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We characterized the frequency of diffusely abnormal white matter (DAWM) across a broad spectrum of multiple sclerosis (MS) participants. 35% of clinically isolated syndrome (CIS), 57% of relapsing remitting and 64% of secondary progressive MS participants demonstrated DAWM. CIS with DAWM had decreased cortical thickness, higher lesion load and a higher concentration of serum neurofilament light chain compared to CIS without DAWM. DAWM may be useful in identifying CIS patients with greater injury to their brains. Larger and longitudinal studies are warranted., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Enhanced prediction of progression in secondary progressive multiple sclerosis (SPMS) could improve clinical trial design. Machine learning (ML) algorithms are methods for training predictive models with minimal human intervention., Objective: To evaluate individual and ensemble model performance built using decision tree (DT)-based algorithms compared to logistic regression (LR) and support vector machines (SVMs) for predicting SPMS disability progression., Methods: SPMS participants ( n  = 485) enrolled in a 2-year placebo-controlled (negative) trial assessing the efficacy of MBP8298 were classified as progressors if a 6-month sustained increase in Expanded Disability Status Scale (EDSS) (≥1.0 or ≥0.5 for a baseline of ≤5.5 or ≥6.0 respectively) was observed. Variables included EDSS, Multiple Sclerosis Functional Composite component scores, T2 lesion volume, brain parenchymal fraction, disease duration, age, and sex. Area under the receiver operating characteristic curve (AUC) was the primary outcome for model evaluation., Results: Three DT-based models had greater AUCs (61.8%, 60.7%, and 60.2%) than independent and ensemble SVM (52.4% and 51.0%) and LR (49.5% and 51.1%)., Conclusion: SPMS disability progression was best predicted by non-parametric ML. If confirmed, ML could select those with highest progression risk for inclusion in SPMS trial cohorts and reduce the number of low-risk individuals exposed to experimental therapies., (© The Author(s) 2019.)

Objective: 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: 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: 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: 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.

Background: Paraneoplastic syndromes are remote effects of cancer caused by an autoimmune response triggered by tumor cells. Paraneoplastic Neuromyelitis Optica Spectrum Disorders (NMOSD) has been previously described, but the underlying mechanism for these rare cases is not well characterized. This paper presents a newly described case series of paraneoplastic NMOSD, including 2 new histological types of cancer and histological validation., Methods: The UBC NMO clinic database was surveyed and identified 6 patients with paraneoplastic NMOSD. In 2 cases, aquaporin-4 (AQP4) immunoreactivity was assessed on patients' tumor specimens., Results: The mean age at NMOSD diagnosis was 56 years old and 5/6 patients were older than 50 years old. 4/6 patients with paraneoplastic NMOSD have positive AQP4 antibodies. The median time between NMOSD and cancer was 12 months. Two new cancer types- serous ovarian carcinoma and adrenocortical carcinoma - were found in paraneoplastic NMOSD cases. A serous ovarian carcinoma and a thymoma, found in patients with AQP4 serological evidence, showed a positive reactivity to AQP4 immunostaining., Conclusions: Our findings will increase the recognition of NMOSD as a paraneoplastic syndrome. Cancer cells can express AQP4, increasing the likelihood of a direct mechanism between cancer cells and the development of NMOSD in paraneoplastic cases., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To determine whether vitamin D status predicts disease activity in patients with multiple sclerosis (MS) taking interferon-β (IFN), glatiramer acetate (GA), and fingolimod (FTY)., Methods: Participants (n = 324) with relapsing-remitting MS on IFN (96), GA (151), or FTY (77) were identified from the Comprehensive Longitudinal Investigation of MS at Brigham and Women's Hospital (CLIMB) Study at the Partners MS Center. FTY-treated participants were analyzed separately because of differences in selection. Serum vitamin 25(OH)D concentration was adjusted for season. We evaluated the relationship between 25(OH)D tertile and time to relapse or gadolinium-enhancing lesion using a Cox model adjusted for age, sex, and disease duration., Results: Higher 25(OH)D was associated with longer time to the combined endpoint in the overall IFN/GA cohort (p for trend = 0.042; hazard ratio [HR] = 0.77) and in the IFN subgroup (HRIFN = 0.58; p IFN = 0.012), but not in GA-treated participants (p = 0.50; HR = 0.89). For gadolinium-enhancing lesions alone, there was a significant association observed in GA and IFN subgroups, although the effect was more pronounced on IFN (HRGA = 0.57; p GA = 0.039 vs HRIFN = 0.41; p IFN = 0.022). No significant associations were found for relapses. For FTY, higher 25(OH)D was associated with longer survival for the combined endpoint (HRFTY = 0.48; p FTY = 0.016) and for relapses (HRFTY = 0.50; p FTY = 0.046), but not for gadolinium-enhancing lesions., Conclusions: Disease activity generally improved with higher 25(OH)D, but this study raises the question of effect modification by treatment class.

Background: The clinical trial design for primary progressive multiple sclerosis (PPMS) requires understanding of disability progression in modern patient cohorts., Objective: The objective of this paper is to characterize demographic and clinical characteristics of PPMS and assess rate of disability progression., Methods: We studied PPMS (n = 73) and relapsing-onset MS (ROMS) patients (n = 1541) enrolled in CLIMB, a longitudinal study of MS patients at the Brigham and Women's Hospital (Boston, MA). Disability progression for each group was compared using interval-censored survival analysis and time to six-month sustained progression., Results: The PP group had a 1.09:1 male:female ratio compared to 1:2.89 for the RO group and greater mean age of onset (PP: 44.4±9.6; RO: 32.7±9.9; p < 0.0001). Motor symptoms at onset and first symptoms localized to spinal cord were each strongly associated with PPMS (p < 0.001). Median time from onset to EDSS 6.0 was faster in PPMS (p < 0.001). PPMS patients progressed faster to EDSS 3 (p < 0.001) and from EDSS 3 to 6 (p < 0.001). Median time to sustained progression in the PP group was 4.85 years (95% CI 2.83-8.35), significantly faster than the RO group (p < 0.001)., Conclusions: Our modern PPMS cohort is demographically similar to previously studied cohorts. PPMS is associated with faster disability accrual than ROMS. Current real-world observations of time to sustained progression will inform design of new clinical trials for PPMS., (© The Author(s), 2014.)

Background: The lack of prospective trial data comparing certain multiple sclerosis (MS) therapies could be addressed with observational research., Objective: The objective of this paper is to investigate outcomes of natalizumab versus fingolimod treatment in an MS cohort using a novel method of patient selection., Methods: We reviewed entries from our clinic's database for all relapsing-remitting MS patients started on fingolimod and natalizumab where JCV serology was used to determine treatment. We analyzed each group for time to first relapse and in a second analysis, time to first relapse or gadolinium-enhancing lesion., Results: Sixty-nine patients on natalizumab and 36 on fingolimod met our inclusion criteria and had adequate follow-up for analysis. The baseline clinical characteristics at the time of treatment switch were similar. With a mean follow-up of 1.5 years for both treatment groups, there was a trend favoring natalizumab in time to first relapse, although this was not statistically significant (2.20 (0.87, 5.55) p = 0.095). There was a significant difference in the secondary outcome, time to relapse or gadolinium-enhancing lesion (2.31 (1.03, 5.17) p = 0.041), favoring natalizumab. Adjusted analyses favored natalizumab for both outcomes (p < 0.05)., Conclusion: This work employed an observational study design where treatment allocation by JCV serology allowed for treatment groups with well-balanced characteristics., (© The Author(s), 2014.)

The natural history and clinical import of Progressive Multifocal Leukoencephalopathy has changed enormously in the last thirty years. After a resurgence of PML during the HIV/AIDS epidemic, advances in the treatment of multiple sclerosis created another group of 'at risk' patients. With a focus on issues pertaining to the multiple sclerosis patient population, this review covers pathophysiology of the JC virus, causes of PML, mechanisms by which natalizumab increases the risk of PML, determinants of PML risk in natalizumab-treated patients, risks of natalizumab discontinuation, PML prevention and surveillance, PML imaging features, PML diagnosis and stumbling blocks to making the diagnosis, PML and PML-Immune Reconstitution Inflammatory Syndrome (IRIS) treatment., (Copyright © 2014 Elsevier B.V. All rights reserved.)

JCV serologic status is used to determine PML risk in natalizumab-treated patients. Given two cases of natalizumab-associated PML in JCV sero-negative patients and two publications that question the false negative rate of the JCV serologic test, clinicians may question whether our understanding of PML risk is adequate. Given that there is no gold standard for diagnosing previous JCV exposure, the test characteristics of the JCV serologic test are unknowable. We propose a model of PML risk in JCV sero-negative natalizumab patients. Using the numbers of JCV sero-positive and -negative patients from a study of PML risk by JCV serologic status (sero-positive: 13,950 and sero-negative: 11,414), we apply a range of sensitivities and specificities in order calculate the number of JCV-exposed but JCV sero-negative patients (false negatives). We then apply a range of rates of developing PML in sero-negative patients to calculate the expected number of PML cases. By using the binomial function, we calculate the probability of a given number of JCV sero-negative PML cases. With this model, one has a means to establish a threshold number of JCV sero-negative natalizumab-associated PML cases at which it is improbable that our understanding of PML risk in JCV sero-negative patients is adequate.