Publications by authors named "Elliot Frohman"

209 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.

View Article and Find Full Text PDF

Download full-text PDF

Source
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".
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jns.2021.117463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055502PMC
July 2021

APOSTEL 2.0 Recommendations for Reporting Quantitative Optical Coherence Tomography Studies.

Neurology 2021 07 28;97(2):68-79. Epub 2021 Apr 28.

From the Department of Neurology, Medical Faculty (A.A., O.A., H.-P.H., O.M., S.M., M.R., P.A.), Heinrich-Heine University Düsseldorf, Germany; Department of Neurology (A.C.-H., A.J.G.), University of California San Francisco; Departments of Neurology, Population Health, and Ophthalmology (L.J.B., R.K.), NYU Grossman School of Medicine, New York, NY; Mulier Institute (L.B.), Centre for Research on Sports in Society, Utrecht, the Netherlands; Scientific Institute San Raffaele (P.B.), Milan, Italy; Centre for Public Health (A.A.B.), Queen's University Belfast, Northern Ireland, UK; Division of Neuroimmunology (P.A.C., S. Saidha), Johns Hopkins University, Baltimore, MD; Departments of Clinical Neurosciences and Surgery (F.C.), University of Calgary, Alberta, Canada; Institut d'Investigacións Biomediques August Pi iSunyer (IDIBAPS) and Hospital Clinic (B.S.-D., E.H.M.-L., P.V.), University of Barcelona, Spain; Bascom Palmer Eye Institute (D.C.D.), University of Miami Miller School of Medicine, FL; Department of Ophthalmology (N.F.), University Medical Center, Göttingen; Department of Ophthalmology (R.P.F., F.G.H.), University of Bonn, Germany; Department of Neurology (J.L.F., G.P.-J.), Rigshospitalet Glostrup and University of Copenhagen, Denmark; Laboratory of Neuroimmunology (E.F., T.F.), Stanford University School of Medicine, CA; Institute of Ophthalmology (D.G.-H.), National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology (D.G.-H.), London, UK; Biocruces Bizkaia Health Research Institute (I.G.), Barakaldo, Spain; Department of Neurosciences (J.S.G.), University of California, San Diego; Brain and Mind Centre (H.-P.H.), University of Sydney, Australia; Department of Neurology (H.-P.H.), Medical University of Vienna, Austria; Institute of Clinical Neuroimmunology (J.H.), LMU Hospital, Ludwig-Maximilians Universität München, Germany; UConn Health Comprehensive MS Center, Division of Multiple Sclerosis and Neuroimmunology, Department of Neurology (J.I.), University of Connecticut School of Medicine, Farmington; Faculty of Medicine and Health Sciences (A.K.), Macquarie University, Sydney, Australia; Department of Neurology (B.K., T.K.), Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Germany; Department of Medicine and Radiology (S.K.), University of Melbourne, Australia; Department of Neurology with Institute of Translational Neurology (J.K.), University of Münster; Eye Center, Medical Center, Faculty of Medicine (W.A.L.), University of Freiburg, Germany; Experimental Neurophysiology Unit (L.L.), Institute of Experimental Neurology (INSPE), IRCCS San Raffaele, University Vita-Salute San Raffaele, Milan, Italy; Lille Neurosciences & Cognition (O.O.), Univ Lille, Inserm, CHU Lille, U1172-LilNCog (JPARC), France; Experimental and Clinical Research Center (F.P., H.G.Z., A.U.B.), Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; Moorfields Eye Hospital (A.P.), The National Hospital for Neurology and Neurosurgery, Queen Square, UCL Institute of Neurology, London, UK; Neuro-ophthalmology Expert Center (A.P.), Amsterdam UMC, the Netherlands; Department of Neurology, First Faculty of Medicine (J.L.P.), Charles University and General University Hospital in Prague, Czech Republic; Department of Ophthalmology (G.R.), Ramon y Cajal Hospital, Medicine University of Alcalá, Madrid, Spain; Department of Neurology (M.R.), Center for Neurology and Neuropsychiatry, LVR-Klinikum, Heinrich-Heine-University Düsseldorf, Germany; Department of Neurology (S. Schippling), University Hospital Zurich, Switzerland; Departments of Ophthalmology, Neuroscience, and Physiology (J.S.S.), NYU Langone Health, NYU Grossman School of Medicine, New York; Departments of Biomedical Engineering, Electrical and Computer Engineering (J.S.S.), NYU Tandon School of Engineering, Brooklyn, NY; Thomas Jefferson University Medical College (R.C.S.), Philadelphia, PA; Queen Square MS Centre, Department of Neuroinflammation (A.T.), UCL Institute of Neurology, University College London, UK; Departments of Ophthalmology and Clinical Research (S.W.), Bern University Hospital, University of Bern, Switzerland; Division of Neurology, Department of Pediatrics (E.A.Y.), Hospital for Sick Children, Division of Neurosciences and Mental Health SickKids Research Institute, University of Toronto, Canada; Department of Clinical Neurosciences (P.Y.-W.-M.), University of Cambridge; Moorfields Eye Hospital (P.Y.-W.-M.), London, UK; University of California (A.U.B.), Irvine; and IMSVISUAL (A.A., A.C.-H., O.A., L.J.B., L.B., P.A.C., F.C., J.L.F., E.F., T.F., I.G., J.S.G., A.J.G., H.-P.H., J.H., J.I., R.K., A.K., B.K., T.K., J.K., L.L., E.H.M.-L., S.M., O.O., F.P., A.P., G.P.-J., J.L.P., M.R., S. Saidha, S. Schippling, R.C.S., P.V., E.A.Y., H.G.Z., A.U.B., P.A.), International Multiple Sclerosis Visual System Consortium, Middleton, WI.

Objective: To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations.

Methods: To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes.

Results: A total of 116 authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans, and suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%.

Conclusions: The modified Delphi method resulted in an expert-led guideline (evidence Class III; Grading of Recommendations, Assessment, Development and Evaluations [GRADE] criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition analysis, nomenclature and abbreviations, and statistical approach. It will be essential to update these recommendations to new research and practices regularly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000012125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279566PMC
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.

View Article and Find Full Text PDF

Download full-text PDF

Source
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.

View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jns.2020.116936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241348PMC
August 2020

Should interferons take front stage as an essential MS disease-modifying therapy in the era of coronavirus disease 2019?

Neurol Neuroimmunol Neuroinflamm 2020 09 11;7(5). Epub 2020 Jun 11.

From the Department of Neurology (C.M., T.F., E.F., E.M.), Dell Medical School, Austin, TX; and Department of Neurology and Program in Immunology (S.S.Z.), University of California, San Francisco, CA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309524PMC
September 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.

View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.

View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1249/MSS.0000000000001821DOI Listing
March 2019

Core temperature is not elevated at rest in people with relapsing-remitting multiple sclerosis.

Mult Scler Relat Disord 2019 Apr 4;29:62-67. Epub 2019 Jan 4.

The University of Sydney, Thermal Ergonomics Laboratory, Faculty of Health Sciences, Lidcombe NSW, Australia; The University of Sydney, Charles Perkins Centre, Camperdown, NSW, Australia. Electronic address:

Purpose: To reassess the notion that people with multiple sclerosis (MS) do not demonstrate an elevated resting core temperature when measured using best-practice precision thermometry.

Method: Across two international data collection sites (Australia and USA), twenty-eight relapsing-remitting MS patients and 27 aged-matched controls (CON) were exposed to either 30 °C, 30% relative humidity (RH) (Sydney) or 25 °C, 30% RH (Dallas). Resting rectal (T) and esophageal (T) temperature and resting oxygen consumption (VO) was measured in MS (n = 28) and CON (n = 27) groups who completed the 25 °C and 30 °C trials. Tympanic membrane (T) temperature was measured in MS (n = 16) and CON (n = 15) groups in the 30 °C condition. A modified fatigue impact scale (MFIS) questionnaire was used to assess subjective measures of psychosocial, physical and cognitive fatigue in the 30 °C condition.

Results: Irrespective of ambient temperature, no group differences were observed for T (MS: 37.07 ± 0.30 °C; CON: 37.18 ± 0.30 °C; P = 0.29), T (MS: 36.84 ± 0.42 °C; CON: 36.92 ± 0.29 °C; P = 0.36) or resting VO (MS: 3.89 ± 0.18 ml⋅kg⋅min; CON: 3.98 ± 0.17 ml⋅kg⋅min; P = 0.67). Similarly, no group differences were observed for T (MS: 36.52 ± 0.38 °C; CON: 36.61 ± 0.33 °C; P = 0.55) in the 30 °C condition. Resting T did not correlate with subjective measures of fatigue: physical: r = -0.11, P = 0.67; cognitive: r = -0.14, P = 0.60; and psychosocial: r = 0.05, P = 0.84.

Conclusion: Contrary to recent reports, resting core temperature is not elevated in relapsing-remitting MS patients compared to healthy controls when measured using precision thermometry. Furthermore, no association was observed between resting T and any subjective measures of fatigue in a subset of participants with MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.msard.2019.01.013DOI Listing
April 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.

View Article and Find Full Text PDF

Download full-text PDF

Source
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.

View Article and Find Full Text PDF

Download full-text PDF

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

Microvascular blood flow velocities measured with a retinal function imager: inter-eye correlations in healthy controls and an exploration in multiple sclerosis.

Eye Vis (Lond) 2018 2;5:29. Epub 2018 Nov 2.

1Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD USA.

Background: The retinal microcirculation has been studied in various diseases including multiple sclerosis (MS). However, inter-eye correlations and potential differences of the retinal blood flow velocity (BFV) remain largely unstudied but may be important in guiding eye selection as well as the design and interpretation of studies assessing or utilizing retinal BFV. The primary aim of this study was to determine inter-eye correlations in BFVs in healthy controls (HCs). Since prior studies raise the possibility of reduced BFV in MS eyes, a secondary aim was to compare retinal BFVs between MS eyes, grouped based on optic neuritis (ON) history and HC eyes.

Methods: Macular arteriole and venule BFVs were determined using a retinal function imager (RFI) in both eyes of 20 HCs. One eye from a total of 38 MS patients comprising 13 eyes with ON (MSON) and 25 eyes without ON (MSNON) history were similarly imaged with RFI.

Results: OD (right) and OS (left) BFVs were not significantly different in arterioles (OD: 3.95 ± 0.59 mm/s; OS: 4.08 ± 0.60 mm/s,  = 0.10) or venules (OD: 3.11 ± 0.46 mm/s; OS: 3.23 ± 0.52 mm/s,  = 0.06) in HCs. Very strong inter-eye correlations were also found between arteriolar ( = 0.84,  < 0.001) and venular ( = 0.87,  < 0.001) BFVs in HCs. Arteriolar (3.48 ± 0.88 mm/s) and venular (2.75 ± 0.53 mm/s) BFVs in MSNON eyes were significantly lower than in HC eyes ( = 0.009 and  = 0.005, respectively). Similarly, arteriolar (3.59 ± 0.69 mm/s) and venular (2.80 ± 0.45 mm/s) BFVs in MSON eyes were also significantly lower than in HC eyes ( = 0.046 and  = 0.048, respectively). Arteriolar and venular BFVs in MSON and MSNON eyes did not differ from each other ( = 0.42 and  = 0.48, respectively).

Conclusions: Inter-eye arteriolar and venular BFVs do not differ significantly in HCs and are strongly correlated. Our findings support prior observations that arteriolar and venular BFVs may be reduced in MS eyes. Moreover, this seems to be the case in both MS eyes with and without a history of ON, raising the possibility of global blood flow alterations in MS. Future larger studies are needed to assess differences in BFVs between MSON and MSNON eyes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40662-018-0123-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217760PMC
November 2018

Brain and retinal atrophy in African-Americans versus Caucasian-Americans with multiple sclerosis: a longitudinal study.

Brain 2018 11;141(11):3115-3129

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

On average, African Americans with multiple sclerosis demonstrate higher inflammatory disease activity, faster disability accumulation, greater visual dysfunction, more pronounced brain tissue damage and higher lesion volume loads compared to Caucasian Americans with multiple sclerosis. Neurodegeneration is an important component of multiple sclerosis, which in part accounts for the clinical heterogeneity of the disease. Brain atrophy appears to be widespread, although it is becoming increasingly recognized that regional substructure atrophy may be of greater clinical relevance. Patient race (within the limitations of self-identified ancestry) is regarded as an important contributing factor. However, there is a paucity of studies examining differences in neurodegeneration and brain substructure volumes over time in African Americans relative to Caucasian American patients. Optical coherence tomography is a non-invasive and reliable tool for measuring structural retinal changes. Recent studies support its utility for tracking neurodegeneration and disease progression in vivo in multiple sclerosis. Relative to Caucasian Americans, African American patients have been found to have greater retinal structural injury in the inner retinal layers. Increased thickness of the inner nuclear layer and the presence of microcystoid macular pathology at baseline predict clinical and radiological inflammatory activity, although whether race plays a role in these changes has not been investigated. Similarly, assessment of outer retinal changes according to race in multiple sclerosis remains incompletely characterized. Twenty-two African Americans and 60 matched Caucasian Americans with multiple sclerosis were evaluated with brain MRI, and 116 African Americans and 116 matched Caucasian Americans with multiple sclerosis were monitored with optical coherence tomography over a mean duration of 4.5 years. Mixed-effects linear regression models were used in statistical analyses. Grey matter (-0.9%/year versus -0.5%: P =0.02), white matter (-0.7%/year versus -0.3%: P =0.04) and nuclear thalamic (-1.5%/year versus -0.7%/year: P =0.02) atrophy rates were approximately twice as fast in African Americans. African Americans also exhibited higher proportions of microcystoid macular pathology (12.1% versus 0.9%, P =0.001). Retinal nerve fibre layer (-1.1% versus -0.8%: P =0.02) and ganglion cell+ inner plexiform layer (-0.7%/year versus -0.4%/year: P =0.01) atrophy rates were faster in African versus Caucasian Americans. African Americans on average exhibited more rapid neurodegeneration than Caucasian Americans and had significantly faster brain and retinal tissue loss. These results corroborate the more rapid clinical progression reported to occur, in general, in African Americans with multiple sclerosis and support the need for future studies involving African Americans in order to identify individual differences in treatment responses in multiple sclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awy245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202573PMC
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.

View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1167/iovs.17-22391DOI Listing
January 2018

Analysis of Agreement of Retinal-Layer Thickness Measures Derived from the Segmentation of Horizontal and Vertical Spectralis OCT Macular Scans.

Curr Eye Res 2018 03 14;43(3):415-423. Epub 2017 Dec 14.

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

Purpose: Optical coherence tomography (OCT) is a reliable method used to quantify discrete layers of the retina. Spectralis OCT is a device used for this purpose. Spectralis OCT macular scan imaging acquisition can be obtained on either the horizontal or vertical plane. The vertical protocol has been proposed as favorable, due to postulated reduction in confound of Henle's fibers on segmentation-derived metrics. Yet, agreement of the segmentation measures of horizontal and vertical macular scans remains unexplored. Our aim was to determine this agreement.

Materials And Methods: Horizontal and vertical macular scans on Spectralis OCT were acquired in 20 healthy controls (HCs) and 20 multiple sclerosis (MS) patients. All scans were segmented using Heidelberg software and a Johns Hopkins University (JHU)-developed method. Agreement was analyzed using Bland-Altman analyses and intra-class correlation coefficients (ICCs).

Results: Using both segmentation techniques, mean differences (agreement at the cohort level) in the thicknesses of all macular layers derived from both acquisition protocols in MS patients and HCs were narrow (<1 µm), while the limits of agreement (LOA) (agreement at the individual level) were wider. Using JHU segmentation mean differences (and LOA) for the macular retinal nerve fiber layer (RNFL) and ganglion cell layer + inner plexiform layer (GCIP) in MS were 0.21 µm (-1.57-1.99 µm) and -0.36 µm (-1.44-1.37 µm), respectively.

Conclusions: OCT segmentation measures of discrete retinal-layer thicknesses derived from both vertical and horizontal protocols on Spectralis OCT agree excellently at the cohort level (narrow mean differences), but only moderately at the individual level (wide LOA). This suggests patients scanned using either protocol should continue to be scanned with the same protocol. However, due to excellent agreement at the cohort level, measures derived from both acquisitions can be pooled for outcome purposes in clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/02713683.2017.1406526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097232PMC
March 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1352458517741206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929206PMC
March 2019