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Background: Zuranolone is an oral, once-daily, 14-day treatment course approved for adults with postpartum depression in the United States. Aims: To assess cognitive effects, pharmacokinetics, and safety of zuranolone, alone or with alprazolam/ethanol. Methods: This was a phase 1, two-part, two-period, randomized, double-blind, placebo-controlled crossover trial. Participants received zuranolone 50 mg or placebo once daily for 9 days, and additionally received alprazolam (1 mg, Part A), ethanol (males: 0.7 g/kg; females: 0.6 g/kg, Part B), or corresponding placebo on days 1, 5, and 9. Within each part, participants received all treatment combinations. Cognition was assessed using a computerized test battery; pharmacokinetics and safety were also evaluated. Results: All participants (Part A, N = 24; Part B, N = 25) received ⩾1 dose of zuranolone/placebo. Compared to placebo, zuranolone produced small-to-moderate cognitive decline (Cohen's | d | = 0.126–0.76); effects were larger with alprazolam (Cohen's | d | = 0.523–0.93) and ethanol (Cohen's | d | = 0.345–0.88). Zuranolone coadministration with alprazolam (Cohen's | d | = 0.6–1.227) or ethanol (Cohen's | d | = 0.054–0.5) generally worsened cognitive decline when compared with zuranolone alone. Maximal pharmacodynamic effects occurred at approximately 5 h and were resolved by 12 h postbaseline. No pharmacokinetic interactions were observed. Incidence of adverse events was similar between groups; most events were mild or moderate in severity. Conclusion: A general small-to-moderate magnitude decline in cognition occurred with zuranolone alone. Coadministration with alprazolam/ethanol increased the magnitude, but not the duration, of effects compared with single-agent administration. Zuranolone prescribers and patients should be aware of the potential for increased central nervous system-depressant effects if coadministered with GABAergic active compounds such as alprazolam and ethanol. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K.H. participated on scientific advisory boards for Bayer, Biogen, Merck, Novartis, Roche, Sanofi, and Teva; received speaker honoraria and research support from Bayer, Biogen, Genzyme, Merck, Novartis, Sanofi, and Teva; received support for congress participation from Bayer, Biogen, Genzyme, Merck, Roche, and Teva. D.R. received consulting and/or speaker fees from Biogen, Celgene, Hikma, Janssen, MedDay, Merck, Novartis, Roche, Sanofi and Teva; research support (paid to institutional fund) from Actelion, Biogen, Janssen, Merck, Mitsubishi, Novartis, Sanofi, Teva and TG Therapeutics. C.M. received honoraria for consultancy work and/or research funding from Actelion, Biogen, Merck, Novartis, Roche, Sandoz, and Sanofi-Genzyme. M.K.H. participated on advisory boards for Biogen, Merck, Novartis, Roche, Sanofi, and Teva; received research support from Biogen, Genzyme, and Merck. D.R.B. participated on advisory boards for Biogen, Celgene, EMDSerono, Genentech, Novartis, and Sanofi-Genzyme. O.M., S.L., N.E., and X.L. are full-time employees of and hold stock/stock options in Biogen. F.B. was a full-time employee of and held stock/stock options in Biogen at the time the research was conducted.

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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: BAS: research grant support from AbbVie, Biogen, Bristol Myers Squibb, Greenwich Biosciences, Novartis, and Sanofi and consulting and/or speaking fees from Alexion, Biogen, Bristol Myers Squibb, Cigna, Cycle, EMD Serono, Genentech, Horizon, Janssen, Novartis, Octave Bioscience, Roche, Sanofi, and TG Therapeutics.DLA: consulting fees from Albert Charitable Trust, Alexion Pharma, Biogen, Celgene, Frequency Therapeutics, Genentech, Med-Ex Learning, Merck, Novartis, Population Council, Receptos, Roche, and Sanofi-Aventis; grants from Biogen, Immunotec, and Novartis; and equity interest in NeuroRx.JD: advisory boards for Amicus, Biogen, Janssen, Medis, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva; speaker bureaus for Biogen, Bayer, Hemofarm, Janssen, Medis, Medtronic, Merck, Novartis, Roche, Sanofi-Genzyme, Teva, and Zentiva; and research grant from Roche.MSF: research/educational grants from Sanofi-Genzyme; honoraria/consultation fees from Alexion/AstraZeneca, BMS (Celgene), EMD Serono, Hoffman La-Roche, Actelion/Janssen (J&J), Novartis, Quanterix, Sanofi-Genzyme, and Teva Canada Innovation; advisory boards/boards of directors for Alexion/AstraZeneca, Atara Biotherapeutics, Bayer Healthcare, Celestra Health, Hoffman La-Roche, Actelion/Janssen (J&J), EMD Serono/Merck Serono, Novartis, and Sanofi-Genzyme; and participated in speakers bureau for Sanofi-Genzyme and EMD Serono.RG: research support and speaker’s honoraria from Bayer-Schering, Biogen Idec, BMS, Chugai, Eisai, Genesis, Janssen, Merck Serono, Nikkiso Pharma, Novartis, Roche, Sanofi-Genzyme, Sandoz, and Teva; consulting honoraria from ZLB Behring, Baxter, Roche, and Talecris; and personal stock options in Bayer, Merck, and Roche.MG: consulting fees from Biogen, EMD Serono, Novartis, and Sanofi-Genzyme; research support from Alkermes; and speaker bureaus for Biogen, EMD Serono, Genentech-Roche, and Sanofi-Genzyme.EJ: advisory boards for Biogen and speaker fees from Biogen, Novartis, Roche, and Sanofi.CLG: consultant/advisory boards/speaker bureaus for Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Janssen, Novartis, Sanofi-Genzyme, and TG Therapeutics.RTN: consultant for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics.DN: research support from and consultant/advisory boards/speaker bureaus for Adamas, Alkermes, Alexion, Bayer, Biogen, Celgene/BMS, EMD Serono, Janssen, Novartis, Roche-Genentech, and Sanofi-Genzyme.JO: research support from Biogen Idec, EMD Serono, and Roche and personal compensation for consulting/speaking from Biogen Idec, BMS, EMD Serono, Eli Lilly, Roche, Sanofi-Genzyme, and Novartis.MAHP: consultant/advisory boards/speaker bureaus for Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Janssen, Novartis, Sanofi-Genzyme, and TG Therapeutics.KS: research support from Merck; advisory boards for Biogen, Celgene/BMS, Merck, Novartis, Roche, Sanofi, and TG Therapeutics.FTB: research support and travel grants, through his institution, from the German Science Fund (DFG), German Federal Ministry of Education and Science (BMBF), Bayer-Schering, Merck, Novartis, Pfizer, Roche, Sanofi, and Teva and speaker fees from and advisory boards for Actelion, Alexion, Bayer, Biogen, CSL Behring, Fresenius, Horizon, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva.AW: adviser fees from AbbVie and research support from AbbVie, Alkermes, and Biogen.TZ: personal compensation for consulting services and speaker honoraria from Bayer, Biogen Idec, Novartis, Sanofi, Synthon, and Teva and financial support for research activities from Bayer, Biogen Idec, Novartis, Sanofi-Aventis, and Teva.WC-B, HC, SL, MS, SLS, and TW: employees of and hold stock/stock options in Biogen.SW: consulting fees from and advisory boards for Biogen, Celgene, and EMD Serono; speaker bureaus for Biogen, Celgene, EMD Serono, Roche-Genentech, and Sanofi-Genzyme; and research support from Biogen, Celgene, EMD Serono, Novartis, Receptos, Roche-Genentech, Sanofi-Genzyme, and TG.

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.

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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)