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Samuel F Hunter,1 Jas Bindra,2 Ishveen Chopra,3 John Niewoehner,4 Mary P Panaccio,4 George J Wan4 1Advanced Neurosciences Institute, Franklin, TN, USA; 2Falcon Research Group, North Potomac, MD, USA; 3Manticore Consultancy, Bethesda, MD, USA; 4Mallinckrodt Pharmaceuticals, Hampton, NJ, USACorrespondence: George J WanMallinckrodt Pharmaceuticals, 53 I-78 Frontage Road, Hampton, NJ, 08827, USAEmail george.wan@mnk.comBackground: Relapses are common among patients with multiple sclerosis (MS) despite treatment with disease-modifying therapies. Repository corticotropin injection (RCI, Acthar® Gel), plasmapheresis (PMP), and intravenous immunoglobulin (IVIg) are alternative therapies for MS relapse. There is a dearth of economic assessments of these therapies for the acute exacerbations of MS. This study estimated the cost-effectiveness of RCI compared to PMP or IVIg.Methods: A Markov state-transition model compared outcomes (costs, relapses, remission, and utilities) with RCI versus PMP or IVIg for the acute exacerbations in MS. The model was developed from the United States (US) payer and societal perspectives over one to three years. Patients initiated on alternative therapies were evaluated in one-day increments for the first 30 days during treatment. The model assumes the natural history of MS after treatment in the first month, adjusting for the effect of treatment. Incremental cost-effectiveness ratios (ICERs) were estimated as cost per quality-adjusted life-year (QALY) gained. The uncertainty in model parameters was evaluated in probabilistic sensitivity analyses.Results: In the base case, RCI has an ICER of USD 42,078 per QALY compared to PMP over one year from the payer perspective and is dominant over two and three years; RCI is dominant compared to PMP from the societal perspective over all three years. Compared to IVIg, RCI is a dominant strategy from both payer and societal perspectives over all three years. Probabilistic sensitivity analysis supports the base case findings, suggesting that RCI may be cost-effective versus PMP and IVIg for acute exacerbations in MS.Conclusion: RCI is a cost-effective alternative treatment for MS relapses compared to PMP and IVIg from the US payer and societal perspectives.Keywords: Acthar® Gel, cost-effectiveness analysis, acute exacerbation, multiple sclerosis, quality-adjusted life-year, repository corticotropin injection

Background: Multiple sclerosis (MS) has not been well studied in racial and ethnic minorities, as these populations are typically underrepresented in clinical trials. Black or African Americans comprise ∼13 % of the US population, yet are represented by as little as 5 % in clinical trials. Differences in disease course and progression have been reported between races and ethnicities, so there is a need to understand the safety and efficacy of disease-modifying therapies (DMTs) in Black patients, to inform evidence-based approaches to treatment in this population., Methods: EVOLVE-MS-1 (NCT0234307) was an open-label, single-arm, phase 3 study assessing the long-term safety, tolerability, and efficacy of diroximel fumarate (DRF) over 96 weeks in adults with relapsing-remitting multiple sclerosis (RRMS). Patients were either newly initiated to DRF or rolled over from completing EVOLVE-MS-2 (NCT03093324). In this post-hoc analysis of the phase 3 EVOLVE-MS-1 study, we evaluate the safety and exploratory efficacy outcomes for DRF in Black and non-Black patient subgroups., Results: Of 1057 patients enrolled, 72 (6.8 %) were Black. In Black vs non-Black patients, mean age was 42 vs 43 years and 75 % vs 72 % were female, respectively. In both groups, median (range) duration of DRF exposure was 1.8 (0.0-2.0) years and mean Expanded Disability Status Scale (EDSS) was 2.7. The most common prior DMTs for both Black vs non-Black patients were interferons (47 % vs 37 %) and glatiramer acetate (36 % vs 24 %). DRF treatment was discontinued in 33 (46 %) Black and 224 (23 %) non-Black patients; most common reasons for discontinuation were withdrawal by patient (n = 11, 15.3 %), adverse events (AEs; n = 7, 9.7 %), and lost to follow-up (n = 7, 9.7 %) in Black patients; AEs (8.2 %) and withdrawal by patient (7.0 %) in non-Black patients. AEs were reported in 90 % Black and 89 % non-Black patients; most AEs were mild or moderate in both groups. Gastrointestinal (GI) AEs were reported in 36 % Black and 32 % non-Black patients; no Black patients discontinued due to GI AEs, vs 7 (0.7 %) non-Black patients. The most commonly reported AE was flushing (18 % Black and 28 % non-Black patients). No AEs of lymphopenia were reported in Black patients compared with 13 % of non-Black patients. Mean absolute lymphocyte count declined from baseline to week 48 by 15 % in Black patients and 29 % in non-Black patients, then plateaued and remained above the lower limit of normal (LLN; 0.91 × 10 9 /L). Adjusted annualized relapse rate (95 % confidence interval) was reduced by 78.2 % (54.6 - 89.5; p < 0.0001) in Black patients, from 12 months before to 96 weeks after DRF treatment; similar to 81.7 % (78.5 - 84.5 %; p < 0.0001) reduction in non-Black patients. Mean number of patients free from confirmed disability progression was 93.4 % by week 48, then 86.2 % vs 90.4 % by week 96 in Black vs non-Black patients, respectively., Conclusion: This study presents the first analysis of safety and efficacy of DRF in Black patients. Relapse rates remained low in Black patients on DRF, consistent with non-Black patients, and there were no new safety signals identified in the Black patient subgroup in EVOLVE-MS-1. Together, these outcomes support DRF as an effective treatment option in Black patients with RRMS., Competing Interests: Declaration of competing interest SFH has received consulting fees from Alexion, Biogen, BMS, Genentech, Horizon, Janssen, Sanofi, and Serono; contracted research at Anokion, Atara, Biogen, Genentech, Janssen, and Sanofi; and served on speaker bureaus for Biogen, BMS, EMD Serono, Horizon, and Janssen. JWL has received personal compensation for consulting from Biogen, Banner Life Sciences, Genentech, Horizon, and Mapi Pharmaceuticals; conducted clinical trials funded by Anokion, Atara, Biogen, EMD Serono, and Genentech; and received research funding from Genentech and the National MS Society. BO has contracted research at Biogen and served on speaker bureaus for Alexion, Biogen, BMS, Genentech, and Roche. SL, JBL, MS, and ZT are employees and stockholders of Biogen. FB was an employee and stockholder at Biogen at the time of analysis. BS and AA have nothing to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Diroximel fumarate (DRF) and dimethyl fumarate (DMF) are orally administered fumarate disease-modifying therapies (DMTs) for multiple sclerosis (MS). The safety, tolerability, and exploratory efficacy of DRF were evaluated in the phase 3 EVOLVE-MS-1 study. No Evidence of Disease Activity (NEDA-3) is a composite efficacy endpoint used in clinical trials for MS defined as no relapse, no 24-week confirmed disability progression (CDP), no new/newly enlarging T2 lesions, and no new gadolinium-enhancing lesions. As NEDA outcomes in studies may be confounded by initial disease activity, the objective of this analysis was to evaluate NEDA-3 in EVOLVE-MS-1 for newly enrolled patients and patients who were re-baselined after approximately 7 weeks., Methods: Patients entered EVOLVE-MS-1 as either newly enrolled or having completed the 5-week phase 3 EVOLVE-MS-2 study of DRF and DMF. Magnetic Resonance Imaging (MRI) was performed at baseline before each study (approx. 7 weeks apart) and at weeks 48 and 96 in EVOLVE-MS-1. Therefore, patients entering from EVOLVE-MS-2 were re-baselined after approximately 7 weeks. NEDA-3 outcomes on DRF are reported for prior DRF, prior DMF, and de novo patient groups., Results: Of 1057 patients in EVOLVE-MS-1, 239 (22.6%) had rolled over from receiving DRF in EVOLVE-MS-2 ("prior DRF"), 225 (21.3%) had rolled over from receiving DMF in EVOLVE-MS-2 ("prior DMF"), and 593 (56.1%) were newly enrolled ("de novo"). At week 48, Kaplan-Meier estimates of NEDA-3 were 72.3% (prior DRF), 72.1% (prior DMF), and 62.1% (de novo); at week 96, estimates were 50.2% (prior DRF), 48.2% (prior DMF), and 36.5% (de novo)., Conclusions: In EVOLVE-MS-1, after re-baselining at approximately 7 weeks, approximately half of DRF-treated patients achieved NEDA-3 at week 96, compared with 36.5% of patients who were not re-baselined. Re-baselining may be useful for assessing efficacy of DMTs by mitigating the influence of disease activity prior to the onset of efficacy., Clinical Trial Registrations: NCT03093324 (EVOLVE-MS-2); NCT02634307 (EVOLVE-MS-1)., (© 2024. The Author(s).)

Background: Alemtuzumab is an effective therapy for relapsing multiple sclerosis. Autoimmune thyroid events are a common adverse event., Objective: Describe endocrine and multiple sclerosis outcomes over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients in the phase 3 CARE-MS I, II, and extension studies who experienced adverse thyroid events., Methods: Endocrine and multiple sclerosis outcomes were evaluated over 6 years. Thyroid event cases, excluding those pre-existing or occurring after Year 6, were adjudicated retrospectively by expert endocrinologists independently of the sponsor and investigators., Results: Thyroid events were reported for 378/811 (46.6%) alemtuzumab-treated patients. Following adjudication, endocrinologists reached consensus on 286 cases (75.7%). Of these, 39.5% were adjudicated to Graves' disease, 2.5% Hashimoto's disease switching to hyperthyroidism, 15.4% Hashimoto's disease, 4.9% Graves' disease switching to hypothyroidism, 10.1% transient thyroiditis, and 27.6% with uncertain diagnosis; inclusion of anti-thyroid antibody status reduced the number of uncertain diagnoses. Multiple sclerosis outcomes of those with and without thyroid events were similar., Conclusion: Adjudicated thyroid events occurring over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients were primarily autoimmune. Thyroid events were considered manageable and did not affect disease course. Thyroid autoimmunity is a common but manageable adverse event in alemtuzumab-treated relapsing multiple sclerosis patients. ClinicalTrials.gov Registration Numbers: CARE-MS I (NCT00530348); CARE-MS II (NCT00548405); CARE-MS Extension (NCT00930553)., Competing Interests: CMD has received compensation for serving on an advisory board and/or speaking fees (Sanofi). BL has nothing to disclose. IM has received honoraria and travel expenses for lecturing (Sanofi). SG has nothing to disclose. SFH has received consulting agreements, speaker honoraria, and grant/research financial support (AbbVie, Acorda, Actelion, Adamas, Avanir, Bayer, Biogen, Novartis, Osmotica, Questcor, Roche, Sanofi, Synthon, and Teva). KWS has received consulting and/or speaking fees (Biogen, Merck, Novartis, Roche, Sanofi, and Synthon). H-PH has received consulting and/or speaking fees (Bayer, Biogen, BMS Celgene, CSL Behring, GeNeuro, Horizon Therapeutics, Merck Serono, Novartis, Octapharma, Roche, Sanofi, and TG Therapeutics). EKH has received honoraria and grant support (Actelion, Biogen, Merck Serono, Novartis, Receptos, Roche, Sanofi, and Teva), and support (Ministry of Education of Czech Republic [PROGRES Q27/LF1]). CCL has received compensation for consulting (Acorda Therapeutics, Bayer, Biogen, Cephalon, EMD Serono, Novartis, Pfizer, Questcor, Sanofi, Strativa, Teva, and UCB). TZ has received consulting and/or speaking fees (Almirall, Bayer, Biogen, Merck, Novartis, Roche, Sanofi, and Teva) and grant/research support (Biogen, Novartis, Sanofi, and Teva). BVW has received advisory board and/or speaking fees (Almirall, Biogen, Merck, Novartis, Roche, and Sanofi); research support (Biogen, Merck, Novartis, and Sanofi), and contracted research (PI) (Biogen, Merck, Sanofi, Novartis, and Roche). SGM has received honoraria for lecturing, travel expenses for attending meetings, and financial research support (Almirall, Amicus Therapeutics, Bayer HealthCare, Biogen, Celgene, Diamed, HERZ Burgdorf, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi, and Teva). DHM and EMP were employees of Sanofi during study conduct and analysis, and may hold shares and/or stock options in the company. DPB is an employee of Sanofi and may hold shares and/or stock options in the company. PAS has received grant research support (Novo Nordisk). The adjudicators (CMD, BL, and PAS), and IM and SG who assisted CMD), received no compensation for review of the cases reported in this study., (© The Author(s), 2023.)

Background: Patient-reported outcomes are increasingly used in the management of patients with multiple sclerosis to understand the patient's perspective of disease and treatment. These measures provide insights into important factors including treatment satisfaction, physical and psychological function, and quality of life., Objective: To present results from the real-world PRO-ACT study in patients with multiple sclerosis who switched to alemtuzumab from another disease-modifying therapy., Methods: This 24-month, prospective, multicenter, observational study had a primary endpoint of change in overall satisfaction, measured using the Treatment Satisfaction Questionnaire for Medication (TSQM) version 1.4. Secondary endpoints included the Multiple Sclerosis Impact Scale-29 (MSIS-29), Modified Fatigue Impact Scale-5 (MFIS-5), and the Patient-Determined Disease Steps (PDDS). Safety was monitored with adverse events (AEs)., Results: Of 199 enrolled patients, improvements were observed in mean TSQM scores for overall satisfaction (baseline, 50.3; year 2, + 13.2; p   <  0.0001), effectiveness (49.3 and + 12.2; p   <  0.0001), and side effects (77.6 and + 4.5; p   =  0.04). Improvements were also observed in MSIS-29 physical (52.4 and -6.0; p   <  0.0001), MSIS-29 psychological (53.4 and -7.0; p   =  0.0003), and MFIS-5 (12.8 and -1.7; p   <  0.0001). Most (95.0%) patients experienced ≥ 1 AE (88.4% mild, 67.8% moderate)., Conclusions: The primary endpoint was met; the safety of alemtuzumab was consistent with pivotal studies., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SW reports receiving consulting, principal investigator, and/or speaking fees (Alkermes, Biogen, Celgene, Genentech, Novartis, Sanofi, and TG Therapeutics). FJ reports receiving honoraria for giving presentations, advisory board participation, research funding, and for an infusion clinic (Biogen, Merck Serono, Novartis, Roche, and Sanofi). TAM reports receiving speaking and/or consulting fees (Abbvie, Amgen, Biogen, Biohaven, BMS, Genentech, Lundbeck, Novartis, Reven, Sanofi, and Teva) and research support (Abbvie, Biogen, BMS, Celgene, Elan, EMD Serono, Genentech, Hoffman-La Roche, Ipsen, Merck, Novartis, Sanofi, and Teva). JAN reports receiving research grants (Biogen Idec, Genentech, Novartis, and PCORI) and consulting and/or speaking fees (Alexion, Bristol Myers Squib, EMD Serono, Genentech, Greenwich Biosciences, Novartis, Sanofi, and Viela Bio). RA reports receiving speaking fees from and advisory board participation for Almirall, Bayer, Biogen, Merck, Novartis, Roche, Sanofi, and Teva. LT reports receiving consulting fees (Acorda, Biogen Idec, EMD Serono, Mallinckrodt, Novartis, Pfizer, and Sanofi), and grant/research support (Biogen, EMD Serono, and Sanofi). BK reports consulting/honorarium (Acorda, Alexion, Biogen, Celgene, Genentech, Novartis, Sanofi, Serono, and Teva); contracted research (Alexion, Biogen, Genentech, Novartis, Ra Pharmaceuticals, and Sanofi). MC, RG, NR, and AMR are employees of Sanofi and may hold shares and/or stock options in the company. AR and LMM were employees of Sanofi at the time the study was conducted, and are currently employees of Ividata Life Sciences. SFH reports receiving consulting agreements, speaker honoraria, and grant/research financial support (AbbVie, Adamas, Alexion, Atara, Avanir, Biogen, Janssen, Mallinckrodt, Novartis, Osmotica, Roche, and Sanofi)., (© The Author(s), 2022.)

Introduction: Diroximel fumarate (DRF) is an oral fumarate for relapsing multiple sclerosis (MS) with the same active metabolite as dimethyl fumarate (DMF). DRF has a safety/efficacy profile similar to DMF but with improved gastrointestinal (GI) tolerability and low (< 1%) treatment discontinuation due to GI adverse events (AEs). Efficacy and safety outcomes in patients who switched to DRF from other disease-modifying therapies (DMTs) have not been evaluated., Methods: EVOLVE-MS-1 is an ongoing, 2-year, open-label, phase 3 study of DRF in adults with relapsing-remitting MS. Patients either entered as newly enrolled to DRF trials, or from the 5-week, randomized, head-to-head, phase 3 EVOLVE-MS-2 study of DRF and DMF. This analysis evaluated safety and GI tolerability in patients continuing on DRF (DRF-rollover) or switching from DMF (DMF-rollover) following EVOLVE-MS-2. Safety and efficacy were evaluated in a subset of newly enrolled patients who had received prior glatiramer acetate (GA; GA/DRF) or interferons (IFN; IFN/DRF) as their most recent DMT, prior to switching to DRF in EVOLVE-MS-1., Results: As of September 1, 2020, 1057 patients were enrolled in EVOLVE-MS-1, including 166, 182, 239, and 225 patients in the GA/DRF, IFN/DRF, DRF-rollover, and DMF-rollover groups, respectively. Treatment discontinuation due to GI AEs was < 1% in all groups. GA/DRF and IFN/DRF patients experienced improvements from baseline in clinical and radiological efficacy outcomes, including significantly reduced annualized relapse rates. Rollover patients had low rates of new or recurrent GI AEs (DRF-rollover, 26.8%/4.2%; DMF-rollover, 27.1%/4.9%)., Conclusion: After 2 years of DRF exposure, patients with prior GA, IFN, or fumarate treatment had safety outcomes consistent with previous fumarate studies. Efficacy in patients with prior GA or IFN treatment was consistent with previous fumarate studies. The data suggest that transition to DRF from GA, IFN, or DMF is a reasonable treatment strategy, with low rates of discontinuation due to GI AEs., Trial Registration: ClinicalTrials.gov (NCT02634307). INFOGRAPHIC., (© 2022. The Author(s).)

Introduction: In the 2-year CARE-MS trials (NCT00530348; NCT00548405) in patients with relapsing-remitting multiple sclerosis, alemtuzumab showed superior efficacy versus subcutaneous interferon beta-1a. Efficacy was maintained in two consecutive extensions (NCT00930553; NCT02255656). This post hoc analysis compared disability outcomes over 9 years among alemtuzumab-treated patients according to whether they experienced confirmed disability improvement (CDI) or worsening (CDW) or neither CDI nor CDW., Methods: CARE-MS patients were randomized to receive two alemtuzumab courses (12 mg/day; 5 days at baseline; 3 days at 12 months), with additional as-needed 3-day courses in the extensions. CDI or CDW were defined as ≥ 1.0-point decrease or increase, respectively, in Expanded Disability Status Scale (EDSS) score from core study baseline confirmed over 6 months, assessed in patients with baseline EDSS score ≥ 2.0. Improved or stable EDSS scores were defined as ≥ 1-point decrease or ≤ 0.5-point change (either direction), respectively, from core study baseline. Functional systems (FS) scores were also assessed., Results: Of 511 eligible patients, 43% experienced CDI and 34% experienced CDW at any time through year 9 (patients experiencing both CDI and CDW were counted in each individual group); 29% experienced neither CDI nor CDW. At year 9, patients with CDI had a -0.58-point mean EDSS score change from baseline; 88% had stable or improved EDSS scores. Improvements occurred across all FS, primarily in sensory, pyramidal, and cerebellar domains. Patients with CDW had a +1.71-point mean EDSS score change; 16% had stable or improved EDSS scores. Patients with neither CDI nor CDW had a -0.10-point mean EDSS score change; 98% had stable or improved EDSS scores., Conclusion: CDI achievement at any point during the CARE-MS studies was associated with improved disability at year 9, highlighting the potential of alemtuzumab to change the multiple sclerosis course. Conversely, CDW at any point was associated with worsened disability at year 9., (© 2021. The Author(s).)

Lysophospholipids are a class of bioactive lipid molecules that produce their effects through various G protein-coupled receptors (GPCRs). Sphingosine 1-phosphate (S1P) is perhaps the most studied lysophospholipid and has a role in a wide range of physiological and pathophysiological events, via signalling through five distinct GPCR subtypes, S1PR 1 to S1PR 5 . Previous and continuing investigation of the S1P pathway has led to the approval of three S1PR modulators, fingolimod, siponimod and ozanimod, as medicines for patients with multiple sclerosis (MS), as well as the identification of new S1PR modulators currently in clinical development, including ponesimod and etrasimod. S1PR modulators have complex effects on S1PRs, in some cases acting both as traditional agonists as well as agonists that produce functional antagonism. S1PR subtype specificity influences their downstream effects, including aspects of their benefit:risk profile. Some S1PR modulators are prodrugs, which require metabolic modification such as phosphorylation via sphingosine kinases, resulting in different pharmacokinetics and bioavailability, contrasting with others that are direct modulators of the receptors. The complex interplay of these characteristics dictates the clinical profile of S1PR modulators. This review focuses on the S1P pathway, the characteristics and S1PR binding profiles of S1PR modulators, the mechanisms of action of S1PR modulators with regard to immune cell trafficking and neuroprotection in MS, together with a summary of the clinical effectiveness of the S1PR modulators that are approved or in late-stage development for patients with MS. Sphingosine 1-phosphate receptor modulator therapy for multiple sclerosis: differential downstream receptor signalling and clinical profile effects (MP4 65540 kb).

Background: Relapses are common in patients with multiple sclerosis (MS) even after the use of disease-modifying therapies. Repository corticotropin injection (RCI), plasmapheresis (PMP), and intravenous immunoglobulin (IVIg) may be utilized as alternative therapies in the management of MS relapse. There is a lack of health economic studies on these alternative therapies for the acute exacerbations of MS. The objective of this study was to estimate the cost per response of RCI compared with PMP or IVIg from the United States (US) commercial payer perspective., Methods: Costs and response rates were sourced from published peer-reviewed observational studies. The cost of care included MS-related inpatient, outpatient, and medication costs. Treatment response was defined as no evidence of additional relapse treatment or procedure claims within 30 days after treatment. The cost per response for each treatment was calculated by dividing the total annual cost of care by the proportion of patients with resolved relapse for each treatment. The incremental cost per response ratio was calculated by dividing the difference in costs and the proportion of responses for RCI versus PMP or IVIg. One-way sensitivity analysis (OWSA) was conducted for both costs and response rates. All included costs were inflated to the 2019 US dollars., Results: With a lower total annual cost of care and a higher response rate, RCI had a lower cost per response (US$141,970) compared with PMP or IVIg (US$253,331). RCI had a lower cost per response even when more stringent estimates for RCI were applied in the OWSA. The annual cost of care had a greater influence on the cost per response in the OWSA., Conclusions: Based on the estimates from the real-world evidence, our economic evaluation suggests that RCI may have real-world clinical and economic benefits for patients with MS relapse who fail on corticosteroid therapy., Competing Interests: Disclosure and potential conflicts of interest: All authors declare that they have no conflicts of interest. GJW and JN are employees of Mallinckrodt Pharmaceuticals and IC was paid consultant fees from at Mallinckrodt Pharmaceuticals for the duration of the project. SFH is a research collaborator and has received speaker honoraria, consulting agreements, and grant/research financial support from AbbVie, Acorda, Actelion, Adamas, Alkermes, Avanir, Bayer, Biogen Idec, Novartis, Osmotica, Mallinckrodt, Roche, Sanofi, Synthon, and Teva. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2020/11/dic.2020-9-4-COI.pdf, (Copyright © 2020 Wan GJ, Chopra I, Niewoehner J, Hunter SF.)

Introduction: In clinical trials of alemtuzumab, autoimmune thyroid adverse events (AEs) were frequent. Here, we assess the impact of thyroid AEs on health-related quality of life (HRQL) in alemtuzumab-treated patients with relapsing-remitting multiple sclerosis (RRMS)., Methods: In phase 3 CARE-MS I (NCT00530348) and II (NCT00548405) trials, patients with RRMS were administered alemtuzumab 12 mg/day on 5 consecutive days at baseline and on 3 consecutive days 12 months later. Patients could participate in an extension study (NCT00930553) through year 6. HRQL was assessed at baseline and annually using the Functional Assessment of Multiple Sclerosis (FAMS), EuroQoL-5 Dimension Visual Analog Scale (EQ-5D VAS), and 36-Item Short-Form Survey (SF-36) questionnaires. Outcomes were analyzed in patients with or without thyroid AEs (nonserious or serious). A subset of patients with thyroid AEs was analyzed to assess HRQL before and during the onset of thyroid AEs., Results: A total of 811 CARE-MS patients were treated with alemtuzumab. Of these, 342 (42%) patients experienced thyroid AEs over 6 years; serious thyroid AEs occurred in 44 (5%) patients. At year 6, HRQL outcomes generally remained slightly improved or similar to core study baseline in alemtuzumab-treated patients with or without thyroid AEs: FAMS (least-squares mean change from baseline without thyroid AEs, 0.7; with nonserious thyroid AEs, 5.1; with serious thyroid AEs, - 5.3), EQ-5D VAS (2.0; 3.0; - 6.8), SF-36 mental component summary (MCS [0.6; 1.6; - 2.8]), SF-36 physical component summary (PCS [0.8; 1.0; 1.1]). Over 6 years, 63-82% of patients in each group had improved/stable SF-36 MCS and PCS scores. Among patients with thyroid AE onset in year 3 (peak incidence), there were minimal differences between HRQL outcomes before onset (year 2) and after onset (year 3)., Conclusion: Autoimmune thyroid AEs (serious and nonserious) had minimal impact on HRQL in alemtuzumab-treated patients. These data may aid therapeutic decisions in patients with relapsing MS.

Background: Injectable disease-modifying therapies (iDMTs) are often used as first-line treatments for relapsing multiple sclerosis. Fingolimod is frequently used following treatment with iDMTs. Whether prior iDMT treatment impacts the effectiveness of subsequent fingolimod therapy is unclear. Here, we assessed switching from iDMTs to fingolimod, and the impact of treatment history on fingolimod escalation using data from the 12-month 'Prospective, Randomized, active-controlled, open-label study to Evaluate patient retention on Fingolimod versus approved first-line disease-modifying thErapies in adults with Relapsing-remitting Multiple Sclerosis' (PREFERMS). The study design and results at the end of randomized treatment (EoRT) in PREFERMS have been published., Methods: Both treatment-naïve patients and those who had previously received an iDMT were eligible for enrolment in PREFERMS, and one treatment switch was permitted on study. Pre-specified exploratory analyses compared outcomes in those randomized to fingolimod or to an iDMT at end of study (EoS), which included time spent on randomized and on switch treatment. Post hoc exploratory analyses (unadjusted for multiplicity owing to the large number of comparisons) among patients randomized to an iDMT who switched to fingolimod, compared outcomes longitudinally before (EoRT) and after (EoS) switching, and compared outcomes at EoRT and EoS among subgroups stratified by iDMT-treatment history. Outcomes included brain volume, various measures of gadolinium-enhancing [Gd+] lesion counts, annualized relapse rate (ARR), Symbol Digit Modalities Test (SDMT) score, patient-reported treatment satisfaction using the Medication Satisfaction Questionnaire (MSQ) and adverse event (AE) rates., Results: At EoS, 255 of 439 patients randomized to an iDMT had switched to fingolimod and 27 of 436 patients randomized to fingolimod had switched to an iDMT. By EoS, 44.2% of total treatment exposure in the iDMT group was to fingolimod and the mean time spent on fingolimod in this group was 220 days (approximately 7 months). Outcomes in the fingolimod group at EoS (brain volume, changes in Gd+ lesion counts, ARR, oral SDMT score and MSQ score) were similar to those seen at EoRT, but in the iDMT group these outcomes were more favorable at EoS than at EoRT and were similar to rates seen in the fingolimod group. Among patients who switched from iDMT to fingolimod, there were longitudinal improvements in ARR (EoRT, 0.3 [95% confidence interval (CI), 0.2-0.4]; EoS, 0.2 [0.1-0.3]; odds ratio, 0.5 [0.3-0.9]) and in treatment satisfaction (proportion of patients with MSQ > 5; EoRT, 67.4%; EoS, 90.4%; odds ratio, 5.7 [95% CI, 3.4-9.4]) after fingolimod treatment, and changes in brain volume, Gd+ lesion count, and AEs or AEs causing discontinuation were also more favorable at EoS than at EoRT. In all patient groups stratified by iDMT-treatment history, differences in outcomes narrowed or disappeared after fingolimod treatment., Conclusion: These analyses indicate that patients in PREFERMS had improved outcomes within months of switching to fingolimod from an iDMT and that improvements occurred irrespective of the number of iDMTs previously administered. These data provide a unique opportunity to explore clinical, radiological and safety outcomes associated with a range of clinically relevant treatment pathways., Competing Interests: Declaration of Competing Interest SFH has received consulting fees and/or research support from and/or served on speakers’ bureaux for Acorda Therapeutics, Avanir, Bayer HealthCare Pharmaceuticals, Novartis, Osmotica, Roche/Genentech, Sanofi Genzyme and Teva Neuroscience. FPT has served as a speaker and/or consultant for Acorda Therapeutics, Biogen, Genzyme, Novartis and Teva Neuroscience, and has received research support from Biogen and Teva Neuroscience. MC has received research support and/or consulting fees from Acorda Therapeutics, Bayer HealthCare, Biogen Idec, EMD Serono, Genzyme, Genentech, Novartis, Roche and Sanofi Aventis. IMW is an employee of Oxford PharmaGenesis Ltd. XM, LS, JLW and NT are employees of Novartis Pharmaceuticals Corporation. BACC has received personal compensation for consulting from AbbVie, Akili, Alexion, Biogen, EMD Serono, Novartis and TG Therapeutics., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Alemtuzumab efficacy versus subcutaneous interferon-β-1a (SC IFNB-1a) was demonstrated over 2 years in patients with relapsing-remitting multiple sclerosis, with continued efficacy over 7 additional years. Alemtuzumab is included as a recommended treatment for patients with highly active disease (HAD) by the American Academy of Neurology Practice Guidelines, and the label indication in Europe was recently restricted to the treatment of HAD patients. There is currently no consensus definition for HAD, and alemtuzumab efficacy across various HAD definitions has not been explored previously., Objectives: In this post hoc analysis, we assess the efficacy and safety of alemtuzumab in Comparison of Alemtuzumab and Rebif ® Efficacy in Multiple Sclerosis (CARE-MS) trial patients who met criteria for at least one of four separate definitions of HAD (one primary and three alternatives). Over 2 years, alemtuzumab-treated HAD patients were compared with SC IFNB-1a-treated HAD patients, with additional 7-year follow-up in patients from the alemtuzumab arm., Methods: Patients in the CARE-MS studies received either alemtuzumab (baseline: 5 days; 12 months later: 3 days) or SC IFNB-1a (3 times weekly). Alemtuzumab-treated patients who enrolled in the extensions could receive additional courses ≥ 12 months apart. Four definitions of HAD were applied to assess alemtuzumab efficacy: the pre-specified primary definition (two or more relapses in the year prior to baseline and at least one gadolinium [Gd]-enhancing lesion at baseline) and three alternative definitions that focused on relapse, magnetic resonance imaging (MRI), or prior treatment response criteria. Efficacy outcomes were annualized relapse rate, change in Expanded Disability Status Scale score, 6-month confirmed disability worsening, 6-month confirmed disability improvement, MRI disease activity, and brain volume change. Adverse events were summarized for HAD patients meeting the primary definition., Results: In the pooled CARE-MS population, 208 alemtuzumab-treated patients met the primary HAD definition. Annualized relapse rate was 0.27 in years 0-2 and 0.16 in years 3-9. Over 9 years, 62% of patients were free of 6-month confirmed disability worsening, 50% had 6-month confirmed disability improvement, and median cumulative change in brain volume was - 2.15%. During year 9, 62% had no evidence of disease activity, and 69% were free of MRI disease activity. Similar efficacy outcomes were observed using an alternative relapse-driven HAD definition. For patients meeting alternative HAD definitions focused on either higher MRI lesion counts or disease activity while on prior therapy, reduced efficacy for some endpoints was seen. Safety was consistent with the overall CARE-MS population through year 9., Conclusions: Over 9 years, alemtuzumab efficacy was maintained in CARE-MS HAD patients based on four HAD definitions. These results support intervention with alemtuzumab in patients with early indicators of HAD, including frequent relapse without high MRI activity. No safety signals were observed over 9 years that were unique to the HAD populations. CLINICALTRIALS., Gov Identifiers: NCT00530348; NCT00548405; NCT00930553; NCT02255656.

Background: Walking impairment causes disability and reduced quality of life in patients with multiple sclerosis (MS)., Objective: Characterize the safety and efficacy of ADS-5102 (amantadine) extended release capsules, 274 mg administered once daily at bedtime in patients with MS with walking impairment., Methods: This randomized, double-blind, placebo-controlled, 4-week study was conducted at 14 trial sites in the United States. Study objectives included safety and tolerability of ADS-5102, and efficacy assessments (Timed 25-Foot Walk (T25FW), Timed Up and Go (TUG), 2-Minute Walk Test, and Multiple Sclerosis Walking Scale-12). Fatigue, depression, and cognition also were assessed., Results: A total of 60 patients were randomized (30 to ADS-5102 and 30 to placebo); 59 of whom were treated. The most frequent adverse events (AEs) were dry mouth, constipation, and insomnia. Five ADS-5102 patients and no placebo patients discontinued treatment due to AEs. One patient in the ADS-5102 group experienced a serious AE-suspected serotonin syndrome. A 16.6% placebo-adjusted improvement was seen in the T25FW test ( p < 0.05). A 10% placebo-adjusted improvement in TUG was also observed. No changes in fatigue, depression, or cognition were observed., Conclusion: ADS-5102 was generally well tolerated. These data demonstrate an effect of ADS-5102 on walking speed. Further studies are warranted to confirm these observations.

Background and Purpose: Evidence is needed to understand the effect of fingolimod on slowing down brain atrophy progression in multiple sclerosis (MS) patients in clinical practice. We investigated the effect of fingolimod on brain atrophy in MS patients with active disease (clinically and/or magnetic resonance imaging [MRI]) versus no evidence of active disease (NEAD)., Methods: MS and clinical outcome and MRI in the United States (MS-MRIUS) is a multicenter, retrospective study that included 590 relapsing-remitting MS patients, who initiated fingolimod, and were followed for a median of 16 months. Patients with active disease at baseline (245, 41.5%) were defined as those who had one or more relapses in the year previous starting fingolimod, and/or displayed gadolinium enhancing lesions(s) at baseline MRI scan, whereas patients with NEAD at baseline (345, 58.5%) did not fulfill these criteria. Annualized percentage brain volume change (PBVC) and percentage lateral ventricle volume change (PLVVC) over the follow-up were analyzed in both groups., Results: Over the follow-up, the rate of PBVC was -.38% in active disease and -.25% in NEAD patients (P = .076), whereas PLLVC was 1.76% in active disease and .28% in NEAD patients (P = .046). No changes in timed 25-foot walk (P = .619) and Expanded Disability Status Scale (P = .275) scores or MRI lesion accumulation (P > 0.08) were detected, although the active disease group had a higher proportion of relapses during the follow-up period (P = .02)., Conclusions: The study provides real-world evidence that rate of brain atrophy in MS patients with underlying active disease and NEAD in fingolimod treated patients is below the established pathological cutoff for loss of whole brain volume (>-.4%) or expansion of lateral ventricles (> 3.5%)., (Copyright © 2018 by the American Society of Neuroimaging.)

Background: Depression is common in patients with multiple sclerosis (MS), may confound evaluation of therapeutic effectiveness and may be impacted by MS-specific treatments., Objective: First, to assess the impact on depressive symptoms of a switch to fingolimod versus remaining on an injectable disease-modifying therapy (iDMT) in a post-hoc analysis of prospectively collected data from the EPOC study. Secondly, to investigate the underlying Beck Depression Inventory-II (BDI-II) factor structure in patients with MS, and estimate treatment differences using the resulting subscales., Methods: EPOC was a 6-month, open-label study assessing patient-reported outcomes after switch from iDMT to oral fingolimod 0.5mg versus remaining on iDMT in 1053 patients with relapsing-remitting MS., Results: At end of study (EOS), a greater proportion of patients on fingolimod versus iDMT no longer had BDI-II scores indicating depression (p<0.001). Fewer mildly and moderately symptomatic patients developed severe depressive symptoms, and fewer severely symptomatic patients continued to have scores indicating severe depression at EOS on fingolimod versus iDMT (p=0.027, p=0.038, p=0.030, respectively). Two BDI-II subscales were identified and labelled Somatic and Affective; fingolimod demonstrated more reduction on both subscales at EOS versus iDMTs (p<0.0001 and p=0.0001, respectively)., Conclusion: A switch to fingolimod versus remaining on/switching to another iDMT was associated with an improvement in depressive symptoms in patients with relapsing-remitting MS., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS), a chronic inflammatory disease of unknown etiology, involves an immunemediated attack of the central nervous system (CNS) that produces demyelination and axonal/neuronal damage, resulting in characteristic multifocal lesions apparent on magnetic resonance imaging and a variety of neurologic manifestations. The disease pathology is characterized by multifocal lesions within the CNS, in both the white matter and gray matter, with perivenular inflammatory cell infiltrates, demyelination, axonal transection, neuronal degeneration, and gliosis. MS pathogenesis is complex, as it involves both T- and B-cell mechanisms and is heterogeneous in presentation. Relatively recently, the historical 4 core clinical categories of MS were revised in an effort to improve characterization of the clinical course, better identify where a given patient is positioned in the disease spectrum, and to guide clinical studies. In young and middle-aged adults, MS is one of the most common contributors to neurologic disability, and it exerts detrimental effects on a patient's productivity and health-related quality of life. Typically, patients with MS have a long life span, although healthcare utilization increases over time. As a consequence, the disease places a substantial burden on patients and their caregivers/families, as well as employers, the healthcare system, and society.

Fingolimod, a structural analog of sphingosine derived from fungal metabolites, is a functional antagonist of the G-protein-coupled sphingosine 1-phosphate (S1P) receptors S1P(1,3,4,5). In the treatment of relapsing forms of multiple sclerosis (RMS), fingolimod acts by reversibly retaining central memory T cells and naïve T cells in lymph nodes, thereby reducing the recirculation of autoreactive lymphocytes to the central nervous system (CNS). Fingolimod also has differential effects on the trafficking and function of B-cell subtypes and natural killer (NK) cells in peripheral blood and the CNS. Fingolimod also crosses the blood-brain barrier (BBB) and accumulates in the CNS. Experimental evidence increasingly supports a direct action of fingolimod within the CNS on brain cells, providing protection against the neurodegenerative component of RMS. We review the direct influence of this compound on CNS pathogenesis in RMS, including the central effects of fingolimod in animal models of MS and on neural cell types that express S1P receptors, such as astrocytes, BBB endothelial cells, microglia, neurones, and oligodendrocytes, which are all involved in RMS pathology.

The treatment paradigm for multiple sclerosis (MS) continues to evolve as additional pharmacotherapeutic options become available. Furthermore, treatment individualization has become more feasible as new medications with distinct mechanisms of action and improved adverse event profiles have reached the market. As such, clinicians should familiarize themselves with the available treatment options, paying particular attention to their various advantages and disadvantages. In order to offer patients optimal MS therapy, it is crucial for clinicians to stay current with the changing landscape of multiple sclerosis. This article provides a review of the available pharmacotherapeutic options for treating MS, discusses the impact of adherence to therapy, and describes the importance of managing comorbidities often experienced by patients with MS.

Multiple sclerosis (MS) is a chronic, often debilitating disease of the central nervous system (CNS) that affects between 400,000 and 570,000 persons in the United States, with an incidence among females 2 to 3 times that of males. The cause of MS is currently unknown, but immediate family history, low blood levels of vitamin D, and cigarette smoking, among other factors, appear to increase the risk of developing MS. MS is considered an immune-mediated disease, whereby immune cells target and attack the CNS, predominantly the axonal membrane known as the myelin sheath. Depending on which areas of the brain or spinal cord are affected, this can result in a variety of waxing and waning neurologic symptoms. Most patients will eventually suffer from progressive disability that can greatly impact their quality of life. Symptoms such as fatigue, difficulty with ambulation, and depression are common among patients with MS and can affect their ability to work and care for themselves. Costs due to treatment and lost productivity place a significant economic burden on patients, caregivers, families, and society. Current and future treatments may help limit the personal and societal costs of MS by delaying disability and disease progression.

Background: The Evaluate Patient OutComes (ClinicalTrials.gov Identifier: NCT01216072) study was conducted in North America to assess patient- and physician-reported treatment satisfaction in patients with relapsing multiple sclerosis (MS) who received oral fingolimod for 6 months after switching from an injectable disease-modifying therapy (iDMT), without an intervening washout., Methods: In this open-label, multicenter study, patients were randomized 3:1 to once-daily fingolimod 0.5mg or iDMT. The primary study objective was to evaluate differences in satisfaction measured using the Treatment Satisfaction Questionnaire for Medication v1.4., Results: Of 1053 patients randomized, 790 patients received fingolimod and 263 patients received iDMT. Treatment satisfaction improved significantly in patients who switched to fingolimod compared with those who continued iDMT. Patients also reported significant improvements in health-related quality of life, reduced depression, and reduced fatigue severity after a switch to fingolimod. No difference between the treatment groups was detected on the Patient Reported Indices for MS Activities scale. The safety profile of fingolimod was consistent with that reported in the pivotal phase 3 studies. The most commonly reported adverse events were more prevalent in patients who switched to fingolimod than in those who continued iDMT (headache: 12% vs 3%; fatigue: 12% vs 6%). No significant relationship between lymphocyte counts and infection rates was observed and there was no evidence of additive immune-system effects, which might be expected when switching to a different class of immunomodulatory therapy with no intervening washout., Conclusion: Patients who switched from iDMT to fingolimod had significant improvements in most self-reported outcomes compared with those who continued iDMT., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) affects an estimated 300,000 individuals in the United States. No cure exists and although there is a lack of consensus on management, strategies to modify disease course are available. These strategies involve initiating disease-modifying therapies that have been found to slow disease progression and prevent disability symptoms, thereby improving function for MS patients. The overall goal of early disease management is to intervene prior to irreversible neuronal destruction in order to delay disability progression and improve quality of life. Maintaining a lower level of disability for a longer period of time postpones and ultimately attempts to prevent reaching a level of immobility and irreversible disability. However, due to the complex nature of disease and its unique, individual patient course, no patient can be treated alike and no patient responds to therapy similarly. Therefore, MS research is continuous in its evolution of therapeutic development, focusing on neuroprotective effects and agents with distinctive mechanisms of action allowing for unique safety and efficacy profiles. Investigations include novel oral agents and monoclonal antibodies. Many of the approved agents also are continually being investigated in order to evaluate comparative data, the most appropriate means of implementing subsequent therapy upon failure, responsiveness to therapeutic agent when switched, and long-term safety and efficacy. This multimedia webcast educational activity will cover the current state of MS science, current therapies in MS, emerging treatments in clinical trials for MS as well as differences between physicians in diagnosis and management of MS and their evolving practices., (Copyright © 2014. Published by Elsevier Inc.)

Background: Opsoclonus-myoclonus syndrome and breast carcinoma were initially described as neurologic and oncologic accompaniments of antineuronal nuclear autoantibody type 2 (ANNA-2, also known as anti-Ri). However, the neurologic spectrum of ANNA-2 autoimmunity is broader, includes a syndrome of jaw dystonia and laryngospasm, and can be accompanied by lung carcinoma., Objective: To describe clinically (with a video) ANNA-2-associated jaw dystonia and laryngospasm, its pathologic correlates, and therapeutic outcomes., Design: Retrospective case series with prospective clinical follow-up., Setting: Mayo Clinic's Neuroimmunology Laboratory, Rochester, Minnesota., Patients: Consecutive patients with ANNA-2 seropositivity identified since January 1, 1990., Main Outcome Methods: Clinical (in 9 patients) and neuropathologic (in 2 patients) findings were reviewed., Results: Of 48 patients with ANNA-2 seropositivity, 9 (19%) had multifocal neurologic manifestations that included jaw dystonia and laryngospasm. Among 6 patients with jaw dystonia, 5 had severely impaired nutrition, causing profound weight loss. Five patients had documented laryngospasm, which contributed to 1 patient's death. Neuropathologic examination revealed diffuse infiltration by CD8(+) T lymphocytes, with axonal loss and gliosis in brainstem and descending spinal cord tracts. Some patients improved symptomatically after immunosuppressant or cytotoxic therapies; 1 patient improved after treatment with botulinum toxin. One patient who underwent tracheostomy because of recurrent laryngospasm was alive and well longer than 3 years after symptom onset., Conclusions: Jaw dystonia and laryngospasm are common accompaniments of ANNA-2 autoimmunity and are associated with significant morbidity. We propose that selective damage to antigen-containing inhibitory fibers innervating bulbar motor nuclei by CD8(+) T lymphocytes (histopathologically observed infiltrating brainstem reticular formation) is the proximal cause of this syndrome. Early and aggressive therapy offers the prospect of neurologic improvement or stabilization.

Objectives: To quantify the coexistence of inflammatory bowel disease (IBD) and multiple sclerosis (MS) and to characterize the diseases when they coexist., Patients and Methods: In this retrospective study of medical records spanning 1950 through 1995, the diagnoses of Crohn disease (CD), ulcerative colitis (UC), and MS were based on review of inpatient and outpatient records by a gastroenterologist and a neurologist., Results: We identified 4 residents of Olmsted County, Minnesota, with IBD (3 UC, 1 CD) who had concurrent, clinically definite MS; all had mild neurologic disease with little disability. These comprised 1% of the IBD and 1.8% of the MS cohort. The CD patient had undergone terminal ileal resection; of the UC patients, 2 had pancolitis, and 1 had proctosigmoiditis. The observed prevalence of MS at onset of IBD was 3.7 times the expected (95% confidence interval, 0.8-10.8). We also reviewed the records of 32 referral patients with both diagnoses. Disability from MS was moderate at median follow-up of 8.5 years. By 15 years, ambulation was impaired in most patients. Neurologic disability was similar between patients with CD and UC., Conclusions: Concurrence of the 2 diseases was greater than expected. Although MS and IBD may share common predisposing factors, not enough information is available to speculate about possible mechanisms.

Objective: To report that the syndrome of orthostatic headaches caused by CSF leak can be seen with persistently normal CSF pressures., Background: CSF leak or shunt overdrainage is known to cause orthostatic headaches and diffuse pachymeningeal gadolinium enhancement (DPGE), typically associated with unmeasurable or very low CSF pressures., Methods: Of 40 consecutive patients with orthostatic headaches and DPGE, all had low or unmeasurable CSF pressures, except seven patients who had consistently normal CSF pressures and are thus reported. All had undergone multiple CSF examinations., Results: Two patients had overdraining shunts, and five had documented CSF leaks. One refused treatment, but the other six patients responded to surgical treatment or epidural blood patch with complete resolution of symptoms and related MRI abnormalities., Conclusions: Some patients with symptomatic CSF leaks may have CSF opening pressures that are consistently within normal limits. In the presence of convincing clinical features and imaging abnormalities, a normal CSF pressure should not discourage the clinician from searching for a source of CSF leak.

Demyelination alone has been considered sufficient for development of neurological deficits following central nervous system (CNS) disease. However, extensive demyelination is not always associated with clinical deficits in patients with multiple sclerosis (MS), the most common primary demyelinating disease in humans. We used the Theiler's murine encephalomyelitis virus model of demyelination to investigate the role of major histocompatibility complex (MHC) class I and class II gene products in the development of functional and neurophysiological deficits following demyelination. We measured spontaneous clinical activity by two independent assays and recorded hind-limb motor-evoked potentials in infected class I-deficient and class II-deficient mice of an identical genetic background as well as in highly susceptible SJL/J mice. The results show that despite a similar distribution and extent of demyelinated lesions in all mice, only class I-deficient mice were functionally normal. We propose that the mechanism by which demyelinated class I-deficient mice maintain neurologic function results from increased sodium channel densities and the relative preservation of axons. These findings are the first to implicate a role for MHC class I in the development of neurological deficits following demyelination.

We studied patches of CNS myelin in human retina in vivo to determine the pattern of myelination and the local influence of axons. We analysed the position, area and thickness of the nerve-fibre layer in 60 patches of retinal myelin in 47 eyes (in 37 adults and two adolescents). Five patches in four eyes were studied serially over 6-11 years. Nerve-fibre layer thickness was obtained from an atlas of primate retina, and volumes of myelinated tissue were then estimated for each patch. Retinal myelination occurred in three patterns: thick patches contiguous with the optic disc (type I); thin, striated patches detached from the disc (type II); or massive myelination of the posterior pole associated with severe amblyopia (type III). The papillomacular bundle did not myelinate in types I and II and was relatively spared in type III patches, suggesting that migratory oligodendrocyte progenitors are not supported by these axons. The local nerve-fibre layer determined patch size, and quantal myelination was evident with modal peaks of patch volume at 0.16 and 0.64 mm3. Myelination advanced at patch edges when observed over time, consistent with the hypothesis that new oligodendrocytes are produced in adulthood. We propose a theoretical model where patches of retinal myelination are the clonal progeny of a few oligodendrocyte progenitors exhibiting two different behaviours. First, a highly migratory, nonmyelinating progenitor uses larger, phylogenetically older axons as the substrate for movement. Secondly, a more mature progenitor generates myelinating oligodendrocytes well into adult life, but traverses only short distances. Using this data, we can estimate the number of oligodendrocytes in these clones and population doubling-time. This study supports a role for axon-derived signals in the regulation of human oligodendrocyte progenitor behaviour and myelination in vivo.

Infection of susceptible strains of mice with Daniel's (DA) strains of Theiler's murine encephalomyelitis virus (DAV) results in virus persistence in the central nervous system (CNS) white matter and chronic demyelination similar to that observed in multiple sclerosis. We investigated whether persistence is due to the immune system more efficiently clearing DAV from gray than from white matter of the CNS. Severe combined immunodeficient (SCID) and immunocompetent C.B-17 mice were infected with DAV to determine the kinetics, temporal distribution, and tropism of the virus in CNS. In early disease (6 h to 7 days postinfection), DAV replicated with similar kinetics in the brains and spinal cords of SCID and immunocompetent mice and in gray and white matter. DAV RNA was localized within 48 h in CNS cells of all phenotypes, including neurons, oligodendrocytes, astrocytes, and macrophages/microglia. In late disease (13 to 17 days postinfection), SCID mice became moribund and permitted higher DAV replication in both gray and white matter. In contrast, immunocompetent mice cleared virus from the gray matter but showed replication in the white matter of their brains and spinal cords. Reconstitution of SCID mice with nonimmune splenocytes or anti-DAV antibodies after establishment of infection demonstrated that both cellular and humoral immune responses decreased virus from the gray matter; however, the cellular responses were more effective. SCID mice reconstituted with splenocytes depleted of CD4+ or CD8+ T lymphocytes cleared virus from the gray matter but allowed replication in the white matter. These studies demonstrate that both neurons and glia are infected early following DAV infection but that virus persistence in the white matter is due to preferential clearance of virus from the gray matter by the immune system.

Chronic inflammatory demyelination of the central nervous system is usually incompletely repaired. However, we previously reported that in vivo treatment with monoclonal antibody SCH 94.03 (produced using spinal cord homogenate as an immunogen) increased myelin repair 4-fold in the Theiler's virus mouse model of chronic progressive multiple sclerosis (Miller et al., 1994; J. Neurosci. 14: 6230-6238). A major issue regarding site and mechanism of action of this antibody is whether SCH 94.03 enters demyelinated CNS lesions and reacts with oligodendrocytes and myelin. To address this question, we radiolabeled SCH 94.03 and studied its distribution into tissues, pharmacokinetics, and binding to cells within demyelinating spinal cord lesions in vivo. SCH 94.03 distributed widely into extracellular water following intraperitoneal injection and was eliminated with a terminal half-life of 3-4.5 days. Only a portion of the total dose (0.4%) entered brain and spinal cord. SCH 94.03 accumulated 1.5-2.0-fold in brain between 1 and 7 days after injection, but its pharmacokinetics were otherwise similar to those of an isotype control IgMkappa antibody. Oligodendrocytes, myelin sheaths and, less frequently, axons were labeled within demyelinating lesions as detected by light and electron microscopic autoradiography. These findings suggest that remyelination-promoting autoantibodies could act within the demyelinating lesion of the central nervous system by binding to the oligodendrocyte, myelin, or axon.

In this article, we assess the roles and the efficacy of immunopharmacologic agents in the treatment of multiple sclerosis (MS) and other demyelinating disease syndromes. The initial clinical manifestations of demyelinating disease, immunotherapeutic goals, efficacy of individual agents, and specific immunopharmacologic recommendations are discussed. MS and other idiopathic demyelinating disease syndromes can be effectively managed with immunotherapy. Exacerbations are treatable, and the frequency and severity of exacerbations can be reduced. Although some agents have a minor effect on progression of disability, current approaches have not proved to have a major influence on treatment of progressive MS. Immunotherapy for inflammatory demyelinating disease necessitates a high degree of clinical certainty about the diagnosis. Because all available therapeutic agents have limitations and significant toxic effects, careful consideration is necessary before use. Treatment should be individualized on the basis of the clinical course of the disease and the degree of patient disability.

Conditioned medium derived from a rat central nervous system neuronal cell line B104 (B104 CM) was shown previously to contain uncharacterized potent mitogen(s) for oligodendrocyte/type-2 astrocyte (O-2A) progenitor cells. In this study, we demonstrated that B104 cells produce and secrete platelet-derived growth factor (PDGF)-AA homodimer, but not PDGF-B chain. B104 cells did not express other known potent mitogens for O-2A progenitor cells, including fibroblast growth factor-2 and neurotrophin-3. Unexpectedly, B104 cells also expressed transcripts of transforming growth factor-beta1 (TGF-beta1) and -beta2 (TGF-beta2), which are known to regulate O-2A progenitor cell differentiation and proliferation, and secreted exclusively the 25-kDa active forms of TGF-beta1 and TGF-beta2. Neutralization of B104 CM with anti-PDGF-AA antibody decreased proliferation of O-2A progenitor cells, whereas neutralization with anti-TGF-beta antibodies had no effect. The combination of PDGF and TGF-beta on proliferation was not equivalent to the effect of B104 CM, indicating the possibility of an unidentified growth factor. B104 CM maintained a high expression of PDGF-alpha receptor in oligodendrocytes. The observation that both a stimulatory factor (PDGF-AA) and a regulatory factor (TGF-beta) for O-2A progenitor cell proliferation and differentiation are produced from a single neuronal cell line emphasizes the potential critical interaction between neurons and O-2A progenitor cells in myelination and possibly in remyelination.

Three weeks after an automobile accident, a 35-year-old man experienced left throat and neck pain, numbness of the left face and tongue, dysphagia, left arm pain and weakness, and left miosis. At age 27, he had suffered an aneurysmal subarachnoid hemorrhage. Angiography at that time had also demonstrated a fenestration of the left intracranial vertebral artery. At the time of the second presentation, angiography showed that one of the limbs of the fenestration had become occluded. Although the vast majority of intracranial arterial fenestrations are asymptomatic, occlusion of one of the limbs of a fenestration may be the cause of stroke.

Published methods for the isolation of cerebral microvessels primarily yield terminal resistance vessels and capillary networks, not the more proximal, subpial penetrating arterioles desired for certain studies. We report a novel method for isolating microvessels from the cerebral cortex of a single guinea-pig brain that yields large arteriolar complexes that are up to 50% intact. Instead of using homogenization to disperse brain parenchyma, we digested cortical fragments with trypsin, gently dispersed the parenchyma mechanically, and recovered microvascular complexes by sieving. Phase-contrast and electron microscopy showed primary (penetrating) arterioles, secondary arterioles, and capillary networks that frequently were in continuity as intact microvascular units. Culture of microvascular cells was carried out by enzymatic dissociation followed by an overnight incubation in a recovery medium at 4 degrees C before plating onto fibronectin-modified surfaces. Viability of isolated cells was demonstrated by good cell attachment and prompt proliferation that resulted in confluent cultures after 10 days. Confluent secondary cultures demonstrated characteristic features of smooth muscle cells, including a "hill-and-valley" growth pattern and expression of alpha-actin. Less than 1% of cells were endothelial or astrocytic cells by immunocytochemical and morphologic criteria. Ultrastructural studies demonstrated evidence of a synthetic phenotype of smooth muscle cell and absence of a significant number of fibroblasts. This method demonstrates that viable smooth muscle cells from the cerebral parenchymal microvasculature can be isolated in bulk quantities for study in vitro.

During development, myelin-forming oligodendrocytes and type 2 astrocytes are believed to arise from bipotential (O-2A) glial progenitors. Previously we found that conditioned medium (CM) from the B104 rat CNS neuronal cell line promotes growth of neonatal rat O-2A progenitors in serum-free culture conditions with subsequent increases in differentiated progeny. We now report that O-2A progenitors are present in mature rat brains and that this CM promotes the growth, motility, and bipolar morphology of these cells from 30- and 65-day-old rat brains, as shown by quantitative studies using double immunostaining and [3H]thymidine-autoradiography. In addition, the growth-promoting action of B104 CM is not neutralized by antibodies to platelet-derived growth factor, a proposed progenitor mitogen. Subsequent to the proliferation of these O-2A progenitors, increases in oligodendrocytes and type 2 astrocytes occur. These data suggest a novel therapeutic strategy for some demyelinating diseases, e.g., multiple sclerosis, where there is a deficit in oligodendrocytes. Although it has been proposed by others that mature brain O-2A progenitors are less proliferative and thereby incapable of adequately replenishing lost oligodendrocytes in these diseases, we present in vitro evidence for continued response of mature brain O-2A progenitors to this neuronal cell line-derived mitogen.

Responses of oligodendrocyte/type 2 astrocyte (O-2A) glial progenitors from neonatal rat brains to different growth factors were studied by a new, serum-free method. Enriched tertiary cultures of O-2A progenitors were produced after 6-7 days in vitro using the growth-promoting factors from the B104 CNS neuronal cell line, heparin, and mechanical separation. These cultures contained about 75-90% A2B5+ cells with less than 10% type 1 astrocytes, and the yield was 4.4 x 10(5) cells/brain. B104 conditioned medium (CM) factors increased both O-2A progenitor number and [3H]thymidine-labeling indices after three days. However, type 1 astrocyte CM was required for continued survival of enriched progenitors beyond 1 day in tertiary culture. Platelet-derived growth factor (PDGF) and glia maturation factor also showed growth-promoting action, but were less effective than B104 CM at tested doses. PDGF-neutralizing antibodies had no effect on progenitor survival or response to B104 CM factors. Thus, type 1 astrocyte-derived PDGF was not required for this response, B104 CM is not likely to contain PDGF, and B104 CM factors act directly on O-2A progenitors. Fibroblast growth factor, transforming growth factor beta, interleukin 2, epidermal growth factor, and triiodothyronine showed no growth-promoting activity; moreover, interleukin 2, epidermal growth factor, transforming growth factor beta, and 0.5% fetal bovine serum inhibited B104 CM action. Enriched progenitors exhibited bipotentiality by slowly differentiating into oligodendrocytes in serum-free medium, whereas culture in 10% fetal bovine serum increased type 2 astrocytes. Thus, this new method selects or produces progenitors which are similar to those from mature brains.

The growth-promoting activity of conditioned medium (CM) from the B104 CNS neuronal cell line was studied in glial cultures from neonatal rat brain. This CM at 33% (v/v; 8-12 micrograms protein/ml) produced large numbers of oligodendrocytes and multipolar glial progenitors after an 8 to 12-day treatment. At all times studied, cells of the oligodendrocyte/type 2 astrocyte (O-2A) lineage were increased due to CM-treatment, while type 1 astrocytes, microglia, and other cell types were not. Furthermore, we observed a large decrease in the percentage of oligodendrocytes in the O-2A lineage, suggesting a delay in differentiation of the progenitors. By 8 days in vitro (DIV), dose-dependent increases in numbers of galactocerebroside (GalC)-positive cells (oligodendrocytes) and A2B5-positive cells (immature oligodendrocytes and glial progenitors) occurred. In contrast, at 4 DIV only A2B5-positive cells were increased in a dose-dependent manner. The latter cells can differentiate primarily into oligodendrocytes or type 2 astrocytes depending on the culture conditions. Complement lysis studies confirmed that the A2B5-positive, but not the GalC-positive, population at 4 DIV was required for increases in oligodendrocytes to occur by 8 DIV. The [3H]thymidine labeling index of the A2B5-positive population also increased in response to CM in a dose-dependent manner, but the GalC-positive labeling index showed only small increases at 4 DIV and none at later times. Our results suggest that the delayed differentiation coupled with the selective stimulation of the bipotential glial progenitors produces the large increases in numbers of oligodendrocytes observed at 8-12 DIV.

Recent studies suggest that heterotypic cell-cell interactions influence gliogenesis in the developing rat central nervous system. CNS neuron-derived factors have been hypothesized to exist, and several have been identified and partially characterized which affect the number of oligodendrocytes in vitro. In order to study further the role of neurons in gliogenesis, we have used serum-free culture conditions, the B104 CNS neuronal cell line as a source of soluble factors, and dissociated neonatal rat brain cells as a source of glial cells. We have analyzed the response of the glial cells to serum-free B104 conditioned medium using morphological, immunocytochemical, autoradiographic, and enzymatic methods. Dose-dependent increases in the number of morphologically identified oligodendrocytes occur in response to this conditioned medium. Galactocerebroside (GalC) is a specific marker for oligodendrocytes, and the A2B5 antigen marks bipotential glial progenitor cells and their progeny: immature oligodendrocytes and type 2 astrocytes. In the presence of conditioned medium, the number of cells expressing GalC and/or A2B5 antigen increases over time when measured at 4, 8, and 12 days in vitro. A significantly weaker effect is seen if serum is also present. Since the vast majority of A2B5-positive cells in conditioned medium treated cultures lack glial fibrillary acidic protein (GFA), indicative of type 2 astrocytes, they represent glial progenitors and immature oligodendrocytes. Double immunostaining combined with autoradiography suggests that the latter cell types are the target cells for the oligodendrocyte-promoting activity. In addition, the conditioned medium markedly increases 2',3' cyclic nucleotide 3'-phosphodiesterase (an oligodendrocyte marker) and to a lesser extent enhances glutamine synthetase activity (an astrocyte marker). Type 1 astrocytes are also more morphologically differentiated in this condition, and their percentage is decreased simultaneously. Conditioned medium from other donor neural cells either has no activity or is much less effective than B104 conditioned medium. The active factors are soluble, sensitive to both trypsin and 100 degrees C treatment for 20 min, and appear to be 30-100 kilodaltons by stirred cell ultrafiltration. In summary, we have identified a potent source of growth-stimulating factors that produce increased numbers of glial progenitor cells and oligodendrocytes; the same conditioned medium also appears to inhibit type 1 astrocyte proliferation.