSF OB, 38 of 55 (69%) had an abnormal VEP, 35 of 55 (64%) had an abnormal SEP, and 21 of 55 (38%) had an abnormal CT when first studied. MRI was the most sensitive single paraclinical test for predicting CDMS. CDMS developed during follow-up in 46 of the 94 patients (49%) whose initial MRI was strongly suggestive of MS.(ABSTRACT TRUNCATED AT 250 WORDS)

The retinal nerve fiber layer, neuroretinal rim area, and visual evoked potentials in MS.

In a prospective study of 57 patients with clinically definite, probable, or possible multiple sclerosis (MS), one-half of whom had a history of optic neuritis, retinal nerve fiber layer (RNFL) defects and the neuroretinal rim (NRR) area were quantitatively determined and compared with the visual evoked potential (VEP). There were abnormal VEP latencies in 63% of all patients (definite and probable = 68%, possible = 50%); local or diffuse RNFL defects in 54%, (definite and probable = 54%, possible = 50%); and an abnormally small NRR area in 30% (definite and probable = 32%, possible = 25%). Abnormalities in one or more of the VEP, RNFL, or NRR area occurred in 86% of all patients (definite and probable = 90%, possible = 75%), thus considerably increasing the yield of optic nerve abnormalities over that of the VEP alone. The predominance and extent of the diffuse RNFL defects, which are axonal abnormalities, suggest a more diffuse optic nerve pathology in MS than can be accounted for by a "plaque" pathology and indicate that extensive axonal loss commonly occurs in the optic nerves of MS.

Multiple sclerosis: a serial study using MRI in relapsing patients.

Prospective monthly magnetic resonance imaging (MRI) studies were done over 6 months in seven relapsing MS patients. MRI and neurologic evaluations were compared for sensitivity in detecting disease activity. Four patients were clinically stable throughout the study. Three patients had five clinical relapses, two localized to the spinal cord and three to the brainstem. Eighteen new and ten enlarging MRI lesions were seen in five patients. Most lesions were less than 10 mm in diameter. All were clinically silent. Two patients developed major enlarging MRI lesions (seen in three slices) which increased in size over 2 months and then gradually became smaller over 2 months, leaving behind small residual areas of abnormality. There were 36 follow-up scans, 17 of which (47%) showed evidence for increasing activity. Thirteen (36%) of the scans had new lesions, most of them being small. This study shows that MRI evidence for disease activity in MS is much more frequent than is clinical evidence.