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ImportanceMaternal cardiac disease is associated with impaired placentation and adverse neonatal outcomes, but whether it increases the risk of subsequent neurodevelopmental disorders in offspring remains unknown.ObjectiveTo assess the associations between pre-existing maternal cardiovascular disease (CVD) and attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID) in offspring.DesignPopulation-based cohort study.SettingSweden and British Columbia (BC), Canada.ParticipantsSingletons live-born without major malformations between 1990 and 2019. The Swedish Medical Birth Register and the BC Vital Statistics were linked to hospital and physician billing records for identification of exposure and outcomes. All children were followed from age 1 until the outcome, death, emigration, or December 2020.ExposureA composite of pre-conception maternal CVDs: cerebrovascular disease, arrhythmia, heart failure, valvular, and congenital heart diseases.Main Outcomes and MeasuresDiagnoses of ADHD, ASD, and ID. The incidence of ADHD, ASD, and ID, comparing offspring of mothers with versus without CVD, was calculated as adjusted hazard ratios (aHRs). These results were compared to models using paternal CVD as negative-control exposure. Fixed-effect meta-analysis was performed to combine the aHRs from Sweden and BC.ResultsWe analysed 3,587,257 offspring (48.9% female) – 2,699,675 in Sweden and 887,582 in BC. The meta-analysis suggests that compared with offspring of mothers without CVD, offspring of mothers with CVD had 1.15-fold higher aHRs of ADHD (95% CI: 1.10-1.20) and ASD (95% CI: 1.07-1.22). No association was found between maternal CVD and ID. Stratification by maternal CVD subtypes showed increased hazards of ADHD for maternal heart failure (aHR 1.31; 95% CI: 1.02-1.61), cerebrovascular disease (aHR 1.20; 95% CI: 1.08-1.32), congenital heart disease (aHR 1.18; 95% CI: 1.08-1.27), arrhythmia (aHR 1.13; 95% CI: 1.08-1.19), and valvular heart disease (aHR 1.12; 95% CI: 1.00-1.24). Increased hazards of ASD were observed for maternal cerebrovascular disease (aHR 1.25; 95% CI: 1.04-1.46), congenital heart disease (aHR 1.17; 95% CI: 1.01-1.33), and arrythmia (HR 1.12; 95% CI: 1.01-1.21). Paternal CVDs, except for cerebrovascular disease, did not show associations.Conclusion and RelevancePre-existing maternal CVD was associated with excess risk of ADHD and ASD in offspring. The associations were broadly robust to genetic confounding, warranting further research to identify the underlying intrauterine mechanisms.

Assess readmissions for depression or suicide attempt (SA) after MS admission versus other chronic inflammatory illnesses.This retrospective cohort study identified MS, asthma, rheumatoid arthritis (RA), depression, and SA in the 2013 National Readmissions Database by International Classification of Diseases codes. Index admissions (MS,MS had more baseline depression (24.7%) versus asthma (15.6%) and RA (14.6%). Ninety-day depression readmission rate was higher in MS (0.5%) than asthma (0.3%) and RA (0.03%). Depression readmission HR was higher after MS admission versus asthma (HR = 1.37, 95% confidence interval (CI) = 1.00-1.86,Depression readmission risk after MS hospitalization was elevated versus asthma/RA. Substance use and baseline psychiatric comorbidity were more strongly associated with depression readmission in MS patients.

To investigate whether cerebrospinal fluid (CSF) markers differ between pediatric-onset multiple sclerosis (PoMS, onset

Background The cause of amyotrophic lateral sclerosis (ALS) is unknown, but occupations have been explored as a potential proxy measure of risk. There is a substantial body of literature connecting military service to ALS. We aimed to summarize and assess the quality of this evidence. Methods Systematic review of the literature, including observational studies which explored one of the following exposures: general military service (army, air force, marines, or navy); or specific exposures associated with military service measured among military personnel. The outcome of interest was ALS incidence, which could include onset, diagnosis, or death from ALS. Results A total of 2642 articles were screened. Following exclusion, 19 articles remained for inclusion in the systematic review, including 1 meta-analysis and 18 original observational studies. Most studies were of moderate quality. In general, the relationship between military service was suggestive of an increased risk, particularly among Gulf War and WWII veterans. Exposure to pesticides (including Agent Orange) certain chemicals (exhaust, burning agents), heavy metals, and head trauma appeared to increase the risk of ALS among military personnel. Conclusions There is a possible association between military service and the subsequent development of ALS; however, the evidence was limited. Studies were generally hindered by small sample sizes and inadequate follow-up time. Future studies should endeavor to objectively measure specific exposures, or combinations thereof, associated with military service, as this will be of vital importance in implementing preventative strategies into military organizations.

Most previous multiple sclerosis (MS) brain atrophy studies using MS impact scale 29 (MSIS-29) or symbol digit modalities test (SDMT) have been cross-sectional with limited sets of clinical outcomes.To investigate which brain and lesion volume metrics show the strongest long-term associations with the expanded disability status scale (EDSS), SDMT, and MSIS-29, and whether MRI-clinical associations vary with age.We acquired MRI and clinical data from a real-world Swedish MS cohort. FreeSurfer and SPM Lesion Segmentation Tool were used to obtain brain parenchymal, cortical and subcortical grey matter, thalamic and white matter fractions as well as TWe included 989 persons with MS followed for a median of 9.3 (EDSS), 10.1 (SDMT), and 9.3 (MSIS-29) years, respectively. In a cross-sectional analysis, the strength of the associations of the MRI metrics with the EDSS and MSIS-29 was found to drastically increase after 40-50 years of age. Low baseline regional grey matter fractions were associated with longitudinal increase of EDSS and physical MSIS-29 scores and decrease in SDMT scores and these atrophy measures were stronger predictors than the lesion volumes.The strength of MRI-clinical associations increase with age. Grey matter volume fractions are stronger predictors of long-term disability measures than lesion volumes.

The purpose of this study was to explore the longitudinal relationship between multiple sclerosis (MS) relapses and information processing efficiency among persons with relapsing-remitting MS.We conducted a Swedish nationwide cohort study of persons with incident relapsing-remitting MS (2001-2019). Relapse information and symbol digit modalities test (SDMT) scores were obtained from the Swedish MS Registry. Follow-up was categorized into 2 periods based on relapse status: "relapse" (90 days pre-relapse to 730 days post-relapse, subdivided into 10 periods) and "remission." Linear mixed models compared SDMT scores during the relapse periods to SDMT scores recorded during remission (reference) with results reported as β-coefficients and 95% confidence intervals (CIs), adjusted for age, sex, SDMT type (written vs oral), time-varying, disease-modifying therapy exposure and sequence of SDMT.Over a mean (SD) follow-up of 10.7 (4.3) years, 31,529 distinct SDMTs were recorded among 3,877 persons with MS. There was a significant decline in information processing efficiency that lasted from 30 days pre-relapse up to 550 days post-relapse, with the largest decline occurring 0 to 30 days post-relapse (β-coefficient: -4.00 (95% CI = -4.61 to -3.39), relative to the period of remission.We found evidence of cognitive change up to 1 month prior to relapse onset. The reduction in SDMT lasted 1.5 years and was clinically significant up to 3 months post-relapse. These results suggest that the effects of a relapse on cognition are longer than previously thought and highlight the importance of reducing relapse rates as a potential means of preserving cognitive function. ANN NEUROL 2022;91:417-423.

Objectives Multiple sclerosis (MS) is a chronic neurodegenerative disease of the central nervous system. Identifying MS at the population level is important for disease surveillance and allocation of resources. The Swedish National Patient Registry (NPR) has been used to study the epidemiology of MS, but the accuracy of this resource is not known. We aimed to validate a definition of MS using the Swedish NPR in Varmland County using a longitudinal cohort design. Materials and Methods Data were extracted from the NPR, the Total Population Register, the Swedish MS Register, and medical records for the years 2001-2013. Fifteen algorithms of hospitalizations and clinic visits for MS were developed and compared with findings in medical records, which acted as the "gold standard" definition. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were estimated. Results Of 805 eligible persons identified in the NPR, 763 had MS (94.8%) according to medical records. Of these, 544 (71.3%) were also registered in the SMSreg. The case definition that had a well-balanced sensitivity and specificity required three or more clinic or hospital visits for MS (sensitivity of 85.3% (95% CI: 82.6-87.8) and specificity of 81.0% (95%CI: 65.9-91.4). Conclusions Multiple case definitions with high sensitivity and moderate specificity were found, suggesting that the NPR can be used to accurately identify persons with MS. Funding Agencies|Swedish Research Council for Health, Working Life and WelfareSwedish Research CouncilSwedish Research Council for Health Working Life & Welfare (Forte) [2019-00190]

ObjectiveTo evaluate long-term disability progression in pediatric-onset multiple sclerosis (POMS) and compare to adult-onset multiple sclerosis (AOMS).MethodsThis was a retrospective cohort study using prospectively collected clinical information from the Swedish MS Registry. Clinical features were compared and Kaplan-Meier and Cox proportional hazards regression were used to assess the risk of reaching sustained Expanded Disability Status Scale (EDSS) 3, 4, and 6 in POMS (multiple sclerosis [MS] onset ResultsA total of 12,482 persons were included; 549 (4.4%) were classified as POMS. The POMS cohort took longer to reach all 3 disability milestones from their MS onset, but did so at a younger age than the AOMS cohort. Primary progressive course (hazard ratio [HR] 4.63; 95% confidence interval [CI] 1.46–14.7), higher relapse rate in the first 5 years of disease (HR 5.35; 95% CI 3.37–8.49), and complete remission from the initial relapse (HR 0.41; 95% CI 0.18–0.94) were associated with an altered risk of progression to EDSS 4 among POMS cases. The same pattern emerged for the risk of reaching EDSS 3 and 6.ConclusionsPatients with pediatric-onset MS follow a distinctive clinical course, which should be considered in the treatment and management of the disease.

Multiple sclerosis (MS) is a complex, chronic disease of the central nervous system that typically is diagnosed in early adulthood but can affect individuals of all ages, including children. Global estimates suggest that between 2.0 and 2.3 million people are living with MS worldwide. There is a marked latitudinal gradient in the prevalence across the globe, with increasing rates further from the equator. Despite substantial efforts, the etiology of MS is not fully understood. Lifestyle and environmental factors, in combination with genetic predisposition, are likely chief contributors. Best evidence to date implicates exposure to the Epstein–Barr virus, low serum vitamin D levels, low dietary intake of vitamin D, and/or insufficient sun exposure with an increased MS risk. Findings with the potential to impact public health include the suggestion that obesity during adolescence and exposure to tobacco smoke throughout the life span increase the risk of MS.

Background: Persons with multiple sclerosis (MS) use health resources with greater frequency than the general population. However, little is known regarding which patient characteristics might contribute. Objective: The study aimed to evaluate characteristics associated with healthcare use in MS patients. Methods: Consecutive MS clinic attendees were recruited (September–November 2010), with clinical, demographic, and patient-completed questionnaires collected at 3 visits over 2 years. Linkage with administrative data (hospital, physician, and pharmacy records) provided healthcare use outcomes until December 31, 2013. Findings were reported as adjusted rate ratios (adjRRs) using negative binomial regression. Results: A total of 340 MS patients with a mean (SD) age of 48.4 (12.0) years and subsequent follow-up of 3.1 (0.34) years were included. Fatigue and high physical comorbidity count (≥3 vs. none) were significantly associated with higher rates of physician encounters (adjRRs: 1.37 and 1.52, respectively), prescriptions filled (adjRRs: 1.25 and 1.40), and hospitalizations (adjRRs: 4.02 and 3.45). In addition, anxiety, disruptive pain, and perceived functional cognitive difficulties were associated with higher rates of physician encounters and prescriptions dispensed (adjRR ranged from 1.28 to 1.48). Discussion: The presence of fatigue and higher physical comorbidity burden were associated with higher rates of health services use. Findings have implications for those examining healthcare burden or organizing health services for persons with MS.

This case-control study examines the risk of severe COVID-19 infection in individuals with multiple sclerosis who were receiving rituximab.

Objective:To evaluate the association between comorbidity and relapse rate in individuals with multiple sclerosis (MS).Methods:We recruited individuals with prevalent relapsing-onset MS from 4 Canadian MS Clinics to participate in a 2-year prospective multicenter cohort study involving cross-sectional assessment of comorbidities and relapses. Comorbidities were recorded using questionnaires, and relapses were captured from medical records at each visit. The association between comorbidities at baseline and relapse rate over the subsequent 2-year follow-up period was examined using Poisson regression, adjusting for age, sex, disability, disease duration, and treatment status.Results:Of 885 participants, 678 (76.6%) were women, averaging age 48.2 years at baseline. Anxiety (40.2%), depression (21.1%), hypertension (17.7%), migraine (18.1%), and hyperlipidemia (11.9%) were the most prevalent comorbidities. The frequency of participants experiencing relapses remained constant at 14.9% and 13.2% in years 1 and 2 post-baseline. After adjustment, participants reporting ≥3 baseline comorbidities (relative to none) had a higher relapse rate over the subsequent 2 years (adjusted rate ratio 1.45, 95% confidence interval [CI] 1.00–2.08). Migraine and hyperlipidemia were associated with increased relapse rate (adjusted rate ratio 1.38; 95% CI 1.01–1.89 and 1.67; 95% CI 1.07–2.61, respectively).Conclusions:Individuals with migraine, hyperlipidemia, or a high comorbidity burden (3 or more conditions) had an increased relapse rate over 2 years. These findings have potential implications for understanding the pathophysiology of MS relapses, and suggest that closer monitoring of individuals with specific or multiple comorbidities may be needed. Future research is needed to understand if the presence of comorbidity warrants a tailored approach to MS management.

Multiple sclerosis (MS) is a chronic disease of the central nervous system with an unidentified etiology. We systematically reviewed the literature on the possible risk factors associated with MS disease onset, relapses and progression from 1960 to 2012 by accessing six databases and including relevant systematic reviews, meta-analyses, case-control or cohort studies. The focus was on identifying modifiable risk factors. Fifteen systematic reviews and 169 original articles were quality assessed and integrated into a descriptive review. Best evidence, which included one or more prospective studies, suggested that lower exposure to sunlight and/or lower serum vitamin D levels were associated with an increased risk of developing MS onset and subsequent relapses, but a similar quality of evidence was lacking for disease progression. Prospective studies indicated that cigarette smoking may increase the risk of MS as well as accelerate disease progression, but whether smoking altered the risk of a relapse was largely unknown. Infections were implicated in both risk of developing MS and relapses, but data for progression were lacking. Specifically, exposure to the Epstein-Barr virus, particularly if this manifested as infectious mononucleosis during adolescence, was associated with increased MS risk. Upper respiratory tract infections were most commonly associated with an increase in relapses. Relapse rates typically dropped during pregnancy, but there was no strong evidence to suggest that pregnancy itself altered the risk of MS or affected long-term progression. Emerging research with the greatest potential to impact public health was the suggestion that obesity during adolescence may increase the risk of MS; if confirmed, this would be of major significance.

ObjectiveTo evaluate risks of disease reactivity during pregnancy and postpartum following rituximab (RTX) and natalizumab (NTZ) suspension in women with MS.MethodsAn observational cohort study of all women with MS disease onset before childbirth between 2006 and 2017. Women were identified through the Swedish MS Registry, a nationwide clinical register, with substratification into 3 groups: women who suspended RTX and NTZ within 6 months before conception and women who were not treated with any disease-modifying treatment (DMT) within 1 year of conception. The primary outcome was the annualized relapse rate (ARR) during pregnancy and 1 year postpartum.ResultsWe identified 2,386 women with MS onset before a live birth; of these, 76 women suspended RTX and 53 suspended NTZ, and 457 were untreated within 1 year before conception. In all women, regardless of the treatment type, the ARR declined from 0.05–0.04 prepregnancy to 0.03–0.02 during pregnancy, returning to prepregnancy rates at 3–6 months (0.05) postpartum. In the suspended cohort, 76% (98/129) of women resumed a DMT after delivery. The relapse rate 1 year postpartum was significantly higher in the suspended NTZ women compared with the suspended RTX women (adjusted rate ratio [aRR] 7.65, 95% CI 2.47–23.6) and was lower in the suspended RTX women compared with the untreated women (aRR 0.21, 95% CI 0.08–0.61).ConclusionDisease reactivity during the postpartum period was lower among women with MS who suspended RTX before pregnancy, relative to those who suspended NTZ and untreated women. These findings suggest that RTX may exert long-acting effects on MS disease activity that encompass pregnancy and postpartum periods.Classification of evidenceThis study provides Class IV evidence that in patients with MS who were on treatment before pregnancy, RTX reduces clinical disease activity compared with NTZ in the postpartum period.

To evaluate quality of life (QoL), measured by the EQ-5D, in adults with pediatric-onset multiple sclerosis (POMS) or adult-onset multiple sclerosis (AOMS) and explore determinants of QoL in both groups.Data were collected from the nationwide Swedish multiple sclerosis (MS) registry. Demographic characteristics, EQ-5D-3 level, Multiple Sclerosis Impact Scale (MSIS-29) score, Expanded Disability Status Scale (EDSS) score, Symbol Digit Modalities Test score, relapses, and disease-modifying therapy (DMT) exposure were collected on an approximately annual basis (2011-2019). Patients with definite MS with ≥2 EQ-5D measurements collected between ages 18 and 50 were included. The principal outcome was the EQ-5D visual analogue scale (EQ-VAS) score. Linear mixed models compared all available EQ-VAS scores between patients with POMS and patients with AOMS and determinants of EQ-VAS among patients with POMS and patients with AOMS (assessed separately).A total of 5,094 persons met inclusion criteria: 354 (6.9%) had POMS. A total of 21,357 unique EQ-5D scores were recorded. Most participants were female (70.0%) with a relapsing-onset disease course (98.1%). There was no difference in EQ-VAS scores between patients with POMS and patients with AOMS following adjustment for confounders (β-coefficient for patients with POMS vs patients with AOMS [reference]: 0.99; 95% confidence interval -0.89 to 2.87). Experiencing a relapse, severe neurologic disability (EDSS ≥6.0 vs3.0), and higher MSIS-29 psychological score were consistently associated with lower QoL, while higher information processing efficiency and exposure to first-line DMTs were associated with higher QoL scores in both groups.There were no differences in QoL between patients with POMS and patients with AOMS in adulthood. Findings provide support for a focus on reducing neurologic disability and improving psychological status as approaches to potentially improve the QoL of persons with MS.

ObjectiveDepression is common in multiple sclerosis (MS), but its impact on disability worsening has not yet been determined. We explored the risk of disability worsening associated with depression in a nationwide longitudinal cohort.MethodsThis retrospective cohort study used linked data from 3 Swedish nationwide registries: the MS Register, National Patient Register, and Prescribed Drug Register. Two incident cohorts were developed: cohort 1 included all registered cases of MS in the MS Registry (2001–2014) with depression defined as ≥1 ICD-10 code for depression; and cohort 2 comprised all cases of MS in the MS Registry (2005–2014) with depression defined as ≥1 prescription filled for an antidepressant. Cox regression models were used to compare the risk of reaching sustained disability milestone scores of 3.0, 4.0, and 6.0 on the Expanded Disability Status Scale (EDSS) between persons with MS with and without depression.ResultsCohort 1 included 5,875 cases; 502 (8.5%) had depression. Cohort 2 had 3,817 cases; 1,289 (33.8%) were prescribed an antidepressant. Persons with depression were at a significantly higher risk of reaching sustained EDSS scores of 3.0, 4.0, and 6.0, with hazard ratios of 1.50 (95% confidence interval [CI] 1.20–1.87), 1.79 (95% CI 1.40–2.29), and 1.89 (95% CI 1.38–2.57), respectively. A similar increased risk among persons exposed to antidepressants was observed, with hazard ratios of 1.37 (95% CI 1.18–1.60), 1.93 (95% CI 1.61–2.31), and 1.86 (95% CI 1.45–2.40) for sustained EDSS scores of 3.0, 4.0, and 6.0, respectively.ConclusionPersons with MS and comorbid depression had a significantly increased risk of disability worsening. This finding highlights the need for early recognition and appropriate treatment of depression in persons with MS.

Importance Pediatric-onset multiple sclerosis (PoMS) is associated with significant cognitive and physical disability. Whether this disability translates into differences in educational achievements and earnings is unknown. Objective To evaluate the association between PoMS and educational level and income throughout adulthood. Design, setting, and participants A prospective register-based cohort study of individuals with PoMS and a population-based matched reference cohort was conducted using nationwide microdata from linked registers in Sweden from January 1, 1990, to December 31, 2016; analyses were completed from May 1, 2019, to September 1, 2020. Of 772 persons with PoMS identified in the Swedish MS registry, 485 had an onset during the period from 1980 to 2014 and had socioeconomic data available. The general population reference cohort without multiple sclerosis (MS) (n = 4850) was randomly selected from the full Swedish population, matched 10:1 on age, sex, and country of birth. Exposure Pediatric-onset MS, diagnosed by a neurologist, with onset before 18 years of age. Main outcomes and measures Highest educational level (elementary school, high school, or university) was assessed using logistic regression. Income, measured as the mean annual earnings from paid work in US dollars, was compared using Tobit models, and net annual sickness absence and disability pension days were compared using zero-inflated negative binomial regression. Earnings and days receiving disability benefits were compared within 4 age periods (19-24, 25-34, 35-44, and 45-54 years). Results The median age of the cohort with PoMS (n = 485) and the matched reference cohort (n = 4850) in 2016 was 32 years (interquartile range, 26-40 years), and most participants were women (348 [71.8%] in the PoMS cohort and 3480 [71.8%] in the matched reference cohort). Persons with PoMS were less likely than persons in the matched reference cohort to attend university (odds ratio, 0.80 [95% CI, 0.66-0.97]) and had significantly lower annual earnings than the reference cohort, ranging from -$1618 (95% CI, -$2558 to -$678) in the youngest age period to -$10 683 (95% CI, -$18 187 to -$3178) in the eldest. Persons with PoMS received higher rates of disability benefits, as sickness absence days in the youngest age period (rate ratio, 3.06 [95% CI, 2.08-4.52]) and disability pension days in the oldest age period (rate ratio, 1.43 [95% CI, 1.11-1.85]). Conclusions and relevance This study suggests that having PoMS is associated with less educational achievement, lower earnings, and greater use of disability benefits throughout the working-age life span. As adults, persons with PoMS never earned as much as their counterparts without MS, and they exhibited a heavier reliance on disability benefits.

Background:Poor adherence to the disease-modifying therapies (DMTs) for multiple sclerosis (MS) may attenuate clinical benefit. A better understanding of characteristics associated with non-adherence could improve outcomes.Objective:To evaluate characteristics associated with non-adherence to injectable DMTs.Methods:Consecutive patients from four Canadian MS Clinics were assessed at three time points over two years. Clinical and demographic information included self-reported DMT use, missed doses in the previous 30 days, health behaviors, and comorbidities. Non-adherence was defined as Results:In all, 485 participants reported use of an injectable DMT, of whom 107 (22.1%) were non-adherent over the study period. Non-adherence was associated with a lower Expanded Disability Status Scale score (0–2.5 vs 3.0–5.5, OR: 1.80; 95% confidence interval (CI): 1.06–3.04), disease duration (⩽5 vs Conclusions:Nearly one-quarter of participants were non-adherent during the study. Alcohol dependence, perceived cognitive difficulties, longer disease duration, and mild disability status were associated with non-adherence. These characteristics may help healthcare professionals identify patients at greatest risk of poor adherence.

Background and purpose Much clinical knowledge about multiple sclerosis (MS) has been gained from patients who attend MS specialty clinics. However, there is limited information about whether these patients are representative of the wider MS population. The objective of this study was to compare incident MS cases who were MS clinic users to non-users of the specialty MS clinics in British Columbia, Canada. Methods This was a retrospective record-linkage cohort study using prospectively collected data from the British Columbia Multiple Sclerosis database and province-wide health administrative databases. Results There were 2841 incident MS cases between 1996 and 2004 including 1648 (58%) that had registered at an MS clinic (‘clinic cases’) and 1193 (42%) that had not (‘non-clinic cases’). Gender and socioeconomic status distributions were similar; however, non-clinic cases were older, accessed health services more frequently and had a higher burden of comorbidity than clinic cases. Only 1% of the non-clinic cases had filled a prescription for an MS-specific disease-modifying therapy, compared to 51% of the clinic cases. Conclusions Our findings have several important implications: even within a publicly funded healthcare system, a high proportion of individuals with MS may not access a specialty MS clinic; the needs of MS patients managed in the community may differ from those referred to an MS clinic; findings from studies involving clinic-based MS cohorts may not always be generalizable to the wider MS population; and access to population-based health administrative data offers the opportunity to gain a broader understanding of MS.

CME/CNE Information Activity Available Online: To access the article, post-test, and evaluation online, go to http://www.cmscscholar.org. Target Audience: The target audience for this activity is physicians, physician assistants, nursing professionals, and other health-care providers involved in the management of patients with multiple sclerosis (MS). Learning Objectives: 1) Be able to discuss the risk of new onset of fatigue and comorbidities associated with increased fatigue with MS patients and their families 2) Be able to identify and address comorbidities that are most associated with fatigue in MS patients Accreditation Statement: This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Consortium of Multiple Sclerosis Centers (CMSC), Nurse Practitioner Alternatives (NPA), and Delaware Media Group. The CMSC is accredited by the ACCME to provide continuing medical education for physicians. The CMSC designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nurse Practitioner Alternatives (NPA) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. NPA designates this enduring material for a maximum of 1.0 Continuing Nursing Education credits. Disclosures: Francois Bethoux, MD, Editor in Chief of the International Journal of MS Care (IJMSC), has served as Physician Planner for this activity. He has disclosed no relevant financial relationships. Laurie Scudder, DNP, NP, has served as Nurse Planner for this activity. She has disclosed no relevant financial relationships. The authors (listed in the article's author byline) and the anonymous peer reviewers for the IJMSC have disclosed no relevant financial relationships. Method of Participation: Release Date: April 1, 2016 Valid for Credit Through: April 1, 2017 In order to receive CME/CNE credit, participants must: 1) Review the CME/CNE information, including learning objectives and author disclosures. 2) Study the educational content. 3) Complete the post-test and evaluation, which are available at http://www.cmscscholar.org. Statements of Credit are awarded upon successful completion of the post-test with a passing score of >70% and the evaluation. There is no fee to participate in this activity. Disclosure of Unlabeled Use: This CME/CNE activity may contain discussion of published and/or investigational uses of agents that are not approved by the FDA. CMSC, NPA, and Delaware Media Group do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the authors and do not necessarily represent the views of CMSC, NPA, or Delaware Media Group. Disclaimer: Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any medications, diagnostic procedures, or treatments discussed in this publication should not be used by clinicians or other health-care professionals without first evaluating their patients' conditions, considering possible contraindications or risks, reviewing any applicable manufacturer's product information, and comparing any therapeutic approach with the recommendations of other authorities.

Knowledge surrounding the trillions of microbes that inhabit the human gut has bloomed exponentially in recent years, and the emerging concept of a gut-brain axis represents a major shift in how we think about neurological health. A recent workshop at the University of British Columbia, Canada brought together multi-disciplinary leaders in the field of microbiomics and brain health and aimed to serve as a springboard for future combined endeavors in these areas. This article provides the motivation for, and overview of, the workshop, and the next steps in establishing a cross-disciplinary initiative on Brain Health and the Microbiome.

Background Persons who develop multiple sclerosis (MS) at a young age may bear a higher genetic risk load than persons who develop MS later in life; however, the contribution of familial influence to the risk of MS, in relation to onset age, has not been established. Objective To investigate the familial risk of MS at two extremes of the spectrum of MS onset age: early onset (first MS symptom

Background:Studies assessing the prevalence of depression and anxiety in multiple sclerosis (MS) have used various ascertainment methods that capture different constructs. The relationships between these methods are incompletely understood. Psychiatric comorbidity is associated with lower health-related quality of life (HRQOL) in MS, but the effects of past diagnoses of depression and anxiety on HRQOL are largely unknown. We compared the prevalence of depression and anxiety in persons with MS using administrative data, self-reported physician diagnoses, and symptom-based measures and compared characteristics of persons classified as depressed or anxious by each method. We evaluated whether HRQOL was most affected by previous diagnoses of depression or anxiety or by current symptoms.Methods:We linked clinical and administrative data for 859 participants with MS. HRQOL was measured by the Health Utilities Index Mark 3. We classified participants as depressed or anxious using administrative data, self-reported physician diagnoses, and the Hospital Anxiety and Depression Scale. Multivariable linear regression examined whether diagnosed depression or anxiety affected HRQOL after accounting for current symptoms.Results:Lifetime prevalence estimates for depression were approximately 30% regardless of methods used, but 35.8% with current depressive symptoms were not captured by either administrative data or self-reported diagnoses. Prevalence estimates of anxiety ranged from 11% to 19%, but 65.6% with current anxiety were not captured by either administrative data or self-reported diagnoses. Previous diagnoses did not decrease HRQOL after accounting for current symptoms.Conclusions:Depression and, to a greater extent, anxiety remain underdiagnosed and undertreated in MS; both substantially contribute to reduced HRQOL in MS.

Comorbidities are common in multiple sclerosis (MS). The high prevalence of pain in MS is well-established but the influence of comorbidities on pain, specifically, pain-related interference in activity is not.To examine the relationship between comorbidity and pain in MS.We recruited 949 consecutive patients with definite MS from four Canadian centres. Participants completed the Health Utilities Index (HUI-Mark III) and a validated comorbidity questionnaire at 3 visits over 2 years. The HUI's pain scale was dichotomized into two groups: those with/without pain that disrupts normal activities. We used logistic regression to assess the association of pain with each comorbidity individually at baseline and over time.The incidence of disruptive pain over two years was 31.1 per 100 persons. Fibromyalgia, rheumatoid arthritis, irritable bowel syndrome, migraine, chronic lung disease, depression, anxiety, hypertension, and hypercholesterolemia were associated with disruptive pain (p0.006). Individual-level effects on the presence of worsening pain were seen for chronic obstructive pulmonary disease (odds ratio [OR]: 1.50 95% CI: 1.08-2.09), anxiety (OR: 1.49 95% CI: 1.07-2.08), and autoimmune thyroid disease (OR: 1.40 95% CI: 1.00-1.97).Comorbidity is associated with pain in persons with MS. Closer examination of these associations may provide guidance for better management of this disabling symptom in MS.

Background: Depression and anxiety are common among people with multiple sclerosis (MS), as are adverse health behaviours, but the associations between these factors are unclear. Objective: To evaluate the associations between cigarette smoking, alcohol use, and depression and anxiety in MS in a cross-Canada prospective study. Methods: From July 2010 to March 2011 we recruited consecutive MS patients from four MS clinics. At three visits over two years, clinical and demographic information was collected, and participants completed questionnaires regarding health behaviours and mental health. Results: Of 949 participants, 75.2% were women, with a mean age of 48.6 years; most had a relapsing−remitting course (72.4%). Alcohol dependence was associated with increased odds of anxiety (OR: 1.84; 95% CI: 1.32–2.58) and depression (OR: 1.53; 95% CI: 1.05–2.23) adjusting for age, sex, Expanded Disability Status Scale (EDSS), and smoking status. Smoking was associated with increased odds of anxiety (OR: 1.29; 95% CI: 1.02–1.63) and depression (OR: 1.37; 95% CI: 1.04–1.78) adjusting for age, sex, EDSS, and alcohol dependence. Alcohol dependence was associated with an increased incidence of depression but not anxiety. Depression was associated with an increased incidence of alcohol dependence. Conclusion: Alcohol dependence and smoking were associated with anxiety and depression. Awareness of the effects of adverse health behaviours on mental health in MS might help target counselling and support for those ‘at risk’.

Multiple sclerosis (MS) is a chronic central nervous system disease with a highly heterogeneous course. The aetiology of MS is not well understood but is likely a combination of both genetic and environmental factors. Approximately 85% of patients present with relapsing-remitting MS (RRMS), while 10–15% present with primary progressive MS (PPMS). PPMS is associated with an older onset age, a different sex ratio, and a considerably more rapid disease progression relative to RRMS. We systematically reviewed the literature to identify modifiable risk factors that may be associated with these different clinical courses. We performed a search of six databases and integrated twenty observational studies into a descriptive review. Exposure to Epstein-Barr virus (EBV) appeared to increase the risk of RRMS, but its association with PPMS was less clear. Other infections, such as human herpesvirus-6 and chlamydia pneumoniae, were not consistently associated with a specific disease course nor was cigarette smoking. Despite the vast literature examining risk factors for the development of MS, relatively few studies reported findings by disease course. This review exposes a gap in our understanding of the risk factors associated with the onset of PPMS, our current knowledge being predominated by relapsing-onset MS.

Background Physical activity may be neuroprotective in multiple sclerosis (MS). One review (2011) of exercise and MS disability was inconclusive, but highlighted the need for more studies. Objective To perform an updated systematic literature review examining the relationship between physical activity and physical ability outcomes in persons with MS. Methods EMBASE and MEDLINE were searched for original interventional studies (2011–2016) evaluating exercise on quantitative outcomes of physical disability in MS. We also assessed any reported adverse outcomes. Results Of the 153 articles identified, 12 were included; 3 examined endurance training; 6 resistance training; and 3 explored less conventional exercises, specifically, tai chi, kickboxing, and vestibular rehabilitation, each lasting 5–24 weeks. In total, 568 unique individuals were included, and >10 different scales used to assess outcomes. Endurance training provided benefits in walking ability, while mindfulness exercises (tai chi and vestibular rehabilitation), and dynamic workouts (kickboxing) led to improvements in balance and coordination. Resistance training alone did not improve walking ability, but improved lower limb muscular strength and endurance. When resistance and endurance training were combined, improvements were seen in mobility, balance and coordination. Four studies assessed discontinuation; most reported a return to pre-intervention function. Adverse outcomes were reported in 6 studies, and appeared generally mild, ranging from mild muscle soreness to exacerbation of MS symptoms. Conclusions Physical activity was associated with measurable benefits on ability outcomes, but continuation is likely required to maintain benefits. While adverse events were generally mild, approximately half of studies actually reported safety outcomes.

ObjectiveEmerging evidence suggests that comorbidity may influence disability outcomes in multiple sclerosis (MS); we investigated the association between psychiatric comorbidity and MS disability progression in a large multiclinic population.MethodsThis retrospective cohort study accessed prospectively collected information from linked clinical and population-based health administrative databases in the Canadian provinces of British Columbia and Nova Scotia. Persons with MS who had depression, anxiety, or bipolar disorder were identified using validated algorithms using physician and hospital visits. Multivariable linear regression models fitted using an identity link with generalized estimating equations were used to determine the association between psychiatric comorbidity and disability using all available Expanded Disability Status Scale (EDSS) scores.ResultsA total of 2,312 incident cases of adult-onset MS were followed for a mean of 10.5 years, during which time 35.8% met criteria for a mood or anxiety disorder. The presence of a mood or anxiety disorder was associated with a higher EDSS score (β coefficient = 0.28, p = 0.0002, adjusted for disease duration and course, age, sex, socioeconomic status, physical comorbidity count, and disease-modifying therapy exposure). Findings were statistically significant among women (β coefficient = 0.31, p = 0.0004), but not men (β coefficient 0.22, p = 0.17).ConclusionPresence of psychiatric comorbidities, which were common in our incident MS cohort, increased the severity of subsequent neurologic disability. Optimizing management of psychiatric comorbidities should be explored as a means of potentially mitigating disability progression in MS.

Background Several environmental and lifestyle factors have been associated with multiple sclerosis (MS) risk, including some pharmacological treatments. We systematically reviewed the literature on prescription drug exposure and MS risk. Methods Six databases were searched for original observational studies reporting drug exposure and MS risk published before 2017. Results Thirteen articles fulfilled inclusion criteria. Exposure to neither amiloride nor valproic acid was associated with MS (adjusted hazard ratio (adj.HR = 1.34;95% CI:0.81–2.20; adj.HR = 1.30;95%CI:0.44–3.80, respectively). Four studies explored oral contraceptive exposure and reported no association with MS; while a single study found an increased risk (odds ratio [adj.OR] = 1.52;95%CI:1.21–1.91). While penicillin exposure was associated with reduced risk of developing MS (adj.OR = 0.5;95%CI:0.3–0.9), a later study observed an elevated risk for penicillin (adj.OR = 1.21;95%CI:1.10–1.27) and all antibiotics (adj.OR = 1.41;95%CI:1.29–1.53), which was potentially attributed to underlying infection. Anti-tumor necrosis factor-alpha (TNFα) was not associated with MS risk in persons with inflammatory bowel disease (standard morbidity ratio = 4.2;95%CI:0.1–23.0) and arthritis (standardized incidence ratio = 1.38;95%CI:0.69–2.77); however, men exposed to anti-TNFα who also had arthritis and individuals with ankylosing spondylitis were at an increased risk (standardized incidence ratios = 3.91;95%CI:1.47–10.42 and 3.48;95%CI:1.45–8.37, respectively). A reduced risk of MS was observed with exposure to the beta2-adrenergic agonist fenoterol (adj.OR = 0.58;95%CI:0.45–0.76), and the sedating histamine 1-receptor antagonists (adj.OR = 0.2;95%CI:0.1–0.8), but not the non-sedating equivalent (adj.OR = 0.8;95%CI:0.4–1.6). Conclusions The suggestion that some drugs may prevent MS is intriguing and warrants further study. In addition, further pharmacovigilance is needed to assess the safety of anti-TNFα drugs in specific populations in the context of MS risk.

ObjectivesMuch clinical knowledge about multiple sclerosis (MS) has been gained from patients who attend MS specialty clinics. However, there is limited information about whether these patients are representative of the wider MS population. The objective of this study was to compare incident MS cases who were MS clinic users to non-users of the specialty MS clinics in British Columbia, Canada. ApproachThis was a retrospective record linkage cohort study using prospectively collected data from the BCMS database and province-wide health administrative databases. Incident MS cases were identified in the general population using a validated algorithm of hospital and physician diagnostic codes. Results There were 2,841 incident MS cases between 1996 and 2004 including 1,648 (58%) that had registered at an MS clinic (‘clinic cases’) and 1,193 (42%) that had not (‘non-clinic cases’). Sex and socioeconomic status distributions were similar; however, non-clinic cases were older, accessed health services more frequently, and had a higher burden of comorbidity than clinic cases. Only 1% of the non-clinic cases had filled a prescription for an MS-specific disease-modifying therapy, compared to 51% of the clinic cases. ConclusionOur findings have several important implications: even within a publicly funded healthcare system, a high proportion of individuals with MS may not access a specialty MS clinic; the needs of MS patients managed in the community may differ from those referred to an MS clinic; findings from studies involving clinic-based MS cohorts may not always be generalizable to the wider MS population; and access to population-based health administrative data offers the opportunity to gain a broader understanding of MS.

Systematic reviews were conducted to identify risk factors associated with the onset and progression of 14 neurological conditions, prioritized as a component of the National Population Health Study of Neurological Conditions. These systematic reviews provided a basis for evaluating the weight of evidence of evidence for risk factors for the onset and progression of the 14 individual neurological conditions considered. A number of risk factors associated with an increased risk of onset for more than one condition, including exposure to pesticides (associated with an increased risk of AD, amyotrophic lateral sclerosis, brain tumours, and PD; smoking (AD, MS); and infection (MS, Tourette syndrome). Coffee and tea intake was associated with a decreased risk of onset of both dystonia and PD. Further understanding of the etiology of priority neurological conditions will be helpful in focusing future research initiatives and in the development of interventions to reduce the burden associated with neurological conditions in Canada and internationally.

Background: Self-report and pharmacy records are often used to measure adherence rates to disease-modifying therapies (DMTs) in multiple sclerosis (MS), but little is known about how the sources compare. Objective: Compare self-report and pharmacy records for assessing DMT use and adherence rates. Methods: Demographic information, self-reported DMT use, and missed DMT doses in the previous 30 days were obtained from consecutive MS patients attending an MS clinic and linked to pharmacy records. A medication possession ratio (MPR) was calculated using pharmacy records for the year before and after the visit; MPR Results: Of 326 participants, 135 reported using an injectable DMT. There was near-perfect and perfect agreement between self-report and pharmacy records for DMT use (κ = 0.95; 95% CI 0.91-0.98) and DMT agent (κ = 1.00). Nonadherence was estimated at 13% (17/128) from the 30-days self-report compared to 30% (34/113) and 43% (53/123) in the year pre- and post-clinic visit from pharmacy records, indicating moderate to fair agreement (year prior: κ = 0.41; 95% CI 0.22-0.59; year post: κ = 0.22; 95% CI 0.09-0.36). Conclusions: Patients self-reports closely reflected pharmacy records when assessing DMT use and product. Moderate to fair agreement was found when comparing adherence rates between sources.

IMPORTANCE: Cognitive impairment in multiple sclerosis (MS) can lead to reduced quality of life, social functioning, and employment. Few studies have investigated cognitive outcomes among patients with pediatric-onset MS (POMS) over the long term. OBJECTIVE: To compare long-term information-processing efficiency between patients with POMS and adult-onset MS (AOMS). DESIGN, SETTING, AND PARTICIPANTS: This population-based longitudinal cohort study accessed the Swedish MS Registry (SMSreg), which collates information from all 64 neurology clinics in Sweden. Registered cases with definite MS in the SMSreg with an onset before April 15, 2018, and at least 2 Symbol Digit Modalities Test (SDMT) scores recorded were included. Only persons aged 18 to 55 years and with duration of disease of less than 30 years at the time of SDMT administration were included, to ensure comparable ranges between patients with POMS and AOMS. Of 8247 persons with an SDMT recorded in the SMSreg, 5704 met inclusion criteria, 300 (5.3%) of whom had POMS. Data were collected from April 1, 2006, through April 15, 2018 and analyzed from April through August 2018. EXPOSURES: Pediatric-onset MS (onset

This paper presents an overview of genetic variation associated with the onset and progression of 14 neurological disorders, focusing primarily on association studies. The 14 disorders are heterogeneous in terms of their frequency, age of onset, etiology and progression. There is substantially less evidence on progression than onset. With regard to onset, the conditions are diverse in terms of their epidemiology and patterns of familial aggregation. While the muscular dystrophies and Huntington’s disease are monogenic diseases, for the other 12 conditions only a small proportion of cases is associated with specific genetic syndromes or mutations. Excluding these, some familial aggregation remains for the majority of cases. There is considerable variation in the volume of evidence by condition, and by gene within condition. The volume of evidence is greatest for Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and amyotrophic lateral sclerosis. As for common complex chronic diseases, genome wide association studies have found that validated genomic regions account for a low proportion of heritability. Apart from multiple sclerosis, which shares several susceptibility loci with other immune-related disorders, variation at HLA-DRB5 being associated both with Parkinson’s disease and Alzheimer’s disease, and the association of the C9orf72 repeat expansion with ALS and frontotemporal degeneration, there was little evidence of gene loci being consistently associated with more than one neurological condition or with other conditions. With the exception of spina bifida, for which maternal MTHFR genotype is associated with risk in the offspring, and corroborates other evidence of the importance of folate in etiology, there was little evidence that the pathways influenced by genetic variation are related to known lifestyle or environmental exposures.

Multiple sclerosis (MS) is a chronic central nervous system disease that is associated with progressive loss of myelin and subsequent axonal degeneration. Cholesterol is an essential component of mammalian cellular and myelin membranes. In this systematic review, we examined the relationship between levels of cholesterol and markers of cholesterol turnover in circulation and/or cerebrospinal fluid (CSF) and disease outcomes in adults with clinically isolated syndrome (CIS) or confirmed MS. Studies suggest that elevated levels of circulating low density lipoprotein cholesterol (LDL), total cholesterol, and particularly, apolipoprotein B and oxidized LDL are associated with adverse clinical and MRI outcomes in MS. These relationships were observed as early as CIS. The studies also suggest that oxysterols, cholesterol precursors, and apolipoprotein E may be markers of specific disease processes in MS, but more research is required to elucidate these processes and relationships. Taken together, the data indicate that cholesterol and markers of cholesterol turnover have potential to be used clinically as biomarkers of disease activity and may even be implicated in the pathogenesis of MS.

Objective: To evaluate the direct and indirect influences of physical comorbidity, symptoms of depression and anxiety, fatigue, and disability on health-related quality of life (HRQoL) in persons with multiple sclerosis (MS). Methods: A large (n = 949) sample of adults with MS was recruited from 4 Canadian MS clinics. HRQoL was assessed using the patient-reported Health Utilities Index Mark 3. Expanded Disability Status Scale scores, physical comorbidity, depression, anxiety, and fatigue were evaluated as predictors of HRQoL in a cross-sectional path analysis. Results: All predictors were significantly associated with HRQoL and together accounted for a large proportion of variance (63%). Overall, disability status most strongly affected HRQoL (β = −0.52) but it was closely followed by depressive symptoms (β = −0.50). The direct associations of physical comorbidity and anxiety with HRQoL were small (β = −0.08 and −0.10, respectively), but these associations were stronger when indirect effects through other variables (depression, fatigue) were also considered (physical comorbidity: β = −0.20; anxiety: β = −0.34). Conclusions: Increased disability, depression and anxiety symptoms, fatigue, and physical comorbidity are associated with decreased HRQoL in MS. Disability most strongly diminishes HRQoL and, thus, interventions that reduce disability are expected to yield the most substantial improvement in HRQoL. Yet, interventions targeting other factors amenable to change, particularly depression but also anxiety, fatigue, and physical comorbidities, may all result in meaningful improvements in HRQoL, as well. Our findings point to the importance of further research confirming the efficacy of such interventions.