Publications by authors named "Fred Lublin"

143 Publications

Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study: A Randomized Clinical Trial.

JAMA Neurol 2021 Mar 29. Epub 2021 Mar 29.

Neurology and Research Center for Clinical Neuroimmunology and Neuroscience Basel, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering University Hospital and University of Basel, Basel, Switzerland.

Importance: To our knowledge, the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial is the first phase 3 study comparing 2 oral disease-modifying therapies for relapsing multiple sclerosis (RMS).

Objective: To compare the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P1) modulator with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with RMS.

Design, Setting, And Participants: This multicenter, double-blind, active-comparator, superiority randomized clinical trial enrolled patients from April 27, 2015, to May 16, 2019, who were aged 18 to 55 years and had been diagnosed with multiple sclerosis per 2010 McDonald criteria, with a relapsing course from the onset, Expanded Disability Status Scale (EDSS) scores of 0 to 5.5, and recent clinical or magnetic resonance imaging disease activity.

Interventions: Patients were randomized (1:1) to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P1 modulators and a follow-up period of 30 days.

Main Outcomes And Measures: The primary end point was the annualized relapse rate. The secondary end points were the changes in symptom domain of Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) at week 108, the number of combined unique active lesions per year on magnetic resonance imaging, and time to 12-week and 24-week confirmed disability accumulation. Safety and tolerability were assessed. Exploratory end points included the percentage change in brain volume and no evidence of disease activity (NEDA-3 and NEDA-4) status.

Results: For 1133 patients (567 receiving ponesimod and 566 receiving teriflunomide; median [range], 37.0 [18-55] years; 735 women [64.9%]), the relative rate reduction for ponesimod vs teriflunomide in the annualized relapse rate was 30.5% (0.202 vs 0.290; P < .001); the mean difference in FSIQ-RMS, -3.57 (-0.01 vs 3.56; P < .001); the relative risk reduction in combined unique active lesions per year, 56% (1.405 vs 3.164; P < .001); and the reduction in time to 12-week and 24-week confirmed disability accumulation risk estimates, 17% (10.1% vs 12.4%; P = .29) and 16% (8.1% vs 9.9; P = .37), respectively. Brain volume loss at week 108 was lower by 0.34% (-0.91% vs -1.25%; P < .001); the odds ratio for NEDA-3 achievement was 1.70 (25.0% vs 16.4%; P < .001). Incidence of treatment-emergent adverse events (502 of 565 [88.8%] vs 499 of 566 [88.2%]) and serious treatment-emergent adverse events (49 [8.7%] vs 46 [8.1%]) was similar for both groups. Treatment discontinuations because of adverse events was more common in the ponesimod group (49 of 565 [8.7%] vs 34 of 566 [6.0%]).

Conclusions And Relevance: In this study, ponesimod was superior to teriflunomide on annualized relapse rate reduction, fatigue, magnetic resonance imaging activity, brain volume loss, and no evidence of disease activity status, but not confirmed disability accumulation. The safety profile was in line with the previous safety observations with ponesimod and the known profile of other S1P receptor modulators.

Trial Registration: ClinicalTrials.gov Identifier: NCT02425644.
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http://dx.doi.org/10.1001/jamaneurol.2021.0405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008435PMC
March 2021

Disability Outcomes in the N-MOmentum Trial of Inebilizumab in Neuromyelitis Optica Spectrum Disorder.

Neurol Neuroimmunol Neuroinflamm 2021 05 26;8(3). Epub 2021 Mar 26.

From the Service de Neurologie Sclérose en Plaques (R.M.), Pathologies de La Myéline et Neuro-inflammation, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, France; University of Colorado School of Medicine (J.L.B.), Anschutz Medical Campus, Aurora; Research Institute and Hospital of National Cancer Center (H.J.K.), Goyang, South Korea; Mayo Clinic (B.G.W., S.J.P.), Rochester, MN; Mayo Clinic (D.W.), Scottsdale, AZ; Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University and Multiple Sclerosis and Neuromyelitis Optica Center, Southern Tohoku Research Institute for Neuroscience, Koriyama, Japan; Experimental and Clinical Research Center (F.P.), Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Germany; University of Alabama at Birmingham (G.R.C.); UCSF Weill Institute for Neurosciences (A.J.G.), Department of Neurology and Department of Ophthalmology, University of California San Francisco; Medical Faculty (O.A., H.-P.H.), Heinrich Heine University, Düsseldorf, Germany; Icahn School of Medicine at Mount Sinai (F.D.L.), New York; Oxford PharmaGenesis Ltd (I.M.W.), UK; Viela Bio (J.D., D.S., D.C., W.R., M.S., J.N.R., E.K.), Gaithersburg, MD; and UCSF Weill Institute for Neurosciences (B.A.C.C.), University of California San Francisco.

Objective: To assess treatment effects on Expanded Disability Status Scale (EDSS) score worsening and modified Rankin Scale (mRS) scores in the N-MOmentum trial of inebilizumab, a humanized anti-CD19 monoclonal antibody, in participants with neuromyelitis optica spectrum disorder (NMOSD).

Methods: Adults (N = 230) with aquaporin-4 immunoglobulin G-seropositive NMOSD or -seronegative neuromyelitis optica and an EDSS score ≤8 were randomized (3:1) to receive inebilizumab 300 mg or placebo on days 1 and 15. The randomized controlled period (RCP) was 28 weeks or until adjudicated attack, with an option to enter the inebilizumab open-label period. Three-month EDSS-confirmed disability progression (CDP) was assessed using a Cox proportional hazard model. The effect of baseline subgroups on disability was assessed by interaction tests. mRS scores from the RCP were analyzed by the Wilcoxon-Mann-Whitney odds approach.

Results: Compared with placebo, inebilizumab reduced the risk of 3-month CDP (hazard ratio [HR]: 0.375; 95% CI: 0.148-0.952; = 0.0390). Baseline disability, prestudy attack frequency, and disease duration did not affect the treatment effect observed with inebilizumab (HRs: 0.213-0.503; interaction tests: all > 0.05, indicating no effect of baseline covariates on outcome). Mean EDSS scores improved with longer-term treatment. Inebilizumab-treated participants were more likely to have a favorable mRS outcome at the end of the RCP (OR: 1.663; 95% CI: 1.195-2.385; = 0.0023).

Conclusions: Disability outcomes were more favorable with inebilizumab vs placebo in participants with NMOSD.

Classification Of Evidence: This study provides Class II evidence that for patients with NMOSD, inebilizumab reduces the risk of worsening disability. N-MOmentum is registered at ClinicalTrials.gov: NCT02200770.
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http://dx.doi.org/10.1212/NXI.0000000000000978DOI Listing
May 2021

Aging and efficacy of disease-modifying therapies in multiple sclerosis: a meta-analysis of clinical trials.

Ther Adv Neurol Disord 2020 28;13:1756286420969016. Epub 2020 Oct 28.

Neurology Section, VA North Texas Health Care System, Medical Service, 4500 South Lancaster Rd., Dallas, TX 75216, USA.

Background: Disease-modifying therapies (DMTs) for multiple sclerosis (MS) are approved for the treatment of disease activity and are effective in reducing relapses and new magnetic resonance imaging (MRI) lesions. However, disease activity generally subsides with time, and age-dependent changes in DMT efficacy are not well-established. We aimed to investigate whether age impacts the efficacy of DMTs in treating disease activity in patients with relapsing-remitting MS (RRMS).

Methods: DMT efficacy related to age was assessed through a meta-analysis of clinical trials that evaluated the efficacy of DMTs in RRMS patients as measured by reductions in the annualized relapse rate (ARR), new T2 lesions, and gadolinium-enhanced lesions on MRI. Using the mean baseline patient age from each trial, a weighted linear regression was fitted to determine whether age was associated with treatment efficacy on a group level.

Results: Group-level data from a total of 28,082 patients from 26 trials of 14 different DMTs were included in the meta-analysis. There were no statistically significant associations between age and reductions in ARR, new T2 lesions, and gadolinium-enhanced lesions of the treatment group compared with placebo.

Conclusion: DMTs for RRMS show efficacy in treating disease activity independent of age as demonstrated by group-level data from DMT clinical trials. Nevertheless, clinical trials select for patients with baseline disease activity regardless of age, thereby not representing real-world patients with RRMS, where disease activity declines with age.
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http://dx.doi.org/10.1177/1756286420969016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838219PMC
October 2020

Pandemic forward: Lessons learned and expert perspectives on multiple sclerosis care in the COVID-19 era.

Mult Scler Relat Disord 2020 Dec 24;49:102715. Epub 2020 Dec 24.

Icahn School of Medicine at Mount Sinai, 5 East 98th Street; Box 1138 New York, NY, 10029 USA. Electronic address:

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http://dx.doi.org/10.1016/j.msard.2020.102715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832784PMC
December 2020

Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial.

Lancet Neurol 2020 12 23;19(12):988-997. Epub 2020 Oct 23.

Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort.

Methods: SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18-65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5-6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29).

Findings: From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15-27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81-2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (<1%) person died in the MD1003 group and there were no deaths in the placebo group. Despite use of mitigation strategies, MD1003 led to inaccurate laboratory results for tests using biotinylated antibodies.

Interpretation: This study showed that MD1003 did not significantly improve disability or walking speed in patients with progressive multiple sclerosis and thus, in addition to the potential of MD1003 for deleterious health consequences from interference of laboratory tests, MD1003 cannot be recommended for treatment of progressive multiple sclerosis.

Funding: MedDay Pharmaceuticals.
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http://dx.doi.org/10.1016/S1474-4422(20)30347-1DOI Listing
December 2020

Depression and cognitive function in early multiple sclerosis: Multitasking is more sensitive than traditional assessments.

Mult Scler 2020 Nov 16:1352458520958359. Epub 2020 Nov 16.

Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: Persons with multiple sclerosis (MS) and depression symptoms report real-world cognitive difficulties that may be missed by laboratory cognitive tests.

Objective: To examine the relationship of depressive symptoms to cognitive monotasking versus multitasking in early MS.

Method: Persons with early MS ( = 185; ⩽5 years diagnosed) reported mood, completed monotasking and multitasking cognitive tests, and received high-resolution 3.0 T magnetic resonance imaging (MRI). Partial correlations analyzed associations between mood and cognition, controlling for age, sex, estimated premorbid IQ, T2 lesion volume, and normalized gray matter volume.

Results: Depression symptoms were more related to worse cognitive multitasking (-0.353,  < 0.001) than monotasking ( = -0.189,  = 0.011). There was a significant albeit weaker link to cognitive efficiency composite score ( = -0.281,  < 0.001), but not composite memory ( = -0.036,  > 0.50). Findings were replicated with a second depression measure. Multitasking was worse in patients with at least mild depression than both patients with no/minimal depression and healthy controls. Multitasking was not related to mood in healthy controls.

Conclusions: Depression symptoms are linked to cognitive multitasking in early MS; standard monotasking cognitive assessments appear less sensitive to depression-related cognition. Further investigation should determine directionality and mechanisms of this relationship, with the goal of enhancing treatment for cognitive dysfunction and depression in MS.
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http://dx.doi.org/10.1177/1352458520958359DOI Listing
November 2020

Treatment Response Score to Glatiramer Acetate or Interferon Beta-1a.

Neurology 2021 01 6;96(2):e214-e227. Epub 2020 Oct 6.

From the Department of Health Sciences (DISSAL) (F.B., M.P.S.), University of Genoa, Italy; CORe (T.K., C.M.), Department of Medicine, University of Melbourne, Australia; Department of Neurology (F.L.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Biostatistics (G.C.), University of Alabama at Birmingham; Department of Neurology and Center for Clinical Neuroscience (D.H., E.K.H.), First Medical Faculty, Charles University, Prague, Czech Republic; Department of Basic Medical Sciences, Neuroscience and Sense Organs (M. Trojano), University of Bari, Italy; Department of Neuroscience (A.P., M.G., P.D.), Faculty of Medicine, Université de Montréal, Quebec, Canada; Department of Neuroscience, Imaging, and Clinical Sciences (M.O.), University G. d'Annunzio, Chieti; IRCCS Istituto delle Scienze Neurologiche di Bologna (A.L.); Dipartimento di Scienze Biomediche e Neuromotorie (A.L.), Università di Bologna, Italy; Hospital Universitario Virgen Macarena (G. Izquierdo. S.E.), Sevilla, Spain; Department of Medical, Surgical Science and Advanced Technology "GF Ingrassia" (F.P.), University of Catania, Italy; Ondokuz Mayis University (M. Terzi), Department of Neurology, Samsun, Turkey; CISSS Chaudi're-Appalache (P.G.), Centre-Hospitalier, Levis, Quebec, Canada; IRCCS Mondino Foundation (R.B.), Pavia; Department of Neuroscience (P.S., D.F.), Azienda Ospedaliera Universitaria, Modena, Italy; Department of Neurology (S.O.), Dokuz Eylul University, Izmir, Turkey; Ospedali Riuniti di Salerno (G. Iuliano), Salerno, Italy; Department of Neurology (C.B.), Karadeniz Technical University, Trabzon, Turkey; Department of Neurology (R.H.), Zuyderland Medical Center, Sittard, the Netherlands; Neuro Rive-Sud (F.G.), Hôpital Charles LeMoyne, Greenfield Park, Quebec, Canada; Clinico San Carlos (C.O.-G), Madrid, Spain; Cliniques Universitaires Saint-Luc (V.v.P.); Université Catholique de Louvain (V.v.P.), Brussels, Belgium; UOC Neurologia (E.C.), Azienda Sanitaria Unica Regionale Marche-AV3, Macerata, Italy; Kommunehospitalet (T.P.), Arhus C, Denmark; Koc University (A.A.), School of Medicine; Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases (A.S.), Istanbul, Turkey; Hospital Germans Trias i Pujol (C.R.-T.), Badalona, Spain; University of Queensland (P.M.), Brisbane, Australia; Haydarpasa Numune Training and Research Hospital (R.T.), Istanbul, Turkey; Central Clinical School (H.B.), Monash University, Melbourne, Australia; The University of Texas Health Science Center at Houston (J.S.W.); Rehabilitation Unit (C.S.), "Mons. L. Novarese" Hospital, Moncrivello; and IRCCS Ospedale Policlinico San Martino (M.P.S.), Genoa, Italy.

Objective: To compare the effectiveness of glatiramer acetate (GA) vs intramuscular interferon beta-1a (IFN-β-1a), we applied a previously published statistical method aimed at identifying patients' profiles associated with efficacy of treatments.

Methods: Data from 2 independent multiple sclerosis datasets, a randomized study (the Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis [CombiRx] trial, evaluating GA vs IFN-β-1a) and an observational cohort extracted from MSBase, were used to build and validate a treatment response score, regressing annualized relapse rates (ARRs) on a set of baseline predictors.

Results: The overall ARR ratio of GA to IFN-β-1a in the CombiRx trial was 0.72. The response score (made up of a linear combination of age, sex, relapses in the previous year, disease duration, and Expanded Disability Status Scale score) detected differential response of GA vs IFN-β-1a: in the trial, patients with the largest benefit from GA vs IFN-β-1a (lower score quartile) had an ARR ratio of 0.40 (95% confidence interval [CI] 0.25-0.63), those in the 2 middle quartiles of 0.90 (95% CI 0.61-1.34), and those in the upper quartile of 1.14 (95% CI 0.59-2.18) (heterogeneity = 0.012); this result was validated on MSBase, with the corresponding ARR ratios of 0.58 (95% CI 0.46-0.72), 0.92 (95% CI 0.77-1.09,) and 1.29 (95% CI 0.97-1.71); heterogeneity < 0.0001).

Conclusions: We demonstrate the possibility of a criterion, based on patients' characteristics, to choose whether to treat with GA or IFN-β-1a. This result, replicated on an independent real-life cohort, may have implications for clinical decisions in everyday clinical practice.
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http://dx.doi.org/10.1212/WNL.0000000000010991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905777PMC
January 2021

A randomized, placebo-controlled, phase 2 trial of laquinimod in primary progressive multiple sclerosis.

Neurology 2020 08 10;95(8):e1027-e1040. Epub 2020 Jul 10.

From Barts and The London School of Medicine and Dentistry (G.G.), Blizard Institute, Queen Mary University of London, UK; Teva Pharmaceuticals R&D (V.K.), Teva Pharmaceutical Industries (T.L.), Great Valley, PA; Department of Neurology, Medical Faculty (V.K., H.-P.H.), Heinrich-Heine Universität Düsseldorf, Germany; Teva Pharmaceutical Industries (J.R.S., A.P.T.), Malvern, PA; Corinne Goldsmith Dickinson Center for Multiple Sclerosis (S.K.) and Neurology (F.L.), Icahn School of Medicine at Mount Sinai, New York, NY; Departments of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health and Center of Excellence for Biomedical Research (A.U.) and Department of Health Sciences (M.P.S.), University of Genoa; Ospedale Policlinico San Martino-IRCCS (A.U.), Genoa, Italy; Department of Neurology (B.M.J.U.), MS Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, the Netherlands; Division of Neurology (X.M.), University of Toronto/MS Centre St Michael's Hospital, Canada; Neurology-Neuroimmunology Department and Neurorehabilitation Unit (X.M.), Multiple Sclerosis Centre of Catalonia; Department of Neurology (X.M.), Hospital Universitari de la Vall d'Hebron, Barcelona, Spain; Weill Institute for Neurosciences (B.A.C.C.), Department of Neurology, University of California San Francisco; Radiology & Nuclear Medicine (F.L.), VU University Medical Center, Amsterdam, the Netherlands; and UCL Institutes of Neurology and Healthcare Engineering (F.B.), London, UK.

Objective: To evaluate efficacy, safety, and tolerability of laquinimod in patients with primary progressive multiple sclerosis (PPMS).

Methods: In the randomized, double-blind, placebo-controlled, phase 2 study, ARPEGGIO (A Randomized Placebo-controlled Trial Evaluating Laquinimod in PPMS, Gauging Gradations in MRI and Clinical Outcomes), eligible patients with PPMS were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 mg or 1.5 mg or matching placebo. Percentage brain volume change (PBVC; primary endpoint) from baseline to week 48 was assessed by MRI. Secondary and exploratory endpoints included clinical and MRI measures. Efficacy endpoints were evaluated using a predefined, hierarchical statistical testing procedure. Safety was monitored throughout the study. The laquinimod 1.5 mg dose arm was discontinued on January 1, 2016, due to findings of cardiovascular events.

Results: A total of 374 patients were randomized to laquinimod 0.6 mg (n = 139) or 1.5 mg (n = 95) or placebo (n = 140). ARPEGGIO did not meet the primary endpoint of significant treatment effect with laquinimod 0.6 mg vs placebo on PBVC from baseline to week 48 (adjusted mean difference = 0.016%, = 0.903). Laquinimod 0.6 mg reduced the number of new T2 brain lesions at week 48 (risk ratio 0.4; 95% confidence interval, 0.26-0.69; = 0.001). Incidence of adverse events was higher among patients treated with laquinimod 0.6 mg (83%) vs laquinimod 1.5 mg (66%) and placebo (78%).

Conclusions: Laquinimod 0.6 mg did not demonstrate a statistically significant effect on brain volume loss in PPMS at week 48.

Clinicaltrialsgov Identifier: NCT02284568.

Classification Of Evidence: This study provides Class I evidence that, although well tolerated, laquinimod 0.6 mg did not demonstrate a significant treatment effect on PBVC in patients with PPMS.
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http://dx.doi.org/10.1212/WNL.0000000000010284DOI Listing
August 2020

Hippocampal volume is more related to patient-reported memory than objective memory performance in early multiple sclerosis.

Mult Scler 2021 Apr 22;27(4):568-578. Epub 2020 Jun 22.

The Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: When persons with multiple sclerosis (MS) report memory decline but objective memory performance is normal, there is a bias toward believing objective test results.

Objective: Investigate whether subjective memory decline or objective memory performance is more related to hippocampal and hippocampal subfield volumes in early MS.

Methods: Persons with early MS ( = 185; ⩽5.0 years diagnosed) completed a subjective memory questionnaire; an objective memory composite was derived from four memory tests. Total hippocampal and subfield volumes were derived from high-resolution 3.0 T magnetic resonance images (MRIs). Partial correlations assessed links between hippocampal volumes and both subjective and objective memory, controlling for age, sex, mood, and pre-morbid intelligence quotient (IQ).

Results: Lower total hippocampal and CA1 volumes were related to worse subjective memory but not objective memory (controlling for multiple comparisons). Correlations between subjective memory and both CA1 and subiculum were significantly stronger than were correlations between objective memory and these subfields. Patients in the worst tertile of subjective memory complaints (but not objective memory) had lower hippocampal volumes than 35 demographically similar healthy controls.

Conclusion: Patient-report is inherently a longitudinal assessment of within-person memory change in everyday life, which may be more sensitive to subtle disease-related changes than cross-sectional objective tests. Findings align with the aging literature.
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http://dx.doi.org/10.1177/1352458520922830DOI Listing
April 2021

The 2013 clinical course descriptors for multiple sclerosis: A clarification.

Neurology 2020 06 29;94(24):1088-1092. Epub 2020 May 29.

From the Department of Neurology (F.D.L.), Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, NY; National Multiple Sclerosis Society (T.C.), New York, NY; Department of Neurology (J.A.C.), Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, OH; Departments of Internal Medicine (Neurology) and Community Health Sciences (R.A.M.), Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada; and Faculty of Brain Sciences (A.J.T.), University College, London, United Kingdom.

The clinical courses of multiple sclerosis were defined in 1996 and refined in 2013 to provide a time-based assessment of the current status of the individual. These definitions have been successfully used by clinicians, clinical trialists, and regulatory authorities. Recent regulatory decisions produced variations and discrepancies in the use of the clinical course descriptions. We provide here a clarification of the concepts underlying these descriptions and restate the principles used in their development. Importantly, we highlight the critical importance of time framing the disease course modifiers activity and progression and clarify the difference between the terms worsening and progressing.
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http://dx.doi.org/10.1212/WNL.0000000000009636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455332PMC
June 2020

A clinically feasible 7-Tesla protocol for the identification of cortical lesions in Multiple Sclerosis.

Eur Radiol 2020 Aug 24;30(8):4586-4594. Epub 2020 Mar 24.

Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.

Objectives: The aim of this study was to evaluate the capability of sequences acquired on a 7-T MRI scanner, within times and anatomical coverage appropriate for clinical studies, to identify cortical lesions (CLs) in patients with Multiple Sclerosis (MS). Furthermore, we aimed to confirm the clinical significance of CL, testing the correlations between gray matter (GM) lesions and clinical scores.

Methods: A 7-T MRI protocol included 3D-T1-weighted and T2*-weighted sequences. Images were evaluated independently by three readers of different experience, and the number of CLs was recorded. Between-rater concordance was assessed calculating the intraclass correlation coefficient (ICC). Lin's concordance correlation coefficient was used to compare CL detection between sequences, while partial correlations and multivariable regression models were used to study the relationship between CL and clinical data.

Results: Forty MS patients (M/F, 17/23; 44.7 ± 12.6 years) were enrolled in this study, and CLs were identified in 35/40 subjects (87.5%). CL detection rate on 3D-T1-weighted images was significantly correlated with the detection rate on T2*-weighted images (r = 0.99; p < 0.001), with high concordance between readers (ICC ≥ 0.995). CLs were significantly correlated with both motor and cognitive scores (all with p ≤ 0.04).

Conclusions: CL can be identified over the whole brain at 7-T in MS using a 3D-T1-weighted volume, acquired in a clinically feasible time and with comparable performance to that achievable using the T2*-weighted sequence. Based on the central role of CL in the development of clinical disability, we suggest that 3D-T1-weighted volume may play a role in the evaluation of CL in MS undergoing MRI on ultra-high-field scanners.

Key Points: • Cortical lesions can be identified in a clinically feasible time with a 7-T protocol, which includes a 3D-T1-weighted volume. • Cortical lesions correlated significantly with both motor and cognitive disability in MS patients. • Given their correlation with clinical disability, evaluation of a cortical lesion on a 7-T clinical protocol could help in the management of MS patients.
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http://dx.doi.org/10.1007/s00330-020-06803-yDOI Listing
August 2020

Detection of subtle gait disturbance and future fall risk in early multiple sclerosis.

Neurology 2020 03 26;94(13):e1395-e1406. Epub 2020 Feb 26.

From the Department of Neurology (R.B.), University of Pennsylvania, Philadelphia; Department of Neurology (O.A.), Kaiser Permanente, Atlanta, GA; Department of Neurology (S.C.K., N.Y.H., M.X.E., I.K.S., M.T.F., S.K., F.D.L., A.E.M., J.F.S.), Icahn School of Medicine at Mount Sinai; James J. Peters Veterans Affairs Medical Center (N.Y.H.); and Department of Neurology (V.M.L, K.B., C.S.R..), Columbia University Medical Center, New York, NY.

Objective: To test the hypothesis that higher-challenge gait and balance tasks are more sensitive than traditional metrics to subtle patient-reported gait dysfunction and future fall risk in early multiple sclerosis (MS).

Methods: Persons with early MS (n = 185; ≤5 years diagnosed) reported gait function (MS Walking Scale) and underwent traditional disability metrics (Expanded Disability Status Scale [EDSS], Timed 25 Foot Walk). Patients and healthy controls (n = 50) completed clinically feasible challenge tasks of gait endurance (2-Minute Walk Test), standing balance (NIH Toolbox), and dynamic balance (balance boards; tandem walk on 2 ten-foot boards of different widths, 4.5 and 1.5 in). MRI assessed global and regional brain volumes, total T2 lesion volume (T2LV), infratentorial T2LVs and counts, and cervical cord lesion counts. Falls, near falls, and fall-related injuries were assessed after 1 year. We examined links between all tasks and patient-reported gait, MRI markers, and fall data.

Results: Patients performed worse on higher challenge balance, but not gait, tasks compared with healthy controls. Worse patient-reported gait disturbance was associated with worse performance on all tasks, but only dynamic balance was sensitive to mild patient-reported gait difficulty. Balance tasks were more correlated with MRI metrics than were walking tasks or EDSS score. Thirty percent of patients reported either a fall or near fall after 1 year, with poor dynamic balance as the only task independently predicting falls.

Conclusions: Balance plays a leading role in gait dysfunction early in MS. Clinically feasible higher-challenge balance tasks were most sensitive to patient-reported gait, MRI disease markers, and risk of future falls, highlighting potential to advance functional outcomes in clinical practice and trials.
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http://dx.doi.org/10.1212/WNL.0000000000008938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274914PMC
March 2020

Deep Learning for Predicting Enhancing Lesions in Multiple Sclerosis from Noncontrast MRI.

Radiology 2020 02 17;294(2):398-404. Epub 2019 Dec 17.

From the Departments of Diagnostic and Interventional Imaging (P.A.N., I.C., S.J.S., R.E.G.) and Neurology (J.S.W.), McGovern Medical School, University of Texas Health Science Center, 6431 Fannin St, Houston, TX 77030; and Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574 (F.D.L.).

Background Enhancing lesions on MRI scans obtained after contrast material administration are commonly thought to represent disease activity in multiple sclerosis (MS); it is desirable to develop methods that can predict enhancing lesions without the use of contrast material. Purpose To evaluate whether deep learning can predict enhancing lesions on MRI scans obtained without the use of contrast material. Materials and Methods This study involved prospective analysis of existing MRI data. A convolutional neural network was used for classification of enhancing lesions on unenhanced MRI scans. This classification was performed for each slice, and the slice scores were combined by using a fully connected network to produce participant-wise predictions. The network input consisted of 1970 multiparametric MRI scans from 1008 patients recruited from 2005 to 2009. Enhanced lesions on postcontrast T1-weighted images served as the ground truth. The network performance was assessed by using fivefold cross-validation. Statistical analysis of the network performance included calculation of lesion detection rates and areas under the receiver operating characteristic curve (AUCs). Results MRI scans from 1008 participants (mean age, 37.7 years ± 9.7; 730 women) were analyzed. At least one enhancing lesion was observed in 519 participants. The sensitivity and specificity averaged across the five test sets were 78% ± 4.3 and 73% ± 2.7, respectively, for slice-wise prediction. The corresponding participant-wise values were 72% ± 9.0 and 70% ± 6.3. The diagnostic performances (AUCs) were 0.82 ± 0.02 and 0.75 ± 0.03 for slice-wise and participant-wise enhancement prediction, respectively. Conclusion Deep learning used with conventional MRI identified enhanced lesions in multiple sclerosis from images from unenhanced multiparametric MRI with moderate to high accuracy. © RSNA, 2019.
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http://dx.doi.org/10.1148/radiol.2019191061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980901PMC
February 2020

Word-finding difficulty is a prevalent disease-related deficit in early multiple sclerosis.

Mult Scler 2020 11 19;26(13):1752-1764. Epub 2019 Nov 19.

The Corinne Goldsmith Dickinson Center for MS, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: Persons with multiple sclerosis (MS) commonly report word-finding difficulty clinically, yet this language deficit remains underexplored.

Objective: To investigate the prevalence and nature of word-finding difficulty in persons with early MS on three levels: patient report, cognitive substrates, and neuroimaging.

Methods: Two samples of early MS patients ( = 185 and  = 55; ⩽5 years diagnosed) and healthy controls ( = 50) reported frequency/severity of cognitive deficits and underwent objective assessment with tasks of rapid automatized naming (RAN), measuring lexical access speed, memory, word generation, and cognitive efficiency. High-resolution brain magnetic resonance imaging (MRI) derived measurements of regional cortical thickness, global and deep gray matter volume, and T2 lesion volume. Relationships among patient-reported word-finding difficulty, cognitive performance, and neural correlates were examined.

Results: Word-finding difficulty was the most common cognitive complaint of MS patients and the only complaint reported more by patients than healthy controls. Only RAN performance discriminated MS patients with subjective word-finding deficits from those without subjective complaints and from healthy controls. Thinner left parietal cortical gray matter independently predicted impaired RAN performance, driven primarily by the left precuneus.

Conclusion: Three levels of evidence (patient-report, objective behavior, regional gray matter) support word-finding difficulty as a prevalent, measurable, disease-related deficit in early MS linked to left parietal cortical thinning.
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http://dx.doi.org/10.1177/1352458519881760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234894PMC
November 2020

Deep-Learning-Based Neural Tissue Segmentation of MRI in Multiple Sclerosis: Effect of Training Set Size.

J Magn Reson Imaging 2020 05 18;51(5):1487-1496. Epub 2019 Oct 18.

Department of Diagnostic and Interventional Imaging, McGovern Medical School, University of Texas Health Science Center, Houston, Texas, USA.

Background: The dependence of deep-learning (DL)-based segmentation accuracy of brain MRI on the training size is not known.

Purpose: To determine the required training size for a desired accuracy in brain MRI segmentation in multiple sclerosis (MS) using DL.

Study Type: Retrospective analysis of MRI data acquired as part of a multicenter clinical trial.

Study Population: In all, 1008 patients with clinically definite MS.

Field Strength/sequence: MRIs were acquired at 1.5T and 3T scanners manufactured by GE, Philips, and Siemens with dual turbo spin echo, FLAIR, and T -weighted turbo spin echo sequences.

Assessment: Segmentation results using an automated analysis pipeline and validated by two neuroimaging experts served as the ground truth. A DL model, based on a fully convolutional neural network, was trained separately using 16 different training sizes. The segmentation accuracy as a function of the training size was determined. These data were fitted to the learning curve for estimating the required training size for desired accuracy.

Statistical Tests: The performance of the network was evaluated by calculating the Dice similarity coefficient (DSC), and lesion true-positive and false-positive rates.

Results: The DSC for lesions showed much stronger dependency on the sample size than gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). When the training size was increased from 10 to 800 the DSC values varied from 0.00 to 0.86 ± 0.016 for T lesions, 0.87 ± 009 to 0.94 ± 0.004 for GM, 0.86 ± 0.08 to 0.94 ± 0.005 for WM, and 0.91 ± 0.009 to 0.96 ± 0.003 for CSF.

Data Conclusion: Excellent segmentation was achieved with a training size as small as 10 image volumes for GM, WM, and CSF. In contrast, a training size of at least 50 image volumes was necessary for adequate lesion segmentation.

Level Of Evidence: 1 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2020;51:1487-1496.
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http://dx.doi.org/10.1002/jmri.26959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165037PMC
May 2020

Lymphocyte counts and infection rates: Long-term fingolimod treatment in primary progressive MS.

Neurol Neuroimmunol Neuroinflamm 2019 11 11;6(6). Epub 2019 Sep 11.

From the Central Texas Neurology Consultants (E.J.F.), Round Rock, TX; Icahn School of Medicine at Mount Sinai (F.D.L.), New York, NY; McGovern Medical School (J.S.W.), The University of Texas Health Science Center at Houston (UTHealth), TX; Mellen Center for Multiple Sclerosis Treatment and Research (J.A.C.), Neurological Institute, Cleveland Clinic Foundation, OH; Oxford PharmaGenesis Ltd (I.M.W.), UK; Novartis Pharmaceuticals Corporation (X.M., M.Z., S.K.), East Hanover, NJ; and The University of California, San Francisco (UCSF); Weill Institute for Neurosciences, Department of Neurology (B.A.C.C.), San Francisco, CA.

Objective: To evaluate lymphocyte counts and incidences of infections in patients with primary progressive MS (PPMS) receiving fingolimod 0.5 mg/d or placebo over 5 years during the INFORMS study, to assess infection rates with longer-term treatment.

Methods: INFORMS was a randomized, multicenter, double-blind, placebo-controlled, parallel-group, phase 3 study of the sphingosine 1-phosphate receptor modulator fingolimod in patients with PPMS. Lymphocyte counts and incidences of infections were compared in patients receiving fingolimod or placebo. Infection rates were assessed in patients receiving fingolimod according to nadir and mean absolute lymphocyte count (ALC).

Results: Overall, 336 patients received fingolimod 0.5 mg/d (total exposure: 908.1 patient-years), and 487 received placebo (1,423.5 patient-years). In patients receiving fingolimod, mean ALC decreased by approximately 70% in the 2 weeks following treatment initiation and remained stable throughout the study. The incidences of all infections in the fingolimod and placebo groups were similar (53.6 vs 51.9 per 100 patient-years). The most common infections in patients receiving fingolimod were urinary tract infections (5.7 per 100 patient-years), upper respiratory tract infections (4.2 per 100 patient-years), and influenza (3.2 per 100 patient-years); incidences were similar in the placebo group (5.9, 4.2, and 3.1 per 100 patient-years, respectively). There was no apparent association between nadir or mean ALC and incidence of infection-related adverse events.

Conclusions: In patients with PPMS, long-term treatment with fingolimod 0.5 mg/d for up to 5 years led to an expected decrease of approximately 70% in mean ALC and did not appear to correlate with increased risk of infection.

Classification Of Evidence: Because this is a secondary analysis, this study provides Class II evidence that long-term PPMS treatment with fingolimod decreased mean ALC by approximately 70%, but did not significantly increase infection risk.
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http://dx.doi.org/10.1212/NXI.0000000000000614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745722PMC
November 2019

Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial.

Lancet 2019 10 5;394(10206):1352-1363. Epub 2019 Sep 5.

Viela Bio, Gaithersburg, MD, USA.

Background: No approved therapies exist for neuromyelitis optica spectrum disorder (NMOSD), a rare, relapsing, autoimmune, inflammatory disease of the CNS that causes blindness and paralysis. We aimed to assess the efficacy and safety of inebilizumab, an anti-CD19, B cell-depleting antibody, in reducing the risk of attacks and disability in NMOSD.

Methods: We did a multicentre, double-blind, randomised placebo-controlled phase 2/3 study at 99 outpatient specialty clinics or hospitals in 25 countries. Eligible participants were adults (≥18 years old) with a diagnosis of NMOSD, an Expanded Disability Status Scale score of 8·0 or less, and a history of at least one attack requiring rescue therapy in the year before screening or at least two attacks requiring rescue therapy in the 2 years before screening. Participants were randomly allocated (3:1) to 300 mg intravenous inebilizumab or placebo with a central interactive voice response system or interactive web response system and permuted block randomisation. Inebilizumab or placebo was administered on days 1 and 15. Participants, investigators, and all clinical staff were masked to the treatments, and inebilizumab and placebo were indistinguishable in appearance. The primary endpoint was time to onset of an NMOSD attack, as determined by the adjudication committee. Efficacy endpoints were assessed in all randomly allocated patients who received at least one dose of study intervention, and safety endpoints were assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT02200770.

Findings: Between Jan 6, 2015, and Sept 24, 2018, 230 participants were randomly assigned to treatment and dosed, with 174 participants receiving inebilizumab and 56 receiving placebo. The randomised controlled period was stopped before complete enrolment, as recommended by the independent data-monitoring committee, because of a clear demonstration of efficacy. 21 (12%) of 174 participants receiving inebilizumab had an attack versus 22 (39%) of 56 participants receiving placebo (hazard ratio 0·272 [95% CI 0·150-0·496]; p<0·0001). Adverse events occurred in 125 (72%) of 174 participants receiving inebilizumab and 41 (73%) of 56 participants receiving placebo. Serious adverse events occurred in eight (5%) of 174 participants receiving inebilizumab and five (9%) of 56 participants receiving placebo.

Interpretation: Compared with placebo, inebilizumab reduced the risk of an NMOSD attack. Inebilizumab has potential application as an evidence-based treatment for patients with NMOSD.

Funding: MedImmune and Viela Bio.
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http://dx.doi.org/10.1016/S0140-6736(19)31817-3DOI Listing
October 2019

Real-world studies provide reliable comparisons of disease modifying therapies in MS - Commentary.

Authors:
Fred Lublin

Mult Scler 2020 02 3;26(2):163-164. Epub 2019 Sep 3.

Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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http://dx.doi.org/10.1177/1352458519872758DOI Listing
February 2020

Early complement genes are associated with visual system degeneration in multiple sclerosis.

Brain 2019 09;142(9):2722-2736

Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Multiple sclerosis is a heterogeneous disease with an unpredictable course and a wide range of severity; some individuals rapidly progress to a disabled state whereas others experience only mild symptoms. Though genetic studies have identified variants that are associated with an increased risk of developing multiple sclerosis, no variants have been consistently associated with multiple sclerosis severity. In part, the lack of findings is related to inherent limitations of clinical rating scales; these scales are insensitive to early degenerative changes that underlie disease progression. Optical coherence tomography imaging of the retina and low-contrast letter acuity correlate with and predict clinical and imaging-based outcomes in multiple sclerosis. Therefore, they may serve as sensitive phenotypes to discover genetic predictors of disease course. We conducted a set of genome-wide association studies of longitudinal structural and functional visual pathway phenotypes in multiple sclerosis. First, we assessed genetic predictors of ganglion cell/inner plexiform layer atrophy in a discovery cohort of 374 patients with multiple sclerosis using mixed-effects models adjusting for age, sex, disease duration, optic neuritis and genetic ancestry and using a combination of single-variant and network-based analyses. For candidate variants identified in discovery, we conducted a similar set of analyses of ganglion cell/inner plexiform layer thinning in a replication cohort (n = 376). Second, we assessed genetic predictors of sustained loss of 5-letters in low-contrast letter acuity in discovery (n = 582) using multivariable-adjusted Cox proportional hazards models. We then evaluated candidate variants/pathways in a replication cohort. (n = 253). Results of both studies revealed novel subnetworks highly enriched for connected genes in early complement activation linked to measures of disease severity. Within these networks, C3 was the gene most strongly associated with ganglion cell/inner plexiform layer atrophy (P = 0.004) and C1QA and CR1 were top results in analysis of sustained low-contrast letter acuity loss. Namely, variant rs158772, linked to C1QA, and rs61822967, linked to CR1, were associated with 71% and 40% increases in risk of sustained LCLA loss, respectively, in meta-analysis pooling discovery and replication cohorts (rs158772: hazard ratio: 1.71; 95% confidence interval 1.30-2.25; P = 1.3 × 10-4; rs61822967: hazard ratio: 1.40; 95% confidence interval: 1.16-1.68; P = 4.1 × 10-4). In conclusion, early complement pathway gene variants were consistently associated with structural and functional measures of multiple sclerosis severity. These results from unbiased analyses are strongly supported by several prior reports that mechanistically implicated early complement factors in neurodegeneration.
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http://dx.doi.org/10.1093/brain/awz188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776113PMC
September 2019

Dissociable cognitive patterns related to depression and anxiety in multiple sclerosis.

Mult Scler 2020 09 24;26(10):1247-1255. Epub 2019 Jun 24.

Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA/Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai Hospital, New York, NY, USA.

Background: Individuals with multiple sclerosis (MS) frequently present with depression and anxiety, as well as cognitive impairment, challenging clinicians to disentangle interrelationships among these symptoms.

Objective: To identify cognitive functions associated with anxiety and depression in MS.

Methods: Mood and cognition were measured in 185 recently diagnosed patients (Reserve Against Disability in Early Multiple Sclerosis (RADIEMS) cohort), and an independent validation sample (MEM CONNECT cohort,  = 70). Partial correlations evaluated relationships of cognition to anxiety and depression controlling for age, sex, education, and premorbid verbal intelligence.

Results: In RADIEMS cohort, lower anxiety was associated with better nonverbal memory ( = -0.220,  = 0.003) and lower depression to better attention/processing speed ( = -0.241,  = 0.001). Consistently, in MEM CONNECT cohort, lower anxiety was associated with better nonverbal memory ( = -0.271,  = 0.028) and lower depression to better attention/processing speed ( = -0.367,  = 0.002). Relationships were unchanged after controlling for T2 lesion volume and fatigue.

Conclusion: Consistent mood-cognition relationships were identified in two independent cohorts of MS patients, suggesting that cognitive correlates of anxiety and depression are separable. This dissociation may support more precise models to inform treatment development. Treatment of mood symptoms may mitigate effects on cognition and/or treatment of cognition may mitigate effects on mood.
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http://dx.doi.org/10.1177/1352458519860319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928451PMC
September 2020

Brain and lesion segmentation in multiple sclerosis using fully convolutional neural networks: A large-scale study.

Mult Scler 2020 09 13;26(10):1217-1226. Epub 2019 Jun 13.

Department of Diagnostic and Interventional Imaging, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.

Objective: To investigate the performance of deep learning (DL) based on fully convolutional neural network (FCNN) in segmenting brain tissues in a large cohort of multiple sclerosis (MS) patients.

Methods: We developed a FCNN model to segment brain tissues, including T2-hyperintense MS lesions. The training, validation, and testing of FCNN were based on ~1000 magnetic resonance imaging (MRI) datasets acquired on relapsing-remitting MS patients, as a part of a phase 3 randomized clinical trial. Multimodal MRI data (dual-echo, FLAIR, and T1-weighted images) served as input to the network. Expert validated segmentation was used as the target for training the FCNN. We cross-validated our results using the leave-one-center-out approach.

Results: We observed a high average (95% confidence limits) Dice similarity coefficient for all the segmented tissues: 0.95 (0.92-0.98) for white matter, 0.96 (0.93-0.98) for gray matter, 0.99 (0.98-0.99) for cerebrospinal fluid, and 0.82 (0.63-1.0) for T2 lesions. High correlations between the DL segmented tissue volumes and ground truth were observed ( > 0.92 for all tissues). The cross validation showed consistent results across the centers for all tissues.

Conclusion: The results from this large-scale study suggest that deep FCNN can automatically segment MS brain tissues, including lesions, with high accuracy.
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http://dx.doi.org/10.1177/1352458519856843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908772PMC
September 2020

Psychological resilience is linked to motor strength and gait endurance in early multiple sclerosis.

Mult Scler 2020 08 7;26(9):1111-1120. Epub 2019 Jun 7.

Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: Psychologically resilient persons persist despite obstacles and bounce back after adversity, leading to better outcomes in non-neurologic populations. It is unknown whether psychological resilience relates to objective functional outcomes in multiple sclerosis (MS).

Objective: To determine whether psychological resilience explains differential objective cognitive and motor functioning in persons with early MS.

Methods: Psychological resilience was assessed in 185 patients with early MS and 50 matched healthy controls with the (CDRS-10). Subjects completed the MS Functional Composite (MSFC) and a comprehensive neurobehavioral evaluation. Correlations assessed links between CDRS-10 and MSFC, motor indices (Total, Fine Motor, Gross Motor), and cognitive indices (Total, Cognitive Efficiency, Memory).

Results: Higher CDRS-10 among patients was linked to better MSFC and motor outcomes (but not cognition), with the most robust relationships for gross motor function (grip strength, gait endurance). Findings were independent of mood and fatigue. CDRS-10 was unrelated to MS disease burden. CDRS-10 was also specifically linked to motor outcomes in healthy controls.

Conclusion: Functional outcomes vary across persons with MS, even when disease burden and neurologic disability are low. These findings identify high psychological resilience as a non-disease-specific contributor to motor strength and endurance, which may explain differential outcomes across patients.
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http://dx.doi.org/10.1177/1352458519852725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898764PMC
August 2020

Open-label, add-on trial of cetirizine for neuromyelitis optica.

Neurol Neuroimmunol Neuroinflamm 2018 Mar 2;5(2):e441. Epub 2018 Feb 2.

Corinne Goldsmith Dickinson Center for Multiple Sclerosis (I.K.S., M.F., C.F., S.E., F.L.), Department of Neurology, Icahn School of Medicine at Mount Sinai, NY; Department of Pediatrics (R.T., L.C.), University of Utah, Salt Lake City; Drug Discovery Institute (T.A.K.), Mount Sinai Center for Eosinophilic Disorders (M.C.), Jaffe Food Allergy Institute (M.M.), Department of Pediatrics, and Department of Microbiology (T.M.), Icahn School of Medicine at Mount Sinai, NY; Department of Neurology (J.R.), University of Utah, Salt Lake City.

Objective: This pilot study preliminarily examined the efficacy and tolerability of cetirizine as an add-on to standard therapy for neuromyelitis optica (NMO).

Methods: Eligible participants met the Wingerchuk 2006 diagnostic criteria or had a single typical episode along with positive NMO immunoglobulin G. After baseline clinical and laboratory assessments, participants began treatment with cetirizine 10 mg orally daily, in addition to their usual disease-modifying therapy for NMO, and continued for 1 year. The primary end point was the annualized relapse rate (ARR) while on the same disease-modifying therapy before starting cetirizine compared with after taking cetirizine. Additional end points included disability (Expanded Disability Status Scale [EDSS]), relapse severity, tolerability, especially with respect to drowsiness measured by the Epworth Sleepiness Scale (ESS), and laboratory parameters.

Results: The ARR before cetirizine was 0.4 ± 0.80 and after cetirizine was 0.1 ± 0.24 ( = 0.047). There was no statistically significant difference in the EDSS (mean 3.9 ± 2.18 before the start of the study and 3.2 ± 2.31 at the conclusion of the study, = 0.500). The ESS remained fairly consistent throughout the study (mean 6.5 ± 5.33 at baseline and 6.9 ± 4.50 at month 12, = 0.740). Laboratory studies were unrevealing.

Conclusions: In this pilot study, cetirizine was well tolerated, and the prespecified primary efficacy end point was satisfied. However, the open-label design and the small sample size of this pilot study preclude definitive conclusions. Further research is needed.

Classification Of Evidence: This study provides Class IV evidence that in patients with NMO, the addition of cetirizine to standard therapy is safe, well tolerated, and reduces relapses.
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http://dx.doi.org/10.1212/NXI.0000000000000441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201737PMC
March 2018

Objective and subjective measures of dalfampridine efficacy in clinical practice.

Mult Scler J Exp Transl Clin 2018 Jul-Sep;4(3):2055217318786742. Epub 2018 Jul 9.

Department of Neurology, Icahn School of Medicine at Mount Sinai, USA.

Background: Multiple sclerosis affects mobility in over 80% of patients. Dalfampridine is the only approved treatment for walking impairment in multiple sclerosis. We assessed dalfampridine utilization in our practice and investigated response using timed 25 foot walk (T25FW) improvement and a patient-reported ambulation inventory.

Methods: Chart review identified patients with multiple sclerosis for whom dalfampridine was prescribed. T25FW data were extracted from medical records. Participants completed a dalfampridine-specific version of the multiple sclerosis walking scale (dMSWS-12) to assess the qualitative impact of dalfampridine on ambulation. We evaluated two responder categories: liberally defined as any improvement in T25FW; and over 20% T25FW improvement.

Results: The dMSWS-12 questionnaire was completed by 39 patients. Eighteen patients (46%) did not show any T25FW improvement. Of the 21 patients (54%) with T25FW improvement, four patients (11%) showed improvement greater than 20%. Analysis of dMSWS-12 scores showed a median score of 40 (range 12-60). Eleven patients (28%) showed no improvement (dMSWS-12 score ≤36). In contrast to objective T25FW improvement (54%), 28 patients (72%) reported improvement in walking ability (dMSWS-12 score ≥37).

Conclusion: Our results suggest that T25FW alone might not be sufficient for response characterization and that adding patient-reported measures may further elucidate the therapeutic response.
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http://dx.doi.org/10.1177/2055217318786742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077903PMC
July 2018

"Location, location, location".

Mult Scler 2018 10 26;24(11):1396-1398. Epub 2018 Jul 26.

The Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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http://dx.doi.org/10.1177/1352458518790385DOI Listing
October 2018

No evidence of disease activity (NEDA) analysis by epochs in patients with relapsing multiple sclerosis treated with ocrelizumab vs interferon beta-1a.

Mult Scler J Exp Transl Clin 2018 Jan-Mar;4(1):2055217318760642. Epub 2018 Mar 12.

Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, UK.

Background: No evidence of disease activity (NEDA; defined as no 12-week confirmed disability progression, no protocol-defined relapses, no new/enlarging T2 lesions and no T1 gadolinium-enhancing lesions) using a fixed-study entry baseline is commonly used as a treatment outcome in multiple sclerosis (MS).

Objective: The objective of this paper is to assess the effect of ocrelizumab on NEDA using re-baselining analysis, and the predictive value of NEDA status.

Methods: NEDA was assessed in a modified intent-to-treat population ( = 1520) from the pooled OPERA I and OPERA II studies over various epochs in patients with relapsing MS receiving ocrelizumab (600 mg) or interferon beta-1a (IFN β-1a; 44 μg).

Results: NEDA was increased with ocrelizumab vs IFN β-1a over 96 weeks by 75% ( < 0.001), from Week 0‒24 by 33% ( < 0.001) and from Week 24‒96 by 72% ( < 0.001). Among patients with disease activity during Weeks 0‒24, 66.4% vs 24.3% achieved NEDA during Weeks 24‒96 in the ocrelizumab and IFN β-1a groups (relative increase: 177%;  < 0.001).

Conclusion: Superior efficacy with ocrelizumab compared with IFN β-1a was consistently seen in maintaining NEDA status in all epochs evaluated. By contrast with IFN β-1a, the majority of patients with disease activity early in the study subsequently attained NEDA status with ocrelizumab.
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http://dx.doi.org/10.1177/2055217318760642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858626PMC
March 2018

Brain atrophy and disability worsening in primary progressive multiple sclerosis: insights from the INFORMS study.

Ann Clin Transl Neurol 2018 03 30;5(3):346-356. Epub 2018 Jan 30.

McGovern Medical School UT Health Houston Texas.

Objective: To investigate the relationship between brain volume and disability worsening over ≥3 years in the natural history of primary progressive multiple sclerosis using data from the placebo group of the INFORMS trial ( = 487; clinicaltrials.gov NCT00731692).

Methods: Magnetic resonance imaging scans were collected annually. Brain volume loss was determined using SIENA. Patients were stratified by baseline normalized brain volume after adjusting for demographic and disease-burden covariates.

Results: Baseline normalized brain volume was predictive of disability worsening: Risk of 3-month confirmed disability progression was reduced by 36% for high versus low baseline normalized brain volume (Cox's model hazard ratio 0.64,  = 0.0339; log-rank test:  = 0.0297). Moreover, on-study brain volume loss was significantly associated with disability worsening ( = 0.012) and was evident in patients with or without new lesions or relapses. Brain volume loss depended significantly on baseline T2 lesion volume ( < 0.0001). Despite low inflammatory activity at baseline (13% of patients had gadolinium-enhancing lesions) and throughout the study (mean 0.5 new/enlarging T2 lesions and 172 mm T2 lesion volume increase per year), baseline T2 lesion volume was substantial (mean 10 cm). Lower normalized brain volume at baseline correlated with higher baseline T2 volume and older age (both  < 0.0001).

Interpretation: Baseline brain volume and the rate of ongoing brain atrophy are significantly associated with disability worsening in primary progressive multiple sclerosis. Brain volume loss is significantly related to baseline T2 lesion volume, but partially independent of new lesion activity, which might explain the limited efficacy of anti-inflammatory treatment.
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http://dx.doi.org/10.1002/acn3.534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846448PMC
March 2018

Brain microstructural injury occurs in patients with RRMS despite 'no evidence of disease activity'.

J Neurol Neurosurg Psychiatry 2018 09 16;89(9):977-982. Epub 2018 Mar 16.

Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Objectives: The accuracy of 'no evidence of disease activity' (NEDA) in predicting long-term clinical outcome in patients with relapsing remitting multiple sclerosis (RRMS) is unproven, and there is growing evidence that NEDA does not rule out disease worsening. We used diffusion tensor imaging (DTI) to investigate whether ongoing brain microstructural injury occurs in patients with RRMS meeting NEDA criteria.

Methods: We performed a retrospective study to identify patients with RRMS visiting our centre over a 3-month period who had undergone prior longitudinal DTI evaluation at our facility spanning ≥2 years. Patients meeting NEDA criteria throughout the evaluation period were included in the NEDA group, and those not meeting NEDA criteria were included in an 'evidence of disease activity' (EDA) group. Fractional anisotropy (FA) and mean diffusivity (MD) maps were created, and annual rates of change were calculated.

Results: We enrolled 85 patients, 39 meeting NEDA criteria. Both NEDA and EDA groups showed longitudinal DTI worsening. Yearly FA decrease was lower in the NEDA group (0.5%, p<0.0001) than in the EDA group (1.2%, p=0.003), while yearly MD increase was similar in both groups (0.8% for NEDA and EDA, both p<0.01). There was no statistical difference in deterioration within and outside of T2 lesions. DTI parameters correlated with disability scores and fatigue complaints.

Conclusions: White matter microstructural deterioration occurs in patients with RRMS over short-term follow-up in patients with NEDA, providing further evidence of the limitations of conventional measures and arguing for DTI in monitoring of the disease process.
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http://dx.doi.org/10.1136/jnnp-2017-317606DOI Listing
September 2018

Editors' Welcome.

Mult Scler Relat Disord 2018 01;19:A1-A2

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http://dx.doi.org/10.1016/j.msard.2018.01.004DOI Listing
January 2018

Clinical Course of Multiple Sclerosis.

Cold Spring Harb Perspect Med 2018 09 4;8(9). Epub 2018 Sep 4.

The CGD Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, New York 10029.

The 1996 originally established multiple sclerosis (MS) subtypes, based solely on clinical impression and consensus, were revised in 2013 to review potential imaging and biological correlates and to reflect recently identified clinical aspects of MS. As a result, potential new disease phenotypes, radiologically isolated syndrome, and clinically isolated syndrome were considered along with the addition of two new descriptor subtypes: activity and progression applied to relapsing remitting and progressive MS phenotypes. In this way, the description of an individual patient's disease course is refined and provides temporal information about the ongoing disease process. There is still a lack of imaging and biological markers that would distinguish MS phenotypes and prognosticate the disease course on an individual patient's level, creating a pressing need for large collaborative research efforts in this field.
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http://dx.doi.org/10.1101/cshperspect.a028928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120692PMC
September 2018