Publications by authors named "Jennifer S Graves"

52 Publications

CNS Lymphocytic Vasculitis in a Young Woman With COVID-19 Infection.

Neurol Neuroimmunol Neuroinflamm 2021 Sep 28;8(5). Epub 2021 Jul 28.

From the Department of Neurosciences (G.M.T., T.R., E.A.B., A.M., J.S.G.), University of California San Diego, School of Medicine; Department of Pathology (V.G.), Department of Rheumatology (A.K.), and Department of Infectious Diseases (M.R.), University of California San Diego, La Jolla; and Department of Neurology (T.R.), University of Florida, College of Medicine, Gainesville.

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http://dx.doi.org/10.1212/NXI.0000000000001048DOI Listing
September 2021

Quantification of smooth pursuit dysfunction in multiple sclerosis.

Mult Scler Relat Disord 2021 Jun 5;54:103073. Epub 2021 Jun 5.

Dept. of Neurosciences, University of California San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address:

Background: Smooth pursuit dysfunction is common in MS, but rarely quantified and may be missed on exam.

Methods: NeuroFitONE™ smooth pursuit performance measures were compared between MS (n = 20) and healthy control (n = 19) participants.

Results: Compared to controls, MS patients had lower proportion of smooth pursuit (0.63 vs. 0.73; p = 0.047), increased directional (10.1 vs. 8°; p = 0.014) and speed noise (4.3 vs. 3.1°/sec; p = 0.021) and reduced initiation acceleration (96.83 vs. 115.33°/sec; p = 0.061). Significant univariate correlations with clinical scores (EDSS, T25-FW) were observed.

Conclusion: Smooth pursuit dysfunction in MS can be readily quantified and distinguishes MS eyes from healthy controls.
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http://dx.doi.org/10.1016/j.msard.2021.103073DOI Listing
June 2021

Current Status and Future Strategies for Mentoring Women in Neurology.

Neurology 2021 07 4;97(1):30-37. Epub 2021 Jun 4.

From the Lebanon VA Medical Center (A.S.F.), PA; Massachusetts General Hospital (I.C.G.), Boston; University of Oklahoma College of Medicine (D.S.), Oklahoma City; Rady Children's Hospital-San Diego (R.M.T., J.S.G.), CA; Drexel University College of Medicine (J.P.), Philadelphia, PA; Stanford Center for Sleep Sciences and Medicine (L.S.); Sierra Pacific Mental Illness Research Education and Clinical Centers (L.S.), VA Palo Alto Health Care System, Palo Alto; UCSF Medical Center (C.L.-H.); Department of Neurosciences (J.S.G.), UCSD, San Diego, CA; Imperial College London (S.S.), UK; University of Mississippi Medical Center (C.O.S.N.), Jackson; and Penn State Hershey Medical Center (A.S.F.).

The American Academy of Neurology's (AAN) 2017 Gender Disparity Report identified improving mentorship as a key intervention to fill the leadership and pay gaps for women in neurology. Here we summarize the literature on mentoring women, provide an outline of ideal components of programs geared toward closing gender gaps, and present a mentoring program for AAN members. The strategies discussed share similarities with those for closing gaps related to race, ethnicity, and religion. Developing effective mentorship and sponsorship programs is essential to ensure a sufficiently diverse pool of academic faculty and private practitioners and to establish equal representation in leadership roles in this field.
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http://dx.doi.org/10.1212/WNL.0000000000012242DOI Listing
July 2021

Artificial intelligence extension of the OSCAR-IB criteria.

Ann Clin Transl Neurol 2021 Jul 19;8(7):1528-1542. Epub 2021 May 19.

Division of Neurology, Department of Pediatrics, Hospital for Sick Children, Division of Neurosciences and Mental Health SickKids Research Institute, University of Toronto, Canada.

Artificial intelligence (AI)-based diagnostic algorithms have achieved ambitious aims through automated image pattern recognition. For neurological disorders, this includes neurodegeneration and inflammation. Scalable imaging technology for big data in neurology is optical coherence tomography (OCT). We highlight that OCT changes observed in the retina, as a window to the brain, are small, requiring rigorous quality control pipelines. There are existing tools for this purpose. Firstly, there are human-led validated consensus quality control criteria (OSCAR-IB) for OCT. Secondly, these criteria are embedded into OCT reporting guidelines (APOSTEL). The use of the described annotation of failed OCT scans advances machine learning. This is illustrated through the present review of the advantages and disadvantages of AI-based applications to OCT data. The neurological conditions reviewed here for the use of big data include Alzheimer disease, stroke, multiple sclerosis (MS), Parkinson disease, and epilepsy. It is noted that while big data is relevant for AI, ownership is complex. For this reason, we also reached out to involve representatives from patient organizations and the public domain in addition to clinical and research centers. The evidence reviewed can be grouped in a five-point expansion of the OSCAR-IB criteria to embrace AI (OSCAR-AI). The review concludes by specific recommendations on how this can be achieved practically and in compliance with existing guidelines.
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http://dx.doi.org/10.1002/acn3.51320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283174PMC
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.
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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.

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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

U-turn speed is a valid and reliable smartphone-based measure of multiple sclerosis-related gait and balance impairment.

Gait Posture 2021 02 25;84:120-126. Epub 2020 Nov 25.

F. Hoffmann-La Roche Ltd, Basel, 4070, Switzerland; Department of Economics, Baden-Wuerttemberg Cooperative State University, Loerrach, 79539, Germany. Electronic address:

Background: People living with multiple sclerosis (MS) experience impairments in gait and mobility, that are not fully captured with manually timed walking tests or rating scales administered during periodic clinical visits. We have developed a smartphone-based assessment of ambulation performance, the 5 U-Turn Test (5UTT), a quantitative self-administered test of U-turn ability while walking, for people with MS (PwMS).

Research Question: What is the test-retest reliability and concurrent validity of U-turn speed, an unsupervised self-assessment of gait and balance impairment, measured using a body-worn smartphone during the 5UTT?

Methods: 76 PwMS and 25 healthy controls (HCs) participated in a cross-sectional non-randomised interventional feasibility study. The 5UTT was self-administered daily and the median U-turn speed, measured during a 14-day session, was compared against existing validated in-clinic measures of MS-related disability.

Results: U-turn speed, measured during a 14-day session from the 5UTT, demonstrated good-to-excellent test-retest reliability in PwMS alone and combined with HCs (intraclass correlation coefficient [ICC] = 0.87 [95 % CI: 0.80-0.92]) and moderate-to-excellent reliability in HCs alone (ICC = 0.88 [95 % CI: 0.69-0.96]). U-turn speed was significantly correlated with in-clinic measures of walking speed, physical fatigue, ambulation impairment, overall MS-related disability and patients' self-perception of quality of life, at baseline, Week 12 and Week 24. The minimal detectable change of the U-turn speed from the 5UTT was low (19.42 %) in PwMS and indicates a good precision of this measurement tool when compared with conventional in-clinic measures of walking performance.

Significance: The frequent self-assessment of turn speed, as an outcome measure from a smartphone-based U-turn test, may represent an ecologically valid digital solution to remotely and reliably monitor gait and balance impairment in a home environment during MS clinical trials and practice.
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http://dx.doi.org/10.1016/j.gaitpost.2020.11.025DOI Listing
February 2021

Biosensor vital sign detects multiple sclerosis progression.

Ann Clin Transl Neurol 2021 01 19;8(1):4-14. Epub 2020 Nov 19.

UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, USA.

Objective: To determine whether a small, wearable multisensor device can discriminate between progressive versus relapsing multiple sclerosis (MS) and capture limb progression over a short interval, using finger and foot tap data.

Methods: Patients with MS were followed prospectively during routine clinic visits approximately every 6 months. At each visit, participants performed finger and foot taps wearing the MYO-band, which includes accelerometer, gyroscope, and surface electromyogram sensors. Metrics of within-patient limb progression were created by combining the change in signal waveform features over time. The resulting upper (UE) and lower (LE) extremity metrics' discrimination of progressive versus relapsing MS were evaluated with calculation of AUROC. Comparisons with Expanded Disability Status Scale (EDSS) scores were made with Pearson correlation.

Results: Participants included 53 relapsing and 15 progressive MS (72% female, baseline mean age 48 years, median disease duration 11 years, median EDSS 2.5, median 10 months follow-up). The final summary metrics differentiated relapsing from secondary progressive MS with AUROC UE 0.93 and LE 0.96. The metrics were associated with baseline EDSS (UE P = 0.0003, LE P = 0.0007). While most had no change in EDSS during the short follow-up, several had evidence of progression by the multisensor metrics.

Interpretation: Within a short follow-up interval, this novel multisensor algorithm distinguished progressive from relapsing MS and captured changes in limb function. Inexpensive, noninvasive and easy to use, this novel outcome is readily adaptable to clinical practice and trials as a MS vital sign. This approach also holds promise to monitor limb dysfunction in other neurological diseases.
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http://dx.doi.org/10.1002/acn3.51187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818086PMC
January 2021

Assessment of Pediatric Optic Neuritis Visual Acuity Outcomes at 6 Months.

JAMA Ophthalmol 2020 12;138(12):1253-1261

Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota.

Importance: Optic neuritis (ON) in children is uncommon. There are limited prospective data for visual acuity (VA) outcomes, associated diseases, and neuroimaging findings. Prospective data from a large sample would be useful for counseling families on treatment decisions and prognosis.

Objective: To prospectively study children with a first episode of ON, describe VA after 6 months, and ascertain the network's (Pediatric Eye Disease Investigator Group and Neuro-Ophthalmology Research Disease Investigator Consortium) ability to enroll pediatric patients with ON prospectively.

Design, Setting, And Participants: This nonrandomized cohort study was conducted from September 20, 2016, to July 20, 2018, at 23 sites in the United States and Canada in pediatric ophthalmology or neuro-ophthalmology clinics. A total of 44 children (aged 3-15 years) presented with a first episode of ON (visual loss, pain on eye movements, or both) within 2 weeks of symptom onset and at least 1 of the following in the affected eye: a distance high-contrast VA (HCVA) deficit of at least 0.2 logMAR below age-based norms, diminished color vision, abnormal visual field, or optic disc swelling. Exclusion criteria included preexisting ocular abnormalities or a previous episode of ON.

Main Outcomes And Measures: Primary outcomes were monocular HCVA and low-contrast VA at 6 months. Secondary outcomes were neuroimaging, associated diagnoses, and antibodies for neuromyelitis optica and myelin oligodendrocyte glycoprotein.

Results: A total of 44 children (mean age [SD], 10.2 [3.5] years; 26 boys [59%]; 23 White individuals [52%]; 54 eyes) were enrolled in the study. Sixteen patients (36%) had bilateral ON. Magnetic resonance imaging revealed white matter lesions in 23 children (52%). Of these children, 8 had myelin oligodendrocyte glycoprotein-associated demyelination (18%), 7 had acute disseminated encephalomyelitis (16%), 5 had multiple sclerosis (11%), and 3 had neuromyelitis optica (7%). The baseline mean HCVA was 0.95 logMAR (20/200), which improved by a mean 0.76 logMAR (95% CI, 0.54-0.99; range, -0.70 to 1.80) to 0.12 logMAR (20/25) at 6 months. The baseline mean distance low-contrast VA was 1.49 logMAR (20/640) and improved by a mean 0.72 logMAR (95% CI, 0.54-0.89; range, -0.20 to 1.50) to 0.73 logMAR (20/100) at 6 months. Baseline HCVA was worse in younger participants (aged <10 years) with associated neurologic autoimmune diagnoses, white matter lesions, and in those of non-White race and non-Hispanic ethnicity. The data did not suggest a statistically significant association between baseline factors and improvement in HCVA.

Conclusions And Relevance: The study network did not reach its targeted enrollment of 100 pediatric patients with ON over 2 years. This indicates that future treatment trials may need to use different inclusion criteria or plan a longer enrollment period to account for the rarity of the disease. Despite poor VA at presentation, most children had marked improvement by 6 months. Associated neurologic autoimmune diagnoses were common. These findings can be used to counsel families about the disease.
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http://dx.doi.org/10.1001/jamaophthalmol.2020.4231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563662PMC
December 2020

Dermatographism associated with ocrelizumab.

Mult Scler Relat Disord 2020 Nov 13;46:102505. Epub 2020 Sep 13.

Department of Neurosciences, University of California San Diego, San Diego, CA, United States. Electronic address:

Dermatographism is a disorder of unknown etiology that results in inducible hives from environmental stimuli. Here we report the first known case of dermatographism associated with ocrelizumab in a patient with relapsing remitting multiple sclerosis. The patient presented with pruritic linear raised rash approximately two weeks after her first infusion with ocrelizumab and was later diagnosed with dermatographism. This case highlights a potential rare adverse reaction to ocrelizumab and may provide insight into the biological underpinnings of dermatographism.
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http://dx.doi.org/10.1016/j.msard.2020.102505DOI Listing
November 2020

Do Pregnancies Forestall the Onset of MS?

JAMA Neurol 2020 12;77(12):1484-1485

Department of Neurosciences, University of California, San Diego, La Jolla.

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http://dx.doi.org/10.1001/jamaneurol.2020.3332DOI Listing
December 2020

Utilization of Visual Acuity Retroilluminated Charts for the Assessment of Afferent Visual System Dysfunction in a Pediatric Neuroimmunology Population.

J Neuroophthalmol 2021 03;41(1):19-23

Multiple Sclerosis Division (PVS, MM, DC, BMG), Department of Neurology and Neurotherapeutics, University of Texas Southwestern, Dallas, Texas; Department of Neurology (JG), University of California San Diego, San Diego, California; Department of Neurology and Pediatrics (LB), Boston Children's Hospital, Boston, Massachusetts; Division of Neurology (ATW), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and Departments of Neurology and Pediatrics (ATW), Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Visual acuity has been a significant outcome measure in clinical trials for patients suffering from neuro-ophthalmological diseases and multiple sclerosis; however, there are limited data on the comparison of various testing strategies in pediatric patients with these disorders. Clinical trials using vision as an outcome could include a variety of tools to assess the acuity, including 2-m and 4-m standardized retroilluminated charts.

Methods: We investigated the difference in Early Treatment Diabetic Retinopathy Study (ETDRS) scores obtained using 2-m and 4-m charts, as well as the impact of optic neuritis, use of vision correction, age, and gender on visual acuity data from 71 patients with pediatric neuroimmunological conditions in a cross-sectional study.

Results: We determine that the ETDRS letter scores obtained using 4-m charts are on average 3.43 points less (P = 0.0034) when testing monocular ETDRS letter scores and on average 4.14 points less (P = 0.0008) when testing binocular ETDRS letter scores, relative to that obtained using the 2-m charts. However, we find that when performing monocular testing, optic neuritis in the eye being tested did not result in a statistically significant difference between 2-m and 4-m ETDRS letter scores.

Conclusions: Although visual acuity charts are formatted by the distance, there are significant differences in the number of letters correctly identified between 2-m and 4-m charts. Although the differences may not impact the clinical acuity, research protocols should consider these differences before collapsing data across disparate studies.
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http://dx.doi.org/10.1097/WNO.0000000000001001DOI Listing
March 2021

Improved relapse recovery in paediatric compared to adult multiple sclerosis.

Brain 2020 09;143(9):2733-2741

Mayo Clinic Paediatric Multiple Sclerosis Center, Mayo Clinic, Rochester, MN, USA.

Incomplete relapse recovery contributes to disability accrual and earlier onset of secondary progressive multiple sclerosis. We sought to investigate the effect of age on relapse recovery. We identified patients with multiple sclerosis from two longitudinal prospective studies, with an Expanded Disability Status Scale (EDSS) score within 30 days after onset of an attack, and follow-up EDSS 6 months after attack. Adult patients with multiple sclerosis (n = 632) were identified from the Comprehensive Longitudinal Investigations in Multiple Sclerosis at Brigham study (CLIMB), and paediatric patients (n = 132) from the US Network of Paediatric Multiple Sclerosis Centers (NPMSC) registry. Change in EDSS was defined as the difference in EDSS between attack and follow-up. Change in EDSS at follow-up compared to baseline was significantly lower in children compared to adults (P = 0.001), as were several functional system scores. Stratification by decade at onset for change in EDSS versus age found for every 10 years of age, EDSS recovery is reduced by 0.15 points (P < 0.0001). A larger proportion of children versus adults demonstrated improvement in EDSS following an attack (P = 0.006). For every 10 years of age, odds of EDSS not improving increase by 1.33 times (P < 0.0001). Younger age is associated with improved recovery from relapses. Age-related mechanisms may provide novel therapeutic targets for disability accrual in multiple sclerosis.
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http://dx.doi.org/10.1093/brain/awaa199DOI Listing
September 2020

Pediatric Multiple Sclerosis Severity Score in a large US cohort.

Neurology 2020 09 20;95(13):e1844-e1853. Epub 2020 Jul 20.

From Partners Pediatric Multiple Sclerosis Center (J.D.S., T.C.), Massachusetts General Hospital; Harvard Medical School (J.D.S.), Boston, MA; Pediatric Multiple Sclerosis and Related Disorders Program at Boston Children's Hospital (J.D.S., L.B., M.G.), MA; Children's Hospital Los Angeles (J.D.S.); Keck School of Medicine at the University of Southern California (J.D.S.), Los Angeles; Data Coordinating and Analysis Center (M.W., S.R., J.R., T.C.C.), University of Utah, Salt Lake City; Pediatric Multiple Sclerosis Center (G.A.), Loma Linda University Children's Hospital, CA; Pediatric MS Center at NYU Langone Health (A.B., L.K.), New York, NY; Washington University (M.S.G., S.M.), St. Louis, MO; Pediatric Multiple Sclerosis Center (J.S.G.), University of California San Diego; UAB Center for Pediatric-Onset Demyelinating Disease (Y.H., J.N.), University of Alabama at Birmingham; The Blue Bird Circle Clinic for Multiple Sclerosis (T.L.), Texas Children's Hospital, Baylor College of Medicine, Houston; Mellen Center for Multiple Sclerosis (M.M., M. Rensel), Cleveland Clinic, OH; Mayo Clinic Pediatric Multiple Sclerosis Center (M. Rodriguez, J.-M.T.), Mayo Clinic, Rochester, MN; Rocky Mountain Multiple Sclerosis Center (T.S.), Children's Hospital Colorado, University of Colorado at Denver, Aurora; Pediatric Multiple Sclerosis Center (E.W.), University of California San Francisco; Jacobs Pediatric Multiple Sclerosis Center (B.W.-G.), State University of New York at Buffalo; and Department of Neurology (B.F.H.), Stanford University School of Medicine, Palo Alto, CA.

Objective: To characterize disease severity and distribution of disability in pediatric-onset multiple sclerosis (POMS) and to develop an optimized modeling scale for measuring disability, we performed a multicenter retrospective analysis of disability scores in 873 persons with POMS over time and compared this to previously published data in adults with multiple sclerosis (MS).

Methods: This was a retrospective analysis of prospectively collected data collected from 12 centers of the US Network of Pediatric MS Centers. Patients were stratified by the number of years from first symptoms of MS to Expanded Disability Status Scale (EDSS) assessment and an MS severity score (Pediatric Multiple Sclerosis Severity Score [Ped-MSSS]) was calculated per criteria developed by Roxburgh et al. in 2005.

Results: In total, 873 patients were evaluated. In our cohort, 52%, 19.4%, and 1.5% of all patients at any time point reached an EDSS of 2.0, 3.0, and 6.0. Comparison of our Ped-MSSS scores and previously published adult Multiple Sclerosis Severity Scores (MSSS) showed slower progression of Ped-MSSS with increasing gaps between higher EDSS score and years after diagnosis. Decile scores in our POMS cohort for EDSS of 2.0, 3.0, and 6.0 were 8.00/9.46/9.94, 7.86/9.39/9.91, and 7.32/9.01/9.86 at 2, 5, and 10 years, respectively. Notable predictors of disease progression in both EDSS and Ped-MSSS models were ever having a motor relapse and EDSS at year 1. Symbol Digit Modalities Test (SDMT) scores were inversely correlated with duration of disease activity and cerebral functional score.

Conclusions: Persons with POMS exhibit lower EDSS scores compared to persons with adult-onset MS. Use of a Ped-MSSS model may provide an alternative to EDSS scoring in clinical assessment of disease severity and disability accrual.
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http://dx.doi.org/10.1212/WNL.0000000000010414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682820PMC
September 2020

Sex effects across the lifespan in women with multiple sclerosis.

Ther Adv Neurol Disord 2020 1;13:1756286420936166. Epub 2020 Jul 1.

Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating central nervous system disorder that is more common in women, with onset often during reproductive years. The female:male sex ratio of MS rose in several regions over the last century, suggesting a possible sex by environmental interaction increasing MS risk in women. Since many with MS are in their childbearing years, family planning, including contraceptive and disease-modifying therapy (DMT) counselling, are important aspects of MS care in women. While some DMTs are likely harmful to the developing fetus, others can be used shortly before or until pregnancy is confirmed. Overall, pregnancy decreases risk of MS relapses, whereas relapse risk may increase postpartum, although pregnancy does not appear to be harmful for long-term prognosis of MS. However, ovarian aging may contribute to disability progression in women with MS. Here, we review sex effects across the lifespan in women with MS, including the effect of sex on MS susceptibility, effects of pregnancy on MS disease activity, and management strategies around pregnancy, including risks associated with DMT use before and during pregnancy, and while breastfeeding. We also review reproductive aging and sexual dysfunction in women with MS.
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http://dx.doi.org/10.1177/1756286420936166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331774PMC
July 2020

Real-World Effectiveness of Initial Disease-Modifying Therapies in Pediatric Multiple Sclerosis.

Ann Neurol 2020 07 14;88(1):42-55. Epub 2020 May 14.

UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA.

Objective: To assess real-world effectiveness of initial treatment with newer compared to injectable disease-modifying therapies (DMTs) on disease activity in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS).

Methods: This is a cohort study of children with MS/CIS followed at 12 clinics in the US Network of Pediatric MS Centers, who received initial therapy with newer (fingolimod, dimethyl fumarate, teriflunomide, natalizumab, rituximab, ocrelizumab) or injectable (interferon-β, glatiramer acetate) DMTs. Propensity scores (PSs) were computed, including preidentified confounders. Relapse rate while on initial DMT was modeled with negative binomial regression, adjusted for PS-quintile. Time to new/enlarging T2-hyperintense and gadolinium-enhancing lesions on brain magnetic resonance imaging were modeled with midpoint survival analyses, adjusted for PS-quintile.

Results: A total of 741 children began therapy before 18 years, 197 with newer and 544 with injectable DMTs. Those started on newer DMTs were older (15.2 vs injectable 14.4 years, p = 0.001) and less likely to have a monofocal presentation. In PS-quintile-adjusted analysis, those on newer DMTs had a lower relapse rate than those on injectables (rate ratio = 0.45, 95% confidence interval (CI) = 0.29-0.70, p < 0.001; rate difference = 0.27, 95% CI = 0.14-0.40, p = 0.004). One would need to treat with newer rather than injectable DMTs for 3.7 person-years to prevent 1 relapse. Those started on newer DMTs had a lower rate of new/enlarging T2 (hazard ratio [HR] = 0.51, 95% CI = 0.36-0.72, p < 0.001) and gadolinium-enhancing lesions (HR = 0.38, 95% CI = 0.23-0.63, p < 0.001) than those on injectables.

Interpretation: Initial treatment of pediatric MS/CIS with newer DMTs led to better disease activity control compared to injectables, supporting greater effectiveness of newer therapies. Long-term safety data for newer DMTs are required. ANN NEUROL 2020 ANN NEUROL 2020;88:42-55.
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http://dx.doi.org/10.1002/ana.25737DOI Listing
July 2020

Novel MS vital sign: multi-sensor captures upper and lower limb dysfunction.

Ann Clin Transl Neurol 2020 03 26;7(3):288-295. Epub 2020 Feb 26.

Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, California.

Objective: To create a novel neurological vital sign and reliably capture MS-related limb disability in less than 5 min.

Methods: Consecutive patients meeting the 2010 MS diagnostic criteria and healthy controls were offered enrollment. Participants completed finger and foot taps wearing the MYO-band© (accelerometer, gyroscope, and surface electromyogram sensors). Signal processing was performed to extract spatiotemporal features from raw sensor data. Intraclass correlation coefficients (ICC) assessed intertest reproducibility. Spearman correlation and multivariable regression methods compared extracted features to physician- and patient-reported disability outcomes. Partial least squares regression identified the most informative extracted textural features.

Results: Baseline data for 117 participants with MS (EDSS 1.0-7.0) and 30 healthy controls were analyzed. ICCs for final selected features ranged from 0.80 to 0.87. Time-based features distinguished cases from controls (P = 0.002). The most informative combination of extracted features from all three sensors strongly correlated with physician EDSS (finger taps r  = 0.77, P < 0.0001; foot taps r  = 0.82, P < 0.0001) and had equally strong associations with patient-reported outcomes (WHODAS, finger taps r  = 0.82, P < 0.0001; foot taps r  = 0.82, P < 0.0001). Associations remained with multivariable modeling adjusted for age and sex.

Conclusions: Extracted features from the multi-sensor demonstrate striking correlations with gold standard outcomes. Ideal for future generalizability, the assessments take only a few minutes, can be performed by nonclinical personnel, and wearing the band is nondisruptive to routine practice. This novel paradigm holds promise as a new neurological vital sign.
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http://dx.doi.org/10.1002/acn3.50988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085995PMC
March 2020

Biosensors to monitor MS activity.

Mult Scler 2020 04 22;26(5):605-608. Epub 2020 Jan 22.

MS Centre, St Michael's Hospital, University of Toronto, Toronto, ON, Canada.

Advances in wearable and wireless biosensing technology pave the way for a brave new world of novel multiple sclerosis (MS) outcome measures. Our current tools for examining patients date back to the 19th century and while invaluable to the neurologist invite accompaniment from these new technologies and artificial intelligence (AI) analytical methods. While the most common biosensor tool used in MS publications to date is the accelerometer, the landscape is changing quickly with multi-sensor applications, electrodermal sensors, and wireless radiofrequency waves. Some caution is warranted to ensure novel outcomes have clear clinical relevance and stand-up to the rigors of reliability, reproducibility, and precision, but the ultimate implementation of biosensing in the MS clinical setting is inevitable.
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http://dx.doi.org/10.1177/1352458519888178DOI Listing
April 2020

Optical Coherence Tomography in Multiple Sclerosis.

Semin Neurol 2019 12 17;39(6):711-717. Epub 2019 Dec 17.

Department of Neurosciences, University of California, San Diego, California.

Optical coherence tomography (OCT) grew out of a convergence of rapid advancements in femtoseconds optics research and fiber optic commercial technology. The basic concept of OCT is to "see" into tissues using light echoes, analogous to the sound echoes of ultrasonography. Multiple A-scans are assembled into a B-scan two-dimensional image of the tissue of interest. Retina is an ideal tissue for evaluation by OCT, since the eye is designed to minimize light scattering through the anterior chamber and vitreous. OCT has had a significant impact on the field of multiple sclerosis, where it has allowed direct imaging of the myelin-free segments of axons and cell bodies of retinal ganglion cells. Together with precise functional measurements of the afferent visual system, the addition of robust structural measurements of retinal injury has allowed for an unprecedented ability to correlate clinical effects with the degree of neuronal loss. In addition, OCT has proven helpful to distinguish different forms of demyelinating disease, such as multiple sclerosis (MS) and neuromyelitis optica, and has provided ideal outcome measures in remyelination and neuroprotection trials.
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http://dx.doi.org/10.1055/s-0039-1700528DOI Listing
December 2019

Clinical Features and Outcomes of Pediatric Monophasic and Recurrent Idiopathic Optic Neuritis.

J Child Neurol 2020 01 30;35(1):77-83. Epub 2019 Sep 30.

Department of Neurology, University of California, San Francisco, CA, USA.

Limited data exist on isolated optic neuritis in children. We report the clinical features and treatment of pediatric subjects with monophasic and recurrent idiopathic optic neuritis. This retrospective cohort study of patients with isolated optic neuritis identified 10 monophasic and 7 recurrent optic neuritis cases. Monophasic optic neuritis patients were older (mean 13.3 ± 4.22) than those with recurrent idiopathic optic neuritis (9.86 ± 3.63). Females represented 50% of monophasic and 85.7% of recurrent idiopathic optic neuritis cases. Patients with monophasic optic neuritis were less likely to have a bilateral onset than recurrent idiopathic optic neuritis (40% vs 57.1%). Only 1 case had oligoclonal bands in the cerebrospinal fluid CSF. Most recurrent idiopathic optic neuritis cases had evidence of anti-myelin oligodendrocyte glycoprotein (MOG) antibodies (5/7). Treatment of recurrent idiopathic optic neuritis cases included intravenous pulse glucocorticosteroids and immunotherapy. We observed differences between recurrent and monophasic idiopathic optic neuritis. Immunosuppression appeared to prevent further relapses in recurrent idiopathic optic neuritis patients. Weaning immunotherapies after several years of quiescence in recurrent idiopathic optic neuritis may be possible, but larger studies are needed.
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http://dx.doi.org/10.1177/0883073819877334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018758PMC
January 2020

Telomere Length Is Associated with Disability Progression in Multiple Sclerosis.

Ann Neurol 2019 11 2;86(5):671-682. Epub 2019 Oct 2.

UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA.

Objective: To assess whether biological aging as measured by leukocyte telomere length (LTL) is associated with clinical disability and brain volume loss in multiple sclerosis (MS).

Methods: Adults with MS/clinically isolated syndrome in the University of California, San Francisco EPIC cohort study were included. LTL was measured on DNA samples by quantitative polymerase chain reaction and expressed as telomere to somatic DNA (T/S) ratio. Expanded Disability Status Scale (EDSS) and 3-dimensional T1-weighted brain magnetic resonance imaging were performed at baseline and follow-up. Associations of baseline LTL with cross-sectional and longitudinal outcomes were assessed using simple and mixed effects linear regression models. A subset (n = 46) had LTL measured over time, and we assessed the association of LTL change with EDSS change with mixed effects models.

Results: Included were 356 women and 160 men (mean age = 43 years, median disease duration = 6 years, median EDSS = 1.5 [range = 0-7], mean T/S ratio = 0.97 [standard deviation = 0.18]). In baseline analyses adjusted for age, disease duration, and sex, for every 0.2 lower LTL, EDSS was 0.27 higher (95% confidence interval [CI] = 0.13-0.42, p < 0.001) and brain volume was 7.4mm lower (95% CI = 0.10-14.7, p = 0.047). In longitudinal adjusted analyses, those with lower baseline LTL had higher EDSS and lower brain volumes over time. In adjusted analysis of the subset, LTL change was associated with EDSS change over 10 years; for every 0.2 LTL decrease, EDSS was 0.34 higher (95% CI = 0.08-0.61, p = 0.012).

Interpretation: Shorter telomere length was associated with disability independent of chronological age, suggesting that biological aging may contribute to neurological injury in MS. Targeting aging-related mechanisms is a potential therapeutic strategy against MS progression. ANN NEUROL 2019;86:671-682.
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http://dx.doi.org/10.1002/ana.25592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135931PMC
November 2019

A retrospective cohort study of plasma exchange in central nervous system demyelinating events in children.

Mult Scler Relat Disord 2019 Oct 8;35:50-54. Epub 2019 Jul 8.

Neurology, University of California San Francisco, San Francisco, CA, USA.

Background: Plasma exchange (PLEX) may improve recovery of acute central nervous system (CNS) demyelinating events related to multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), transverse myelitis (TM), acute disseminated encephalomyelitis (ADEM), and MOG-antibody associated demyelination (MOG) if recovery with pulse steroids (PS) is incomplete. Although there is a single randomized controlled trial in adults, there are limited case series in children. We aimed to describe the effectiveness and safety of PLEX in children with acute events of MS, NMOSD, TM, ADEM, and MOG with limited improvement after PS.

Methods: This was a retrospective cohort study of children with acute CNS demyelinating events seen at a single tertiary referral center who received PLEX as a second- or third-line therapy between 2006 and 2018. Through chart review of clinical notes, presence of clinical improvement by physician assessment was recorded pre- and post-PS and pre- and post-PLEX. Expanded Disability Status Scale (EDSS) scores were collected pre- and post-PLEX. We evaluated the number who improved clinically with PLEX and compared pre- and post-PLEX EDSS with Wilcoxon matched pairs signed-rank test.

Results: 26 patients followed at the Pediatric MS Center at the University of California, San Francisco received PLEX for acute events of MS (n = 15), NMOSD (n = 7), MOG (n = 2), TM (n = 1), and ADEM (n = 1). At time of PLEX initiation, median age was 13.5 years (range 3-17) and median time between the acute event onset and PLEX initiation was 22 days (range 3-94). 14 of 24 patients had documented clinical improvement after PS. Of those who improved during PS (n = 14), 13 had additional improvement after PLEX. Of those with no improvement after PS (n = 10), 8 improved after PLEX. 16 of 26 patients had pre- and post-PLEX EDSS scores available. Median pre-PLEX EDSS score was 4.0 (range 3.0-8.0), and median post-PLEX EDSS score was 3.75 (range 0-8.0) (p = 0.062). 5 patients had improved EDSS scores by 1 or more points. Adverse events during PLEX included hypotension (n = 3), nausea (n = 2), headache (n = 2), hypocalcemia (n = 2), hypofibrinogenemia (n = 2), thrombocytopenia (n = 1), spinal cord hemorrhage (n = 1), acute non-occlusive thrombosis of internal jugular vein (n = 1), occlusion of the central line (n = 1), edema of the neck (n = 1), and gastrointestinal discomfort (n = 1).

Conclusions: PLEX is an overall well-tolerated second-line treatment option for pediatric patients with severe acute CNS demyelinating events with limited response to PS.
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http://dx.doi.org/10.1016/j.msard.2019.07.004DOI Listing
October 2019

miRNA contributions to pediatric-onset multiple sclerosis inferred from GWAS.

Ann Clin Transl Neurol 2019 Jun 15;6(6):1053-1061. Epub 2019 May 15.

Department of Neurology University of California San Francisco California.

Objective: Onset of multiple sclerosis (MS) occurs in childhood for approximately 5% of cases (pediatric MS, or ped-MS). Epigenetic influences are strongly implicated in MS pathogenesis in adults, including the contribution from microRNAs (miRNAs), small noncoding RNAs that affect gene expression by binding target gene mRNAs. Few studies have specifically examined miRNAs in ped-MS, but individuals developing MS at an early age may carry a relatively high burden of genetic risk factors, and miRNA dysregulation may therefore play a larger role in the development of ped-MS than in adult-onset MS. This study aimed to look for evidence of miRNA involvement in ped-MS pathogenesis.

Methods: GWAS results from 486 ped-MS cases and 1362 controls from the U.S. Pediatric MS Network and Kaiser Permanente Northern California membership were investigated for miRNA-specific signals. First, enrichment of miRNA-target gene network signals was evaluated using MIGWAS software. Second, SNPs in miRNA genes and in target gene binding sites (miR-SNPs) were tested for association with ped-MS, and pathway analysis was performed on associated target genes.

Results: MIGWAS analysis showed that miRNA-target gene signals were enriched in GWAS ( = 0.038) and identified 39 candidate biomarker miRNA-target gene pairs, including immune and neuronal signaling genes. The miR-SNP analysis implicated dysregulation of miRNA binding to target genes in five pathways, mainly involved in immune signaling.

Interpretation: Evidence from GWAS suggests that miRNAs play a role in ped-MS pathogenesis by affecting immune signaling and other pathways. Candidate biomarker miRNA-target gene pairs should be further studied for diagnostic, prognostic, and/or therapeutic utility.
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http://dx.doi.org/10.1002/acn3.786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562070PMC
June 2019

Mitochondrial Dysfunction and Multiple Sclerosis.

Biology (Basel) 2019 May 11;8(2). Epub 2019 May 11.

Department of Neurosciences, University of California San Diego, San Diego, CA 92093-0935, USA.

In recent years, several studies have examined the potential associations between mitochondrial dysfunction and neurodegenerative diseases such as multiple sclerosis (MS), Parkinson's disease and Alzheimer's disease. In MS, neurological disability results from inflammation, demyelination, and ultimately, axonal damage within the central nervous system. The sustained inflammatory phase of the disease leads to ion channel changes and chronic oxidative stress. Several independent investigations have demonstrated mitochondrial respiratory chain deficiency in MS, as well as abnormalities in mitochondrial transport. These processes create an energy imbalance and contribute to a parallel process of progressive neurodegeneration and irreversible disability. The potential roles of mitochondria in neurodegeneration are reviewed. An overview of mitochondrial diseases that may overlap with MS are also discussed, as well as possible therapeutic targets for the treatment of MS and other neurodegenerative conditions.
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http://dx.doi.org/10.3390/biology8020037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627385PMC
May 2019

Vitamin D genes influence MS relapses in children.

Mult Scler 2020 07 13;26(8):894-901. Epub 2019 May 13.

Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.

Objective: The aim of this study was to determine whether a vitamin D genetic risk score (vitDGRS) is associated with 25-hydroxyvitamin D (25(OH)D) level and multiple sclerosis (MS) relapses in children.

Methods: DNA samples were typed for single nucleotide polymorphisms (SNPs) from four genes previously identified to be associated with 25(OH)D levels. SNPs with strong associations with 25(OH)D after multiple comparison correction were used to create a genetic risk score (vitDGRS). Cox regression models tested associations of vitDGRS with relapse hazard.

Results: Two independent SNPs within or near and genes were strongly associated with 25(OH)D levels in the discovery cohort ( = 182) after Bonferroni correction. The vitDGRS of these SNPs explained 4.5% of the variance of 25(OH)D level after adjustment for genetic ancestry. Having the highest versus lowest vitDGRS was associated with 11 ng/mL lower 25(OH)D level (95% confidence interval (CI) = -17.5, -4.5,  = 0.001) in the discovery cohort. Adjusting for ancestry, sex, disease-modifying therapy (DMT), and carrier status, the highest versus lowest vitDGRS was associated with 2.6-fold (95% CI = 1.37, 5.03,  = 0.004) and 2.0-fold (95% CI = 0.75, 5.20,  = 0.16) higher relapse hazard in the discovery and replication cohorts, respectively.

Conclusion: The vitDGRS identifies children at greater risk of relapse. These findings support a causal role for vitamin D in MS course.
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http://dx.doi.org/10.1177/1352458519845842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851448PMC
July 2020

Several household chemical exposures are associated with pediatric-onset multiple sclerosis.

Ann Clin Transl Neurol 2018 Dec 9;5(12):1513-1521. Epub 2018 Oct 9.

Pediatric Multiple Sclerosis Center University of California San Francisco San Francisco California.

Background: There is limited information about the potential associations of multiple sclerosis (MS) and commonly used household chemicals.

Methods: We performed a case-control study of exposures to common household chemicals during childhood in children with MS and healthy pediatric controls. Exposures to household products were collected from a comprehensive questionnaire (http://www.usnpmsc.org/Documents/EnvironmentalAssessment.pdf) completed by parents at the time of enrollment in the study. Cases included children diagnosed with MS or clinically isolated syndrome with at least two silent T2 bright lesions on MRI, recruited within 4 years of disease onset from 16 pediatric MS clinics in the USA. Multivariate analyses using logistic regression were adjusted for possible confounders including age, sex, race, ethnicity, mother's highest level of education, and urban versus rural living.

Results: Questionnaire responses to household chemicals were available for 312 eligible cases (median age 15.7 years, 63% girls) and 490 healthy controls (median age 15.0, 57% girls). Exposure to rodenticides (odds ratio [OR] 2.10, 95% confidence interval [CI] 1.35-3.26,  ≤ 0.001), weed control agents (OR 1.99, 95% CI 1.36-2.92,  ≤ 0.001) and products for plant/tree disease control (OR 2.72, 95% CI 1.54-4.82,  ≤ 0.001) anytime during childhood were associated with an increased risk for pediatric-onset MS in adjusted and multiple comparisons analyses.

Conclusions: Our findings suggest that exposure to specific household chemicals during early childhood is associated with the risk of developing pediatric-onset MS. Future studies are needed to elucidate a causal relationship and the exact agents involved.
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http://dx.doi.org/10.1002/acn3.663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292189PMC
December 2018

Subclinical Saccadic Eye Movement Dysfunction in Pediatric Multiple Sclerosis.

J Child Neurol 2019 01 21;34(1):38-43. Epub 2018 Nov 21.

1 Department of Neurology, University of California San Francisco, San Francisco, CA, USA.

Background: Efferent visual dysfunction in children could lead to impaired quality of life at home and school. Eye-tracking can detect subtle efferent dysfunction missed on bedside examination but has not been validated in the pediatric multiple sclerosis population.

Objective: We sought to determine the feasibility of eye-tracking in children and associations with multiple sclerosis.

Methods: Participants meeting criteria for pediatric multiple sclerosis without acute efferent vision abnormalities and healthy controls were recruited. Multiple sclerosis participants underwent a clinical assessment and saccade and antisaccade testing paradigms. Intraclass correlation coefficients were generated for intertest repeatability. Adjusting for age and intereye correlations, generalized estimating equations compared latencies with case status, Expanded Disability Status Scale and Symbol Digit Modalities Test (SDMT) scores.

Results: We eye-tracked 15 children with multiple sclerosis (n = 30 eyes, mean age 15.6 ± 2.1, mean disease duration 3.9 years, median Expanded Disability Status Scale 1.5) compared to 6 healthy controls (n = 12 eyes, age 14.3 ± .95). The intraclass correlation coefficient for repeated trials was 0.85. Adjusting for age, saccadic latency was 60 milliseconds (ms) longer for cases than controls (95% confidence interval = 26.4, 93.8; P = .0005). For antisaccadic latency, we observed a similar trend of 60 ms longer for cases than controls ( P = .06).

Conclusion: Eye-tracking is a short noninvasive examination, and high intertest repeatability supports use of eye-tracking technology in pediatric multiple sclerosis. Longer saccadic latencies were seen in children with multiple sclerosis despite short disease duration and low Expanded Disability Status Scale scores.
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http://dx.doi.org/10.1177/0883073818807787DOI Listing
January 2019
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