Faculty Bibliography

Objective/UNASSIGNED:To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment. Methods/UNASSIGNED:To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks. Results/UNASSIGNED:As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female. Conclusions/UNASSIGNED:Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD.

Objective: Recurrence of migraine pain and associated symptoms often causes dissatisfaction with acute treatment. Rimegepant is a small molecule calcitonin generelated peptide receptor antagonist with efficacy in migraine; its half-life may provide sustained benefits in acute treatment. The objective of this analysis was to assess the clinical benefits of rimegepant versus placebo through 24 and 48 h postdose.
Method(s): Three double-blind, randomized, placebo-controlled, multicenter trials (Studies 301, 302, 303) were conducted in adults with migraine. Subjects randomized to rimegepant 75 mg tablet (301 & 302), 75 mg ODT (303), or placebo treated a single moderate-severe migraine attack. Endpoints were pain freedom, pain relief, freedom from functional disability, freedom from the most bothersome symptom (MBS), and use of rescue medication.
Result(s): In total, 3507 subjects were evaluated (rimegepant n=1749, placebo n=1758). In pooled results, rimegepant was superior to placebo on sustained pain freedom and pain relief through 24 and 48 h postdose. In Study 303, rimegepant was significantly superior to placebo for sustained freedom from functional disability and the MBS 2-24 and 2-48 h postdose (p<=.0018 for each). Rimegepant was well-tolerated; no individual AEs were reported in >2% of subjects.
Conclusion(s): Rimegepant 75 mg significantly outperformed placebo on a range of endpoints through 48 h postdose. Few rimegepant-treated subjects used rescue medication; tolerability was similar to placebo

BACKGROUND AND PURPOSE/OBJECTIVE:Studies have shown an association between infarct patterns and recurrent stroke in patients with symptomatic intracranial stenosis (sICAS) but there are limited data on associations with perfusion imaging mismatch profile. We aim to determine the association between infarct pattern, optimal mismatch profile definition, and recurrent cerebrovascular events (RCVE) in patients with anterior circulation sICAS. METHODS:This is a retrospective study of consecutive patients with acutely sICAS admitted to a comprehensive stroke center over 18 month's period. Patients with sICAS underwent magnetic resonance perfusion (MRP) imaging within 24 hours from admission. Infarct patterns (internal BZ [IBZ], cortical BZ [CBZ], and core/perforator [C/P]) and RCVE within 90 days, were independently adjudicated by two reviewers. We compared mismatch profiles and recurrent event rates across infarct patterns. RESULTS:> 6 seconds (60% vs. 6.7%, P = .007) and RCVE (62.5% vs. 11.8%, P = .01). There were no associations between CBZ and C/P infarcts and target mismatch profiles and RCVE. CONCLUSION/CONCLUSIONS:IBZ infarcts may be a surrogate marker of distal perfusion status and RCVE risk. Larger multicenter, prospective, core-lab blindly adjudicated studies are needed to confirm our findings.

OBJECTIVE:We aimed to identify the current status and major unmet needs in the management of neurological complications in Sturge-Weber syndrome. METHODS:An expert panel consisting of neurologists convened during the Sturge-Weber Foundation Clinical Care Network conference in September 2018. Literature regarding current treatment strategies for neurological complications was reviewed. RESULTS:Although strong evidence-based standards are lacking, the implementation of consensus-based standards of care and outcome measures to be shared across all Sturge-Weber Foundation Clinical Care Network Centers are needed. Each patient with Sturge-Weber syndrome should have an individualized seizure action plan. There is a need to determine the appropriate abortive and preventive treatment of migraine headaches in Sturge-Weber syndrome. Likewise, a better understanding and better diagnostic modalities and treatments are needed for stroke-like episodes. As behavioral problems are common, the appropriate screening tools for mental illnesses and the timing for screening should be established. Brain magnetic resonance imaging (MRI) preferably done after age one year is the primary imaging modality of choice to establish the diagnosis, although advances in MRI techniques can improve presymptomatic diagnosis to identify patients eligible for preventive drug trials. CONCLUSION/CONCLUSIONS:We identified the unmet needs in the management of neurological complications in Sturge-Weber syndrome. We define a minimum standard brain MRI protocol to be used by Sturge-Weber syndrome centers. Future multicenter clinical trials on specific treatments of Sturge-Weber syndrome-associated neurological complications are needed. An improved national clinical database is critically needed to understand its natural course, and for retrospective and prospective measures of treatment efficacy.

Background: Walking impairments are one of the most impactful consequences of multiple sclerosis (MS). Recently, physical rehabilitation research has focused on developing synergistic protocols to enhance clinical benefit. Recent studies have shown that transcranial direct current stimulation (tDCS) and aerobic physical activity (PA) have converging activation pathways and when completed simultaneously, they may promote cortical neuroplasticity.
Objective(s): To harness cortical plasticity to improve gait for individuals with MS.
Aim(s): To investigate the effects of multiple sessions of PA with simultaneously administered tDCS on walking abilities.
Method(s): MS participants (EDSS: 1-6.5, Relapsing-Remitting or Secondary-Progressive subtype) with clinically significant gait deviations were recruited for a randomized controlled trial of 10 sessions of either active or sham tDCS paired with unloaded cycling for 20 minutes. Stimulation was administered over the primary motor cortex (2.5 mA-2.0 mA; anode over C3/cathode over FP2). Walking speed was assessed quantitatively by using a single inertial sensor placed on the lower back and perceived walking abilities were evaluated using the 12-Item MS Walking Scale (MSWS-12), a self-report questionnaire. Measurements were collected at baseline, the end of tDCS intervention, and 4-weeks post-intervention. Two-way repeated measures-ANOVA (Time, Treatment) was performed to investigate differences between active and sham conditions.
Result(s): Thirty-two participants were enrolled in the study, 22 underwent active treatment. No demographic differences were detected between active and sham groups (active:EDSS 4.3+/-1.2, age 55.5+/-10.3; sham:EDSS 4.5+/-1.5, age 49.7+/-13.9). Statistical analysis showed significant Treatment by Time interactions for gait speed and MSWS-12 score. Post-hoc analysis revealed that gait speed increased significantly after active treatment (Baseline vs. End Treatment, 0.98 vs. 1.16 m/s, p< 0.001; Baseline vs. Follow-up, 0.98 vs. 1.20 m/s, p< 0.001). Active group further reported significant improvement in self-report measure (Baseline vs. End Treatment, 58.04 vs. 49.73, p< 0.05). No significant difference was detected after sham stimulation.
Conclusion(s): Our results indicate that multiple sessions of tDCS administered simultaneously with PA induce cumulative and selfreport improvement in walking and benefits persisted until 4-week post-intervention

Introduction: Psychological resilience is a dynamic process of positive adaptation to adversity based on maintenance of positive adjustments under challenging life circumstances. Multiple sclerosis is a chronic and unpredictable illness, accompanied by physical and emotional challenges, yet the role of psychological resilience in MS is understudied. We analyzed the impact of psychological resilience on disability measures in Multiple Sclerosis (MS).
Objective(s): To investigate the effect of psychological resilience on standard measures of disability in MS.
Aim(s): To assess a role of psychological resilience in MS.
Method(s): One hundred and one patients with relapsing-remitting MS: 52 African-American (AA) patients with mean age 38.56 +/- 11.05 yrs and mean disease duration 7.79 +/- 5.38 yrs and 49 Caucasian (CA) patients with mean age 38.92 +/- 10.43 yrs and mean disease duration 6.65 +/- 5.31 yrs were enrolled as part of an ongoing study. Psychological resilience was assessed with the Connor-Davidson Resilience Scale 10 item, a validated measure of psychological resilience. Partial correlations were evaluated between resilience and standard measures of disability in MS (Symbol Digit Modalities Test -SDMT, Nine Hole Peg Test- NHPT, Timed 25 Foot Walk -T25FW), controlling for demographics (age, gender, disease duration), disease burden (brain atrophy and T2 lesion volume), and depression.
Result(s): Psychological resilience was not related to demographics or disease burden however psychological resilience was related to depression (r=-0.65, p< 0.001). Psychological resilience was associated with better performance on SDMT (r=0.39, p=0.001) and NHPT (r=-0.31, p=0.010) with a trend toward significance on T25FW (r=-0.22, p=0.074). After controlling for demographics and disease burden, no difference in resilience or depression was seen between AA and CA patients. Stratified by race, higher psychological resilience was associated with better performance on SDMT (r=0.38, p=0.021) and NHPT (r=-0.43, p=0.008) in AA patients and on SDMT (r=0.46, p=0.019) and T25FW in CA patients (r=-0.42, p=0.035).
Conclusion(s): Our results show a positive impact of psychological resilience on disability in MS, independent from disease severity and mood changes. Identification of patients with lower resilience suggests potential targets for therapeutic intervention. Longitudinal studies are needed to confirm a protective effect of psychological resilience against MS disability

Introduction: A model of individual response to therapy based on demographic and clinical information ('The MSBase model'; Brain. 2017, 140:2426) improves clinicians' ability to predict how individual patient will fare on specific disease-modifying therapy (DMT) during a 4-year follow up period. However, the range of predicted outcomes is often too wide to make it the arbiter of decision- making. MS severity score (MSSS), a decile rank of Extended Disability Severity Scale (EDSS) scores in patients from the reference dataset, was shown to be longitudinally stable in MS cohorts, but not for individual patients.
Objective(s): To test whether the addition of MSSS will improve the accuracy and robustness of the existing MSBase predictive model.
Method(s): All eligible patients from the global MSBase cohort who commenced a new DMT during the prospectively recorded follow-up were included. For each DMT, Andersen-Gill survival models were constructed for confirmed disability and relapse events. Principal component analysis was used to reduce dimensionality of the models, as previously described. MSSS was added to these models separate from the principal components.
Result(s): Among 13,780 MSBase enrollees (72% female; 86% with Relapsing MS; age 38.4 [10.6] years, disease duration 8.49 [7.73] years, EDSS 2.65 [1.80]), the most common DMTs were Interferon (IFN)b-1a sc (18%), IFNb-1b sc (12%) and Glatiramer acetate (11%). Higher MSSS was associated with an increased chance of 6-month confirmed recovery from disability (Hazard ratio (HR) 1.17-1.64 p< 0.003; no evidence of association only for alemtuzumab) and with relapse risk (HR 1.03-1.18 p< 0.04, and non-significant for 3 DMTs), but did not predict risk of confirmed disability progression for any DMT. The amount of variance that MSSS helped to explain in addition to the original MSBase model was modest, largest for disability regression (partial adjusted R2 0.01-0.05) and less substantial for risk of relapses (partial adjusted R2 - 0.001-0.026).
Conclusion(s): Mostly independent of DMT identity, higher MSSS was positively associated with a chance of confirmed disability regression, and relapse risk, but not disability worsening. Addition of MSSS to the MSBase model yielded improvements in its predictive accuracy, especially with regard to disability regression and relapse risk. MSSS adds to the prediction of recovery from disability and relapse activity but is not a suitable indicator of individual treatment response