Cerebellar volume measures may differentiate multiple sclerosis fallers from non-fallers.

Introduction: The cerebellum is a common lesion site in persons with multiple sclerosis (PwMS). Physiologic and anatomic studies have identified a topographic organization of the cerebellum including functionally distinct motor and cognitive areas. This study implemented a recent parcellation algorithm developed by Han et al., 2020 to a sample of PwMS and healthy controls to examine relationships among specific cerebellar regions, fall status, and common clinical measures of motor and cognitive functions. Methods: Thirty-one PwMS and 29 age and sex-matched controls underwent an MRI scan and motor and cognitive testing. The parcellation algorithm was applied to all images and divided the cerebellum into 28 regions. Mann-Whitney U tests were used to compare cerebellar volumes among PwMS and controls, and MS fallers and MS non-fallers. Relationships between cerebellar volumes and motor and cognitive function was evaluated using Spearman correlations. Results: PwMS performed significantly worse on functional measures compared to controls. We found significant differences in volumetric measures between PwMS and controls in the corpus medullare, lobules I-III, and lobule V. Volumetric differences seen between PwMS and controls were primarily driven by the MS fallers. Finally, functional performance on motor and cognitive tasks was associated with cerebellar volumes. Conclusions: Using the parcellation tool, our results showed that volumes of motor and cognitive lobules impact both motor and cognitive performance, and that functional performance and cerebellar volumes distinguishes MS fallers from non-fallers. Future studies should explore the potential of cerebellar imaging to predict falls in PwMS.

Lessons learned from clinical trials of exercise and physical activity in people with MS - guidance for improving the quality of future research.

The body of research on exercise and physical activity among persons with multiple sclerosis(MS) has expanded rapidly in quantity, but not necessarily quality, over the past 20+ years. There is evidence for beneficial effects of exercise and physical activity on immune cells and neurotrophic factors, brain structure and function, walking and cognitive performance, fatigue, depression, and pain, and quality of life among persons with MS. Nevertheless, there is heterogeneity in the outcomes of exercise and physical activity, and a recognition of substantial challenges for improving the effectiveness of those behaviors in MS. To move the field forward, members of the National MS Society physical wellness research working-group pooled collective experiences for identifying challenges, logistic complexities, and opportunities for researchers in designing and conducting interventions of exercise and physical activity among persons with MS. We examined the scope of our experiences and identified collective "lessons learned" regarding the behaviors themselves; study design features and stage of research; study setting, safety, and sample selection; and implementation of randomized controlled trials(RCTs) and treatment fidelity. This paper provides a resource that can inform researchers, particularly new investigators or established investigators transitioning into MS, on conducting high-quality RCTs on exercise and physical activity in MS.

From the prodromal stage of multiple sclerosis to disease prevention.

A prodrome is an early set of signs or symptoms that indicate the onset of a disease before more typical symptoms develop. Prodromal stages are well recognized in some neurological and immune-mediated diseases such as Parkinson disease, schizophrenia, type 1 diabetes mellitus and rheumatoid arthritis. Emerging evidence indicates that a prodromal stage exists in multiple sclerosis (MS), raising the possibility of intervention at this stage to delay or prevent the development of classical MS. However, much remains unclear about the prodromal stage of MS and considerable research is needed to fully characterize the prodrome and develop standardized criteria to reliably identify individuals with prodromal MS who are at high risk of progressing to a diagnosis of MS. In this Roadmap, we draw on work in other diseases to propose a disease framework for MS that incorporates the prodromal stage, and set out key steps and considerations needed in future research to fully characterize the MS prodrome, identify early disease markers and develop standardized criteria that will enable reliable identification of individuals with prodromal MS, thereby facilitating trials of interventions to slow or stop progression beyond the prodrome.

Cerebellar Contributions to Motor and Cognitive Control in Multiple Sclerosis✰✰✰.

OBJECTIVE: To evaluate relationships between specific cerebellar regions and common clinical measures of motor and cognitive function in persons with multiple sclerosis (PwMS). DESIGN: Cross-sectional. SETTING: Laboratory. PARTICIPANTS: Twenty-nine PwMS and 28 age- and sex-matched controls without multiple sclerosis (MS) (N=57). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Both diffusion and lobule magnetic resonance imaging analyses and common clinical measures of motor and cognitive function were used to examine structure-function relationships in the cerebellum. RESULTS: PwMS demonstrate significantly worse motor and cognitive function than controls, including weaker strength, slower walking, and poorer performance on the Symbol Digit Modalities Test, but demonstrate no differences in cerebellar volume. However, PwMS demonstrate significantly worse diffusivity (mean diffusivity: P=.0003; axial diffusivity: P=.0015; radial diffusivity: P=.0005; fractional anisotropy: P=.016) of the superior cerebellar peduncle, the primary output of the cerebellum. Increased volume of the motor lobules (I-V, VIII) was significantly related to better motor (P<.022) and cognitive (P=.046) performance, and increased volume of the cognitive lobules (VI-VII) was also related to better motor (P<.032) and cognitive (P=.008) performance, supporting the role of the cerebellum in both motor and cognitive functioning. CONCLUSIONS: These data highlight the contributions of the cerebellum to both motor and cognitive function in PwMS. Using novel neuroimaging techniques to examine structure-function relationships in PwMS improves our understanding of individualized differences in this heterogeneous group and may provide an avenue for targeted, individualized rehabilitation aimed at improving cerebellar dysfunction in MS.

Sensorimotor outcomes in adrenomyeloneuropathy show significant disease progression.

Current outcomes used to evaluate adrenomyeloneuropathy are limited by rater bias, not sensitive to preclinical changes, and require years to decades to detect disease progression. Quantitative outcomes are needed that detect meaningful change in a short time period over a broad range of disability. The study aim was to track sensorimotor outcomes in adults with adrenomyeloneuropathy and evaluate differences in progression between men and women. This prospective observational cohort study analyzes data collected annually in the Phase III study of adults with adrenomyeloneuropathy. Outcomes include postural sway in four static standing conditions, great-toe vibration, hip strength, walking velocity, timed up-and-go, and 6-minute walk distance. Linear mixed model analysis was used to detect change in the outcomes in 2 years, correcting for age, sex, disability, symptom duration, and treatment across the cohort. Modeling was repeated for each sex to evaluate differences. Power computations were carried out by sex and for the full dataset. Sixty-one men and 87 women participated. Average age, 46 ± 12 years; Expanded Disability Status Scale, 3 (1-6.5); symptom duration, 10.8 ± 9.4 years. The cohort showed significant worsening in all standing conditions (P < .001), sensation (P = .0223) and strength (P = .001); but more stability in walking with only velocity (P < .0337) significantly declining. For each sex, postural sway declines significantly in all conditions (P < .01) except for eyes closed feet together for women. Strength declines significantly by sex for hip flexion (P < .03). Sex-specific significant decline is seen in walking (velocity P = .0276; distance P = .0072) for men only. Quantitative measures of postural sway, sensation strength, and walking are effective measures of adrenomyeloneuropathy progression in 2 years.

Exercise leads to metabolic changes associated with improved strength and fatigue in people with MS.

OBJECTIVE: The goal of this exploratory study was to evaluate the effects of an exercise intervention - progressive resistance training (PRT) on the metabolome of people with MS (pwMS) and to link these to changes in clinical outcomes. METHODS: 14 pwMS with EDSS <4.0 and 13 age- and sex-matched healthy controls completed a 12-week in-person PRT exercise intervention. Outcome measures included: plasma metabolomics analysis, cardiovascular fitness tests, EDSS, timed 25-foot walk (T25FW), six-minute walk test (6MWT), hip strength, and modified fatigue impact scale (MFIS). We identified changes in the metabolome with PRT intervention in both groups using individual metabolite abundance and weighted correlation network defined metabolite module eigenvalues and then examined correlations in changes in metabolite modules with changes in various clinical outcomes. RESULTS: In both groups PRT intervention improved hip strength, distance walked in 6WMT, speed of walking, while fatigue (MFIS) was improved in pwMS. Fatty acid, phospholipid, and sex steroid metabolism were significantly altered by PRT in pwMS but not in controls. Changes in fatigue (MFIS score) were strongly inversely correlated and hip strength was moderately correlated with change in sex steroid metabolite module in pwMS. A similar relationship was noted between change in dehydroepiandrosterone sulfate abundance (sex steroid metabolite) and fatigue in pwMS. We also noted an inverse correlation between changes in fatty acid metabolism and cardiovascular fitness in pwMS. INTERPRETATION: PRT-induced metabolic changes may underlie improved clinical parameters in pwMS and may warrant investigation as potential therapeutic targets in future studies.

Prioritizing progressive MS rehabilitation research: A call from the International Progressive MS Alliance.

BACKGROUND: People with multiple sclerosis (MS) experience myriad symptoms that negatively affect their quality of life. Despite significant progress in rehabilitation strategies for people living with relapsing-remitting MS (RRMS), the development of similar strategies for people with progressive MS has received little attention. OBJECTIVE: To highlight key symptoms of importance to people with progressive MS and stimulate the design and implementation of high-quality studies focused on symptom management and rehabilitation. METHODS: A group of international research experts, representatives from industry, and people affected by progressive MS was convened by the International Progressive MS Alliance to devise research priorities for addressing symptoms in progressive MS. RESULTS: Based on information from the MS community, we outline a rationale for highlighting four symptoms of particular interest: fatigue, mobility and upper extremity impairment, pain, and cognitive impairment. Factors such as depression, resilience, comorbidities, and psychosocial support are described, as they affect treatment efficacy. CONCLUSIONS: This coordinated call to action-to the research community to prioritize investigation of effective symptom management strategies, and to funders to support them-is an important step in addressing gaps in rehabilitation research for people affected by progressive MS.

Combining Magnetization Transfer Ratio MRI and Quantitative Measures of Walking Improves the Identification of Fallers in MS.

Multiple sclerosis (MS) impacts balance and walking function, resulting in accidental falls. History of falls and clinical assessment are commonly used for fall prediction, yet these measures have limited predictive validity. Falls are multifactorial; consideration of disease-specific pathology may be critical for improving fall prediction in MS. The objective of this study was to examine the predictive value of clinical measures (i.e., walking, strength, sensation) and corticospinal tract (CST) MRI measures, both discretely and combined, to fall status in MS. Twenty-nine individuals with relapsing-remitting MS (mean ± SD age: 48.7 ± 11.5 years; 17 females; Expanded Disability Status Scale (EDSS): 4.0 (range 1-6.5); symptom duration: 11.9 ± 8.7 years; 14 fallers) participated in a 3T brain MRI including diffusion tensor imaging and magnetization transfer ratio (MTR) and clinical tests of walking, strength, sensation and falls history. Clinical measures of walking were significantly associated with CST fractional anisotropy and MTR. A model including CST MTR, walk velocity and vibration sensation explained >31% of the variance in fall status (R2 = 0.3181) and accurately distinguished 73.8% fallers, which was superior to stand-alone models that included only MRI or clinical measures. This study advances the field by combining clinical and MRI measures to improve fall prediction accuracy in 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.

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.

Longitudinal assessment of hand function in individuals with multiple sclerosis.

OBJECTIVE: Little is known about the frequency and severity of hand dysfunction in individuals with multiple sclerosis (MS). Hence, we sought to determine the extent that quantitative tests of hand function detect changes over time, evaluate their relationship to global disability measures, and identify predictors of hand function. METHODS: One-hundred and forty-seven individuals with MS were included (96 women, 84 relapsing-remitting MS [RRMS]) along with 35 age-and-sex matched controls. Quantitative tests of hand function (grip strength, pinch strength, 9 hole peg test [9HPT], finger tapping) and leg strength were acquired and normalized to age and sex. Expanded Disability Status Scale (EDSS) and timed 25 foot walk were also obtained. Spearman correlations, multivariate regression models and mixed effects linear regression were used for analysis. RESULTS: Our cohort had an EDSS of 3.6 ±â€¯2.2 (median ± SD) and age 44.6 ±â€¯11.9 years. Follow up time was up to 5 years. At baseline, 14/63 individuals with progressive MS (PMS) required more than twice as much time to complete the 9HPT using their dominant hand, compared to controls. Similarly, 11 individuals with PMS had less than 50% of grip strength and 6 had less than 50% of pinch strength, compared to controls. Additionally, 7 individuals with PMS were found to be at least 50% slower than controls in finger tapping. Over two years, 27/85 individuals with MS had more than 20% worsening in their 9HPT results from baseline (17 RRMS, 10 PMS) and 37/74 (20 RRMS, 17 PMS) had more than 20% worsening in their grip strength compared to baseline. CONCLUSIONS: Hand function is commonly impaired in individuals with MS. Assessing hand dysfunction with dynamometry and the 9HPT could help improve the precision of detecting changes in hand function over time in MS, and may be more sensitive in detecting changes in PMS. These quantitative tests may be useful as outcome measures in clinical trials using neuroprotective or reparative therapies and rehabilitative interventions.

Quantitative vibratory sensation measurement is related to sensory cortical thickness in MS.

Objective: Vibratory sensation is a quantifiable measure of physical dysfunction and is often related to spinal cord pathology; however, its association with relevant brain areas has not been fully explored. Our objective was to establish a cortical structural substrate for vibration sensation. Methods: Eighty-four individuals with multiple sclerosis (MS) (n = 54 relapsing, n = 30 progressive) and 28 controls participated in vibratory sensation threshold quantification at the great toe and a 3T MRI evaluating volume of the thalamus and cortical thickness primary and secondary sensory cortices. Results: After controlling for age, sex, and disability level, vibratory sensation thresholds were significantly related to cortical thickness of the anterior cingulate (P = 0.041), parietal operculum (P = 0.022), and inferior frontal gyrus pars operculum (P = 0.044), pars orbitalis (P = 0.007), and pars triangularis (P = 0.029). Within the progressive disease subtype, there were significant relationships between vibratory sensation and thalamic volume (P = 0.039) as well as reduced inferior frontal gyrus pars operculum (P = 0.014) and pars orbitalis (P = 0.005) cortical thickness. Conclusions: The data show significant independent relationships between quantitative vibratory sensation and measures of primary and secondary sensory cortices. Quantitative clinical measurement of vibratory sensation reflects pathological changes in spatially distinct brain areas and may supplement information captured by brain atrophy measures. Without overt relapses, monitoring decline in progressive forms of MS has proved challenging; quantitative clinical assessment may provide a tool to examine pathological decline in this cohort. These data suggest that quantitative clinical assessment may be a reliable way to examine pathological decline and have broader relevance to progressive forms of MS.

Distinguishing among multiple sclerosis fallers, near-fallers and non-fallers.

BACKGROUND: Fall rates among adults with multiple sclerosis are consistently greater than 50%, but near-falls (i.e. a trip or stumble) are often undocumented. Furthermore, little is known about the circumstances surrounding fall and near-fall events. The purpose of this study was to examine the similarities and differences among non-fallers, near-fallers and fallers with multiple sclerosis, including the circumstances that surround falls and near-falls. METHODS: In a single visit, 135 multiple sclerosis participants completed the Hopkins Falls Grading Scale, a custom questionnaire investigating circumstances surrounding falls and near-falls, and performed the Timed Up and Go and Timed 25-Foot Walk tests. Mann-Whitney tests were used to examine differences between fallers, near-fallers and non-fallers. Multiple logistic regression with AIC criterion was used to examine associations of circumstances with the odds of falling vs. near-falling. Cumulative odds ordinal logistic regression was used to analyze the association between each of the walking tests and the susceptibility of the individual for falls or near-falls. RESULTS: 30% of individuals reported falls, while 44% reported near-falls over a 1-year period. Non-fallers completed the walking tests more quickly than near-fallers (p < 0.0045), and fallers (p < 0.0001); near-fallers and fallers demonstrated similar motor profiles. Individuals were more likely to sustain a fall rather than a near-fall under the following circumstances: transferring outside the home (p = 0.015) and tripping over an obstacle (p = 0.025). Performing 1-second slower on the walking tests increased the odds of a history of a fall by 6-20%. CONCLUSION: Near-falls occur commonly in individuals with MS; near-fallers and fallers reported similar circumstances surrounding fall events and demonstrated similar performance on standard timed walking tests. Clinicians monitoring individuals with MS should consider evaluation of the circumstances surrounding falls in combination with quantitative walking measures to improve determination of fall risk and appropriate rehabilitation interventions.

Randomized, Placebo-controlled Crossover Study of Dalfampridine Extended-release in Transverse Myelitis.

BACKGROUND: Dalfampridine has the potential to be effective in patients with transverse myelitis (TM) as this rare disorder shares some clinical and pathogenic similarities with multiple sclerosis. METHODS: This is a randomized, double-blind, placebo-controlled crossover study of dalfampridine extended-release (D-ER, Ampyra®). Sixteen adult study participants with monophasic TM confirmed by MRI were enrolled if their baseline timed 25-foot walking speed was between 5 and 60 seconds. Participants were randomized to receive 10 mg twice-daily doses of either D-ER or placebo control for eight weeks, then crossed over to the second arm of placebo or dalfampridine for eight weeks. The primary outcome measure was the timed 25-foot walk. RESULTS: Of 16 enrolled participants, three withdrew and 13 completed the trial. Among the 13 completers, nine individuals showed an average timed walk that was faster in the D-ER arm compared to the placebo arm, but only four participants met the stricter statistical threshold to be classified as a responder. Analyses of secondary clinical outcome measures including strength, balance assessments, spasticity, and Expanded Disability Status Scale (EDSS) score showed trends toward improvement with D-ER. CONCLUSIONS: D-ER may be beneficial in TM to improve walking speed and other neurological functions.

A Framework of Care in Multiple Sclerosis, Part 2: Symptomatic Care and Beyond.

The Consortium of Multiple Sclerosis Centers (CMSC) convened a Framework Taskforce composed of a multidisciplinary group of clinicians and researchers to examine and evaluate the current models of care in multiple sclerosis (MS). The methodology of this project included analysis of a needs assessment survey and an extensive literature review. The outcome of this work is a two-part continuing education series of articles. Part 1, published previously, covered the updated disease phenotypes of MS along with recommendations for the use of disease-modifying therapies. Part 2, presented herein, reviews the variety of symptoms and potential complications of MS. Mobility impairment, spasticity, pain, fatigue, bladder/bowel/sexual dysfunction, cognitive dysfunction, and neuropsychiatric issues are examined, and both pharmacologic and nonpharmacologic interventions are described. Because bladder and bowel symptoms substantially affect health-related quality of life, detailed information about elimination dysfunction is provided. In addition, a detailed discussion about mental health and cognitive dysfunction in people with MS is presented. Part 2 concludes with a focus on the role of rehabilitation in MS. The goal of this work is to facilitate the highest levels of independence or interdependence, function, and quality of life for people with MS.

Quantitative measures of walking and strength provide insight into brain corticospinal tract pathology in multiple sclerosis.

At least 85% of individuals with multiple sclerosis report walking dysfunction as their primary complaint. Walking and strength measures are common clinical measures to mark increasing disability or improvement with rehabilitation. Previous studies have shown an association between strength or walking ability and spinal cord MRI measures, and strength measures with brainstem corticospinal tract magnetization transfer ratio. However, the relationship between walking performance and brain corticospinal tract magnetization transfer imaging measures and the contribution of clinical measurements of walking and strength to the underlying integrity of the corticospinal tract has not been explored in multiple sclerosis. The objectives of this study were explore the relationship of quantitative measures of walking and strength to whole-brain corticospinal tract-specific MRI measures and to determine the contribution of quantitative measures of function in addition to basic clinical measures (age, gender, symptom duration and Expanded Disability Status Scale) to structural imaging measures of the corticospinal tract. We hypothesized that quantitative walking and strength measures would be related to brain corticospinal tract-specific measures, and would provide insight into the heterogeneity of brain pathology. Twenty-nine individuals with relapsing-remitting multiple sclerosis (mean(SD) age 48.7 (11.5) years; symptom duration 11.9(8.7); 17 females; median[range] Expanded Disability Status Scale 4.0 [1.0-6.5]) and 29 age and gender-matched healthy controls (age 50.8(11.6) years; 20 females) participated in clinical tests of strength and walking (Timed Up and Go, Timed 25 Foot Walk, Two Minute Walk Test ) as well as 3 T imaging including diffusion tensor imaging and magnetization transfer imaging. Individuals with multiple sclerosis were weaker (p = 0.0024) and walked slower (p = 0.0013) compared to controls. Quantitative measures of walking and strength were significantly related to corticospinal tract fractional anisotropy (r > 0.26; p < 0.04) and magnetization transfer ratio (r > 0.29; p < 0.03) measures. Although the Expanded Disability Status Scale was highly correlated with walking measures, it was not significantly related to either corticospinal tract fractional anisotropy or magnetization transfer ratio (p > 0.05). Walk velocity was a significant contributor to magnetization transfer ratio (p = 0.006) and fractional anisotropy (p = 0.011) in regression modeling that included both quantitative measures of function and basic clinical information. Quantitative measures of strength and walking are associated with brain corticospinal tract pathology. The addition of these quantitative measures to basic clinical information explains more of the variance in corticospinal tract fractional anisotropy and magnetization transfer ratio than the basic clinical information alone. Outcome measurement for multiple sclerosis clinical trials has been notoriously challenging; the use of quantitative measures of strength and walking along with tract-specific imaging methods may improve our ability to monitor disease change over time, with intervention, and provide needed guidelines for developing more effective targeted rehabilitation strategies.