Faculty Bibliography

Background: SymptoMScreen is a new patient-reported outcome (PRO) tool for the rapid assessment of multiple sclerosis (MS) symptom severity in 12 domains (walking, hand function/dexterity, spasticity, bodily pain, sensory, bladder, fatigue, vision, dizziness, cognitive, depression and anxiety) on 7-point Likert scales (0 [not affected] to 6 [total limitation]). SymptoMScreen is used for the first time as an outcome measure in two ongoing, openlabel, single-arm Phase IIIb clinical trials of ocrelizumab (OCR) in treatment naive patients with early-stage relapsing-remitting MS (RRMS; ENSEMBLE [NCT03085810]) and patients with RRMS who had a prior suboptimal response to disease-modifying treatment (DMT; CASTING [NCT02861014]).
Objective(s): To report ENSEMBLE and CASTING baseline SymptoMScreen results.
Method(s): Patients in ENSEMBLE (Expanded Disability Status Scale [EDSS] score <=3.5 at screening) had a disease duration of <=3 years and >=1 clinically reported relapse or >=1 sign of MRI activity within 12 months of enrolment; patients in CASTING (EDSS <=4.0 at screening) had a disease duration <=10 years and discontinued a prior DMT of >=6 months' duration for reasons of suboptimal disease control. SymptoMScreen was performed in all study patients at baseline. OCR 600mg/24 weeks (first dose, 2x300mg, 14 days apart) was administered intravenously in both ENSEMBLE (192 weeks; maximum 8 doses) and CASTING (96 weeks; maximum 4 doses).
Result(s): ENSEMBLE patient (N=676) baseline characteristics were: female=65%, mean (SD) baseline EDSS score=1.7 (1.0), disease duration=1.1 (0.9) years; and in CASTING (N=681): female=64%, baseline EDSS score=2.1 (1.1), disease duration= 5.0 (2.7) years. In CASTING, 61% of patients had received one DMT prior to enrolment (most frequently dimethyl fumarate [25%]). Total mean (SD) baseline SymptoMScreen scores were 12.2 (10.9) in ENSEMBLE and 15.3 (12.6) in CASTING; individual domain scores ranged from 0.8 (1.1) to 1.8 (1.5) and 1.0 (1.2) to 2.1 (1.6), respectively, with numerically higher scores in ENSEMBLE (all domains) and fatigue having the highest score in both studies. Moderate to severe fatigue (domain score >=3) was reported in 31% (ENSEMBLE) to 41% (CASTING) of patients.
Conclusion(s): SymptoMScreen scores were generally low, though expectedly higher in CASTING than ENSEMBLE, consistent with greater disability in the patients who experienced suboptimal control; differences were consistent in all domains, but were most pronounced in fatigue and ambulation

Introduction: Optical coherence tomography (OCT) is a valuable tool for quantifying retinal neuro-axonal damage in Neuromyelitis Optica Spectrum Disorders (NMOSD). However, existing OCT studies in NMOSD reveal inconsistencies due to non-standardised methods and limited sample sizes.
Objective(s): To collect and uniformly analyze a large international OCT dataset with corresponding clinical data for correlates of retinal damage in NMOSD in a multicenter approach (Collaborative Retrospective Study on retinal OCT in Neuromyelitis Optica, CROCTINO).
Aim(s): To facilitate optimization of international OCT standards, reveal potential correlates of NMOSD disease and retinal pathology, and generate hypotheses for prospective studies.
Method(s): Centers were mainly recruited from the GJCF-ICC network including experts in NMOSD clinical care and research. OCT images were collected as source data to allow for standardised quality control and analysis. Demographic and clinical metadata were obtained with electronic record forms, adhering to institutional review board approval. We included subjects with a) NMOSD per the 2015 International Panel criteria; b) longitudinal extensive transverse myelitis; c) recurrent optic neuritis; and d) healthy controls. Only subjects with available OCT source data and a complete information on age, sex, disease subtype and attack history were included.
Result(s): Data from 501 cases from 20 international centers were collected (148 Asia, 249 Europe, 36 North America, 68 South America). Age was 44+/-15 years (range, 10-85 years), with 84% female. A total of 470 patients fulfilled the 2015 NMOSD criteria, with 345 (73.4%) seropositive for aquaporin4 antibodies (AQP4- IgG) using a validated method. Of the AQP4-IgG-negative patients, 47 (37.6%; 9.4% of all patients) were MOG antibody seropositive, and 78 (62.4%, 15.6% of all patients) were double negative or had unknown antibody status. OCT was performed in 344 patients using Spectralis SD-OCT, in 102 using Cirrus HD-OCT and 55 using Topcon 3D OCT instruments. Healthy control data were available from 90 subjects from 4 centers (all Spectralis)
Conclusion(s): CROCTINO has collected the largest OCT dataset from NMOSD patients to date. Results from this international collaborative study should facilitate improved OCT practices in NMOSD, highlight clinical correlates of disease and retinal status, and prioritize hypothesis-testing to advance clinical care and research goals in the future

BACKGROUND:Discontinuation of disease-modifying therapies (DMTs) for MS is common. MSBase, a large global observational registry, affords a unique opportunity to investigate predictors of 'post-DMT' relapses and confirmed disability progression (CDP) in a diverse group of patients exposed to different DMTs. MATERIALS/METHODS/METHODS:Main inclusion criteria: clinician-confirmed MS diagnosis (2010 McDonald criteria); age ≥ 18 at index DMT start; ≥12 months on index DMT prior to discontinuation; ≥24 months of follow-up post-discontinuation; did not restart DMT for ≥6 months. Predictors of time to first relapse and 3-month CDP were analyzed using Cox proportional hazards regression adjusted for age, gender, baseline EDSS, EDSS stability and relapse-free period for ≥1 year prior to discontinuation, calendar epoch, index DMT and reason for discontinuation. RESULTS:4842 patients (74.2% female) from 20 MSBase Centers met our inclusion criteria. 3556 (73%) discontinued one of IFNβ preparations, 849 (18%) - glatiramer acetate, 308 (6%) - natalizumab and 129 (3%) - fingolimod; other DMTs were excluded because too few records were available. Overall post-discontinuation annualized relapse rate (95% CI) was 0.224 (0.219, 0.229) and CDP rate was 8.23 (7.72, 8.76) per 100 person-years. Risk of post-DMT relapse was higher in younger patients, female patients, those with moderate disability and a relapse within 1 year of discontinuation. Hazard of CDP increased with increasing disability at baseline and disease progression within 3 years prior to stopping DMT. Of all the DMTs, only natalizumab was associated with increased risk of both post-DMT relapse and CDP. CONCLUSIONS:Knowledge of post-DMT relapse and disability progression rates and predictors of post-DMT disease activity allows for a more informed discussion of DMT discontinuation in those patients who are considering this option.

Background/UNASSIGNED:Hip and knee replacements for osteoarthritis are established procedures for improving joint pain and function, yet their safety in patients with multiple sclerosis (MS) is unknown. Patients with MS face unique surgical challenges due to underlying neurologic dysfunction. Current literature on arthroplasty in MS is limited to case reports focusing on adverse events. Methods/UNASSIGNED:Of 40 identified patients who underwent hip or knee replacement, 30 had sufficient data for inclusion. We reviewed their medical records and recorded reasons for surgery, age at surgery, MS characteristics, surgical complications, and ambulatory aid status before and after surgery. We supplemented medical record review with questionnaires regarding preoperative and postoperative pain and satisfaction with surgical outcomes. Results/UNASSIGNED:Median follow-up was 26 months. Complications of surgery were reported in ten patients (33%), mostly mild and self-limited, although four patients (13%) required repeated operation. Six patients (20%) reported improvements in ambulatory aid use compared with presurgery baseline, ten (33%) worsened, and 14 (47%) were unchanged. In 20 patients who completed the questionnaire, mean ± SD joint pain scores (on 0-10 scale) decreased from 8.6 ± 2.0 preoperatively to 2.9 ± 2.4 postoperatively (P < .001). Five patients (25%) were free of joint pain at last follow-up. Conclusions/UNASSIGNED:These results suggest that pain reduction is a realistic outcome of total knee or hip arthroplasty in people with MS and that improved functional gait outcomes are possible in some patients. Prospective, multicenter, collaborative studies are needed to optimize selection and improve outcomes in people with MS considering arthroplasty.

Background and aims: Natalizumab, approved for intravenous 300mg every 4 weeks dosing, is associated with a risk of PML. Previous analyses of US TOUCH registry data found that, in anti-JC virus antibody positive (JCV Ab+) patients, natalizumab EID was associated with significantly lower PML risk compared with standard interval dosing (SID; Table). Those analyses were limited to patients with known JCV Ab seropositive status and excluded patients with infusions at >12-week intervals (ie, dosing gaps). Sensitivity and post-hoc analyses were conducted to explore the robustness of these results. Methods: In the previous primary analysis, SID was based on average dosing intervals (ADIs) of >=3 to <5 weeks; EID was based on ADIs of >5 to <=12 weeks. In prespecified sensitivity analyses, alternative EID definitions and inclusion of PML cases occurring pre-2012, prior to JCV Ab testing, was evaluated. A post hoc analysis included patients with dosing gaps. EID and SID PML hazard ratios (HRs) were compared with covariate (age, sex, prior immunosuppressant use, initiation calendar year, and infusion number)-adjusted Cox regression models and Kaplan-Meier estimates. Results: Across all sensitivity and post-hoc analyses, HRs and 95% CIs were similar to those in the primary analysis. Conclusion: In the US, natalizumab EID is associated with a statistically significant, clinically meaningful lower PML risk in JCV Ab+ patients compared with SID; changes in EID definition and inclusion/exclusion criteria did not reveal differences from the primary analysis. As TOUCH does not collect effectiveness data, EID's benefit-risk could not be evaluated

We describe four patients who experienced optic neuritis (ON) and seizures and were found to have antibodies to myelin oligodendrocyte glycoprotein (MOG) in serum. The index case was a previously healthy 39-year-old man who developed steroid dependent ON and had a generalized seizure when steroids were tapered. He tested positive for antibodies to MOG. We have reviewed the charts of all 11 anti-MOG antibody positive patients in our practice and found that 4 patients, all of whom had experienced one or more episodes of ON, also had a generalized seizure during the course of their illness. In 2 patients - including the index case - seizure occurred during steroid taper and in 2 others at the time of an episode of acute disseminated encephalomyelitis (ADEM). Association of anti-MOG antibodies and relapsing demyelinating disorders of the central nervous system is increasingly recognized. Testing for anti-MOG antibodies should be considered in patients with optic neuritis and seizures, especially in those with who also have a history of ADEM.