Faculty Bibliography

Background and aims: The Work Productivity and Activity Impairment (WPAI) questionnaire is a patientreported outcome assessing percentage of work time missed, impairment while working, overall work impairment and activity impairment over seven days prior. We report 2-year changes in WPAI, and associations with the 29-item Multiple Sclerosis Impact Scale (MSIS-29) and SymptoMScreen (self-reported symptom burden) among patients with relapsing-remitting MS (RRMS) in the Phase IIIb CASTING trial (NCT02861014). Method(s): Patients (n=680; Expanded Disability Status Scale score <=4.0) with a suboptimal response to one or two prior disease-modifying therapies (DMTs) received intravenous ocrelizumab 600mg every 24 weeks for 96 weeks. WPAI, MSIS-29 and SymptoMScreen were completed at baseline, Week 24, Year 1 and Year 2. Spearman correlations were assessed between change in WPAI subscores from baseline to Year 2, MSIS-29 subscores, and SymptoMScreen total score. Result(s): WPAI improved from baseline to Year 2, with significant reduction in overall work impairment (-3.08, p=0.020) and activity impairment (-5.69, p<0.001), and consistent trends in work time missed (-2.54, p=0.102) and impairment while working (-1.66, p=0.129). Improvement in SymptoMScreen score correlated with reduction in all WPAI measures: work time missed (rs=0.196), impairment while working (rs=0.387), overall work impairment (rs=0.362) and activity impairment (rs=0.421) over two years (all p<0.01). MSIS-29 improvements correlated with WPAI improvements over two years (Table 1). Table 1 Conclusion(s): Patients with a suboptimal response to one or two prior DMTs who switched to ocrelizumab showed improvement in work productivity (WPAI), which correlated with improvement in physical/psychological impacts of MS (MSIS-29) and decrease in symptom burden (SymptoMScreen) over two years

PURPOSE OF REVIEW:The newer, higher-efficacy disease-modifying therapies (DMTs) for multiple sclerosis (MS)-orals and monoclonals-have more profound immunomodulatory and immunosuppressive properties than the older, injectable therapies and require risk mitigation strategies to reduce the risk of serious infections. This review will provide a systematic framework for infectious risk mitigation strategies relevant to these therapies. RECENT FINDINGS:We classify risk mitigation strategies according to the following framework: (1) screening and patient selection, (2) vaccinations, (3) antibiotic prophylaxis, (4) laboratory and MRI monitoring, (5) adjusting dose and frequency of DMT, and (6) behavioral modifications to limit the risk of infection. We systematically apply this framework to the infections for which risk mitigations are available: hepatitis B, herpetic infections, progressive multifocal leukoencephalopathy, and tuberculosis. We also discuss up-to-date recommendations regarding COVID-19 vaccinations for patients on DMTs. We offer a practical, comprehensive, DMT-specific framework of derisking strategies designed to minimize the risk of infections associated with the newer MS therapies.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare, relapsing-remitting neuroinflammatory disorder of the central nervous system. Advances in the understanding of NMOSD pathogenesis and identification of the NMO-specific pathogenic anti-AQP4 autoantibody have led to the development of highly effective disease-modifying strategies. Five placebo-controlled, randomized trials for NMOSD have been successfully completed as of 2020. These trials support the efficacy of rituximab and tocilizumab and led to the FDA approval of eculizumab, satralizumab and inebilizumab for NMOSD. Our review provides an update on these evidence-based disease-modifying therapies and discussed the treatment of acute relapses in NMOSD.

Recurrent episodes of neurological dysfunction and white matter lesions in a young adult raise suspicion for multiple sclerosis (MS). However, occlusive retinopathy, hearing loss and absence of CSF oligoclonal bands are atypical for MS and should make the clinician consider an alternative diagnosis. We describe a man with hearing loss, visual signs and symptoms, and an accumulating burden of brain lesions, who was treated for a clinical diagnosis of MS for nearly two decades. Genetic testing revealed a unifying diagnosis.

Multiparametric flow cytometry (FC) of CSF allows one to easily estimate the percentage of lymphocyte subpopulations in CSF. We hypothesized that an increased ratio of B-lineage cells in CSF of MS patients, as assessed with FC, could be useful for diagnostics. We analyzed CSF of 137 patients (70 MS, 24 infectious/autoimmune neurologic disorders (INDs), and 43 non-infectious/autoimmune neurologic disorders (NINDs)), and showed that CSF plasmablasts of >0.1% had a sensitivity of 40% for MS and specificity of 92% when comparing MS and IND, while plasmablasts of >0.25% had sensitivity of 36%, and 100% specificity.

INTRODUCTION/BACKGROUND:While monophasic and relapsing forms of myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD) are increasingly diagnosed world-wide, consensus on management is yet to be developed. OBJECTIVE:To survey the current global clinical practice of clinicians treating MOGAD. METHOD/METHODS:Neurologists worldwide with expertise in treating MOGAD participated in an online survey (February-April 2019). RESULTS:Fifty-two responses were received (response rate 60.5%) from 86 invited experts, comprising adult (78.8%, 41/52) and paediatric (21.2%, 11/52) neurologists in 22 countries. All treat acute attacks with high dose corticosteroids. If recovery is incomplete, 71.2% (37/52) proceed next to plasma exchange (PE). 45.5% (5/11) of paediatric neurologists use IV immunoglobulin (IVIg) in preference to PE. Following an acute attack, 55.8% (29/52) of respondents typically continue corticosteroids for ≥ 3 months; though less commonly when treating children. After an index event, 60% (31/51) usually start steroid-sparing maintenance therapy (MT); after ≥ 2 attacks 92.3% (48/52) would start MT. Repeat MOG antibody status is used by 52.9% (27/51) to help decide on MT initiation. Commonly used first line MTs in adults are azathioprine (30.8%, 16/52), mycophenolate mofetil (25.0%, 13/52) and rituximab (17.3%, 9/52). In children, IVIg is the preferred first line MT (54.5%; 6/11). Treatment response is monitored by MRI (53.8%; 28/52), optical coherence tomography (23.1%; 12/52) and MOG antibody titres (36.5%; 19/52). Regardless of monitoring results, 25.0% (13/52) would not stop MT. CONCLUSION/CONCLUSIONS:Current treatment of MOGAD is highly variable, indicating a need for consensus-based treatment guidelines, while awaiting definitive clinical trials.

BACKGROUND:It is well documented that ambulatory disability in MS worsens over time, but there is a dearth of information on symptom evolution in other domains commonly affected by MS. METHODS:SymptoMScreen (SyMS) is a validated tool for assessing symptom severity in 12 domains commonly affected by MS. Patients who attended two specialized MS centers filled out SyMS at each visit. We included in the study patients with neurologist-diagnosed MS who completed two SyMS questionnaires separated at least 12 months. We used the first and final assessment and adjusted for time on study, baseline SyMS score, age, sex, race, MS type, disability strata, and site. Changes over time were also examined using Markov chain estimates of moving from one level of botheration to another for each domain over 1-year periods. RESULTS:A total of 1,014 MS patients met the inclusion criteria. Mean composite SyMS score was 1.4 (±1.16) at baseline and increased by 0.084 (±0.73) points during 21.0 (±5.5) months of followup (p<0.0001). The initial mean composite SyMS score correlated strongly with the final mean composite SyMS score (r=0.81). Individual domain SyMS scores at baseline were highest for fatigue: 2.2 (±1.7), and lowest for vision: 1.1 (±1.3) and dexterity: 1.1 (±1.4). Small but significant increases during followup were seen in dexterity, bladder, vision, and pain domains, while significant decreases were seen in anxiety and sensory domains. We observed a high degree of inter-individual variability in symptom severity with the more extreme scores tending to resolve over time. CONCLUSIONS:Symptom botheration increases modestly year-to-year, as would be expected in a slowly progressive disease that evolves over decades. Initial symptom burden strongly correlated with final symptom burden, but there was a high degree of individual variability in symptom severity.