Publications by authors named "Elliot M Frohman"

167 Publications

Encephalitis and Myelitis in a Young Woman: Overlap Syndrome, Thyroiditis, and Occult Tumor From the National Multiple Sclerosis Society Case Conference Proceedings.

Neurol Neuroimmunol Neuroinflamm 2021 07 23;8(5). Epub 2021 Jun 23.

From the Department of Neurology (N.Z.E.), Kaiser Permanente Washington, Seattle; Department of Neurology (A.W.), University of Washington, Seattle; Neuroimmunology (T.V.), Stanford University of California; Colangelo College of Business (T.V.), Grand Canyon University, Phoenix, AZ; Department of Neurology (R.P.L.), Wayne State University, Detroit, MI; Department of Neurology (A.G.), University of Rochester, NY; Department of Neurosciences (J.G.), University of California at San Diego; Department of Neurology and Program in Immunology (S.S.Z.), University of California San Francisco; Laboratory of Neuroimmunology of Professor Laurence Steinman (E.M.F., T.C.F.), Stanford University School of Medicine, CA; Department of Neurology (S.D.N.), Johns Hopkins Hospital, Baltimore, MD.

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http://dx.doi.org/10.1212/NXI.0000000000001026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223881PMC
July 2021

Application of an evidence-based, out-patient treatment strategy for COVID-19: Multidisciplinary medical practice principles to prevent severe disease.

J Neurol Sci 2021 Jul 20;426:117463. Epub 2021 Apr 20.

Laboratory of Neuroimmunology, Professor Lawrence Steinman, Stanford University School of Medicine, United States of America. Electronic address:

The COVID-19 pandemic has devastated individuals, families, and institutions throughout the world. Despite the breakneck speed of vaccine development, the human population remains at risk of further devastation. The decision to not become vaccinated, the protracted rollout of available vaccine, vaccine failure, mutational forms of the SARS virus, which may exhibit mounting resistance to our molecular strike at only one form of the viral family, and the rapid ability of the virus(es) to hitch a ride on our global transportation systems, means that we are will likely continue to confront an invisible, yet devastating foe. The enemy targets one of our human physiology's most important and vulnerable life-preserving body tissues, our broncho-alveolar gas exchange apparatus. Notwithstanding the fear and the fury of this microbe's potential to raise existential questions across the entire spectrum of human endeavor, the application of an early treatment intervention initiative may represent a crucial tool in our defensive strategy. This strategy is driven by evidence-based medical practice principles, those not likely to become antiquated, given the molecular diversity and mutational evolution of this very clever "world traveler".
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http://dx.doi.org/10.1016/j.jns.2021.117463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055502PMC
July 2021

Treating MS after surviving PML: Discrete strategies for rescue, remission, and recovery patient 2: From the National Multiple Sclerosis Society Case Conference Proceedings.

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

From the Department of Neurology (R.A.C., E. Melamed, T.C.V., E. Meltzer), Dell Medical School, University of Texas at Austin; Department of Ophthalmology (N.H.), University of Texas Southwestern, Dallas; Wellness Care Centers and Pediatric Rehabilitation (J.S.), Denton, TX; Ascension Seton Medical Center (M.S.), Austin, TX; National Institutes of Health (E.O.M.), Bethesda, MD; Departments of Neurology, and Biochemistry, Microbiology and Immunology (R.P.L.), Wayne State University, Detroit, MI; Colangelo College of Business (T.C.V.), Grand Canyon University, Phoenix, AZ; Department of Neurology (A.G.), University of Rochester, NY; Department of Computer Science (O.K.), Texas State University, San Marcos; Division of Microbiology and Immunology (M.S.P.), Yerkes National Primate Research Center, and Department of Pathology and Laboratory Medicine (M.S.P.), Emory University, Atlanta, GA; The National Multiple Sclerosis Society (K.C.), New York, NY; Department of Neurology (J.S.G.), University of California at San Diego; Department of Neurology (S.N.), Johns Hopkins Hospital, Bethesda, MD; Department of Neurology and Program in Immunology (S.S.Z.), University of California, San Francisco; andDepartments of Neurology, Ophthalmology & Neurosurgery (E.M.F., T.C.F.), Dell Medical School at the University of Texas at Austin.

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http://dx.doi.org/10.1212/NXI.0000000000000930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803334PMC
January 2021

Treating MS after surviving PML: Discrete strategies for rescue, remission, and recovery patient 1: From the National Multiple Sclerosis Society Case Conference Proceedings.

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

From the University of Rochester (N.A.), NY. N. Anadani is now with Department of Neurology, University of Oklahoma Health Science Center; Department of Neurology (M.H., A.D.G.), University of Rochester, NY; Department of Neurology (R.A.C., E.M., T.C.V.), Dell Medical School at the University of Texas at Austin; Department of Neurology (R.L.), Wayne State University, Detroit, MI; The National Multiple Sclerosis Society (K.C.), New York, NY; Laboratory of Molecular Medicine and Neuroscience (E.O.M.), Neurological Institute of Neurological Disorder and Stroke (Y.J.), Bethesda, MD. Y. Jassam is now with Department of Neurology, The University of Kansas Health System; Colangelo College of Business (T.C.V.), Grand Canyon University, Phoenix, AZ; Division of Microbiology and Immunology (M.S.P.), Yerkes National Primate Research Center, and Department of Pathology and Laboratory Medicine (M.S.P.), Emory University, Atlanta, GA; Department of Neurosciences (J.S.G.), University of California at San Diego; Department of Neurology (S.N.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology and Program in Immunology (S.S.Z.), University of California San Francisco; and Department of Neurology, Neurosurgery, and Ophthalmology (E.M.F., T.C.F.), Dell Medical School at the University of Texas at Austin.

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http://dx.doi.org/10.1212/NXI.0000000000000929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803340PMC
January 2021

Mitigating alemtuzumab-associated autoimmunity in MS: A "whack-a-mole" B-cell depletion strategy.

Neurol Neuroimmunol Neuroinflamm 2020 11 7;7(6). Epub 2020 Aug 7.

From the Department of Neurology (E.M., S.C., B.E., R.A.C.), Dell Medical School, University of Texas at Austin; Department of Neurology (L.S.), Stanford University School of Medicine, Palo Alto, CA; Division of Microbiology and Immunology (M.S.P.), Yerkes National Primate Research Center, and Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA; Department of Neurology and Program in Immunology (S.S.Z.), University of California San Francisco; and Departments of Neurology (E.M.F., T.C.F.), Ophthalmology & Neurosurgery, Dell Medical School at the University of Texas at Austin.

Objective: To determine whether the punctuated administration of low-dose rituximab, temporally linked to B-cell hyperrepopulation (defined when the return of CD19 B cells approximates 40%-50% of baseline levels as measured before alemtuzumab treatment inception), can mitigate alemtuzumab-associated secondary autoimmunity.

Methods: In this hypothesis-driven pilot study, 10 patients received low-dose rituximab (50-150 mg/m), a chimeric anti-CD20 monoclonal antibody, after either their first or second cycles of alemtuzumab. These patients were then routinely assessed for the development of autoimmune disorders and safety signals related to the use of dual monoclonal antibody therapy.

Results: Five patients received at least 1 IV infusion of low-dose rituximab, following alemtuzumab therapy, with a mean follow-up of 41 months. None of the 5 patients developed secondary autoimmune disorders. An additional 5 patients with follow-up over less than 24 months received at least 1 infusion of low-dose rituximab treatment following alemtuzumab treatment. No secondary autoimmune diseases were observed.

Conclusions: An anti-CD20 "whack-a-mole" B-cell depletion strategy may serve to mitigate alemtuzumab-associated secondary autoimmunity in MS by reducing the imbalance in B- and T-cell regulatory networks during immune reconstitution. We believe that these observations warrant further investigation.

Classification Of Evidence: This study provides Class IV evidence that for people with MS, low-dose rituximab following alemtuzumab treatment decreases the risk of alemtuzumab-associated secondary autoimmune diseases.
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http://dx.doi.org/10.1212/NXI.0000000000000868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643549PMC
November 2020

Part II. high-dose methotrexate with leucovorin rescue for severe COVID-19: An immune stabilization strategy for SARS-CoV-2 induced 'PANIC' attack.

J Neurol Sci 2020 08 21;415:116935. Epub 2020 May 21.

Department of Neurology, The Dell Medical School, The University of Texas at Austin, Austin, TX, United States of America; Department of Neurosurgery, The Dell Medical School, The University of Texas at Austin, Austin, TX, United States of America; Department of Ophthalmology, The Dell Medical School, The University of Texas at Austin, Austin, TX, United States of America. Electronic address:

Here, in Part II of a duology on the characterization and potential treatment for COVID-19, we characterize the application of an innovative treatment regimen for the prevention of the transition from mild to severe COVID-19, as well as detail an intensive immunotherapy intervention hypothesis. We propose as a putative randomized controlled trial that high-dose methotrexate with leucovorin (HDMTX-LR) rescue can abolish 'PANIC', thereby 'left-shifting' severe COVID-19 patients to the group majority of those infected with SARS-CoV-2, who are designated as having mild, even asymptomatic, disease. HDMTX-LR is endowed with broadly pleiotropic properties and is a repurposed, generic, inexpensive, and widely available agent which can be administered early in the course of severe COVID-19 thus rescuing the critical and irreplaceable gas-exchange alveoli. Further, we describe a preventative treatment intervention regimen for those designated as having mild to moderate COVID-19 disease, but who exhibit features which herald the transition to the severe variant of this disease. Both of our proposed hypothesis-driven questions should be urgently subjected to rigorous assessment in the context of randomized controlled trials, in order to confirm or refute the contention that the approaches characterized herein, are in fact capable of exerting mitigating, if not abolishing, effects upon SARS-CoV-2 triggered 'PANIC Attack'. Confirmation of our immunotherapy hypothesis would have far-reaching ramifications for the current pandemic, along with yielding invaluable lessons which could be leveraged to more effectively prepare for the next challenge to global health.
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http://dx.doi.org/10.1016/j.jns.2020.116935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241359PMC
August 2020

Part I. SARS-CoV-2 triggered 'PANIC' attack in severe COVID-19.

J Neurol Sci 2020 08 21;415:116936. Epub 2020 May 21.

Department of Neurology, The Dell Medical School, The University of Texas at Austin, Austin, TX, United States of America; Department of Neurosurgery, The Dell Medical School, The University of Texas at Austin, Austin, TX, United States of America; Department of Ophthalmology, The Dell Medical School, The University of Texas at Austin, Austin, TX, United States of America. Electronic address:

The coronavirus disease 2019 (COVID-19) pandemic has produced a world-wide collapse of social and economic infrastructure, as well as constrained our freedom of movement. This respiratory tract infection is nefarious in how it targets the most distal and highly vulnerable aspect of the human bronchopulmonary tree, specifically, the delicate yet irreplaceable alveoli that are responsible for the loading of oxygen upon red cell hemoglobin for use by all of the body's tissues. In most symptomatic individuals, the disease is a mild immune-mediated syndrome, with limited damage to the lung tissues. About 20% of those affected experience a disease course characterized by a cataclysmic set of immune activation responses that can culminate in the diffuse and irreversible obliteration of the distal alveoli, leading to a virtual collapse of the gas-exchange apparatus. Here, in Part I of a duology on the characterization and potential treatment for COVID-19, we define severe COVID-19 as a consequence of the ability of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to trigger what we now designate for the first time as a 'Prolific Activation of a Network-Immune-Inflammatory Crisis', or 'PANIC' Attack, in the alveolar tree. In Part II we describe an immunotherapeutic hypothesis worthy of the organization of a randomized clinical trial in order to ascertain whether a repurposed, generic, inexpensive, and widely available agent is capable of abolishing 'PANIC'; thereby preventing or mitigating severe COVID-19, with monumental ramifications for world health, and the global pandemic that continues to threaten it.
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http://dx.doi.org/10.1016/j.jns.2020.116936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241348PMC
August 2020

Cataclysmically disseminating neurologic presentation in an immunosuppressed lupus patient: From the National Multiple Sclerosis Society Case Conference Proceedings.

Neurol Neuroimmunol Neuroinflamm 2019 07 13;6(4):e582. Epub 2019 Jun 13.

Hospital of the University of Pennsylvania (C.M.P., E.T., D.J., ), Philadelphia, PA; Department of Neurology (R.P.L.), Wayne State University, Detroit, MI; Department of Neurology (E. I. Meltzer, E. Melamed, A.L., L.F., E.J.F.), Dell Medical School at the University of Texas at Austin, TX; Department of Neurology (P.S.), MS Fellowship Training Program, UT Southwestern School of Medicine, Dallas, TX; Oklahoma Medical Research Foundation (G.P.), Oklahoma City, OK; Department of Neurology (A.G.), University of Rochester, NY; Central Texas Neurology Consultants, and Department of Neurology (E.J.F.), Dell Medical School at the University of Texas at Austin, TX; The National Multiple Sclerosis Society (K.C.), New York, NY; Yerkes National Primate Research Center (M.S.P.), Emory University, Atlanta, GA; Department of Neurology and Program in Immunology (S.S.Z.), University of California San Francisco, San Francisco, CA; and Departments of Neurology and Ophthalmology (E.M.F., T.C.F.), Dell Medical School at the University of Texas at Austin, TX.

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http://dx.doi.org/10.1212/NXI.0000000000000582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624090PMC
July 2019

Alterations in the retinal vasculature occur in multiple sclerosis and exhibit novel correlations with disability and visual function measures.

Mult Scler 2020 06 16;26(7):815-828. Epub 2019 May 16.

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

Background: The retinal vasculature may be altered in multiple sclerosis (MS), potentially acting as a biomarker of disease processes.

Objective: To compare retinal vascular plexus densities in people with MS (PwMS) and healthy controls (HCs), and examine correlations with visual function and global disability.

Methods: In this cross-sectional study, 111 PwMS (201 eyes) and 50 HCs (97 eyes) underwent optical coherence tomography angiography (OCTA). Macular superficial vascular plexus (SVP) and deep vascular plexus (DVP) densities were quantified, and poor quality images were excluded according to an artifact-rating protocol.

Results: Mean SVP density was 24.1% (SD = 5.5) in MS eyes (26.0% (SD = 4.7) in non-optic neuritis (ON) eyes vs. 21.7% (SD = 5.5) in ON eyes,  < 0.001), as compared to 29.2% (SD = 3.3) in HC eyes ( < 0.001 for all MS eyes and multiple sclerosis optic neuritis (MSON) eyes vs. HC eyes,  = 0.03 for MS non-ON eyes vs. HC eyes). DVP density did not differ between groups. In PwMS, lower SVP density was associated with higher levels of disability (expanded disability status scale (EDSS):  = 0.26,  = 0.004; multiple sclerosis functional composite (MSFC):  = 0.27,  = 0.03) and lower letter acuity scores (100% contrast:  = 0.29; 2.5% contrast:  = 0.40; 1.25% contrast:  = 0.31;  < 0.001 for all).

Conclusions: Retinal SVP density measured by OCTA is reduced across MS eyes, and correlates with visual function, EDSS, and MSFC scores.
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http://dx.doi.org/10.1177/1352458519845116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858526PMC
June 2020

Macular Ganglion Cell and Inner Plexiform Layer Thickness Is More Strongly Associated With Visual Function in Multiple Sclerosis Than Bruch Membrane Opening-Minimum Rim Width or Peripapillary Retinal Nerve Fiber Layer Thicknesses.

J Neuroophthalmol 2019 12;39(4):444-450

Department of Neurology (JN, AR, NG, AA, EO, PAC, and SS), Johns Hopkins University School of Medicine, Baltimore, Maryland; Departments of Neurology (LJB and SLG), Population Health (LJB and SLG), and Ophthalmology (LJB and SLG), New York University School of Medicine, New York, New York; Departments of Neurology (EMF and TF) and Ophthalmology (EMF and TF), Dell Medical School, University of Texas at Austin, Austin, Texas; and Department of Biostatistics (CC), Johns Hopkins University, Baltimore, Maryland.

Background: Optical coherence tomography (OCT) measurements of ganglion cell + inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thicknesses are associated with visual function (VF) and disability in multiple sclerosis (MS). However, the value of measuring Bruch membrane opening-minimum rim width (BMO-MRW) thickness in MS remains unclear.

Methods: Sixty-eight patients with MS and 22 healthy controls (HCs) underwent spectral domain OCT, 100%-contrast visual acuity (VA), 2.5%- and 1.25%-contrast letter acuity (LA), and Expanded Disability Status Scale (EDSS) testing. Mixed-effects linear regression models, accounting for within-subject, intereye correlations, were used to assess relationships.

Results: The MS cohort exhibited significantly lower BMO-MRW (P = 0.01), pRNFL at 3.7-, 4.1-, and 4.7-mm diameters surrounding the optic disc (P < 0.001 for all), and GCIPL (P < 0.001) thicknesses than HCs. BMO-MRW thickness was associated with 100%-VA (P < 0.001, R = 0.08), 2.5%-LA (P < 0.001; R = 0.13), and 1.25%-LA (P = 0.002; R = 0.11). All measured pRNFL thicknesses were associated with high- and low-contrast VF (all: P < 0.001). GCIPL thickness was more strongly associated with 100%-VA (P < 0.001; R = 0.23), 2.5%-LA (P < 0.001; R = 0.27), and 1.25%-LA (P < 0.001; R = 0.21) than the other OCT measures assessed. All OCT measures were significantly, but weakly, associated with EDSS scores.

Conclusions: BMO-MRW and pRNFL thicknesses are reduced and associated with VF and disability in MS, but GCIPL thickness is a stronger marker of visual impairment. Our findings corroborate the utility of OCT in providing valuable information regarding the MS disease process.
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http://dx.doi.org/10.1097/WNO.0000000000000768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763365PMC
December 2019

Cerebellar syndrome in a man treated with natalizumab: From the National Multiple Sclerosis Society Case Conference Proceedings.

Neurol Neuroimmunol Neuroinflamm 2019 05 7;6(3):e546. Epub 2019 Mar 7.

Departments of Neurology (D.A.L., M.D.G.), and Radiology and Medical Imaging (P.P.B., J.H.D.), Charlottesville, VA; Department of Neurology (R.P.L.), Wayne State University, Detroit, MI; Department of Neurology (E.I.M.), Dell Medical School at the University of Texas at Austin; Department of Neurology (R.N.N.), Barrows Neuroscience Institute, Phoenix, AZ; Neuroimmunology Branch (A.N.), National Institutes of Health, Bethesda, MD; Department of Neurology and Ophthalmology (T.C.F., E.M.F.), Dell Medical School at the University of Texas at Austin; The National Multiple Sclerosis Society (K.C.), New York; and Department of Neurology and Program in Immunology (S.S.Z.), University of California San Francisco.

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http://dx.doi.org/10.1212/NXI.0000000000000546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410929PMC
May 2019

Optimal intereye difference thresholds by optical coherence tomography in multiple sclerosis: An international study.

Ann Neurol 2019 05 10;85(5):618-629. Epub 2019 Apr 10.

Department of Neurology, New York University School of Medicine, New York, NY.

Objective: To determine the optimal thresholds for intereye differences in retinal nerve fiber and ganglion cell + inner plexiform layer thicknesses for identifying unilateral optic nerve lesions in multiple sclerosis. Current international diagnostic criteria for multiple sclerosis do not include the optic nerve as a lesion site despite frequent involvement. Optical coherence tomography detects retinal thinning associated with optic nerve lesions.

Methods: In this multicenter international study at 11 sites, optical coherence tomography was measured for patients and healthy controls as part of the International Multiple Sclerosis Visual System Consortium. High- and low-contrast acuity were also collected in a subset of participants. Presence of an optic nerve lesion for this study was defined as history of acute unilateral optic neuritis.

Results: Among patients (n = 1,530), receiver operating characteristic curve analysis demonstrated an optimal peripapillary retinal nerve fiber layer intereye difference threshold of 5μm and ganglion cell + inner plexiform layer threshold of 4μm for identifying unilateral optic neuritis (n = 477). Greater intereye differences in acuities were associated with greater intereye retinal layer thickness differences (p ≤ 0.001).

Interpretation: Intereye differences of 5μm for retinal nerve fiber layer and 4μm for macular ganglion cell + inner plexiform layer are robust thresholds for identifying unilateral optic nerve lesions. These thresholds may be useful in establishing the presence of asymptomatic and symptomatic optic nerve lesions in multiple sclerosis and could be useful in a new version of the diagnostic criteria. Our findings lend further validation for utilizing the visual system in a multiple sclerosis clinical trial setting. Ann Neurol 2019;85:618-629.
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http://dx.doi.org/10.1002/ana.25462DOI Listing
May 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

Impaired Thermoregulatory Function during Dynamic Exercise in Multiple Sclerosis.

Med Sci Sports Exerc 2019 03;51(3):395-404

Applied Physiology and Wellness, Southern Methodist University, Dallas, TX.

Introduction: Impairments in sudomotor function during passive whole-body heating have been reported in multiple sclerosis (MS), a demyelinating disease of the CNS that disrupts autonomic function. However, the capability of the thermoregulatory system to control body temperature during exercise has never been assessed in MS. Thus, the aim of the present study was to test the hypothesis that thermoregulatory function is impaired in MS patients compared with healthy controls (CON) exercising at similar rates of metabolic heat production.

Methods: Sweating and skin blood flow responses were compared between 12 individuals diagnosed with relapsing-remitting MS (9 females, 3 males) and 12 sex-, age-, mass-, and BSA-matched CON during a single bout of cycling exercise (rate of metabolic heat production: ∼4.5 W·kg) for 60 min in a climate-controlled room (25°C, 30% RH).

Results: Individuals with MS exhibited an attenuated increase in cumulative whole-body sweat loss after 30 min (MS, 72 ± 51 g; CON, 104 ± 37 g; P = 0.04) and 60 min (MS, 209 ± 94 g; CON, 285 ± 62 g; P = 0.02), as well as lower sweating thermosensitivity (MS, 0.49 ± 0.26 mg·cm·min·°C; CON, 0.86 ± 0.30 mg·cm·min·°C; P = 0.049). Despite evidence for thermoregulatory dysfunction, there were no differences between MS and CON in esophageal or rectal temperatures at 30- or 60-min time points (P > 0.05). Cutaneous vasculature responses were also not different in MS compared with CON (P > 0.05).

Conclusion: Taken together, MS blunts sweating responses during exercise while cutaneous vasculature responses are preserved. Altered mechanisms of body temperature regulation in persons with MS may lead to temporary worsening of disease symptoms and limit exercise tolerance under more thermally challenging conditions.
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http://dx.doi.org/10.1249/MSS.0000000000001821DOI Listing
March 2019

A young man in "double-trouble": Hallucinations and cranial nerve palsies: From the National Multiple Sclerosis Society Case Conference Proceedings.

Neurol Neuroimmunol Neuroinflamm 2019 01 19;6(1):e526. Epub 2018 Dec 19.

Partners Multiple Sclerosis Center (M.J.B., T.C.), Brigham and Women's Hospital; Massachusetts General Hospital (M.J.B., T.C.); Harvard Medical School (M.J.B., T.C.), Boston, MA; Department of Neurology (R.P.L.), Wayne State University, Detroit, MI; Department of Neurology (E. Meltzer, E. Melamed, A.L.), Dell Medical School at the University of Texas at Austin; Department of Neurology (L.F.), McGovern Medical School at UT Health, Houston; Department of Neurology and Ophthalmology (T.C.F., E.M.F.), Dell Medical School at the University of Texas at Austin; The National Multiple Sclerosis Society (K.C.), New York; Departments of Neurology (L.B., S.G.), Population Health and Ophthalmology, New York University School of Medicine; and Department of Neurology and Program in Immunology (S.S.Z.), University of California San Francisco.

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http://dx.doi.org/10.1212/NXI.0000000000000526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310360PMC
January 2019

A young man with numbness in arms and legs: From the National Multiple Sclerosis Society Case Conference Proceedings.

Neurol Neuroimmunol Neuroinflamm 2018 Nov 23;5(6):e509. Epub 2018 Oct 23.

Department of Neurology (A.R.R., S.S.Z., J.M.G.) and Program in Immunology (S.S.Z.), University of California San Francisco; Department of Neurology (R.P.L.), Wayne State University, Detroit, MI; Partner's Neurology Training Program (E.M.); MGH and Brigham and Women's Hospitals, Harvard Medical School, Boston, MA; and E.M. is now with the Department of Neurology, Dell Medical School at the University of Texas at Austin; Central Texas Neurology Consultants (E.J.F.), and Department of Neurology, Dell Medical School at the University of Texas at Austin; Department of Neurology (E.M., A.L.), and Department of Neurology and Ophthalmology (T.C.F., E.F), Dell Medical School at the University of Texas at Austin; Department of Neurology (L.F.), University of Texas at Houston; and the National Multiple Sclerosis Society, New York, NY.

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http://dx.doi.org/10.1212/NXI.0000000000000509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225923PMC
November 2018

Should Spinal MRI Be Routinely Performed in Patients With Clinically Isolated Optic Neuritis?

J Neuroophthalmol 2018 12;38(4):502-510

Partner's Neurology Residency Training Program (EM), Massachusetts General & Brigham & Women's Hospitals, Harvard Medical School, Boston, Massachusetts; The Department of Neurology (TCF, EMF), The Dell Medical School, The University of Texas at Austin, Austin, Texas; and Departments of Clinical Neurosciences (FEC, JMB), Surgery (FEC) and Community Health Sciences (JMB), University of Calgary, Calgary, Canada.

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http://dx.doi.org/10.1097/WNO.0000000000000685DOI Listing
December 2018

Visual Pathway Measures are Associated with Neuropsychological Function in Multiple Sclerosis.

Curr Eye Res 2018 07 1;43(7):941-948. Epub 2018 May 1.

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

Purpose: To determine the relationships between visual function and ganglion cell and inner plexiform layer thickness and neuropsychological measures in multiple sclerosis (MS).

Methods: Ninety-five relapsing-remitting MS (RRMS) and 36 progressive MS patients underwent 100%-contrast visual acuity (VA), 2.5%- and 1.25%-contrast letter acuity (LA) testing, Cirrus-HD-optical coherence tomography, and neuropsychological assessments. Mixed-effects regression models were used to assess relationships.

Results: Across the cohort, 1.25%-contrast LA was associated with Symbol Digit Modalities Test (SDMT; β = 2.17, p = 0.005) and Brief Visuospatial Memory Test-Revised (BVMT-R) total recall (TR) and delayed recall (DR) scores (β = 0.31, p < 0.001; β = 0.15, p = 0.039, respectively). 2.5%-contrast LA was associated with BVMT-R TR scores (β = 0.27, p = 0.006). In the RRMS cohort, 1.25%-contrast LA was generally more significantly associated with cognitive measures: SDMT (β = 2.97, p = 0.001) and BVMT-R TR (β = 0.32, p < 0.001) and DR (β = 0.22, p = 0.012).

Conclusion: This study suggests that visual pathway measures, particularly visual function measures, reflect aspects of cognitive function in MS, further supporting their roles as complementary outcomes in MS neuroprotection trials.
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http://dx.doi.org/10.1080/02713683.2018.1459730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298605PMC
July 2018

Identification and treatment of the visual processing asymmetry in MS patients with optic neuritis: The Pulfrich phenomenon.

J Neurol Sci 2018 04 3;387:60-69. Epub 2018 Feb 3.

Department of Neurology, Dell Medical School, University of Texas at Austin, TX, USA; School of Biomedical Engineering, University of Texas at Dallas, Richardson, TX, USA; Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA. Electronic address:

Background: The Pulfrich phenomenon (PF) is the illusory perception that an object moving linearly along a 2-D plane appears to instead follow an elliptical 3-D trajectory, a consequence of inter-eye asymmetry in the timing of visual object identification in the visual cortex; with optic neuritis as a common etiology.

Objective: We have designed an objective method to identify the presence and magnitude of the PF, in conjunction with a cooresponding strategy by which to abolish the effect; with monocular application of neutral density filters to the less affected fellow eye, in patients with MS and a history of optic neuropathy (e.g. related to acute optic neuritis or subclinical optic neuropathy).

Methods: Twenty-three MS patients with a history of acute unilateral or bilateral optic neuritis, and ten healthy control subjects (HC) were recruited to participate in a pilot study to assess our strategy. Subjects were asked to indicate whether a linearly moving pendulum ball followed a linear 2-D path versus an illusory 3-D elliptical object-motion trajectory, by reporting the ball's approximation to one of nine horizontally-oriented colored wires that were positioned parallel to one another and horizontal to the linear pendulum path. Perceived motion of the bob that moved along wires behind or in front (along the 'Z' plane) of the middle reference wire indicated an illusory elliptical trajectory of ball motion consistent with the PF.

Results: When the neutral density filter titration was applied to the fellow eye the severity of the PF decreased, eventually being fully abolished in all but one patient. The magnitude of neutral density filtering required correlated to the severity of the patient's initial PF magnitude (p < 0.001).

Conclusions: We ascertained the magnitude of the visual illusion associated with the PF, and the corresponding magnitude of neutral density filtering necessary to abolish it.
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http://dx.doi.org/10.1016/j.jns.2018.01.029DOI Listing
April 2018

Preserved canonicality of the BOLD hemodynamic response reflects healthy cognition: Insights into the healthy brain through the window of Multiple Sclerosis.

Neuroimage 2019 04 15;190:46-55. Epub 2018 Feb 15.

School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA; Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address:

The hemodynamic response function (HRF), a model of brain blood-flow changes in response to neural activity, reflects communication between neurons and the vasculature that supplies these neurons in part by means of glial cell intermediaries (e.g., astrocytes). Intact neural-vascular communication might play a central role in optimal cognitive performance. This hypothesis can be tested by comparing healthy individuals to those with known white-matter damage and impaired performance, as seen in Multiple Sclerosis (MS). Glial cell intermediaries facilitate the ability of neurons to adequately convey metabolic needs to cerebral vasculature for sufficient oxygen and nutrient perfusion. In this study, we isolated measurements of the HRF that could quantify the extent to which white-matter affects neural-vascular coupling and cognitive performance. HRFs were modeled from multiple brain regions during multiple cognitive tasks using piecewise cubic spline functions, an approach that minimized assumptions regarding HRF shape that may not be valid for diseased populations, and were characterized using two shape metrics (peak amplitude and time-to-peak). Peak amplitude was reduced, and time-to-peak was longer, in MS patients relative to healthy controls. Faster time-to-peak was predicted by faster reaction time, suggesting an important role for vasodilatory speed in the physiology underlying processing speed. These results support the hypothesis that intact neural-glial-vascular communication underlies optimal neural and cognitive functioning.
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http://dx.doi.org/10.1016/j.neuroimage.2017.12.081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093806PMC
April 2019

New Ways of "Seeing" the Mechanistic Heterogeneity of Multiple Sclerosis Plaque Pathogenesis.

J Neuroophthalmol 2018 03;38(1):91-100

Department of Neurology (EM), Partner's Neurology Residency Training Program, Massachusetts General and Brigham and Women's Hospitals, Harvard Medical School, Massachusetts; The Department of Neurology (TCF, EMF), The Dell Medical School, The University of Texas, Austin, Texas; and Department of Neurology (FC), University of Calgary, Calgary, Canada.

Background: Over the past few decades, we have witnessed a transformation with respect to the principles and pathobiological underpinnings of multiple sclerosis (MS). From the traditional rubric of MS as an inflammatory and demyelinating disorder restricted to central nervous system (CNS) white matter, our contemporary view has evolved to encompass a broader understanding of the variable mechanisms that contribute to tissue injury, in a disorder now recognized to affect white and grey matter compartments.

Evidence Acquisition: A constellation of inflammation, ion channel derangements, bioenergetic supply: demand mismatches within the intra-axonal compartment, and alterations in the dynamics and oximetry of blood flow in CNS tissue compartments are observed in MS. These findings have raised questions regarding how histopathologic heterogeneity may influence the diverse clinical spectrum of MS; and, accordingly, how individual treatment needs vary from 1 patient to the next.

Results: We are now on new scaffolding in MS; one that promises to translate key clinical and laboratory observations to the application of emerging patient-centered therapies.

Conclusions: This review highlights our current knowledge of the underlying disease mechanisms in MS, explores the inflammatory and neurodegenerative consequences of tissue damage, and examines physiologic factors that contribute to bioenergetic homeostasis within the CNS of affected patients.
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http://dx.doi.org/10.1097/WNO.0000000000000633DOI Listing
March 2018

Optimal Intereye Difference Thresholds in Retinal Nerve Fiber Layer Thickness for Predicting a Unilateral Optic Nerve Lesion in Multiple Sclerosis.

J Neuroophthalmol 2018 12;38(4):451-458

Departments of Neurology (RCN, SLG, and LJB), Population Health (LJB), and Ophthalmology (SLG and LJB), New York University School of Medicine, New York, New York; Department of Neurology (TCF and EMF), Dell Medical School at University of Texas Austin, Austin, Texas; Department of Neurology (PAC), Johns Hopkins University School of Medicine, Baltimore, Maryland; Clinical Development Department (CCV), Biogen, Cambridge, Massachusetts; and Clinical Development Group (DC), Fulcrum Therapeutics, Cambridge, Massachusetts.

Background: The optic nerve is a frequent site for involvement in multiple sclerosis (MS). Optical coherence tomography (OCT) detects thinning of the retinal nerve fiber layer (RNFL) in eyes of patients with MS and in those meeting criteria for clinically or radiologically isolated demyelinating syndromes. Current international diagnostic criteria for MS do not include the optic nerve as an imaging lesion site despite the high prevalence of acute optic neuritis (ON), or occult optic neuropathy, among early MS and clinically isolated syndrome patients; as well as most MS patients over the course of the disease. We sought to determine optimal thresholds for intereye difference in peripapillary RNFL thickness that are most predictive of a unilateral optic nerve lesion.

Methods: We analyzed spectral domain OCT data of 31 healthy volunteers and 124 patients with MS at a single center as part of an ongoing collaborative investigation of visual outcomes. Intereye differences in peripapillary (360°) RNFL thickness were calculated as the absolute value of the difference. First, we determined the 95th percentile value of intereye difference for the healthy volunteers. This value was applied to the convenience sample group of MS patients as a validation cohort determining how well this threshold could distinguish patients with vs without a history of unilateral ON. The relation of intereye differences in peripapillary RNFL thickness to binocular low-contrast letter acuity scores was also examined.

Results: Among healthy volunteer participants (n = 31), the 95th percentile value for intereye difference (upper boundary of expected for normal controls) was 6.0 μm. This value was applied to the convenience sample group of MS patients (n = 124, validation cohort). Positive predictive value, negative predictive value, sensitivity, and specificity for identifying MS patients with a history of unilateral ON were calculated for the 6-μm threshold value in a 2 × 2 table analysis with the application of χ tests (P < 0.0001). The 6-μm threshold was predictive of worse binocular low-contrast acuity scores at 2.5% (P = 0.03) and 1.25% (P = 0.002 by linear regression analyses). A receiver operating characteristic curve analysis demonstrated an optimal intereye difference threshold of 5 μm for identifying unilateral ON in the MS cohort.

Conclusions: An intereye difference of 5-6 μm in RNFL thickness is a robust structural threshold for identifying the presence of a unilateral optic nerve lesion in MS.
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http://dx.doi.org/10.1097/WNO.0000000000000629DOI Listing
December 2018

Visual Fixation Instability in Multiple Sclerosis Measured Using SLO-OCT.

Invest Ophthalmol Vis Sci 2018 01;59(1):196-201

Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, United States.

Purpose: Precise measurements of visual fixation and its instability were recorded during optical coherence tomography (OCT) as a marker of neural network dysfunction in multiple sclerosis (MS), which could be used to monitor disease progression or response to treatment.

Methods: A total of 16 MS patients and 26 normal subjects underwent 30 seconds of scanning laser ophthalmoscope (SLO)-based eye tracking during OCT scanning of retinal layer thickness. Study groups consisted of normal eyes, MS eyes without prior optic neuritis (MS wo ON), and MS eyes with prior optic neuritis (MS + ON). Kernel density estimation quantified fixation instability from the distribution of fixation points on the retina. In MS wo ON eyes, fixation instability was compared to other measures of visual and neurologic function.

Results: Fixation instability was increased in MS wo ON eyes (0.062 deg2) compared to normal eyes (0.030 deg2, P = 0.015). A further increase was seen for MS + ON eyes (0.11 deg2) compared to MS wo ON (P = 0.04) and normal (P = 0.006) eyes. Fixation instability correlated weakly with ganglion cell layer (GCL) volume and showed no correlation with low-contrast letter acuity, EDSS score, or SDMT score.

Conclusions: Fixation instability reflects the integrity of a widespread neural network germane to visual processing and ocular motor control, and is disturbed in MS. Further study of visual fixation, including the contribution of microsaccades to fixation instability, may provide insight into the localization of fixation abnormalities in MS and introduce innovative and easily measured outcomes for monitoring progression and treatment response.
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http://dx.doi.org/10.1167/iovs.17-22391DOI Listing
January 2018

Characteristics of morphologic macular abnormalities in neuroimmunology practice.

Mult Scler 2019 03 10;25(3):361-371. Epub 2017 Nov 10.

Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins Hospital, Baltimore, MD, USA.

Background: Morphologic macular abnormalities (MMAs) are frequently seen on macular optical coherence tomography (OCT) imaging in neuroimmunology practice, yet studies pragmatically assessing prevalence and risk factors of MMAs to date are limited.

Objective: To describe the characteristics of MMAs in a neuroimmunology-based academic practice.

Methods: Cross-sectional study of 1450 patients (2900 eyes) who underwent spectral-domain macular OCT between June 2010 and June 2012. The association between MMAs and demographic variables was analyzed using mixed-effects logistic regression. Odds ratios (ORs) were calculated per 5-year age increments.

Results: MMAs were observed in 338/2872 eyes (11.7%) of 232/1445 participants (16.1%). The most common abnormalities identified, included drusen (6.0%), epiretinal membrane (ERM; 5.5%), and microcystoid macular pathology (MMP; 1.9%). Overall, patients with MMAs were older (OR: 1.79, p = 5 × 10) and more likely to be males (OR: 2.45, p = 0.014). In particular, advancing age was associated with higher risk of drusen and ERM (OR: 1.80 and 4.26, p = 2 × 10 and 7 × 10, respectively). MMP prevalence declined with age (OR: 0.73, p = 0.015) and was associated with African-American ethnicity (OR: 15.0, p = 5 × 10).

Conclusion: Unexpected or incidental MMAs are common in patients assessed with OCT in neuroimmunology practice, emphasizing the importance of comprehensive OCT image review for risk stratification and appropriate ophthalmology referral.
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http://dx.doi.org/10.1177/1352458517741206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929206PMC
March 2019

Retinal layer segmentation in multiple sclerosis: a systematic review and meta-analysis.

Lancet Neurol 2017 10 12;16(10):797-812. Epub 2017 Sep 12.

Department of Neurology, Amsterdam Neuroscience, VUmc MS Center Amsterdam and Dutch Expertise Centre for Neuro-ophthalmology, VU University Medical Center, Amsterdam, Netherlands.

Background: Structural retinal imaging biomarkers are important for early recognition and monitoring of inflammation and neurodegeneration in multiple sclerosis. With the introduction of spectral domain optical coherence tomography (SD-OCT), supervised automated segmentation of individual retinal layers is possible. We aimed to investigate which retinal layers show atrophy associated with neurodegeneration in multiple sclerosis when measured with SD-OCT.

Methods: In this systematic review and meta-analysis, we searched for studies in which SD-OCT was used to look at the retina in people with multiple sclerosis with or without optic neuritis in PubMed, Web of Science, and Google Scholar between Nov 22, 1991, and April 19, 2016. Data were taken from cross-sectional cohorts and from one timepoint from longitudinal studies (at least 3 months after onset in studies of optic neuritis). We classified data on eyes into healthy controls, multiple-sclerosis-associated optic neuritis (MSON), and multiple sclerosis without optic neuritis (MSNON). We assessed thickness of the retinal layers and we rated individual layer segmentation performance by random effects meta-analysis for MSON eyes versus control eyes, MSNON eyes versus control eyes, and MSNON eyes versus MSON eyes. We excluded relevant sources of bias by funnel plots.

Findings: Of 25 497 records identified, 110 articles were eligible and 40 reported data (in total 5776 eyes from patients with multiple sclerosis [1667 MSON eyes and 4109 MSNON eyes] and 1697 eyes from healthy controls) that met published OCT quality control criteria and were suitable for meta-analysis. Compared with control eyes, the peripapillary retinal nerve fibre layer (RNFL) showed thinning in MSON eyes (mean difference -20·10 μm, 95% CI -22·76 to -17·44; p<0·0001) and in MSNON eyes (-7·41 μm, -8·98 to -5·83; p<0·0001). The macula showed RNFL thinning of -6·18 μm (-8·07 to -4·28; p<0·0001) in MSON eyes and -2·15 μm (-3·15 to -1·15; p<0·0001) in MSNON eyes compared with control eyes. Atrophy of the macular ganglion cell layer and inner plexiform layer (GCIPL) was -16·42 μm (-19·23 to -13·60; p<0·0001) for MSON eyes and -6·31 μm (-7·75 to -4·87; p<0·0001) for MSNON eyes compared with control eyes. A small degree of inner nuclear layer (INL) thickening occurred in MSON eyes compared with control eyes (0·77 μm, 0·25 to 1·28; p=0·003). We found no statistical difference in the thickness of the combined outer nuclear layer and outer plexiform layer when we compared MSNON or MSON eyes with control eyes, but we found a small degree of thickening of the combined layer when we compared MSON eyes with MSNON eyes (1·21 μm, 0·24 to 2·19; p=0·01).

Interpretation: The largest and most robust differences between the eyes of people with multiple sclerosis and control eyes were found in the peripapillary RNFL and macular GCIPL. Inflammatory disease activity might be captured by the INL. Because of the consistency, robustness, and large effect size, we recommend inclusion of the peripapillary RNFL and macular GCIPL for diagnosis, monitoring, and research.

Funding: None.
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http://dx.doi.org/10.1016/S1474-4422(17)30278-8DOI Listing
October 2017

Calibrated imaging reveals altered grey matter metabolism related to white matter microstructure and symptom severity in multiple sclerosis.

Hum Brain Mapp 2017 11 16;38(11):5375-5390. Epub 2017 Aug 16.

School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas.

Multiple sclerosis (MS) involves damage to white matter microstructures. This damage has been related to grey matter function as measured by standard, physiologically-nonspecific neuroimaging indices (i.e., blood-oxygen-level dependent signal [BOLD]). Here, we used calibrated functional magnetic resonance imaging and diffusion tensor imaging to examine the extent to which specific, evoked grey matter physiological processes were associated with white matter diffusion in MS. Evoked changes in BOLD, cerebral blood flow (CBF), and oxygen metabolism (CMRO ) were measured in visual cortex. Individual differences in the diffusion tensor measure, radial diffusivity, within occipital tracts were strongly associated with MS patients' BOLD and CMRO . However, these relationships were in opposite directions, complicating the interpretation of the relationship between BOLD and white matter microstructural damage in MS. CMRO was strongly associated with individual differences in patients' fatigue and neurological disability, suggesting that alterations to evoked oxygen metabolic processes may be taken as a marker for primary symptoms of MS. This work demonstrates the first application of calibrated and diffusion imaging together and details the first application of calibrated functional MRI in a neurological population. Results lend support for neuroenergetic hypotheses of MS pathophysiology and provide an initial demonstration of the utility of evoked oxygen metabolism signals for neurology research. Hum Brain Mapp 38:5375-5390, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/hbm.23727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877313PMC
November 2017

Capturing saccades in multiple sclerosis with a digitized test of rapid number naming.

J Neurol 2017 May 7;264(5):989-998. Epub 2017 Apr 7.

Department of Neurology, New York University School of Medicine, 240 East 38th Street, 20th Floor, New York, NY, 10016, USA.

The King-Devick (K-D) test of rapid number naming is a visual performance measure that captures saccadic eye movements. Patients with multiple sclerosis (MS) have slowed K-D test times associated with neurologic disability and reduced quality of life. We assessed eye movements during the K-D test to identify characteristics associated with slowed times. Participants performed a computerized K-D test with video-oculography. The 25-Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and its 10-Item Neuro-Ophthalmic Supplement measured vision-specific quality of life (VSQOL). Among 25 participants with MS (age 37 ± 10 years, range 20-59) and 42 controls (age 33 ± 9 years, range 19-54), MS was associated with significantly longer (worse) K-D times (58.2 ± 19.8 vs. 43.8 ± 8.6 s, P = 0.001, linear regression models, accounting for age). In MS, test times were slower among patients with higher (worse) Expanded Disability Status Scale scores (P = 0.01). Average inter-saccadic intervals (ISI) were significantly longer in MS participants compared to controls (362 ± 103 vs. 286 ± 50 ms, P = 0.001), and were highly associated with prolonged K-D times in MS (P = 0.006). MS participants generated greater numbers of saccades (P = 0.007). VSQOL scores were reduced in MS patients with longer (worse) K-D times (P = 0.04-0.001) and longer ISI (P = 0.002-0.001). Patients with MS have slowed K-D times that may be attributable to prolonged ISI and greater numbers of saccades. The K-D test and its requisite eye movements capture VSQOL and make rapid number naming a strong candidate efferent visual performance measure in MS.
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http://dx.doi.org/10.1007/s00415-017-8484-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027588PMC
May 2017

Impaired sweating responses to a passive whole body heat stress in individuals with multiple sclerosis.

J Neurophysiol 2017 07 8;118(1):7-14. Epub 2017 Mar 8.

Department of Applied Physiology & Wellness, Southern Methodist University, Dallas, Texas; and

Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system (CNS), disrupting autonomic function. The aim of this study was to test the hypothesis that individuals with MS have blunted control of thermoregulatory reflex increases in sweat rate (SR) and cutaneous vasodilation compared with controls during a passive whole body heat stress (WBH). Eighteen individuals with relapsing-remitting MS and 18 healthy controls (Con) participated in the study. Core temperature (T), skin temperature, heart rate, arterial blood pressure (10-min intervals), skin blood flow (laser-Doppler flux, LDF), and SR were continuously measured during normothermic baseline (34°C water perfusing a tube-lined suit) and WBH (increased T 0.8°C via 48°C water perfusing the suit). Following WBH, local heaters were warmed to 42°C, inducing peak cutaneous vasodilation at the site of LDF collection. Cutaneous vascular conductance (CVC) was calculated as the ratio of LDF to mean arterial pressure and expressed as a percentage of peak achieved during local heating. Individuals with MS had attenuated SR responses to WBH (ΔSR from baseline: Con, 0.65 ± 0.27; MS, 0.42 ± 0.17 mg·cm·min, = 0.003), whereas Δ%CVC from baseline was similar between groups (Con, 42 ± 16%; MS, 38 ± 12%, = 0.39). SR responses were blunted as a function of T in MS (interaction: group × T, = 0.03), of which differences were evident at ΔT 0.7°C and 0.8°C ( < 0.05). No interaction was observed in Δ%CVC Taken together, the findings show MS blunts sweating responses, whereas control of the cutaneous vasculature is preserved, in response to WBH. This study is the first to assess the reflex control of the thermoregulatory system in individuals living with multiple sclerosis (MS). The novel findings are twofold. First, attenuated increases in sweat rate in subjects with MS compared with healthy controls were observed in response to a moderate increase (0.8°C) in core temperature via passive whole body heat stress. Second, it appears the reflex control of the cutaneous vasculature is preserved in MS.
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http://dx.doi.org/10.1152/jn.00897.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534491PMC
July 2017

Retinal Architecture and Melanopsin-Mediated Pupillary Response Characteristics: A Putative Pathophysiologic Signature for the Retino-Hypothalamic Tract in Multiple Sclerosis.

JAMA Neurol 2017 05;74(5):574-582

Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas7Department of Bioengineering, University of Texas at Dallas11Department of Ophthalmology, University of Texas Southwestern Medical Center at Dallas.

Importance: A neurophysiologic signature of the melanopsin-mediated persistent constriction phase of the pupillary light reflex may represent a surrogate biomarker for the integrity of the retinohypothalamic tract, with potential utility for investigating alterations in homeostatic mechanisms associated with brain disorders and implications for identifying new treatments.

Objective: To characterize abnormalities of retinal architecture in patients with multiple sclerosis (MS) and corresponding alterations in the melanopsin-mediated sustained pupillary constriction response.

Design, Setting, And Participants: The case-control study was an experimental assessment of various stimulus-induced pupillary response characteristics and was conducted at a university clinical center for MS from September 6, 2012, to February 2015. Twenty-four patients with MS (48 eyes) and 15 individuals serving as controls (30 eyes) participated. The melanopsin-mediated, sustained pupillary constriction phase response following cessation of a blue light stimulus was compared with the photoreceptor-mediated pupillary constriction phase response following cessation of a red light stimulus. Optical coherence tomography was used to characterize the association between pupillary response characteristics and alterations in retinal architecture, specifically, the thickness of the retinal ganglion cell layer and inner plexiform layer (GCL + IPL).

Main Outcomes And Measures: Association of pupillary response characteristics with alterations in retinal architecture.

Results: Of 24 patients with MS included in the analysis, 17 were women (71%); mean (SD) age was 47 (11) years. Compared with eyes from individuals with MS who had normal optical coherence tomography-derived measures of retinal GCL + IPL thickness, eyes of patients who had GCL + IPL thickness reductions to less than the first percentile exhibited a correspondingly significant attenuation of the melanopsin-mediated sustained pupillary response (mean [SD] pupillary diameter ratios at a point in time, 0.18 [0.1] vs 0.33 [0.09]; P < .001, generalized estimating equation models accounting for age and within-patient intereye correlations).

Conclusions And Relevance: In this case-control study, attenuation of the melanopsin-mediated sustained pupillary constriction response was significantly associated with thinning of the GCL + IPL sector of the retina in the eyes of patients with MS, particularly those with a history of acute optic neuritis. Melanopsin-containing ganglion cells in the retina represent, at least in part, the composition of the retinohypothalamic tract. As such, our findings may signify the ability to elucidate a putative surrogate neurophysiologic signature that correlates with a constellation of homeostatic mechanisms in both health and illness.
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http://dx.doi.org/10.1001/jamaneurol.2016.5131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822208PMC
May 2017

Disease-modifying therapies modulate retinal atrophy in multiple sclerosis: A retrospective study.

Neurology 2017 02 11;88(6):525-532. Epub 2017 Jan 11.

From the Departments of Neurology (J.B., O.A.-L., P.B., S.D.N., P.A.C., S.S.) and Electrical and Computer Engineering (A.L., J.P.), Johns Hopkins University, Baltimore, MD; Department of Internal Medicine (O.A.-L.), North Shore Medical Center, Salem, MA; Department of Neurology and Ophthalmology (T.F., E.M.F.), University of Texas Southwestern, Dallas; and Department of Neurology (L.J.B.), New York University Langone Medical Center, New York.

Objective: To retrospectively investigate whether disease-modifying therapies (DMTs) exert differential effects on rates of retinal atrophy in relapsing-remitting multiple sclerosis (RRMS), as assessed using optical coherence tomography (OCT).

Methods: A total of 402 patients with RRMS followed at the Johns Hopkins MS Center who underwent Cirrus-HD OCT were assessed for eligibility. Inclusion criteria included at least 1 year of OCT follow-up and adherence to a single DMT during the period of follow-up. Combined thickness of the ganglion cell + inner plexiform (GCIP) and other retinal layers was computed utilizing automated macular segmentation. Retinal thickness changes were analyzed using mixed-effects linear regression.

Results: The effects of glatiramer acetate (GA; n = 48), natalizumab (NAT; n = 46), and interferon-β-1a subcutaneously (IFN; n = 35) and intramuscularly (IFN; n = 28) were assessed. Baseline analyses revealed no significant differences between groups in terms of age, sex, optic neuritis history, or follow-up duration. During follow-up, relative to NAT-treated patients, IFN- and GA-treated patients exhibited 0.37 μm/y (p < 0.001) and 0.14 μm/y (p = 0.035) faster rates of GCIP thinning, respectively, adjusting for the interval between initiation of DMT and OCT monitoring (gap time), age, sex, relapses, and disease duration. In the IFN group, GCIP thinning was 1.53 μm/y faster during the first year of therapy vs during the time interval afterwards (p < 0.001).

Conclusions: Rates of GCIP atrophy in patients with RRMS vary according to DMT utilization. Our findings support OCT for monitoring neurodegenerative treatment effects in the retina, an easily accessible tissue, and as a practical outcome measure in RRMS clinical trials.
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http://dx.doi.org/10.1212/WNL.0000000000003582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304463PMC
February 2017
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