Background Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system and is the most common cause of neurologic disability in young adults. Despite antiinflammatory or immunosuppressive therapy, most patients have progressive neurologic deterioration that may reflect axonal loss. We conducted pathological studies of brain tissues to define the changes in axons in patients with multiple sclerosis. Methods Brain tissue was obtained at autopsy from 11 patients with multiple sclerosis and 4 subjects without brain disease. Fourteen active multiple-sclerosis lesions, 33 chronic active lesions, and samples of normal-appearing white matter were examined for demyelination, inflammation, and axonal pathologic changes by immunohistochemistry and confocal microscopy. Axonal transection, identified by the presence of terminal axonal ovoids, was detected in all 47 lesions and quantified in 18 lesions. Results Transected axons were a consistent feature of the lesions of multiple sclerosis...

Axonal transection in the lesions of multiple sclerosis.

Background Natalizumab is the first α4 integrin antagonist in a new class of selective adhesion-molecule inhibitors. We report the results of a two-year phase 3 trial of natalizumab in patients with relapsing multiple sclerosis. Methods Of a total of 942 patients, 627 were randomly assigned to receive natalizumab (at a dose of 300 mg) and 315 to receive placebo by intravenous infusion every four weeks for more than two years. The primary end points were the rate of clinical relapse at one year and the rate of sustained progression of disability, as measured by the Expanded Disability Status Scale, at two years. Results Natalizumab reduced the risk of sustained progression of disability by 42 percent over two years (hazard ratio, 0.58; 95 percent confidence interval, 0.43 to 0.77; P<0.001). The cumulative probability of progression (on the basis of Kaplan–Meier analysis) was 17 percent in the natalizumab group and 29 percent in the placebo group. Natalizumab reduced the rate of clinical relapse at one year...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa044397

A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis

Background There is increasing evidence that B lymphocytes are involved in the pathogenesis of multiple sclerosis, and they may be a therapeutic target. Rituximab, a monoclonal antibody, selectively targets and depletes CD20+ B lymphocytes. Methods In a phase 2, double-blind, 48-week trial involving 104 patients with relapsing–remitting multiple sclerosis, we assigned 69 patients to receive 1000 mg of intravenous rituximab and 35 patients to receive placebo on days 1 and 15. The primary end point was the total count of gadolinium-enhancing lesions detected on magnetic resonance imaging scans of the brain at weeks 12, 16, 20, and 24. Clinical outcomes included safety, the proportion of patients who had relapses, and the annualized rate of relapse. Results As compared with patients who received placebo, patients who received rituximab had reduced counts of total gadolinium-enhancing lesions at weeks 12, 16, 20, and 24 (P<0.001) and of total new gadolinium-enhancing lesions over the same period (P<0.001); th...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa0706383

B-cell depletion with rituximab in relapsing-remitting multiple sclerosis.

Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis

Summary Background Previous trials of interferon in multiple sclerosis (MS) have shown efficacy, but the degree of clinical benefit remains uncertain, and the optimum dose is not known. We undertook a double-blind, placebo-controlled study in relapsing/remitting MS to investigate the effects of subcutaneous interferon -1a. Methods 560 patients with Kurtzke expanded disability status scale (EDSS) scores of 0–5·0, from 22 centres in nine countries, were randomly assigned subcutaneous recombinant interferon -1a 22 g (n=189), or 44 g (n=184), or placebo (n=187) three times a week for 2 years. Neurological examinations were done every 3 months. All patients had MRI twice yearly and 205 had monthly scans in the first 9 months of treatment. Analysis was by intention to treat. Findings Clinical data on 533 (95%) patients were available at 2 years. The relapse rate was significantly lower at 1 and 2 years with both doses of interferon -1a than with placebo (mean number per patient 1·82 for 22 g group, 1·73 for 44 g group vs 2·56 for placebo group: risk reductions 27% [95% CI 14–39] and 33 [21–44]). Time to first relapse was prolonged by 3 and 5 months in the 22 g and 44 g groups respectively, and the proportion of relapse-free patients was significantly increased (p<0·05). Interferon -1a delayed progression in disability, and decreased accumulated disability during the study. The accumulation of burden of disease and number of active lesions on MRI was lower in both treatment groups than in the placebo group. Interpretation Subcutaneous interferon -1a is an effective treatment for relapsing/remitting MS in terms of relapse rate, defined disability, and all MRI outcome measures in a dose-related manner, and it is well tolerated. Longer-term benefits may become clearer with further follow-up and investigation.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(98)03334-0.pdf

Randomised double-blind placebo-controlled study of interferon -1a in relapsing/remitting multiple sclerosis

The outcome of multiple sclerosis (MS), assessed according to the Kurtzke Disability Status Scale (DSS), was reviewed in 1,099 consecutive patients followed in London, Canada, between 1972 and 1984. A geographically based subgroup of 196 patients representing 90% of Middlesex County MS patients as well as a group of 197 patients seen from onset of disease were separately analysed. The clinical course was progressive from onset in 33% of the total population and in 28% of the Middlesex County subgroup. Of those with duration of 6-10 yrs, 30-40% with initially remitting disease developed progressive MS. The cross-sectional distribution of disability was bimodal with peaks at DSS 1 (no disability) and DSS 6 (assistance required for walking). Actuarial analysis showed that the median time to reach DSS 6 from onset of MS was 14.97 +/- 0.31 yrs in the total population and 9.42 +/- 0.44 yrs in the "seen from onset' subgroup. Survival was minimally altered; 87% of patients followed up to 40 yrs were still alive, although ascertainment of cases with this duration of MS was incomplete. Data describing the rate at which disability develops after the onset of a progressive phase of MS are also presented. The implications of these data in planning and interpretation of clinical therapeutic trials are discussed.

The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability.

Controversy exists regarding the predictive value of the early clinical course of multiple sclerosis (MS). Three parameters often considered are the attack rate, the first interattack interval and the rate at which disability develops in the early years of the disease. We have recorded the time to reach successive levels of disability defined by the Kurtzke Disability Status Scale (DSS) in 1,099 MS patients followed at University Hospital, London, Canada between 1972 and 1984. Our population is particularly suitable because of its size, the high degree of ascertainment of cases in the community, and the regular follow-up provided. Life table analysis was used to compare survival in patients stratified according to the above three parameters using DSS 6 as end point. Significant differences were evident in the survival distributions. Despite the extensive interindividual variation in the rate at which disability developed, the early course of MS may be useful in determining the relative risk of rapid progression.

The natural history of multiple sclerosis: a geographically based study. 2. Predictive value of the early clinical course.

A multivariate hierarchical analysis was used to assess the significance of several demographic and clinical factors in multiple sclerosis patients. We used the time to reach level 6 on the disability status scale (DSS) of Kurtzke as endpoint. Several factors at presentation were significantly associated with an adverse outcome including older age at onset, male sex, cerebellar involvement or insidious onset of a motor deficit as first symptom. Factors ascertained later which were associated significantly with a worse outcome, even after controlling for those previously mentioned, included persisting deficits in brainstem, cerebellar or cerebral systems, a higher frequency of attacks in the first 2 yrs after onset of disease, a short first interattack interval and higher DSS at 2 yrs and 5 yrs from onset. An analysis similar to multiple regression was used to generate predictive models which permit the calculation of the median time to DSS 6 for patients with a given set of covariates. The goodness of fit of these models to the data and their predictive accuracy are discussed.

The natural history of multiple sclerosis: a geographically based study. 3. Multivariate analysis of predictive factors and models of outcome.

We used hypothetical entry criteria typical of those used in clinical therapeutic trials to determine the patients who would have been eligible among those followed in a clinic-based study of multiple sclerosis (MS) in London, Ontario, between 1972 and 1984. For these patients, we determined the observed frequency of deterioration by 1 point on the disability status scale (DSS) of Kurtzke, which is the most feasible and frequently used endpoint in clinical trials. We calculated the number of patients required for a randomized clinical trial to detect a significant result (alpha = 0.05) with 80% or 90% power based on the observed rate of deterioration. To assess the linearity of the DSS, we determined the frequency of progression and staying time at each level of the DSS. Overall the frequency of progression was lower and the staying times were longer at higher levels of disability. There was considerable intrapatient as well as interpatient variation in staying time. These data have major implications for the design and conduct of clinical therapeutic trials in MS.

The natural history of multiple sclerosis: a geographically based study. 4. Applications to planning and interpretation of clinical therapeutic trials.

When multiple sclerosis (MS) presents late in life (after the age of 50), it frequently gives diagnostic difficulty. In a large MS clinic population (N = 838), 9.4% of the patients had late onset of MS. Slow deterioration of motor function characterized the initial symptoms and subsequent course of this group of older patients. Progression of disability was more rapid than in younger patients. Evoked response studies and CSF electrophoresis were of high diagnostic yield in the older patient group. Reasons for the differing clinical features in the late-onset patients are discussed. We suggest that the age-of-onset criterion for MS be raised to 60 in adequately investigated cases.

John H. Noseworthy

Papers

The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability.

The natural history of multiple sclerosis: a geographically based study. 2. Predictive value of the early clinical course.

The natural history of multiple sclerosis: a geographically based study. 3. Multivariate analysis of predictive factors and models of outcome.

The natural history of multiple sclerosis: a geographically based study. 4. Applications to planning and interpretation of clinical therapeutic trials.

Multiple sclerosis after age 50