Migration and multiple sclerosis in immigrants to Australia from United Kingdom and Ireland: a reassessment. I. Risk of MS by age at immigration

A previous study of the prevalence of multiple sclerosis (MS) in 1981 among immigrants from the United Kingdom and Ireland to Australia found that the prevalence for those with age at immigration (AAI) under 15 years of age did not differ from the older immigrants. We have reanalysed the original materials as well as census data for 1901–1981 for UKI and other high MS risk country immigrants. There was a highly significant trend in the prevalence rates of all Australians from New South Wales (NSW) to South Australia (SA) to Western Australia (WA) to Queensland (QLD). Rates by state among the Australian-born were almost identical to these, but there was no prevalence gradient for the UKI-born. The denominator population at risk of MS by AAI was calculated from special census tables of length of residence in Australia by age 0–79 in 1981 for UKI immigrants 1947–1981. The numerator was limited to the subset of 258 MS (Group II) also immigrating in 1947 and later, and age 0–79 in 1981. The absolute risk of MS for these migrants to the four states entering at age 0–14 was 22/100,000, significantly less than for all older age groups; age 15–39 immigrants had a risk of 54/100,000. Similar risk ratios for 0–14 versus 15–39 by state were 31 versus 61 (NSW), 29 versus 44 (QLD), 11 versus 50 (SA), 15 versus 51 (WA)

The multiple sclerosis risk sharing scheme monitoring study - early results and lessons for the future

Background: Risk sharing schemes represent an innovative and important approach to the problems of rationing and achieving cost-effectiveness in high cost or controversial health interventions. This study aimed to assess the feasibility of risk sharing schemes, looking at long term clinical outcomes, to determine the price at which high cost treatments would be acceptable to the NHS. Methods: This case study of the first NHS risk sharing scheme, a long term prospective cohort study of beta interferon and glatiramer acetate in multiple sclerosis ( MS) patients in 71 specialist MS centres in UK NHS hospitals, recruited adults with relapsing forms of MS, meeting Association of British Neurologists (ABN) criteria for disease modifying therapy. Outcome measures were: success of recruitment and follow up over the first three years, analysis of baseline and initial follow up data and the prospect of estimating the long term cost-effectiveness of these treatments. Results: Centres consented 5560 patients. Of the 4240 patients who had been in the study for a least one year, annual review data were available for 3730 (88.0%). Of the patients who had been in the study for at least two years and three years, subsequent annual review data were available for 2055 (78.5%) and 265 (71.8%) patients respectively. Baseline characteristics and a small but statistically significant progression of disease were similar to those reported in previous pivotal studies. Conclusion: Successful recruitment, follow up and early data analysis suggest that risk sharing schemes should be able to deliver their objectives. However, important issues of analysis, and political and commercial conflicts of interest still need to be addressed

Optimization of treatment with interferon beta in multiple sclerosis. Usefulness of automatic system application criteria

<p>Abstract</p> <p>Background</p> <p>A software based tool has been developed (Optem) to allow automatize the recommendations of the Canadian Multiple Sclerosis Working Group for optimizing MS treatment in order to avoid subjective interpretation.</p> <p>Methods</p> <p>Treatment Optimization Recommendations (TORs) were applied to our database of patients treated with IFN β1a IM. Patient data were assessed during year 1 for disease activity, and patients were assigned to 2 groups according to TOR: "change treatment" (CH) and "no change treatment" (NCH). These assessments were then compared to observed clinical outcomes for disease activity over the following years.</p> <p>Results</p> <p>We have data on 55 patients. The "change treatment" status was assigned to 22 patients, and "no change treatment" to 33 patients. The estimated sensitivity and specificity according to last visit status were 73.9% and 84.4%. During the following years, the Relapse Rate was always higher in the "change treatment" group than in the "no change treatment" group (5 y; CH: 0.7, NCH: 0.07; p < 0.001, 12 m – last visit; CH: 0.536, NCH: 0.34). We obtained the same results with the EDSS (4 y; CH: 3.53, NCH: 2.55, annual progression rate in 12 m – last visit; CH: 0.29, NCH: 0.13).</p> <p>Conclusion</p> <p>Applying TOR at the first year of therapy allowed accurate prediction of continued disease activity in relapses and disability progression.</p

Influence of FK 506 (tacrolimus) on circulating CD4 ⁺ t cells expressing cd25 and cd45ra antigens in 19 patients with chronic progressive multiple sclerosis participating in an open label drug safety trial

We have taken the opportunity of a clinical trial of the potential efficacy and safety of FK 506 (tacrolimus) in chronic progressive multiple sclerosis (MS) to examine the influence of this potent new immunosuppressant on circulating T-lymphocytes in an otherwise healthy non-transplant population. Peripheral blood levels of subsets of CD4+ T lymphocytes expressing the activation molecule interleukin-2 receptor (p55 α chain; CD25) or the CD45RA isoform were determined sequentially in 19 patients that were treated continuously with oral FK 506 (starting dose 0.15 mg/kg/day) for 12 months. No significant change in the proportion of circulating CD25 + CD4+ cells was observed over the study period in which the mean trough plasma FK 506 level rose from 0.3 ±0.2 to 0.5 ±0.4 ng/ml. There was also no significant effect of FK 506 on the percentage of CD45RA + CD4 + cells in the peripheral blood at 12 months compared with pretreatment values. Analysis of a subgroup of 7 patients, who showed a sustained reduction in CD25 + CD4+ cells and a reciprocal increase in CD45RA* CD4 * cells for at least 6 months after start of treatment, did not reveal any difference in disability at one year compared with the treatment group as a whole. The side effects of FK 506 were mild and the overall degree of disability estimated by the mean Kurtzke expanded disability status scale (EDSS) score or the ambulation index did not deteriorate significantly in the 19 patients studied over the 12 months of FK 506 administration. © 1994 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted

Variational Approach to the Modulational Instability

We study the modulational stability of the nonlinear Schr\"odinger equation (NLS) using a time-dependent variational approach. Within this framework, we derive ordinary differential equations (ODEs) for the time evolution of the amplitude and phase of modulational perturbations. Analyzing the ensuing ODEs, we re-derive the classical modulational instability criterion. The case (relevant to applications in optics and Bose-Einstein condensation) where the coefficients of the equation are time-dependent, is also examined

Protocol for the saMS trial (supportive adjustment for multiple sclerosis): a randomized controlled trial comparing cognitive behavioral therapy to supportive listening for adjustment to multiple sclerosis

BackgroundMultiple Sclerosis (MS) is an incurable, chronic, potentially progressive and unpredictable disease of the central nervous system. The disease produces a range of unpleasant and debilitating symptoms, which can have a profound impact including disrupting activities of daily living, employment, income, relationships, social and leisure activities, and life goals. Adjusting to the illness is therefore particularly challenging. This trial tests the effectiveness of a cognitive behavioural intervention compared to supportive listening to assist adjustment in the early stages of MS.MethodsThis is a two arm randomized multi-centre parallel group controlled trial. 122 consenting participants who meet eligibility criteria will be randomly allocated to receive either Cognitive Behavioral Therapy or Supportive Listening. Eight one hour sessions of therapy (delivered over a period of 10 weeks) will be delivered by general nurses trained in both treatments. Self-report questionnaire data will be collected at baseline (0 weeks), mid-therapy (week 5 of therapy), post-therapy (15 weeks) and at six months (26 weeks) and twelve months (52 weeks) follow-up. Primary outcomes are distress and MS-related social and role impairment at twelve month follow-up. Analysis will also consider predictors and mechanisms of change during therapy. In-depth interviews to examine participants’ experiences of the interventions will be conducted with a purposively sampled sub-set of the trial participants. An economic analysis will also take place. DiscussionThis trial is distinctive in its aims in that it aids adjustment to MS in a broad sense. It is not a treatment specifically for depression. Use of nurses as therapists makes the interventions potentially viable in terms of being rolled out in the NHS. The trial benefits from incorporating patient input in the development and evaluation stages. The trial will provide important information about the efficacy, cost-effectiveness and acceptability of the interventions as well as mechanisms of psychosocial adjustment.Trial registrationCurrent Controlled Trials ISRCTN91377356<br/

Longitudinal Assessment of Antisaccades in Patients with Multiple Sclerosis

We have previously demonstrated that assessment of antisaccades (AS) provides not only measures of motor function in multiple sclerosis (MS), but measures of cognitive control processes in particular, attention and working memory. This study sought to demonstrate the potential for AS measures to sensitively reflect change in functional status in MS. Twenty-four patients with relapsing-remitting MS and 12 age-matched controls were evaluated longitudinally using an AS saccade task. Compared to control subjects, a number of saccade parameters changed significantly over a two year period for MS patients. These included saccade error rates, latencies, and accuracy measures. Further, for MS patients, correlations were retained between OM measures and scores on the PASAT, which is considered the reference task for the cognitive evaluation of MS patients. Notably, EDSS scores for these patients did not change significantly over this period. These results demonstrate that OM measures may reflect disease evolution in MS, in the absence of clinically evident changes as measured using conventional techniques. With replication, these markers could ultimately be developed into a cost-effective, non-invasive, and well tolerated assessment tool to assist in confirming progression early in the disease process, and in measuring and predicting response to therapy

On non-local variational problems with lack of compactness related to non-linear optics

We give a simple proof of existence of solutions of the dispersion manage- ment and diffraction management equations for zero average dispersion, respectively diffraction. These solutions are found as maximizers of non-linear and non-local vari- ational problems which are invariant under a large non-compact group. Our proof of existence of maximizer is rather direct and avoids the use of Lions' concentration compactness argument or Ekeland's variational principle.Comment: 30 page

Evidence for a two-stage disability progression in multiple sclerosis

It is well documented that disability accumulation in multiple sclerosis is correlated with axonal injury and that the extent of axonal injury is correlated with the degree of inflammation. However, the interdependence between focal inflammation, diffuse inflammation and neurodegeneration, and their relative contribution to clinical deficits, remains ambiguous. A hypothesis might be that early focal inflammation could be the pivotal event from which all else follows, suggesting the consideration of multiple sclerosis as a two-stage disease. This prompted us to define two phases in the disease course of multiple sclerosis by using two scores on the Kurtzke Disability Status Scale as benchmarks of disability accumulation: an early phase, ‘Phase 1’, from multiple sclerosis clinical onset to irreversible Disability Status Scale 3 and a late phase, ‘Phase 2’, from irreversible Disability Status Scale 3 to irreversible Disability Status Scale 6. Outcome was assessed through five parameters: Phase 1 duration, age at Disability Status Scale 3, time to Disability Status Scale 6 from multiple sclerosis onset, Phase 2 duration and age at Disability Status Scale 6. The first three were calculated among all patients, while the last two were computed only among patients who had reached Disability Status Scale 3. The possible influence of early clinical markers on these outcomes was studied using Kaplan–Meier estimates and Cox models. The analysis was performed in the Rennes multiple sclerosis database (2054 patients, accounting for 26 273 patient-years) as a whole, and according to phenotype at onset (1609 relapsing/445 progressive onset). Our results indicated that the disability progression during Phase 2 was independent of that during Phase 1. Indeed, the median Phase 2 duration was nearly identical (from 6 to 9 years) irrespective of Phase 1 duration (<3, 3 to <6, 6 to <10, 10 to <15, ≥15 years) in the whole population, and in both phenotypes. In relapsing onset multiple sclerosis, gender, age at onset, residual deficit after the first relapse and relapses during the first 2 years of multiple sclerosis were found to be independent predictive factors of disability progression, but only during Phase 1. Our findings demonstrate that multiple sclerosis disability progression follows a two-stage process, with a first stage probably dependant on focal inflammation and a second stage probably independent of current focal inflammation. This concept has obvious implications for the future therapeutic strategy in multiple sclerosis

A comparative analysis of Patient-Reported Expanded Disability Status Scale tools.

BACKGROUND: Patient-Reported Expanded Disability Status Scale (PREDSS) tools are an attractive alternative to the Expanded Disability Status Scale (EDSS) during long term or geographically challenging studies, or in pressured clinical service environments. OBJECTIVES: Because the studies reporting these tools have used different metrics to compare the PREDSS and EDSS, we undertook an individual patient data level analysis of all available tools. METHODS: Spearman's rho and the Bland-Altman method were used to assess correlation and agreement respectively. RESULTS: A systematic search for validated PREDSS tools covering the full EDSS range identified eight such tools. Individual patient data were available for five PREDSS tools. Excellent correlation was observed between EDSS and PREDSS with all tools. A higher level of agreement was observed with increasing levels of disability. In all tools, the 95% limits of agreement were greater than the minimum EDSS difference considered to be clinically significant. However, the intra-class coefficient was greater than that reported for EDSS raters of mixed seniority. The visual functional system was identified as the most significant predictor of the PREDSS-EDSS difference. CONCLUSION: This analysis will (1) enable researchers and service providers to make an informed choice of PREDSS tool, depending on their individual requirements, and (2) facilitate improvement of current PREDSS tools.University of Southampton and National Institute of Health Research (NIHR)