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Individuals diagnosed with autism spectrum disorder (ASD) exhibit deficits in social interaction and communication. Kronfli, Vollmer, et al. developed an in-person assessment to evaluate participant response to social cues indicating uninterest in a conversation. In the current study, we sought to extend these procedures to the assessment of conversation skills via telehealth given the ongoing pandemic and so that participants in remote areas could receive services. Participants were exposed to a hierarchy of social cues of uninterest ranging in salience from one-word responses to a clear verbal statement of uninterest until they demonstrated sensitivity to a social cue. One participant who did not demonstrate sensitivity to any cues received instruction using Behavioral Skills Training. Initial results support the utility of using a remote assessment model to screen for sensitivity to specific social cues in conversations and to provide services to participants via telehealth.

CE Information Activity Available Online: To access the article, post-test, and evaluation online, go to https://www.highmarksce.com/mscare. Target Audience: The target audience for this activity is physicians, physician assistants, nursing professionals, and other health care providers involved in the management of patients with multiple sclerosis (MS). Learning Objectives: 1) Describe what constitutes a registry. 2) Discuss the difference(s) between clinician-driven and patient-driven registries, including potential advantages of patient-driven registries. Accreditation Statement: In support of improving patient care, this activity has been planned and implemented by the Consortium of Multiple Sclerosis Centers (CMSC) and Delaware Media Group. The CMSC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. Physician Credit: The CMSC designates this journal-based activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nurse Credit: The CMSC designates this enduring material for 1.0 contact hour of nursing continuing professional development (NCPD) (none in the area of pharmacology). Disclosures: Francois Bethoux, MD, Editor in Chief of the International Journal of MS Care (IJMSC), has served as Physician Planner for this activity. He has disclosed relationships with Springer Publishing (royalty); Qr8 (receipt of intellectual property rights/patent holder); Biogen (receipt of intellectual property rights/patent holder, speakers’ bureau); MedRhythms (consulting fee, contracted research); GW Pharmaceuticals, Genentech, Helius Medical Technologies, Osmotica, Ipsen (consulting fee); and Adamas Pharmaceuticals (contracted research). Ruth Ann Marrie, MD, PhD, has disclosed being a co-investigator on a study funded by Biogen and Roche. Gary R. Cutter, PhD, has disclosed serving on the data/safety monitoring committees for AstraZeneca, Avexis Pharmaceuticals, BioLineRx, BrainStorm Cell Therapeutics, Bristol Myers Squibb/Celgene, CSL Behring, Galmed, Green Valley Pharma, Mapi Pharmaceuticals, Merck, Merck/Pfizer, Mitsubishi Tanabe, OPKO Biologics, Neurim, Novartis, Orphazyme, Sanofi, Reata, Teva, Viela Bio, the National Heart, Lung, and Blood Institute (Protocol Review Committee), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Obstetric-Fetal Pharmacology Research Unit Oversight Committee); serving on consulting/advisory boards for Alexion, Antisense Therapeutics, Biodelivery Sciences International, Biogen, Clinical Trial Solutions LLC, Genzyme, Genentech, GW Pharmaceuticals, Immunic, Klein Buendel, MedImmune/Viela Bio, MedDay, Merck/Serono, Neurogenesis Ltd, Novartis, Osmotica, Perception Neuroscience, Protolix Biotherapeutics, Recursion/Cerexis Pharmaceuticals, Regeneron, Reckover Pharmaceuticals, Roche, SAB Biotherapeutics, and TG Therapeutics; and being president of Pythagoras, Inc, a private consulting company. Robert J. Fox, MD, MSc, has disclosed receiving consulting fees from AB Science, Biogen, Celgene, EMD Serono, Genentech, Genzyme, Immunic, Janssen, Novartis, Sanofi, and TG Therapeutics; research funding from Biogen, Novartis, and Sanofi; and royalties from Demos Publishing. Timothy Vollmer, MD, has disclosed receiving compensation for lectures and consultancy from Biogen, Genentech/Roche, Viela Bio, Celgene, EMD Serono, and Novartis; and research support from Rocky Mountain Multiple Sclerosis Center, Celgene, Biogen, Anokion, Genentech, F. Hoffmann-La Roche Ltd, GW Pharmaceuticals, and TG Therapeutics Inc. Tuula Tyry, PhD, has disclosed no relevant financial relationships. Amber Salter, PhD, has disclosed serving as a statistical editor for Circulation: Cardiovascular Imaging. The staff at IJMSC, CMSC, and Delaware Media Group who are in a position to influence content have disclosed no relevant financial relationships. Laurie Scudder, DNP, NP, Continuing Education Director CMSC, has served as Reviewer for this activity. She has disclosed no relevant financial relationships. One peer reviewer for IJMSC has disclosed relationships with Alexion (consulting fee, speakers’ bureau); Biogen, Bristol Myers Squibb, EMD Serono, Genentech (consulting fee, speakers’ bureau, contracted research); Celgene, Novartis, Sanofi Genzyme (consulting fee, contracted research); Viela Bio (consulting fee); National MS Society, PCORI, Atara Biotherapeutics, Roche (contracted research); and Taro Pharmaceuticals, AstraZeneca, Pfizer, Johnson & Johnson, Inovio, GlaxoSmithKline, Viatris, Gilead, Altimmune Inc, CytoDyn Inc (ownership interest [common stocks]). The other peer reviewer has disclosed relationships with Celgene (speakers’ bureau, contracted research); and Merck, EMD Serono, Roche, AbbVie (contracted research). Note: Financial relationships may have changed in the interval between listing these disclosures and publication of the article. Method of Participation: Release Date: December 1, 2021 Valid for Credit Through: December 1, 2022 In order to receive CME/NCPD/CPE credit, participants must: 1) Review the continuing education information, including learning objectives and author disclosures.2) Study the educational content.3) Complete the post-test and evaluation, which are available at https://www.highmarksce.com/mscare. Statements of Credit are awarded upon successful completion of the evaluation and the post-test with a passing score of >70%. The post-test may be retaken if necessary. There is no fee to participate in this activity. Disclosure of Unlabeled Use: This educational activity may contain discussion of published and/or investigational uses of agents that are not approved by the FDA. The CMSC and Delaware Media Group do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the CMSC or Delaware Media Group. Disclaimer: Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any medications, diagnostic procedures, or treatments discussed in this publication should not be used by clinicians or other health care professionals without first evaluating their patients’ conditions, considering possible contraindications or risks, reviewing any applicable manufacturer’s product information, and comparing any therapeutic approach with the recommendations of other authorities.

In December 2020, Congress passed the Copyright Alternative in Small-Claims Enforcement (CASE) Act that aims to “provide an efficient and user-friendly option to resolve certain copyright disputes that involve less than $30,000,” by ostensibly creating an alternative venue for creators to bring copyright infringement claims outside the Federal courts.Participation in small-claims proceedings are voluntary, but respondents must make an affirmative choice to opt-out. The CASE Act generates significant implications for college and research libraries, their workers, and library stakeholders, including academic researchers, faculty, and students.

Purpose of ReviewThis review presents the hypothesis that loss of neurologic reserve explains onset of progressive multiple sclerosis (PrMS).Recent FindingsEvidence supporting the separate classification of PrMS and relapsing multiple sclerosis (RMS) is limited and does not explain PrMS or the response of these patients to therapy.SummaryWe argue that multiple sclerosis (MS) progresses along a continuum from RMS to PrMS, with differing levels of neurologic reserve accounting for phenotypic differences. In early MS, inflammation causes brain atrophy with symptoms buffered by neurologic reserve. As brain loss from normal aging and MS continues, reserve is depleted and effects of subclinical MS disease activity and aging are unmasked, manifesting as PrMS. Most therapies show limited benefit in PrMS; patients are older, have fewer inflammatory events, and the effects of aging cause continued loss of neurologic function, even if inflammation is terminated. Loss of neurologic reserve means patients with PrMS cannot recover function, unlike patients with RMS.

Bear attacks, although rare, can inflict life-threatening injuries. We present the case of a 50-y-old woman from rural Pennsylvania who was attacked by a North American black bear, Ursus americanus. She sustained multiple complex injuries including near-complete scalp avulsion, bilateral ear avulsions, and fractures of the face, ribs, and pelvis. These injuries are similar to those sustained in other bear maulings reported in the literature and required both acute intervention and a multidisciplinary approach to recovery.

Observational studies and registries can play a critical role in elucidating the natural and treated history of multiple sclerosis (MS) and identifying factors associated with outcomes such as disability and health-related quality of life. The North American Research Committee on Multiple Sclerosis (NARCOMS) Registry is one of multiple registries worldwide that focuses on people with MS, but one of the very few patient-driven MS registries. On the 25th anniversary of the first data collection for the NARCOMS Registry, we discuss the importance of disease registries in the MS field, describe key concepts related to registry design and management, and highlight findings from MS registries relevant to clinical care or health policy.

Introduction Limited comparative effectiveness data for rituximab (RTX) versus natalizumab (NTZ), fingolimod (FTY), and dimethyl fumarate (DMF) for the treatment of multiple sclerosis (MS) exist. Methods Clinician‐reported data on patients prescribed RTX, NTZ, FTY, or DMF for the treatment of MS at the Rocky Mountain MS Center at the University of Colorado were retrospectively collected. Outcomes included a composite effectiveness measure consisting of clinical relapse, contrast‐enhancing lesions, and/or new T2 lesions, individual effectiveness outcomes, and discontinuation. Logistic regression was used on patients matched by propensity scores and using average treatment effect on treated doubly robust weighting estimator. Results A total of 182, 451, 271, and 342 patients initiated RTX, NTZ, FTY, and DMF and were followed for 2 years. Before and after adjustment, the odds of experiencing disease activity was significantly higher for FTY [adjusted OR (aOR) = 3.17 (95% CI: 1.81–5.55), P

Background: Interventions targeting the adaptive immune response are needed in multiple sclerosis (MS). Objective: Evaluate laquinimod’s efficacy, safety, and tolerability in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: CONCERTO was a randomized, double-blind, placebo-controlled, phase-3 study. RRMS patients were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 or 1.2 mg or placebo for ⩽24 months ( n = 727, n = 732, and n = 740, respectively). Primary endpoint was time to 3-month confirmed disability progression (CDP). The laquinimod 1.2-mg dose arm was discontinued (1 January 2016) due to cardiovascular events at high doses. Safety was monitored throughout the study. Results: CONCERTO did not meet the primary endpoint of significant effect with laquinimod 0.6-mg versus placebo on 3-month CDP (hazard ratio: 0.94; 95% confidence interval: 0.67–1.31; p = 0.706). Secondary endpoint p values were nominal and non-inferential. Laquinimod 0.6 mg demonstrated 40% reduction in percent brain volume change from baseline to Month 15 versus placebo ( p Conclusion: Laquinimod 0.6 mg demonstrated only nominally significant effects on clinical relapses and magnetic resonance imaging (MRI) outcomes and was generally well tolerated. Clinical trial registration number: ClinicalTrials.gov (NCT01707992).

Biomarkers are needed to guide therapeutic decision making in autoimmune and paraneoplastic neurologic disorders. Here, we describe a case of paraneoplastic collapsing response-mediator protein-5 (CRMP5)-associated transverse myelitis (TM) where plasma neurofilament light (NfL) chain and glial fibrillary protein (GFAP) levels were observed over a 14-month clinical course, correlating with radiographical and clinical outcome measures in response to treatment. Blood and CSF samples obtained at diagnosis as well as 7 and 14 months into treatment. At the time of initial diagnosis, both plasma NfL (782.62 pg/ml) and GFAP (283.26 pg/ml) were significantly elevated. Initial treatment was with IV steroids and plasma exchange (PLEX) followed by neuroendocrine tumor removal, chemotherapy, and radiation. After initial improvement with chemotherapy, the patient experienced clinical worsening and transient elevation of plasma NfL (103.27 pg/ml and GFAP (211.58 pg/ml) levels. Whole body positron emission tomography PET scan did not demonstrate recurrence of malignancy. Repeat PLEX and rituximab induction resulted in improvements in patient function, neurologic exam, and plasma biomarker levels. To our knowledge, this is the first described longitudinal, prospective analysis of neuronal injury biomarkers and association of clinical treatment outcomes in CRMP5 myelitis. Our findings suggest that clinical improvement correlates with NfL and GFAP concentrations.

A hallmark of the inflammatory response in multiple sclerosis (MS) is the presence of intrathecal Immunoglobulin G (IgG) antibodies and oligoclonal bands (OCBs). The biological activity of IgGs is modulated by changes in glycosylation. Using multiple immunoassays with common lectins for sialylation and galactosylation, we investigated levels of IgG glycosylation in 28 MS and 37 control sera as well as paired CSF and serum. We demonstrated the presence of significantly lower levels of IgG sialylation in MS CSF compared to paired serum. Further, we showed that in MS there was no correlation between sialylated IgG and total IgG antibodies, or between sialylated IgG in CSF and serum. ELISA with native IgG antibodies showed significantly higher levels of sialylated and galactosylated IgG in MS compared to other neurological disorders and normal healthy controls. We conclude that lower levels of sialylated intrathecal IgG and higher levels of serum IgG galactosylation in MS may play significant role in disease pathogenesis. The unique IgG glycosylation profiles suggest a complexed nature of the IgG antibodies which may influence its effector functions in MS.

Objective To compare 2‐year effectiveness and discontinuation of natalizumab (NTZ) versus fingolimod (FTY) and dimethyl fumarate (DMF) in the treatment of multiple sclerosis (MS). Methods Patients prescribed NTZ, FTY, or DMF at the Rocky Mountain MS Center at University of Colorado were identified. Clinician‐reported data were retrospectively collected. Outcomes include a composite effectiveness measure consisting of new T2 lesion, gadolinium‐enhancing lesion, and/or clinical relapse, individual effectiveness outcomes and discontinuation over 2 years. Logistic regression was used for data analysis on patients matched by propensity scores and using ATT doubly robust weighting estimator. Results A total of 451, 271, and 342 patients were evaluated on NTZ, FTY, and DMF over 2 years, respectively. Patients had a mean age of 39.8 (NTZ), 42.5(FTY), and 45.8 (DMF) years; were predominantly female (76.7% NTZ; 72.0% FTY; 69.6% DMF); and had a mean MS disease duration of 11–12 years for all groups. At ≤24 months, 22.2%, 34.7%, and 33.6% experienced a new T2 lesion, gadolinium‐enhancing lesion, and/or clinical relapse on NTZ, FTY, and DMF, respectively. Using ATT doubly robust weighting estimator, FTY versus NTZ and DMF versus NTZ had an odds ratio of 2.00 (95%CI:[1.41–2.85], P

Background: Time matters in multiple sclerosis (MS). Irreversible neural damage and cell loss occur from disease onset. The MS community has endorsed a management strategy of prompt diagnosis, timely intervention and regular proactive monitoring of treatment effectiveness and disease activity to improve outcomes in people with MS. Objectives: We sought to develop internationally applicable quality standards for timely, brain health–focused MS care. Methods: A panel of MS specialist neurologists participated in an iterative, online, modified Delphi process to define ‘core’, ‘achievable’ and ‘aspirational’ time frames reflecting minimum, good and high care standards, respectively. A multidisciplinary Reviewing Group (MS nurses, people with MS, allied healthcare professionals) provided insights ensuring recommendations reflected perspectives from multiple stakeholders. Results: Twenty-one MS neurologists from 19 countries reached consensus on most core (25/27), achievable (25/27) and aspirational (22/27) time frames at the end of five rounds. Agreed standards cover six aspects of the care pathway: symptom onset, referral and diagnosis, treatment decisions, lifestyle, disease monitoring and managing new symptoms. Conclusion: These quality standards for core, achievable and aspirational care provide MS teams with a three-level framework for service evaluation, benchmarking and improvement. They have the potential to produce a profound change in the care of people with MS.

Growing evidence indicates that B cells play a key role in the pathogenesis of multiple sclerosis (MS). B cells occupy distinct central nervous system (CNS) compartments in MS, including the cerebrospinal fluid and white matter lesions. Also, it is now known that, in addition to entering the CNS, B cells can circulate into the periphery via a functional lymphatic system. Data suggest that the role of B cells in MS mainly involves their in situ activation in demyelinating lesions, leading to altered pro- and anti-inflammatory cytokine secretion, and a highly effective antigen-presenting cell function, resulting in activation of memory or naïve T cells. Clinically, B cell-depleting agents show significant efficacy in MS. In addition, many disease-modifying therapies (DMTs) traditionally understood to target T cells are now known to influence B cell number and function. One of the earliest DMTs to be developed, glatiramer acetate (GA), has been shown to reduce the total frequency of B cells, plasmablasts, and memory B cells. It also appears to promote a shift toward reduced inflammation by increasing anti-inflammatory cytokine release and/or reducing pro-inflammatory cytokine release by B cells. In the authors' opinion, this may be mediated by cross-reactivity of B cell receptors for GA with antigen (possibly myelin basic protein) expressed in the MS lesion. More research is required to further characterize the role of B cells and their bidirectional trafficking in the pathogenesis of MS. This may uncover novel targets for MS treatments and facilitate the development of B cell biomarkers of drug response.

The Copyright Alternative in Small-Claims Enforcement Act of 2020 (CASE Act) was swept into law during the final days of 2020 as a part of the 5,500 page federal spending bill. In theory, the CASE Act aims to provide a venue for individual creators (such as photographers, graphic artists, musicians) to address smaller copyright infringement claims without spending the time and money required to pursue a copyright infringement lawsuit in Federal court. In reality, however, this additional bureaucratic structure created outside of the traditional court system is fraught with problems that will mostly incentivize large, well-resourced rightsholders or overly litigious copyright owners to take advantage of the system. At the same time, it will confuse and harm innocuous users of content, who may not understand the complexities of copyright law, and who do not know whether or how to respond to a notice of infringement via this small claims process. From our perspective, it will chill users who rely on crucial statutory exceptions to copyright, such as fair use, in their research and teaching activities.

Background Ocrelizumab is an approved MS treatment administered as two 300-mg intravenous infusions 2 weeks apart (Dose 1), each lasting approximately 2.5 hours, followed by single 600-mg infusions every 6 months lasting approximately 3.5 hours. Our objective was to evaluate shorter-duration ocrelizumab infusions in the Phase IIIb open-label SaROD study (NCT03606460). Methods Eligible patients received ocrelizumab 600-mg Dose 2 or 3 infused over approximately 2 hours (Cohort 1) or ocrelizumab 300-mg Dose 1, Infusion 2 over approximately 1.5 hours (Cohort 2). The primary endpoint was the number and proportion of patients experiencing Grade 3–4 infusion-related reactions (IRRs) in Cohort 1. Secondary endpoints included Grade 1–4 IRRs in both cohorts and Grade 3–4 IRRs in Cohort 2. Results Mean infusion times decreased by approximately 1.09 and 0.79 hours in Cohorts 1 and 2, respectively, compared with US prescribing information. IRRs, reported by 36% of 141 patients, were mild-to-moderate, with no observed Grade 3–4 IRRs. No IRR-related discontinuations occurred. No serious AEs, deaths, or new safety signals were observed. Conclusion The IRR rate with ocrelizumab shorter-duration infusions was similar to that observed in the pivotal Phase III trials. Ocrelizumab can be infused over a shorter time without sacrificing patient safety.

A wealth of digital texts and the proliferation of automated research methodologies enable researchers to analyze large sets of data at a speed that would be impossible to achieve through manual review. When researchers use these automated techniques and methods for identifying, extracting, and analyzing patterns, trends, and relation- ships across large volumes of un- or thinly structured digital content, they are applying a methodology called text data mining or TDM.TDM is also referred to, with slightly different emphases, as “computational text analysis” or “content mining.” The “distant reading” that TDM makes possible supports the discovery of scientific and social insights, such as how gender is depicted in fiction over time or evidence of racial disparity in police camera footage.Libraries are eager to provide and expand institutional access to data sets so that scholars can continue exploring unknown connections, yet both scholars and professional staff who support TDM research often run into roadblocks.Law and policy questions are paramount and shape not only how TDM scholarship is disseminated, but also the very questions being asked. If researchers are limited to corpora unencumbered by legal restrictions, they risk perpetuating bias in the scholarly record. With a basic set of law and policy literacies in hand, libraries can help scholars navigate these issues so that they can confidently use, create, and share a far wider set of corpora and research results.

IgG oligoclonal bands (OCBs) are present in the cerebrospinal fluid (CSF) of more than 95% of patients with multiple sclerosis (MS), and are considered to be the immunological hallmark of disease. However, the target specificities of the IgG in MS OCBs have remained undiscovered. Nevertheless, evidence that OCBs are associated with increased levels of disease activity and disability support their probable pathological role in MS. We investigated the antigen specificity of individual MS CSF IgG from 20 OCB-positive patients and identified 40 unique peptides by panning phage-displayed random peptide libraries. Utilizing our unique techniques of phage-mediated real-time Immuno-PCR and phage-probed isoelectric focusing immunoblots, we demonstrated that these peptides were targeted by intrathecal oligoclonal IgG antibodies of IgG1 and IgG3 subclasses. In addition, we showed that these peptides represent epitopes sharing sequence homologies with proteins of viral origin, and proteins involved in cell stress, apoptosis, and inflammatory processes. Although homologous peptides were found within individual patients, no shared peptide sequences were found among any of the 42 MS and 13 inflammatory CSF control specimens. The distinct sets of oligoclonal IgG-reactive peptides identified by individual MS CSF suggest that the elevated intrathecal antibodies may target patient-specific antigens.

BackgroundDimethyl fumarate (DMF) and fingolimod (FTY) are approved oral disease-modifying therapies for relapsing multiple sclerosis (MS). Observational studies are valuable when randomized clinical trials cannot be done due to ethical or practical reasons. Two-site studies allow investigators to further ascertain external validity of previously examined treatment effect differences. Limited head-to-head 2-site studies exist comparing DMF and FTY.MethodsPatients prescribed DMF (n = 737) and FTY (n = 535) from 2 academic multiple sclerosis (MS) centers (Cleveland Clinic and University of Colorado) were identified. Discontinuation and disease activity endpoints were assessed using propensity score (PS) weighting. Covariates used in the PS model included demographics and clinical and MRI characteristics.ResultsPS weighting demonstrated excellent covariate balance. Discontinuation was more common in DMF (44.2%) compared to FTY (34.8%) over 24 months (odds ratio [OR] 1.55, 95% confidence interval [CI] 1.21–1.99, p < 0.001). The leading cause for discontinuation was intolerability for both DMF (56.1% of DMF discontinuations) and FTY (46.2% of FTY discontinuations) (OR 1.65, 95% CI 1.21–2.25, p = 0.002). The proportion of patients with clinical relapses was low for both medications (DMF, 15.1%; FTY, 13.1%). There was no difference in the proportion of patients with relapses (OR 1.27, 95% CI 0.90–1.80, p = 0.174), gadolinium-enhancing lesions (OR 1.42, 95% CI 0.92–2.20, p = 0.114), or new T2 lesions on brain MRI (OR 1.13, 95% CI 0.83–1.55, p = 0.433).ConclusionsThis combined analysis suggests DMF and FTY have similar effectiveness in a large, 2-site clinical population over 24 months. Discontinuation of both DMTs was common and occurred more frequently with DMF, largely driven by intolerability.

Clinically stable multiple sclerosis (MS) patients often have negligible inflammatory MRI changes. Brain atrophy may provide insight into subclinical disease progression. The objective was to compare brain atrophy rates in stable patients on long term natalizumab treatment vs. age and gender matched healthy non-MS controls (HC) prospectively over two-years examining brain volume, cognition, and patient reported outcomes (PROs).MS patients treated with natalizumab for a minimum of 2 years, age 18-60 were recruited and compared with age- and gender-matched healthy controls (HC). Both groups were followed prospectively to obtain two years of consecutive magnetic resonance imaging, clinical and PRO data. Baseline normalized brain volume (NBV), yearly T2 lesion volume (T2LV), and percent brain volume change (PBVC) were measured using SIENAX, JIM 6.0, and SIENA respectively. Neuropsychological tests from the MACFIMS battery were selected to optimize assessments for impairments in the domains of information processing speed and memory. Patient reported outcomes (PROs) for domains of physical, mental and social quality of life were evaluated using the NeuroQol short forms.Forty-eight natalizumab and 62 HC completed all study visits. At baseline, unadjusted mean NBV (natalizumab=1508.80cm (Popescu et al., 2013) vs. HC=1539.23cm (Popescu et al., 2013); p=0.033) and median baseline T2LV (natalizumab=1724.62mm (Popescu et al., 2013) vs. HC=44.20mm (Popescu et al., 2013); p=0.0001) were different. The mean PBVC at year 2, adjusted for gender and baseline age was -0.57% (CI: 0.7620, -0.3716) for natalizumab and -0.50% (-0.7208, -0.2831) for HC, but the difference between groups was not statistically significant (0.073%; p=0.62). Over the 2-year period, HC demonstrated mild improvements in some cognitive tests vs. natalizumab subjects. However, PROs were similar between the two groups.Stable MS patients on natalizumab have similar brain volume loss as people who do not have MS, suggesting normalization of brain atrophy.

Background: Laquinimod 0.6 mg is a once-daily, oral, disease-modifying therapy in development for the treatment of multiple sclerosis (MS) that was investigated in two double-blind, placebo-controlled, phase 3 trials: ALLEGRO and BRAVO. Methods: Data from these studies were pooled to assess the safety profile of laquinimod versus placebo. Adverse events (AEs), laboratory value changes, and potential risks identified in preclinical studies were evaluated in participants in ALLEGRO and BRAVO treated with at least one dose of laquinimod or matching placebo (1:1 random assignment). Results: In total, 1988 patients received at least one dose of study drug (laquinimod: n = 983 [mean ± SD duration, 639 ± 190 days]; placebo: n = 1005 [mean ± SD duration, 627 ± 198 days]). Early terminations due to AEs were infrequent (laquinimod: 6.4%; placebo: 4.7%). Death was reported in four patients (laquinimod: n = 1; placebo: n = 3). Rates of serious AEs (including malignancies, infections, and cardiovascular AEs) were similar between groups. The most common AEs identified with laquinimod use were back and neck pain and appendicitis. Laquinimod was also associated with asymptomatic changes in liver enzyme levels, fibrinogen levels, and hematologic parameters that followed a consistent temporal pattern: mild, nonprogressive, and occurring within 90 days of treatment initiation, then stabilizing or reverting to baseline levels during continued treatment. Conclusions: Data from these pivotal laquinimod studies demonstrate a safety profile comprising benign or manageable AEs and asymptomatic laboratory findings with a clear temporal pattern. Potential risks noted in preclinical studies were not observed.

Rituximab is a chimeric anti-CD20 monoclonal antibody that is an effective therapy for multiple sclerosis. Rituximab has been associated with the development of serum sickness (type III hypersensitivity) characterized by arthralgia, fever, and rash during the treatment of other conditions, such as rheumatoid arthritis. Here we describe serum sickness associated with rituximab in multiple sclerosis patients and discuss both the management of serum sickness itself and implications for utilizing alternative anti-CD20 monoclonal antibodies for disease management in this patient population.

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

ObjectiveBrain atrophy has been correlated with objective cognitive dysfunction in multiple sclerosis but few studies have explored self-reported subjective cognitive concerns and their relationship to brain volume changes. This study explores the relationship between subjective cognitive concerns in multiple sclerosis and reduced brain volume in regions of interest implicated in cognitive dysfunction.MethodsA total of 158 patients with multiple sclerosis completed the Quality of Life in Neurologic Disorders Measures (Neuro-QoL) short forms to assess subjective cognitive concerns and underwent brain magnetic resonance imaging. Regional brain volumes from regions of interest implicated in cognitive dysfunction were measured using NeuroQuant automated volumetric quantitation. Linear regression was used to analyze the relationship between subjective cognitive concerns and brain volume.ResultsControlling for age, disease duration, gender, depression and fatigue, increased subjective cognitive concerns were associated with reduced thalamic volume (standardized β = 0.223, t150 =2.406, P = 0.017) and reduced cortical gray matter volume (standardized β = 0.240, t150 = 2.777, P = 0.006). Increased subjective cognitive concerns were not associated with any other regions of interest that were analyzed.ConclusionsSubjective cognitive concern in MS is associated with reduced thalamic and cortical gray matter volumes, areas of the brain that have been implicated in objective cognitive impairment. These findings may lend neuroanatomical significance to subjective cognitive concerns and patient-reported outcomes as measured by Neuro-QoL.

Highlights • Infusion-related reaction rates were similar in shorter and conventional infusions • The majority of infusion-related reactions were mild to moderate • No infusion-related reactions were serious, life-threatening or fatal • No new safety signals were observed with a shorter infusion time • Shortening the infusion time may lessen the burden on patients and site staff, Background: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). Shortening the 600 mg infusion to 2 hours reduces the total site stay from 5.5–6 hours (approved infusion duration including mandatory pre-medication and post-infusion observation) to 4 hours. The safety profile of shorter-duration ocrelizumab infusions was investigated using results from ENSEMBLE PLUS. Methods: ENSEMBLE PLUS is a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810). In ENSEMBLE, patients with early-stage relapsing-remitting MS received ocrelizumab 600 mg infusions every 24 weeks for 192 weeks. In ENSEMBLE PLUS, ocrelizumab 600 mg administered over the approved 3.5-hour infusion time (conventional duration) is compared with a 2-hour infusion (shorter duration); the durations of the initial infusions (2×300 mg, 14 days apart) were unaffected. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first Randomized Dose. Results: From November 1, 2018, to December 13, 2019, 745 patients were randomized 1:1 to the conventional or shorter infusion group. At the first Randomized Dose, 99/373 patients (26.5%) in the conventional and 107/372 patients (28.8%) in the shorter infusion group experienced IRRs. The majority of IRRs were mild or moderate; >99% of all IRRs resolved without sequelae in both groups (conventional infusion group, 99/99; shorter infusion group, 106/107). No IRRs were serious, life-threatening, or fatal. No IRR-related discontinuations occurred. During the first Randomized Dose, 22/373 (5.9%) and 39/372 (10.5%) patients in the conventional and shorter infusion groups, respectively, had IRRs leading to infusion slowing/interruption. Adverse events were consistent with the known safety profile of ocrelizumab. Conclusion: The rates and severity of IRRs were similar between conventional and shorter infusions. No new safety signals were detected. Shortening the infusion time to 2 hours reduces the total site stay time (including mandatory pre-medication/infusion/observation) from 5.5–6 hours to 4 hours, and may reduce patient and site staff burden.

Background Patient-reported treatment satisfaction is associated with medication adherence and persistence, making it increasingly important in the multiple sclerosis (MS) population, where disease modifying treatments (DMTs) can be vital in preventing accumulation of disability. Therefore, the valid assessment of treatment satisfaction is critical in MS care. The current study aimed to examine the validity of the Functional Assessment of Chronic Illness Therapy – General Treatment Satisfaction (FACIT-TS-G) in an MS population. Methods Patient-reported outcome (PRO) data were collected from 555 MS patients (mean age 47.99±11.57; 76.4% female; 78.7% White/Caucasian) as part of routine clinical care. The FACIT-TS-G reliability, validity, and factor structure were examined. FACIT-TS-G scores were compared between DMT administration type (oral, injection, infusion) and examined as a possible predictor of switching DMT type at 1-to-2-year follow-up. Results The FACIT-TS-G showed good internal consistency (Cronbach's α=0.836), convergent validity, and known-group validity. Confirmatory factor analyses supported a single factor. DMT infusion administration was associated with slightly greater FACIT-TS-G scores than injection (p = 0.013, 95% CI: 0.269, 2.273) and oral administration (p = 0.030, 95% CI: 0.087, 1.717). FACIT-TS-G scores did not predict the likelihood of switching DMT type at follow-up (p>0.05). Conclusion Our findings support the use of the FACIT-TS-G as a PRO measure of treatment satisfaction in MS. Moreover, results suggest DMT administration via infusion is associated with greater treatment satisfaction. Future research is needed to examine treatment satisfaction in the context of other outcomes.

Introduction We present international consensus recommendations for improving diagnosis, management and treatment access in multiple sclerosis (MS). Our vision is that these will be used widely among those committed to creating a better future for people with MS and their families. Methods Structured discussions and literature searches conducted in 2015 examined the personal and economic impact of MS, current practice in diagnosis, treatment and management, definitions of disease activity and barriers to accessing disease-modifying therapies (DMTs). Results Delays often occur before a person with symptoms suggestive of MS sees a neurologist. Campaigns to raise awareness of MS are needed, as are initiatives to improve access to MS healthcare professionals and services. We recommend a clear treatment goal: to maximize neurological reserve, cognitive function and physical function by reducing disease activity. Treatment should start early, with DMT and lifestyle measures. All parameters that predict relapses and disability progression should be included in the definition of disease activity and monitored regularly when practical. On suboptimal control of disease activity, switching to a DMT with a different mechanism of action should be considered. A shared decision-making process that embodies dialogue and considers all appropriate DMTs should be implemented. Monitoring data should be recorded formally in registries to generate real-world evidence. In many jurisdictions, access to DMTs is limited. To improve treatment access the relevant bodies should consider all costs to all parties when conducting economic evaluations and encourage the continuing investigation, development and use of cost-effective therapeutic strategies and alternative financing models. Conclusions The consensus findings of an international author group recommend a therapeutic strategy based on proactive monitoring and shared decision-making in MS. Early diagnosis and improved treatment access are also key components.

Background: Delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) is indicated for relapsing multiple sclerosis (MS). The objective of this study was to explore the safety and tolerability of DMF when administered with interferon beta (IFNβ) or glatiramer acetate (GA). Methods: Patients with relapsing-remitting MS receiving established therapy with the same dose of IFNβ or GA for at least 12 months continued their prescribed therapy for 2 months (monotherapy period) and then received DMF 240 mg three times daily in addition to their prescribed MS therapy for 6 months (add-on therapy period). Safety and magnetic resonance imaging outcomes were monitored monthly. Results: During the add-on therapy period, in the DMF+IFNβ (n = 57) and DMF+GA (n = 47) groups, the overall incidence of adverse events was 95% and 100%, respectively; the most common adverse events were flushing, diarrhea, and abdominal pain. In both groups, mean lymphocyte counts decreased but remained within normal limits, and hepatic transaminase levels increased transiently; no case met Hy's law criteria. There was no overall increased risk of infection. In both groups, gadolinium-enhancing lesion activity and new/enlarging T2 lesions decreased compared with the monotherapy period (exploratory endpoints). Conclusions: The safety profile of DMF taken with IFNβ or GA was acceptable and consistent with the known safety profile of DMF monotherapy.

Background The SELECT study demonstrated superior effects of daclizumab high-yield process (DAC HYP) to placebo in key endpoints in patients with relapsing and remitting multiple sclerosis (RRMS). Objective To assess the impact of DAC HYP and disease activity on health-related quality of life (HRQoL) using data from this study. Methods HRQoL was assessed at baseline, 12, 24, and 52 weeks using the Multiple Sclerosis Impact Scale (MSIS-29), the 12-items Short Form Health Survey, and the EuroQoL-5 Dimensions. An analysis of covariance model was used to compare treatment difference in change from baseline. Mixed-effects models were used to assess the impact of disability progression, relapse, treatment, and interaction between treatment and these events on HRQoL outcome. Results DAC HYP 150mg resulted in significant positive impacts on HRQoL compared to placebo. It was also found to significantly reduce the adverse impact of relapse on the MSIS-29 physical scale (−12.45; p =0.0006). Relapse and disability progression were significantly associated with impaired HRQoL. Conclusion DAC HYP 150mg improved HRQoL in patients with RRMS compared to placebo. The treatment benefit can be partially attributed to reduction in disease activity and attenuation of the adverse impact of relapse on HRQoL.

Background and purpose In the SELECT study, treatment with daclizumab high-yield process (DAC HYP) versus placebo reduced the frequency of gadolinium-enhancing (Gd+) lesions in patients with relapsing−remitting multiple sclerosis (RRMS). The objective of this post hoc analysis of SELECT was to evaluate the effect of DAC HYP on the evolution of new Gd+ lesions to T1 hypointense lesions (T1 black holes). Methods SELECT was a randomized double-blind study of subcutaneous DAC HYP 150 or 300 mg or placebo every 4 weeks. Magnetic resonance imaging (MRI) scans were performed at baseline and weeks 24, 36 and 52 in all patients and monthly between weeks 4 and 20 in a subset of patients. MRI scans were evaluated for new Gd+ lesions that evolved to T1 black holes at week 52. Data for the DAC HYP groups were pooled for analysis. Results Daclizumab high-yield process reduced the number of new Gd+ lesions present at week 24 (P = 0.005) or between weeks 4 and 20 (P = 0.014) that evolved into T1 black holes at week 52 versus placebo. DAC HYP treatment also reduced the percentage of patients with Gd+ lesions evolving to T1 black holes versus placebo. Conclusions Treatment with DAC HYP reduced the evolution of Gd+ lesions to T1 black holes versus placebo, suggesting that inflammatory lesions that evolved during DAC HYP treatment are less destructive than those evolving during placebo treatment.

Patients with multiple sclerosis (MS) experience varying rates of brain volume (BV) loss ranging from 0.5 to 1.5 % per year. In addition, 66 % of patients with MS experience cognitive impairment, resulting in impact on daily activities. A systematic literature review (2003-2013) was conducted to identify all studies reporting a relationship between whole BV measures and selected patient outcomes measuring cognition, including the Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT) and MS Functional Composite (MSFC) scores. We identified 18 studies reporting associations between whole BV and cognitive outcomes. Six studies (33 %) examined the association between BV and SDMT; all six studies reported that BV loss (BVL) was significantly associated with a decline in SDMT scores (all p < 0.05). Among 14 studies (78 %) that examined the association between BV and PASAT scores, 12 (86 %) found a significant relationship between BVL and lower PASAT scores (all p < 0.05). Of the seven studies (39 %) that looked at BV and MSFC, six studies (86 %) found BVL significantly associated with lower MSFC scores (all p < 0.05). Our study demonstrated that BVL is associated with declines in cognition in MS patients across several cognition measures. The results of this study suggest that BV is a critical component of disease activity and progression in MS and has implications for treatment decisions to minimize BVL and preserve cognitive functioning.

Importance One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders. Observations National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings. Conclusions and Relevance NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions.

ObjectiveTo examine whether rituximab induction followed by glatiramer acetate (GA) monotherapy is more effective than GA alone for the treatment of relapsing multiple sclerosis with active disease.MethodsThis was a single-center, double-blind, placebo-controlled study. Fifty-five participants were randomly assigned (1:1 ratio) to either rituximab (R-GA) or placebo (P-GA) induction, followed by GA therapy initiated in all participants. Participants were followed up to 3 years. The primary endpoint was the number of participants with no evidence of disease activity (NEDA): those without relapse, new MRI lesions, and sustained change in disability.ResultsTwenty-eight and 27 participants received rituximab and placebo induction, respectively, with one participant in each arm withdrawing before 6-month MRI. There were no significant differences in baseline characteristics. At end of study, 44.44% of R-GA participants demonstrated NEDA vs 19.23% of P-GA participants (p = 0.049). Treatment failed for a smaller proportion of R-GA participants (37.04% R-GA vs 69.23% P-GA, p = 0.019), and time to treatment failure was longer (23.32 months R-GA vs 11.29 months P-GA, p = 0.027). Fewer participants in the R-GA arm had new lesions (25.93% R-GA vs 61.54% P-GA, p = 0.009), and there were fewer new T2 lesions (0.48 R-GA vs 1.96 P-GA, p = 0.027). Probability of demonstrating NEDA in the R-GA arm returned to baseline within the study period. There were no differences in adverse events.ConclusionsInduction therapy with rituximab followed by GA may provide superior efficacy in the short term than GA alone in relapsing multiple sclerosis, but this benefit appears to wane within the study period. Larger studies are needed to assess sustainability of results.ClinicalTrials.gov identifierNCT01569451.

Due to the recurrence of disease activity in multiple sclerosis (MS) patients, a washout period of3 months has been suggested for the transition from natalizumab (NTZ) to fingolimod (FTY). However, very short transition periods of1 month may be more beneficial.Retrospective analysis of patients from the Rocky Mountain MS Center at the University of Colorado who were: a) on NTZ for ≥6 months prior to switching to FTY; b) had a transition period ≤ 6 months; and c) initiated FTY treatment prior to November 2013. Transition periods were grouped as follows:1 month, 1-2 months, and 3-6 months. Outcomes assessed include clinical and MRI measures within one year of FTY initiation.Thirty-seven, 56 and 24 patients had a transition period 1 month, 1-2 months and 3-6 months, respectively. Baseline characteristics were well matched: mean age 45-49 years (p = 0.17), disease duration 11-13 years (p = 0.42), and ~70% women (p = 1.00). Following the switch (including transition period), clinical relapses were observed in 0% (1 month), 12.5% (1-2 months), 37.5% (3-6 month) (p 0.001) of patients. New gadolinium enhancing lesions occurred in 3.3% (1 month), 13% (1-2 months), 21.4% (3-6 months) (p = 0.13) patients. New T2 lesions were observed in 11.1% (1 month), 16.3% (1-2 months), 33.3% (3-6 months) (p = 0.28) of patients. There were no unexpected adverse events or PML observed.Minimizing transition times from NTZ to FTY was beneficial and safe.

Introduction Intrathecal immunoglobulin G (IgG) and oligoclonal bands (OCBs) are the most consistent and characteristic features of Multiple Sclerosis (MS). OCBs in MS are considered products of clonally expanded B cells in the cerebrospinal fluid (CSF), representing the sum of contributions from B cells in the brain. However, large amounts of IgG can be eluted from MS plaques in which lymphocytes are absent, and there is no correlation between levels of plaque-associated IgG and the presence of lymphocytes. It is calculated that it would take 3.2 billion lymphocytes to generate such large amounts of intrathecal IgG (30 mg in 500 ml CSF) in MS patients. Therefore, circulating lymphocytes in CSF could only account for