Publications by authors named "Ellen M Mowry"

87 Publications

Optic Neuritis-Independent Retinal Atrophy in Neuromyelitis Optica Spectrum Disorder.

J Neuroophthalmol 2021 May 17. Epub 2021 May 17.

Department of Neurology (AGF, ESV, KCF, GK, JL, MAM, EMM, SS, PAC, ESS), Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Electrical and Computer Engineering (YH, YL, JLP), Johns Hopkins University, Baltimore, Maryland; Viela Bio (MAM), Gaithersburg, Maryland; and Department of Neurology (ML), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Background: A limited number of studies have investigated the presence of ongoing disease activity independent of clinical relapses in neuromyelitis optica spectrum disorder (NMOSD), and data are conflicting. The objective of our study was to examine whether patients with aquaporin-4 (AQP4)-IgG seropositive NMOSD exhibit progressive retinal neuroaxonal loss, independently of optic neuritis (ON) attacks.

Methods: In this single-center, longitudinal study, 32 AQP4-IgG+ NMOSD patients and 48 healthy controls (HC) were followed with serial spectral-domain optical coherence tomography and visual acuity (VA) assessments. NMOSD patients with ON less than 6 months before baseline were excluded, whereas data from patients with ON during follow-up were censored at the last visit before ON. VA worsening was defined as a decrease in monocular letter acuity ≥5 letters for high-contrast VA and ≥7 letters for low-contrast VA. Analyses were performed with mixed-effects linear regression models adjusted for age, sex, and race.

Results: The median follow-up duration was 4.2 years (interquartile range: 1.8-7.5). Relative to HC, NMOSD eyes had faster peripapillary retinal nerve fiber layer (pRNFL) (β = -0.25 µm/year faster, 95% confidence interval [CI]: -0.45 to -0.05, P = 0.014) and GCIPL thinning (β = -0.09 µm/year faster, 95% CI: -0.17 to 0, P = 0.05). This difference seemed to be driven by faster pRNFL and GCIPL thinning in NMOSD eyes without a history of ON compared with HC (GCIPL: β = -0.15 µm/year faster; P = 0.005; pRNFL: β = -0.43 µm/year faster, P < 0.001), whereas rates of pRNFL (β: -0.07 µm/year, P = 0.53) and GCIPL (β = -0.01 µm/year, P = 0.90) thinning did not differ between NMOSD-ON and HC eyes. Nine NMOSD eyes had VA worsening during follow-up.

Conclusions: In this longitudinal study, we observed progressive pRNFL and GCIPL atrophy in AQP4-IgG+ NMOSD eyes unaffected by ON. These results support that subclinical involvement of the anterior visual pathway may occur in AQP4-IgG+ NMOSD.
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http://dx.doi.org/10.1097/WNO.0000000000001282DOI Listing
May 2021

Early Aggressive Treatment Approaches for Multiple Sclerosis.

Curr Treat Options Neurol 2021 15;23(7):19. Epub 2021 May 15.

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

Purpose Of Review: This review presents a comprehensive analysis of the current high-efficacy disease-modifying therapies (DMTs) available for treatment of multiple sclerosis (MS). We discuss the existing approved and emerging therapeutics in patients with relapsing and progressive forms of MS using data from clinical trials and observational studies. Treatment considerations in pediatric and pregnant populations are also reviewed. Finally, we discuss the treatment paradigms of the escalation and early aggressive approaches to treatment of MS, with review of ongoing clinical trials to compare these approaches.

Recent Findings: Natalizumab has shown promising data on efficacy in not only randomized trials but also observational studies when compared with placebo, the injectable DMTs, and fingolimod. The anti-CD20 B cell depleting therapies (rituximab, ocrelizumab, and ofatumumab) have also demonstrated superiority in randomized clinical trials compared to their comparator group (placebo, interferon, and teriflunomide, respectively) and rituximab has shown in observational studies to be more effective than older injectable therapies and some of the oral therapies. Alemtuzumab has shown good efficacy in randomized controlled trials and observational studies yet has several potentially severe side effects limiting its use. Mitoxantrone has similarly demonstrated significant reduction in new disease activity compared to placebo but is rarely used due to its severe side effects. Cladribine is an oral DMT often grouped in discussion with other higher efficacy DMTs but may be slightly less effective than the other therapies described in this review. Many emerging targets for therapeutic intervention are currently under investigation that may prove to be beneficial in early aggressive MS, including autologous hematopoietic stem cell transplantation.

Summary: Traditionally, MS has been treated with an escalation approach, starting patients on a modestly effective DMT and subsequently escalating to a higher efficacy DMT when there is evidence of clinical and/or radiologic breakthrough activity. With the development of higher efficacy therapies and emerging data showing the potential positive long-term impact of these therapies when started earlier in the disease course, many clinicians have shifted to an early aggressive treatment approach in which patients are initially started on a higher efficacy DMT. Two clinical trials, the TRaditional versus Early Aggressive Therapy for MS (TREAT-MS) trial and the Determining the Effectiveness of earLy Intensive Versus Escalation approaches for the treatment of Relapsing-remitting MS (DELIVER-MS) trial, aim to directly compare these treatment strategies and their impact on clinical and radiologic outcomes.
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http://dx.doi.org/10.1007/s11940-021-00677-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121641PMC
May 2021

Risk Factors For Infection And Health Impacts Of The Covid-19 Pandemic In People With Autoimmune Diseases.

Clin Infect Dis 2021 May 6. Epub 2021 May 6.

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

Background: People with autoimmune or inflammatory conditions taking immunomodulatory/suppressive medications may have higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences.

Methods: We included participants with autoimmune or inflammatory conditions followed by specialists at Johns Hopkins. Participants completed periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare. We assessed whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterized pandemic-associated changes to care and mental health.

Results: 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medications) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in models incorporating behavior and other potential confounders (OR: 1.43; 95%CI: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95%CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95%CI: 1.24, 2.28), and kidney disease (OR: 1.76; 95%CI: 1.04, 2.97) were associated with higher odds of COVID-19. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions therein, which disproportionately affected individuals experiencing changes to employment or income.

Conclusions: Glucocorticoid exposure may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions.
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http://dx.doi.org/10.1093/cid/ciab407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135997PMC
May 2021

Association of Spectral-Domain OCT With Long-term Disability Worsening in Multiple Sclerosis.

Neurology 2021 04 2;96(16):e2058-e2069. Epub 2021 Mar 2.

From the Department of Neurology (J.L., K.C.F., O.C.M., A.G.F., E.S.S., G.K., E.V., N.P., E.O., B.T., N.J.L., S.D., N.F., O.K., H.R., S.D.N., E.M.M., S.S., P.A.C.), Johns Hopkins University School of Medicine; and Departments of Biostatistics (C.M.C.) and Electrical and Computer Engineering (J.L.P.), Johns Hopkins University, Baltimore, MD.

Objective: To evaluate whether a retinal spectral-domain optical coherence tomography (SD-OCT) assessment at baseline is associated with long-term disability worsening in people with multiple sclerosis (PwMS), we performed SD-OCT and Expanded Disability Status Scale (EDSS) assessments among 132 PwMS at baseline and at a median of 10 years later.

Methods: In this prospective, longitudinal study, participants underwent SD-OCT, EDSS, and visual acuity (VA) assessments at baseline and at follow-up. Statistical analyses were performed using generalized linear regression models, adjusted for age, sex, race, multiple sclerosis (MS) subtype, and baseline disability. We defined clinically meaningful EDSS worsening as an increase of ≥2.0 if baseline EDSS score was <6.0 or an increase of ≥1.0 if baseline EDSS score was ≥6.0.

Results: A total of 132 PwMS (mean age 43 years; 106 patients with relapsing-remitting MS) were included in analyses. Median duration of follow-up was 10.4 years. In multivariable models excluding eyes with prior optic neuritis, relative to patients with an average baseline ganglion cell + inner plexiform layer (GCIPL) thickness ≥70 µm (the mean GCIPL thickness of all eyes at baseline), an average baseline GCIPL thickness <70 µm was associated with a 4-fold increased odds of meaningful EDSS worsening (adjusted odds ratio [OR] 3.97, 95% confidence interval [CI] 1.24-12.70; = 0.02) and an almost 3-fold increased odds of low-contrast VA worsening (adjusted OR 2.93, 95% CI 1.40-6.13; = 0.04).

Conclusions: Lower baseline GCIPL thickness on SD-OCT is independently associated with long-term disability worsening in MS. Accordingly, SD-OCT at a single time point may help guide therapeutic decision-making among individual PwMS.

Classification Of Evidence: This study provides Class I evidence that lower baseline GCIPL thickness on SD-OCT is independently associated with long-term disability worsening in MS.
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http://dx.doi.org/10.1212/WNL.0000000000011788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166450PMC
April 2021

RISK FACTORS FOR INFECTION AND HEALTH IMPACTS OF THE COVID-19 PANDEMIC IN PEOPLE WITH AUTOIMMUNE DISEASES.

medRxiv 2021 Feb 5. Epub 2021 Feb 5.

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

Background: People with autoimmune or inflammatory conditions who take immunomodulatory/suppressive medications may have a higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences.

Objective: Assess whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterize pandemic-associated changes to care.

Design: Longitudinal registry study.

Participants: 4666 individuals with autoimmune or inflammatory conditions followed by specialists in neurology, rheumatology, cardiology, pulmonology or gastroenterology at Johns Hopkins.

Measurements: Periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare.

Results: A total of 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medication exposure) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in multivariable models incorporating behavior and other potential confounders (OR: 1.43; 95%CI: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95%CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95%CI: 1.24, 2.28), and chronic kidney disease (OR: 1.76; 95%CI: 1.04, 2.97) were each associated with higher odds of COVID-19. Pandemic-related disruption to care was common. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions. Individuals experiencing changes to employment or income were at highest odds of care disruption.

Limitations: Results may not be generalizable to all patients with autoimmune or inflammatory conditions. Information was self-reported.

Conclusions: Exposure to glucocorticoids may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions.
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http://dx.doi.org/10.1101/2021.02.03.21251069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872366PMC
February 2021

Obesity's role in MS: An intervention target with possible interactions.

Neurol Neuroimmunol Neuroinflamm 2021 01 15;8(1). Epub 2020 Dec 15.

From the Department of Neurology (K.C.F., E.M.M.), Johns Hopkins School of Medicine; and Department of Epidemiology (K.C.F., E.M.M.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

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http://dx.doi.org/10.1212/NXI.0000000000000932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745727PMC
January 2021

Vascular comorbidity is associated with lower brain volumes and lower neuroperformance in a large multiple sclerosis cohort.

Mult Scler 2021 Jan 8:1352458520984746. Epub 2021 Jan 8.

Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA/Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Objective: The objective of this study is to assess the association between vascular comorbidity burden with clinical and imaging features of disease burden in a large population of people with multiple sclerosis (MS).

Methods: We included participants from the MS Partners Advancing Technology Health Solutions (MS PATHS) cohort. We evaluated if vascular comorbidities (diabetes, hypertension, and dyslipidemia) or a composite sum of comorbidities was associated with MS characteristics, including objective neurologic function assessments and quantitative brain magnetic resonance imaging (MRI) measurements in propensity score-weighted models.

Results: In total, 11,506 participants (6409 (55%) with brain MRI) were included. Individuals with 2+ vascular comorbidities had slower walking speed (standard deviation (SD) = -0.49; 95% confidence interval (CI) = -0.78, -0.19; = 0.001), slower manual dexterity (SD = -0.41; 95% CI = -0.57, -0.26; < 0.0001), and fewer correct scores on cognitive processing speed (SD = -0.11; 95% CI = -0.20, -0.02; = 0.02) versus those with no comorbidities. Those with 2+ had lower brain parenchymal (-0.41%, 95% CI = -0.64, -0.17) and gray matter fractions (-0.30%, 95% CI = -0.49, -0.10), including reduced cortical (-10.10 mL, 95% CI = -15.42, -4.78) and deep (-0.44 mL, 95% CI = -0.84, -0.04) gray matter volumes versus those with no comorbidity.

Conclusion: Increased vascular comorbidity burden was associated with clinical and imaging markers of neurologic dysfunction and neurodegeneration in MS. Strategies to optimize comorbidity management in people with MS are warranted.
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http://dx.doi.org/10.1177/1352458520984746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263795PMC
January 2021

Evidence of subclinical quantitative retinal layer abnormalities in AQP4-IgG seropositive NMOSD.

Mult Scler 2020 Dec 14:1352458520977771. Epub 2020 Dec 14.

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

Background: Prior studies have suggested that subclinical retinal abnormalities may be present in aquaporin-4 immunoglobulin G (AQP4-IgG) seropositive neuromyelitis optica spectrum disorder (NMOSD), in the absence of a clinical history of optic neuritis (ON).

Objective: Our aim was to compare retinal layer thicknesses at the fovea and surrounding macula between AQP4-IgG+ NMOSD eyes without a history of ON (AQP4-nonON) and healthy controls (HC).

Methods: In this single-center cross-sectional study, 83 AQP4-nonON and 154 HC eyes were studied with spectral-domain optical coherence tomography (OCT).

Results: Total foveal thickness did not differ between AQP4-nonON and HC eyes. AQP4-nonON eyes exhibited lower outer nuclear layer (ONL) and inner photoreceptor segment (IS) thickness at the fovea (ONL: -4.01 ± 2.03 μm,  = 0.049; IS: -0.32 ± 0.14 μm,  = 0.029) and surrounding macula (ONL: -1.98 ± 0.95 μm,  = 0.037; IS: -0.16 ± 0.07 μm,  = 0.023), compared to HC. Macular retinal nerve fiber layer (RNFL: -1.34 ± 0.51 μm,  = 0.009) and ganglion cell + inner plexiform layer (GCIPL: -2.44 ± 0.93 μm,  = 0.009) thicknesses were also lower in AQP4-nonON compared to HC eyes. Results were similar in sensitivity analyses restricted to AQP4-IgG+ patients who had never experienced ON in either eye.

Conclusions: AQP4-nonON eyes exhibit evidence of subclinical retinal ganglion cell neuronal and axonal loss, as well as structural evidence of photoreceptor layer involvement. These findings support that subclinical anterior visual pathway involvement may occur in AQP4-IgG+ NMOSD.
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http://dx.doi.org/10.1177/1352458520977771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200372PMC
December 2020

Depression in multiple sclerosis across the adult lifespan.

Mult Scler 2020 Dec 14:1352458520979304. Epub 2020 Dec 14.

Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Objectives: The objective of this study is to examine the burden of depressive symptoms across the adult age span in people with multiple sclerosis (MS) and test if the relationship between depressive symptoms and MS characteristics vary across age groups.

Methods: In analyses of the MS Partners Advancing Technology and Health Solutions (MS PATHS) network of adults with MS, we compared the prevalence of depression in MS PATHS with non-MS controls across age and evaluated for effect modification by age in the association between depressive symptoms and clinical and neuroperformance measures via multivariable-adjusted regression models.

Results: In total, 13,821 individuals with MS were included. The prevalence of depression was higher in MS versus non-MS controls, but was similar between men/women across age. The association between depression and processing speed (PST; for interaction = 0.009) or walking speed ( for interaction = 0.04) varied by age. For example, younger depressed individuals had 0.45 standard deviation (SD) (95% confidence interval (CI) = -0.62, -0.29) worse PST -scores versus non-depressed younger participants, whereas older depressed individuals had 0.20 SD (95% CI = -0.32, -0.08) worse PST -scores versus non-depressed older participants.

Conclusion: Depressive symptoms and age should be considered when interpreting measures of walking speed and cognitive function; these findings may have implications for analyses of neuroperformance change.
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http://dx.doi.org/10.1177/1352458520979304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200363PMC
December 2020

Clinical characteristics of a large multi-center cohort of people with multiple sclerosis over age 60.

Mult Scler Relat Disord 2021 Jan 23;47:102637. Epub 2020 Nov 23.

Johns Hopkins University, Baltimore, MD, USA.

Background: As the peak prevalence of multiple sclerosis (MS) shifts due to an aging patient population, understanding the characteristics that define this older cohort to improve overall management is critical. We sought to determine the clinical characteristics of people with MS over age 60.

Methods: Demographics, clinical characteristics, MS disease history, and Multiple Sclerosis Performance Test (MSPT) patient-reported outcomes and neuroperformance tests (NPTs) were collected from 10 academic MS centers in the US and Europe participating in the MS Partners Advancing Technology Health Solutions (MS PATHS) system. We characterized demographic and disease characteristics of included participants using descriptive statistics. We characterized prevalence of comorbidities and compared with estimated prevalences from the National Health and Nutrition Examination Survey (NHANES) respondents aged ≥60 years in 2017-2018.

Results: We identified 2738 individuals over age 60 from MS PATHS, with 58.1% relapsing-remitting (RR) and 41.9% progressive. Our results showed median age (RR=65.7 years, progressive=66.0 years), age of symptom onset (RR and progressive=40.9 years), and disease duration (RR=22.8 years, progressive=23.3 years). Over two-thirds of individuals in our cohort were treated with DMTs. The most common DMT used in RR patients were interferons (17.6%) and glatiramer acetate (16.3%), while glatiramer acetate was the most common (12.0%) in progressive patients. Progressive patients had higher disability (higher median PDDS scores, worse Neuro-Qol T-scores, and worse NPTs) compared to the RR group. Pain was the most common comorbidity, followed by cardiac disease, depression, hypertension, dyslipidemia, and obesity. Compared to older NHANES participants, older people with MS were more likely to have depression (MS PATHS: 51.5% [95% CI: 49.5% to 53.5%] vs. NHANES: 21.7% [95% CI: 1619.3% to 22.2%]) and osteoporosis (MS PATHS: 12.7% [95% CI: 11.3% to 14.1%] vs. NHANES: 8.2% [95% CI: 6.2% to 10.3%]); they were less likely to be obese (MS PATHS: 29.4% [95% CI: 27.7% to 31.2%] vs. NHANES: 45.1% [95% CI: 38.9% to 51.3%]) and have diabetes (MS PATHS: 12.3% [95% CI: 11.1% to 13.6%] vs. NHANES: 22.5% [95% CI: 18.8% to 25.7%]).

Conclusions: Our study characterizes a large multi-center international cohort of people with MS over age 60. This contemporary cohort appears less disabled than prior studies, which may reflect long term impact of DMT availability on the natural history of MS. The burden of comorbidity in this population was generally high. Information on DMT use, comorbidity, and disability outcome measures will be beneficial in future studies evaluating the impact of therapeutic interventions in older individuals.
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http://dx.doi.org/10.1016/j.msard.2020.102637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293698PMC
January 2021

Specific dietary interventions to tackle obesity should be a routine part of recommended MS care - Commentary.

Mult Scler 2020 11 9;26(13):1631-1632. Epub 2020 Oct 9.

Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA/Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

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http://dx.doi.org/10.1177/1352458520963907DOI Listing
November 2020

Reliability and validity of the multiple sclerosis resiliency scale (MSRS).

J Neurol Sci 2020 Nov 5;418:116983. Epub 2020 Jul 5.

Depatment of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.

Objective: The objective of this study was to determine the internal reliability and construct validity of the Multiple Sclerosis Resiliency Scale (MSRS) in comparison with a common measure of global resilience.

Methods: Participants were 216 community-dwelling adults with MS (mean age: 48.8 ± 12.5 years; 77% female; median disease duration: 8 years) recruited through a university-affiliated MS Center. Participants completed the MSRS, 10-item Connor Davidson Resilience Scale (CDRS), Perceived Stress Scale (PSS), and depressive and anxious symptom items from the SymptoMScreen.

Results: The MSRS exhibited fair to excellent internal consistency (αs 0.74 to 0.91) and divergent validity with disability severity (r = -0.19), MS duration (r = 0.07), and MS subtype (r = -0.01). The MSRS total and Emotional and Cognitive Strategies subscale scores were moderately correlated with the CDRS (rs = 0.50 and 0.62), PSS (rs = -0.56 and - 0.62), depressive symptoms (rs = -0.49 and - 0.54), and anxious symptoms (rs = -0.38 and - 0.047). The MSRS total and Emotional and Cognitive Strategies subscale scores exhibited fair to good accuracy (AUCs = 0.73 to 0.83) for identifying participants in the highest and lowest CDRS quartiles; however, cutoff scores yielded only fair sensitivity and specificity, and the measures differed significantly in classification of participants into highest and lowest quartiles.

Conclusion: Although the MSRS may be useful in assessing resilience to MS-specific challenges, use of a global resilience measure may still be indicated depending on the clinical and research context.
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http://dx.doi.org/10.1016/j.jns.2020.116983DOI Listing
November 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

Association of body mass index with longitudinal rates of retinal atrophy in multiple sclerosis.

Mult Scler 2020 06 16;26(7):843-854. Epub 2020 Apr 16.

Division of Neuroimmunology and Neurological Infections, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Studies evaluating associations between body mass index (BMI) and optical coherence tomography (OCT) measures in multiple sclerosis (MS) are lacking.

Objective: To assess whether elevated BMI is associated with accelerated retinal atrophy.

Methods: In this observational study, 513 MS patients were followed with serial spectral-domain OCT for a median of 4.4 years. Participants were categorized as normal weight (BMI: 18.5-24.9 kg/m), overweight (BMI: 25-29.9 kg/m), and obese (BMI: ⩾30 kg/m). Participants with diabetes mellitus or uncontrolled hypertension and eyes with optic neuritis (ON) ⩽6 months prior to baseline OCT or during follow-up were excluded. Statistical analyses were performed with mixed-effects linear regression.

Results: Obese patients ( = 146) exhibited accelerated rates of ganglion cell + inner plexiform layer (GCIPL) atrophy relative to normal weight patients ( = 214; -0.57%/year (95% confidence interval (CI): -0.65% to -0.48%) versus -0.42%/year (95% CI: -0.49% to -0.35%);  = 0.012). GCIPL atrophy rate did not differ between overweight ( = 153) and normal weight patients (-0.47%/year vs -0.42%/year;  = 0.41). Each 1 kg/m higher BMI was associated with accelerated GCIPL (-0.011%/year; 95% CI: -0.019% to -0.004%;  = 0.003) atrophy. Multivariable analyses accounting for age, sex, race, MS subtype, and ON history did not alter the above findings.

Conclusions: Elevated BMI, in the absence of overt metabolic comorbidities, may be associated with accelerated GCIPL atrophy. Obesity, a modifiable risk factor, may be associated with accelerated neurodegeneration in MS.
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http://dx.doi.org/10.1177/1352458519900942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293552PMC
June 2020

Breastfeeding may reduce postpartum relapse in some women with multiple sclerosis.

Neurology 2020 05 13;94(18):769-770. Epub 2020 Apr 13.

From the Preventive Neurology Unit (R.D.), Wolfson Institute of Preventive Medicine, Queen Mary University of London, England; and Johns Hopkins University (E.M.M.), Baltimore, MD.

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http://dx.doi.org/10.1212/WNL.0000000000009369DOI Listing
May 2020

Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation.

J Clin Invest 2020 07;130(7):3467-3482

Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including in the CNS and the immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric patients with MS compared with controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid, tauroursodeoxycholic acid (TUDCA), on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and proinflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced the severity of disease through its effects on G protein-coupled bile acid receptor 1 (GPBAR1). We demonstrate that bile acid metabolism was altered in MS and that bile acid supplementation prevented polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorated neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.
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http://dx.doi.org/10.1172/JCI129401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324171PMC
July 2020

Socioeconomic status and race are correlated with affective symptoms in multiple sclerosis.

Mult Scler Relat Disord 2020 Jun 14;41:102010. Epub 2020 Feb 14.

Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe St.Pathology 627, Baltimore, MD 21287, USA.

Objective: Investigate the relationship between socioeconomic status (SES) and race with self-reported fatigue, depression, and anxiety levels in multiple sclerosis (MS).

Methods: Cross-sectional review of the MS Partners Advancing Technology and Health Solutions (MS PATHS) database for adults with MS in the United States. We evaluated race and socioeconomic status (available markers: insurance, employment status, or level of education) as predictors of fatigue, depression, and anxiety sub-scores of the Neuro-QoL (Quality of life in neurological disorders), with particular interest between Caucasians/whites (CA) and African Americans/blacks (AA). Multivariate linear regression models included as covariates age, sex, disability status, smoking status, body mass index, and disease-modifying therapy.

Results: 7,430 individuals were included; compared to CA, AA tended to be younger, more female-predominant, and had a higher level of disability. AA had completed slightly less education, had a higher level of Medicaid coverage or uninsured status, and had higher rates of unemployed or disabled status. In the univariate model, markers of lower SES, by whichever definition we used, correlated with worse affective symptoms. In the multivariate model stratified by race, CA showed similar trends. In contrast, in AA, only lower SES by employment status was correlated with worse affective symptoms. In both CA and AA, moderate and severe level of disability correlated with worse affective symptoms.

Conclusion: SES and race may influence affective symptoms reported by individuals with MS. The reasons for the correlation are likely multifactorial. Longitudinal studies should strive to identify factors associated with risk of affective symptoms in MS that may be modifiable.
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http://dx.doi.org/10.1016/j.msard.2020.102010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311313PMC
June 2020

Leveraging real-world data to investigate multiple sclerosis disease behavior, prognosis, and treatment.

Mult Scler 2020 01 28;26(1):23-37. Epub 2019 Nov 28.

Departments of Internal Medicine (Neurology) and Community Health Sciences, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada.

Randomized controlled clinical trials and real-world observational studies provide complementary information but with different validity. Some clinical questions (disease behavior, prognosis, validation of outcome measures, comparative effectiveness, and long-term safety of therapies) are often better addressed using real-world data reflecting larger, more representative populations. Integration of disease history, clinician-reported outcomes, performance tests, and patient-reported outcome measures during patient encounters; imaging and biospecimen analyses; and data from wearable devices increase dataset utility. However, observational studies utilizing these data are susceptible to many potential sources of bias, creating barriers to acceptance by regulatory agencies and the medical community. Therefore, data standardization and validation within datasets, harmonization across datasets, and application of appropriate analysis methods are important considerations. We review approaches to improve the scope, quality, and analyses of real-world data to advance understanding of multiple sclerosis and its treatment, as an example of opportunities to better support patient care and research.
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http://dx.doi.org/10.1177/1352458519892555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950891PMC
January 2020

Conducting dietary intervention trials in people with multiple sclerosis: Lessons learned and a path forward.

Mult Scler Relat Disord 2020 Jan 29;37:101478. Epub 2019 Oct 29.

Department of Neurology, Johns Hopkins School of Medicine, 600N Wolfe St, Pathology 627, Baltimore MD, 21287, USA. Electronic address:

Disease course in people with multiple sclerosis (MS) is heterogeneous. The impact of dietary and nutritional factors on MS prognosis is of interest to both patients and clinicians; differences in diet are hypothesized to contribute to disease evolution over time. However, studying diet, especially in people with MS, introduces methodologic complexity that should be recognized. In this review, we focus on methodological aspects relevant to the conduct of dietary interventions in people with MS, given our experience in leading such studies and the challenges we encountered in the realization of this work. We summarize key aspects of study design and important considerations, regardless of the specifics of the actual study (e.g. the particular diet of interest, target MS population, etc.). We discuss strategies for the design of the intervention as well as the selection of appropriate study endpoints. Finally, we provide an overview of strategies to improve the rigor of conducting dietary studies in people with MS.
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http://dx.doi.org/10.1016/j.msard.2019.101478DOI Listing
January 2020

Pragmatic clinical trials for treating relapsing multiple sclerosis.

Lancet Neurol 2019 12;18(12):1075

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

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http://dx.doi.org/10.1016/S1474-4422(19)30386-2DOI Listing
December 2019

Evaluation of multiple sclerosis disability outcome measures using pooled clinical trial data.

Neurology 2019 11 22;93(21):e1921-e1931. Epub 2019 Oct 22.

From the University of Virginia (M.D.G.), Charlottesville; National Multiple Sclerosis Society (N.G.L.), New York, NY; Biogen (R.A.R., G.P.), Cambridge, MA; Critical Path Institute (L.D.H.), Tucson, AZ; Genentech (P.S.C.), South San Francisco, CA; Independent Neurology Clinical Development Consultant (G.S.F.); Premier Research (A.J.), Wokingham, UK; UCL Institute of Neurology (R.K.), London, UK; Imperial College London and UK Dementia Research Institute (P.M.M.); Johns Hopkins (E.M.M.), Baltimore, MD; New York University School of Medicine (L.J.B.), NY; Wave Life Sciences (M.P.), Cambridge, MA; VU University Medical Center (B.M.J.U.), Amsterdam, the Netherlands; and Cleveland Clinic (J.A.C.), OH.

Objective: We report analyses of a pooled database by the Multiple Sclerosis Outcome Assessments Consortium to evaluate 4 proposed components of a multidimensional test battery.

Methods: Standardized data on 12,776 participants, comprising demographics, multiple sclerosis disease characteristics, Expanded Disability Status Scale (EDSS) score, performance measures, and Short Form-36 Physical Component Summary (SF-36 PCS), were pooled from control and treatment arms of 14 clinical trials. Analyses of Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), Low Contrast Letter Acuity (LCLA), and Symbol Digit Modalities Test (SDMT) included measurement properties; construct, convergent, and known group validity; and longitudinal performance of the measures individually and when combined into a multidimensional test battery relative to the EDSS and SF-36 to determine sensitivity and clinical meaningfulness.

Results: The performance measures had excellent test-retest reliability and showed expected differences between subgroups based on disease duration and EDSS level. Progression rates in detecting time to 3-month confirmed worsening were lower for T25FW and 9HPT compared to EDSS, while progression rates for LCLA and SDMT were similar to EDSS. When the 4 measures were analyzed as a multidimensional measure rather than as individual measures, progression on any one performance measure was more sensitive than the EDSS. Worsening on the performance measures analyzed individually or as a multidimensional test battery was associated with clinically meaningful SF-36 PCS score worsening, supporting clinical meaningfulness of designated performance test score worsening.

Conclusion: These results support the use of the 4 proposed performance measures, individually or combined into a multidimensional test battery as study outcome measures.
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http://dx.doi.org/10.1212/WNL.0000000000008519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885577PMC
November 2019

Natalizumab wearing-off symptoms: Patients with MS on extended interval dosing may not "mind the gap".

Neurology 2019 10 24;93(17):735-736. Epub 2019 Sep 24.

From Johns Hopkins University (E.M.M.), Baltimore, MD; and Oregon Health and Sciences University (D.B.), Portland.

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http://dx.doi.org/10.1212/WNL.0000000000008358DOI Listing
October 2019

Another sphingosine 1-phosphate receptor modulator for the treatment of patients with multiple sclerosis.

Lancet Neurol 2019 11 3;18(11):983-985. Epub 2019 Sep 3.

University of Colorado, Aurora, CO 80045, USA. Electronic address:

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http://dx.doi.org/10.1016/S1474-4422(19)30333-3DOI Listing
November 2019

The prevalence and utility of screening for urinary tract infection at the time of presumed multiple sclerosis relapse.

Mult Scler Relat Disord 2019 Oct 2;35:61-66. Epub 2019 Jul 2.

Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA. Electronic address:

Background: Methods of screening for infections at the time of suspected relapse in people with multiple sclerosis (MS) vary across physicians. People with multiple sclerosis (MS) are at an increased risk of urinary tract infection (UTI). Data evaluating the utility of screening for potential UTI at the time of suspected relapse and whether there are key subgroups of patients in which screening would be most effective are sparse.

Objectives: To evaluate demographic and clinical predictors of UTI in the context of a suspected acute relapse in (1) a retrospective hospital admission cohort and (2) a prospectively-enrolled, ambulatory care-based cohort, and to determine an approximate number needed to screen to detect one UTI in both healthcare settings.

Methods: For the hospital admissions cohort, we included individuals with a known or new diagnosis of MS or clinically isolated syndrome who were admitted at least once to the Johns Hopkins Neurology Inpatient Service (March 2012 to December 2014). We considered those screened via urinalysis. Possible UTI was defined as leukocyte esterase OR nitrite positive. For the ambulatory population, we enrolled a cohort of RRMS patients aged 18-65 who were suspected of suffering from an acute MS relapse who either called or came into clinic. Participants were screened via urinalysis; possible UTI was similarly defined. Participants also completed questionnaires (disability, history of Uhthoff's-type phenomenon, recent sexual intercourse, and new urologic symptoms). For both cohorts, we calculated an approximate number needed to screen, and tested if demographic and patient characteristics were associated with possible UTI using logistic regression models.

Results: For the hospital admissions cohort, we included 158 individuals; 48 (30.4%) were identified as possibly having a UTI. For possible UTI, the approximate number needed to screen in order to detect 1 possible UTI is 3 (95% CI: 2, 6). Female sex was the only factor associated with increased odds of UTI (odds ratio [OR]: 3.90; 95% CI: 1.59-9.61; p = 0.003). For the ambulatory cohort, we included 50 participants; 10 (20.0%) with possible UTI. The approximate number needed to screen in order to detect 1 possible UTI was 5 (95% CI: 3, 11) in this cohort. Foul-smelling urine was positively associated with UTI (OR: 5.36; 95% CI: 1.10, 26.17; p = 0.04); no men had a possible UTI in this cohort, so we could not estimate odds ratios associated with sex.

Conclusion: UTIs at the time of a suspected MS relapse are relatively uncommon. Female sex is a strong risk factor for UTI in people with MS; foul-smelling urine is a potential predictor of UTI in people with MS. Larger studies are needed to comprehensively evaluate the utility of screening and risk factors for UTI at the time of suspected MS relapse.
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http://dx.doi.org/10.1016/j.msard.2019.06.038DOI Listing
October 2019

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

Multiple Sclerosis Risk Factors and Pathogenesis.

Continuum (Minneap Minn) 2019 Jun;25(3):596-610

Purpose Of Review: This article summarizes recent advances in the identification of genetic and environmental factors that affect the risk of developing multiple sclerosis (MS) and the pathogenic processes involved in acute relapses and relapse-independent disability progression.

Recent Findings: The number of single-nucleotide polymorphisms associated with increased risk of MS has increased to more than 200 variants. The evidence for the association of Epstein-Barr virus infection, vitamin D deficiency, obesity, and smoking with increased risk of MS has further accumulated, and, in cases of obesity and vitamin D deficiency, the evidence for causal association has strengthened. Interactions between genetic and environmental factors have been studied more extensively. Dietary factors and changes in the gut microbiota are emerging as possible modulators of the disease risk. Several processes important to MS pathogenesis have been newly investigated or investigated more comprehensively, including the role of B cells, innate immune cells, meningeal inflammation, cortical and gray matter demyelination, and early axonal and neuronal loss.

Summary: MS is a complex disease in which the interaction between genetic and environmental factors causes a cascade of events, including activation of the adaptive and innate immune system, blood-brain barrier breakdown, central nervous system demyelination, and axonal and neuronal damage with variable degrees of repair. These events manifest as potentially reversible focal neurologic symptoms or progressive nonremitting physical and cognitive disability, or both. Advances in the understanding of the risk factors and pathogenic mechanisms of MS have resulted in improved therapeutic strategies. The results of ongoing or future studies are needed to successfully and fully translate these advances into clinical practice.
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http://dx.doi.org/10.1212/CON.0000000000000725DOI Listing
June 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

Retinal measurements predict 10-year disability in multiple sclerosis.

Ann Clin Transl Neurol 2019 02 19;6(2):222-232. Epub 2019 Jan 19.

Department of Neurology Johns Hopkins University Baltimore Maryland.

Objective: Optical coherence tomography (OCT)-derived measures of the retina correlate with disability and cortical gray matter atrophy in multiple sclerosis (MS); however, whether such measures predict long-term disability is unknown. We evaluated whether a single OCT and visual function assessment predict the disability status 10 years later.

Methods: Between 2006 and 2008, 172 people with MS underwent Stratus time domain-OCT imaging [160 with measurement of total macular volume (TMV)] and high and low-contrast letter acuity (LCLA) testing ( = 150; 87%). All participants had Expanded Disability Status Scale (EDSS) assessments at baseline and at 10-year follow-up. We applied generalized linear regression models to assess associations between baseline TMV, peripapillary retinal nerve fiber layer (pRNFL) thickness, and LCLA with 10-year EDSS scores (linear) and with clinically significant EDSS worsening (binary), adjusting for age, sex, optic neuritis history, and baseline disability status.

Results: In multivariable models, lower baseline TMV was associated with higher 10-year EDSS scores (mean increase in EDSS of 0.75 per 1 mm loss in TMV (mean difference = 0.75; 95% CI: 0.11-1.39;  = 0.02). In analyses using tertiles, individuals in the lowest tertile of baseline TMV had an average 0.86 higher EDSS scores at 10 years (mean difference = 0.86; 95% CI: 0.23-1.48) and had over 3.5-fold increased odds of clinically significant EDSS worsening relative to those in the highest tertile of baseline TMV (OR: 3.58; 95% CI: 1.30-9.82; = 0.008). pRNFL and LCLA predicted the 10-year EDSS scores only in univariate models.

Interpretation: Lower baseline TMV measured by OCT significantly predicts higher disability at 10 years, even after accounting for baseline disability status.
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http://dx.doi.org/10.1002/acn3.674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389740PMC
February 2019

Trial of intrathecal rituximab in progressive multiple sclerosis patients with evidence of leptomeningeal contrast enhancement.

Mult Scler Relat Disord 2019 May 11;30:136-140. Epub 2019 Feb 11.

Department of Neurology, Johns Hopkins University School of Medicine, 600 N Wolfe St, Pathology 627, Baltimore, MD 21287, USA.

Background: Leptomeningeal inflammation is associated with increased cortical damage and worse clinical outcomes in MS. It may be detected on contrast-enhanced T2-FLAIR imaging as focal leptomeningeal contrast-enhancement (LME).

Objective: To assess the safety of intrathecal (IT) rituximab in progressive MS (PMS) and to assess its effects on LME and CSF biomarkers.

Methods: PMS patients had a screening MRI to detect LME. Participants satisfying eligibility criteria underwent two IT administrations of 25 mg rituximab 2 weeks apart. Follow-up lumbar puncture and MRI were performed at 8 and 24 weeks after the first treatment.

Results: Of 36 patients screened 15 had LME, 11 consented, and 8 received study treatment. Mean age was 56.7 years and number of LME lesions ranged from 1 to 3. No serious adverse effects occurred. We noted profound reductions in peripheral B cells from baseline to week 2 and 8 with some return at week 24. We also observed transient reductions in CSF B cells and CXCL-13 levels with an increase in BAFF levels. However, the number of LME did not change following treatment.

Conclusions: IT rituximab was well tolerated in PMS patients and had transient effects on CSF biomarkers but did not change LME.
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http://dx.doi.org/10.1016/j.msard.2019.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325522PMC
May 2019
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