Research interrupted: The impact of the COVID-19 pandemic on multiple sclerosis research in the field of rehabilitation and quality of life.

BACKGROUND: The COVID-19 pandemic has likely had a negative impact on rehabilitation and quality of life (QoL) research in multiple sclerosis (MS). METHOD: We explored perceived barriers to research among 87 researchers, representing 18 countries, both prior to and since COVID-19. RESULTS: A Wilcoxon signed-rank test found that significantly more researchers reported experiencing barriers to research since the onset of the pandemic compared to pre-COVID-19 (p < .001), with 78% of respondents reporting at least some barriers since COVID-19. The most commonly-cited barriers related to participant access (n = 38) and interruptions/delays to projects (n = 19). Although no gender differences were found in the number of barriers reported, female respondents were more likely to cite time or competing demands as barriers to research. Females were also more likely to perceive being negatively impacted by the pandemic compared to other genders (p = .007). CONCLUSIONS: Implications for the future landscape of rehabilitation research in MS are discussed.

Dalfampridine for Mobility Limitations in People With Multiple Sclerosis May Be Augmented by Physical Therapy: A Non-randomized Two-Group Proof-of-Concept Pilot Study.

Purpose: To demonstrate proof-of-concept for a combined physical therapy and pharmacological intervention and obtain preliminary estimates of the therapeutic efficacy of a motor-relearning physical therapy intervention with and without concurrent dalfampridine treatment on gait speed in people with mobility limitations due to multiple sclerosis (MS). Methods: Using a non-randomized, two-group design, 4 individuals with MS newly prescribed dalfampridine as part of their routine medical care, and 4 individuals with MS not taking dalfampridine completed a 3-week drug run-in or no-treatment baseline, respectively. After 3 weeks, all participants commenced physical therapy twice weekly for 6 weeks. Participants taking dalfampridine took the medication for the study duration. The physical therapy program comprised functional strengthening, gait training, balance training, and dual-task training. The primary outcome was Timed 25-foot Walk (T25FW) at the end of the 6-week physical therapy program. Results: For the 4 participants taking dalfampridine, average improvement in T25FW on drug only was 12.8% (95% CI 1.2 to 24.4%). During the 6-week physical therapy phase, both groups significantly improved T25FW, but the effect tended to favor the group taking dalfampridine (mean difference = -0.93 s, 95% CI -1.9 to 0.07 s, p = 0.064, d = 1.6). Whereas the physical therapy group had average T25FW improvement of 10.8% (95% CI 1.0 to 20.5%), the physical therapy plus dalfampridine group demonstrated average improvement of 20.7% (95% CI 3.8 to 37.6%). Conclusions: Further research is warranted to examine whether dalfampridine for mobility impairment may be augmented by physical therapy in people with MS.

Exercise and lifestyle physical activity recommendations for people with multiple sclerosis throughout the disease course.

OBJECTIVES: To provide clinicians who treat multiple sclerosis (MS) patients with evidence-based or expert opinion-based recommendations for promoting exercise and lifestyle physical activity across disability levels. METHODS: The National MS Society ("Society") convened clinical and research experts in the fields of MS, exercise, rehabilitation, and physical activity to (1) reach consensus on optimal exercise and lifestyle physical activity recommendations for individuals with MS at disability levels 0-9.0 on the Expanded Disability Status Scale (EDSS) and (2) identify and address barriers/facilitators for participation. RECOMMENDATIONS: Based on current evidence and expert opinion, the Society makes the following recommendations, endorsed by the Consortium of Multiple Sclerosis Centers:Healthcare providers should endorse and promote the benefits/safety of exercise and lifestyle physical activity for every person with MS.Early evaluation by a physical or occupational therapist or exercise or sport scientist, experienced in MS (hereafter referred to as "specialists"), is recommended to establish an individualized exercise and/or lifestyle physical activity plan.Taking into account comorbidities and symptom fluctuations, healthcare providers should encourage ⩾150 min/week of exercise and/or ⩾150 min/week of lifestyle physical activity.Progress toward these targets should be gradual, based on the person's abilities, preferences, and safety.If disability increases and exercise/physical activity becomes more challenging, referrals to specialists are essential to ensure safe and appropriate prescriptions.When physical mobility is very limited, exercise should be facilitated by a trained assistant.

Telemedicine in neurology: Telemedicine Work Group of the American Academy of Neurology update.

PURPOSE: While there is strong evidence supporting the importance of telemedicine in stroke, its role in other areas of neurology is not as clear. The goal of this review is to provide an overview of evidence-based data on the role of teleneurology in the care of patients with neurologic disorders other than stroke. RECENT FINDINGS: Studies across multiple specialties report noninferiority of evaluations by telemedicine compared with traditional, in-person evaluations in terms of patient and caregiver satisfaction. Evidence reports benefits in expediting care, increasing access, reducing cost, and improving diagnostic accuracy and health outcomes. However, many studies are limited, and gaps in knowledge remain. SUMMARY: Telemedicine use is expanding across the vast array of neurologic disorders. More studies are needed to validate and support its use.

Conducting dietary intervention trials in people with multiple sclerosis: Lessons learned and a path forward.

Disease course in people with multiple sclerosis (MS) is heterogeneous. The impact of dietary and nutritional factors on MS prognosis is of interest to both patients and clinicians; differences in diet are hypothesized to contribute to disease evolution over time. However, studying diet, especially in people with MS, introduces methodologic complexity that should be recognized. In this review, we focus on methodological aspects relevant to the conduct of dietary interventions in people with MS, given our experience in leading such studies and the challenges we encountered in the realization of this work. We summarize key aspects of study design and important considerations, regardless of the specifics of the actual study (e.g. the particular diet of interest, target MS population, etc.). We discuss strategies for the design of the intervention as well as the selection of appropriate study endpoints. Finally, we provide an overview of strategies to improve the rigor of conducting dietary studies in people with MS.

Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers.

BACKGROUND: Multiple Sclerosis (MS) specialists routinely evaluate misdiagnosed patients, or patients incorrectly assigned a diagnosis of MS. Misdiagnosis has significant implications for patient morbidity and healthcare costs, yet its contemporary incidence is unknown. We examined the incidence of MS misdiagnosis in new patients referred to two academic MS referral centers, their most common alternate diagnoses, and factors associated with misdiagnosis. METHODS: Demographic data, comorbidities, neurological examination findings, radiographic and laboratory results, a determination of 2010 McDonald Criteria fulfillment, and final diagnoses were collected from all new patient evaluations completed at the Cedars-Sinai Medical Center and the University of California, Los Angeles MS clinics over twelve months. RESULTS: Of the 241 new patients referred with an established diagnosis of MS, 17% at Cedars-Sinai and 19% at UCLA were identified as having been misdiagnosed. The most common alternative diagnoses were migraine (16%), radiologically isolated syndrome (9%), spondylopathy (7%), and neuropathy (7%). Clinical syndromes and radiographic findings atypical for MS were both associated with misdiagnosis. The misdiagnosed group received approximately 110 patient-years of unnecessary MS disease modifying therapy. CONCLUSION: MS misdiagnosis is common; in our combined cohort, almost 1 in 5 patients who carried an established diagnosis of MS did not fulfill contemporary McDonald Criteria and had a more likely alternate diagnosis.

Case Report: Combining Dalfampridine with Multicomponent Exercise and Gait Training in a Person with Multiple Sclerosis.

BACKGROUND: Dalfampridine extended release (D-ER) improves gait speed in some people with multiple sclerosis (MS), but many patients who take D-ER demonstrate only small improvements of questionable clinical significance. Physical therapy (PT) may augment the treatment effects of D-ER on the nervous system and improve clinical outcomes. This case report describes the successful use of D-ER combined with multicomponent PT in a patient who did not have a clinically important change in gait speed with D-ER alone. METHODS: A 59-year-old woman with a 6-year history of relapsing-remitting MS was prescribed D-ER by her neurologist. After 3 weeks of D-ER therapy (10 mg twice daily), she demonstrated only a 7.1% improvement in the Timed 25-Foot Walk test. She then commenced PT consisting of two 40-minute sessions per week for 6 weeks while continuing D-ER therapy. Training focused on gait, balance, coordination, functional strengthening, and dual-task performance. RESULTS: After 6 weeks of D-ER + PT, she had a further 14.6% improvement in Timed 25-Foot Walk gait speed, for a total improvement of 20.7%, which elevated her above the clinically meaningful threshold of 20%. Similar patterns of improvement were also observed for self-selected gait speed in single- and dual-task conditions. Improvements in fast and dual-task gait speed were retained 3 weeks later. CONCLUSIONS: For this patient, combining PT with D-ER therapy improved gait speed more than the use of D-ER alone. Further investigation of D-ER + PT or PT as an alternative to D-ER in patients with submeaningful medication response is warranted.

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.

BACKGROUND: There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS: We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS: Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS: In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

Multiple sclerosis management and reproductive changes: A guide for general neurologists.

PURPOSE OF REVIEW: Multiple sclerosis (MS) disease activity and symptoms are tied to hormonal changes. This review explains the current standard of care in MS at various stages of a woman's reproductive life and helps neurologists answer patients' most common questions surrounding MS care and fertility, pregnancy, and menopause. RECENT FINDINGS: Recent work has focused on MS risk and exacerbation with variables related to reproductive health. Management of disease-modifying therapies prenatally and postnatally is also a focus. SUMMARY: This review is a concise, practical guide for general neurologists caring for women with MS. MS is a disease that requires adaptation of management as a woman moves through reproductive stages. With proper planning and management, pregnancy is safe for women with MS. We describe the current standard of care based on trials, when available, and on expert opinion.

Projecting the Adequacy of the Multiple Sclerosis Neurologist Workforce.

BACKGROUND: Anecdotal reports suggest shortages among neurologists who provide multiple sclerosis (MS) patient care. However, little information is available regarding the current and future supply of and demand for this neurologist workforce. METHODS: We used information from neurologist and neurology resident surveys, professional organizations, and previously reported studies to develop a model assessing the projected supply and demand (ie, expected physician visits) of neurologists providing MS patient care. Model projections extended through 2035. RESULTS: The capacity for MS patient visits among the overall neurologist workforce is projected to increase by approximately 1% by 2025 and by 12% by 2035. However, the number of individuals with MS may increase at a greater rate, potentially resulting in decreased access to timely and high-quality care for this patient population. Shortages in the MS neurologist workforce may be particularly acute in small cities and rural areas. Based on model sensitivity analyses, potential strategies to substantially increase the capacity for MS physicians include increasing the number of patients with MS seen per neurologist, offering incentives to decrease neurologist retirement rates, and increasing the number of MS fellowship program positions. CONCLUSIONS: The neurologist workforce may be adequate for providing MS care currently, but shortages are projected over the next 2 decades. To help ensure access to needed care and support optimal outcomes among individuals with MS, policies and strategies to enhance the MS neurologist workforce must be explored now.

Wellness and multiple sclerosis: The National MS Society establishes a Wellness Research Working Group and research priorities.

BACKGROUND: People with multiple sclerosis (MS) have identified "wellness" and associated behaviors as a high priority based on "social media listening" undertaken by the National MS Society (i.e. the Society). OBJECTIVE: The Society recently convened a group that consisted of researchers with experience in MS and wellness-related research, Society staff members, and an individual with MS for developing recommendations regarding a wellness research agenda. METHOD: The members of the group engaged in focal reviews and discussions involving the state of science within three approaches for promoting wellness in MS, namely diet, exercise, and emotional wellness. RESULTS: That process informed a group-mediated activity for developing and prioritizing research goals for wellness in MS. This served as a background for articulating the mission and objectives of the Society's Wellness Research Working Group. CONCLUSION: The primary mission of the Wellness Research Working Group is the provision of scientific evidence supporting the application of lifestyle, behavioral, and psychosocial approaches for promoting optimal health of mind, body, and spirit (i.e. wellness) in people with MS as well as managing the disease and its consequences.

Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis.

BACKGROUND: Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials. METHODS: SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100mg/day) or placebo for 96weeks. Imaging is conducted every 24weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening. RESULTS: A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017. CONCLUSION: SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials.

Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Relapses of multiple sclerosis decrease during pregnancy, when the hormone estriol is increased. Estriol treatment is anti-inflammatory and neuroprotective in preclinical studies. In a small single-arm study of people with multiple sclerosis estriol reduced gadolinium-enhancing lesions and was favourably immunomodulatory. We assessed whether estriol treatment reduces multiple sclerosis relapses in women. METHODS: We did a randomised, double-blind, placebo-controlled phase 2 trial at 16 academic neurology centres in the USA, between June 28, 2007, and Jan 9, 2014. Women aged 18-50 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1) with a random permuted block design to either daily oral estriol (8 mg) or placebo, each in combination with injectable glatiramer acetate 20 mg daily. Patients and all study personnel, except for pharmacists and statisticians, were masked to treatment assignment. The primary endpoint was annualised relapse rate after 24 months, with a significance level of p=0.10. Relapses were confirmed by an increase in Expanded Disability Status Scale score assessed by an independent physician. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00451204. FINDINGS: We enrolled 164 patients: 83 were allocated to the estriol group and 81 were allocated to the placebo group. The annualised confirmed relapse rate was 0.25 relapses per year (95% CI 0.17-0.37) in the estriol group versus 0.37 relapses per year (0.25-0.53) in the placebo group (adjusted rate ratio 0.63, 95% CI 0.37-1.05; p=0.077). The proportion of patients with serious adverse events did not differ substantially between the estriol group and the placebo group (eight [10%] of 82 patients vs ten [13%] of 76 patients). Irregular menses were more common in the estriol group than in the placebo group (19 [23%] vs three [4%], p=0.0005), but vaginal infections were less common (one [1%] vs eight [11%], p=0.0117). There were no differences in breast fibrocystic disease, uterine fibroids, or endometrial lining thickness as assessed by clinical examination, mammogram, uterine ultrasound, or endometrial lining biopsy. INTERPRETATION: Estriol plus glatiramer acetate met our criteria for reducing relapse rates, and treatment was well tolerated over 24 months. These results warrant further investigation in a phase 3 trial. FUNDING: National Institutes of Health, National Multiple Sclerosis Society, Conrad N Hilton Foundation, Jack H Skirball Foundation, Sherak Family Foundation, and the California Community Foundation.

Exercise in the management of persons with multiple sclerosis.

For decades, persons with multiple sclerosis (MS) were counseled to avoid excessive physical activity and exercise because of concerns about worsening disease activity. Recent studies indicate that, not only can those with MS tolerate physical exercise, but that it is helpful in managing symptoms, preventing complications and comorbidities, and may possibly have neuroprotective actions. This article reviews previous studies on the effects of different exercise protocols in people with MS, and provides summaries of suggested exercise regimens that may be appropriate and beneficial for this patient population.

Neuroprotective effects of testosterone treatment in men with multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system. While current medication reduces relapses and inflammatory activity, it has only a modest effect on long-term disability and gray matter atrophy. Here, we have characterized the potential neuroprotective effects of testosterone on cerebral gray matter in a pilot clinical trial. Ten men with relapsing-remitting MS were included in this open-label phase II trial. Subjects were observed without treatment for 6 months, followed by testosterone treatment for another 12 months. Focal gray matter loss as a marker for neurodegeneration was assessed using voxel-based morphometry. During the non-treatment phase, significant voxel-wise gray matter decreases were widespread (p≤ 0.05 corrected). However, during testosterone treatment, gray matter loss was no longer evident. In fact, a significant gray matter increase in the right frontal cortex was observed (p≤ 0.05 corrected). These observations support the potential of testosterone treatment to stall (and perhaps even reverse) neurodegeneration associated with MS. Furthermore, they warrant the investigation of testosterone's neuroprotective effects in larger, placebo controlled MS trials as well as in other neurodegenerative diseases. This is the first report of gray matter increase as the result of treatment in MS.

Fornix damage limits verbal memory functional compensation in multiple sclerosis.

Selective atrophy of the hippocampus, in particular the left CA1 subregion, is detectable in relapsing-remitting MS (RRMS) and is correlated with verbal memory performance. We used novel high-resolution imaging techniques to assess the role that functional compensation and/or white matter integrity of mesial temporal lobe (MTL) structures may play in mediating verbal memory performance in RRMS. High-resolution cortical unfolding of structural MRI in conjunction with functional magnetic resonance imaging (fMRI) was used to localize MTL activity in 18 early RRMS patients and 16 healthy controls during an unrelated word-pairs memory task. Diffusion tensor imaging (DTI) and Tract-Based Spatial Statistics (TBSS) were used to assess the integrity of the fornix and the parahippocampal white matter (PHWM), the major efferents and afferents of the hippocampus. RRMS patients showed greater activity in hippocampal and extra-hippocampal areas during unrelated word-pair learning and recall. Increased hippocampal activity, particularly in the right anterior hippocampus and left anterior CA1 was associated with higher verbal memory scores. Furthermore, increased fractional anisotropy (FA) in the fornix was correlated with both greater fMRI activity in this region and better memory performance. Altered hippocampal fMRI activity in RRMS patients during verbal learning may result from both structural damage and compensatory mechanisms. Successful functional compensation for hippocampal involvement in RRMS may be limited in part by white matter damage to the fornix, consistent with the critical role of this pathway in the clinical expression of memory impairment in MS.

Diagnosis of multiple sclerosis.

There is no pathognomonic symptom, sign, or paraclinical result that provides an unfailingly accurate diagnosis of multiple sclerosis (MS), and hence, MS remains largely a clinical diagnosis. However, being a clinical diagnosis does not mean that the diagnosis of MS is one of exclusion. Increasingly sophisticated guidelines and objective paraclinical findings are generally sufficient to allow the clinician to confirm or rule out the diagnosis with confidence. This article presents the most recent guidelines for using clinical, radiological, and other paraclinical information and the red flags that should alert the clinician to investigate other diagnostic possibilities.