Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis.

BACKGROUND: On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also known as a clinically isolated syndrome) to multiple sclerosis. METHODS: During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on T2-weighted MRI, cumulative number of new lesions enhanced on T1-weighted MRI ["enhancing lesions"], and cumulative combined number of unique lesions [new enhancing lesions on T1-weighted MRI plus new and newly enlarged lesions on T2-weighted MRI]). RESULTS: A total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 to 43.9; P=0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P=0.01); the unadjusted risk difference was not significant at the 24-month secondary outcome time point (P=0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo. CONCLUSIONS: The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887 .).

Multiple sclerosis in the Iranian immigrant population of BC, Canada: prevalence and risk factors.

BACKGROUND: There is a well-documented increase in the risk of multiple sclerosis (MS) when migrating from a region of low prevalence to one of high prevalence. OBJECTIVE: We present here an investigation of MS prevalence and candidate environmental and genetic risk factors among Iranian immigrants to British Columbia (BC), Canada. METHODS: MS cases of Iranian ancestry were ascertained from a population-based Canadian study. We collected blood samples for genetic and serological analyses, and administered a personal history questionnaire to the cases. RESULTS: The crude prevalence of MS in this population of Iranian ancestry was 287/100,000 (95% CI: 229 - 356/100,000). MS cases were more likely to have a history of infectious mononucleosis (odds ratio (OR) = 7.5; p = 0.005) and smoking (OR = 17.0; p < 0.0001), as compared to healthy controls from previous studies in Iran. Cases were also more likely than controls to have been born between April and September (OR = 2.1; p = 0.019). CONCLUSION: The prevalence of MS among Iranian immigrants to Canada is greater than the overall prevalence of MS in Iran by a factor of at least four, and is similar to that recently observed among Iranian immigrants in other western nations. No major genetic susceptibility variants were identified, suggesting the environment in Canada may be what is increasing the risk of MS in this population.

Gammaherpesvirus infection drives age-associated B cells toward pathogenicity in EAE and MS.

While age-associated B cells (ABCs) are known to expand and persist following viral infection and during autoimmunity, their interactions are yet to be studied together in these contexts. Here, we directly compared CD11c+T-bet+ ABCs using models of Epstein-Barr virus (EBV), gammaherpesvirus 68 (γHV68), multiple sclerosis (MS), and experimental autoimmune encephalomyelitis (EAE), and found that each drives the ABC population to opposing phenotypes. EBV infection has long been implicated in MS, and we have previously shown that latent γHV68 infection exacerbates EAE. Here, we demonstrate that ABCs are required for γHV68-enhanced disease. We then show that the circulating ABC population is expanded and phenotypically altered in people with relapsing MS. In this study, we show that viral infection and autoimmunity differentially affect the phenotype of ABCs in humans and mice, and we identify ABCs as functional mediators of viral-enhanced autoimmunity.

A retrospective analysis of changes in lymphocyte levels in patients with multiple sclerosis during and after Tecfidera® treatment.

BACKGROUND: There are currently no best practice recommendations for lymphocyte subset monitoring for patients with multiple sclerosis (pwMS) on disease-modifying therapies including Tecfidera® (dimethyl fumarate, DMF). However, there have been several cases of pwMS on DMF without severe lymphopenia who had high CD4:CD8 T cell ratios and went on to develop progressive multifocal leukoencephalopathy. OBJECTIVE: Our objective was to characterize the changes in immune profile during and after DMF treatment in pwMS. METHODS: A retrospective analysis of longitudinal data from 299 pwMS who have been treated with DMF at the Fraser Health Multiple Sclerosis Clinic in British Columbia, Canada. The blood test results were taken from January 1, 2013 to April 1, 2020. RESULTS: Our results suggest that CD8+ T cells had the highest proportional decrease compared to other lymphocyte subset populations and overall lymphocyte count in response to DMF treatment. CD56+ Natural Killer cells were similarly decreased in response to DMF treatment. CD4:CD8 T cell ratio was the measurement that had the highest rate of change in response to DMF initiation and discontinuation. CONCLUSION: CD8+ T cell count and CD4:CD8 T cell ratio may be a more sensitive measurement of the immune landscape of patients with MS on DMF.

Multiple sclerosis and related challenges to young women's health: Canadian expert review.

Multiple sclerosis (MS) is among the most common chronic neurological diseases, with a highly variable degree of disability during its long-term course. The majority of patients develop significant permanent disability later in life. MS is often diagnosed in women of childbearing age, with a 3:1 ratio of young women to young men with MS. Comorbidities such as depression, anxiety, migraines and reproductive, urological and bowel issues are common and negatively impact patients' quality of life. The objective of this supplement is to review the most common comorbidities occurring in young women with MS, and to propose a multidisciplinary, holistic approach to management.

Short-Term Motor Learning and Retention During Visually Guided Walking in Persons With Multiple Sclerosis.

BACKGROUND: The ability to adapt, a form of short-term motor learning, and retain this adaptation, is essential for rehabilitation and for day-to-day living. Yet little research is available on this topic in persons with multiple sclerosis (PwMS), particularly in relation to complex walking tasks. OBJECTIVE: To determine the ability of PwMS to learn and retain a novel relationship between visual input and motor output-or visuomotor map-during visually guided walking. METHODS: Nineteen PwMS and 17 healthy controls performed a precision walking task while adapting to prism lenses that altered the normal visuomotor map on 1 day, and again after a 1-week delay. The task required individuals to walk and step onto 2 targets without stopping. To quantify motor performance, we determined foot placement error relative to the targets. RESULTS: PwMS with mild disability and healthy controls attenuated foot placement error over repeated trials when exposed to the novel mapping and demonstrated a similar rate and magnitude of adaptation in the first learning session. Both groups equally retained the adaptation 1 week later, reflected by reduced foot placement error and a faster rate of error reduction in that session. CONCLUSION: PwMS can learn and retain a novel visuomotor mapping during a precision-based walking task. This suggests that PwMS with mild disability have the capacity for short-term motor learning and retention, indicating that neural plasticity is preserved.