Publications by authors named "Ilya Kister"

79 Publications

Another 'BEE'? - Brain-Eye-Ear (BEE) Disease Secondary to HbSC Disease Masquerading as Multiple Sclerosis.

J Stroke Cerebrovasc Dis 2021 Apr 20;30(4):105618. Epub 2021 Jan 20.

NYU MS Comprehensive Care Center, Department of Neurology, NYU Langone Health, New York, USA.

Recurrent episodes of neurological dysfunction and white matter lesions in a young adult raise suspicion for multiple sclerosis (MS). However, occlusive retinopathy, hearing loss and absence of CSF oligoclonal bands are atypical for MS and should make the clinician consider an alternative diagnosis. We describe a man with hearing loss, visual signs and symptoms, and an accumulating burden of brain lesions, who was treated for a clinical diagnosis of MS for nearly two decades. Genetic testing revealed a unifying diagnosis.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105618DOI Listing
April 2021

A longitudinal study of symptom botheration in Multiple Sclerosis.

Mult Scler Relat Disord 2020 Nov 17;46:102585. Epub 2020 Oct 17.

Department of Biostatistics, UAB School of Public Health, Birmingham, AL.

Background: It is well documented that ambulatory disability in MS worsens over time, but there is a dearth of information on symptom evolution in other domains commonly affected by MS.

Methods: SymptoMScreen (SyMS) is a validated tool for assessing symptom severity in 12 domains commonly affected by MS. Patients who attended two specialized MS centers filled out SyMS at each visit. We included in the study patients with neurologist-diagnosed MS who completed two SyMS questionnaires separated at least 12 months. We used the first and final assessment and adjusted for time on study, baseline SyMS score, age, sex, race, MS type, disability strata, and site. Changes over time were also examined using Markov chain estimates of moving from one level of botheration to another for each domain over 1-year periods.

Results: A total of 1,014 MS patients met the inclusion criteria. Mean composite SyMS score was 1.4 (±1.16) at baseline and increased by 0.084 (±0.73) points during 21.0 (±5.5) months of followup (p<0.0001). The initial mean composite SyMS score correlated strongly with the final mean composite SyMS score (r=0.81). Individual domain SyMS scores at baseline were highest for fatigue: 2.2 (±1.7), and lowest for vision: 1.1 (±1.3) and dexterity: 1.1 (±1.4). Small but significant increases during followup were seen in dexterity, bladder, vision, and pain domains, while significant decreases were seen in anxiety and sensory domains. We observed a high degree of inter-individual variability in symptom severity with the more extreme scores tending to resolve over time.

Conclusions: Symptom botheration increases modestly year-to-year, as would be expected in a slowly progressive disease that evolves over decades. Initial symptom burden strongly correlated with final symptom burden, but there was a high degree of individual variability in symptom severity.
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http://dx.doi.org/10.1016/j.msard.2020.102585DOI Listing
November 2020

Paroxysmal symptoms in neuromyelitis optica spectrum disorder: Results from an online patient survey.

Mult Scler Relat Disord 2020 Nov 13;46:102578. Epub 2020 Oct 13.

Division of Neuroimmunology & Neuroinfectious Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, USA.

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.
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http://dx.doi.org/10.1016/j.msard.2020.102578DOI Listing
November 2020

Advances in the Treatment of Neuromyelitis Optica Spectrum Disorder.

Neurol Clin 2021 02 7;39(1):35-49. Epub 2020 Nov 7.

Department of Neurology, Comprehensive MS Center, NYU Grossman School of Medicine, 240 East 38th Street, New York, NY 10016, USA.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare, relapsing-remitting neuroinflammatory disorder of the central nervous system. Advances in the understanding of NMOSD pathogenesis and identification of the NMO-specific pathogenic anti-AQP4 autoantibody have led to the development of highly effective disease-modifying strategies. Five placebo-controlled, randomized trials for NMOSD have been successfully completed as of 2020. These trials support the efficacy of rituximab and tocilizumab and led to the FDA approval of eculizumab, satralizumab and inebilizumab for NMOSD. Our review provides an update on these evidence-based disease-modifying therapies and discussed the treatment of acute relapses in NMOSD.
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http://dx.doi.org/10.1016/j.ncl.2020.09.003DOI Listing
February 2021

The Expanding Clinical Spectrum of Myelin Oligodendrocyte Glycoprotein (MOG) Antibody Associated Disease in Children and Adults.

Front Neurol 2020 9;11:960. Epub 2020 Sep 9.

New York University Langone Medical Center, Multiple Sclerosis Comprehensive Care Center, New York, NY, United States.

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http://dx.doi.org/10.3389/fneur.2020.00960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509044PMC
September 2020

Pearls & Oy-sters: Leukoencephalopathy in critically ill patients with COVID-19.

Neurology 2020 10 11;95(16):753-757. Epub 2020 Aug 11.

From the Departments of Neurology (H.H., H.E., M.C., E.V., I.K., L.K., H.W., S.G., J.F., T.Z., D.E.K., A. Lord, A. Lewis) and Neurosurgery (J.F., T.Z., D.E.K., A. Lord, A. Lewis), NYU Langone Medical Center, New York, NY.

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http://dx.doi.org/10.1212/WNL.0000000000010636DOI Listing
October 2020

Serious safety events in rituximab-treated multiple sclerosis and related disorders.

Ann Clin Transl Neurol 2020 09 6;7(9):1477-1487. Epub 2020 Aug 6.

NYU Grossman School of Medicine, Department of Neurology, New York University School of Medicine, New York City, New York.

Introduction: 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: 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.
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http://dx.doi.org/10.1002/acn3.51136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480911PMC
September 2020

COVID-19 outcomes in MS: Observational study of early experience from NYU Multiple Sclerosis Comprehensive Care Center.

Neurol Neuroimmunol Neuroinflamm 2020 09 9;7(5). Epub 2020 Jul 9.

From the NYU Langone Multiple Sclerosis Comprehensive Care Centers (E.P., I.K., L.C., C.S., V.S., R.E.C., J.H., J.M.G., M.G., N.A.-F., R.W., M.K., L.B.K., L.Z.R.), New York, NY; and Cohen's Children Medical Center Northwell Health (C.F.-C.), Lake Success, NY.

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.
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http://dx.doi.org/10.1212/NXI.0000000000000835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357412PMC
September 2020

Longitudinal ultra-high field MRI of brain lesions in neuromyelitis optica spectrum disorders.

Mult Scler Relat Disord 2020 Jul 25;42:102066. Epub 2020 Mar 25.

Department of Neurology, New York University School of Medicine, Prague, New York, NY 10016, United States.

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: 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.
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http://dx.doi.org/10.1016/j.msard.2020.102066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410392PMC
July 2020

Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study.

Lancet Neurol 2020 04 18;19(4):307-316. Epub 2020 Mar 18.

CORe, Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia. Electronic address:

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: 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: 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: National Health and Medical Research Council Australia and MS Society UK.
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http://dx.doi.org/10.1016/S1474-4422(20)30067-3DOI Listing
April 2020

Clinical Reasoning: A 63-year-old man with gastroenteritis progressing to stupor and quadriparesis.

Neurology 2020 03 25;94(10):e1107-e1111. Epub 2020 Feb 25.

From the Department of Neurology (A.I.W., I.K.), NYU Multiple Sclerosis Comprehensive Care Center, and Department of Radiology (E.R.), Bernard and Irene Schwartz Interventional Neuroradiology Section, New York University School of Medicine, New York.

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http://dx.doi.org/10.1212/WNL.0000000000009057DOI Listing
March 2020

Pharmacodynamics of natalizumab extended interval dosing in MS.

Neurol Neuroimmunol Neuroinflamm 2020 03 4;7(2). Epub 2020 Feb 4.

From NYU Multiple Sclerosis Comprehensive Care Center (L.Z.R., I.K.), New York; Division of Biostatistics (X.L., J.D.G.), New York University School of Medicine; and Rocky Mountain MS Research Group (T.H., A.C., R.R.M., J.F.), Salt Lake City, UT.

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: In a cross-sectional assessment of patients with multiple sclerosis (MS) who received standard interval dosing (every 4 weeks) or EID, serum NTZ concentrations were measured using ELISA, and α-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.
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http://dx.doi.org/10.1212/NXI.0000000000000672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057061PMC
March 2020

Progressive myelopathy associated with spinal epidural lipomatosis in three non-obese patients with type 1 diabetes mellitus.

J Neurol Sci 2020 Apr 16;411:116688. Epub 2020 Jan 16.

Department of Neurology, Multiple Sclerosis Comprehensive Care Center, NYU Langone Medical Center, New York, NY, United States of America.

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.
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http://dx.doi.org/10.1016/j.jns.2020.116688DOI Listing
April 2020

Multiple Sclerosis Severity Score: Concept and applications.

Mult Scler 2020 04 22;26(5):548-553. Epub 2020 Jan 22.

Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA.

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.
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http://dx.doi.org/10.1177/1352458519880125DOI Listing
April 2020

Effectiveness of subcutaneous tocilizumab in neuromyelitis optica spectrum disorders.

Mult Scler Relat Disord 2019 Dec 30;39:101920. Epub 2019 Dec 30.

New York University Langone Medical Center, Multiple Sclerosis Comprehensive Care Center, New York, USA.

Background: Tocilizumab (TCZ), a humanized monoclonal antibody against the interleukin-6 receptor, is approved for treatment of rheumatoid arthritis and several other immune-mediated disorders. Off-label use of the intravenous formulation of tocilizumab for Neuromyelitis Optica Spectrum Disorder (NMOSD) decreased relapse rates in two small case series. However, treatment protocol that requires frequent intravenous infusions may adversely affect adherence to therapy, especially in the more disabled patients, thereby reducing effectiveness. A subcutaneous formulation of tocilizumab was shown to be noninferior to the IV formulation for approved rheumatologic diseases. The effectiveness of subcutaneous TCZ for NMOSD is unknown.

Methods: We retrospectively reviewed clinical, radiological and serological data on all NMOSD patients who received subcutaneous TCZ in two tertiary referral centers between 2014-2019.

Results: Twelve NMOSD patients who received at least 6 months of subcutaneous TCZ were identified. Eleven were female; mean age was 46.9 ± 14.5 years and mean disease duration was 6.6 ± 4.6 years. Seven patients were seropositive for AQP-4 antibodies, two - for MOG-IgG antibodies, and three were doubly seronegative. During subcutaneous TCZ treatment, eight patients (66.6%) were relapse-free, one patient (8.3%) experienced 1 relapse, two patients (16.6%) - 2 relapses, and one patient (8.3%) - 3 relapses. The median relapse rate within 1 year after starting subcutaneous TCZ - 0 (interquartile range =1.75-0) - was significantly lower than in the year prior to treatment initiation (2, interquartile range = 4.0-0.25; p = 0.04). Overall, the annual relapse rate (ARR) decreased from a median of 2 (interquartile range = 5.75-1.29) prior to subcutaneous TCZ to 0 (interquartile range= = 1.0-0) on treatment (p = 0.0015). One TCZ-treated patient died following a severe myelitis attack.

Conclusions: Effectiveness of subcutaneous TCZ in NMOSD appears to be similar to that reported for the IV formulation and has an advantage of at-home administration. Prospective, comparative studies of subcutaneous TCZ for NMOSD are warranted.
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http://dx.doi.org/10.1016/j.msard.2019.101920DOI Listing
December 2019

Clinical and therapeutic predictors of disease outcomes in AQP4-IgG+ neuromyelitis optica spectrum disorder.

Mult Scler Relat Disord 2020 Feb 25;38:101868. Epub 2019 Nov 25.

CORe, Department of Medicine, University of Melbourne, Melbourne, Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia. Electronic address:

Background: Aquaporin-4-IgG positive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD) is an uncommon central nervous system autoimmune disorder. Disease outcomes in AQP4-IgG+NMOSD are typically measured by relapse rate and disability. Using the MSBase, a multi-centre international registry, we aimed to examine the impact immunosuppressive therapies and patient characteristics as predictors of disease outcome measures in AQP4-IgG+NMOSD.

Method: This MSBase cohort study of AQP4-IgG+NMOSD patients examined modifiers of relapse in a multivariable proportional hazards model and expanded disability status score (EDSS) using a mixed effects model.

Results: 206 AQP4-IgG+ patients were included (median follow-up 3.7 years). Age (hazard ratio [HR] = 0.82 per decade, p = 0.001), brainstem onset (HR = 0.45, p = 0.009), azathioprine (HR = 0.46, p<0.001) and mycophenolate mofetil (HR = 0.09, p = 0.012) were associated with a reduced risk of relapse. A greater EDSS was associated with age (β = 0.45 (per decade), p<0.001) and disease duration (β = 0.07 per year, p<0.001). A slower increase in EDSS was associated with azathioprine (β = -0.48, p<0.001), mycophenolate mofetil (β = -0.69, p = 0.04) and rituximab (β = -0.35, p = 0.024).

Interpretation: This study has demonstrated that azathioprine and mycophenolate mofetil reduce the risk of relapses and disability progression is modified by azathioprine, mycophenolate mofetil and rituximab. Age and disease duration were the only patient characteristics that modified the risk of relapse and disability in our cohort.
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http://dx.doi.org/10.1016/j.msard.2019.101868DOI Listing
February 2020

Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing.

Neurology 2019 10 12;93(15):e1452-e1462. Epub 2019 Sep 12.

From the Department of Neurology (L.Z.R., I.K.), NYU Langone Health, New York University, New York; Rocky Mountain MS Clinic (J.F., R.R.M.), Salt Lake City, UT; Biogen (I.C., E.R., K.S., R.K., Z.R., C.H., P-R.H., N.C.), Cambridge, MA; University of Alabama School of Public Health (G.C.), Birmingham; and Division of Biostatistics (J.D.G., X.L.), New York University School of Medicine, New York.

Objective: To use the large dataset from the Tysabri Outreach: Unified Commitment to Health (TOUCH) program to compare progressive multifocal leukoencephalopathy (PML) risk with natalizumab extended interval dosing (EID) vs standard interval dosing (SID) in patients with multiple sclerosis (MS).

Methods: This retrospective cohort study included anti-JC virus antibody-positive patients (n = 35,521) in the TOUCH database as of June 1, 2017. The effect of EID on PML risk was evaluated with 3 planned analyses using Kaplan-Meier methods stratified by prior immunosuppressant use. Risk of PML was analyzed by Cox regression adjusted for age, sex, prior immunosuppressants, time since natalizumab initiation, and cumulative number of infusions.

Results: This study included 35,521 patients (primary analysis: 1,988 EID, 13,132 SID; secondary analysis: 3,331 EID, 15,424 SID; tertiary analysis: 815 EID, 23,168 SID). Mean average dosing intervals were 35.0 to 43.0 and 29.8 to 30.5 days for the EID and SID cohorts, respectively. Hazard ratios (95% confidence intervals) of PML risk for EID vs SID were 0.06 (0.01-0.22, < 0.001) and 0.12 (0.05-0.29, < 0.001) for the primary and secondary analyses, respectively. Relative risk reductions were 94% and 88% in favor of EID for the primary and secondary analyses, respectively. The tertiary analysis included no cases of PML with EID.

Conclusion: Natalizumab EID is associated with clinically and statistically significantly lower PML risk than SID.

Classification Of Evidence: This study provides Class III evidence that for patients with MS, natalizumab EID is associated with a lower PML risk than SID.
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http://dx.doi.org/10.1212/WNL.0000000000008243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010325PMC
October 2019

Chronic Dengue Virus Panencephalitis in a Patient with Progressive Dementia with Extrapyramidal Features.

Ann Neurol 2019 11 11;86(5):695-703. Epub 2019 Sep 11.

Section of Infections of the Nervous System, Translational Neuroscience Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.

Objective: To determine the underlying etiology in a patient with progressive dementia with extrapyramidal signs and chronic inflammation referred to the National Institutes of Health Undiagnosed Diseases Program.

Methods: Extensive investigations included metabolic profile, autoantibody panel, infectious etiologies, genetic screening, whole exome sequencing, and the phage-display assay, VirScan, for viral immune responses. An etiological diagnosis was established postmortem.

Results: Using VirScan, enrichment of dengue viral antibodies was detected in cerebrospinal fluid as compared to serum. No virus was detected in serum or cerebrospinal fluid, but postmortem analysis confirmed dengue virus in the brain by immunohistochemistry, in situ hybridization, quantitative polymerase chain reaction, and sequencing. Dengue virus was also detectable by polymerase chain reaction and sequencing from brain biopsy tissue collected 33 months antemortem, confirming a chronic infection despite a robust immune response directed against the virus. Immunoprofiling and whole exome sequencing of the patient did not reveal any immunodeficiency, and sequencing of the virus demonstrated wild-type dengue virus in the central nervous system.

Interpretation: Dengue virus is the most common arbovirus worldwide and represents a significant public health concern. Infections with dengue virus are usually self-limiting, and chronic dengue infections have not been previously reported. Our findings suggest that dengue virus infections may persist in the central nervous system causing a panencephalitis and should be considered in patients with progressive dementia with extrapyramidal features in endemic regions or with relevant travel history. Furthermore, this work highlights the utility of comprehensive antibody profiling assays to aid in the diagnosis of encephalitis of unknown etiology. ANN NEUROL 2019;86:695-703.
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http://dx.doi.org/10.1002/ana.25588DOI Listing
November 2019

Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD.

Neurol Neuroimmunol Neuroinflamm 2019 09 28;6(5):e583. Epub 2019 Jun 28.

University of Utah School of Medicine (L.J.C., J.W.R., J.S.A., A.M.J., R.K., B.M., M.P., R.E., J.Y., S.M.), Salt Lake City; Division of Neuroimmunology and Multiple Sclerosis Center (M.H.H.), Department of Neurology and Neurological Sciences, Stanford University; Department of Neurology and Neurological Sciences (A.J.T.), Stanford School of Medicine, CA; Department of Neurology, Johns Hopkins University School of Medicine (M.L., M.A.M., J.C.), Baltimore, MD; Departments of Neurology and Ophthalmology (J.L.B., R.J., M.B.-G.), University of Colorado School of Medicine, Aurora; Department of Medicine & Neurology (A.L.T., R.L.C., L.E.L., J.J.S., K.M.), University of British Columbia, Vancouver, Canada; NYU Langone Health (I.K., Z.R., A.R.), New York; Department of Neurology, Cedars-Sinai Medical Center (N.L.S.), Los Angeles, CA; Mellen Center for MS Treatment and Research (S.M.P., J.A.C., D.I., J.L.S.), Neurological Institute, Cleveland Clinic, OH; Icahn School of Medicine at Mount Sinai (I.K.S.), New York; Multiple Sclerosis Center (P.R.), Swedish Neuroscience Institute, Seattle, WA; Department of Neurology (L.A., A.P., E.A.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Neurology (T.C., D.S.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Neurology (E.C.K., A.W.R.), Massachusetts General Hospital, Harvard Medical School, Boston; Department of Neurology (C.S.R., K.B.O., L.L., K.E.N.), Columbia University Medical Center; Weill Cornell Medicine (M.M.N., C.E., M.K.-H., M.M.), New York; Department of Neurology (L.T.), Division of Multiple Sclerosis, University of Miami Miller School of Medicine, FL; PPD (A.R., A.G.), Wilmington, NC; The Guthy-Jackson Charitable Foundation (M.K.B., R.R.R., D.W. Behne., D.W. Blackway, B.C., J.S., J.M.B.), Beverly Hills; Departments of Medicine and of Molecular Pharmacology (T.F.B.), Stanford University School of Medicine, CA; Kellogg Eye Center (T.J.S.), University of Michigan Medical School, Ann Arbor; Department of Medicine, University of California, Los Angeles (M.R.Y.); and Harbor-UCLA Medical Center/LABioMed (M.R.Y.), Torrance, CA.

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.
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http://dx.doi.org/10.1212/NXI.0000000000000583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624150PMC
September 2019

Multiple sclerosis and sarcoidosis: A case for coexistence.

Neurol Clin Pract 2019 Jun;9(3):218-227

New York University Langone Medical Center (CT, LZR, IK), Multiple Sclerosis Comprehensive Care Center, New York, NY; the Vanderbilt University Medical Center (SP), Neuroimmunology Division, Nashville, TN; the Brigham and Women's Hospital (MJB, DJK, TC), Massachusetts General Hospital, Harvard Medical School, Boston, MA; and the Division of Neuroinflammation and Glial Biology (JMG), UCSF Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA.

Background: Patients with biopsy-proven systemic sarcoidosis who develop a chronic CNS disorder are often presumed to have neurosarcoidosis (NS), however, the possibility of comorbid neurologic disease, such as MS, must be considered if presentation and course are not typical for NS.

Methods: Retrospective chart review across 4 academic MS centers was undertaken to identify patients with diagnosis of MS (2017 McDonald criteria) and biopsy-confirmed extraneural sarcoidosis. Data were abstracted from each chart using a case report form that systematically queried for demographic, clinical, and paraclinical characteristics relevant to NS and MS.

Results: Ten patients met our inclusion criteria (mean age 47.7 [±5.9] years; 80% female). Noncaseating granulomas consistent with sarcoidosis were found on biopsy in all cases (lung 7/10, mediastinum 2/10, liver 1/10, spleen 1/10, and skin 1/10). Diagnosis of MS was based on clinical history of MS-like relapses and MRI findings characteristic of demyelination and typical disease evolution during follow-up (average of 7 years). No patient developed features of NS that could be considered a "red flag" against the diagnosis of MS (such as meningeal enhancement, hydrocephalus, and pituitary involvement). All patients were treated with disease-modifying therapy for MS.

Conclusions: We propose a rational diagnostic approach to patients with sarcoidosis who may have comorbid MS. When the clinical picture is equivocal, the presence of multiple "MS-typical lesions" and the absence of any "NS-typical lesions" on MRI favor diagnosis of MS. Close follow-up is required to ascertain whether clinical and radiologic disease evolution and response to MS therapies conform to the proposed diagnosis of MS.
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http://dx.doi.org/10.1212/CPJ.0000000000000629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615652PMC
June 2019

Linear scleroderma "en coup de sabre" with extensive brain involvement-Clinicopathologic correlations and response to anti-Interleukin-6 therapy.

Orphanet J Rare Dis 2019 05 16;14(1):110. Epub 2019 May 16.

Community Care Rheumatology, 1 West Avenue, Saratoga Springs, NY, 12866, USA.

Linear scleroderma "en coup de sabre" (LSES) variant is a cephalic subtype of localized scleroderma that can be associated with extracutaneous stigmata, such as epilepsy, dementia syndromes, as well as focal central nervous system neurologic deficits. While the pathophysiology of cutaneous linear scleroderma includes endothelial cell injury and up regulation of pro-fibrogenic pathways, the basis of LSES-associated neurologic complications is largely unknown. We report a patient with a history of LSES who developed intractable epilepsy and cognitive decline. Magnetic resonance imaging (MRI) of the brain exhibited numerous persistently enhancing brain lesions. Due to progressive neurologic deterioration over a period of 7 years, despite interventional therapy, a brain biopsy was performed. Neuropathologic analysis exhibited acute and chronic cortical ischemia associated with a small vessel lymphocytic vasculitis. Direct immunofluorescent studies showed C5b-9 and IgG deposition on endothelium while indirect immunofluorescent studies demonstrated reactivity of the patient's serum with the microvasculature of the patient's own brain tissue and generic human umbilical vein endothelial cells indicative of anti-endothelial cell antibodies. Therapy focusing on damaged endothelium was implemented. The interleukin-6 (IL-6) receptor inhibitor tocilizumab was used and the patient improved dramatically, likely reflecting the drug's effect on the replenishment of endothelial progenitor cells.
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http://dx.doi.org/10.1186/s13023-019-1015-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524280PMC
May 2019

Spinal dural fistula and anterior spinal artery supply from the same segmental artery: Case report of volumetric T2 MRI diagnosis and rational endovascular treatment.

Interv Neuroradiol 2019 Oct 9;25(5):579-584. Epub 2019 May 9.

Neurointerventional Radiology Section, NYU School of Medicine, New York, USA.

Spinal dural fistulas (SDAVFs) occasionally arise from the same segmental artery as the radiculomedullary branch to the anterior spinal artery. In such cases, selective fistula embolization that does not endanger the anterior spinal artery is not possible, and surgical fistula disconnection is recommended. We present an exceptional case in which rational embolization strategy of SDAVF was feasible because of separate origins from a common segmental artery pedicle of the ventral radiculomedullary artery and the dorsal radicular artery branch supplying the fistula.
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http://dx.doi.org/10.1177/1591019918825017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777115PMC
October 2019

Protean Neurologic Manifestations of Two Rare Dermatologic Disorders: Sweet Disease and Localized Craniofacial Scleroderma.

Curr Neurol Neurosci Rep 2019 02 12;19(3):11. Epub 2019 Feb 12.

NYU Multiple Sclerosis Comprehensive Care Center, Department of Neurology, New York University School of Medicine, New York, NY, USA.

Purpose Of Review: To describe diverse neurologic and neuroradiologic presentations of two rare, immunologically mediated skin conditions: Sweet disease and localized scleroderma (morphea).

Recent Findings: Core syndromes of neuro-Sweet disease (NSD) are steroid responsiveness, recurrent meningitis, and encephalitis. Focal neurologic, neuro-vascular, and neuro-ophthalmologic syndromes have been reported recently in NSD. A variety of steroid-sparing treatments and biologics have been used for relapsing NSD. Localized craniofacial scleroderma is associated with seizures, headaches, and, less commonly, focal deficits and cognitive decline. Immunosuppressive therapy may be required in patients with disease progression; some refractory cases have responded to IL-6 inhibition. Our review provides an up-to-date reference for neurologists faced with a patient with a history or skin findings consistent with Sweet disease or localized scleroderma. We hope that it will stimulate collaborative studies aimed at unraveling the pathogenesis of these disorders, better characterization of their neurologic manifestations, and discovery of optimal therapeutic solutions.
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http://dx.doi.org/10.1007/s11910-019-0929-8DOI Listing
February 2019

Clinical characteristics of 153 Brazilian patients with neuromyelitis optica spectrum disorder (NMOSD).

Mult Scler Relat Disord 2019 Jan 28;27:392-396. Epub 2018 Nov 28.

Department of Neurology, New York University, New York, NY, USA.

Background: The 2015 criteria for diagnosing neuromyelitis optica spectrum disorder (NMOSD) have encouraged several groups across the world to report on their patients using these criteria. The disease typically manifests with severe relapses of optic neuritis, longitudinally extensive myelitis and/or brainstem syndromes, often leading to severe disability. Some patients are seropositive for antibodies against aquaporin-4 (AQP4), others are positive for anti-myelin oligodendrocyte glycoprotein (MOG), while a few are negative for both biomarkers. The disease is complex, and only now are specific therapeutic clinical trials being carried out. The present study adds to the literature through detailed clinical data from 153 medical records of Brazilian patients.

Methods: Retrospective assessment of medical records from nine specialized units in Brazil.

Results: NMOSD was more prevalent in females (4.1:1), who had significantly fewer relapses than males (p = 0.007) but presented similar levels of disability over time. African ancestry was associated with higher levels of disability throughout the disease course (p < 0.001), although the number of relapses was similar to that observed in white patients. Concomitant autoimmune diseases were relatively rare in this population (6.5%). Positivity for anti-AQP4 antibodies was identified in 62% of the patients tested, while 3% presented anti-MOG antibodies. Anti-AQP4 antibodies were not associated to worse disease course. The last medical record showed that six patients had died and 13 were wheelchair-bound. Seventy percent of the patients did not respond to first-line therapy (azathioprine and/or corticosteroids), and five patients continued to relapse even after four different courses of treatment.

Conclusion: The present study adds to the reports from other countries presenting original data on Brazilian patients diagnosed with NMOSD according to the 2015 criteria.
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http://dx.doi.org/10.1016/j.msard.2018.11.031DOI Listing
January 2019

Total Hip and Knee Arthroplasty in Patients with Multiple Sclerosis.

Int J MS Care 2018 Sep-Oct;20(5):244-250

Background: 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: 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: 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: 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.
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http://dx.doi.org/10.7224/1537-2073.2017-093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200122PMC
October 2018

Short-term disability progression in two multiethnic multiple sclerosis centers in the treatment era.

Ther Adv Neurol Disord 2018 11;11:1756286418793613. Epub 2018 Sep 11.

Department of Biostatistics, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.

Background: Short-term disease progression is well documented in clinical trials, but there are limited published data on disease course in real-life practice.

Methods: Patient-derived Multiple Sclerosis Severity Score (PMSSS), a disease severity rank score, was computed at each visit for consecutive MS patients attending two large, ethnically diverse MS centers in New York metropolitan area. Disability was assessed Patient-Determined Disease Steps (PDDS). Clinicians recorded disease subtype and relapse status at each visit, but did not rate disability. PMSSS change from the first to the last visit was calculated for the cohort as a whole and for subgroups of interest. Multivariable regression models were constructed for predicting final PMSSS based on readily available predictor variables collected at the initial visit and relapse history during follow up.

Results: A total of 1740 consecutive patients from New York University (1079) and Barnabas (661) MS Care Centers were included. During follow up (mean 2.4 ± 0.82years, range 1-4years), mean PDDS score increased from 1.9 ± 2.2 to 2.3 ± 2.2 (0.0001), while PMSSS remained roughly unchanged (initial PMSSS = 3.71 ± 2.73, last PMSSS = 3.81 ± 2.76, paired test, 0.28). The only major predictor of final PMSSS was the initial PMSSS. Demographic variables (age, sex, race) or relapse status did not predict final severity score.

Conclusions: Baseline disability in two MS clinics was much lower than in the reference population from which PMSSS was derived. We observed no discernable slowing of disability accumulation during the short-term follow up in our cohort compared with the reference cohort. Overwhelmingly the most important predictor of final disease severity rank score was the initial disease severity rank score.
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http://dx.doi.org/10.1177/1756286418793613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134488PMC
September 2018

Longitudinal study of multiple sclerosis lesions using ultra-high field (7T) multiparametric MR imaging.

PLoS One 2018 13;13(9):e0202918. Epub 2018 Sep 13.

Center for Advanced Imaging Innovation and Research (CAI2R) and Bernard and Irene Schwartz Center for Biomedical Imaging, Departments of Radiology, New York, New York, United States of America.

Pathophysiology of multiple sclerosis (MS) lesions is dynamic and changes over time. The purpose of this exploratory study was to determine the longitudinal changes in MS lesions over time on ultra-high field MR imaging. Nine patients with MS underwent high-resolution 3D-susceptibility weighted imaging (SWI) and 2D-gradient-echo-T2*-weighted imaging on 7T MRI at baseline and after ~2.4 years of follow-up. Morphologic imaging characteristics, signal intensity patterns and quantitative susceptibility mapping (QSM) values of lesions were recorded at both time points. Lesions were classified as "iron-laden" if they demonstrated hypointense signal on T2*-weighted images and/or SWI as well as hyperintense signal on QSM. Lesions were considered "non-iron-laden" if they were hyperintense on T2*/SWI and isointense or hyperintense on QSM. Total of 162 non-iron-laden and 29 iron-laden lesions were observed at baseline. No change in baseline lesion size during follow up was recorded in 92.7%; no change in lesion-vessel relationship in 86.5%; and no change in signal intensity pattern in 96.9% of lesions. Three lesions which were non-iron-laden at baseline, exhibited iron at follow-up. In two iron-laden lesions, redistribution of iron content was observed at follow-up. Two-thirds of these iron-laden lesions showed an increase in QSM at follow-up relative to baseline, and the remaining one-third exhibited decrease in QSM. Most of the newly formed lesions (11/13, 84.6%) at follow-up were iron-laden. 7T multiparametric MRI is a useful tool for tracking the evolution of MS lesions, especially with regard to changes in iron content.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202918PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136714PMC
February 2019

Predictors of relapse and disability progression in MS patients who discontinue disease-modifying therapy.

J Neurol Sci 2018 08 2;391:72-76. Epub 2018 Jun 2.

Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia; Department of Neurology, Alfred Hospital, Melbourne, VIC, Australia; Box Hill Hospital, Melbourne, VIC, Australia.

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: 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.
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http://dx.doi.org/10.1016/j.jns.2018.06.001DOI Listing
August 2018

Mortality in neuromyelitis optica is strongly associated with African ancestry.

Neurol Neuroimmunol Neuroinflamm 2018 Jul 7;5(4):e468. Epub 2018 Jun 7.

Department of Neurology (M.A.M., R.A.K., L.T., M.L.), Johns Hopkins University, Baltimore, MD; the Department of Neurology (Z.R., A.R., I.K.), New York University; and the University of Alabama (G.C.), Birmingham, AL.

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http://dx.doi.org/10.1212/NXI.0000000000000468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994702PMC
July 2018

Effectiveness of alternative dose fingolimod for multiple sclerosis.

Neurol Clin Pract 2018 Apr;8(2):102-107

Yale University (EEL), New Haven, CT; Medical Partnership 4 MS (MP4MS) (DK), Coconut Creek, FL; Vanderbilt University (SP, MJB), Nashville, TN; University of Washington (GvG), Seattle; Washington University (SC, AHC, BJP), St. Louis, MO; MS Center of Tidewater (MR), Norfolk, VA; Nehme & Therese Tohme MS Center (SJK, BY, MZ), Beirut, Lebanon; RWJ Barnabas Health (SR-G, IK), West Orange, NJ; C/Fuentes Claras 1 (AC-R), Avila, Spain; MS Center of Northeastern NY (KE), Latham; Elliot Lewis Center for MS Care (EL), Wellesley, MA; Spectrum Health Medical Group (DV), Grand Rapids, MI; University of Alabama (WM), Birmingham; University of Southern California (RB), Los Angeles; and NYU Langone Health (LG, TEB, IK), New York, NY.

Background: Fingolimod is a daily oral medication used to treat relapsing multiple sclerosis (MS). Clinicians often adopt less frequent dosing for patients with profound drug-induced lymphopenia or other adverse events. Data on the effectiveness of alternate dose fingolimod are limited.

Methods: We conducted a multicenter, retrospective, observational study at 14 sites and identified 170 patients with MS taking alternate doses of fingolimod for ≥1 month. Clinical and radiologic outcomes were collected and compared during daily and alternate fingolimod dosing.

Results: Profound lymphopenia (77%), liver function abnormalities (9%), and infections (7%) were the most common reasons for patients to switch to alternate fingolimod dosing. The median follow-up was 12 months on daily dose and 14 months on alternate dose. Most patients (64%) took fingolimod every other day during alternate dosing. Disease activity was similar on alternate dose compared to daily dose: annualized relapse rate was 0.1 on daily dose vs 0.2 on alternate dose ( = 0.25); proportion of patients with contrast-enhancing MRI lesions was 7.6% on daily vs 9.4% on alternate ( = 0.55); proportion of patients with cumulative MS activity (clinical and radiologic disease) was 13.5% on daily vs 18.2% on alternate ( = 0.337). Patients who developed contrast-enhancing lesions while on daily dose were at higher risk for breakthrough disease while on alternate dose fingolimod (odds ratio 11.4, < 0.001).

Conclusions: These data support the clinical strategy of alternate dosing of fingolimod in patients with good disease control but profound lymphopenia or other adverse events while on daily dose.

Classification Of Evidence: This study provides Class IV evidence that for patients with MS on daily dose fingolimod with adverse events, alternate dose fingolimod is associated with disease activity similar to daily dose fingolimod.
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http://dx.doi.org/10.1212/CPJ.0000000000000434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914753PMC
April 2018