A comparison of sporadic and familial multiple sclerosis.

We compared demographic and clinical features, including outcome defined by a failure time analysis of disability, in 143 patients with a family history of multiple sclerosis (familial MS) compared with 956 patients without such a history (sporadic MS). Patients with familial MS did not differ from those with sporadic MS even when patients with 1st-degree relatives or multiple relatives with MS were considered separately. An intraclass correlation analysis of 13 pairs of affected 1st-degree relatives, both members of which were followed in our clinic, failed to reveal heterogeneity among different families. We were unable to find any support for differences between familial and sporadic MS.

The influence of pregnancy on disability from multiple sclerosis: a population-based study in Middlesex County, Ontario.

We analyzed the effect of pregnancy on long-term disability resulting from multiple sclerosis in 185 women ascertained through a retrospective population-based survey of MS in Middlesex County, Ontario, Canada. There was no association between disability and total number of term pregnancies, timing of pregnancy relative to onset of MS, or either onset or worsening of MS in relation to a pregnancy. The mean number of pregnancies both before and after onset of MS was no different among groups stratified according to disability. This study addresses some of the difficulties inherent in studying the effect of pregnancy on disability resulting from MS.

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

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. 4. Applications to planning and interpretation of clinical therapeutic trials.

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. 2. Predictive value of the early clinical course.

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. I. Clinical course and disability.

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.