Faculty Bibliography

BACKGROUND:Paroxysmal symptoms (PS), defined as short-lasting, recurrent, and stereotyped neurological symptoms, are frequently reported by patients with Neuromyelitis Optica Spectrum Disorder (NMOSD). Their prevalence and spectrum of presentations in NMOSD have not been fully characterized. METHODS:Patients with NMOSD, who were members of a closed international Facebook Group, were recruited to complete an anonymous survey on REDCap. Participants were queried regarding demographic and NMOSD-related characteristics and PS history. RESULTS:The sample consisted of 219 responders with self-reported NMOSD, of whom 134 (63.8%) reported testing positive for AQP4 Antibody. 156 responders (71.9%) reported ≥1 type of PS during the disease course. The most common PS were intermittent tingling/numbness sensation (N=106, 67.9%), followed by involuntary muscle contractions/abnormal posture (N=95, 60.9%), hot/cold/burning sensations (N=87, 55.8%), and shock-like sensations along the spine or limbs (N=77, 49.4%). 150 responders (96% of those with PS) reported that PS were painful; in 82 responders (54.6%), the pain intensity reached ≥ 8/10 and in 40 responders (26.0%) - 10/10 level. PS were most commonly aggravated by fatigue (105 responders, 70.0%), physical activity (N=86, 57.3%), and neck flexion (N=39 responders, 26.0%). 82 patients (52.5% of those with PS) reported having been prescribed one or more medications for PS. Less than 50% reported them to be 'very helpful.' CONCLUSIONS:This survey highlights that PS occurs commonly in NMOSD patients. The symptomatology of PS is diverse. PS are often painful and not adequately treated. Our study represents a novel method to learn more about a rare disease from the patient's perspective. Given the fact that the study was conducted using an anonymous questionnaire and the diagnosis of NMOSD was self-reported by the survey participants, its' results should be regarded as a first step towards the understanding of PS in NMOSD, which should be further validated in a larger, controlled study.

INTRODUCTION/BACKGROUND:Studies investigating rates and risk factors for serious safety events (SSEs) during rituximab treatment of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and related disorders are limited. METHODS:Rituximab-treated patients with MS, NMOSD, or related disorders at the Rocky Mountain and New York University MS Care Centers were included. The follow-up period was defined as the time from the initial dose of rituximab up to 12 months of last dose of rituximab or ocrelizumab (in patients who switched). Clinician-reported and laboratory data were retrospectively collected from electronic medical records. RESULTS:One-thousand patients were included comprising 907 MS, 77 NMOSD, and 16 related disorders. Patients had a mean follow-up of 31.1 months and a mean cumulative rituximab dose of 4012 mg. Of the 169 patients who switched to ocrelizumab, the mean ocrelizumab dose was 1141 mg. Crude incidence rate per 1000 person-years (PY) for lymphopenia was 19.2, neutropenia 5.6, and hypogammaglobulinemia 17.8. Infections resulting in either hospitalization, IV antibiotics, or using antibiotics ≥14 days occurred at a rate of 38.6/1000 PY. Risk factors for infection were duration of therapy, male gender, increased disability, prior exposure to immunosuppression/chemotherapy, lymphopenia, and hypogammaglobulinemia. Particularly, wheelchair-bound patients had 8.56-fold increased odds of infections. Crude incidence rates of malignant cancer were 3.5, new autoimmune disease 2.3, thromboembolic event 3.1, and mortality of 5.4 per 1000 PY. INTERPRETATION/CONCLUSIONS:Rates of SSEs in patients with MS, NMOSD, and related disorders were low. Through properly assessing risk:benefit of B-cell depleting therapy in neuroinflammatory disorders and continual monitoring, clinicians may decrease the risk of serious infections.

OBJECTIVE:To report outcomes on patients with multiple sclerosis (MS) and related disorders with coronavirus disease 2019 (COVID-19) illness. METHODS:From March 16 to April 30, 2020, patients with MS or related disorders at NYU Langone MS Comprehensive Care Center were identified with laboratory-confirmed or suspected COVID-19. The diagnosis was established using a standardized questionnaire or by review of in-patient hospital records. RESULTS:We identified 76 patients (55 with relapsing MS, of which 9 had pediatric onset; 17 with progressive MS; and 4 with related disorders). Thirty-seven underwent PCR testing and were confirmed positive. Of the entire group, 64 (84%) patients were on disease-modifying therapy (DMT) including anti-CD20 therapies (n = 34, 44.7%) and sphingosine-1-phosphate receptor modulators (n = 10, 13.5%). The most common COVID-19 symptoms were fever and cough, but 21.1% of patients had neurologic symptom recrudescence preceding or coinciding with the infection. A total of 18 (23.7%) were hospitalized; 8 (10.5%) had COVID-19 critical illness or related death. Features more common among those hospitalized or with critical illness or death were older age, presence of comorbidities, progressive disease, and a nonambulatory status. No DMT class was associated with an increased risk of hospitalization or fatal outcome. CONCLUSIONS:Most patients with MS with COVID-19 do not require hospitalization despite being on DMTs. Factors associated with critical illness were similar to the general at-risk patient population. DMT use did not emerge as a predictor of poor COVID-19 outcome in this preliminary sample.

BACKGROUND:High-efficacy therapies in multiple sclerosis are traditionally used after unsuccessful treatment with first-line disease modifying therapies. We hypothesised that early commencement of high-efficacy therapy would be associated with reduced long-term disability. We therefore aimed to compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with those who started 4-6 years after disease onset. METHODS:In this retrospective international observational study, we obtained data from the MSBase registry and the Swedish MS registry, which prospectively collect patient data that are specific to multiple sclerosis as part of routine clinical care. We identified adult patients (aged ≥18 years) with relapsing-remitting multiple sclerosis, with at least 6 years of follow-up since disease onset, and who started the high-efficacy therapy (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0-2 years (early) or 4-6 years (late) after clinical disease onset. We matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. The primary outcome was disability, measured with the Expanded Disability Status Score (EDSS; an ordinal scale of 0-10, with higher scores indicating increased disability), at 6-10 years after disease onset, assessed with a linear mixed-effects model. FINDINGS/RESULTS:We identified 6149 patients in the MSBase registry who had been given high-efficacy therapy, with data collected between Jan 1, 1975, and April 13, 2017, and 2626 patients in the Swedish MS Registry, with data collected between Dec 10, 1997, and Sept 16, 2019. Of whom, 308 in the MSBase registry and 236 in the Swedish MS registry were eligible for inclusion. 277 (51%) of 544 patients commenced therapy early and 267 (49%) commenced therapy late. For the primary analysis, we matched 213 patients in the early treatment group with 253 in the late treatment group. At baseline, the mean EDSS score was 2·2 (SD 1·2) in the early group and 2·1 (SD 1·2) in the late group. Median follow-up time for matched patients was 7·8 years (IQR 6·7-8·9). In the sixth year after disease onset, the mean EDSS score was 2·2 (SD 1·6) in the early group compared with 2·9 (SD 1·8) in the late group (p<0·0001). This difference persisted throughout each year of follow-up until the tenth year after disease onset (mean EDSS score 2·3 [SD 1·8] vs 3·5 [SD 2·1]; p<0·0001), with a difference between groups of -0·98 (95% CI -1·51 to -0·45; p<0·0001, adjusted for proportion of time on any disease-modifying therapy) across the 6-10 year follow-up period. INTERPRETATION/CONCLUSIONS:High-efficacy therapy commenced within 2 years of disease onset is associated with less disability after 6-10 years than when commenced later in the disease course. This finding can inform decisions regarding optimal sequence and timing of multiple sclerosis therapy. FUNDING/BACKGROUND:National Health and Medical Research Council Australia and MS Society UK.

BACKGROUND:In neuromyelitis optica spectrum disorder (NMOSD), clinical disability in NMOSD patients is relapse-related and progressive phase is rare. This observation raises the question whether there is any radiographic disease activity. The aim of present study was to determine the longitudinal changes in cerebral lesion number, lesion size, lesion-to-venule relationship, and morphological patterns of lesions in NMOSD using multiparametric 7T MR imaging. We also aimed to assess brain volume changes in NMOSD. METHODS:A cohort of 22 patients with NMOSD underwent high-resolution 3D-susceptibility weighted imaging (SWI) and 2D-gradient-echo (GRE-T2*) weighted imaging on 7T MRI of brain at baseline and after ~2.8 years of follow-up. Morphologic imaging characteristics, and signal intensity patterns of lesions were recorded at both time points. Lesions were classified as "iron-laden" if they demonstrated hypointense signal on GRE-T2* images and/or SWI as well as hyperintense signal on quantitative susceptibility mapping (QSM). Lesions were considered "non-iron-laden" if they were hyperintense on GRE-T2*/SWI and isointense or hyperintense on QSM. Additionally, fractional brain parenchymal volume (fBPV) was computed at both time points. RESULTS:A total of 169 lesions were observed at baseline. At follow-up, 6 new lesions were found in 5 patients. In one patient, a single lesion could not be detected on the follow-up scan. No appreciable change in lesion size and vessel-lesion relationship was observed at follow up. All lesions demonstrated hyperintense signal intensity on GRE-T2* weighted images and isointense signal on QSM at both time points. Therefore, these lesions were considered as non-associated with iron pathology. Additionally, no significant change in brain volume was observed: fBPV 0.78 ± 0.06 at baseline vs. 0.77 ± 0.05 at follow up, p>0.05. CONCLUSION/CONCLUSIONS:Cerebral lesions in NMOSD patients remain 'inert' and do not show any substantial variations in morphological characteristics during a 2-3-year follow-up period.

OBJECTIVE:To determine if the concentration and saturation of natalizumab (NTZ) administration at extended interval dosing (EID; every 5-8 weeks) over 18 months is able to be maintained in the range considered adequate to sustain the clinical efficacy of NTZ. METHODS:-integrin receptor saturations were analyzed via cytometry, in blood samples obtained at trough timepoints. RESULTS:Trough serum concentration was above the "therapeutic" concentration of 2.0 μg/mL in 72% of EID patients. Trough saturation was above the "therapeutic" 50% threshold in 79% of EID-treated patients. Our model predicted that at least 9 NTZ infusions/year are required to maintain adequate trough saturation and concentration levels. Higher body mass index (BMI) was a predictor of suboptimal trough saturation on EID NTZ. CONCLUSIONS:Trough α4-integrin receptor saturation >50% correlated with high clinical efficacy of NTZ in previous studies. A continual treatment with EID maintains receptor saturation and concentration that are in the "therapeutic range" for most patients. This finding provides biological plausibility for the clinical efficacy of NTZ EID. Patients with higher BMI may require closer clinical and MRI follow-up.

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.

BACKGROUND:Spinal epidural lipomatosis (SEL) is a rare condition defined as pathological overgrowth of the normally present epidural fat within the spinal canal. SEL is associated with Cushing disease, obesity and chronic corticosteroid therapy. Diabetes mellitus type 1 (DM1) has not known to be a risk factor for SEL. The neurological symptoms of SEL are attributed mainly to mechanical compression on the spinal cord and the cauda equina. METHODS:A retrospective chart review of patients evaluated at NYU Multiple Sclerosis Care Center identified three diabetic patients with progressive myelopathy associated with SEL. We report the clinical course, diagnostic workup and outcomes in these three patients with SEL-associated myelopathy. RESULTS:Three patients (2 females and 1 male) had long-standing DM1 and developed progressive myelopathy in their early 40's. All were found to have thoracic SEL (extensive extradural T1, T2 hyperintense signal; biopsy confirmed in one case) with associated extensive abnormal cord signal in lower cervical/upper thoracic spinal cord. A comprehensive evaluation for metabolic, infectious, autoimmune and vascular causes of myelopathy that included serologies, cerebrospinal fluid analyses, and spinal angiography did not reveal an alternative cause for myelopathy. One of the patients underwent a surgical decompression of SEL with subsequent clinical and radiologic improvement. CONCLUSIONS:Our case series suggest that patients with DM1 and myelopathy of unknown cause should be evaluated for SEL. Timely diagnosis and appropriate intervention may forestall progression of neurological disability and even result in neurologic improvement. SEL should be considered on the short list of diagnoses that cause potentially reversible progressive myelopathy.