Helen Tremlett

Higher 25-hydroxyvitamin D Is Associated with Lower Relapse Risk in Multiple Sclerosis

A protective association between higher vitamin D levels and the onset of multiple sclerosis (MS) has been demonstrated; however, its role in modulating MS clinical course has been little studied. We investigated whether higher levels of serum 25‐hydroxyvitamin D (25‐OH‐D) were associated with a lower risk of relapses in people with MS.

Disability progression in multiple sclerosis is slower than previously reported

Objective: To investigate disease progression and risk factors in a large geographically based population with multiple sclerosis (MS), using two different inception points—clinical onset and date of birth. Methods: The authors reviewed a database of subjects with definite MS and symptom onset prior to July 1988. The main outcome was sustained progression to Expanded Disability Status Scale (EDSS) 6 (requires a cane), using the date of birth and date of MS onset as inception points in separate analyses. Risk factors examined were sex, relapsing vs primary progressive course, onset age, and onset symptoms. Results: The study included 2,837 patients, followed prospectively for 22,723 patient years. The median time to EDSS 6 was 27.9 years, 15 years after onset; only 21% reached EDSS 6, and by age 50, 28% required a cane. Men progressed 38% more quickly than women from onset (p < 0.0005), yet both required canes at similar ages: 58.8 years for men and 60.1 for women (p = 0.082). A younger onset age predicted a slower progression, but those older at onset were consistently older when reaching EDSS 6. A primary progressive course predicted a more rapid progression from both onset (p < 0.0005) and birth (hazard ratio = 2.7 [95% CI: 2.2 to 3.3]). No onset symptom consistently predicted progression. Conclusion: Disability progression in multiple sclerosis (MS) accrued more slowly than found in earlier longitudinal studies. The authors also challenged two fundamental concepts in MS, demonstrating that neither male sex nor older onset age was associated with worse disease outcome.

Atlas of Multiple Sclerosis 2013: A growing global problem with widespread inequity

Multiple sclerosis (MS) is one of the worlds most common neurologic disorders, and in many countries it is the leading cause of nontraumatic neurologic disability in young adults. Despite this, global information on the epidemiology of MS and the availability of resources and services for people with MS is scarce in many regions of the world. The first Atlas of MS, published in 2008 as a joint project of the Multiple Sclerosis International Federation (MSIF) and the World Health Organization (WHO),1 endeavored to fill this knowledge gap with information from 112 countries. Here, we outline important updates in the recently launched Atlas of MS 2013: Mapping Multiple Sclerosis around the World.2

Association Between Use of Interferon Beta and Progression of Disability in Patients With Relapsing-Remitting Multiple Sclerosis

CONTEXT Interferon beta is widely prescribed to treat multiple sclerosis (MS); however, its relationship with disability progression has yet to be established. OBJECTIVE To investigate the association between interferon beta exposure and disability progression in patients with relapsing-remitting MS. DESIGN, SETTING, AND PATIENTS Retrospective cohort study based on prospectively collected data (1985-2008) from British Columbia, Canada. Patients with relapsing-remitting MS treated with interferon beta (n = 868) were compared with untreated contemporary (n = 829) and historical (n = 959) cohorts. MAIN OUTCOME MEASURES The main outcome measure was time from interferon beta treatment eligibility (baseline) to a confirmed and sustained score of 6 (requiring a cane to walk 100 m; confirmed at >150 days with no measurable improvement) on the Expanded Disability Status Scale (EDSS) (range, 0-10, with higher scores indicating higher disability). A multivariable Cox regression model with interferon beta treatment included as a time-varying covariate was used to assess the hazard of disease progression associated with interferon beta treatment. Analyses also included propensity score adjustment to address confounding by indication. RESULTS The median active follow-up times (first to last EDSS measurement) were as follows: for the interferon beta-treated cohort, 5.1 years (interquartile range [IQR], 3.0-7.0 years); for the contemporary control cohort, 4.0 years (IQR, 2.1-6.4 years); and for the historical control cohort, 10.8 years (IQR, 6.3-14.7 years). The observed outcome rates for reaching a sustained EDSS score of 6 were 10.8%, 5.3%, and 23.1% in the 3 cohorts, respectively. After adjustment for potential baseline confounders (sex, age, disease duration, and EDSS score), exposure to interferon beta was not associated with a statistically significant difference in the hazard of reaching an EDSS score of 6 when either the contemporary control cohort (hazard ratio, 1.30; 95% CI, 0.92-1.83; P = .14) or the historical control cohort (hazard ratio, 0.77; 95% CI, 0.58-1.02; P = .07) were considered. Further adjustment for comorbidities and socioeconomic status, where possible, did not change interpretations, and propensity score adjustment did not substantially change the results. CONCLUSION Among patients with relapsing-remitting MS, administration of interferon beta was not associated with a reduction in progression of disability.

Interrupted therapy Stopping and switching of the β-interferons prescribed for MS

A retrospective chart review of patients in British Columbia with multiple sclerosis prescribed β-interferon (IFNβ) between 1995 and 2001 was carried out to investigate reasons for the interruption of therapy. The highest proportion of interruptions (76/281; 27%) occurred in the first 6 months. The single most common reason was perceived lack of efficacy, cited by 84 of 281 (30%). Gender, disability, and disease duration were identified as factors influencing interruption of IFNβ therapy.

New perspectives in the natural history of multiple sclerosis

Multiple sclerosis (MS) has entered an era of immunomodulatory drug treatment, the impact of which on long-term disease progression remains controversial. The increasing use of these therapies has intensified our need to understand the true natural history of MS. The MS community is poised to establish whether the immunomodulatory drugs exhibit long-term benefits, with a suitable untreated natural history cohort likely the most practical and ethical comparator group. Thus, a thorough understanding of the natural history of MS is fundamental. In this review, we highlight recent advances in MS natural history over the last 5 years, with a focus on long-term population-based cohorts and factors associated with disease progression. Survival in MS has increased and longer times to irreversible disability have been reported in contemporary studies, indicating a slower accumulation of disability. Wide variation in the MS disease trajectory is evident within and between natural history studies, reflecting both methodologic considerations related to data collection and heterogeneity of disease activity. Recent publications have indicated that a younger age at disease onset is no longer indicative of a favorable outcome and further evidence supports the dissociation between relapses and long-term disability, although windows of opportunity may exist for some patients. We are now perhaps faced with our last chance to examine the true natural history of MS, so whether the reader is a practicing physician, health care provider, or researcher, or engaged in the pharmaceutical industry or in clinical trial design, recent advances in our understanding of the natural history of MS are of key significance.

Impact of multiple sclerosis relapses on progression diminishes with time.

Objective: The relationship between relapses and long-term disability in multiple sclerosis (MS) remains to be fully elucidated. Current literature is conflicting and focused on early relapses. We investigated the effects of relapses at different stages on disability progression. Methods: We conducted a retrospective review of 2,477 patients with definite relapsing-onset MS followed until July 2003 in British Columbia, Canada. Time-dependent Cox proportional hazards models examined the effect of relapses at different time periods (0–5; >5–10; >10 years postonset) on time to cane (Expanded Disability Status Scale [EDSS]) and secondary progressive MS (SPMS). Findings were derived from hazard ratios with 95% confidence intervals (CIs), adjusted for sex, onset age, and symptoms. Results: Mean follow-up was 20.6 years; 11,722 postonset relapses were recorded. An early relapse (within 5 years postonset) was associated with an increased hazard in disease progression over the short term, by 48%; 95% CI 37%–60% for EDSS 6 and 29%; 95% CI 20%–38% for SPMS. However, this substantially lessened to 10%; 95% CI 4%–16% (EDSS 6) and 2%; 95% CI −2%–7% (SPMS) after 10 years postonset. The impact of later relapses (>5–10 years postonset) also lessened over time. Effects were modulated by age, impact being greatest in younger (<25 years at onset) and least in older (≥35 years) patients where relapses beyond 5–years postonset typically failed to reach significance. Relapses during SPMS had no measurable impact on time to EDSS 6 from SPMS. Conclusion: Relapses within the first 5 years of disease impacted on disease progression over the short term. However, the long-term impact was minimal, either for early or later relapses. Long-term disease progression was least affected by relapses in patients with an extended disease duration (>10 years) or already in the secondary progressive phase.

Randomized multicenter trial of natalizumab in acute MS relapses Clinical and MRI effects

concept. 3) The authors go on to make the curious claim that the term “new onset epilepsy” is not of importance, and that “efficacy and safety of AEDs are not determined by how long the diagnosis has been established.” In fact, there has been a great deal of recent investigation regarding the prognosis in patients with newly diagnosed epilepsy, vs those who have already failed AEDs. The studies seem to provide evidence that in fact whether a patient is newly diagnosed may be equally as important as epilepsy syndrome in determining outcome of AED therapy.19 In addition, as noted above, since this is the way patients were defined for the purposes of the studies that were performed (newly diagnosed vs refractory), we had very little choice in selection of terms. 4) The authors are concerned about a study that in their minds presents “violations of evidence-based clinical management.” The study in question evaluated topiramate in patients with newly diagnosed epilepsy.20 In this blinded study, patients were randomized to topiramate vs either valproate or carbamazepine, based on the choice of the treating physician. They correctly point out that 27% of the patients randomized to treatment with carbamazepine in fact had IGE. Randomization to treatment based on physician preference, may be considered to be as valid a methodology as any other, since it may mimic “real life.” In fact, the guideline does not specifically say that topiramate is effective in either partial or generalized epilepsy. 5) Another concern is that seizure freedom was not used as an outcome measure, and this “might bias towards less effective drugs.” In fact, as noted in the guidelines, seizure freedom is rarely reported in the literature, and therefore could not consistently be used. 6) Again, the authors are concerned about imprecise and ambiguous classification with respect to generalized tonic clonic convulsions (GTCCs). As noted above, the recommendations are based on the populations that were included in the trial, whether they represent a precise seizure classification or not. It is unclear where the authors concerns rest. They claim that “GTCS are erroneously evaluated either as a type of epilepsy or as any type of generalized seizures.” In fact, this is not the case. Under the category of generalized epilepsy, the data is presented for any study that would be included in that category. The only study that was identified, was one performed with topiramate in generalized tonic clonic convulsions. It is clearly stated both in the practice parameter as well as in the table that accompanies it, that the evidence specifically addresses refractory GTCC. In addition, there is a discussion that this may not be translatable to patients with similar syndromes, but not refractory disease. 7) The authors claim that the QSS and TTA do not provide any recommendations regarding established documentation of harmful effects of certain AEDs. We had a great deal of difficulty handling adverse events in an evidence-based fashion. Of course, most adverse event data derives from case reports rather than randomized controlled trials. Determining attribution can be very tricky in these cases. Going beyond the adverse events that are listed in the parameter, would have been going beyond the available evidence. 8) The final, and perhaps most damning claim, is that the QSS and TTA report “make invalid presumptions in favor of gabapentin and applications of the recommendations in specified group such as children.” We truly hope that this is not the case. Since no examples are provided, we cannot address this claim specifically, other than to indicate that gabapentin was evaluated in the same way as all other drugs, and the recommendations for children also followed a strict evidence-based methodology. In summary, we totally support the authors’ conclusion that clinical trials should insist on precise diagnostic definition of populations studied. However, we cannot agree that our practice parameter was in any way misleading, incorrect, or biased. The authors would like to see recommendations that “reinforce best clinical practice.” However, evidence-based guidelines are specifically designed not to make recommendations that go beyond the available evidence.

Monthly Ambient Sunlight, Infections and Relapse Rates in Multiple Sclerosis

Background: Monthly variation in multiple sclerosis (MS) relapses has been found. The relationship between seasonal environmental factors, infections, serum vitamin D [25(OH)D] and MS relapses is undetermined. Methods: We prospectively followed a population-based cohort of relapsing-remitting (RR) MS patients in Southern Tasmania for a mean 2.3 years (January 2002–April 2005). Associations between monthly ambient environmental factors, estimated serum 25(OH)D, upper respiratory tract (URT) infections and relapse rates were examined using weighted Pearson’s correlation and linear regression. Results: Of 199 definite MS patients, 142 had RRMS. The lowest relapse rate of 0.5 per 1,000 days (95% CI: 0.2–1.3) occurred in February (mid-late summer) versus the March–January RR of 1.1 per 1,000 days (95% CI: 0.9–1.3; p = 0.018, weighted regression). Monthly relapse rates correlated with: (1) prior erythemal ultraviolet radiation (EUV): lagged 1.5 months, r = –0.32, p = 0.046; (2) URT infection rate: no lag, r = 0.39, p = 0.014; (3) 25(OH)D: no lag, r = –0.31, p = 0.057. The association between URT infections and relapses was reduced after adjustment for monthly EUV. Conclusions: Relapse rates were inversely associated with EUV and serum 25(OH)D levels and positively associated with URT infections. The demonstrated lag between EUV but not 25(OH)D and relapse rates is consistent with a role for EUV-generated 25(OH)D in the alteration of relapse rates. Future work on the association between URT infections and relapses should be considered in the context of ultraviolet radiation and vitamin D.

Longitudinal follow-up of "benign" multiple sclerosis at 20 years.

Objective: To evaluate disease status after 20 years in a cohort defined as “benign multiple sclerosis (MS)” (Expanded Disability Status Scale [EDSS] score ≤ 3) at 10 years from onset. Methods: Patients with an EDSS score ≤ 3 at 10 (± 1) years from onset were selected from the British Columbia MS clinic database. The 20-year EDSS score was the primary outcome. Potential risk factors differentiating those who “continued benign” (EDSS score ≤ 3.0) from those who were “no longer benign” (EDSS score > 3.0) at 20 years, including age at onset, onset symptoms, and 10-year EDSS score, were analyzed, and lower 10-year EDSS score cutoffs were investigated. Results: Twenty-year EDSS scores were obtained for 169 of 200 patients (84.5%); of these, 88 (52.1%) continued benign, but 36 (21.3%) progressed to require the use of a cane (EDSS score ≥ 6). Conversion to secondary progressive MS occurred in 45 of 196 patients (23%) with a relapsing–remitting onset. The only variable associated with disease progression at 20 years was the 10-year EDSS score (p < 0.0005); no 10-year EDSS score seemed ideal in predicting benign status, and an EDSS score ≤ 2 resulted in 32% becoming no longer benign. Discussion: At 10 years from onset, neither an Expanded Disability Status Scale (EDSS) score ≤ 3 nor an EDSS score ≤ 2 adequately represented “benign multiple sclerosis (MS)” because an appreciable proportion of patients progressed in disease severity. Appropriate and reliable criteria to identify which patients with MS remain with mild disability over the long term have yet to be determined.