Publications by authors named "Robert A Bermel"

55 Publications

Vitamin D Levels and Visual System Measurements in Progressive Multiple Sclerosis: A Cross-sectional Study.

Int J MS Care 2021 Mar-Apr;23(2):53-58. Epub 2020 Apr 28.

Background: Vitamin D deficiency is associated with increased disease activity in multiple sclerosis (MS), but its role in progressive MS has not been elucidated. The objective was to determine the correlation between vitamin D levels and visual parameters in primary progressive MS (PPMS) and secondary progressive MS (SPMS).

Methods: Serum 25-hydroxyvitamin D (25[OH]D) and 25-hydroxyvitamin D (25[OH]D) levels were obtained from the Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in MS (SPRINT-MS). Visual function measurements and vitamin D associations were determined using the Pearson correlation and the generalized linear mixed model.

Results: The analysis included 258 patients (mean ± SD age of 55.6 ± 7.3 years, 52.7% female, and 52.3% PPMS). Mean vitamin D values were above sufficiency and were similar between PPMS and SPMS ( = .47 and = .31). There was no association between 25(OH)D levels and any visual markers, including peripapillary retinal nerve fiber layer thickness (Spearman = -0.08), macular volume ( = -0.03), ganglion cell-inner plexiform layer ( = -0.07), and 2.5% low-contrast visual acuity test ( = -0.10). No statistically significant associations between vitamin D levels and visual system measurements were detected in the PPMS and SPMS subgroups.

Conclusions: Vitamin D levels were not associated with optical coherence tomography findings or low-contrast letter acuity in this group of patients with progressive MS.
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http://dx.doi.org/10.7224/1537-2073.2020-005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047686PMC
April 2020

Use of a Smartphone to Gather Parkinson's Disease Neurological Vital Signs during the COVID-19 Pandemic.

Parkinsons Dis 2021 8;2021:5534282. Epub 2021 Apr 8.

Cleveland Clinic, Lerner Research Institute, Department of Biomedical Engineering, Cleveland, OH, USA.

Introduction: To overcome travel restrictions during the COVID-19 pandemic, consumer-based technology was rapidly deployed to the smartphones of individuals with Parkinson's disease (PD) participating in a 12-month exercise trial. The aim of the project was to determine the feasibility of utilizing a combined synchronous and asynchronous self-administered smartphone application to characterize PD symptoms.

Methods: A synchronous video virtual visit was completed for the administration of virtual Movement Disorder Society-Unified Parkinson's Disease Rating Scale III (vMDS-UPDRS III). Participants asynchronously completed a mobile application consisting of a measure of upper extremity bradykinesia (Finger Tapping Test) and information processing.

Results: Twenty-three individuals completed the assessments. The mean vMDS-UPDRS III was 23.65 ± 8.56 points. On average, the number of taps was significantly greater for the less affected limb, 97.96 ± 17.77 taps, compared to the more affected, 89.33 ± 18.66 taps ( = 0.025) with a significantly greater number of freezing episodes for the more affected limb ( < 0.05). Correlation analyses indicated the number of errors and the number of freezing episodes were significantly related to clinical ratings of vMDS-UPDRS III bradykinesia (Rho = 0.44, < 0.01;  = 0.43, < 0.01, resp.) and finger tapping performance (Rho = 0.31, = 0.03; Rho = 0.32, = 0.03, resp.). . The objective characterization of bradykinesia, akinesia, and nonmotor function and their relationship with clinical disease metrics indicate smartphone technology provides a remote method of characterizing important aspects of PD performance. While theoretical and position papers have been published on the potential of telemedicine to aid in the management of PD, this report translates the theory into a viable reality.
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http://dx.doi.org/10.1155/2021/5534282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035908PMC
April 2021

The Calm Between Storms: Serum Biomarkers in Assessing Interattack Astrocytopathy in Neuromyelitis Optica Spectrum Disorder.

Neurol Neuroimmunol Neuroinflamm 2021 05 9;8(3). Epub 2021 Apr 9.

From the Mellen Center for MS Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, Ohio.

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http://dx.doi.org/10.1212/NXI.0000000000000988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042782PMC
May 2021

Neurofilament light chain in a phase 2 clinical trial of ibudilast in progressive multiple sclerosis.

Mult Scler 2021 Feb 26:1352458520986956. Epub 2021 Feb 26.

Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine, and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.

Background: Sensitive and specific biomarkers for use in progressive multiple sclerosis (MS) have not been established. We investigate neurofilament light (NfL) as a treatment response biomarker in progressive MS.

Objective: To evaluate whether ibudilast 100 mg/day alters serum and cerebrospinal fluid (CSF) levels of NfL in progressive MS.

Methods: In a protocol-defined exploratory analysis from a 2-year, phase 2 clinical trial of ibudilast in progressive MS (NCT01982942), serum samples were collected from 239 subjects and a subset contributed CSF and assayed using single-molecule assay (SIMOA) immunoassay. A mixed model for repeated measurements yielded log(NfL) as the response variable.

Results: The geometric mean baseline serum NfL was 31.9 and 28.8 pg/mL in placebo and ibudilast groups, respectively. The geometric mean baseline CSF NfL was 1150.8 and 1290.3 pg/mL in placebo and ibudilast groups, respectively. Serum and CSF NfL correlations were  = 0.52 and  = 0.78 at weeks 48 and 96, respectively. Over 96 weeks, there was no between-group difference in NfL in either serum ( = 0.76) or CSF ( = 0.46). After controlling for factors that may affect NfL, no effect of ibudilast on NfL in either serum or CSF was observed.

Conclusion: Ibudilast treatment was not associated with a change in either serum or CSF NfL.
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http://dx.doi.org/10.1177/1352458520986956DOI Listing
February 2021

Safety evaluation of shorter infusion for ocrelizumab in a substudy of the Phase IIIb CHORDS trial.

Ann Clin Transl Neurol 2021 03 23;8(3):711-715. Epub 2021 Feb 23.

UC Waddell Center for Multiple Sclerosis, Cincinnati, OH, USA.

The CHORDS trial evaluated ocrelizumab (OCR) in patients with relapsing-remitting multiple sclerosis who had a suboptimal response to previous disease-modifying treatment. The objective of the present study was to assess the safety of shorter OCR infusions in a substudy of CHORDS. After completing four doses of OCR per initial US prescribing recommendations in the main study, participants in the substudy (N = 129) received a fifth dose over a 2-h duration (vs. 3.5 h). Infusion-related reactions occurred in 12.4% of patients. None were severe, life-threatening or led to treatment discontinuation. Shorter infusion time did not change the safety profile of OCR. Clinicaltrials.gov (NCT0237856).
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http://dx.doi.org/10.1002/acn3.51310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951110PMC
March 2021

Response to ibudilast treatment according to progressive multiple sclerosis disease phenotype.

Ann Clin Transl Neurol 2021 01 18;8(1):111-118. Epub 2021 Jan 18.

Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, Ohio, USA.

Objective: Determine whether a treatment effect of ibudilast on brain atrophy rate differs between participants with primary (PPMS) and secondary (SPMS) progressive multiple sclerosis.

Background: Progressive forms of MS are both associated with continuous disability progression. Whether PPMS and SPMS differ in treatment response remains unknown.

Design/methods: SPRINT-MS was a randomized, placebo-controlled 96-week phase 2 trial in both PPMS (n = 134) and SPMS (n = 121) patients. The effect of PPMS and SPMS phenotype on the rate of change of brain atrophy measured by brain parenchymal fraction (BPF) was examined by fitting a three-way interaction linear-mixed model. Adjustment for differences in baseline demographics, disease measures, and brain size was explored.

Results: Analysis showed that there was a three-way interaction between the time, treatment effect, and disease phenotype (P < 0.06). After further inspection, the overall treatment effect was primarily driven by patients with PPMS (P < 0.01), and not by patients with SPMS (P = 0.97). This difference may have been due to faster brain atrophy progression seen in the PPMS placebo group compared to SPMS placebo (P < 0.02). Although backward selection (P < 0.05) retained age, T2 lesion volume, RNFL, and longitudinal diffusivity as significant baseline covariates in the linear-mixed model, the adjusted overall treatment effect was still driven by PPMS (P < 0.01).

Interpretation: The previously reported overall treatment effect of ibudilast on worsening of brain atrophy in progressive MS appears to be driven by patients with PPMS that may be, in part, because of the faster atrophy progression rates seen in the placebo-treated group.
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http://dx.doi.org/10.1002/acn3.51251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818089PMC
January 2021

Early age of onset predicts severity of visual impairment in patients with neuromyelitis optica spectrum disorder.

Mult Scler 2021 Jan 6:1352458520981736. Epub 2021 Jan 6.

Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.

Background: Severe residual visual loss (SRVL) is frequent in neuromyelitis optica spectrum disorders (NMOSD). Identifying higher-risk patients at onset is important to prevent disability accumulation.

Objective: To determine predictors of SRVL in a large NMOSD cohort.

Methods: Patient characteristics at last visual acuity (VA) evaluation were retrospectively collected. VA was scored 0: better than 20/40, 1: 20/40-20/99, 2: 20/100-20/200, and 3: worse than 20/200. SRVL was defined as a combined score (VA worst + best eye) ⩾ 4. Descriptive statistics were used to compare groups and logistic regression to evaluate predictors of VA.

Results: 106 patients (mean age at disease onset (AO): 35.8 ± 16.5 years) were included. Patients with SRVL had earlier AO (mean: 26.7 vs 38.0 years) compared to non-SRVL group ( = 0.005). Patients with AO < 21 years were more likely to have SRVL, be blind, present with binocular optic neuritis, have recurrent optic neuritis, and receive oral therapy first-line than those with AO ⩾ 21. After adjusting for race, sex, and disease duration, the odds of SRVL were 4.68 times higher in patients < 21 at disease onset (95% CI: 1.53-14.34, = 0.007).

Conclusion: Early AO predicts SRVL in NMOSD, independent of disease duration. High-efficacy therapies should be considered for first-line treatment in this group.
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http://dx.doi.org/10.1177/1352458520981736DOI Listing
January 2021

Comorbidity effect on processing speed test and MRI measures in multiple sclerosis patients.

Mult Scler Relat Disord 2020 Nov 21;46:102593. Epub 2020 Oct 21.

Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.

Background: Comorbid conditions are known to affect the clinical course of multiple sclerosis (MS). Our objective was to determine the impact of comorbidities on the processing speed test (PST).

Methods: We conducted a retrospective, longitudinal analysis of all patients who completed PST testing from June 2015 - August 2019 at our center. Our electronic medical record was queried to determine the presence of the following comorbidities: diabetes mellitus (DM), hypertension (HTN), hyperlipidemia (HLD), coronary artery disease, and depression. To help address baseline PST performance and practice effect, patients were also divided into four quartiles by baseline PST scores. Brain MRIs obtained within a 90-day window from the initial clinical assessment were quantitatively analyzed via fully-automated methods to calculate whole brain fraction (WBF), T2 lesion volume (T2LV), gray matter fraction (GMF), and thalamic volume (TV). Univariable and multivariable linear regression models were used to determine the relationship between the comorbidities, PST performance and MRI metrics over time.

Results: A total of 4,344 patients (mean age 49.5 ± 12.4 years, 72.3% female, and 63.7% relapsing remitting MS) were included in the analysis with 13,375 individual patient encounters. Over half the cohort (52.4%) suffered from at least one comorbidity with the most common being depression (37.4%), HLD (20.9%), HTN (19.6%), and DM (6.4%). Patients with one or more comorbidity had lower baseline PST scores. Longitudinally, patients with two comorbidities lost 1.46 points on the PST per year relative to those with no comorbidities (95% CI -2.46 - -0.46, p = 0.004). Individuals with depression had lower PST scores than those without, and this difference persisted over time (β = -2.40, 95% CI -3.08 - -1.73, p < 0.001). At baseline, HLD patients had higher PST scores than non-HLD patients (β = 1.10, 95% CI 0.15 - 2.05, p = 0.022), but this difference did not remain over time. Individuals in the highest PST performance quartile were negatively impacted when diagnosed with depression, HTN, and DM relative to those without the comorbidities. There were no other correlations with PST scores and the remaining comorbidities. Depression was associated with lower baseline WBF (β = -0.0043, 95% CI -0.0084 - -0.0003, p = 0.033) and GMF (β = -0.0046, 95% CI -0.0078 - -0.0015, p = 0.004) along with larger T2LV (β = 0.1605, 95% CI 0.0082 - 0.3128, p = 0.039). HLD patients had more favorable baseline MRI measures, including higher WBF (β = 0.0076, 95% CI 0.0017 - 0.0135, p = 0.012) and TV (β = 0.0002, 95% CI 0.0000 - 0.0005, p = 0.041), with a lower T2LV (β = -0.2963, 95% CI -0.5219 - -0.0706, p = 0.010).

Conclusions: Comorbidities are common within a MS cohort and adversely impact processing speed. Depression adversely impacted PST scores with worse MRI outcomes. HLD was associated with lower longitudinal PST measures but favorable quantitative MRI metrics. MS patients with faster baseline processing speeds were most sensitive to comorbid conditions. Our findings suggest a complex interplay between cognition and comorbid conditions in MS patients.
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http://dx.doi.org/10.1016/j.msard.2020.102593DOI Listing
November 2020

Effects of Ibudilast on MRI Measures in the Phase 2 SPRINT-MS Study.

Neurology 2021 01 2;96(4):e491-e500. Epub 2020 Dec 2.

From Washington University (R.T.N.), St. Louis, MO; Cleveland Clinic Foundation (R.A.B., K.N., C.G., R.J.F.), OH; University of Iowa (C.S.C., J.F., J.Y., E.K.), Iowa City; University of Rochester (A.D.G.), NY; Massachusetts General Hospital (M.K., E.C.K.), Harvard Medical School, Boston; McConnell Brain Imaging Centre (S.N.), Montreal Neurological Institute, McGill University; and NeuroRx Research (S.N.), Montreal, Canada.

Objective: To determine whether ibudilast has an effect on brain volume and new lesions in progressive forms of multiple sclerosis (MS).

Methods: A randomized, placebo-controlled, blinded study evaluated ibudilast at a dose of up to 100 mg over 96 weeks in primary and secondary progressive MS. In this secondary analysis of a previously reported trial, secondary and tertiary endpoints included gray matter atrophy, new or enlarging T2 lesions as measured every 24 weeks, and new T1 hypointensities at 96 weeks. Whole brain atrophy measured by structural image evaluation, using normalization, of atrophy (SIENA) was a sensitivity analysis.

Results: A total of 129 participants were assigned to ibudilast and 126 to placebo. New or enlarging T2 lesions were observed in 37.2% on ibudilast and 29.0% on placebo ( = 0.82). New T1 hypointense lesions at 96 weeks were observed in 33.3% on ibudilast and 23.5% on placebo ( = 0.11). Gray matter atrophy was reduced by 35% for those on ibudilast vs placebo ( = 0.038). Progression of whole brain atrophy by SIENA was slowed by 20% in the ibudilast group compared with placebo ( = 0.08).

Conclusion: Ibudilast treatment was associated with a reduction in gray matter atrophy. Ibudilast treatment was not associated with a reduction in new or enlarging T2 lesions or new T1 lesions. An effect on brain volume contributes to prior data that ibudilast appears to affect markers associated with neurodegenerative processes, but not inflammatory processes.

Classification Of Evidence: This study provides Class II evidence that for people with MS, ibudilast does not significantly reduce new or enlarging T2 lesions or new T1 lesions.
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http://dx.doi.org/10.1212/WNL.0000000000011314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905793PMC
January 2021

Optical coherence tomography outcomes from SPRINT-MS, a multicenter, randomized, double-blind trial of ibudilast in progressive multiple sclerosis.

Mult Scler 2020 Oct 15:1352458520964409. Epub 2020 Oct 15.

Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA.

Background: The SPRINT-MS trial demonstrated benefit of ibudilast on brain atrophy over 96 weeks in progressive multiple sclerosis (MS). Optical coherence tomography (OCT) was performed in all trial participants.

Objective: Report the OCT results of the SPRINT-MS trial.

Methods: OCT was obtained at baseline and every 6 months using spectral domain OCT and analyzed by an OCT reading center. Change in each OCT outcome measure by treatment group was estimated using linear mixed models.

Results: Change in pRNFL thickness was +0.0424 uM/year (95% confidence interval (CI): -0.3091 to 0.3939) for ibudilast versus -0.2630 uM (95% CI: -0.5973 to 0.0714) for placebo ( = 244,  = 0.22). Macular volume change was -0.00503 mm/year (-0.02693 to 0.01688) with ibudilast versus -0.03659 mm/year (-0.05824 to -0.01494) for placebo in the Spectralis cohort ( = 61,  = 0.044). For the Cirrus cohort, macular volume change was -0.00040 mm/year (-0.02167, 0.020866) with ibudilast compared to -0.02083 mm/year (-0.04134 to -0.00033) for placebo ( = 183,  = 0.1734). Ganglion cell-inner plexiform layer thickness change, available from Cirrus, was -0.4893 uM/year (-0.9132, -0.0654) with ibudilast versus -0.9587 uM/year (-1.3677, -0.5498) with placebo ( = 183,  = 0.12).

Conclusion: Retinal thinning in MS may be attenuated by ibudilast. Sample size estimates suggest OCT can be a viable outcome measure in progressive MS trials if a therapy has a large treatment effect.

Trial Registration: NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942.
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http://dx.doi.org/10.1177/1352458520964409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046841PMC
October 2020

Harnessing Real-World Data to Inform Decision-Making: Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS).

Front Neurol 2020 7;11:632. Epub 2020 Aug 7.

Biogen, Cambridge, MA, United States.

Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is the first example of a learning health system in multiple sclerosis (MS). This paper describes the initial implementation of MS PATHS and initial patient characteristics. MS PATHS is an ongoing initiative conducted in 10 healthcare institutions in three countries, each contributing standardized information acquired during routine care. Institutional participation required the following: active MS patient census of ≥500, at least one Siemens 3T magnetic resonance imaging scanner, and willingness to standardize patient assessments, share standardized data for research, and offer universal enrolment to capture a representative sample. The eligible participants have diagnosis of MS, including clinically isolated syndrome, and consent for sharing pseudonymized data for research. MS PATHS incorporates a self-administered patient assessment tool, the Multiple Sclerosis Performance Test, to collect a structured history, patient-reported outcomes, and quantitative testing of cognition, vision, dexterity, and walking speed. Brain magnetic resonance imaging is acquired using standardized acquisition sequences on Siemens 3T scanners. Quantitative measures of brain volume and lesion load are obtained. Using a separate consent, the patients contribute DNA, RNA, and serum for future research. The clinicians retain complete autonomy in using MS PATHS data in patient care. A shared governance model ensures transparent data and sample access for research. As of August 5, 2019, MS PATHS enrolment included participants ( = 16,568) with broad ranges of disease subtypes, duration, and severity. Overall, 14,643 (88.4%) participants contributed data at one or more time points. The average patient contributed 15.6 person-months of follow-up (95% CI: 15.5-15.8); overall, 166,158 person-months of follow-up have been accumulated. Those with relapsing-remitting MS demonstrated more demographic heterogeneity than the participants in six randomized phase 3 MS treatment trials. Across sites, a significant variation was observed in the follow-up frequency and the patterns of disease-modifying therapy use. Through digital health technology, it is feasible to collect standardized, quantitative, and interpretable data from each patient in busy MS practices, facilitating the merger of research and patient care. This approach holds promise for data-driven clinical decisions and accelerated systematic learning.
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http://dx.doi.org/10.3389/fneur.2020.00632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426489PMC
August 2020

Multiple sclerosis management during the COVID-19 pandemic.

Mult Scler 2020 09 10;26(10):1163-1171. Epub 2020 Aug 10.

Division of Neuroimmunology and Neurological Infections, Johns Hopkins University, Baltimore, MA, USA.

Background: People with multiple sclerosis (MS) may be at higher risk for complications from the 2019 coronavirus (COVID-19) pandemic due to use of immunomodulatory disease modifying therapies (DMTs) and greater need for medical services.

Objectives: To evaluate risk factors for COVID-19 susceptibility and describe the pandemic's impact on healthcare delivery.

Methods: Surveys sent to MS patients at Cleveland Clinic, Johns Hopkins, and Vall d'Hebron-Centre d'Esclerosi Múltiple de Catalunya in April and May 2020 collected information about comorbidities, DMTs, exposures, COVID-19 testing/outcomes, health behaviors, and disruptions to MS care.

Results: There were 3028/10,816 responders. Suspected or confirmed COVID-19 cases were more likely to have a known COVID-19 contact (odds ratio (OR): 4.38; 95% confidence interval (CI): 1.04, 18.54). In multivariable-adjusted models, people who were younger, had to work on site, had a lower education level, and resided in socioeconomically disadvantaged areas were less likely to follow social distancing guidelines. 4.4% reported changes to therapy plans, primarily delays in infusions, and 15.5% a disruption to rehabilitative services.

Conclusion: Younger people with lower socioeconomic status required to work on site may be at higher exposure risk and are potential targets for educational intervention and work restrictions to limit exposure. Providers should be mindful of potential infusion delays and MS care disruption.
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http://dx.doi.org/10.1177/1352458520948231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424611PMC
September 2020

Technology-enabled assessments to enhance multiple sclerosis clinical care and research.

Neurol Clin Pract 2020 Jun;10(3):222-231

Mellen Center for Multiple Sclerosis (GM, BPM, LEB, MW, MA, FB, AB, DC, DSC, CF, RJF, SG, BG, CH-C, KRM, MPM, DMM, MN, AR-G, MR, HY, MAW, DO, JAC, RAB), Neurological Institute, Cleveland Clinic Foundation; Department of Quantitative Health Sciences (HL), Cleveland Clinic; Schey Center for Cognitive Neuroimaging (SMR), Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic Foundation; Department of Biomedical Engineering (DS, JLA), Lerner Research Institute, Cleveland Clinic Foundation, OH; and Epic Systems Corporation (NJ), Verona, WI.

Background: Comprehensive and efficient assessments are necessary for clinical care and research in chronic diseases. Our objective was to assess the implementation of a technology-enabled tool in MS practice.

Method: We analyzed prospectively collected longitudinal data from routine multiple sclerosis (MS) visits between September 2015 and May 2018. The MS Performance Test, comprising patient-reported outcome measures (PROMs) and neuroperformance tests (NPTs) self-administered using a tablet, was integrated into routine care. Descriptive statistics, Spearman correlations, and linear mixed-effect models were used to examine the implementation process and relationship between patient characteristics and completion of assessments.

Results: A total of 8022 follow-up visits from 4199 patients (median age 49.9 [40.2-58.8] years, 32.1% progressive course, and median disease duration 13.6 [5.9-22.3] years) were analyzed. By the end of integration, the tablet version of the Timed 25-Foot Walk was obtained in 89.0% of patients and the 9-Hole Peg Test in 94.8% compared with 74.2% and 64.3%, respectively before implementation. The greatest increase in data capture occurred in processing speed and low-contrast acuity assessments (0% prior vs 78.4% and 36.7%, respectively, following implementation). Four PROMs were administered in 41%-98% of patients compared with a single depression questionnaire with a previous capture rate of 70.6%. Completion rates and time required to complete each NPT improved with subsequent visits. Younger age and lower disability scores were associated with shorter completion time and higher completion rates.

Conclusions: Integration of technology-enabled data capture in routine clinical practice allows acquisition of comprehensive standardized data for use in patient care and clinical research.
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http://dx.doi.org/10.1212/CPJ.0000000000000710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292568PMC
June 2020

Optical coherence tomography and multiple sclerosis: Update on clinical application and role in clinical trials.

Mult Scler 2020 05 6;26(6):624-639. Epub 2019 Sep 6.

Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, Ohio, USA.

Optical coherence tomography (OCT) has emerged as a fast, non-invasive, inexpensive, high-resolution imaging technique in multiple sclerosis (MS). Retinal layer quantification by OCT facilitates a 'window' into not only local retinal pathology but also global neurodegenerative processes, recognised to be the principal substrates of disability accumulation in MS. While OCT measures in MS have been demonstrated to reflect visual function, inflammatory activity outside of the visual pathways, disability measures including the prediction of disability progression, whole brain atrophy, and the differential neuroprotective effects of disease-modifying therapies, debate continues regarding the clinical utility of OCT in everyday practice. This review presents an overview of the evidence supporting OCT, with particular focus on its application in the MS clinic. We will also discuss the role of OCT in MS clinical trials to develop novel neuroprotective and potential remyelinating therapies.
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http://dx.doi.org/10.1177/1352458519872751DOI Listing
May 2020

Technology-enabled comprehensive characterization of multiple sclerosis in clinical practice.

Mult Scler Relat Disord 2020 Feb 14;38:101525. Epub 2019 Nov 14.

Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH, United States. Electronic address:

Background: Objective and longitudinal measurements of disability in patients with multiple sclerosis (MS) are desired in order to monitor disease status and response to disease-modifying and symptomatic therapies. Technology-enabled comprehensive assessment of MS patients, including neuroperformance tests (NPTs), patient-reported outcome measures (PROMs), and MRI, is incorporated into clinical care at our center. The relationships of each NPT with PROMs and MRI measures in a real-world setting are incompletely studied, particularly in larger datasets.

Objectives: To demonstrate the utility of comprehensive neurological assessment and determine the association between NPTs, PROMs, and quantitative MRI measures in a large MS clinical cohort.

Methods: NPTs (processing speed [PST], contrast sensitivity [CST], manual dexterity [MDT], and walking speed [WST]) and physical disability-related PROMs (Quality of Life in Neurological Disorders [Neuro-QoL], Patient Determined Disease Steps [PDDS], and Patient-Reported Outcomes Measurement Information System Global-10 [PROMIS-10] physical) were collected as part of routine clinical care. Fully-automated MRI analysis calculated T2-lesion volume (T2LV), whole brain fraction (WBF), thalamic volume (TV), and cervical spinal cord cross-sectional area (CA) for brain MRIs completed within 3 months of a clinic visit during which NPTs and PROMs were assessed. Spearman's rank correlation coefficients evaluated the cross-sectional associations of NPTs with PROMs and MRI measures. Linear regression was utilized to determine which combination of clinical characteristics, patient demographics, MRI measures, and PROMs best cross-sectionally explained each NPT result.

Results: 997 unique patients (age 47.7 ± 11.4 years, 71.8% female) who underwent assessments over a 2-year period were included. Correlations among NPTs and PROMs were moderate. PST correlations were strongest for Neuro-QoL upper extremity (NQ-UE) (Spearman's rho = 0.43) and lower extremity (NQ-LE) (0.47). CST correlations were strongest for NQ-UE (0.33), NQ-LE (0.36), and PDDS (-0.31). MDT correlations were strongest for NQ-UE (-0.53), NQ-LE (-0.54), and PDDS (0.53). WST correlations were strongest for PDDS (0.64) and NQ-LE (-0.65). NPTs also had moderate correlations with MRI metrics, the strongest of which were observed with PST (with T2LV (-0.44) and WBF (0.49)). Spearman's rho for other NPT-MRI correlations ranged from 0.23 to 0.36. Linear regression identified age, disease duration, PROMIS-10 physical, NQ-UE, NQ-LE, T2LV and WBF as significant cross-sectional explanatory variables for PST (adjusted R=0.46). For CST, significant variables included age and NQ-LE (adjusted R = 0.30). For MDT, significant variables included PDDS, PROMIS-10 physical, NQ-UE, NQ-LE, T2LV, and WBF (adjusted R=0.37). For WST, significant variables included sex, PDDS, NQ-LE, T2LV, and CA (adjusted R=0.39).

Conclusions: Impaired performance on NPTs correlated with worse physical disability-related PROMs and MRI disease severity, but the strongest cross-sectional explanatory variables for each NPT component varied. This study supports the use of comprehensive, objective quantification of MS status in clinical and research settings. Future longitudinal analyses can determine predictors of treatment response and disability worsening.
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http://dx.doi.org/10.1016/j.msard.2019.101525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943942PMC
February 2020

Serum neurofilament light chain concentration in a phase 1/2 trial of autologous mesenchymal stem cell transplantation.

Mult Scler J Exp Transl Clin 2019 Oct-Dec;5(4):2055217319887198. Epub 2019 Nov 5.

Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, USA.

Background: Serum neurofilament light chain concentration is a proposed biomarker of axonal injury in multiple sclerosis. Mesenchymal stem cells have anti-inflammatory and repair-promoting activities, making them of interest for potential multiple sclerosis treatment.

Objectives: The purpose of this study was to assess correlation of serum neurofilament light chain concentration and measures of multiple sclerosis disease activity/severity, longitudinal stability of serum neurofilament light chain concentration, and treatment effect of mesenchymal stem cell transplantation on serum neurofilament light chain concentration.

Methods: Twenty-four multiple sclerosis patients underwent intravenous infusion of autologous mesenchymal stem cells. Clinical assessments, serum collection, and brain magnetic resonance imaging were performed at months -1, 0 (transplant), 1, 3, and 6. Matched control serum was collected once ( = 10). Serum neurofilament light chain concentration was measured by single-molecule array. Serum neurofilament light chain concentration correlations with disease measures were analyzed by Spearman correlations and linear mixed effect models. Pre-post transplant serum neurofilament light chain concentration was compared by Wilcoxon signed rank testing.

Results: There were significant (<0.01) correlations between serum neurofilament light chain concentration and gadolinium-enhancing lesion number (rho = 0.55) and volume (rho = 0.65), and new/enlarging T2 lesions (rho = 0.65). Patients without disease activity had lower fluctuation in serum neurofilament light chain concentration ( = 0.01). Mean pre- versus post-treatment serum neurofilament light chain concentration values were not significantly different.

Conclusions: Serum neurofilament light chain concentration correlated with magnetic resonance imaging measures of disease activity cross sectionally and longitudinally, and was stable in patients without disease activity. There was no clear treatment effect of mesenchymal stem cell transplantation on serum neurofilament light chain concentration.
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http://dx.doi.org/10.1177/2055217319887198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831979PMC
November 2019

Comparative discontinuation, effectiveness, and switching practices of dimethyl fumarate and fingolimod at 36-month follow-up.

J Neurol Sci 2019 Dec 15;407:116498. Epub 2019 Oct 15.

Lou Ruvo Center for Brain Health, Cleveland Clinic, Las Vegas, NV, United States. Electronic address:

Background: Dimethyl fumarate (DMF) and fingolimod (FTY) are approved oral disease modifying therapies (DMTs) for relapsing multiple sclerosis (MS). There are currently no known head-to-head studies comparing DMF and FTY over 36 months, which leaves their relative effectiveness unknown.

Objective: To assess real-world discontinuation, effectiveness, and switching practices of DMF and FTY over 36 months along with disease activity after switching DMT.

Methods: Patients prescribed DMF (n = 737) and FTY (n = 535) from two academic MS centers were retrospectively reviewed. Discontinuation and effectiveness outcomes were assessed using propensity score (PS) weighting. PS model covariates included sociodemographics and clinical and MRI characteristics.

Results: Discontinuation was more common in DMF (58.3%) versus FTY (45.2%) over 36 months [OR = 1.81, 95% CI (1.41-2.31), p < .001], largely driven by intolerance [OR = 1.63, 95% CI (1.18-1.73), p < .001]. There were no differences in clinical relapses [OR = 1.27, 95% CI (0.90-1.79), p = .17], gadolinium-enhancing (GdE) lesions [OR = 1.25, 95% CI (0.85-1.84), p = .26], or new T2-hyperintense lesions [OR = 0.99, 95% CI (0.74-1.32), p = .93]. Within 12 months of DMF/FTY discontinuation, switchers to highly effective therapy (HET) versus other DMTs (injectables/orals) had fewer relapses (DMF/HET, 5.9% versus DMF/Other, 14.2%, p = .03; FTY/HET, 11.6% versus FTY/Other, 18.0%, p = .04) and fewer GdE lesions post-FTY (DMF/HET, 10.3% versus DMF/Other, 14.3%, p = .36; FTY/HET, 11.9% versus FTY/Other, 21.5%, p = .04).

Conclusion: This combined analysis showed similar effectiveness for DMF and FTY over 36 months with higher DMF discontinuations. Disease activity was lower in switchers to HET versus injectable/oral therapies after DMF/FTY cessation.
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http://dx.doi.org/10.1016/j.jns.2019.116498DOI Listing
December 2019

Multiple Sclerosis Performance Test: Technical Development and Usability.

Adv Ther 2019 07 3;36(7):1741-1755. Epub 2019 May 3.

Biogen, Cambridge, MA, USA.

Introduction: In the clinic, the assessment of patients with multiple sclerosis (MS) is typically qualitative and non-standardized.

Objectives: To describe the MS Performance Test (MSPT), an iPad Air 2 (Apple, Cupertino, CA, USA)-based neurological assessment platform allowing patients to input relevant information without the aid of a medical technician, creating a longitudinal, clinically meaningful, digital medical record. To report results from human factor (HF) and usability studies, and the initial large-scale implementation in a practice setting.

Methods: The HF study examined use-error patterns in small groups of MS patients and healthy controls (n = 14), the usability study assessed the effectiveness of patient interaction with the tool by patients with a range of MS disability (n = 60) in a clinical setting, and the implementation study deployed the MSPT across a diverse population of patients (n = 1000) in a large MS center for routine clinical care.

Results: MSPT assessments were completed by all users in the HF study; minor changes to design were recommended. In the usability study, 73% of patients with MS completed the MSPT, with an average administration time of 32 min; 85% described their experience with the tool as satisfactory. In the initial implementation for routine care, 84% of patients with MS completed the MSPT, with an average administration time of 28 min.

Conclusion: Patients with MS with varying disability levels completed the MSPT with minimal or no supervision, resulting in comprehensive, efficient, standardized, quantitative, clinically meaningful data collection as part of routine medical care, thus allowing for large-scale, real-world evidence generation.

Funding: Biogen.

Trial Registration: NCT02664324.
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http://dx.doi.org/10.1007/s12325-019-00958-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824297PMC
July 2019

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.

N Engl J Med 2018 08;379(9):846-855

From the Mellen Center for Multiple Sclerosis, Neurological Institute (R.J.F., S. Natarajan, R.A.B., D.O.), the Imaging Institute (X.H., M.J.L., K.E.S., X.Z.), and the Department of Biomedical Engineering (P.J., K.N., B. Thoomukuntla), Cleveland Clinic, Cleveland, Ohio State University, Columbus (M.R.), and University of Cincinnati, Cincinnati (A.Z.) - all in Ohio; the Data Coordinating Center, Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT), University of Iowa, Iowa City (C.S.C., J.B., D.E., E.K., M.K., J.D.L., J.Y.); the National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C.); the Clinical Coordinating Center, NeuroNEXT, Massachusetts General Hospital, Neurological Clinical Research Institute, Harvard Partners (M.E.C., M.M., A.A., B. Thornell), the Department of Neurology, Massachusetts General Hospital, Harvard Medical School (E.C.K.), and Brigham and Women's Hospital (C.S.), Boston; patient advocate (T.G.) and Swedish Medical Center at Seattle (P.R.), Seattle; University of Rochester Medical Center, Rochester (A.G.), Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai Medical Center (S.K.), Weill Cornell Medical College (J.S.P.), Columbia University Medical Center (C.S.R.), and Montefiore Medical Center, Albert Einstein College of Medicine (S.S.), New York, State University of New York (SUNY) at Stony Brook, Stony Brook (P.K.C.), SUNY Upstate Medical University, Syracuse (B.J.), and SUNY at Buffalo, Buffalo (B.W.-G.) - all in New York; MediciNova, La Jolla (K.M.), University of California at Davis, Sacramento (M.A.), and University of California at Los Angeles, Los Angeles (B.S.G.) - all in California; Washington University School of Medicine, St. Louis (R.T.N.); Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ (J.P.D.); NeuroRx Research, Montreal (S. Narayanan); the School of Health Sciences, College of Health and Human Sciences, Purdue University, West Lafayette, IN (X.Z.); University of Colorado Denver, Aurora (E.A.); University of Alabama at Birmingham, Birmingham (K.B.); Feinberg School of Medicine, Northwestern University, Chicago (B.A.C.); University of Miami Miller School of Medicine, Miami (S.D.); University of Utah, Salt Lake City (L.D.D.); University of Texas Southwestern Medical Center, Dallas (A.F.); University of Virginia at Charlottesville, Charlottesville (M.D.G.); Emory University, Atlanta (N.L.); University of Kansas Medical Center, Kansas City (S.G.L.); Vanderbilt University, Nashville (H.M.); University of Pittsburgh Medical Center, Pittsburgh (V.S.); and Oregon Health and Science University, Portland (V.Y.).

Background: There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis.

Methods: We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis.

Results: Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression.

Conclusions: In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).
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http://dx.doi.org/10.1056/NEJMoa1803583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172944PMC
August 2018

Discontinuation and comparative effectiveness of dimethyl fumarate and fingolimod in 2 centers.

Neurol Clin Pract 2018 Aug;8(4):292-301

Rocky Mountain Multiple Sclerosis Center at Anschutz Medical Campus (BV, KN, SS, JRC, TV, EA), University of Colorado, Denver; Mellen Center for Multiple Sclerosis Treatment and Research (DO, RAB, RJF, JAC), Cleveland Clinic, OH; Emory University (AB), Atlanta, GA; Department of Neurology (SC), Cleveland Clinic, OH; and Lou Ruvo Center for Brain Health (CMH), Cleveland Clinic, Las Vegas, NV.

Background: Dimethyl fumarate (DMF) and fingolimod (FTY) are approved oral disease-modifying therapies for relapsing multiple sclerosis (MS). Observational studies are valuable when randomized clinical trials cannot be done due to ethical or practical reasons. Two-site studies allow investigators to further ascertain external validity of previously examined treatment effect differences. Limited head-to-head 2-site studies exist comparing DMF and FTY.

Methods: Patients prescribed DMF (n = 737) and FTY (n = 535) from 2 academic multiple sclerosis (MS) centers (Cleveland Clinic and University of Colorado) were identified. Discontinuation and disease activity endpoints were assessed using propensity score (PS) weighting. Covariates used in the PS model included demographics and clinical and MRI characteristics.

Results: PS weighting demonstrated excellent covariate balance. Discontinuation was more common in DMF (44.2%) compared to FTY (34.8%) over 24 months (odds ratio [OR] 1.55, 95% confidence interval [CI] 1.21-1.99, < 0.001). The leading cause for discontinuation was intolerability for both DMF (56.1% of DMF discontinuations) and FTY (46.2% of FTY discontinuations) (OR 1.65, 95% CI 1.21-2.25, = 0.002). The proportion of patients with clinical relapses was low for both medications (DMF, 15.1%; FTY, 13.1%). There was no difference in the proportion of patients with relapses (OR 1.27, 95% CI 0.90-1.80, = 0.174), gadolinium-enhancing lesions (OR 1.42, 95% CI 0.92-2.20, = 0.114), or new T2 lesions on brain MRI (OR 1.13, 95% CI 0.83-1.55, = 0.433).

Conclusions: This combined analysis suggests DMF and FTY have similar effectiveness in a large, 2-site clinical population over 24 months. Discontinuation of both DMTs was common and occurred more frequently with DMF, largely driven by intolerability.
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http://dx.doi.org/10.1212/CPJ.0000000000000487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105060PMC
August 2018

The role of the thalamus and hippocampus in episodic memory performance in patients with multiple sclerosis.

Mult Scler 2019 04 7;25(4):574-584. Epub 2018 Mar 7.

Intermountain Healthcare, Salt Lake City, UT, USA.

Background: Episodic memory loss is one of the most common cognitive symptoms in patients with multiple sclerosis (MS), but the pathophysiology of this symptom remains unclear. Both the hippocampus and thalamus have been implicated in episodic memory and show regional atrophy in patients with MS.

Objective: In this work, we used functional magnetic resonance imaging (fMRI) during a verbal episodic memory task, lesion load, and volumetric measures of the hippocampus and thalamus to assess the relative contributions to verbal and visual-spatial episodic memory.

Methods: Functional activation, lesion load, and volumetric measures from 32 patients with MS and 16 healthy controls were used in a predictive analysis of episodic memory function.

Results: After adjusting for disease duration, immediate recall performance on a visual-spatial episodic memory task was significantly predicted by hippocampal volume ( p < 0.003). Delayed recall on the same task was significantly predicted by volume of the left thalamus ( p < 0.003). For both memory measures, functional activation of the thalamus during encoding was more predictive than that of volume measures ( p < 0.002).

Conclusion: Our results suggest that functional activation may be useful as a predictive measure of episodic memory loss in patients with MS.
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http://dx.doi.org/10.1177/1352458518760716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119546PMC
April 2019

Unravelling neurodegeneration in multiple sclerosis.

Authors:
Robert A Bermel

Lancet Neurol 2017 10 12;16(10):764-766. Epub 2017 Sep 12.

Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address:

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http://dx.doi.org/10.1016/S1474-4422(17)30302-2DOI Listing
October 2017

Comparative efficacy and discontinuation of dimethyl fumarate and fingolimod in clinical practice at 24-month follow-up.

Mult Scler J Exp Transl Clin 2017 Jul-Sep;3(3):2055217317715485. Epub 2017 Aug 24.

Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, USA.

Background: Dimethyl fumarate and fingolimod are oral disease-modifying therapies approved to treat relapsing multiple sclerosis. Prior observational studies and our previous 12-month investigation showed comparable clinical efficacy.

Objective: The purpose of this study was to assess real-world efficacy and discontinuation of dimethyl fumarate and fingolimod over 24 months in patients with multiple sclerosis.

Methods: Patients treated with dimethyl fumarate ( = 395) or fingolimod ( = 264) completed 24-month follow-up in a large academic multiple sclerosis center. Discontinuation rates and measures of disease activity were compared after propensity score weighting. The primary outcome was on-treatment annualized relapse rate ratio. Other measures included rate of drug discontinuation and brain magnetic resonance imaging activity defined as new T2 and/or gadolinium-enhancing lesions.

Results: Propensity score weighting showed excellent covariate balance. At 24 months, dimethyl fumarate demonstrated comparable annualized relapse rate (rate ratio = 1.45, 95% confidence interval 0.53-3.99) and brain magnetic resonance imaging activity (odds ratio = 1.38, 95% confidence interval 0.83-2.32). Dimethyl fumarate patients discontinued therapy earlier compared to fingolimod (hazard ratio = 1.40, 95% confidence interval 1.11-1.77) and were more likely to discontinue therapy due to intolerability (odds ratio = 1.98, 95% confidence interval 1.18-3.23).

Conclusion: Dimethyl fumarate and fingolimod had similar reductions in annualized relapse rate in clinical trials, and our real-world experience supports this observation. Dimethyl fumarate-treated patients had higher likelihood of early discontinuation, and this was mostly due to intolerability.
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http://dx.doi.org/10.1177/2055217317715485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574489PMC
August 2017

Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis.

Mult Scler 2018 04 6;24(4):501-511. Epub 2017 Apr 6.

Case Comprehensive Cancer Center and National Center for Regenerative Medicine, Case Western Reserve University and Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.

Background: Mesenchymal stem cells (MSCs) exhibit immunomodulatory, tissue-protective, and repair-promoting properties in vitro and in animals. Clinical trials in several human conditions support the safety and efficacy of MSC transplantation. Published experience in multiple sclerosis (MS) is modest.

Objective: To assess feasibility, safety, and tolerability and explore efficacy of autologous MSC transplantation in MS.

Methods: Participants with relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS), Expanded Disability Status Scale score 3.0-6.5, disease activity or progression in the prior 2 years, and optic nerve involvement were enrolled. Bone-marrow-derived MSCs were culture-expanded and then cryopreserved. After confirming fulfillment of release criteria, 1-2 × 10 MSCs/kg were thawed and administered IV.

Results: In all, 24 of 26 screened patients were infused: 16 women and 8 men, 10 RRMS and 14 SPMS, mean age 46.5, mean Expanded Disability Status Scale score 5.2, 25% with gadolinium-enhancing magnetic resonance imaging (MRI) lesions. Mean cell dosage (requiring 1-3 passages) was 1.9 × 10 MSCs/kg (range, 1.5-2.0) with post-thaw viability uniformly ⩾95%. Cell infusion was tolerated well without treatment-related severe or serious adverse events, or evidence of disease activation.

Conclusion: Autologous MSC transplantation in MS appears feasible, safe, and well tolerated. Future trials to assess efficacy more definitively are warranted.
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http://dx.doi.org/10.1177/1352458517703802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623598PMC
April 2018

Processing speed test: Validation of a self-administered, iPad-based tool for screening cognitive dysfunction in a clinic setting.

Mult Scler 2017 Dec 12;23(14):1929-1937. Epub 2017 Jan 12.

Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.

Background: Cognitive dysfunction is common in multiple sclerosis (MS) patients and has important consequences for daily activities, yet, unlike motor function, is not routinely assessed in the clinic setting. We developed the Processing Speed Test (PST), a self-administered iPad-based tool to measure MS-related deficits in processing speed.

Objective: To determine whether the PST is valid for screening cognitive dysfunction by comparing it to the paper-and-pencil Symbol Digit Modalities Test (SDMT).

Methods: We assessed PST test-retest reliability, sensitivity of PST and SDMT in discriminating MS patients from healthy controls (HC), convergent validity between PST and SDMT, correlations between T2 lesion load and PST and SDMT, and PST performance with and without technician present during administration.

Results: PST had excellent test-retest reliability, was highly correlated with SDMT, was slightly more sensitive than SDMT in discriminating MS from HC groups, and correlated better with cerebral T2 lesion load than did SDMT. Finally, PST performance was no different with or without a technician in the testing environment.

Conclusion: PST has advantages over SDMT because of its efficient administration, scoring, and potential for medical record or research database integration. PST is a practical tool for routine screening of processing speed deficits in the MS clinic.
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http://dx.doi.org/10.1177/1352458516688955DOI Listing
December 2017

Comparative efficacy and discontinuation of dimethyl fumarate and fingolimod in clinical practice at 12-month follow-up.

Mult Scler Relat Disord 2016 Nov 8;10:44-52. Epub 2016 Aug 8.

Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH, 44195 USA.

Background: Dimethyl fumarate (DMF) and fingolimod (FTY) are approved oral disease modifying therapies (DMT) for relapsing multiple sclerosis (MS). Phase 3 trials established these agents as effective and generally well tolerated, though comparative efficacy and discontinuation remain unknown.

Objective: To assess real-world efficacy and discontinuation of DMF and FTY over 12 months in patients with MS.

Methods: We identified 458 DMF-treated and 317 FTY-treated patients in a large academic MS center. Measures of disease activity and discontinuation were compared using propensity score (PS) weighting. Covariates in the PS model included demographics and baseline clinical and MRI characteristics within 12 months of DMT initiation. The primary outcome measure was on-treatment annualized relapse rate (ARR) ratio, which was analyzed using a Poisson regression model. Other measures included time to first relapse, drug discontinuation, time to discontinuation, and new brain MRI lesions at 12 months.

Results: The on-treatment ARR for DMF was 0.16 (95% CI (0.12, 0.18)) and 0.13 (95% CI (0.08, 0.16)) for FTY. PS weighting, which demonstrated excellent covariate balance, showed no differences between groups on ARR (rate ratio=1.56, 95% CI (0.78, 3.14)), overall brain MRI activity defined as new T2 and/or gadolinium enhancing (GdE) lesions (OR=1.38, 95% CI (0.78, 2.42)), new T2 lesions (OR=1.33, 95% CI (0.71, 2.49)), and discontinuation (OR=1.30, 95% CI (0.84, 1.99)). DMF had higher odds of GdE lesions (OR=2.19, 95% CI (1.10, 4.35)), earlier time to discontinuation (HR=1.35, 95% CI (1.05, 1.74)), and earlier relapses (HR=1.64, 95% CI (1.10, 2.46)) compared to FTY.

Conclusion: Assessment in our clinical practice cohort showed comparable clinical efficacy, overall brain MRI activity, and discontinuation between DMF and FTY at 12 months. DMF had increased GdE lesions and intolerability early after treatment initiation.
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http://dx.doi.org/10.1016/j.msard.2016.08.002DOI Listing
November 2016

Heterogeneous depression trajectories in multiple sclerosis patients.

Mult Scler Relat Disord 2016 Sep 5;9:163-9. Epub 2016 Aug 5.

Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA. Electronic address:

Background: Trajectories of depression over time may be heterogeneous in Multiple Sclerosis (MS) patients. Describing these trajectories will help clinicians understand better the progression of depression in MS patients to aid in patient care decisions.

Methods: Latent class growth analysis (LCGA) was applied to 3507 MS patients using an electronic health records (EHR) data base to identify subgroups of MS patients based on self-reported depression screening (PHQ-9). Latent trajectory classes were used for group comparisons based on baseline clinical characteristics.

Results: Three subgroups were found characterized by high (10.0% [of participants]), wavering above and below moderate (26.2%) and low and variable (63.8%) depression level trajectories. The subpopulation trajectories, respectively, were also characterized by high, moderate and low MS disability at baseline. In contrast, the overall average trajectory was slightly declining and below the moderate depression threshold.

Conclusion: The LCGA approach described in this paper and applied to MS patients provides a template for improved use of an EHR data base for understanding heterogeneous depression screening trajectories. Clinicians may use such information to more closely monitor patients that are expected to maintain high or unstable depression levels.
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http://dx.doi.org/10.1016/j.msard.2016.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031243PMC
September 2016

Incidence, characterization, and clinical impact analysis of peginterferon beta1a immunogenicity in patients with multiple sclerosis in the ADVANCE trial.

Ther Adv Neurol Disord 2016 Jul 10;9(4):239-49. Epub 2016 Mar 10.

14 Cambridge Center, Building 6A, Floor 6, Office K01, Cambridge, MA 02142, USA.

Background: Efficacy of interferon beta in multiple sclerosis (MS) can be dampened in patients who develop neutralizing antidrug antibodies (NAbs). Peginterferon beta1a is an interferon conjugated with a polyethylene glycol (PEG) moiety. Pegylation increases a drug's half life and exposure, and may also reduce immunogenicity.

Objective: The objective of this study was to characterize the incidence and impact of immunogenicity to peginterferon beta1a over 2 years in patients with MS.

Methods: Patients with relapsing-remitting MS (N = 1512) were randomized to subcutaneous peginterferon beta1a 125 μg every 2 or 4 weeks, or placebo, for 1 year; patients in the placebo group were rerandomized to active treatment in year 2. The incidence and titers of binding antibodies (BAbs) and NAbs to interferon and antibodies to PEG (anti-PEG) were assessed in analytically validated assays. The clinical impact of immunogenicity on relapse and magnetic resonance imaging endpoints was evaluated.

Results: Over 2 years, 6%, less than 1%, and 7% of patients developed anti-interferon BAbs, NAbs, and anti-PEG antibodies, respectively. There was no discernible clinically meaningful effect of antibody status on the pharmacodynamic, efficacy, or safety parameters evaluated, although these analyses were limited by the low incidence of treatment-emergent antibodies.

Conclusion: The treatment effect of peginterferon beta1a in patients with relapsing-remitting MS is not expected to be attenuated by immunogenicity.
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http://dx.doi.org/10.1177/1756285616633967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916515PMC
July 2016

Relapses in multiple sclerosis: Relationship to disability.

Mult Scler Relat Disord 2016 Mar 8;6:10-20. Epub 2015 Sep 8.

UCSF Regional Pediatric MS Center, Race to Erase MS, San Francisco, CA, United States.

Multiple sclerosis (MS) is a recurrent inflammatory disease of the central nervous system, which ultimately causes substantial disability in many patients. A key clinical feature of this disease is the occurrence of relapses, consisting of episodes of neurological dysfunction followed by periods of remission. This review considers in detail the importance of the occurrence of relapses to the ultimate course of MS and the impact of relap setreatment (both acutely and prophylactically) on the long-term outcome for individuals. The ultimate goal of therapy in MS is the reduction of long-term disability. Clinical trials in MS, however, typically only extend for a very short time period compared to the time it takes for disability to evolve. Consequently, short-term outcome measures that are associated with, and predict, future disability need to be identified. In this regard, not only are relapses a characteristic feature of MS, they have also been proven to be associated with the occurrence of long-term disability. Moreover, treatments that reduce the number and severity of these attacks improve the long-term prognosis.
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http://dx.doi.org/10.1016/j.msard.2015.09.002DOI Listing
March 2016

Optical Coherence Tomography for the Detection of Remote Optic Neuritis in Multiple Sclerosis.

J Neuroimaging 2016 05 15;26(3):283-8. Epub 2016 Jan 15.

Cole Eye Institute, Cleveland Clinic, Cleveland, OH.

Background And Purpose: Evidence of remote optic neuritis is often used to support a diagnosis of multiple sclerosis (MS). Optical coherence tomography (OCT) can provide qualitative and quantitative data on the retina, where the effects of optic neuritis can be seen. Our aim was to determine whether there is a quantitative difference in retinal structures in eyes with optic neuritis compared with those without, and which measures were best able to discriminate eyes with a history of optic neuritis from nonoptic neuritis eyes in MS patients.

Methods: We performed a prospective cohort study of 30 MS-optic neuritis patients, 22 MS-nonoptic neuritis patients, and 24 healthy participants. Patients underwent visual acuity testing and OCT imaging. Retinal measurements were compared across groups. OCT measurements and visual acuities were analyzed for their ability to discriminate between optic neuritis and nonoptic neuritis eyes.

Results: Optic neuritis eyes exhibited a thinner peripapillary retinal nerve fiber layer, papillomacular bundle, and ganglion cell + inner plexiform layer thicknesses compared to MS eyes without optic neuritis and healthy controls. Papillomacular bundle thickness was the best model to discriminate between eyes with optic neuritis and nonoptic neuritis eyes in MS patients. Visual acuity alone yielded rather poor models.

Conclusions: Optic neuritis is associated with thinning in multiple regions of the retina. Optic neuritis eyes can be differentiated most accurately from nonoptic neuritis eyes using OCT. Our work suggests a potential role for OCT in documenting a remote history of optic neuritis to corroborate a diagnosis of MS.
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http://dx.doi.org/10.1111/jon.12326DOI Listing
May 2016