Academic Multiple Sclerosis Center Research Articles

The Canadian Prospective Cohort Study to understand progression in multiple sclerosis: baseline characteristics.

Disease progression is observed across the spectrum of people with multiple sclerosis (MS) and identification of effective treatment strategies to halt progression remains one of the greatest unmet clinical needs. The Canadian Prospective Cohort Study to Understand Progression in MS (CanProCo) was designed to evaluate a wide range of factors associated with the onset and rate of clinical disease progression in MS and to describe the interplay between these factors. A prospective cohort study. CanProCo is a national, prospective, observational cohort study that has recruited 944 individuals from 5 large academic MS centers in Canada. Participants include people with radiologically isolated syndrome (RIS), early relapsing-remitting and primary progressive MS (RRMS, PPMS), and healthy controls (HCs). Annually, participants complete self-reported questionnaires, undergo clinical evaluation and, if clinically indicated, magnetic resonance images (MRIs) of the brain and cervical spinal cord; in a subset of participants (n = 399), blood, and research MRIs of the brain and cervical spinal cord are collected. Linkages to health administrative databases are available at three sites. Overall, 944 participants were recruited (53 HCs, 63 RIS, 751 RRMS, 77 PPMS). RIS and MS participants had a mean age of 39.0 years and 70.5% female. The mean time since diagnosis was 2.7 years. There were differences observed in the Expanded Disability Status Scale score and components of the MS performance test (walking speed test, manual dexterity test, processing speed test, and low-contrast visual acuity) between RIS and MS subtypes. Questionnaires revealed more symptoms of depression and anxiety and impaired physical and mental quality of life in people with RIS/MS versus HCs and differences across RIS/MS subtypes. Physical and mental neurological disability is prevalent even in the earliest stages of MS. Transdisciplinary approaches such as those used in CanProCo are needed to better characterize clinical progression in MS. Additional CanProCo results, including MRI, biological, and pharmaco-economic data will be forthcoming. Going forward, CanProCo's data sharing and collaborative vision will facilitate numerous global collaborations, which will inform the development and implementation of effective interventions for people with MS around the world.

Social determinants of health and disparate disability accumulation in a cohort of Black, Hispanic, and White patients with multiple sclerosis.

Black and Hispanic patients with multiple sclerosis (MS) have been shown to accumulate greater multiple sclerosis-associated disability (MSAD) than White patients. Disparities in social determinants of health (SDOH) among these groups have also been reported. To determine the extent to which associations of race and ethnicity with MSAD may be attributable to differences in SDOH. Retrospective chart analysis of patients at an academic MS center grouped by self-identified Black (n = 95), Hispanic (n = 93), and White (n = 98) race/ethnicity. Individual patient addresses were geocoded and matched with neighborhood-level area deprivation index (ADI) and social vulnerability index (SVI). Average Expanded Disability Status Scale (EDSS) scores at last-recorded evaluations of White patients (1.7 ± 2.0) were significantly lower than Black (2.8 ± 2.4, p = 0.001) and Hispanic (2.6 ± 2.6, p = 0.020) patients. Neither Black race nor Hispanic ethnicity was significantly associated with EDSS in multivariable linear regression models that included individual-level SDOH indicators and either ADI or SVI. Black race and Hispanic ethnicity are not significantly associated with EDSS in models that include individual and neighborhood-level SDOH indicators. Further research should elucidate mechanisms by which structural inequities affect MS disease course.

Implementing physical activity vital sign as a self-reported measure of physical activity in patients with multiple sclerosis in a clinical setting.

Routinely assessing exercise levels during clinical visits may be a starting point for clinicians to support physical activity inpersons with multiple sclerosis (MS). To evaluate the feasibility and findings of routinely implementing a self-reported physical activity vital sign during clinical visits. Retrospective database review. Outpatient academic MS center. All adult patients of our MS center with confirmed MS presenting for an in-person or telemedicine clinic visit with a physician or nurse practitioner. None. A standard physical activity vital sign representing minutes per week of moderate-to-vigorous exercise was collected. Percentage of persons with MS with a recorded physical activity vital sign was retrospectively evaluated along with demographic characteristics and key findings. Ninety-three percent of patients with MS at our center had a physical activity vital sign recorded in at least one visit, and 86% at the most recent visit. Of 1560 patients with a recorded physical activity vital sign, 24.3% of patients were consistently active (≥150 min/week of exercise), 20.8% were consistently inactive (0 min/week), and the remaining 54.9% were inconsistently active. The physical activity vital sign was inversely associated with BMI (p < .001) and 25-foot walk test times (p < .001), but not associated with biological sex or age. Approximately a quarter of patients with MS with a documented physical activity vital sign met national aerobic exercise guidelines of 150 min/week per the U.S. Department of Health and Human Services. Routine implementation of the physical activity vital sign at our MS center was feasible and helped identify inactive patients who may benefit from physical activity counseling.

Thyroid autoimmunity following alemtuzumab treatment in multiple sclerosis patients: a prospective study.

Autoimmune thyroid disease (AITD) is the most common adverse effect in alemtuzumab (ALZ)treated relapsing-remitting (RR) multiple sclerosis (MS) patients. The objective of this prospective study was to analyze the occurrence, timing of onset, clinical course, and laboratory characteristics of AITD post-ALZ. We evaluated 35 RRMS patients treated with ALZ at a single academic MS center; clinical and laboratory data were collected before ALZ initiation and thereafter quarterly on follow-up with a median of 43.5months. Seventeen out of 31 patients (54.8%) with no prior history of thyroid dysfunction developed AITD with a mean onset of 19.4months ± 10.2 (SD) after the first ALZ cycle; Graves' disease (GD) (n = 9); hypothyroidism with positive stimulating thyrotropin receptor antibodies (TRAb) (n = 1); Hashimoto thyroiditis (HT) (n = 6); HT with hypothyroidism (n = 1). Interestingly, seven of nine (77.7%) GD patients showed a fluctuating course. Three out of four patients with preexisting thyroid disease remained stable, whereas one with prior HT and hypothyroidism developed fluctuating GD. All patients with GD commenced antithyroid drugs (ATDs); five continued on "block and replace" treatment; one required radioactive iodine, and one total thyroidectomy. Our analysis showed earlier onset of ALZ-induced AITD in comparison to most other ALZ cohorts; overall, these patients required complex therapeutic approaches of the AITD. We observed a higher rate of fluctuating GD, with earlier onset and lower remission rate than previously reported, which in the majority of patients required prolonged "block and replace" therapy in the minimum dose of each therapeutic agent or more definitive interventions.

MeTooMS: Sexual, physical, and emotional abuse experience among women with multiple sclerosis

Background: Sexual and physical violence against disabled individuals is widespread and linked to negative public health and social outcomes. The real-world prevalence of abuse in women with multiple sclerosis (MS) has not been well studied. Objectives: To explore abuse prevalence in a real-world cohort of females with MS attending an academic MS Center. Methods: Prospective and retrospective abuse data were confidentially collected during neurology clinic visits and extracted from medical records for women attending an academic MS Center. Self-reported and provider-documented prevalence of abuse experiences were correlated with socio-economic and disease-specific factors. Results: In total, 200 women completed prospective questionnaires, and 121 non-overlapping independent health records were retrospectively reviewed. Mean age (SD) was 49.055 (11.39). Seventy-six (38%) reported lifetime abuse incidents; 15% were abused within the previous year. Intimate partners were the most likely verbal (p ⩽ 0.01)) and physical (p = 0.04) abuse perpetrators. Neurologic disability correlated with greater likelihood of verbal abuse (p = 0.021) in prospective cohort. There was no billing or encounter documentation for any form of abuse. Conclusion: Intimate partner violence is common in women with MS, correlates with neurologic disability, and is underreported by the health system. Future research needs to focus on abuse detection and mitigation strategies.

Brainstem lesions are associated with diffuse spinal cord involvement in early multiple sclerosis

BackgroundEarly infratentorial and focal spinal cord lesions on magnetic resonance imaging (MRI) are associated with a higher risk of long-term disability in patients with multiple sclerosis (MS). The role of diffuse spinal cord lesions remains less understood. The purpose of this study was to evaluate focal and especially diffuse spinal cord lesions in patients with early relapsing-remitting MS and their association with intracranial lesion topography, global and regional brain volume, and spinal cord volume.MethodsWe investigated 58 MS patients with short disease duration (< 5 years) from a large academic MS center and 58 healthy controls matched for age and sex. Brain, spinal cord, and intracranial lesion volumes were compared among patients with- and without diffuse spinal cord lesions and controls. Binary logistic regression models were used to analyse the association between the volume and topology of intracranial lesions and the presence of focal and diffuse spinal cord lesions.ResultsWe found spinal cord involvement in 75% of the patients (43/58), including diffuse changes in 41.4% (24/58). Patients with diffuse spinal cord changes exhibited higher volumes of brainstem lesion volume (p = 0.008). The presence of at least one brainstem lesion was associated with a higher probability of the presence of diffuse spinal cord lesions (odds ratio 47.1; 95% confidence interval 6.9–321.6 p < 0.001) as opposed to focal spinal cord lesions (odds ratio 0.22; p = 0.320). Patients with diffuse spinal cord lesions had a lower thalamus volume compared to patients without diffuse spinal cord lesions (p = 0.007) or healthy controls (p = 0.002).ConclusionsDiffuse spinal cord lesions are associated with the presence of brainstem lesions and with a lower volume of the thalamus. This association was not found in patients with focal spinal cord lesions. If confirmed, thalamic atrophy in patients with diffuse lesions could increase our knowledge on the worse prognosis in patients with infratentorial and SC lesions.

Immune signature of multiple sclerosis-associated depression

Multiple neurobiological pathways have been implicated in the pathobiology of major depressive disorder (MDD). The identification of reliable biological substrates across the entire MDD spectrum, however, is hampered by a vast heterogeneity in the clinical presentation, presumably as a consequence of heterogeneous pathobiology. One way to overcome this limitation could be to explore disease subtypes based on biological similarity such as “inflammatory depression”. As such a subtype may be particularly enriched in depressed patients with an underlying inflammatory condition, multiple sclerosis (MS) could provide an informative disease context for this approach. Few studies have explored immune markers of MS-associated depression and replications are missing. To address this, we analyzed data from two independent case-control studies on immune signatures of MS-associated depression, conducted at two different academic MS centers (overall sample size of n = 132). Using a stepwise data-driven approach, we identified CD4+CCR7lowTCM cell frequencies as a robust correlate of depression in MS. This signature was associated with core symptoms of depression and depression severity (but not MS severity per se) and linked to neuroinflammation as determined by magnetic resonance imaging (MRI). Furthermore, exploratory analyses of T cell polarization revealed this was largely driven by cells with a TH1-like phenotype. Our findings suggest (neuro)immune pathways linked to affective symptoms of autoimmune disorders such as MS, with potential relevance for the understanding of “inflammatory” subtypes of depression.

The Canadian prospective cohort study to understand progression in multiple sclerosis (CanProCo): rationale, aims, and study design

BackgroundNeurological disability progression occurs across the spectrum of people living with multiple sclerosis (MS). Although there are a handful of disease-modifying treatments approved for use in progressive phenotypes of MS, there are no treatments that substantially modify the course of clinical progression in MS. Characterizing the determinants of clinical progression can inform the development of novel therapeutic agents and treatment approaches that target progression in MS, which is one of the greatest unmet needs in clinical practice. Canada, having one of the world’s highest rates of MS and a publicly-funded health care system, represents an optimal country to achieve in-depth analysis of progression. Accordingly, the overarching aim of the Canadian Prospective Cohort Study to Understand Progression in MS (CanProCo) is to evaluate a wide spectrum of factors associated with the clinical onset and rate of disease progression in MS, and to describe how these factors relate to one another to influence progression.MethodsCanProCo is a prospective, observational cohort study with investigators specializing in epidemiology, neuroimaging, neuroimmunology, health services research and health economics. CanProCo’s study design was approved by an international review panel, comprised of content experts and key stakeholders. One thousand individuals with radiologically-isolated syndrome, relapsing-remitting MS, and primary-progressive MS within 10–15 years of disease onset will be recruited from 5 academic MS centres in Canada. Participants will undergo detailed clinical evaluation annually over 5 years (including advanced, app-based clinical data collection). In a subset of participants within 5–10 years of disease onset (n = 500), blood, cerebrospinal fluid, and research MRIs will be collected allowing an integrated, in-depth evaluation of factors contributing to progression in MS from multiple perspectives. Factors of interest range from biological measures (e.g. single-cell RNA-sequencing), MRI-based microstructural assessment, participant characteristics (self-reported, performance-based, clinician-assessed, health-system based), and micro and macro-environmental factors.DiscussionHalting the progression of MS remains a fundamental need to improve the lives of people living with MS. Achieving this requires leveraging transdisciplinary approaches to better characterize why clinical progression occurs. CanProCo is a pioneering multi-dimensional cohort study aiming to characterize these determinants to inform the development and implementation of efficacious and effective interventions.

Association of a Marker of N-Acetylglucosamine With Progressive Multiple Sclerosis and Neurodegeneration

N-glycan branching modulates cell surface receptor availability, and its deficiency in mice promotes inflammatory demyelination, reduced myelination, and neurodegeneration. N-acetylglucosamine (GlcNAc) is a rate-limiting substrate for N-glycan branching, but, to our knowledge, endogenous serum levels in patients with multiple sclerosis (MS) are unknown. To investigate a marker of endogenous serum GlcNAc levels in patients with MS. A cross-sectional discovery study and cross-sectional confirmatory study were conducted at 2 academic MS centers in the US and Germany. The discovery study recruited 54 patients with MS from an outpatient clinic as well as 66 healthy controls between April 20, 2010, and June 21, 2013. The confirmatory study recruited 180 patients with MS from screening visits at an academic MS study center between April 9, 2007, and February 29, 2016. Serum samples were analyzed from December 2, 2013, to March 2, 2015. Statistical analysis was performed from February 23, 2020, to March 18, 2021. Serum levels of GlcNAc plus its stereoisomers, termed N-acetylhexosamine (HexNAc), were assessed using targeted tandem mass spectroscopy. Secondary outcomes (confirmatory study) comprised imaging and clinical disease markers. The discovery cohort included 66 healthy controls (38 women; mean [SD] age, 42 [20] years), 33 patients with relapsing-remitting MS (RRMS; 25 women; mean [SD] age, 50 [11] years), and 21 patients with progressive MS (PMS; 14 women; mean [SD] age, 55 [7] years). The confirmatory cohort included 125 patients with RRMS (83 women; mean [SD] age, 40 [9] years) and 55 patients with PMS (22 women; mean [SD] age, 49 [80] years). In the discovery cohort, the mean (SD) serum level of GlcNAc plus its stereoisomers (HexNAc) was 710 (174) nM in healthy controls and marginally reduced in patients with RRMS (mean [SD] level, 682 [173] nM; P = .04), whereas patients with PMS displayed markedly reduced levels compared with healthy controls (mean [SD] level, 548 [101] nM; P = 9.55 × 10-9) and patients with RRMS (P = 1.83 × 10-4). The difference between patients with RRMS (mean [SD] level, 709 [193] nM) and those with PMS (mean [SD] level, 405 [161] nM; P = 7.6 × 10-18) was confirmed in the independent confirmatory cohort. Lower HexNAc serum levels correlated with worse expanded disability status scale scores (ρ = -0.485; P = 4.73 × 10-12), lower thalamic volume (t = 1.7; P = .04), and thinner retinal nerve fiber layer (B = 0.012 [SE = 7.5 × 10-11]; P = .008). Low baseline serum HexNAc levels correlated with a greater percentage of brain volume loss at 18 months (t = 1.8; P = .04). This study suggests that deficiency of GlcNAc plus its stereoisomers (HexNAc) may be a biomarker for PMS. Previous preclinical, human genetic, and ex vivo human mechanistic studies revealed that N-glycan branching and/or GlcNAc may reduce proinflammatory responses, promote myelin repair, and decrease neurodegeneration. Combined, the data suggest that GlcNAc deficiency may be associated with progressive disease and neurodegeneration in patients with MS.

Expanded access to multiple sclerosis teleneurology care following the COVID-19 pandemic.

BackgroundTeleneurology for multiple sclerosis (MS) care was considered feasible, but utilization was limited.ObjectiveTo describe how the existing teleneurology populations at two academic MS Centers changed during the COVID-19 pandemic.MethodsIn this cross-sectional study, we captured all in-person and teleneurology visits at two academic MS Centers between January 2019 and April 2020. We compared group differences between the Centers, and COVID-related changes using T-, chi-squared Kruskal-Wallis and Fisher exact tests.Results2268 patients completed 2579 teleneurology visits (mean age 48.3 ± 13.3 years, 72.9% female). Pre-COVID, the Centers’ teleneurology populations were similar for age, sex, MS type, and disability level (all p > 0.1), but differed for race (96.5% vs 80.7% white, p ≤ 0.001), MS treatment (49.1% vs 32.1% infusible, p ≤ 0.001), and median distance from Center (72 vs 186 miles, p ≤ 0.001). Post-COVID, both Centers’ teleneurology populations had more black (12.7% vs 4.37%, p ≤ 0.001) and local (median 34.5 vs 102 miles, p ≤ 0.001) patients.ConclusionTeleneurology visits in 2019 reflected the organizational and local teleneurology reimbursement patterns of our Centers. Our post-COVID-19 changes illustrate the potential for payors and policy to change disparities in access to, or utilization of, remote care. Patients’ perception of care quality and value following this shift warrants study.

Safety and efficacy of amantadine, modafinil, and methylphenidate for fatigue in multiple sclerosis: a randomised, placebo-controlled, crossover, double-blind trial

Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications with each other and placebo in patients with multiple sclerosis fatigue. In this randomised, placebo-controlled, four-sequence, four-period, crossover, double-blind trial, patients with multiple sclerosis who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic multiple sclerosis centres in the USA. Participants received oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, each given for up to 6 weeks. All patients were intended to receive all four study medications, in turn, in one of four different sequences with 2-week washout periods between medications. A biostatistician prepared a concealed allocation schedule, stratified by site, randomly assigning a sequence of medications in approximately a 1:1:1:1 ratio, in blocks of eight, to a consecutive series of numbers. The statistician and pharmacists had no role in assessing the participants or collecting data, and the participants, caregivers, and assessors were masked to allocation. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week 5 of each medication period, analysed by use of a linear mixed-effect regression model. This trial is registered with ClinicalTrials.gov, NCT03185065 and is closed. Between Oct 4, 2017, and Feb 27, 2019, of 169 patients screened, 141 patients were enrolled and randomly assigned to one of four medication administration sequences: 35 (25%) patients to the amantadine, placebo, modafinil, and methylphenidate sequence; 34 (24%) patients to the placebo, methylphenidate, amantadine, and modafinil sequence; 35 (25%) patients to the modafinil, amantadine, methylphenidate, and placebo sequence; and 37 (26%) patients to the methylphenidate, modafinil, placebo, and amantadine sequence. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51·3 (95% CI 49·0-53·6) at baseline, 40·6 (38·2-43·1) with placebo, 41·3 (38·8-43·7) with amantadine, 39·0 (36·6-41·4) with modafinil, and 38·6 (36·2-41·0) with methylphenidate (p=0·20 for the overall medication effect in the linear mixed-effect regression model). As compared with placebo (38 [31%] of 124 patients), higher proportions of participants reported adverse events while taking amantadine (49 [39%] of 127 patients), modafinil (50 [40%] of 125 patients), and methylphenidate (51 [40%] of 129 patients). Three serious adverse events occurred during the study (pulmonary embolism and myocarditis while taking amantadine, and a multiple sclerosis exacerbation requiring hospital admission while taking modafinil). Amantadine, modafinil, and methylphenidate were not superior to placebo in improving multiple sclerosis fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis. Patient-Centered Outcomes Research Institute.

Clinical characteristics of a large multi-center cohort of people with multiple sclerosis over age 60

Background: As the peak prevalence of multiple sclerosis (MS) shifts due to an aging patient population, understanding the characteristics that define this older cohort to improve overall management is critical. We sought to determine the clinical characteristics of people with MS over age 60.Methods: Demographics, clinical characteristics, MS disease history, and Multiple Sclerosis Performance Test (MSPT) patient-reported outcomes and neuroperformance tests (NPTs) were collected from 10 academic MS centers in the US and Europe participating in the MS Partners Advancing Technology Health Solutions (MS PATHS) system. We characterized demographic and disease characteristics of included participants using descriptive statistics. We characterized prevalence of comorbidities and compared with estimated prevalences from the National Health and Nutrition Examination Survey (NHANES) respondents aged ≥60 years in 2017-2018.Results: We identified 2738 individuals over age 60 from MS PATHS, with 58.1% relapsing-remitting (RR) and 41.9% progressive. Our results showed median age (RR=65.7 years, progressive=66.0 years), age of symptom onset (RR and progressive=40.9 years), and disease duration (RR=22.8 years, progressive=23.3 years). Over two-thirds of individuals in our cohort were treated with DMTs. The most common DMT used in RR patients were interferons (17.6%) and glatiramer acetate (16.3%), while glatiramer acetate was the most common (12.0%) in progressive patients. Progressive patients had higher disability (higher median PDDS scores, worse Neuro-Qol T-scores, and worse NPTs) compared to the RR group. Pain was the most common comorbidity, followed by cardiac disease, depression, hypertension, dyslipidemia, and obesity. Compared to older NHANES participants, older people with MS were more likely to have depression (MS PATHS: 51.5% [95% CI: 49.5% to 53.5%] vs. NHANES: 21.7% [95% CI: 1619.3% to 22.2%]) and osteoporosis (MS PATHS: 12.7% [95% CI: 11.3% to 14.1%] vs. NHANES: 8.2% [95% CI: 6.2% to 10.3%]); they were less likely to be obese (MS PATHS: 29.4% [95% CI: 27.7% to 31.2%] vs. NHANES: 45.1% [95% CI: 38.9% to 51.3%]) and have diabetes (MS PATHS: 12.3% [95% CI: 11.1% to 13.6%] vs. NHANES: 22.5% [95% CI: 18.8% to 25.7%]).Conclusions: Our study characterizes a large multi-center international cohort of people with MS over age 60. This contemporary cohort appears less disabled than prior studies, which may reflect long term impact of DMT availability on the natural history of MS. The burden of comorbidity in this population was generally high. Information on DMT use, comorbidity, and disability outcome measures will be beneficial in future studies evaluating the impact of therapeutic interventions in older individuals.

Association of social network structure and physical function in patients with multiple sclerosis.

To test the association between physical function and the social environment in multiple sclerosis (MS), we quantified personal social networks. In this cross-sectional study, we analyzed data from 2 academic MS centers, with center 1 serving as a discovery group and center 2 as the extension group. We performed a meta-analysis of the centers to extend the analysis. We used responses from a questionnaire to map the structure and health habits of participants' social networks as well as the NIH Patient-Reported Outcomes Measurement Information System (PROMIS) physical function scale (0-100, mean 50 for US general population) as the primary outcome. We applied multivariable models to test the association between network metrics and physical function. The discovery cohort included 263 patients with MS: 81% were women, 96% non-Hispanic European, 78% had relapsing MS, average age was 50 (12.4) years, and mean disease duration was 17 (12.3) years. The extension group included 163 patients, who were younger, more racially diverse, and less physically disabled, and had shorter disease duration. In the meta-analysis, higher network constraint, a measure of tightly bound networks, was associated with worse physical function (β = -0.163 ± 0.047, p < 0.001), while larger network effective size, a measure of clustered groups in the network, correlated with better physical function (β = 0.134 ± 0.046, p = 0.003). Our study highlights personal networks as an important environmental factor associated with physical function in MS. Patients with close-knit networks had worse function than those with more open networks. Longitudinal studies are warranted to evaluate a causal relationship between network structure and physical impairment.

Autoencoder as a New Method for Maintaining Data Privacy While Analyzing Videos of Patients With Motor Dysfunction: Proof-of-Concept Study.

BackgroundIn chronic neurological diseases, especially in multiple sclerosis (MS), clinical assessment of motor dysfunction is crucial to monitor the disease in patients. Traditional scales are not sensitive enough to detect slight changes. Video recordings of patient performance are more accurate and increase the reliability of severity ratings. When these recordings are automated, quantitative disability assessments by machine learning algorithms can be created. Creation of these algorithms involves non–health care professionals, which is a challenge for maintaining data privacy. However, autoencoders can address this issue.ObjectiveThe aim of this proof-of-concept study was to test whether coded frame vectors of autoencoders contain relevant information for analyzing videos of the motor performance of patients with MS.MethodsIn this study, 20 pre-rated videos of patients performing the finger-to-nose test were recorded. An autoencoder created encoded frame vectors from the original videos and decoded the videos again. The original and decoded videos were shown to 10 neurologists at an academic MS center in Basel, Switzerland. The neurologists tested whether the 200 videos were human-readable after decoding and rated the severity grade of each original and decoded video according to the Neurostatus-Expanded Disability Status Scale definitions of limb ataxia. Furthermore, the neurologists tested whether ratings were equivalent between the original and decoded videos.ResultsIn total, 172 of 200 (86.0%) videos were of sufficient quality to be ratable. The intrarater agreement between the original and decoded videos was 0.317 (Cohen weighted kappa). The average difference in the ratings between the original and decoded videos was 0.26, in which the original videos were rated as more severe. The interrater agreement between the original videos was 0.459 and that between the decoded videos was 0.302. The agreement was higher when no deficits or very severe deficits were present.ConclusionsThe vast majority of videos (172/200, 86.0%) decoded by the autoencoder contained clinically relevant information and had fair intrarater agreement with the original videos. Autoencoders are a potential method for enabling the use of patient videos while preserving data privacy, especially when non–health-care professionals are involved.

Non-compliance with disease modifying therapies in patients with Multiple Sclerosis: A qualitative analysis

BackgroundFactors associated with adherence to disease modifying therapies (DMT) in patients with Multiple Sclerosis (MS) have been reported before, but little has been studied on compliance to a physician's initial treatment recommendations. The objective of this study was to assess the factors associated with compliance to physician recommended treatment in treatment-naïve patients with MS. MethodsWe studied a cohort of patients with MS followed at an academic MS center in Toronto, Canada between January 2015 and May 2018. We used log-binomial models to identify patient-level factors (age, sex, and smoking history), and MS-specific clinical details (delay in diagnosis, and age at diagnosis) associated with compliance. ResultsOf the 332 patients, 256 (77.1%) were recommended DMT and 80 (31.3%) did not follow the recommendation. The most common causes for refusal to initiate DMT were: personal preference to not embark on a medication (46.2%), wishing to use a conservative approach (22.5%) or use of complementary medical approaches (18.8%). Twenty-one () patients who initially were compliant to treatment recommendations subsequently stopped DMT against medical advice. The two most common reasons for this nonadherence included adverse effects (61.8%) and personal preference (19.0%). Every year delay in the diagnosis of MS was associated with a lower risk of compliance (risk ratio 0.97, 95% CI, 0.94–1.00). ConclusionNon-compliance to DMT recommendation in patients with MS in a Canadian practice is sizable, due to patients’ own perspectives of disease and their belief in alternative complementary medicine.

Comparative discontinuation, effectiveness, and switching practices of dimethyl fumarate and fingolimod at 36-month follow-up

BackgroundDimethyl fumarate (DMF) and fingolimod (FTY) are approved oral disease modifying therapies (DMTs) for relapsing multiple sclerosis (MS). There are currently no known head-to-head studies comparing DMF and FTY over 36 months, which leaves their relative effectiveness unknown. ObjectiveTo assess real-world discontinuation, effectiveness, and switching practices of DMF and FTY over 36 months along with disease activity after switching DMT. MethodsPatients prescribed DMF (n = 737) and FTY (n = 535) from two academic MS centers were retrospectively reviewed. Discontinuation and effectiveness outcomes were assessed using propensity score (PS) weighting. PS model covariates included sociodemographics and clinical and MRI characteristics. ResultsDiscontinuation was more common in DMF (58.3%) versus FTY (45.2%) over 36 months [OR = 1.81, 95% CI (1.41–2.31), p < .001], largely driven by intolerance [OR = 1.63, 95% CI (1.18–1.73), p < .001]. There were no differences in clinical relapses [OR = 1.27, 95% CI (0.90–1.79), p = .17], gadolinium-enhancing (GdE) lesions [OR = 1.25, 95% CI (0.85–1.84), p = .26], or new T2-hyperintense lesions [OR = 0.99, 95% CI (0.74–1.32), p = .93]. Within 12 months of DMF/FTY discontinuation, switchers to highly effective therapy (HET) versus other DMTs (injectables/orals) had fewer relapses (DMF/HET, 5.9% versus DMF/Other, 14.2%, p = .03; FTY/HET, 11.6% versus FTY/Other, 18.0%, p = .04) and fewer GdE lesions post-FTY (DMF/HET, 10.3% versus DMF/Other, 14.3%, p = .36; FTY/HET, 11.9% versus FTY/Other, 21.5%, p = .04). ConclusionThis combined analysis showed similar effectiveness for DMF and FTY over 36 months with higher DMF discontinuations. Disease activity was lower in switchers to HET versus injectable/oral therapies after DMF/FTY cessation.

Complementary and Alternative Medicine Usage by Multiple Sclerosis Patients: Results from a Prospective Clinical Study.

To investigate the factors associated with complementary and alternative medicine (CAM) usage by multiple sclerosis (MS) patients. Design, Setting/Location: Single-center, prospective clinical study at an academic MS center in the northeastern United States. This study included CAM data from 524 MS patients and 304 healthy controls (HC) enrolled in a prospective study of clinical, neuroimaging, and environmental risk factors in MS at an academic MS Center. Clinical, neuroimaging, and disease-modifying treatment data were obtained. In addition, data on usage of CAM modalities, including acupuncture, aromatherapy, Ayurveda, Chinese herbal medicine, chiropractor, electromagnetic therapy, homeopathy, hypnosis, massage, naturopathy, Qi gong, Reiki, therapeutic touch, and bee stings were collected in an in-person interview. The percentages of HC reporting usage of any CAM (32%) was similar to that in MS patients after diagnosis (30.5%). The usage of any CAM was higher in MS patients after MS diagnosis compared to before MS diagnosis (p < 0.001). The three most frequently used CAM for MS patients after MS diagnosis and HC were chiropractor, massage, and acupuncture. The most frequent reasons for CAM use were MS symptom relief, back problems, and pain. In multivariate analysis, female gender, higher education level, MS disease course, and not currently on disease-modifying therapies (DMT) treatment status were associated with CAM usage. Gender, education level, DMT treatment status, and MS disease course are associated with CAM usage in MS patients. Ever-CAM usage patterns in MS patients are similar to those in HC.

The financial contribution of the multiple sclerosis specialist.

To examine the financial effect of the multiple sclerosis (MS) specialist on the academic health center (AHC).Using data derived from an academic MS center with respect to patient numbers and practice pattern regarding diagnostic studies and disease-modifying therapies (DMT) coupled with reasonable assumptions regarding the profit margin for tests and treatments, 1 full-time MS specialist (1 clinical full-time equivalent [cFTE]) may annually generate downstream revenue exceeding $8,000,000. If all diagnostic studies and therapies were obtained at the facility, the potential revenue generated for the facility can exceed $25,000,000 per 1 cFTE. These calculations do not include the professional net revenue generated by referrals to other professionals.With current models of reimbursement for health care, the MS specialist provides an enormous potential source of revenue for the AHC. This information is critically important in obtaining institutional support for the provision of labor-intensive MS care.

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OBJECTIVES/SPECIFIC AIMS: To identify brain regions with the highest and least variable rate of multiple sclerosis (MS)-specific atrophy using an agnostic approach, and to perform simulation-based sample size calculations for Phase II s using these regions as primary endpoint. METHODS/STUDY POPULATION: In total, 601 subjects (2638 MRI scans) were analyzed; 520 subjects with relapsing forms of MS across the spectrum of disease severity and duration were followed in a single-center prospective cohort study at an academic MS Center between 2005 and 2010 with annual 3 T MRIs and clinical visits for 5 years, including standardized 1 mm3 3D T1-weighted images (3DT1s; 2483 MRIs). Separately, a convenience sample of 81 healthy controls (HC) was recruited from the same center and scanned longitudinally using the same MRI scanner and protocol (155 MRIs). 3DT1s were processed using FreeSurfer’s longitudinal pipeline (software version 5.3). Rates of change in all cortical and subcortical regions (n=119 brain regions) were estimated in MS patients and HC with linear mixed effects models. An effect size was calculated for each region as the difference in change over time between MS patients and HC divided by the standard error of the difference [d=β(MS×time)/SE β(MS×time)]. Regions were ranked according to absolute effect size, and the top regions were chosen for simulation-based sample size calculations to estimate the number of subjects needed to achieve 80% power to detect a slowing of MS atrophy down to normal aging, assuming significance levels of 5% and 10%. Ten percent was included because some have advocated for a more relaxed alpha in Phase II s. RESULTS/ANTICIPATED RESULTS: Four regions (putamen, subcortical grey matter, caudate, and thalamus) yielded the smallest sample sizes. At 80% power, ~50 subjects per arm would be needed with putamen or subcortical grey matter volume, or ~80–85 subjects per arm with caudate or thalamic volume as primary endpoint. For the remaining regions, &gt;140 subjects per arm would be needed. A 20%–30% increase in sample size was observed when α=5% was used. DISCUSSION/SIGNIFICANCE OF IMPACT: Using an agnostic approach considering all brain regions and simulation-based sample size calculations specifically designed for longitudinal studies, putaminal, subcortical grey, caudate, and thalamic volumes are sensitive to change over time and yield feasible sample sizes for Phase II studies in MS. Because the effect size estimates incorporate normal aging, these regions represent the most sensitive outcomes for testing therapeutic interventions that target irreversible, MS-specific brain atrophy. The clinical relevance of these regions is our next focus to help inform which of these regions should be favored as primary endpoint.

SUMMIT (Serially Unified Multicenter Multiple Sclerosis Investigation): creating a repository of deeply phenotyped contemporary multiple sclerosis cohorts

Background: There is a pressing need for robust longitudinal cohort studies in the modern treatment era of multiple sclerosis. Objective: Build a multiple sclerosis (MS) cohort repository to capture the variability of disability accumulation, as well as provide the depth of characterization (clinical, radiologic, genetic, biospecimens) required to adequately model and ultimately predict a patient’s course. Methods: Serially Unified Multicenter Multiple Sclerosis Investigation (SUMMIT) is an international multi-center, prospectively enrolled cohort with over a decade of comprehensive follow-up on more than 1000 patients from two large North American academic MS Centers (Brigham and Women’s Hospital (Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women’s Hospital (CLIMB; BWH)) and University of California, San Francisco (Expression/genomics, Proteomics, Imaging, and Clinical (EPIC))). It is bringing online more than 2500 patients from additional international MS Centers (Basel (Universitätsspital Basel (UHB)), VU University Medical Center MS Center Amsterdam (MSCA), Multiple Sclerosis Center of Catalonia-Vall d’Hebron Hospital (Barcelona clinically isolated syndrome (CIS) cohort), and American University of Beirut Medical Center (AUBMC-Multiple Sclerosis Interdisciplinary Research (AMIR)). Results and conclusion: We provide evidence for harmonization of two of the initial cohorts in terms of the characterization of demographics, disease, and treatment-related variables; demonstrate several proof-of-principle analyses examining genetic and radiologic predictors of disease progression; and discuss the steps involved in expanding SUMMIT into a repository accessible to the broader scientific community.