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PubMed1990

Childhood infections in multiple sclerosis: a study of North African-born patients who migrated to France. The French Collaborative Group on Multiple Sclerosis.

We conducted a study on 152 patients with multiple sclerosis (MS) who were born in North Africa and migrated to France. Information was obtained from patients on common childhood infections. We found that, in most cases, common childhood illnesses occurred before migration, but these infections occurred at later ages when the patients were in France: the mean differences were equal to 3 years for measles, 2.1 years for chickenpox, and 4.5 years for mumps. In comparison with data available for the general populations of Algeria and France, the mean ages of childhood infections, and particularly measles, were higher in MS patients. Data confirm that, wherever they live, MS patients tend to have childhood infections at a relatively late age and suggest that migration delays the age of viral infections. This might be one of the possible explanations for the effect of migration on the risk of MS.

Africa, Northern↗
PubMed2001

A meta-analysis of genomic screens in multiple sclerosis. The Transatlantic Multiple Sclerosis Genetics Cooperative.

We combined the raw genotyping data from three large multiple sclerosis genome screens and performed a global meta-analysis in order to compare and summarize the linkage results from the different studies. In alphabetical order, the screens provided data from 442 markers typed in 52 multiplex families with a total of 133 affected individuals (the American screen), 314 markers typed in 128 families with 264 affecteds (the British screen) and 257 markers typed in 61 families with a total of 139 affected subjects (the Canadian screen). Multipoint analysis of these data was performed using the GENEHUNTER program. The highest non-parametric linkage (NPL) score in the meta-analysis was observed on chromosome 17q11 (NPL score 2.58), although this score falls short of genome-wide significance. A total of eight regions had NPL scores greater than 2.0. One of the regions with an NPL score greater than 2.0 was the HLA region on chromosome 6p21 (NPL=2.2). This region is known, from association studies, to be involved in MS susceptibility, but the modest linkage result observed here suggests the encoded susceptibility effect is not large compared with the high familial recurrence in MS (lambda approximately 20). Overall, our linkage results suggest that MS is likely to be multigenic in its genetic susceptibility.

Autoimmune Diseases↗
PubMed2006

The Italian Multiple Sclerosis Database Network (MSDN): the risk of worsening according to IFNbeta exposure in multiple sclerosis.

We evaluated the risk of worsening according to the length of exposure to interferon beta (IFNbeta) in a large cohort of 2090 multiple sclerosis patients collected by the Italian MS Database Network. Overall 44,140 patient-visits with a follow-up of 22,143 patient-years were evaluated. Forty-one per cent of patients were exposed to IFNbeta for up to 2 years, 39% for 2-4 years and 20% for more than 4 years. A Cox regression model was used to analyse two clinical outcomes: disability progression and worsening of relapse rate. The technique of propensity score was applied to reduce bias in the comparison of non-randomized groups. The risks of disability progression (HR =0.23; 95% CI: 0.17-0.30) and worsening of relapse rate (HR =0.19; 95% CI: 0.14-0.27) were reduced by about 4-5-fold in patients exposed to IFNbeta for more than four years, compared with patients exposed for up to two years. The propensity score technique confirmed the findings. The proportion of days covered by IFNbeta treatment was lower (P <0.0001) in patients exposed to IFNbeta for up to two years than in other groups. A clinical stabilization over two years of IFNbeta exposure may predict a subsequent good clinical response to treatment.

Adjuvants, Immunologic↗
PubMed1996

Guidelines for MRI monitoring of the treatment of multiple sclerosis: recommendations of the US Multiple Sclerosis Society's task force.

In relapsing-remitting and secondary progressive multiple sclerosis (MS), MRI activity on monthly brain scans is a sensitive primary outcome measure in short term exploratory treatment trials. Because conventional MRI findings have a limited correlation with disability, the primary outcome in definitive trials should be clinical, although MRI is useful in providing an index of pathological progression. In trials aimed at preventing evolution from a clinically isolated syndrome to MS, MRI findings should be used in the entry criteria. The likely pathological substrates of irreversible disability are demyelination and axonal loss. Putative MR markers for these pathologies appear to relate more closely to disability than conventional MRI findings. Further technical developments should lead to improved quantitation, pathological specificity and clinical correlations.

Clinical Trials as Topic↗
PubMed1996

Comparative evaluations of neuroperformance and clinical outcome assessments in chronic progressive multiple sclerosis: I. Reliability, validity and sensitivity to disease progression. Multiple Sclerosis Study Group.

There remains controversy regarding the most sensitive and valid outcome assessments to use in multiple sclerosis (MS) clinical trials. A double blind, placebo controlled, parallel group multicenter clinical trial to evaluate the clinical efficacy of cyclosporine A in chronic progressive MS incorporated several major clinical and performance outcome assessment modalities and a large sample size, both of which provide a unique opportunity to explore the relationship among MS disease status and the various outcome measures over time. The measures included a structured neurological examination, the Kurtzke Functional System scales and Expanded Disability Status Score, and the Incapacity Status Scale from the MS Minimal Record of Disability, the Harvard Ambulation Index, and neuroperformance testing. A test-retest reliability index, principal component analyses and a signal-to-noise ratio metric were used to comparatively evaluate the reliability, validity and sensitivity to disease progression of the various outcome assessments. The goal was to provide a rational basis for selection of behavioral outcome assessments in future MS clinical trials by identifying the primary dimensions of MS measured by the candidate outcome assessments and providing an objective basis for selecting tests that are most sensitive to MS disease and its progression over a two year trial period. We conclude that the components of the major clinical and performance measures show excellent reliability and cross validation. Principal component analyses of all outcome assessments yielded six primary underlying factors for describing disease status in chronic progressive MS that included lower extremity/pyramidal dysfunction, cerebellar/brainstem and upper extremity dysfunction, somatosensory dysfunction, visual dysfunction, mental or intellectual dysfunction and bowel/bladder problems. Signal-to-noise ratios indicated that upper and lower extremity composites of neuroperformance test items provided the most sensitive indicators of MS disease progression in the placebo group over the 2 year trial period.

Activities of Daily Living↗
PubMed2003

Development and validation of a self-efficacy measure for people with multiple sclerosis: the Multiple Sclerosis Self-efficacy Scale.

The aim of this study is to develop and validate a brief measure of self-efficacy specifically for use with people with multiple sclerosis (MS). Self-efficacy is the subjective belief that one can overcome challenges that one is faced with. In order to incorporate the subjective experiences of individuals with MS, a 'patient-focused' methodology has been adopted. Open-ended interviews were used to generate potential scale items. Items were piloted on an initial sample of individuals with MS and reduced to 14 items on the basis of their perceived relevance to this patient group. The final 14-item scale was then used with a further 142 individuals in order to assess its psychometric properties. The scale demonstrated high internal consistency (Cronbach's alpha = 0.81) and test-retest reliability (r = 0.81, P < 0.001) and acceptable validity. Issues concerning the assessment of validity are discussed in terms of the scale's relevancy to individuals with MS and the theoretical issues around the construct of self-efficacy. The scale has shown sensitivity to detect change following a brief therapeutic intervention, with an effect size of 0.502. This MS Self-efficacy Scale could, therefore, be a useful tool in the assessment of psychological adjustment and quality-of-life of individuals with MS.

Adult↗
PubMed2003

Clinical presentation of primary progressive multiple sclerosis 10 years after the incidental finding of typical magnetic resonance imaging brain lesions: the subclinical stage of primary progressive multiple sclerosis may last 10 years.

BACKGROUND: Subclinical multiple sclerosis (MS) has been identified incidentally at autopsy; apparently unaffected individuals with an affected twin have demonstrated magnetic resonance imaging (MRI) changes consistent with MS, and 'MRI relapses' are several times more common than clinical relapses. CASE DESCRIPTION: A 39-year-old, right-handed man underwent MRI and PET scanning in 1986 as a 'normal' control in a Parkinson's disease study, where his father was the proband. MRI indicated multiple areas of abnormal signal intensity in a periventricular and grey-white matter junction distribution. Repeated clinical evaluations over the next 10 years were unchanged until 1996, when he complained of progressive weakness of the right foot and clumsiness in the right hand. MRI now indicated a further area of high signal intensity in the right posterior cord at the level of C5/C6. There was mild pyramidal distribution weakness in the right leg with an extensor plantar response on the same side. Over the next five years there has been mild progression in weakness and fatigue and intermittent Lhermitte's phenomenon. At no stage has there been a history of relapse, cerebrospinal fluid examination was normal and evoked responses (visual and somatosensory) are normal. CONCLUSION: This case demonstrates the phenomenon of subclinical MS, unusually supported by prolonged clinical and MRI follow-up. The patient eventually became symptomatic nine years after MRI diagnosis and is following a primary progressive course. Although MRI is known to be sensitive in identifying subclinical 'attacks', the pattern illustrated here may actually be quite typical of primary progressive MS and is compatible with the later onset seen in this subgroup of patients.

Adult↗
PubMed2004

A prospective study of conditions associated with multiple sclerosis in a cohort of 658 consecutive outpatients attending a multiple sclerosis clinic.

The cause of multiple sclerosis (MS) remains unknown. It is largely regarded as being an inflammatory autoimmune disease and has been reported in association with other inflammatory/autoimmune diseases. We performed a prospective study in 658 consecutive patients diagnosed with MS attending our outpatient MS management clinic between June 2002 and June 2003. Prevalence of associated conditions in these patients was calculated and compared with values from population studies using chi-square tests, odds ratios and confidence intervals. The MS population had significantly increased rates of asthma, inflammatory bowel disease, type 1 diabetes mellitus, pernicious anaemia, autoimmune thyroid disease, uveitis, seronegative spondyloarthropathies, bipolar disorder and melanoma compared to the general population. Both T helper type 1 (Th1)-mediated and T helper type 2 (Th2)-mediated diseases were significantly increased compared to the general population. There were also interesting associations seen with polyglandular autoimmune syndrome and rare single case associations. MS is associated with several other conditions. This work does not give evidence for the hypothesis that MS and atopy, reflecting Th1 and Th2 polarization, respectively, are mutually exclusive. Further work, ideally with a matched control population, is indicated.

Adjuvants, Immunologic↗
PubMed2005

Nursing home residents with multiple sclerosis and dementia compared to other multiple sclerosis residents.

Cognitive impairment may be a significant symptom in multiple sclerosis (MS), affecting about one half of MS patients in study samples similar to the general MS population. An interesting question is what role dementia, of any aetiology, plays in the cognitive ability of people with MS. The objective of this research is to learn more about nursing home residents with MS and dementia, identifying how they differ from other residents with MS. We developed profiles of MS residents with dementia using the Minimum Data Set and compared these profiles to other residents with MS. Nursing home residents with MS and dementia are admitted to nursing facilities at an older age and seem less likely to have physical impairments but more mood and behaviour problems than other MS residents at admission. A cortical variant of MS may be more prevalent than previously suspected and may be a factor responsible leading to nursing home admission in this subgroup of patients. Further clinical analysis of this subgroup would be necessary to support this contention.

Adult↗
PubMed2005

Apo E in multiple sclerosis and optic neuritis: the apo E-epsilon4 allele is associated with progression of multiple sclerosis.

OBJECTIVE: To investigate the association between apolipoprotein E (Apo E) genotype in multiple sclerosis (MS) and acute monosymptomatic optic neuritis (ON) in a genetically homogeneous population with a high frequency of the Apo epsilon4 allele. BACKGROUND: The association between heterozygosity of Apo epsilon4 and the development of MS is thoroughly investigated, while the association between homozygosity of Apo epsilon4 and the development of MS is insufficiently studied. The association between Apo E genotype and disease progression remains controversial. METHODS: 475 patients were included, 385 with MS and 90 with ON, consecutively seen in the MS clinic in the County of Copenhagen. Clinical data were obtained from medical records and degree of disability was determined prospectively using the Kurtzke expanded disability status scale (EDSS). Blood samples were used for Apo E genotyping. Disease progression was evaluated by the progression index (PI = EDSS/disease duration). Apo E genotype distribution was compared with 361 healthy controls. RESULTS: The Apo epsilon genotype distribution in the MS and ON groups was similar to the controls. The rate of disease progression in the group of MS patients with a disease duration of 10 years or less was significantly faster in the Apo epsilon4 positive group (heterozygosity and homozygosity for Apo epsilon4) (PI = 1.41) compared to the Apo epsilon4 negative group (PI =0.92) (P =0.009). Observing the MS subgroups, we found that the group of patients with RRMS had a faster rate of disease progression in the Apo epsilon4 positive group (PI =1.12) compared to the Apo epsilon4 negative group (P =0.77) (P =0.024). CONCLUSIONS: Apo E genotypes do not influence the development of MS and ON. The Apo epsilon4 allele seems to predispose carriers with MS to a faster progression of disease.

Adult↗
PubMed2005

The future of multiple sclerosis therapies: redesigning multiple sclerosis clinical trials in a new therapeutic era.

Due to past success in testing and gaining regulatory approval for a variety of therapies in multiple sclerosis (MS), the conduct of future clinical trials has become increasingly problematic. An international workshop has met to discuss the issues facing the MS clinical trial community and to examine possible new strategies for the design of trials. Particular focus has been placed on trials that either avoid the use of a placebo because of ethical considerations or on designs that allow new therapies to be studied more rapidly or with fewer patients than needed in a conventional placebo-controlled trial. The discussions resulting from the workshop should provide a basis for the examination and implementation of innovative clinical trial designs in MS.

Adjuvants, Immunologic↗
PubMed1978

Anamnestic studies in multiple sclerosis: a relationship between familial multiple sclerosis and neoplasia.

A survey of family histories of malignant neoplasia in multiple sclerosis (MS) patients indicates that a positive history of cancer in near relatives is present in 44 percent of patients and 46 percent of controls. However, those MS patients having such a positive history were much more likely than others to also have a family history of MS. Contrariwise, MS patients with a positive family history of MS had a significantly higher rate of cancer in first degree relatives (71 percent) than others. There was a trend indicating less cancer in families of MS patients possessing the HLA-B7 and DW2 histocompatibility antigens.

Female↗
PubMed1993

Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group.

We report a multicenter, randomized, double-blind, placebo-controlled trial of interferon beta-1b (IFNB) in 372 ambulatory patients with relapsing-remitting multiple sclerosis (MS). Entry criteria included an Expanded Disability Status Scale (EDSS) score of 0 to 5.5 and at least two exacerbations in the previous 2 years. One-third of the patients received placebo, one-third 1.6 million international units (MIU) of IFNB, and one-third 8 MIU of IFNB, self-administered by subcutaneous injections every other day. The primary end points were differences in exacerbation rates and proportion of patients remaining exacerbation-free. The annual exacerbation rate for patients receiving placebo was 1.27; for 1.6 MIU IFNB, 1.17; and for 8 MIU IFNB, 0.84 after 2 years. Exacerbation rates were significantly lower in both treatment groups compared with the placebo group (8 MIU versus placebo, p = 0.0001; 1.6 MIU versus placebo, p = 0.0101; and 8 MIU versus 1.6 MIU, p = 0.0086), suggesting a dosage effect. The reduction in exacerbation severity in the 8 MIU group was attributable to a twofold reduction in the frequency of moderate and severe attacks. More patients in the 8 MIU group (n = 36) were exacerbation-free at 2 years compared with the placebo group (n = 18; p = 0.007). EDSS scores changed little from baseline in both the placebo and treatment arms. Accordingly, a significant change in disability could not be discerned in this trial. Finally, in serial MRIs, MS activity was significantly less in the high-dose IFNB group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Intermittent cyclophosphamide pulse therapy in progressive multiple sclerosis: final report of the Northeast Cooperative Multiple Sclerosis Treatment Group.

Previous studies reported that a 2- to 3-week course of IV cyclophosphamide plus adrenocorticotropic hormone (ACTH) induction can temporarily halt progressive MS for a period of 12 months in the majority of patients treated, after which reprogression occurs. The Northeast Cooperative Multiple Sclerosis Treatment Group was formed to determine whether outpatient pulse cyclophosphamide therapy could affect reprogression and whether there were differences between a modified induction regimen and the previously published regimen. Two hundred fifty-six progressive MS patients were randomized into four groups to receive IV cyclophosphamide/ACTH via the previously published versus a modified induction regimen, with or without outpatient IV cyclophosphamide boosters (700 mg/m2 every other month for 2 years). There were blinded evaluations performed every 6 months. Results demonstrate that (1) there were no differences between the modified and the published induction regimens either in terms of initial stabilization or subsequent progression; (2) without boosters, the majority of patients continued to progress; and (3) in patients receiving boosters, there was a statistically significant benefit at 24 months and 30 months (p = 0.04). Time to treatment failure after 1 year was also significantly prolonged in the booster versus the nonbooster group (p = 0.03). Age was the most important variable that correlated with response to therapy in that amelioration of disease progression occurred primarily in patients 40 years of age or younger. Boosters had a significant benefit on time to treatment failure in patients ages 18 to 40, p = 0.003, but not in patients ages 41 to 55, p = 0.97.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1995

Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group.

We studied copolymer 1 (Copaxone) in a multicenter (11-university) phase III trial of patients with relapsing-remitting multiple sclerosis (MS). Two hundred fifty-one patients were randomized to receive copolymer 1 (n = 125) or placebo (n = 126) at a dosage of 20 mg by daily subcutaneous injection for 2 years. The primary end point was a difference in the MS relapse rate. The final 2-year relapse rate was 1.19 +/- 0.13 for patients receiving copolymer 1 and 1.68 +/- 0.13 for those receiving placebo, a 29% reduction in favor of copolymer 1 (p = 0.007) (annualized rates = 0.59 for copolymer 1 and 0.84 for placebo). Trends in the proportion of relapse-free patients and median time to first relapse favored copolymer 1. Disability was measured by the Expanded Disability Status Scale (EDSS), using a two-neurologist (examining and treating) protocol. When the proportion of patients who improved, were unchanged, or worsened by > or = 1 EDSS step from baseline to conclusion (2 years) was evaluated, significantly more patients receiving copolymer 1 were found to have improved and more receiving placebo worsened (p = 0.037). Patient withdrawals were 19 (15.2%) from the copolymer 1 group and 17 (13.5%) from the placebo group at approximately the same intervals. The treatment was well tolerated. The most common adverse experience was an injection-site reaction. Rarely, a transient self-limited systemic reaction followed the injection in 15.2% of those receiving copolymer 1 and 3.2% of those receiving placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1996

Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b: experience during the first three years. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group.

Evidence of diminution of therapeutic efficacy in 35% of interferon beta-1b (IFNB)-treated multiple sclerosis (MS) patients who developed neutralizing antibodies (NABs) led to extensive study of the effects of NABs on therapeutic benefits, side effects, and magnetic resonance imaging (MRI) data. First, we validated the IFNB NAB assay used in the multicenter trial by having representative stored serum samples reanalyzed by an independent laboratory. When NABs developed (as defined), usually in the first year, the exacerbation rates after 18 months resembled placebo rates, the numbers of enlarging MRI lesions significantly increased compared with those in NAB-negative patients, and there was increased new lesion formation in the MRI (p = 0.067). However, worsening of the mean Expanded Disability Status Scale score in the 8-MIU treatment arm was higher in patients who remained NAB-negative in the third year (p = 0.083). NAB-positive patients were not overrepresented among the noncompleters, or in five patients having at least one episode of skin-site necrosis. After 18 months, flu-like symptoms were about twice as common in NAB-negative as in NAB-positive patients, although the frequency did not exceed 21% in any semester. Decisions to discontinue IFNB therapy should be made individually based on clinical response and a positive titer of NABs in the serum with the use of a reliable assay. ELISA and Western blot techniques measure binding antibodies, not NABs specifically, and are unsuitable for use. Possible, but as yet unproven, means of dealing with NAB positivity should be studied in properly designed trials. IFNB-1b remains an effective therapy for a majority (65%) of MS patients having relapses. The annual exacerbation rates in NAB-negative patients receiving the 8-MIU dosage regimen are about 50% of those seen in untreated patients, a greater reduction than the one-third reduction earlier reported for the entire high-dose arm, and a meaningful treatment benefit.

Antibodies↗
PubMed1996

Placebo-controlled trial of gabapentin in patients with amyotrophic lateral sclerosis. WALS Study Group. Western Amyotrophic Lateral Sclerosis Study Group.

We designed a phase II trial to evaluate the efficacy of gabapentin in slowing the rate of decline in muscle strength of patients with amyotrophic lateral sclerosis (ALS) and to assess safety and tolerability. Gabapentin (800 mg) or placebo was administered t.i.d. in a randomized, double-blinded, placebo-controlled, trial for 6 months. We enrolled 152 patients at eight sites in the United States. The primary outcome measure was the slope of the arm megascore, the average maximum voluntary isometric strength from eight arm muscles standardized against a reference ALS population. A secondary outcome measure was forced vital capacity. Slopes of arm megascores for patients on gabapentin were compared with slopes of those taking placebo using a two-way ANOVA. We observed a nonstatistically significant trend (p = 0.057-0.08) toward slower decline of arm strength in patients taking gabapentin compared with those taking placebo (mean difference 24%, median 37%). We observed no treatment effect on forced vital capacity. Gabapentin was well tolerated by patients with ALS. These results suggest that further studies of gabapentin in ALS are warranted.

Acetates↗
PubMed1998

Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group.

When 251 relapsing-remitting patients with multiple sclerosis were randomized to receive daily subcutaneous injections of glatiramer acetate, previously called copolymer 1 (Copaxone; n = 125) or placebo (n = 126) for 24 months, there were no laboratory abnormalities associated with glatiramer acetate treatment and it was well tolerated with few side effects. Patients receiving glatiramer acetate had significantly fewer relapses and were more likely to be neurologically improved, whereas those receiving placebo were more likely to worsen. This study was extended for 1 to 11 months (mean of 5.2 months for the glatiramer acetate group and 5.9 months for the placebo group). The blinding and study conditions used during the core 24-month study were unchanged throughout the extension. The results of this extension study confirm the excellent tolerance and safety profile of glatiramer acetate for injection. The clinical benefit of glatiramer acetate for both the relapse rate and for neurologic disability was sustained at the end of the extension trial.

Adult↗