Final analysis of 379 pregnancy outcomes after exposure to dimethyl fumarate in a prospective international registry.

BACKGROUND: Dimethyl fumarate (DMF) has a favorable benefit-risk profile treating people with multiple sclerosis and should be used in pregnant women only if the potential benefits outweigh potential risks to the fetus. OBJECTIVE: Assess pregnancy outcomes in a completed international registry (TecGistry) of women with MS exposed to DMF. METHODS: TecGistry included pregnant women with MS exposed to DMF, with data collected at enrollment, 6-7 months gestation, 4 weeks after estimated due date, and at postpartum weeks 4, 12, and 52. Outcomes included live births, gestational size, pregnancy loss, ectopic/molar pregnancies, birth defects, and infant/maternal death. RESULTS: Of 397 enrolled, median (range) age was 32 years (19-43). Median (range) gestational week at enrollment was 10 (0-39) and at first DMF exposure was 1 (0-13). Median (range) duration of gestational DMF exposure was 5 weeks (0-40). Fifteen (3.8%) spontaneous abortions occurred. Of 360 (89.1%) live births, 323 were full term and 37 were premature. One neonatal death and no maternal deaths occurred. Adjudicator-confirmed EUROCAT birth defects were found in 2.2%. CONCLUSION: DMF exposure during pregnancy did not adversely affect pregnancy outcomes; birth defects, preterm birth, and spontaneous abortion were in line with rates from the general population.

Long-Term Safety and Efficacy of Initial and Repeat Treatment Courses With Zuranolone in Adult Patients With Major Depressive Disorder: Interim Results From the Open-Label, Phase 3 SHORELINE Study.

Objective: Zuranolone is a positive allosteric modulator of both synaptic and extrasynaptic γ-aminobutyric acid (GABA) type A receptors and a neuroactive steroid approved in the United States as an oral, once-daily, 14-day treatment course for adults with postpartum depression and under investigation for adults with major depressive disorder (MDD). Interim results from the open-label, longitudinal, phase 3 SHORELINE Study (NCT03864614) that evaluated the long-term safety and efficacy of zuranolone in adults with MDD are reported.Methods: This interim report includes patients who were enrolled and had the opportunity to be on study for up to 1 year between February 2019 and September 2021. Adults aged 18-75 years with MDD diagnosed per DSM-5 criteria and a 17-item Hamilton Rating Scale for Depression (HAMD-17) total score ≥ 20 received an initial 30-mg or 50-mg 14-day zuranolone course. HAMD-17 responders (≥ 50% reduction from baseline) at Day (D)15 of the initial treatment period were allowed to continue in the study beyond D28 and were followed up for ≤ 1 year, during which repeat treatment courses were permitted. The primary endpoint was safety and tolerability of the initial and repeat treatment courses through 1 year. Secondary endpoints included change from baseline (CFB) in HAMD-17 total score and need for repeat treatment course(s).Results: As of September 2021, among patients in the 30-mg (n = 725) and 50-mg (n = 199) Cohorts who received a zuranolone dose, 493 (68.0%) and 137 (68.8%), respectively, reported a treatment-emergent adverse event (TEAE); most patients who experienced TEAEs reported mild/moderate events (30-mg Cohort, 90.9% [448/493]; 50-mg Cohort, 85.4% [117/137]). Mean (standard deviation) CFB HAMD-17 total score at D15 of the initial treatment period was -15.2 (7.1) and -16.0 (6.0) for the 30-mg and 50-mg Cohorts, respectively; similar improvements were observed after repeat treatment courses. The proportion of patients who received only 1 treatment course during their time on study was 42.9% (210/489) in the 30-mg Cohort and 54.8% (80/146) in the 50-mg Cohort; 57.1% (279/489) and 45.2% (66/146) patients, respectively, received 2-5 total treatment courses. The majority of patients who initially responded to zuranolone received ≤ 2 total treatment courses (30-mg Cohort, 68.5% [335/489]; 50-mg Cohort, 79.5% [116/146]).Conclusions: Of patients who experienced TEAEs, most reported mild or moderately severe events, and responders to zuranolone experienced improvements in depressive symptoms with initial and repeat treatment courses.Trial Registration: ClinicalTrials.gov identifier: NCT03864614.

Diroximel fumarate in patients with relapsing-remitting multiple sclerosis: Final safety and efficacy results from the phase 3 EVOLVE-MS-1 study.

BACKGROUND: Diroximel fumarate (DRF) is approved for adults with relapsing-remitting multiple sclerosis (RRMS) in Europe and for relapsing forms of MS in the United States. DRF and dimethyl fumarate (DMF) yield bioequivalent exposure of the active metabolite monomethyl fumarate. Prior studies indicated fewer gastrointestinal (GI)-related adverse events (AEs) with DRF compared with DMF. OBJECTIVE: To report final outcomes from EVOLVE-MS-1. METHODS: EVOLVE-MS-1 was an open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in patients with RRMS. The primary endpoint was safety and tolerability; efficacy endpoints were exploratory. RESULTS: Overall, 75.7% (800/1057) of patients completed the study; median exposure was 1.8 (range: 0.0-2.0) years. AEs occurred in 938 (88.7%) patients, mostly of mild (28.9%) or moderate (50.3%) severity. DRF was discontinued due to AEs in 85 (8.0%) patients, with < 2% discontinuing due to GI or flushing/flushing-related AEs. At Week 96, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (72.7%; p < 0.0001); adjusted annualized relapse rate was 0.13 (95% confidence interval: 0.11-0.15). CONCLUSION: DRF was generally well tolerated over 2 years, with few discontinuations due to AEs; radiological measures indicated decreased disease activity from baseline. These outcomes support DRF as a treatment option in patients with RRMS.

Vaccine response in people with multiple sclerosis treated with fumarates.

People with multiple sclerosis (pwMS) have an increased risk of infection. As disease-modifying therapies (DMTs) and other treatments may interact with the immune system, there may be concerns about vaccine efficacy and safety. Therefore, it is important to evaluate possible interactions between DMTs and vaccines. The fumarates, dimethyl fumarate, diroximel fumarate, and monomethyl fumarate, are approved for the treatment of relapsing multiple sclerosis. This review assesses the evidence on vaccine response in pwMS treated with fumarates, with a particular focus on COVID-19 vaccines. Treatment with fumarates does not appear to result in blunting of humoral responses to vaccination; for COVID-19 vaccines, particularly RNA-based vaccines, evidence indicates antibody responses similar to those of healthy recipients. While data on the effect of fumarates on T-cell responses are limited, they do not indicate any significant blunting. COVID-19 vaccines impart a similar degree of protection against severe COVID-19 infection for pwMS on fumarates as in the general population. Adverse reactions following vaccination are generally consistent with those observed in the wider population; no additional safety signals have emerged in those on fumarates. Additionally, no increase in relapse has been observed in pwMS following vaccination. In pwMS receiving fumarates, vaccination is generally safe and elicits protective immune responses.

Effect of Dimethyl Fumarate vs Interferon ß-1a in Patients With Pediatric-Onset Multiple Sclerosis: The CONNECT Randomized Clinical Trial.

Importance: With few approved multiple sclerosis therapies in the pediatric population, there is a need for further approved treatment options. Limited data exist for dimethyl fumarate (DMF) treatment in pediatric-onset multiple sclerosis (POMS). Objective: To compare the efficacy, safety, and tolerability of DMF vs intramuscular interferon ß-1a (IFNß-1a) in POMS. Design, Setting, and Participants: The CONNECT study was an active-controlled, open-label, rater-blinded 96-week randomized clinical trial in patients with POMS aged 10 to less than 18 years treated between August 2014 and November 2020. Data were analyzed from January through October 2021. Interventions: Patients were randomized to DMF or IFNß-1a. Main Outcomes and Measures: The primary end point was the proportion of patients free of new or newly enlarging (N or NE) T2 hyperintense lesions at week 96 among trial completers. Secondary end points included number of N or NE T2 lesions, proportion of patients free of relapse, annualized relapse rate (ARR), and safety. The estimated proportion of participants who were relapse free up to week 96 was calculated based on the Kaplan-Meier method. Adjusted ARR was obtained from a negative binomial regression adjusted for baseline relapse rate, baseline Expanded Disability Status Scale (EDSS) score, and age group. Results: Among 150 patients with POMS in the intention-to-treat (ITT) population (median [range] age, 15 [10-17] years; 101 [67.3%] female patients), 78 individuals received DMF and 72 individuals received IFNß-1a. At week 96, the proportion of patients with no N or NE T2 hyperintense lesions among 103 trial completers was 16.1% (95% CI, 8.0%-27.7%) for DMF vs 4.9% (95% CI, 0.6%-16.5%) for IFNß-1a, and in a sensitivity analysis among the ITT population, the proportions were 10 patients receiving DMF (12.8%) vs 2 patients receiving IFNß-1a (2.8%). The estimated proportion of patients who remained relapse free at week 96 was 66.2% for DMF vs 52.3% for IFNß-1a. Adjusted ARR (95% CI) at week 96 was 0.24 (95% CI, 0.15-0.39) for DMF vs 0.53 (95% CI, 0.33-0.84) for IFNß-1a; the rate ratio for DMF vs IFNß-1a was 0.46 (95% CI, 0.26-0.80; P = .006). The number of treatment-emergent adverse events (TEAEs; 74 patients [94.9%] vs 69 patients [95.8%]), serious TEAEs (18 patients [23.1%] vs 21 patients [29.2%]), and treatment discontinuations due to TEAEs (5 patients [6.4%] vs 8 patients [11.1%]) was similar for DMF vs IFNß-1a. Conclusions and Relevance: This study found that more pediatric patients with POMS treated with DMF were free of new or newly enlarging T2 lesions and that the adjusted ARR was lower among these patients compared with those treated with interferon ß-1a. DMF was well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT02283853.

Associations of social network structure with cognition and amygdala volume in multiple sclerosis: An exploratory investigation.

BACKGROUND: Humans are inherently social, biologically programmed to connect with others. Social connections are known to impact mental and physical health. OBJECTIVE: The aim of this study was to test whether social network structure is linked to cognition, mood, fatigue, and regional brain volumes in persons with multiple sclerosis (MS). METHODS: A questionnaire quantifying individual-level social network structure (size, density, effective size, and constraint), a comprehensive battery of neuropsychological tests, and magnetic resonance imaging (MRI) was administered to 51 persons with relapsing-remitting MS. Linear regressions assessed associations of network variables to cognition, depression, fatigue, and structural brain volumes. RESULTS: Higher network density and constraint, indicating stronger connections among network members, were associated with worse language functions. Conversely, larger network effective size, a measure of non-redundant network members, was associated with better language functions. No relationships of network structure to depression or fatigue were found. Larger network size was related to larger amygdala volume. CONCLUSION: Findings suggest that social network structure is linked to language function and amygdala volume in persons with MS. Patients with close-knit networks showed worse language function than those with open networks. Longitudinal studies with larger samples are warranted to evaluate potential causal links between social network structure and MS-related cognitive impairment.

Myelin oligodendrocyte glycoprotein (MOG) antibody-mediated disease: The difficulty of predicting relapses.

BACKGROUND: While many patients with myelin oligodendrocyte glycoprotein antibody-mediated disease (MOG-AD) will have a monophasic course, 30-80% of patients will relapse after the initial attack. It is not known which factors predict relapse. Here we describe our clinical experience with MOG-AD and evaluate for factors that correlate with relapsing disease. METHODS: This was a retrospective, multi-institutional study of 54 patients with MOG-AD, including 17 children and 37 adults. Mann-Whitney U and Fischer's Exact tests were used for comparisons and logistic regression for correlations. RESULTS: Incident attack phenotype included acute disseminated encephalomyelitis (15%), unilateral optic neuritis (ON; 39%), bilateral ON (24%), transverse myelitis (TM; 11%) and ON with TM (11%). Pediatric patients were more likely than adults to present with ADEM (p = .009) and less likely to present with unilateral ON (p = .04). 31 patients (57%) had a relapsing disease course, with time to first relapse of 8.2 months and median annualized relapse rate of 0.97 months. In 40% of patients (n = 22) the first relapse occurred following the withdrawal of treatment for the incident attack. 5 patients converted to seronegative at follow up, 2 of whom later relapsed. Logistic regression revealed no significant relationship between age, gender, race, presentation phenotype, antibody titer, or cerebrospinal fluid results with risk of relapse. For patients who started disease modifying therapy (DMT) prior to the first relapse (n = 11), 64% remained monophasic. 50% (n = 15) of patients on DMT continued to have disease activity, requiring treatment adjustment. CONCLUSIONS: It is difficult to predict which patients with MOG-AD will relapse. Research is needed to determine the optimal timing and choice of treatment.

Manifestations and impact of the COVID-19 pandemic in neuroinflammatory diseases.

OBJECTIVE: To report initial results of a planned multicenter year-long prospective study examining the risk and impact of COVID-19 among persons with neuroinflammatory disorders (NID), particularly multiple sclerosis (MS). METHODS: In April 2020, we deployed online questionnaires to individuals in their home environment to assess the prevalence and potential risk factors of suspected COVID-19 in persons with NID (PwNID) and change in their neurological care. RESULTS: Our cohort included 1115 participants (630 NID, 98% MS; 485 reference) as of 30 April 2020. 202 (18%) participants, residing in areas with high COVID-19 case prevalence, met the April 2020 CDC symptom criteria for suspected COVID-19, but only 4% of all participants received testing given testing shortages. Among all participants, those with suspected COVID-19 were younger, more racially diverse, and reported more depression and liver disease. PwNID had the same rate of suspected COVID-19 as the reference group. Early changes in disease management included telemedicine visits in 21% and treatment changes in 9% of PwNID. After adjusting for potential confounders, increasing neurological disability was associated with a greater likelihood of suspected COVID-19 (ORadj  = 1.45, 1.17-1.84). INTERPRETATIONS: Our study of real-time, patient-reported experience during the COVID-19 pandemic complements physician-reported MS case registries which capture an excess of severe cases. Overall, PwNID seem to have a risk of suspected COVID-19 similar to the reference population.

ASPIRE trial: study protocol for a double-blind randomised controlled trial of aspirin for overheating during exercise in multiple sclerosis.

INTRODUCTION: The many benefits of exercise for persons with multiple sclerosis (MS) are well established, yet patients often refrain from exercise due to overheating and exhaustion. The present randomised controlled trial tests aspirin (acetylsalicylic acid (ASA)) as a convenient method to prevent overheating and improve exercise performance in persons with MS. The effects of ASA are compared with those of acetaminophen (APAP) and placebo. METHODS AND ANALYSIS: Participants are seen for a laboratory maximal exercise test on 3 separate days separated by at least 1 week. At each session, body temperature is measured before oral administration of a standard adult dose (650 mg) of ASA, APAP or placebo. One hour after drug administration, participants perform a maximal ramp test on a cycle ergometer. Primary outcomes are (a) time to exhaustion (that is, time spent cycling to peak exertion) and (b) body temperature change. Crossover analyses will include tests for effects of treatment, period, treatment-period interaction (carryover effect) and sequence. ETHICS AND DISSEMINATION: Ethical approval was granted by the institutional review board at Columbia University Irving Medical Center (reference: AAAS2529). Results of the trial will be published in peer-reviewed scientific journals and presented at national and international conferences. Neurologists, physiatrists, primary care physicians and physiotherapists are important stakeholders and will be targeted during dissemination. Positive trial results have the potential to promote aspirin therapy, an inexpensive and readily available treatment, to reduce overheating and allow more persons with MS to benefit from exercise. TRIAL REGISTRATION NUMBER: NCT03824938.

Fatal COVID-19 in an MS patient on natalizumab: A case report.

We report a fatal case of COVID-19 in a 51-year-old African American woman with multiple sclerosis on natalizumab. She had multiple risk factors for severe COVID-19 disease including race, obesity, hypertension, and elevated inflammatory markers, but the contribution of natalizumab to her poor outcome remains unknown. We consider whether altered dynamics of peripheral immune cells in the context of natalizumab treatment could worsen the cytokine storm syndrome associated with severe COVID-19. We discuss extended interval dosing as a risk-reduction strategy for multiple sclerosis patients on natalizumab, and the use of interleukin-6 inhibitors in such patients who contract COVID-19.

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

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

Neuroimmunologic disorders in pregnancy.

Pregnancy influences the course of neuroimmunologic conditions, which include multiple sclerosis (MS), neuromyelitis optica spectrum disorder, and autoimmune encephalitis. The outcomes differ significantly for each disorder, reflecting the impact of hormonal changes, T-cell subsets, and placental factors on disease pathogenesis. In recent years, numerous data have emerged regarding MS activity throughout pregnancy and postpartum. Historically, the misconception that pregnancy worsens MS outcomes led patients to abstain from childbearing. Now, more women with these disorders, empowered by up-to-date information and better baseline disease control, are choosing to conceive. Nevertheless, the management of MS and related disorders in the pregnancy and postpartum period is complicated and requires a nuanced approach. Since standardized treatment guidelines around pregnancy are currently lacking, neurologists, together with obstetricians, must engage patients in a shared decision-making process that weighs the benefits to the mother and risks to the fetus. This chapter outlines the pathophysiology of neuroimmunologic disorders during pregnancy and postpartum, the impact of these diseases on childbearing, including fertility, pregnancy, delivery, and peurperium, as well as existing recommendations for treatment.

Paraneoplastic PRES from lymphoma induced hypercalcemia: Case report and review of the literature.

Hypercalcemia from tumors has been associated with Posterior Reversible Encephalopathy Syndrome (PRES) but the mechanism remains unclear. In this article, we describe a case of PRES caused by hypercalcemia from lymphoma. We summarize the available scientific evidence linking hypercalcemia to failure of cerebral autoregulation and potentially PRES. A major link is the hypomagnesemia induced by hypercalcemia. While this concept requires further clinical testing and validation, it is clinically significant for the management of PRES, even when not directly caused by hypercalcemia.

HIV and spinal cord disease.

The epidemiology of spinal cord disease in human immunodeficiency virus (HIV) infection is largely unknown due to a paucity of data since combination antiretroviral therapy (cART). HIV mediates spinal cord injury indirectly, by immune modulation, degeneration, or associated infections and neoplasms. The pathologies vary and range from cytotoxic necrosis to demyelination and vasculitis. Control of HIV determines the differential for all neurologic presentations in infected individuals. Primary HIV-associated acute transverse myelitis, an acute inflammatory condition with pathologic similarities to HIV encephalitis, arises in early infection and at seroconversion. In contrast, HIV vacuolar myelopathy and opportunistic infections predominate in uncontrolled disease. There is systemic immune dysregulation as early as primary infection due to initial depletion of gut-associated lymphoid tissue CD4 cells and allowance of microbial translocation across the gut that never fully recovers throughout the course of HIV infection, regardless of how well controlled. The subsequent proinflammatory state may contribute to spinal cord diseases observed even after cART initiation. This chapter will highlight an array of spinal cord pathologies classified by stage of HIV infection and immune status.

Infections of the Nervous System.

Microorganisms can affect the entire neuraxis, producing a variety of neurologic complications that frequently entail prolonged hospitalizations and complicated treatment regimens. The spread of pathogens to new regions and the reemergence of opportunistic organisms in immunocompromised patients pose increasing challenges to health care professionals. Because rapid diagnosis and treatment may prevent long-term neurologic sequelae, providers should approach these diseases with a structured, neuroanatomic framework, incorporating a thorough history, examination, laboratory analysis, and neuroimaging in their clinical reasoning and decision-making.

Cognitive status in patients hospitalized with acute decompensated heart failure.

BACKGROUND: Cognitive impairment is highly prevalent in patients with heart failure and is associated with adverse outcomes. However, whether specific cognitive abilities (eg, memory vs executive function) are impaired in heart failure has not been fully examined. We investigated the prevalence of impairment in 3 cognitive domains in patients hospitalized with acute decompensated heart failure (ADHF) and the associations of impairment with demographic and clinical characteristics. METHODS: The sample included 744 patients hospitalized with ADHF (mean age 72 years, 46% female) at 5 medical centers. Impairment was assessed in 3 cognitive domains (memory, processing speed, executive function) using standardized measures. Demographic and clinical characteristics were obtained from a structured interview and medical record review. RESULTS: A total of 593 (80%) of 744 patients were impaired in at least 1 cognitive domain; 32%, 31%, and 17% of patients were impaired in 1, 2, or all 3 cognitive domains, respectively. Patients impaired in more than 1 cognitive domain were significantly older, had less formal education, and had more noncardiac comorbidities (all P values < .05). In multivariable adjusted analyses, patients with older age and lower education had higher odds of impairment in 2 or more cognitive domains. Depressed patients had twice the odds of being impaired in all 3 cognitive domains (odds ratio 1.98, 95% CI 1.08-3.64). CONCLUSION: Impairments in executive function, processing speed, and memory are common among patients hospitalized for ADHF. Recognition of these prevalent cognitive deficits is critical for the clinical management of these high-risk patients.