J. Deans

The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy.

AbstractFrom 1991–2002, we treated 58 patients with multiple sclerosis (MS) using the humanised monoclonal antibody, Campath–1H, which causes prolonged T lymphocyte depletion. Clinical and surrogate markers of inflammation were suppressed. In both the relapsing–remitting (RR) and secondary progressive (SP) stages of the illness, Campath–1H reduced the annual relapse rate (from 2.2 to 0.19 and from 0.7 to 0.001 respectively; both p < 0.001). Remarkably, MRI scans of patients with SP disease, treated with Campath–1H 7 years previously, showed no new lesion formation. However, despite these effects on inflammation, disability was differently affected depending on the phase of the disease. Patients with SPMS showed sustained accumulation of disability due to uncontrolled progression marked by unrelenting cerebral atrophy, attributable to ongoing axonal loss. The rate of cerebral atrophy was greatest in patients with established cerebral atrophy and highest inflammatory lesion burden before treatment (2.3 versus 0.7 ml/year; p = 0.04). In contrast, patients with RR disease showed an impressive reduction in disability at 6 months after Campath–1H (by a mean of 1.2 EDSS points) perhaps owing to a suppression of on–going inflammation in these patients with unusually active disease. In addition, there was a further significant, albeit smaller, mean improvement in disability up to 36 months after treatment.We speculate that this represents the beneficial effects of early rescue of neurons and axons from a toxic inflammatory environment, and that prevention of demyelination will prevent long–term axonal degeneration. These concepts are currently being tested in a controlled trial comparing Campath–1H and IFN–beta in the treatment of drug–naïve patients with early, active RR MS.

Myasthenia gravis: a population based epidemiological study in Cambridgeshire, England

OBJECTIVES To perform a comprehensive survey of myasthenia gravis in the county of Cambridgeshire, England, establishing contemporary epidemiological data. METHODS Cases were ascertained from multiple sources. Prevalent patients were visited and assessed by means of a standardised questionnaire and examination complemented by review of medical case notes. RESULTS One hundred cases were identified in a population of 684 000 (prevalence 15 per 100 000 population, 95% confidence intervals (95% CIs) 12–18). Thirty eight new diagnoses were made over a five year period providing an incidence of 1.1/100 000 population/year. The sex ratio was 2:1 F:M. After a mean follow up of 11.7 years, symptomatic disease was still restricted to ocular muscles in 25 patients. Thirty four of 100 patients underwent thymectomy a mean of 0.8 years after presentation, and a thymoma was present in 12. Highest remission rates were seen in patients presenting with generalised disease who underwent thymectomy but did not have a thymoma (27%). Cosegregation of an additional autoimmune disease occurred in 27 patients and in 24/49 (49%) women with onset<50 years of age. CONCLUSIONS This, the second highest reported prevalence for myasthenia, is likely to be the result of optimum case ascertainment, increased disease duration, application of complex diagnostic tests, and the impact of an aging population leading to a relative increase in the prevalence of ocular myasthenia.

Clinical concordance in sibling pairs with multiple sclerosis

As part of a linkage study, we obtained clinical, demographic, and genetic information on 210 families with siblings concordant for multiple sclerosis (MS).Twenty-eight pairs were excluded and information was incomplete in a further 16 pairs; intrafamilial comparisons of the clinical course are reported on the remaining 166 families (155 pairs and 11 trios) in whom complete data sets were available. The demographic characteristics were comparable to those of recently performed prevalence studies in the United Kingdom, supporting the application of results in these families for genetic linkage studies in MS. We observed no significant correlation for age at onset after correction for selection bias but found a minor correlation for year at onset, which we speculate is due to earlier recognition of symptoms in second affected siblings. There was no pair-wise concordance for presenting symptoms or disability at time of assessment. However, there was a strong correlation for disease course and to a lesser degree for gender. In addition, the familial recurrence rate was 33%, almost twice that previously recorded in a local prevalence study. These results suggest that the etiology of MS involves random exposure to an, as yet unidentified, environmental trigger and the clinical features of familial disease are modified by inherited factors. That the risk of developing MS is not spread uniformly among families has important implications for the counseling of individuals with familial disease. NEUROLOGY 1996;47: 347-352

Multiple sclerosis in the north Cambridgeshire districts of East Anglia

The Cambridgeshire multiple sclerosis register was established in 1989 and initially reported a prevalence of 130/10(5) population for south and east Cambridgeshire (south Cambs). This survey has now been extended to the northern county districts where there were 449 patients with multiple sclerosis in population of 378,959 on 1 July 1993 (118/10(5); 95% confidence interval (95% CI) 108-130). Four hundred and four had either definite or probable disease (107/10(5); 95% CI: 98-118). This matches the highest figures in the series of seven epidemiological surveys carried out in southern England over the past decade. Comparison with these and other studies indicates that no latitudinal gradient of disease is found in southern England despite spanning four degrees of latitude.

Multiple sclerosis in sibling pairs: an analysis of 250 families

OBJECTIVES To assess the potential contribution of genetic factors to clinical phenotype in multiple sclerosis. METHODS Using a cohort of 262 pairs of coaffected siblings from 250 families with multiple sclerosis, intersibling concordance analysis was used to explore underlying genetic mechanisms in disease pathogenesis by assessing parameters of disease course, clinical presentation, age and year of onset, and measures of disability and handicap. RESULTS Adjusted intraclass correlation coefficients were not significant for either age of onset or for year of first symptom. One third of sibling pairs were concordant for presenting symptom (81/262), a result that was non-significant. However, course type was identical in 50% of the sibling pairs (κ=0.17 (95% confidence interval (95% CI) 0.08 to 0.26)) indicating a significant result. Severity of the disease at assessment, using the Kurtzke and CAMBS scales, demonstrated that whereas there was no agreement for relapse rate in the previous year within the sibship, there was significant concordance for measures of disability (κ=0.11 (95% CI 0.04 to 0.19)), progression (κ=0.09 (95% CI 0.01 to 0.18)) and handicap (κ=0.08 (95% CI 0.02 to 0.14)). CONCLUSIONS Within a sibship, the clinical presentation tends to be different. However, once established, concordance is more likely to be seen for the ultimate course, leading in the end to similar disability and handicap scores. These results are consistent with the hypothesis that genes influence both disease susceptibility and evolution in multiple sclerosis.

Multiple sclerosis in south Cambridgeshire: incidence and prevalence based on a district register.

STUDY OBJECTIVE: To establish an updated prevalence and incidence figure for multiple sclerosis on 1 July 1993, to determine the fate of the 374 patients prevalent in 1990, and to establish the origin of incident patients. DESIGN: Case ascertainment was from several sources including departmental records, local branches of the Multiple Sclerosis Society, general practitioners, nursing homes, and residential facilities for the disabled. Data collection was by personal interview using a standardised questionnaire and by retrospective analysis of departmental case notes. A prospective incidence register of newly diagnosed patents was maintained from 1990. SETTING: The Cambridge Health District of East Anglia covering 340,910 hectares in area and a population of 290,700. PATIENTS: Altogether 441 patients prevalent on 1 July 1993 were identified, of whom 328 were contacted so that clinical data could be collected. Seventy patients (16%) either declined to take part or access was denied by their general practitioner; 8 (2%) had died; and 35 (8%) were too ill or failed to respond to several requests for contact. MAIN RESULTS: A comprehensive re-evaluation of the south Cambridgeshire multiple sclerosis register revealed a prevalence of 441/290,700 population (152/10(5)) for all disease classifications on 1 July 1993. This represented an increase of 18% from 1990 and was a result of 138 additions and 71 deletions from the original list of 374 patients. The sex ratio of prevalent patients was 2.6 F:M, the mean age at disease onset was 31.7 years, and the mean age was 49 years. Mortality for 1990-93 was 3.3/10(5)/year and prospective maintenance of an incidence register recorded 96 new diagnoses for all classifications of multiple sclerosis over the five year period 1990-94 (6.6/10(5)/year). CONCLUSIONS: The increase in prevalence mainly resulted from improved case ascertainment identifying a further 58 patients who had been prevalent in 1990. Comparisons with other serial studies within the United Kingdom show similarities in proportional increase with successive studies indicating that serial survey may in part account for the observed latitudinal gradient within the United Kingdom. However, the observed prevalence (152/10(5)) in this second survey still falls short of the figure estimated from incidence and mortality data (186/10(5)).

Multiple sclerosis and tonsillectomy: no evidence for an influence on the development of disease or clinical phenotype

The notion that cervical lymphatic surgery may influence the development of multiple sclerosis has been suggested before. Recent work in experimental allergic encephalomyelitis lends further support to this idea. We, therefore conducted a case: control study of tonsillectomy in multiple sclerosis. We found no evidence to suggest that tonsillectomy affect susceptibility to multiple sclerosis. This result support previous studies, which have largely failed to show any link between prior tonsillectomy and the subsequent development of multiple sclerosis. In addition, we failed to show any effect of tonsillectomy on the extent of cerebral demyelination as assessed clinically or with magnetic resonance imaging.