A Qualitative Study of Facilitators, Barriers, and Gender Disparities in Academic Neurology.

BACKGROUND AND OBJECTIVES: To understand the challenges and facilitators of a successful academic neurology research career broadly and to identify gender-based disparities specifically. METHODS: In 2019, participants self-identifying as researchers, preregistered for the American Academy of Neurology (AAN) Annual Meeting, ≥7 years out of residency, and authors of ≥1 AAN meeting abstract submission (2006-2009) were selected to participate in the qualitative study (purposeful sampling strategy). To increase diversity, 15 participants were invited by members involved in the AAN until interviews were complete. The AAN at the time of the study asked gender using sex-based terms. Participants were asked predetermined and open-ended questions. Themes were generated using a flexible coding methodology. RESULTS: Sixty neurologists (31 women, 29 men) participated in the focus groups and individual interviews. Six predetermined domains relevant to a successful neurology research career were explored: success definitions, facilitators, barriers, biases and harassment, mitigation strategies, and participant recommendations. Gender-based differences were noted during discussions focused on barriers and biases and harassment. Lack of women mentors, under-representation of women in senior faculty positions, and competing responsibilities when children are young were identified as barriers to women's success. Participants acknowledged that known gender disparities in compensation, academic promotion, and publications disproportionately affect women. Women shared more experiences of bias and harassment. Some men felt that gender-based biases were minimal to nonexistent. Participants shared their recommendations on ways to mitigate gender disparities and pursue a neurology research career. Leadership involvement locally and nationally in advocating and implementing change outside academic institutions was also mentioned as being valuable. DISCUSSION: Our findings may not be generalizable to academic neurologists outside the United States. Women academic neurology researchers experienced disparities across several domains affecting success: lower compensation, fewer women mentors, bias, and harassment. Women are less likely to be promoted, have less research success, and job satisfaction. Shared experiences of bias and harassment among women neurology researchers indicate continuing opportunity for education among departments and colleagues for preventive measures. These qualitative results indicate gender disparities among US-based neurology researchers and highlight the importance of the continued need to work toward equality and equity in disparate gender-related issues in the careers of neurology researchers.

A 42-Year-Old Woman With Rapidly Expanding White Matter Lesions: From the National Multiple Sclerosis Society Case Conference Proceedings.

A 42-year-old woman and active cocaine user complained of subacutely worsening blurred vision and imbalance. Examination of the brain MRI showed rapidly expanding white matter lesions. Brain biopsy was consistent with inflammatory demyelination. Given an unusual presentation and a history of cocaine use, a broad differential diagnosis was considered including neurologic toxidromes.

Multiple Sclerosis and Family Planning: A Survey Study of the Patient Experience.

Background and Objectives: Multiple sclerosis (MS) commonly affects women in their childbearing years, necessitating discussion between patients and their MS treatment team around the issues of family planning, pregnancy, and postpartum experiences. This study assessed the impact of a diagnosis of MS on women's reproductive decision-making and on their perception of counseling received surrounding pregnancy. It also sought to evaluate trends in pregnancy and postpartum experiences and determine whether experiences differed by race, ethnicity, and zip code. Methods: Women with an MS diagnosis seen at the University of Virginia MS Clinic or at Virginia Commonwealth University (VCU) MS Clinic were invited to participate in a survey study. MS disease and pregnancy history, and, when appropriate, reasons for pregnancy avoidance were collected. Respondents who had >1 pregnancy following MS diagnosis were asked to evaluate the counseling they received from medical professionals and to share their pregnancy experiences including complications during pregnancy, delivery outcomes, and postpartum experience including breastfeeding. Results: Of the 280 respondents, 76.6% were currently receiving MS specialty care. Most of them (79.3%) had not been pregnant following MS diagnosis. Of them, 20.1% indicated that this decision was driven by MS-related concerns: MS worsening with pregnancy (47%); ability to care for child secondary to MS (35%); passing MS onto child (19%); stopping disease-modifying therapies to attempt pregnancy (14%); lack of knowledge about options for pregnancy and MS (9%). Women with a more recent estimated decade of pregnancy were more likely to report neurologist counseling regarding MS and pregnancy (pregnancy before 2000: 40%, 2000-2010: 64.7%, 2010- present: 83.3%; χ2 0.020). Breastfeeding initiation was reported in 71.4% of postdiagnosis pregnancies (median duration 6 months, interquartile range 1.75-11). Discussion: Over the past few decades, women with MS have received a wide range of evolving guidance surrounding family planning, pregnancy, and postpartum care. Survey data suggest improvements in MS/pregnancy counseling and medical management in recent years, which may be driven by an increase in research in the field. There remains an important need and opportunity to improve counseling of women with MS who are considering pregnancy.

Progression risk stratification with six-minute walk gait speed trajectory in multiple sclerosis.

Background: Multiple Sclerosis (MS) disease progression has notable heterogeneity among patients and over time. There is no available single method to predict the risk of progression, which represents a significant and unmet need in MS. Methods: MS and healthy control (HC) participants were recruited for a 2-year observational study. A latent-variable growth mixture model (GMM) was applied to cluster baseline 6-min walk gait speed trajectories (6MWGST). MS patients within different 6 MWGST clusters were identified and stratified. The group membership of these MS patients was compared against 2-year confirmed-disease progression (CDP). Clinical and patient-reported outcome (PRO) measures were compared between HC and MS subgroups over 2 years. Results: 62 MS and 41 HC participants completed the 2-year study. Within the MS cohort, 90% were relapsing MS. Two distinct patterns of baseline 6 MWGST emerged, with one cluster displaying a faster gait speed and a typical "U" shape, and the other showing a slower gait speed and a "flattened" 6 MWGST curve. We stratified MS participants in each cluster as low- and high-risk progressors (LRP and HRP, respectively). When compared against 2-year CDP, our 6 MWGST approach had 71% accuracy and 60% positive predictive value. Compared to the LRP group, those MS participants stratified as HRP (15 out of 62 MS participants), were on average 3.8 years older, had longer MS disease duration and poorer baseline performance on clinical outcomes and PROs scores. Over the subsequent 2 years, only the HRP subgroup showed a significant worsened performance on 6 MW, clinical measures and PROs from baseline. Conclusion: Baseline 6 MWGST was useful for stratifying MS participants with high or low risks for progression over the subsequent 2 years. Findings represent the first reported single measure to predict MS disease progression with important potential applications in both clinical trials and care in MS.

Ketogenic diet in relapsing multiple sclerosis: Patient perceptions, post-trial diet adherence & outcomes.

BACKGROUND: Ketogenic diets (KDs) are safe and tolerable in people with multiple sclerosis (MS). While many patient-reported and clinical benefits are noted, the sustainability of these diets outside of a clinical trial is unknown. AIMS: Evaluate patient perceptions of the KD following intervention, determine the degree of adherence to KDs post-trial, and examine what factors increase the likelihood of KD continuation following the structured diet intervention trial. METHODS: Sixty-five subjects with relapsing MS previously enrolled into a 6-month prospective, intention-to-treat KD intervention. Following the 6-month trial, subjects were asked to return for a 3-month post-study follow-up, at which time patient reported outcomes, dietary recall, clinical outcome measures, and laboratory values were repeated. In addition, subjects completed a survey to evaluate sustained and attenuated benefits following completion of the intervention phase of the trial. RESULTS: Fifty-two subjects (81%) returned for the 3-month post-KD intervention visit. Twenty-one percent reported continued adherence to a strict KD and an additional 37% reported adhering to a liberalized, less restrictive form of the KD. Those subjects with greater reductions in body mass index (BMI) and fatigue at 6-months on-diet were more likely to continue on KD following trial completion. Using intention-to-treat analysis, patient-reported and clinical outcomes at 3-months post-trial remained significantly improved from baseline (pre-KD), though the degree of improvement was slightly attenuated relative to outcomes at 6-months on KD. Regardless of diet type following the KD intervention, dietary patterns shifted toward greater protein and polyunsaturated fats and less carbohydrate/added sugar consumption. CONCLUSIONS: Following the 6-month KD intervention study, the majority of subjects elected to continue on KD, though many pursued a more liberal limit for carbohydrate restriction. Those who experienced a greater reduction in BMI or fatigue were more likely to continue with strict KD. The 6-month KD intervention induced persistent changes to dietary habits in the months following study completion. TRIAL REGISTRATION INFORMATION: Registered on Clinicaltrials.gov under registration number NCT03718247, posted on Oct 24, 2018. First patient enrollment date: Nov 1, 2018. Link: https://clinicaltrials.gov/ct2/show/NCT03718247?term=NCT03718247&draw=2&rank=1.

Serum neurofilament light chain in relapsing multiple sclerosis patients on a ketogenic diet.

BACKGROUND: Ketogenic diets have anti-inflammatory and neuroprotective properties which make these diets an attractive complimentary treatment approach for patients living with multiple sclerosis (MS). The objective of this study was to assess the impact of ketogenic diets on neurofilament light chain (NfL), a biomarker of neuroaxonal injury. METHODS: Thirty-nine subjects with relapsing MS completed a 6-month ketogenic diet intervention. NfL levels were assayed at both baseline (pre-diet) and 6-months on-diet. In addition, ketogenic diet study participants were compared to a cohort (n = 31) of historical, untreated MS controls. RESULTS: Baseline (pre-diet) mean NfL was 5.45 pg/ml (95% CI 4.59 - 6.31). After 6 months on ketogenic diet, mean NfL was not significantly changed (5.49 pg/ml; 95% CI 4.82 - 6.19). Compared to untreated MS controls (mean 15.17 pg/ml), NfL levels for the ketogenic diet cohort were relatively low. MS subjects with higher levels of ketosis (as measured by serum beta-hydroxybutyrate) exhibited greater reductions in NfL between baseline and 6-months on ketogenic diet. CONCLUSIONS: Ketogenic diets do not worsen biomarkers of neurodegeneration in relapsing MS patients, with stable, low levels of NfL observed throughout the diet intervention. Subjects with greater biomarkers of ketosis experienced a higher degree of improvement in serum NfL. CLINICAL TRIAL IDENTIFIER: NCT03718247 - "Utilization of the Ketogenic Diet in Patients with Relapsing-Remitting MS" https://clinicaltrials.gov/ct2/show/NCT03718247.

Gender Disparities in the Career of Neurology Researchers.

BACKGROUND AND OBJECTIVES: To assess gender disparities in neurology researcher careers in the United States. METHODS: A 34-question survey was distributed to 4,644 US-based American Academy of Neurology members who self-identified as researchers in 2020 addressing the following domains: research and funding, scholarly activities, coronavirus disease 2019 (COVID-19) effect, and local institutional climate. RESULTS: A total of 700 (15%) individuals completed the survey (women, n = 231; men, n = 426), with 71% White and >80% conducting research. Women respondents were significantly younger than men, more likely to be assistant professors (32% vs 21%), and less likely to be full professors (18% vs 39%). Compared with men, women received equivalent grants and research support and had comparable or additional formal research training and mentorship. Women had less middle author publications (mean 5.8 [SD 9.2] vs mean 8.2 [SD 11.8], p = 0.03) compared with men but similar first or last author publications (mean 4.3[5.4] vs 6.1 [9.8], p = 0.05). A lower proportion of women presented research at grand rounds or at a national/international conference compared with men (58% vs 69%, p = 0.01). Women spent more time in nonprofessional responsibilities, were less satisfied with their work-life balance, and were less likely to agree with statements addressing equity/diversity and institutional climate. Respondents shared their concerns regarding how the pandemic was affecting neurology research careers, with a higher proportion of women reporting that family responsibilities affected research activities and lead to delayed submission of non-COVID-19-related manuscripts. DISCUSSION: Our survey of US-based neurology researchers demonstrated continued gender-based disparities in academic rank, manuscript authorship, and invited speaking engagements, although funding opportunities and access to additional training were equivalent. Women were less likely than men to agree that neurology departments support diversity and equity and that the institutional climate was inclusive and transparent. The pandemic had affected both genders in research, but areas were different for women related to family responsibilities. This article also highlights additional areas of research and areas for intervention to improve and reduce gender disparities among neurology researchers.

Visit-to-visit systolic blood pressure variability is associated with increased fatigue symptoms in multiple sclerosis patients.

OBJECTIVE: To evaluate the relationship between visit-to-visit systolic blood pressure variability (SBPv) and fatigue symptoms in Multiple Sclerosis (MS) patients. METHODS: This is a cross-sectional study using data for MS patients who completed the Fatigue Subscale in the Performance Scales (PS), a validated, self-reported measure of MS-related disability, between 2011 and 2015 at an academic medical center. Those who had at least 3 available SBP measures within the prior 12 months of the survey were included in the analysis. Ordinal logistic regression was used to model fatigue as a function of SBP variability, adjusting for demographic factors and mean SBP. RESULTS: Data for 91 MS subjects were analyzed. We found that, compared to those with the lowest SBP variability (Tertile 1), subjects in Tertile 2 had 2.2 times higher odds (OR = 2.19; 95% CI, 0.82-5.87; p = 0.120) and those in Tertile 3 (highest variability) 4.2 times higher odds (OR = 4.16; 95% CI, 1.56-11.13; p = 0.005) of being in a higher fatigue level group, independent of age, sex, race/ethnicity, and mean SBP. CONCLUSIONS: Our data show that MS patients with higher SBP variability had a greater degree of fatigue. Future research is needed to further explore this relationship and the potential for therapeutic opportunities to improve fatigue.

Six-Minute Walk as a Measure of Walking Capacity and Endurance in Patients With Pediatric-Onset Multiple Sclerosis.

BACKGROUND: Despite low levels of disability, youth with pediatric-onset MS (POMS) engage in less physical activity compared to peers. The contribution of walking capacity, endurance, behavior, and MS co-morbidities remain relatively undefined and may provide valuable insights into the limitations toward physical activity in youth with MS. OBJECTIVE: Investigate differences in walking capacity, endurance and real-world behaviors of daily activity between youth with POMS and controls. DESIGN/METHODS: Youth diagnosed with MS prior to 18 years and aged ≤21 years were recruited in addition to healthy controls. Subjects completed questionnaires to quantify fatigue, depression, and physical activity levels and the timed 2- and 6-minute walk (2MW, 6MW) as an assessment of walk capacity and endurance. Subjects were sent home with a waist-worn accelerometer to assess real-world walking behavior. RESULTS: Forty-five POMS and 85 control subjects were enrolled. The POMS cohort had a mean age of 16.9±2.7 years with a mean disease duration of 2.8±2.6 years. A greater proportion of the POMS cohort was overweight/obese compared to controls (60% versus 33%). Subjects with MS walked a significantly shorter distance in 6 minutes compared to controls (1848 feet vs 2134 feet, p<0.0001) and, unlike controls, were unable to accelerate to their peak speed at the end of the 6MW. BMI category and MS disease significantly impacted 6MW performance. Using continuous accelerometry, subjects with MS spent less time in moderate-to-vigorous physical activity compared to controls (20.4 minutes/day vs 35.4 minutes/day, p=0.0003). The POMS cohort reported significantly higher levels of depression and fatigue, but self-reported similar levels of daily physical activity as controls. CONCLUSIONS: Youth with POMS exhibit slower 6MW performance and less daily engagement in moderate-to-vigorous physical activity, suggesting limitations in functional walking capacity, endurance, and daily activity behavior. Limitations in walking endurance and capacity are most prominent in those youth who are overweight/obese and living with MS. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, compared to healthy controls, patients with pediatric-onset MS walk shorter distances on the 6 minute walk test, are less able to accelerate to peak speed at the end of the test, and are less physically active.

Epidemiology and Pathophysiology of Multiple Sclerosis.

PURPOSE OF REVIEW: This article provides an overview of genetic, environmental, and lifestyle risk factors affecting the disease course of multiple sclerosis (MS) and reviews the pathophysiologic characteristics of both relapsing and progressive MS. RECENT FINDINGS: The prevalence of MS has increased in recent decades, and costs of care for patients with MS have risen dramatically. Black, Asian, and Hispanic individuals may be at risk for more severe MS-related disability. Multiple genetic MS risk factors have been identified. Factors such as low vitamin D levels and a history of Epstein-Barr virus, smoking, and obesity, especially during childhood, also influence MS risk. Traditionally thought to be a T-cell-mediated disease, recent research has highlighted the additional roles of B cells and microglia in both relapsing and progressive MS. SUMMARY: Complex interactions between genetic, environmental, and lifestyle factors affect the risk for MS as well as the disease course. People of color have historically been underrepresented in both MS clinical trials and literature, but current research is attempting to better clarify unique considerations in these groups. MS pathology consists of the focal inflammatory lesions that have been well characterized in relapsing MS, as well as a more widespread neurodegenerative component that is posited to drive progressive disease. Recent advances in characterization of both the inflammatory and neurodegenerative aspects of MS pathophysiology have yielded potential targets for future therapeutic options.

Phase II study of ketogenic diets in relapsing multiple sclerosis: safety, tolerability and potential clinical benefits.

BACKGROUND: Dietary changes impact human physiology and immune function and have potential as therapeutic strategies. OBJECTIVE: Assess the tolerability of a ketogenic diet (KD) in patients with relapsing multiple sclerosis (MS) and define the impact on laboratory and clinical outcome metrics. METHODS: Sixty-five subjects with relapsing MS enrolled into a 6-month prospective, intention-to-treat KD intervention. Adherence was monitored with daily urine ketone testing. At baseline, fatigue, depression and quality of life (QoL) scores were obtained in addition to fasting adipokines and MS-related clinical outcome metrics. Baseline metrics were repeated at 3 and/or 6 months on-diet. RESULTS: Eighty-three percent of participants adhered to the KD for the study duration. Subjects exhibited significant reductions in fat mass and showed a nearly 50% decline in self-reported fatigue and depression scores. MS QoL physical health (67±16 vs 79±12, p<0.001) and mental health (71±17 vs 82±11, p<0.001) composite scores increased on-diet. Significant improvements were noted in Expanded Disability Status Scale scores (2.3±0.9 vs 1.9±1.1, p<0.001), 6-minute walk (1631±302 vs 1733±330 ft, p<0.001) and Nine-Hole Peg Test (21.5±3.6 vs 20.3±3.7 s, p<0.001). Serum leptin was lower (25.5±15.7 vs 14.0±11.7 ng/mL, p<0.001) and adiponectin was higher (11.4±7.8 vs 13.5±8.4 µg/mL, p=0.002) on the KD. CONCLUSION: KDs are safe and tolerable over a 6-month study period and yield improvements in body composition, fatigue, depression, QoL, neurological disability and adipose-related inflammation in persons living with relapsing MS. TRIAL REGISTRATION INFORMATION: Registered on ClinicalTrials.gov under registration number NCT03718247, posted on 24 October 2018. First patient enrolment date: 1 November 2018. Link: https://clinicaltrials.gov/ct2/show/NCT03718247?term=NCT03718247&draw=2&rank=1.

A Phase 3, double-blind, placebo-controlled efficacy and safety study of ADS-5102 (Amantadine) extended-release capsules in people with multiple sclerosis and walking impairment.

BACKGROUND: ADS-5102, a delayed-release, extended-release (DR/ER) amantadine, improved walking speed in MS in a Phase 2 trial. OBJECTIVE: The aim of this study was to present primary results of a Phase 3, double-blind, ADS-5102 trial (INROADS) for walking speed. METHODS: Adult participants with MS and walking impairment, not currently using amantadine or dalfampridine, underwent 4-week placebo run-in before randomization 1:1:1 to placebo, 137 or 274 mg/day ADS-5102 for 12 weeks. Primary outcome was the proportion of responders (20% increase in Timed 25-Foot Walk (T25FW) speed) for 274 mg ADS-5102 versus placebo at end of double-blind (Study Week 16). Additional measures included Timed Up and Go (TUG), 2-Minute Walk Test (2MWT), and 12-item Multiple Sclerosis Walking Scale (MSWS-12). RESULTS: In total, 558 participants were randomized and received double-blind treatment. Significantly more participants responded with 274 mg ADS-5102 (21.1%) versus placebo (11.3%). Mean T25FW speed also significantly improved (0.19 ft/s) versus placebo (0.07 ft/s). Other measures were not significant using prespecified hierarchical testing procedure. Adverse events led to discontinuation for 3.8% (placebo), 6.4% (137 mg ADS-5102), and 20.5% (274 mg ADS-5102). CONCLUSION: INROADS met its primary endpoint, showing a significantly greater proportion of participants with meaningful improvement in walking speed for 274 mg ADS-5102 versus placebo. Numeric dose response was seen for some secondary efficacy outcomes and adverse events.

Relationship between balance confidence and social engagement in people with multiple sclerosis.

OBJECTIVE: To evaluate the relationships among patient-reported balance confidence and social satisfaction and social participation in people with multiple sclerosis (pwMS). METHODS: 75 ambulatory pwMS who had sustained at least two falls or near falls in the prior two months self-reported their balance confidence (Activities-specific Balance Confidence (ABC) questionnaire) and social satisfaction and participation (Patient Reported Outcomes Measurement Information System (PROMIS) measures). Correlations between the ABC and PROMIS measures were examined using Spearman's rank correlation. RESULTS: In a cross-sectional analysis, ABC scores and PROMIS scores for social satisfaction and social participation were statistically significantly correlated (ρ 0.37-0.54, p ≤ 0.001). The correlation between balance confidence and social satisfaction was consistently stronger at each time point than between balance confidence and social participation. CONCLUSION: Self-reported balance confidence is associated with both social satisfaction and social participation in pwMS who fall. The causal direction of this relationship remains uncertain.

Evaluation of Treatment Practices for Urinalyses and Urine Cultures at an Outpatient Multiple Sclerosis Clinic.

BACKGROUND: Patients with multiple sclerosis (MS) experience disease flares that can be precipitated by the presence of infection. Discerning asymptomatic bacteriuria from urinary tract infection (UTI) in patients with MS is complicated by lower urinary tract dysfunction, leading to potentially inappropriate antimicrobial use. In this study the antimicrobial treatment practices for positive urine cultures in patients with MS were evaluated. METHODS: In this single-center, retrospective study, positive cultures in patients with MS were included. The primary outcome was the proportion of patients appropriately treated with or without antimicrobial therapy. Secondary end points included antimicrobial selection and urinalysis positivity. RESULTS: Two hundred thirty-six cultures from 139 patients were evaluated. Treatment was inappropriate in 81 of 201 treated cultures (40%). Frequency, nocturia, dysuria, and foul-smelling urine were reported by patients in 54 (23%), 10 (4%), 25 (11%), and 14 (6%) cultures, respectively. The antimicrobial selected was too broad in spectrum for 35 of 201 (17%). Of those, fluoroquinolones were the agents used in 33 of 35 cases (94%). A urinalysis was sent in 203 cases (86%), with 197 (84%) positive for at least one predefined positivity criteria. CONCLUSIONS: Urinalyses and urine cultures are performed frequently in patients with MS, often independent of symptoms. Patients with MS could be treated for asymptomatic bacteriuria at higher rates than the general population, and traditional urinary symptoms may not be appropriate indicators of infection. Empirical therapy for UTI is frequently used in this population, often resulting in inappropriate and/or too broad of antimicrobial therapy.

Consensus Curriculum for Fellowship Training in Multiple Sclerosis and Neuroimmunology.

Management of multiple sclerosis and neuroimmunologic disorders has become increasingly complex because of the expanding number of recognized neuroimmune disorders, increased number of therapeutic options, and multidisciplinary care management needs of people with multiple sclerosis and neuroimmunologic disorders. More subspecialists are needed to optimize care of these patients, and many fellowship programs have been created or expanded to increase the subspecialty workforce. Consequently, defining the scope and standardizing fellowship training is essential to ensure that trainees receive high-quality training. A workgroup was created to develop a consensus fellowship curriculum to serve as a resource for all current and future training programs. This curriculum may also serve as a basis for future accreditation efforts.

Gait Speed Trajectory During the Six-Minute Walk Test in Multiple Sclerosis: A Measure of Walking Endurance.

Background: The six-minute walk (6MW) test is a validated assessment method in Multiple Sclerosis (MS) research. While the total distance covered during six minutes (6MWTD ) is often used as the standard measurement of gait capacity (i.e., the maximum distance one can achieve), we hypothesize that endurance (i.e., ability to maintain speed over a prolonged time) can be inferred by the gait speed trajectory (GST) during the 6MW test (6MWGST ). Objective: To characterize group differences in 6MWGST between MS patients and healthy controls (HCs), and to assess information added by 6MWGST for discerning between MS patients and HCs. Methods: We performed a secondary data analysis on a cross-sectional cohort of 40 MS and 20 HC subjects with three repeated 6MW tests. We modeled 6MWGST using a linear mixed-effects model with time in minutes and replicated walks nested within individuals. We compared the discernibility of 6MWGST with that of conventional metrics using likelihood ratio tests and receiver operating characteristic (ROC) analysis on logistic regression models. Results: MS subjects showed a concave, quadratic GST during 6MW tests, slowing down more than the HC subjects, especially at the beginning of 6MW tests. Despite accelerating at the end of the 6MW, MS subjects were unable to attain or surpass their initial 6MW gait speeds. 6MWGST added useful information (p = 0.002) to the conventional metrics (e.g., 6MWTD ) for discerning between MS and HC subjects, and increased the area under the ROC curve from 0.83 to 0.93 (p = 0.037). Conclusions: The distinctive 6MWGST pattern of MS patients provided increased discernibility compared with currently used gait metrics. Both gait capacity measured by the 6MWTD , and gait endurance measured by parameters of 6MWGST , are significant functional indicators for the MS population.

Efficacy and Safety of 2 Fingolimod Doses vs Glatiramer Acetate for the Treatment of Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial.

IMPORTANCE: Doses of fingolimod lower than 0.5 mg per day were not investigated during the fingolimod clinical development program. Whether lower doses of fingolimod might retain efficacy with fewer safety risks remains unknown. OBJECTIVE: To evaluate the efficacy and safety of fingolimod, 0.5 mg, and fingolimod, 0.25 mg, compared with glatiramer acetate and to assess whether these doses of fingolimod show superior efficacy to glatiramer acetate in adult patients with relapsing-remitting multiple sclerosis. INTERVENTIONS: Fingolimod, 0.5 mg, or fingolimod, 0.25 mg, orally once per day or glatiramer acetate, 20 mg, subcutaneously once per day. DESIGN, SETTING, AND PARTICIPANTS: The Multiple Sclerosis Study Evaluating Safety and Efficacy of Two Doses of Fingolimod Versus Copaxone (ASSESS) was a phase 3b multicenter randomized rater-blinded and dose-blinded 12-month clinical trial conducted between August 9, 2012, and April 30, 2018 (including the time required to recruit participants). A total of 1461 patients aged 18 to 65 years with relapsing-remitting multiple sclerosis were screened, and 1064 participants were randomized. These participants had at least 1 documented relapse during the previous year or 2 documented relapses during the previous 2 years and an Expanded Disability Status Scale score of 0 to 6 at screening. Data were analyzed between September and November 2018. MAIN OUTCOMES AND MEASURES: The superiority of the fingolimod doses was tested hierarchically, with fingolimod, 0.5 mg, vs glatiramer acetate, 20 mg, tested first, followed by fingolimod, 0.25 mg, vs glatiramer acetate, 20 mg. The primary end point was the reduction in annualized relapse rate (ARR). Magnetic resonance imaging parameters, safety, and tolerability were also assessed. RESULTS: Of 1461 adult patients screened, 1064 participants (72.8%) were randomized (mean [SD] age, 39.6 [11.0] years; 792 women [74.4%]) to 3 treatment groups: 352 participants received fingolimod, 0.5 mg, 370 participants received fingolimod, 0.25 mg, and 342 participants received glatiramer acetate, 20 mg. In total, 859 participants (80.7%) completed the study. Treatment with fingolimod, 0.5 mg, was superior to treatment with glatiramer acetate, 20 mg, in reducing ARR (40.7% relative reduction); the relative reduction with fingolimod, 0.25 mg, was 14.6%, which was not statistically significant (for fingolimod, 0.5 mg, ARR, 0.15; 95% CI, 0.11-0.21; for fingolimod, 0.25 mg, ARR, 0.22; 95% CI, 0.17-0.29; for glatiramer acetate, 20 mg, ARR, 0.26; 95% CI, 0.20-0.34). Treatment with both fingolimod doses (0.5 mg and 0.25 mg) significantly reduced new or newly enlarging T2 and gadolinium-enhancing T1 lesions compared with treatment with glatiramer acetate. Adverse events were reported in similar proportions across treatment groups (312 participants [90.4%] in the fingolimod, 0.5 mg, group, 323 participants [88.3%] in the fingolimod, 0.25 mg, group, and 283 participants [87.3%] in the glatiramer acetate group). CONCLUSIONS AND RELEVANCE: Fingolimod, 0.5 mg, demonstrated superior clinical efficacy compared with glatiramer acetate, 20 mg, and had a superior benefit-risk profile compared with fingolimod, 0.25 mg, in adult participants with relapsing-remitting multiple sclerosis. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01633112.

Retrospective cohort study of the relationship between systolic blood pressure variability and multiple sclerosis disability.

OBJECTIVE: To examine the relationship between visit-to-visit systolic blood pressure (SBP) variability and patient-reported outcome measure of disability in multiple sclerosis (MS) patients. DESIGN: A retrospective cohort study of individuals with MS who completed a patient-determined disease steps (PDDS) scale between 2011 and 2015 at an MS specialty clinic. PARTICIPANTS: Individuals with MS for whom both a completed PDDS scale and ≥3 SBP measures within the prior 12 months of the survey were available. MAIN OUTCOME MEASURE: Participants were grouped into three classes of disability (no or mild (PDDS 0-1), moderate (2-3), severe (4-7)). SBP variability was calculated as within-subject SD using all SBP measures taken during the past 12 months. SBP variability was analysed by Tertile groups. RESULTS: Ninety-two subjects were included in this analysis. Mean PDDS score was 2.22±1.89. Compared with subjects in Tertile 1 (lowest variability), the odds of being in a higher disability group was 3.5 times higher (OR=3.48; 95% CI: 1.08 to 11.25; p=0.037) in Tertile 2 and 5.2 times higher (OR=5.19; 95% CI: 1.53 to 17.61; p=0.008) in Tertile 3 (highest variability), independent of mean SBP, age, sex, race/ethnicity, body mass index and comorbidities (p for trend=0.008). Mean PDDS scores were 1.52±1.18 in Tertile 1, 2.73±1.02 in Tertile 2 and 2.42±0.89 in Tertile 3 after adjusting for the same covariates. CONCLUSIONS: Our results show a significant gradient relationship between SBP variability and MS-related disability. More research is needed to determine the underlying pathophysiological relationship between SBP variability and MS disability progression.

Patient-specific factors modulate leukocyte response in dimethyl fumarate treated MS patients.

OBJECTIVE: Determine if patient-specific factors modulate absolute lymphocyte count (ALC), neutrophil count (ANC), and/or Neutrophile-lymphocyte ratio (NLR) in Dimethyl Fumarate (DMF) treated patients. METHODS: A retrospective study of patients who initiated DMF between 2013-2018. A multicenter study of two MS clinics: Charlottesville, VA (UVA) and Dallas, TX (DaVA). RESULTS: 103 patients (67-UVA, 36-DaVA) met eligibility. At baseline, the DaVa population was younger (mean±sd: 38.6±9.0 vs 42.2±12.5, p 0.152) and had a higher proportion of males (61% vs. 35%), consistent with a veteran cohort. Pre-treatment, all other laboratory parameters were similar between the two groups. On treatment there was a 30% lowering of mean ALC, with 3% having grade-3 lymphopenia (ALC < 500). Sustained neutropenia occurred in 3.9% of patients and was more common in males. Over 50% of patients had a high NLR at baseline, with a further 44% increase in NLR on-treatment. Age was significantly predictive of lymphopenia, with grade-3 lymphopenia found in 33% of patients ≥ 55 years. Neutropenia was more common in males. Serum BG (sBG) has modest correlation to leukocyte parameters. BMI was not correlated with any leukocyte-related outcomes. CONCLUSIONS: Patient-specific factors, specifically-age, sex, and serum blood glucose, modulate leukocyte response and ratios in DMF treated MS patients. Age appears to be a relevant predictor of lymphopenia and should be a factor in treatment decision making. Neutropenia, independent of lymphopenia, can occur and males may be at increased risk. High sBG may impact leukocyte count and ratios in MS patients and merits further study, particularly in patients with diabetes. NLR is abnormal in MS and increased with DMF-treatment, the clinical implications of this will require further study.

Smoking Cessation Considerations for People with Multiple Sclerosis.

BACKGROUND: Comprehensive care of people with multiple sclerosis integrates disease modifying therapy, symptom management and minimization of risk factors for disease progression. Cigarette smoking is a modifiable risk factor associated with development and progression of disease and increased disability. However, little is known about specific factors that affect smoking cessation in patients with multiple sclerosis or how to integrate smoking cessation into specialized multiple sclerosis care. METHODS: Twenty-nine active smokers with multiple sclerosis were surveyed at the James Q. Miller Multiple Sclerosis clinic at the University of Virginia Health. Demographics, smoking history, multiple sclerosis history, interest in quitting, barriers to quitting and cessation modalities of interest were collected, specifically interest in working with a clinical pharmacist for cessation. RESULTS: Seventy-six percent of individuals believed that there was no relationship between smoking and MS diagnosis and 52% were unaware of any relationship between smoking and disease progression. Less than half of patients (41%) reported receiving counseling from a primary care physician or neurologist about the importance of smoking cessation. Common barriers to quitting included enjoyment of smoking (76%) and cravings (55%). Seventy-six percent of patients expressed interest in utilizing pharmacotherapy and 37% were interested in working closely with a clinical pharmacist. CONCLUSIONS: It is critical that providers caring for patients with multiple sclerosis assess smoking status and educate smokers about the relationship between smoking and disease progression. Efforts should be made to better understand patient-specific barriers to quitting and preferred methods of treatment, including pharmacotherapy and behavioral therapy. A multidisciplinary approach to smoking cessation that includes a clinical pharmacist may aid in the development of individualized care plans with frequent monitoring to improve patient success.