D. A. S. Compston

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

AbstractFrom 1991–2002, wentreated 58 patients with multiplensclerosis (MS) using the humanisednmonoclonal antibody, Campath–1H, which causes prolonged Tnlymphocyte depletion. Clinical andnsurrogate markers of inflammationnwere suppressed. In both the relapsing–remitting (RR) and secondarynprogressive (SP) stages ofnthe illness, Campath–1H reducednthe annual relapse rate (from 2.2 ton0.19 and from 0.7 to 0.001 respectively;nboth p < 0.001). Remarkably,nMRI scans of patients with SPndisease, treated with Campath–1H 7nyears previously, showed no newnlesion formation. However, despitenthese effects on inflammation,ndisability was differently affectedndepending on the phase of thendisease. Patients with SPMSnshowed sustained accumulation ofndisability due to uncontrolled progressionnmarked by unrelentingncerebral atrophy, attributable to ongoingnaxonal loss. The rate ofncerebral atrophy was greatest in patientsnwith established cerebralnatrophy and highest inflammatorynlesion burden before treatment (2.3nversus 0.7 ml/year; p = 0.04). Inncontrast, patients with RR diseasenshowed an impressive reduction inndisability at 6 months after Campath–1H (by a mean of 1.2 EDSSnpoints) perhaps owing to a suppressionnof on–going inflammationnin these patients with unusuallynactive disease. In addition, therenwas a further significant, albeitnsmaller, mean improvement inndisability up to 36 months afterntreatment.We speculate that thisnrepresents the beneficial effects ofnearly rescue of neurons and axonsnfrom a toxic inflammatory environment,nand that prevention of demyelinationnwill prevent long–termnaxonal degeneration. These conceptsnare currently being tested in ancontrolled trial comparing Campath–1H and IFN–beta in the treatmentnof drug–naïve patients withnearly, active RR MS.

The British Isles survey of multiple sclerosis in twins

During a 27-month recruitment period, we identified 146 individuals with multiple sclerosis (MS) who have a twin. A single clinician interviewed and examined 105 pairs of twins, and we confirmed zygosity using minisatellite probes. Including two suspected cases, 11 of 44 (25%) monozygotic twin pairs were concordant compared with two of 61 (3%) dizygotic twin pairs–two of 33 (6%) like-sexed and zero of 28 (0%) opposite-sexed. MRI was performed in 64 of 105 co-twins, and showed abnormalities consistent with demyelination in 13% of monozygotic and 9% of dizygotic co-twins who were clinically unaffected. These findings are similar to the results of most previous studies of MS in twins in which zygosity was not unequivocally established and where the majority of clinically unaffected co-twins were not studied by MRI; the difference in concordance rates in monozygotic and dizygotic twins indicates a significant genetic component in the etiology of MS.

Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 Clinical Trial

Objective: To report the long-term safety and efficacy results from CAMMS223 comparing alemtuzumab with interferon β-1a in early, active relapsing-remitting multiple sclerosis (RRMS). What are the long-term effects of alemtuzumab treatment, received 36 to 48 months previously, on relapse and disability in early, active RRMS? This study provides evidence of the effectiveness of alemtuzumab in reducing the relapse rate and accumulation of disability compared with interferon β-1a (IFNβ-1a) through extended follow-up (up to 60 months from baseline). Methods: Of 334 patients originally randomized, 198 participated in the extension phase (151 [68%] alemtuzumab and 47 [42%] IFNβ-1a). Disability, relapses, and safety were assessed as in the original study period. Efficacy outcomes were analyzed from baseline of the original trial period to 60 months. Safety data extended beyond 60 months. Results: Over 5 years, alemtuzumab lowered the risk of sustained accumulation of disability by 72% and the rate of relapse by 69% compared with IFNβ-1a (both p < 0.0001). The annualized relapse rate from baseline to month 60 was 0.11 for alemtuzumab and 0.35 for IFNβ-1a. Complete safety follow-up reflected 988 and 376 person-years for alemtuzumab and IFNβ-1a patients, respectively. Serious infections were seen in 7% of alemtuzumab patients and 3% of IFNβ-1a patients, and thyroid disorders were seen in 30% of alemtuzumab patients vs 4% of IFNβ-1a patients. Immune thrombocytopenia occurred in 3% of alemtuzumab patients and 0.9% of IFNβ-1a patients during the initial study period; no additional events were reported during the extension phase. One alemtuzumab patient developed Goodpasture disease 39 months after the second annual cycle of alemtuzumab. Conclusions: Through extended follow-up, alemtuzumab remained significantly more efficacious than IFNβ-1a, with a safety profile consistent with previous reports. Classification of Evidence: This study provides Class III evidence that alemtuzumab is more effective than interferon β-1a in reducing relapses and disability in patients with RRMS in a long-term follow-up of a rater-blinded, randomized clinical trial with 59.5% of patients participating in the extended follow-up period.

EDMUS, a European database for multiple sclerosis.

EDMUS is a minimal descriptive record developed for research purposes to document clinical and laboratory data in patients with multiple sclerosis (MS). It has been designed by a committee of the European Concerted Action for MS, organised under the auspices of the Commission of the European Communities. The software is user-friendly and fast, with a minimal set of obligatory data. Priority has been given to analytical data and the system is capable of automatically generating data, such as diagnosis classification, using appropriate algorithms. This procedure saves time, ensures a uniform approach to individual cases and allows automatic updating of the classification whenever additional information becomes available. It is also compatible with future developments and requirements since new algorithms can be entered in the programme when necessary. This system is flexible and may be adapted to the users needs. It is run on Apple and IBM-PC personal microcomputers. Great care has been taken to preserve confidentiality of the data. It is anticipated that this common language will enable the collection of appropriate cases for specific purposes, including population-based studies of MS and will be particularly useful in projects where the collaboration of several centres is needed to recruit a critical number of patients.

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.

Increasing prevalence and incidence of multiple sclerosis in South East Wales

Background and aim: Epidemiological studies of multiple sclerosis suggest a trend of increasing disease prevalence in susceptible populations. The reasons for this are unclear and may be the results of methodological differences between studies, incomplete ascertainment or advances in technologies that allow the increased identification of early or mild disease. In addition, direct comparison of cross sectional prevalence estimates performed in different epochs in ethnically and geographically distinct populations may be inappropriate. Methods: Using detailed phenotypic information and standardised methodology, a geographically defined Welsh population was resurveyed after a significant interval, establishing contemporary prevalence rates and examining demographic and clinical data to determine causes of changing disease frequency. Results: Disease prevalence increased 45% from 101 to 146 per 100u2009000 population over 20 years. The greatest increase was observed in women between the ages of 45 and 54 years. No significant increase in disease frequency was observed in the male population overall, or within specific age groups. There was no demographic evidence for a pattern of earlier age at onset or diagnosis to explain increased disease frequency or decrease in mean age of the prevalent population. In addition, we failed to identify a pattern of recognition of patients with less severe disability. Although there was a modest 13% increase of 2.2 years in mean disease duration, and eight new previously prevalent patients were identified, the main cause of rising disease frequency was related to a 2.8-fold increase in disease incidence for women over 23 years from 2.65 to 7.30/100u2009000/year increasing the sex ratio of incident patients from 1.8 to 4.3 (women:men). Conclusion: Recent change in disease incidence and prevalence in this population is likely to be the result of environmental factors that have been operative in the past few decades in women alone and infers avoidable risk factors. Modelling of current overall incidence suggests a further increase in prevalence to 260 per 100u2009000 population within the next 20–40 years. Further studies are needed in order to identify recent changes in sex specific environment and lifestyle that confer susceptibility.

Survival and cause of death in multiple sclerosis: a prospective population-based study

Background: Detailed studies of mortality in multiple sclerosis (MS) are limited. Studying death certificates in a prospective cohort of patients known to have MS is of value in establishing mortality data and can also provide important information on the accuracy and use of death certificates for epidemiological studies. Methods: A population-based survey performed in South Wales in 1985 identified 441 patients. Cases were flagged with the Office of Population Censuses and Surveys and death certificates collected prospectively for more than 20 years. Results: Median observed survival time was 38.0 years from symptom onset. Mean age at death was 65.3 for women and 65.2 years for men. Mean age at death in patients dying from MS-related causes was 62.5 and 69.3 years (p<0.001) for unrelated deaths. Those dying of MS-related causes had a younger age at disease onset (32.5) compared with those dying of unrelated causes (36.8 years) (pu200a=u200a0.01). Cause of death was related to MS in 57.9% and unrelated in 42.1% of individuals. In 27% of patients, “MS” was absent from the death certificate. The most common cause of death was respiratory disease (47.5%). The standardised mortality ratio was 2.79 (95% CI 2.44 to 3.18) so that MS patients were almost three times more likely to die prematurely relative to the general population. Conclusions: These results confirm a continuing trend of premature death in patients with MS. Relying on data derived from death certificates will underestimate disease prevalence. Differences were identified between those dying from MS-related causes and those dying from other causes.

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

Microglia-derived IGF-2 prevents TNFα induced death of mature oligodendrocytes in vitro

Insulin-like growth factor-2 (IGF-2) present in media conditioned by non-activated and interferon gamma (IFN gamma)-treated microglia reduces galactocerebroside(+) (GalC) oligodendrocyte apoptosis in cultures derived both from the CG4 cell line and primary rat cortices. Microglia-derived IGF-2 also acts in each culture system to block GalC(+) oligodendrocyte toxicity resulting from soluble microglial-derived tumour necrosis factor alpha (TNF alpha). IGF-2 inhibits TNF alpha-induced c-Jun kinase (JNK) activation of the CG4 cell line. Microglial activation results in the release of soluble factors that are potentially toxic to oligodendrocytes but this may be offset by the production of soluble factors that protect these vulnerable cells. Allowing for extrapolation of these in vitro findings to intact tissue, our observations suggest one mechanism for limiting bystander damage in the context of inflammatory brain disease.

Change in disability in patients with multiple sclerosis: a 20-year prospective population-based analysis

Background: In patients with multiple sclerosis (MS), the natural history of the disease is of considerable importance to predict and understand long-term outcome and inform choices made by patients and clinicians. This information should ideally be derived from data that reflects the entire disease course. Methods: In this study, morbidity data from a prevalent cohort established in 1985 have been re-examined after an interval of 20 years to assess factors that may be important in determining outcome. Results: Of 379 patients who fulfilled criteria for definite or probable MS in the original population-based cohort, 221 (58.3%) had died, 149 (39.3%) were alive and 9 (2.4%) were untraceable. Mean Expanded Disability Status Scale (EDSS) score in 1985 was 5.15 (SD 2.7, range 0–9.5) and 8.01 (SD 2.6, range 0–10) in those alive in 2005. Mean worsening of EDSS scores in surviving patients was +3.02 EDSS points, but 14.0% had worsened by <1 EDSS point over 20 years. 61.4% of patients with EDSS 3.5–5.5 and 82.2% of those with an EDSS of ⩽3 in 1985 had an EDSS of ⩾6 after 20 years. Lower baseline EDSS scores (p<0.0001), higher pyramidal functional system score (pu200a=u200a0.02) and a greater number of functional systems involved (pu200a=u200a0.001) were significantly more likely to be associated with greater worsening of disability. Of those with benign disease in 1985, only 19% remained benign after 20 years of follow-up; however, 12.6% of patients had minimal disability after at least 20 years after their disease onset and 14% of patients failed to worsen by ⩾1 EDSS point. Conclusions: This study emphasises the importance of long-term epidemiological studies and the development of clinically relevant measures that effectively predict outcome and can guide decisions on therapeutic management.