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Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease primarily affecting the optic nerves and spinal cord, which is usually associated with anti-aquaporin-4 antibodies. Here, we present two individuals who were negative for anti-aquaporin-4 antibodies and were initially diagnosed with seronegative NMOSD. Each patient's clinical course and radiographic features raised suspicion for an alternative disease process. Both individuals were found to have pathogenic variants of MT-ND5 , encoding subunit 5 of mitochondrial complex I, ultimately leading to a revised diagnosis of a primary mitochondrial disorder. These cases illustrate the importance of biochemical and genetic testing in atypical cases of NMOSD.

Background: The MSBase prediction model of treatment response leverages multiple demographic and clinical characteristics to estimate hazards of relapses, confirmed disability accumulation (CDA), and confirmed disability improvement (CDI). The model did not include Multiple Sclerosis Severity Score (MSSS), a disease duration-adjusted ranked score of disability., Objective: To incorporate MSSS into the MSBase prediction model and compare model accuracy with and without MSSS., Methods: The associations between MSSS and relapse, CDA, and CDI were evaluated with marginal proportional hazards models adjusted for three principal components representative of patients' demographic and clinical characteristics. The model fit with and without MSSS was assessed with penalized r2 and Harrell C., Results: A total of 5866 MS patients were started on disease-modifying therapy during prospective follow-up (age 38.4 ± 10.6 years; 72% female; disease duration 8.5 ± 7.7 years). Including MSSS into the model improved the accuracy of individual prediction of relapses by 31%, of CDA by 23%, and of CDI by 24% (Harrell C) and increased the amount of variance explained for relapses by 49%, for CDI by 11%, and for CDA by 10% as compared with the original model., Conclusion: Addition of a single, readily available metric, MSSS, to the comprehensive MSBase prediction model considerably improved the individual accuracy of prognostics in MS.

Severity score represents disease duration-adjusted mean rank of disability in multiple sclerosis (MS) patients from the reference population. This measure allows one to compare the relative rates of disease progression among patients, patient subgroups, and across epochs, which opens up new question of what accounts for the observed differences in severity, and can be used to assess correlation between disease severity and clinical, radiologic, immunologic, genetic, and environmental variables of interest. Severity score can also prove useful for developing prognostic tools in MS. This article discusses the diverse applications of severity score concept in MS research, and (re)introduces Herbert's proposal of severity-based MS classification in the context of variability of MS severity.

Whether disease course in Hispanic Americans (HA) with multiple sclerosis (MS) is different from Caucasian Americans (CA) or African Americans (AA) is unknown. We compared MS severity in the three main ethnic populations in our tertiary MS clinics using disease duration-adjusted rank score of disability: Patient-Derived Multiple Sclerosis Severity Score (P-MSSS). The age- and gender-adjusted P-MSSS was significantly higher in HA (3.9 ± 2.6) and AA (4.5 ± 3.0) compared to CA (3.4 ± 2.6; p < 0.0001 for both). Adjusting for insurance did not change these results. These findings suggest that HA, as AA, have more rapid disability accumulation than CA.

Objective: This study evaluated the effect of relapse phenotype on disability accumulation in multiple sclerosis., Methods: Analysis of prospectively collected data was conducted in 19,504 patients with relapse-onset multiple sclerosis and minimum 1-year prospective follow-up from the MSBase cohort study. Multivariable linear regression models assessed associations between relapse incidence, phenotype and changes in disability (quantified with Expanded Disability Status Scale and its Functional System scores). Sensitivity analyses were conducted., Results: In 34,858 relapses recorded during 136,462 patient-years (median follow-up 5.9 years), higher relapse incidence was associated with greater disability accumulation (β = 0.16, p < 0.001). Relapses of all phenotypes promoted disability accumulation, with the most pronounced increase associated with pyramidal (β = 0.27 (0.25-0.29)), cerebellar (β = 0.35 (0.30-0.39)) and bowel/bladder (β = 0.42 (0.35-0.49)) phenotypes (mean (95% confidence interval)). Higher incidence of each relapse phenotype was associated with an increase in disability in the corresponding neurological domain, as well as anatomically related domains., Conclusion: Relapses are associated with accumulation of neurological disability. Relapses in pyramidal, cerebellar and bowel/bladder systems have the greatest association with disability change. Therefore, prevention of these relapses is an important objective of disease-modifying therapy. The differential impact of relapse phenotypes on disability outcomes could influence management of treatment failure in multiple sclerosis.

Objective: We aimed to analyse the effect of the introduction of fingolimod, the first oral disease-modifying therapy, on treatment utilisation and persistence in an international cohort of patients with multiple sclerosis (MS)., Methods: MSBASIS, a prospective, observational sub-study of the MSBase registry, collects demographic, clinical and paraclinical data on patients followed from MS onset (n=4718). We conducted a multivariable conditional risk set survival analysis to identify predictors of treatment discontinuation, and to assess if the introduction of fingolimod has altered treatment persistence., Results: A total of 2640 patients commenced immunomodulatory therapy. Following the introduction of fingolimod, patients were more likely to discontinue all other treatments (hazard ratio 1.64, p<0.001) while more patients switched to fingolimod than any other therapy (42.3% of switches). Patients switched to fingolimod due to convenience. Patients treated with fingolimod were less likely to discontinue treatment compared with other therapies (p<0.001). Female sex, country of residence, younger age, a high Expanded Disability Status Scale score and relapse activity were all independently associated with higher rates of treatment discontinuation., Conclusion: Following the availability of fingolimod, patients were more likely to discontinue injectable treatments. Those who switched to fingolimod were more likely to do so for convenience. Persistence was improved on fingolimod compared to other medications., (© The Author(s), 2015.)

AQP4 water channels are thought to be the target of autoimmune attack in neuromyelitis optica-spectrum disorders (NMOsd). AQP4 are highly expressed on ventricular ependyma. The objective of this study was to describe a novel pattern of linear, 'pencil-thin' enhancement of ventricular ependyma in NMOsd. We report two NMOsd patients with pencil-thin ependymal enhancement along the frontal and occipital horns of lateral ventricles. Differential diagnosis of ependymal enhancement should include NMOsd alongside with infectious and neoplastic etiologies. Pencil-thin ependymal enhancement may be a helpful radiological marker of NMOsd that can be used to differentiate this condition from multiple sclerosis.

Background: The prospective Nurses' Health Study II (NHS-II), which enrolled over 116,000 female nurses, provides a unique opportunity to test the hypothesis of whether migraine is associated with multiple sclerosis (MS) and to explore the temporal aspects of the interrelationship., Objectives: To calculate relative risk of MS among NHS-II participants with and without migraine and to estimate odds ratio (OR) of being diagnosed with migraine in women with and without pre-existing MS., Methods: Cox proportional hazards regression was used to estimate rate ratios and 95% confidence intervals (CIs) of being diagnosed with MS in women with and without pre-existing migraine adjusted for potential confounders. Multivariate adjusted ORs of being diagnosed with migraine in women with and without pre-existing MS were estimated using logistic regression., Results: The prevalence of migraine in women with MS at baseline (26%, p = 0.11) and those diagnosed with MS after enrolment (29%, p < 0.0001) was higher than in the non-MS cases (21%). The relative risk of developing MS in migraineurs was 1.39 times higher than in non-migraineurs (95% CI 1.10-1.77, p = 0.008). The absolute risk of developing MS in women migraineurs over a 15-year follow-up was 0.47% and among non-migraineurs 0.32%. The odds of being diagnosed with migraine was higher in women with pre-existing MS compared with those without MS, but did not reach statistical significance (OR = 1.57, 95% CI 0.97-2.52; p = 0.06)., Conclusions: Using a large, cohort of women-nurses, history of migraine was associated with an increased risk of MS. However, the difference in absolute risk of MS in migraineurs and non-migraineurs was small.

Background: Although the natural history of multiple sclerosis has been charted extensively, it is still not known whether the trajectory of disability accumulation has changed in the era of disease-modifying therapies (DMTs)., Objective: The objective of this study was to examine trends in Multiple Sclerosis Severity Score (MSSS) with regard to calendar year of enrollment into the New York State MS Consortium (NYSMSC)., Methods: Distributions of MSSS were calculated for each year of enrollment, from 1996 to 2007. Quantile regression was used in a multivariable analysis to model for conditional distribution of MSSS quantiles as functions of potential confounders., Results: The cohort consisted of 6238 patients. Mean age at enrollment was 38 years (SD=10) and mean disease duration was 10.1 years (SD=7.3); 57% were on DMTs. The quantile regression model of trends in MSSS between 1996 and 2007 controlled for age, sex, ethnicity, diagnostic delay, and disease duration and demonstrated a robust trend toward lower MSSS with increasing year of enrollment. The model-predicted median MSSS at enrollment in 1996 was 5.04 (95% CI, 4.86-5.21), and in 2007 was 3.78 (95%CI, 3.36-4.20; p<0.001). The downward trend in MSSS during the enrollment period was confirmed by analysis of Expanded Disability Status Scale (EDSS) distributions, adjusted for disease duration, in successive years of enrollment., Conclusions: The recent enrollees into the NYSMSC had lower MSSSs compared to the earlier enrollees. The apparent slowing in disability accumulation is likely due to a complex combination of factors: advent of DMTs and improvements in MS care, as well as selection, migration, and recall biases.