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ARTICLE OPEN ACCESS Retinal Optical Coherence Tomography in Neuromyelitis Optica Frederike Cosima Oertel, MD/PhD, Svenja Specovius, MSc, Hanna G. Zimmermann, PhD, Claudia Chien, PhD, Seyedamirhosein Motamedi, PhD, Charlotte Bereuter, BSc, Lawrence Cook, PhD, Marco Aur´ elio Lana Peixoto, MD, PhD, Mariana Andrade Fontanelle, MD, Ho Jin Kim, MD, PhD, Jae-Won Hyun, MD, PhD, Jacqueline Palace, MD, Adriana Roca-Fernandez, MSc, Maria Isabel Leite, MD, PhD, Srilakshmi Sharma, MD, PhD, Fereshteh Ashtari, MD, Rahele Kafieh, PhD, Alireza Dehghani, PhD, Mohsen Pourazizi, PhD, Lekha Pandit, MD, PhD, Anitha D’Cunha, PhD, Orhan Aktas, MD, Marius Ringelstein, MD, Philipp Albrecht, MD, Eugene May, MD, Caryl Tongco, Letizia Leocani, MD, PhD, Marco Pisa, MD, Marta Radaelli, MD, PhD, Elena H. Martinez-Lapiscina, MD, PhD, Hadas Stiebel-Kalish, MD, Sasitorn Siritho, MD, J´ erome de Seze, MD, PhD, Thomas Senger, MD, Joachim Havla, MD, Romain Marignier, MD, PhD, Alvaro Cobo Calvo, MD, PhD, Denis Bichuetti, MD, PhD, Ivan Maynart Tavares, MD, PhD, Nasrin Asgari, MD, PhD, Kerstin Soelberg, MD, Ayse Altintas, MD, Rengin Yildirim, MD, Uygur Tanriverdi, MD, Anu Jacob, MD, Saif Huda, MD, PhD, Zoe Rimler, BSc, Allyson Reid, MD, Yang Mao-Draayer, MD, PhD, Ibis Soto de Castillo, MD, Axel Petzold, MD, PhD, Ari J. Green, MD, Michael R. Yeaman, MD, PhD, Terry Smith, MD, Alexander U. Brandt, MD,* and Friedemann Paul, MD* Neurol Neuroimmunol Neuroinflamm 2021;8:e1068. doi:10.1212/NXI.0000000000001068 Correspondence Dr. Paul [email protected] Abstract Background and Objectives To determine optic nerve and retinal damage in aquaporin-4 antibody (AQP4-IgG)-sero- positive neuromyelitis optica spectrum disorders (NMOSD) in a large international cohort after previous studies have been limited by small and heterogeneous cohorts. Methods The cross-sectional Collaborative Retrospective Study on retinal optical coherence tomogra- phy (OCT) in neuromyelitis optica collected retrospective data from 22 centers. Of 653 screened participants, we included 283 AQP4-IgG–seropositive patients with NMOSD and 72 healthy controls (HCs). Participants underwent OCT with central reading including quality *These authors contributed equally to this work. From the Experimental and Clinical Research Center (F.C.O., Svenja Specovius, H.G.Z., C.C., S.M., C.B., A.U.B., F.P.), Max Delbr¨ uck Center for Molecular Medicine and Charit´ e– Universit¨ atsmedizin Berlin, Corporate Member of Freie Universit¨ at Berlin and Humboldt-Universit¨ at zu Berlin, Germany: NeuroCure Clinical Research Center (F.C.O., Svenja Specovius, H.G.Z., C.C., S.M., C.B., A.U.B., F.P.), Charit´ e–Universit¨ atsmedizin Berlin, Corporate Member of Freie Universit¨ at Berlin, Humboldt-Universit¨ at zu Berlin, Germany; Department of Neurology (F.C.O., A.J.G.), University of California San Francisco, CA; Department of Pediatrics (L.C.), University of Utah, Salt Lake City; CIEM MS Research Center (M.A.L.P., M.A.F.), University of Minas Gerais, Medical School, Belo Horizonte, Brazil; Department of Neurology (H.J.K., J.-W.H.), National Cancer Center, Goyang, Republic of Korea; Department of Neurology (J.P., A.R.-F., M.I.L.), and Department of Ophthalmology (Srilakshmi Sharma), and Department of Ophthalmology (Srilakshmi Sharma), Oxford University Hospitals, National Health Service Trust, UK; Kashani MS Center (F.A.), School of Advanced Technologies in Medicine and Medical Image and Signal Processing Research Center (R.K.), Department of Ophthalmology, Isfahan Eye Research Center (A.D., Mohsen Pourazizi), Isfahan University of Medical Sciences, Iran; Department of Neurology (L.P., A.D’C.), KS Hegde Medical Academy, Nitte University, Mangalore, India; Department of Neurology (O.A., Marius Ringelstein, P.A.), Medical Faculty, Heinrich Heine University D¨ usseldorf, Germany; Swedish Neuroscience Institute Neuro-Ophthalmology (E.M., C.T.), Seattle, WA; Experimental Neurophysiology Unit (L.L., Marco Pisa, Marta Radaelli), Institute of Experimental Neurology (INSPE) Scientific Institute Hospital San Raffaele and University Vita-Salute San Raffaele, Milan, Italy; Hospital Clinic of Barcelona-Institut d’Investigacions (E.H.M.-L.), Biom` ediques August Pi Sunyer, (IDIBAPS), Spain; Sackler School of Medicine (H.S.-K.), Tel Aviv University, Israel; Neuro-Ophthalmology Division (H.S.-K.), Department of Ophthalmology, Rabin Medical Center, Petah Tikva, Israel; Division of Neurology (Sasitorn Siritho), Department of Medicine, Siriraj Hospital and Bumrungrad International Hospital, Bangkok, Thailand; Neurology Service (J.d.S., Thomas Senger), University Hospital of Strasbourg, France; Institute of Clinical Neuroimmunology (J.H.), Biomedical Center and University Hospital, Ludwig-Maximilians Universitaet Muenchen, Munich, Germany; Neurology (R.M., A.C.C.), Multiple Sclerosis, Myelin Disorders and Neuroinflammation, Pierre Wertheimer Neurological Hospital, Hospices Civils de Lyon, France; Centre d’Esclerosi M´ ultiple de Catalunya (Cemcat) (A.C.C.), Department of Neurology/Neuroimmunology, Hospital Universitari Vall d’Hebron, Universitat Aut` onoma de Barcelona, Spain; Department of Neurology and Neurosurgery (D.B., I.M.T.), Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil; Departments of Neurology (N.A.), Slagelse Hospitals, Institute of Regional Health Research, University of Southern Denmark, Odense; Institute of Regional Health Research (N.A., K.S.), University of Southern Denmark, Odense; Department of Neurology (A.A., U.T.), and Department of Ophthalmology (R.Y.), Cerrahpasa Medical Faculty, Istanbul University, Turkey; The Walton Centre for Neurology and Neurosurgery (A.J., S.H.), Liverpool, UK; The Cleveland Clinic Abu Dhabi (A.J.), United Arab Emirates; NYU Multiple Sclerosis Comprehensive Care Center (Z.R., A.R.), Department of Neurology, NYU School of Medicine, New York; Department of Neurology (Y.M.-D.), University of Michigan Medical School, Ann Arbor; Department of Neurology (I.S.C.), Hospital Cl´ ınico de Maracaibo, Venezuela; Moorfield’s Eye Hospital (A.P.), University College London, UK; Department of Medicine (M.R.Y.), Los Angeles Biomedical Research Institute at Harbor- University of California at Los Angeles (UCLA) Medical Center, Torrance, CA, United States of America; Department of Medicine (M.R.Y.), David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America; Departments of Ophthalmology and Visual Sciences (Terry Smith), Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, United States of America; Division of Metabolism (Terry Smith), Endocrine and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor; Department of Neurology (A.U.B.), University of California, Irvine; and Department of Neurology (F.P.), Charit´ e–Universit¨ atsmedizin Berlin, Corporate Member of Freie Universit¨ at Berlin and Humboldt-Universit¨ at zu Berlin, Germany. Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article. The Article Processing Charge was funded by the authors. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1

Retinal Optical Coherence Tomography in Neuromyelitis Optica

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Page 1: Retinal Optical Coherence Tomography in Neuromyelitis Optica

ARTICLE OPEN ACCESS

Retinal Optical Coherence Tomography inNeuromyelitis OpticaFrederike Cosima Oertel MDPhD Svenja Specovius MSc Hanna G Zimmermann PhD Claudia Chien PhD

Seyedamirhosein Motamedi PhD Charlotte Bereuter BSc Lawrence Cook PhD

Marco Aurelio Lana Peixoto MD PhD Mariana Andrade Fontanelle MD Ho Jin Kim MD PhD

Jae-Won Hyun MD PhD Jacqueline Palace MD Adriana Roca-Fernandez MSc Maria Isabel Leite MD PhD

Srilakshmi Sharma MD PhD Fereshteh Ashtari MD Rahele Kafieh PhD Alireza Dehghani PhD

Mohsen Pourazizi PhD Lekha Pandit MD PhD Anitha DrsquoCunha PhD Orhan Aktas MD

Marius Ringelstein MD Philipp Albrecht MD Eugene May MD Caryl Tongco Letizia Leocani MD PhD

Marco Pisa MD Marta Radaelli MD PhD Elena H Martinez-Lapiscina MD PhD Hadas Stiebel-Kalish MD

Sasitorn Siritho MD Jerome de Seze MD PhD Thomas Senger MD Joachim Havla MD

Romain Marignier MD PhD Alvaro Cobo Calvo MD PhD Denis Bichuetti MD PhD

Ivan Maynart Tavares MD PhD Nasrin Asgari MD PhD Kerstin Soelberg MD Ayse Altintas MD

Rengin Yildirim MD Uygur Tanriverdi MD Anu Jacob MD Saif Huda MD PhD Zoe Rimler BSc

Allyson Reid MD Yang Mao-Draayer MD PhD Ibis Soto de Castillo MD Axel Petzold MD PhD

Ari J Green MD Michael R Yeaman MD PhD Terry Smith MD Alexander U Brandt MD and

Friedemann Paul MD

Neurol Neuroimmunol Neuroinflamm 20218e1068 doi101212NXI0000000000001068

Correspondence

Dr Paul

friedemannpaulcharitede

AbstractBackground and ObjectivesTo determine optic nerve and retinal damage in aquaporin-4 antibody (AQP4-IgG)-sero-positive neuromyelitis optica spectrum disorders (NMOSD) in a large international cohortafter previous studies have been limited by small and heterogeneous cohorts

MethodsThe cross-sectional Collaborative Retrospective Study on retinal optical coherence tomogra-phy (OCT) in neuromyelitis optica collected retrospective data from 22 centers Of 653screened participants we included 283 AQP4-IgGndashseropositive patients with NMOSD and 72healthy controls (HCs) Participants underwent OCT with central reading including quality

These authors contributed equally to this work

From the Experimental and Clinical Research Center (FCO Svenja Specovius HGZ CC SM CB AUB FP) Max Delbruck Center for Molecular Medicine and CharitendashUniversitatsmedizin Berlin CorporateMember of Freie Universitat Berlin andHumboldt-Universitat zu Berlin Germany NeuroCure Clinical Research Center (FCO Svenja SpecoviusHGZ CC SM CB AUB FP) CharitendashUniversitatsmedizin Berlin Corporate Member of Freie Universitat Berlin Humboldt-Universitat zu Berlin Germany Department ofNeurology (FCO AJG) University of California San Francisco CA Department of Pediatrics (LC) University of Utah Salt Lake City CIEM MS Research Center (MALP MAF)University of Minas Gerais Medical School Belo Horizonte Brazil Department of Neurology (HJK J-WH) National Cancer Center Goyang Republic of Korea Department ofNeurology (JP AR-F MIL) and Department of Ophthalmology (Srilakshmi Sharma) and Department of Ophthalmology (Srilakshmi Sharma) Oxford University Hospitals NationalHealth Service Trust UK Kashani MS Center (FA) School of Advanced Technologies in Medicine and Medical Image and Signal Processing Research Center (RK) Department ofOphthalmology Isfahan Eye Research Center (AD MohsenPourazizi) IsfahanUniversity ofMedical Sciences Iran Department of Neurology (LP ADrsquoC) KSHegdeMedical AcademyNitte University Mangalore India Department of Neurology (OA Marius Ringelstein PA) Medical Faculty Heinrich Heine University Dusseldorf Germany Swedish NeuroscienceInstitute Neuro-Ophthalmology (EM CT) Seattle WA Experimental Neurophysiology Unit (LL Marco Pisa Marta Radaelli) Institute of Experimental Neurology (INSPE) ScientificInstitute Hospital San Raffaele and University Vita-Salute San Raffaele Milan Italy Hospital Clinic of Barcelona-Institut drsquoInvestigacions (EHM-L) Biomediques August Pi Sunyer(IDIBAPS) Spain Sackler School of Medicine (HS-K) Tel Aviv University Israel Neuro-Ophthalmology Division (HS-K) Department of Ophthalmology Rabin Medical Center PetahTikva Israel Division of Neurology (Sasitorn Siritho) Department of Medicine Siriraj Hospital and Bumrungrad International Hospital Bangkok Thailand Neurology Service (JdSThomas Senger) University Hospital of Strasbourg France Institute of Clinical Neuroimmunology (JH) Biomedical Center and University Hospital Ludwig-Maximilians UniversitaetMuenchen Munich Germany Neurology (RM ACC) Multiple Sclerosis Myelin Disorders and Neuroinflammation Pierre Wertheimer Neurological Hospital Hospices Civils deLyon France Centre drsquoEsclerosi Multiple de Catalunya (Cemcat) (ACC) Department of NeurologyNeuroimmunology Hospital Universitari Vall drsquoHebron Universitat Autonoma deBarcelona Spain Department of Neurology and Neurosurgery (DB IMT) Escola Paulista de Medicina Universidade Federal de Satildeo Paulo Brazil Departments of Neurology (NA)Slagelse Hospitals Institute of Regional Health Research University of Southern Denmark Odense Institute of Regional Health Research (NA KS) University of Southern DenmarkOdense Department of Neurology (AA UT) andDepartment of Ophthalmology (RY) CerrahpasaMedical Faculty Istanbul University Turkey TheWalton Centre for Neurology andNeurosurgery (AJ SH) Liverpool UK The Cleveland Clinic Abu Dhabi (AJ) United Arab Emirates NYU Multiple Sclerosis Comprehensive Care Center (ZR AR) Department ofNeurology NYU School ofMedicine New York Department of Neurology (YM-D) University ofMichiganMedical School Ann Arbor Department of Neurology (ISC) Hospital Clınicode Maracaibo Venezuela Moorfieldrsquos Eye Hospital (AP) University College London UK Department of Medicine (MRY) Los Angeles Biomedical Research Institute at Harbor-University of California at Los Angeles (UCLA) Medical Center Torrance CA United States of America Department of Medicine (MRY) David Geffen School of Medicine at UCLA LosAngeles CA United States of America Departments of Ophthalmology and Visual Sciences (Terry Smith) Kellogg Eye Center University of MichiganMedical School Ann Arbor UnitedStates of America Division of Metabolism (Terry Smith) Endocrine and Diabetes Department of Internal Medicine University of Michigan Medical School Ann Arbor Department ofNeurology (AUB) University of California Irvine and Department of Neurology (FP) CharitendashUniversitatsmedizin Berlin Corporate Member of Freie Universitat Berlin andHumboldt-Universitat zu Berlin Germany

Go to NeurologyorgNN for full disclosures Funding information is provided at the end of the article

The Article Processing Charge was funded by the authors

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

Copyright copy 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 1

control and intraretinal segmentation The primary outcome was thickness of combined ganglion cell and inner plexiform(GCIP) layer secondary outcomes were thickness of peripapillary retinal nerve fiber layer (pRNFL) and visual acuity (VA)

ResultsEyes with ON (NMOSD-ON N = 260) or without ON (NMOSD-NON N = 241) were assessed compared with HCs (N =136) In NMOSD-ON GCIP layer (574 plusmn 122 μm) was reduced compared with HC (GCIP layer 814 plusmn 57 μm p lt 0001)GCIP layer loss (minus227 μm) after the first ON was higher than after the next (minus35 μm) and subsequent episodes pRNFLobservations were similar NMOSD-NON exhibited reduced GCIP layer but not pRNFL compared with HC VA was greatlyreduced in NMOSD-ON compared with HC eyes but did not differ between NMOSD-NON and HC

DiscussionOur results emphasize that attack prevention is key to avoid severe neuroaxonal damage and vision loss caused by ON inNMOSD Therapies ameliorating attack-related damage especially during a first attack are an unmet clinical need Mild signs ofneuroaxonal changes without apparent vision loss in ON-unaffected eyes might be solely due to contralateral ON attacks and donot suggest clinically relevant progression but need further investigation

Patients with neuromyelitis optica spectrum disorder (NMOSD)experience recurrent optic neuritis (ON)1 resulting in vision lossand decreased quality of life1-4 According to our understandingthere are at least 3 subtypes based on serostatus Up to 3 of 4patients manifest as antindashaquaporin-4 IgG (AQP4-IgG) sero-positive Approximately half of the AQP4-IgGndashseronegative pa-tients manifest as antindashmyelin oligodendrocyte glycoprotein IgG(MOG-IgG) seropositive and half are double seronegative5 Yetclinical correlates of serologic phenotypes including subclinical orclinical retinal degeneration and vision loss remain unclear67

Optical coherence tomography (OCT) is an interferometrictechnique producing high-resolution retinal images18 OCThas become a reliable tool for diagnosing and monitoringneurologic and neuro-ophthalmologic diseases especially forquantifying neurodegeneration after ON1 Because of limitedsamples and varying methods existing OCT studies inNMOSD are inconsistent regarding the amount of retinalneurodegeneration with and without ON Previous studies alsofailed to address the influence of retinal neurodegeneration onmicrocystic macular edema (MME) and function267 Theseissues together with heterogeneities and the often monocentriccharacter of previous cohorts limit the relevance of meta-analyses

To overcome these limitations we performed anOCT analysis ofAQP4-IgGndashseropositive patients with NMOSD in an in-ternational multicenter study termed Collaborative RetrospectiveStudy on retinal OCT in Neuromyelitis Optica (CROCTINO)9

It represents the largest NMOSD OCT data set and additionallyvalidated an OCT postprocessing approach to circumvent dif-ferences in acquisition and imaging processing protocols inherentto pooled analyses10 Outcomes include (1) distinguishing retinalneurodegeneration after ON from subtle damage in clinicallyunaffected eyes (2) defining frequency ofMME and (3) derivingstructure-function correlations

MethodsStudy DesignThis cross-sectional international multicenter study was per-formed under the aegis of the CROCTINO study which wasa collaborative effort within the Guthy-Jackson CharitableFoundation network9 Participating centers contributed OCTdata (acquired between 2008 and 2018) and clinical metadata(acquired between 2000 and 2018 eTable 1 linkslwwcomNXIA557)

Cohort SelectionInclusion criteria for this analysis were (1) patients diagnosedwith NMOSD per the 2015 International Panel of NMOSDdiagnosis criteria11 and (2) having confirmed serum AQP4-IgG Exclusion criteria were (1) comorbidities potentiallyconfounding interpretation of OCT results (eg maculardegeneration glaucoma and intracranial hypertension) (2) gt3months distance between clinical andOCT data acquisition(3) lt 6 months between OCT imaging and most recent ONor (4) an uncertain history of ON The inclusion and

GlossaryAQP4-IgG = aquaporin-4 IgG CROCTINO = Collaborative Retrospective Study on retinal OCT in Neuromyelitis OpticaEDSS = Expanded Disability Status Scale GCIP = ganglion cell and inner plexiform HC = healthy control HC-VA = high-contrast visual acuity INL = inner nuclear layer MME = microcystic macular edema MS = multiple sclerosis MOG-IgG =myelin oligodendrocyte glycoprotein IgG NMOSD = neuromyelitis optica spectrum disorder NMOSD-NON = NMOSDeyes without a history of ONOCT = optical coherence tomographyON = optic neuritis pRNFL = peripapillary retinal nervefiber layer SE = standard error VA = visual acuity VEP = visually evoked potential

2 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

exclusion criteria are depicted in eFigure 1 linkslwwcomNXIA556 AQP4-IgG testing was performed at the discre-tion of each investigator

Standard Protocol Approvals Registrationsand Patient ConsentsAll participants gave written informed consent and the studywas approved by local ethics committees and conducted inaccordance with the applicable laws and the current version ofthe Declaration of Helsinki Data are reported according toSTROBE reporting guidelines12

OCTHigh-resolution imaging data were acquired using 3 differ-ent spectral domain OCT devices Spectralis SD-OCT(Heidelberg Engineering Heidelberg Germany) at 15 cen-ters (194 patients358 eyes 72 healthy controls [HCs]136eyes) Cirrus HD-OCT (Carl Zeiss Meditec Dublin CA) at6 centers (58 patients87 eyes) or Topcon 3D OCT-1(Topcon Tokyo Japan) at 1 center (31 patients56 eyes)All reading of OCT data was performed at CharitendashUniversitatsmedizin Berlin Translational Neuroimaging Groupby 5 graders Image quality was assessed using modifiedOSCAR-IB criteria by one of the graders respectively1314

OCT segmentation for the combined ganglion cell and innerplexiform (GCIP) layer and inner nuclear layer (INL) thick-nesses was corrected semi-automatically using an in-housesoftware1015 In brief GCIP layer and INL thicknesses werecalculated from a 5-mm diameter cylinder around the foveaexcluding the central 1-mm diameter cylinder from a macularvolume scan10 The peripapillary retinal nerve fiber layer(pRNFL) thickness was measured and corrected according tothe device protocol (Spectralis peripapillary ring scan with12deg or approximately 34 mm diameter around the optic discTopcon and Cirrus extraction from optic disc volume scan)For the current analysis eyes were excluded from the analysisif neither ring nor macular scan passed quality control Wefurther excluded data from the less common instrument for 1center The final cohort included 364 macular and 481 per-ipapillary scans of 501 eyes from 283 patients and 136 eyesfrom 72 HCs Lower numbers of macular scans comparedwith peripapillary scans were due to both lower submissionof macular data and more exclusions based on qualityconcerns

Visual and Global Function TestingHigh-contrast visual acuity (HC-VA) was available for 497(992) patient and 10 (139) HC eyes HC-VA was bestcorrected for 212 (423) patient and 56 (412) HC eyeshabitually corrected for 145 (289) patient and 2 (lt01)HC eyes and without correction for 140 (279) patient eyesand 17 (13) HC eyes All VA data are reported as logMARVA measurement method was decided on discretion of eachcenter Visually evoked potentials (VEPs) were available for167 (333) patient eyes and 40 (294) HC eyes with P100latency recorded as a binary value (normalprolonged) Ex-panded Disability Status Scale (EDSS) scores were de-termined at the discretion of each center with data availablefor 180 (636) patients

Statistical AnalysisStatistical analyses were performed with R version 361using RStudio and R Markdown (RStudio Inc BostonMA)16 p Values less than 005 were considered significantWe considered p values less than 010 a trend Groupmatching by age and sex for confirmatory analyses wasperformed using automatic matching by R package MatchIt(method exact) Group comparisons and correlations ofOCT and VA values were performed using linear mixed-

Table 1 Cohort Description for AQP4-IgGndashSeropositivePatients With NMOSD and HCs

AQP4-IgGndashseropositiveNMOSD HC

Subjects (N) 283 72

Eyes (N) 501 136

Sex (malefemale NN []) 28255 (99901) 2646 (361639)

Age (y mean plusmn SD) 441 plusmn 142 309 plusmn 77

Ethnicity (N [])

Asian 77 (272) 16 (222)

BlackAfrican American 13 (46) 0 (0)

White HispanicLatino 4 (14) 1 (14)

White Non-Hispanic 159 (562) 55 (764)

Othernonreported 30 (106) 0 (0)

Disease-modifying therapy (N[])

Rituximab 73 (258)

Azathioprine 67 (237)

Oral prednisolone 53 (187)

Mycophenolate mofetil 48 (170)

Methotrexate 8 (28)

Time since onset (y mean plusmn SD) 72 plusmn 67

EDSS score (median [IQR]) 35 (20ndash45)

Patients with a clinical history ofON (N [])

204 (721)

Eyes with a clinical history of ON(N [])

260 (52)

No of ON episodeseye (Nmedian [minndashmax])

1 (1ndash6)

Time since last ON (mo mean plusmnSD)

71 plusmn 57

Abbreviations AQP4-IgG = aquaporin-4 antibodies NMOSD = neuromyelitisoptica spectrum disorder HC = healthy control N = number OCT = opticalcoherence tomography ON = optic neuritis episodeAge (p lt 00001) and sex (p lt 00001) were not matched

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 3

effect models Intereye within-subject effects and effects ofthe center were included as random effects Sex ethnicityand age were included as fixed effects for the analyses in theentire cohort Age and sex were not included for thematched subset For OCT parameters the model was usedfor data from all devices separately and combined by Fishercombined probability test The marginal and conditionalcoefficients of determination of the linear models werecalculated with pseudo R-squared All results are reported

combined and individually for Spectralis SD-OCT theanalyses of data acquired by Cirrus HD-OCT or Topcon3D OCT-1 and for the matched subset are reported asonline-only supplement

Data AvailabilityThe data supporting the findings of this study are availablewithin the article and from the corresponding author byreasonable request

Figure 1 Group Comparisons of GCIP Layer Thickness

Boxplots of GCIP layer thicknesses (μm) acquired by Heidelberg SD-OCT with values of individual eyes (jitter) for (A) HC (grayleft) NMOSD-NON(dark bluemiddle) NMOSD-ON (dark redright) for (B) number of ON episodes (NMOSD-NON dark blueleft NMOSD-1-ON light redleft-middleNMOSD-2-ON medium-redright-middle NMOSD-ge3-ON medium-dark redright) and for (C) HC (grayleft) NMOSD-NONnon (light bluemiddle)NMOSD-NONcon (blueright) (D) Forest plots for results from different OCT devices for (Da) NMOSD-NON vs NMOSD-ON (Db) NMOSD-NON vsNMOSD-1-ON and (Dc) NMOSD-1-ON vs NMOSD-2-ON (eFigure 2 and eTable 2 linkslwwcomNXIA556 and linkslwwcomNXIA557) GCIP =ganglion cell and inner plexiform HC = eyes of HCs NMOSD-NON = eyes of patients with neuromyelitis optica without a history of ON NMOSD-NON-con =eyes of patients with neuromyelitis optica without a history of ON but a history of contralateral ON NMOSD-NONnon = eyes of patients withneuromyelitis optica without a history of ipsilateral or contralateral ON NMOSD-ON = eyes of patients with neuromyelitis optica with a history ofON NMOSD-1-ON = eyes of patients with neuromyelitis optica with a history of 1 ON episode NMOSD-2-ON = eyes of patients with neuromyelitisoptica with a history of 2 ON episodes ON = optic neuritis

4 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

ResultsFive hundred one eyes of 283 AQP4-IgGndashseropositive pa-tients and 136 eyes of 72 HCs were included in the analysis(Table 1)

Neuroaxonal Damage After ONGCIP layer and pRNFL were reduced in NMOSD-ONcompared with NMOSD eyes without a history of ON

(NMOSD-NON) and HC (GCIP layer 814 plusmn 57 μmpRNFL 1011 plusmn 90 μm) (Figures 1A and 2A Tables 2 and3) The absolute (GCIP layer minus227 μm pRNFL minus385 μm)and relative (GCIP layer minus388 pRNFL minus616) loss ineyes with 1 ON episode (NMOSD-1-ON) compared withNMOSD-NON was higher than in eyes with 2 ON episodes(NMOSD-2-ON) compared with NMOSD-1-ON (GCIPlayer absolute loss minus35 μm relative loss minus60 pRNFLabsolute loss minus91 μm relative loss minus145 ns) The loss in

Figure 2 Group Comparisons of pRNFL Thickness

Boxplots of pRNFL thicknesses acquired by Heidelberg SD-OCT [μm] with values of individual eyes (jitter) for (A) HC (grayleft) NMOSD-NON (dark bluemiddle) and NMOSD-ON (dark redright) for (B) number of ON episodes (NMOSD-NON dark blueleft NMOSD-1-ON light redleft-middle NMOSD-2-ONmedium-redright-middle and NMOSD-ge3-ON medium-dark redright) and for (C) HC (grayleft) NMOSD-NONnon (light bluemiddle) and NMOSD-NONcon

(blueright) (D) Forest plots for results from different OCT devices for (Da) NMOSD-NON vs NMOSD-ON (Db) NMOSD-NON vs NMOSD-1-ON and (Dc)NMOSD-1-ON vs NMOSD-2-ON (eFigure 3 and eTable 3 linkslwwcomNXIA556 and linkslwwcomNXIA557) HC = eyes of HCs NMOSD-NON = eyes ofpatients with neuromyelitis optica without a history of optic neuritis NMOSD-NON-con = eyes of patients with neuromyelitis optica without a history of opticneuritis but a history of contralateral optic neuritis NMOSD-NONnon = eyes of patients with neuromyelitis optica without a history of ipsilateral or contra-lateral optic neuritis NMOSD-ON = eyes of patients with neuromyelitis optica with a history of optic neuritis NMOSD-1-ON = eyes of patients withneuromyelitis optica with a history of 1 optic neuritis episode NMOSD-2-ON = eyes of patients with neuromyelitis optica with a history of 2 optic neuritisepisodes ON = optic neuritis pRNFL = peripapillary retinal nerve fiber layer

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 5

eyes with ge3-ON episodes (NMOSD-3-ON) was lowercompared with NMOSD-2-ON (ns) (Figures 1B and 2B)Five NMOSD-NON eyes had pRNFL values lt 60 μm thesepatients had no relevant comorbidities but a history of con-tralateral ON1718 In sensitivity analyses to account for devicedifferences all significant analyses within the NMOSD cohortwere confirmed for data acquired by Cirrus and Topcon OCTdevices (eFigures 2 and 3 eTables 3 and 4 linkslwwcomNXIA556 linkslwwcomNXIA557)

Neuroaxonal Damage Without ONNMOSD-NON eyes had a reduced GCIP layer (759 plusmn 77 μmplt 0001) but not pRNFL (953 plusmn 144 μm) comparedwithHC(GCIP layer 814 plusmn 57 μm pRNFL 1011 plusmn 90 μm Figures 1Aand 2A Tables 2 and 3) By comparison only 28 NMOSD-NON eyes (51) had a GCIP layer le the 5th percentile of HCGCIP layer was also reduced inNMOSD-NONwith a history ofcontralateral ON (729 plusmn 102 μm) compared with NMOSD-NON without a history of contralateral ON (773 plusmn 59 μm p =0025 NMOSD-NONnon) This effect vanished when onlyconsidering NMOSD-NONcon with a history of 1 contralateralON (736 plusmn 94 μm) However only NMOSD-NONcon (p lt

0001) but not NMOSD-NONnon (p = 0061) had thinnedGCIP layer compared with HC (Figures 1C and 2C)

INL ChangesINL was thicker in NMOSD-ON compared with HC (394 plusmn26 μm) and NMOSD-NON (eTable 4 linkslwwcomNXIA557) Specifically INL was thicker in eyes with 1 ON episodecompared with NMOSD-NON but did not differ between eyeswith different numbers of ON episodes Also INL did not differbetween NMOSD-NONcon (389 plusmn 32 μm) and NMOSD-NONnon (385 plusmn 32 μm p = 0931) In all patients INLthickness (as the dependent variable in the linear mixed modeldescribed above) was correlated with thinner GCIP layer (B =minus011 standard error [SE] = 001 p lt 0001) and pRNFL (B =minus006 SE = 001 p lt 0001) This correlation existed inNMOSD-ON (GCIP layer B = minus 008 SE = 003 p = 0005pRNFL B = minus 006 SE = 001 p lt 0001) and not present inNMOSD-NON (eFigure 4 linkslwwcomNXIA556)

Scans of 363 NMOSD eyes were clearly suitable for MMEinvestigations (high quality eFigure 4C linkslwwcomNXIA556) MMEs were visible in 24 (66) eyes of 21 patients

Table 2 Group Comparisons of GCIP Layer Thickness for Heidelberg SD-OCT

No ofeyes

Thickness (μmmean plusmn SD)

Comparisonto

Absolutedifference (μmmean)

Relativedifference (mean) B SE p Value R2

marg R2cond

Combinedp value

NMOSD 268 673 plusmn 136 HCs minus140 minus208 156 20 lt00001 0143 0690 mdash

NMOSD-ON

124 574 plusmn 122 minus240 minus418 250 20 lt00001 0482 0839 mdash

NMOSD-NON

144 759 plusmn 77 minus54 minus72 58 14 lt00001 0088 0947 mdash

NMOSD-NONnon

99 773 plusmn 59 minus40 minus50 269 142 0061 0189 0924 mdash

NMOSD-NONcon

45 729 plusmn 102 minus85 minus104 844 177 lt00001 0260 0985 mdash

NMOSD-ON

124 574 plusmn 122 NMOSD-NON

minus185 minus244 minus158 11 lt00001 0430 0795 59e245

NMOSD-1-ON

76 586 plusmn 129 minus173 minus228 minus145 12 lt00001 0417 0803 14e233

NMOSD-2-ON

28 551 plusmn 94 NMOSD-1-ON

minus35 minus60 minus57 26 0028 0143 0729 0038

NMOSD-ge3-ON

20 559 plusmn 128 NMOSD-2-ON

08 14 49 26 0070 0311 0781 0222

NMOSD-NONcon

45 729 plusmn 102 NMOSD-NONnon

minus44 minus61 minus38 17 0025 0111 0701 0004

NMOSD-NON1-con

37 736 plusmn 94 minus37 minus51 minus35 16 0037 0149 0906 0154

Abbreviations AQP4-IgG = aquaporin-4 IgG B = estimate GCIP = ganglion cell and inner plexiformNMOSD=AQP4-IgGndashseropositiveNMOSD NMOSD-NON=AQP4-IgGndashseropositive NMOSD eyeswithout a history of ON NMOSD-NONnon = AQP4-IgGndashseropositive NMOSD eyeswithout a history ofONor contralateralON NMOSD-NONcon = AQP4-IgGndashseropositive NMOSD eyes without a history of ON but with a history of contralateral ON NMOSD-NON1-con = AQP4-IgGndashseropositive NMOSD eyes without a history of ON but with a history of 1 contralateral ON NMOSD-ON = AQP4-IgGndashseropositive NMOSD eyes with ahistory of ON NMOSD-1-ON =AQP4-IgGndashseropositive NMOSD eyeswith a history of 1ON NMO-2-ON =AQP4-IgGndashseropositive NMOSD eyeswith a history of2 ONs NMOSD-ge3-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 3 or more ONs NMOSD = neuromyelitis optica spectrum disorder NMOSD-NON = NMOSD eyes without a history of ON OCT = optical coherence tomography ON = optic neuritis episode Rcon = conditional R-squared Rmarg =marginal R-squared SE = standard error

6 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

Twenty-three eyes (131) of NMOSD-ON and 1 eye (05)of NMOSD-NON (with a history of contralateral ON) wereaffected The number of ON episodes did not influence theincidence of MMEs (NMOSD-1-ONN = 16 (14) NMOSD-2-ON N = 4 (114) NMOSD-ge3-ON N = 3 (111))

Including only the most frequent ethnicities in our data set(Asian and non-HispanicWhite) results did not differ and noethnicity was singled out regarding its pattern of injury (datanot shown)

OCT and Vision LossHC-VA was numerically reduced in NMOSD (025 plusmn 048)compared with HC (minus001 plusmn 008) and known healthy referencevalues NMOSD-ON also had reduced HC-VA (044 plusmn 058)compared with NMOSD-NON (004 plusmn 020 p lt 0001 p =0401) and HChealthy reference populations HC-VA wascorrelated with GCIP layer (B = minus0016 SE = 0002 p lt 0001)and pRNFL thicknesses (B = minus0010 SE = 0001 p lt 0001) inAQP4-IgGndashseropositive NMOSD AQP4-IgGndashseropositiveNMOSD eyes with prolonged VEP latency had a thinned GCIP

layer (B = minus11647 SE = 3628 p = 0002) and pRNFL (B =minus21965 SE = 3724 p lt 0001) EDSS score as ametric of globaldisability was inversely correlated with GCIP layer (B = minus1370SE= 0566 p= 0017) and pRNFL thicknesses (B= minus3148 SE=1080 p = 0004)

DiscussionOur study specifies a severe and functionally relevant decreaseof GCIP layer and pRNFL in NMOSD-ON compared withNMOSD-NON and HCs in AQP4-IgGndashseropositive pa-tients Neuroaxonal damage is particularly large from the firstepisode of ON where contribution to retinal damage insubsequent episodes of ON is still considerable but smaller Incontrast to previous smaller studies the current study ascer-tains GCIP layer but not pRNFL thinning in NMOSD-NONcompared with HC619 This effect was driven by eyes withcontralateral ON and not statistically significant in eyeswithout a history of ON INL was thicker in NMOSD-ONand was inversely correlated with GCIP layer Of note 131

Table 3 GroupComparisons of pRNFL ThicknessWith (A) Spectralis SD-OCTData for Comparisons vsHC (B) Data FromAllDevices for Intrapatient Cohort Comparisons

No ofeyes

Thickness (μmmean plusmn SD)

Comparisonto

Absolute difference(μm mean)

Relativedifference (mean) B SE p Value R2

marg R2cond

Combinedp value

NMOSD 344 763 plusmn 274 HCs minus140 minus326 242 43 lt00001 0143 0690 mdash

NMOSD-ON

170 569 plusmn 237 minus443 minus779 431 41 lt00001 0482 0839 mdash

NMOSD-NON

174 953 plusmn 144 minus59 minus62 46 30 0129 0088 0947 mdash

NMOSD-NONnon

116 974 plusmn 109 minus37 minus37 minus29 22 0204 0107 0893 mdash

NMOSD-NONcon

58 910 plusmn 191 minus47 minus46 71 42 0097 0100 0975 mdash

NMOSD-ON

170 569 plusmn 237 NMOSD-NON

minus384 minus403 minus338 21 lt00001 0436 0741 44e260

NMOSD-1-ON

97 626 plusmn 249 minus327 minus343 minus296 22 lt00001 0379 0712 46e240

NMOSD-2-ON

35 535 plusmn 213 NMOSD-1-ON

minus91 minus145 minus107 47 0024 0087 0528 0010

NMOSD-ge3-ON

38 452 plusmn 178 NMOSD-2-ON

minus83 minus155 minus04 43 0924 0087 0719 0838

NMOSD-NONcon

58 910 plusmn 191 NMOSD-NONnon

minus65 minus71 minus40 29 0173 0061 0939 0157

NMOSD-NON1-con

47 932 plusmn 181 minus42 minus46 minus32 29 0276 0056 0925 0616

Abbreviations AQP4-IgG = aquaporin-4 IgG NMOSD = AQP4-IgGndashseropositive NMOSD NMOSD-NON = AQP4-IgGndashseropositive NMOSD eyes without ahistory of ON NMOSD-NONnon = AQP4-IgGndashseropositive NMOSD eyes without a history of ON or contralateral ON NMOSD-NONcon = AQP4-IgGndashseropositive NMOSD eyes without a history of ON but with a history of contralateral ON NMOSD-NONcon = AQP4-IgGndashseropositive NMOSD eyes without ahistory of ON but with a history of 1 contralateral ON NMOSD-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of ON NMOSD-1-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 1 ON NMOSD-2-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 2 ONs NMOSD-ge3-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 3 or more ONs NMOSD = neuromyelitis optica spectrum disorder NMOSD-NON = NMOSD eyes without ahistory of ON OCT = optical coherence tomography ON = optic neuritis episode pRNFL = peripapillary retinal nerve fiber layer VEP = visually evokedpotential

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 7

of NMOSD-ON eyes showed MME indicative of secondaryinflammatory changes2021 This investigation overcame limitsof small samples and OCT data heterogeneity of earlierstudies through use of an international consortium ofNMOSD specialists This framework substantiated theCROCTINO studymdasha large multicenter retrospectiveevaluation of retinal pathology in NMOSD using OCT

The neuroaxonal degeneration in NMOSD-ON demon-strated here is substantially greater than reported changes inmultiple sclerosis (MS) a common differential diagnosis222

In a meta-analysis an average pRNFL loss of 20 μm wasestimated in MS after ON which is nearly 2-fold higher in ourNMOSD-ON cohort (minus384 μm)22 For GCIP layer our datasuggested approximately 15-fold higher loss in NMOSD(minus240 μm) compared with MS22 These differences not onlyresult from a higher ON frequency but may also be caused bymore severe retinal damage in NMOSD after a singular ON23

It is intriguing that the damage is particularly large after thefirst ON episode with smaller losses after subsequent epi-sodes which might be due to less neuroaxonal content insubsequent episodes224 Alternatively although the analysisof treatment effects exceeds the scope of this study it ispossible that the longer time to effective anti-inflammatorytherapy and the typical choice of less effective therapies (egsteroids instead of plasma exchange) at the first attack com-pared with following attacks may significantly contribute tothis difference Independent of the number of ONs the per-cent loss is smaller in GCIP layer compared with pRNFLndashpointing toward either (1) stronger loss of retinal nerve fibersthan retinal ganglion cells (2) impairment of ganglion cellsnot leading to extinction but axonal loss (3) a larger amountof non-neuronal tissue in GCIP layer or (4) RNFL loss in theperiphery beyond the macular area measured by GCIP layerThese hypotheses are not mutually exclusive and each mightcontribute to the effect Consistent with these concepts ex-cessive vision loss relative to neuroaxonal content and VEPlatency in AQP4-IgGndashseropositive patients compared withMOG-IgGndashseropositive and MS patients implies damage ofthe peripheral retina and optic nerve tissues which are notreflected in the macula and pattern VEP measurements4

Whether attack-independent neurodegeneration inAQP4-IgGndashseropositive NMOSD occurs has beencontroversial26725-28 The current study identifies de-creased GCIP layer in NMOSD-NON compared withHC but not pRNFL Such subclinical changes could becaused by contralateral involvement after unilateralON1718 Indeed our cohort suggests pronounced neu-rodegeneration in eyes with contralateral ON Howevereyes of patients without ON also exhibit a trend for thinnerGCIP layer compared with HCs Underscored by longitu-dinal studies showing ON-independent neurodegenerationand VEP latency prolongation729 such patterns suggest atleast 2 mechanisms of injury (1) a primary retinopathy oroptic neuropathy in context of an astrocytopathy or causedby direct damage to AQP4-expressing cells such as astrocytes

and Muller cells by either AQP4-IgG or AQP4-specificT cells or (2) a global or afferent visual system specificchronic or episodic neurodegenerative process Because le-sions often spare the brain and most studies outside ofpredisposed areas such as optic nerve and spinal cord failedto detect effects30 a constant global involvement seemsunlikely Several studies described changes affecting AQP4expression and astrocytic end feet31 parafoveal changes inagreement with an involvement of AQP4-expressing Mullercell6262732 and attack-independent spinal cord atrophy33

These findings are consistent with tissue infiltration byAQP4-IgGndashspecific T cells34 and the attack-independentloss of retinal ganglion cells7mdashfurther supporting the exis-tence of an ON-independent pathology which might berestricted to the main disease foci The latter hypothesescould be addressed by region-specific pathology or advancedimaging studies

INL changes have been suggested as a marker of neuro-inflammation and potential treatment response in MS213536

MME may develop as a consequence of neurodegenerationor othermdashnonndashdisease-specificmdashprocesses35 Patients withNMOSD were described to have INL thickening andMME2037 In our cohort 131 of NMOSD-ON eyes wereaffected byMME which is higher than the 2ndash5 described inMS but comparable to incidences in NMOSD described beforeby Gelfand and colleagues3537 However INL thickening itselfremained comparable to changes reported in MS35 This dis-parity could reflect a disrupted fluid homeostasis due to Mullercell involvement or loss of content of the INL with a parallelinflammatory reaction and development of MME The limitedaccessibility of MMEs especially in severely affected eyes due tolimited image quality has hindered their detailed assessmentsand most likely leads to underestimation of their incidence38

We demonstrate that the INL thickness is inversely correlatedwith neuroaxonal content and could be a valuable marker ofdisease severity also in NMOSD

Our study cohort was representative of patients with AQP4-IgGndashseropositive NMOSD with respect to a female pre-dominance and ON history1139 This OCT study includedmultiple ethnicity backgrounds although the distribution wasshifted toward CaucasianWhite patients and other ethnic-ities were underrepresented (eg Hispanic White and Black)limiting the generalizability of results40 Patients from differ-ent heritages presented similar findings

The current study was based on source data instead of a meta-analysis Using the Guthy-Jackson Charitable Foundation net-work this multicentric study was conducted without investigatorreimbursement and illustrated how collaboration integratinginternational perspectives can produce meaningful results Toovercome technical challenges of heterogeneous source data wedeveloped novel OCT postprocessing techniques allowing us toperform standardized analyses and enabling the uniform analysisof the largest OCT image data set in NMOSD to date10 Thusthe strengths of CROCTINO include its established

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

infrastructure large international network of experts represent-ing multiple ethnicities and geographic regions and the use ofstate-of-the-art OCT postprocessing techniques41

We recognize limitations of the current investigation Theretrospective and heterogeneous data acquisition might haveled to biases and impreciseness beyond the ability of ourquality control We addressed this by excluding uncertaincases HCs were only included from a limited number ofcenters The unbalanced data set limited some analyses suchas the influence of ethnicities or acute and disease-modifyingtreatments Case-control matching was impossible particu-larly with respect to subclinical progression dependent orindependent of ON and to ethnicity Similarly comparisonswith other NMOSD subtypes or MS were beyond the scopeof this study Longitudinal data acute ON data and AQP4-IgGndashseronegative and MOG-IgGndashseropositive patient dataare part of the CROCTINO data set and will be analyzed inthe future Also OCT data processing was performed bymultiple raters potentially introducing interrater variabilityMRI data and posterior visual pathway involvement were notinvestigated in this study However the current study ach-ieved an unprecedented worldwide assessment of retinaldamage in AQP4-IgGndashseropositive NMOSD

To conclude AQP4-IgGndashseropositive NMOSD is characterizedby a severe functionally relevant retinal neurodegeneration as aconsequence of ON Although the majority of damage occursduring the first episode there is cumulative loss with each suc-ceeding relapse TheON-associated damage is not limited to theneuroaxonal content but can also inducemdashlikely inflammation-mediatedmdashINL increase and occurrence ofMMEOur data alsosuggest attack-independent retinal damage in AQP4-IgGndashseropositive NMOSD Our study supports that at-tack prevention is key in avoiding neuroaxonal damage andvision loss in patients with NMOSD It further suggests thatthe first ON episode causes the most damage where onlysome patients with then established diagnosis will be on im-munosuppressive therapy This highlights the need for ef-fective therapies that can ameliorate an ongoing attack orregenerate attack-generated damage which is an unmet clin-ical need Last the study emphasizes the utility of OCT as asensitive structural metric and its potential for monitoringprogression and even treatment response in AQP4-IgGndashseropositive NMOSD The international CROCTINOprogram provides an unprecedented opportunity to applyOCT in a standardized manner to assess pathophysiologyclinical course and therapeutic efficacy in NMOSD

Study FundingGuthy-Jackson Charitable Foundation (GJCF) and GermanResearch Foundation (DFG)

DisclosureFC Oertel was employee of Nocturne GmbH and receivesresearch support by the American Academy of Neurology andthe National Multiple Sclerosis Society unrelated to this work

S Specovius reports no disclosures HG Zimmerman reportsresearch grants from Novartis and speaking honoraria fromBayer Healthcare unrelated to this study C Chien reportsspeaking honoraria from Bayer Healthcare unrelated to thiswork S Motamedi and C Bereuter report no disclosures LCook reports grants from Guthy Jackson Charitable Founda-tion during the conduct of the study EH Martinez-Lapiscinais employed by the European Medicines Agency (HumanMedicines) since 16 April 2019 This article is related with heractivity under Hospital Clinic of BarcelonaIDIBAPS affiliationand consequently as external activity it does not represent theviews of the Agency its Committees or working parties Beforeenrolling EMA Dr Martinez-Lapiscina reports grants fromInstituto de Salud Carlos III (Spain) amp Fondo Europeo deDesarrollo Regional grants from MS Innovation GMSI otherfromFundacio Privada Cellex and personal fees fromNovartisRoche Sanofi-Genzyme outside the submitted work MALana Peixoto and MA Fontanelle report no disclosures HJKim reports grants from the National Research Foundation ofKorea personal fees from Alexion Pharmaceuticals AprilbioBiogen Celltrion Eisai HanAll BioPharma MDimune MerckSerono Novartis Sanofi Genzyme Teva-Handok and VielaBio other from Viela Bio (formerly MedImmune) MultipleSclerosis Journal and Journal of Clinical Neurology outsidethe submitted work J-W Hyun reports grants from the Na-tional Research Foundation of Korea outside the submittedwork J Palace reports personal fees from Abide TherapeuticsAlexion Pharmaceuticals ARGENX Bayer Schering BiogenIdec Chugai Pharma EuroImmun Genzyme MedDayMedImmuneMerck Serono Novartis Roche Teva UCB andViela Bio grants from Abide Therapeutics Alexion Pharma-ceuticals Bayer Schering Biogen Idec Chugai Pharma Gen-zyme MedImmune Merck Serono Novartis and Teva grantsfrom Merck Serono Novartis Biogen Idec Teva AbideMedImmune Bayer Schering Genzyme Chugai and AlexionEugene Devic European Network the Grant for MultipleSclerosis Innovation the John Fell Fund the Medical ResearchCouncil the MS Society Myaware the UK National Institutefor Health Research Oxford Health Services Research Com-mittee and theGuthy-JacksonCharitable Foundation AMPLOand SPARKS Great Ormond Street for research studies out-side the submitted work MI Leite and S Sharma report nodisclosures A Roca-Fernandez is sponsored by Abide Thera-peutic outside of the submitted work and reports no potentialconflicts of interest R Kafieh A Dehghani M Pourazizi LPandit and A DrsquoCunha report no disclosures O Aktas reportsgrants from German Research Foundation (DFG) and Ger-man Ministry of Education and Research (BMBF) personalfees from Alexion and Almirall grants and personal fees fromBiogen personal fees from Merck grants and personal feesfrom Novartis grants and personal fees from Roche personalfees from Sanofi personal fees from Teva personal fees fromViela Bio outside the submitted work M Ringelstein receivedspeaker honoraria from Novartis Bayer Vital GmbH RocheAlexion and Ipsen and travel reimbursement from BayerSchering Biogen Idec Merz Genzyme Teva Roche andMerck none related to this study P Albrecht reports grants

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 9

personal fees and non-financial support from Allergan BiogenMerck Merz Pharmaceuticals Novartis Ipsen CelgeneRoche and personal fees and non-financial support from Tevaoutside the submitted work E May and C Tongco report nodisclosures L Leocani reports personal fees from RocheMerck Bristol Myers Squibb andMed-ex learning outside thesubmitted work M Pisa reports no disclosures M Radaellireports personal fees from Merck Serono Sanofi-GenzymeNovartis and Biogen outside the submitted work H Stiebel-Kalish reports no disclosures S Siritho reports personal feesfromNovartis Thailand Biogen Idec Eisai Thailandmarketingco ltd Merck Serono Teva Thailand and Menarini outsidethe submitted work J de Seze and T Senger report no dis-closures J Havla reports grants personal fees and non-financialsupport from Merck personal fees from Novartis CelgeneRoche Santhera Biogen Alexion Sanofi non-financial supportfrom Guthy-Jackson Charitable Foundation and grants fromFriedrich Baur Foundation outside the submitted work RMarignier AC Calvo D Bichuetti IM Tavares N Asgari KSoelberg A Altintas R Yildirim U Tanriverdi A Jacob SHuda Z Rimler and A Reid report no disclosures Y Mao-Draayer reports grants from NIH NIAID grants and personalfees from Genzyme grants from Chugai personal fees fromBiogen and EMD Serono grants and personal fees fromGenentech and Novartis during the conduct of the studygrants from NIH NIAID grants and personal fees from Gen-zyme grants fromChugai personal fees fromBiogen and EMDSerono grants and personal fees fromGenentech andNovartisoutside the submitted work I Soto de Castillo reports nodisclosures A Petzold reports personal fees and grants fromNovartis outside the submitted work and is part of the steeringcommittee of the OCTiMS study which is sponsored byNovartis He has not received honoraria for this activity AJGreen reports other from Bionure grants personal fees andother from Inception Sciences grants from Sherak Foundationpersonal fees and other from Pipeline Pharmaceuticals grantsfrom Hilton Foundation Adelson Foundation and NationalMS Society personal fees from JAMANeurology personal feesand other from MediimmuneViela outside the submittedwork In addition Dr Green has a patent Small Molecule drugfor Remyelination pending and has worked on testing off labelcompounds for remyelination MR Yeaman serves as an ad-visor to the Guthy-Jackson Charitable Foundation T Smithreports no disclosures AU Brandt reports grants from theGuthy Jackson Charitable Foundation during the conduct ofthe study shares from Motognosis GmbH and shares fromNocturne GmbH outside the submitted work In addition DrBrandt has a patent pending describing Foveal MorphometryF Paul reports grants from the Guthy Jackson CharitableFoundation during the conduct of the study grants from theGerman Research Foundation andGerman FederalMinistry ofEducation and research grants and other fromNovartis grantsand other from Bayer Novartis Biogen Idec Teva Sanofi-AventisGenzyme Merck Serono Chugai other from PLoSONE other from Neurologyreg Neuroimmunology amp Neuro-inflammation other from SanofiGenzyme Biogen Idec grantsfrom German Research Council Werth Stiftung of the City of

Cologne German Ministry of Education and Research ArthurArnstein Stiftung Berlin EU FP7 Framework Program ArthurArnstein Foundation Berlin National Multiple Sclerosis(USA) other from MedImmune Shire Alexion outside thesubmitted work In addition Dr Paul has a patent FovealMorphometry pending to Nocturne GmbH Go to NeurologyorgNN for full disclosures

Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationMarch 23 2021 Accepted in final form June 15 2021

Appendix Authors

Name Location Contribution

Frederike CosimaOertel MDPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data anddrafting a significantportion of themanuscript or figuresconception and designof the study

Svenja SpecoviusMSc

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of dataconception and designof the study

Hanna GZimmermannPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of dataconception and designof the study

Claudia ChienPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

SeyedamirhoseinMotamedi PhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

CharlotteBereuter BSc

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

Appendix (continued)

Name Location Contribution

Lawrence CookPhD

University of UtahSalt Lake City UT

Acquisition andanalysis of data andconception and designof the study

Marco AurelioLana Peixoto MDPhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Mariana AndradeFontanelle MD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Ho Jin Kim MDPhD

National Cancer CenterGoyang Republic of Korea

Acquisition andanalysis of data

Jae-Won HyunMD PhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

JacquelinePalace MD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Adriana Roca-Fernandez MSc

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Maria IsabelLeite MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

SrilakshmiSharma MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

FereshtehAshtari MD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Rahele KafiehPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Alireza DehghaniPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

MohsenPourazizi PhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Lekha PanditMD PhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Anitha DrsquoCunhaPhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Orhan Aktas MD Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

MariusRingelstein MD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Philipp AlbrechtMD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Eugene May MD Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Caryl Tongco Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Appendix (continued)

Name Location Contribution

Letizia LeocaniMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marco Pisa MD Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marta RadaelliMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Elena H Martinez-Lapiscina MDPhD

Hospital Clinic of Barcelona-Institut drsquoInvestigacionsBiomediques August PiSunyer Barcelona Spain

Acquisition andanalysis of data

Hadas Stiebel-Kalish MD

Sackler School of MedicineTel Aviv University Tel AvivIsrael

Acquisition andanalysis of data

Sasitorn SirithoMD

Siriraj Hospital andBumrungrad InternationalHospital Bangkok Thailand

Acquisition andanalysis of data

Jerome de SezeMD PhD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Thomas SengerMD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Joachim HavlaMD

Ludwig-MaximiliansUniversitat MuenchenMunich Germany

Acquisition andanalysis of data

RomainMarignier MDPhD

Pierre Wertheimer NeurologicalHospital Hospices Civils deLyon France

Acquisition andanalysis of data

Alvaro CoboCalvo MD PhD

Pierre WertheimerNeurological HospitalHospices Civils de LyonFrance Hospital UniversitariVall drsquoHebron UniversitatAutonoma de BarcelonaSpain

Acquisition andanalysis of data

Denis BichuettiMD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Ivan MaynartTavares MD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Nasrin AsgariMD PhD

University of SouthernDenmark OdenseDenmark

Acquisition andanalysis of data

Kerstin SoelbergMD

University of SouthernDenmark Odense Denmark

Acquisition andanalysis of data

Ayse Altintas MD Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Rengin YildirimMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 11

References1 Oertel FC Zimmermann H Paul F Brandt AU Optical coherence tomog-

raphy in neuromyelitis optica spectrum disorders potential advantages forindividualized monitoring of progression and therapy EPMA J 20189(1)21-33

2 Schneider E Zimmermann H Oberwahrenbrock T et al Optical coherence to-mography reveals distinct patterns of retinal damage in neuromyelitis optica andmultiple sclerosis PLoS One 20138(6)e66151

3 Bouyon M Collongues N Zephir H et al Longitudinal follow-up of vision in aneuromyelitis optica cohort Mult Scler 201319(10)1320-1322

4 Sotirchos ES Filippatou A Fitzgerald KC et al Aquaporin-4 IgG seropositivity isassociated with worse visual outcomes after optic neuritis than MOG-IgG seroposi-tivity and multiple sclerosis independent of macular ganglion cell layer thinningMultScler 201926(11)1360-1371

5 Hamid SHM Whittam D Mutch K et al What proportion of AQP4-IgG-negativeNMO spectrum disorder patients are MOG-IgG positive A cross sectional study of132 patients J Neurol 2017264(10)2088-2094

6 Oertel FC Kuchling J ZimmermannH et al Microstructural visual system changes inAQP4-antibody-seropositive NMOSD Neurol Neuroimmunol Neuroinflamm 20174(3)e334

7 Oertel FC Havla J Roca-Fernandez A et al Retinal ganglion cell loss in neuromyelitisoptica a longitudinal study J Neurol Neurosurg Psychiatry 201889(12)1259-1265

8 Huang D Swanson EA Lin CP et al Optical coherence tomography Science 1991254(5035)1178-1181

9 Specovius S Zimmermann HG Oertel FC et al Cohort profile a collaborativemulticentre study of retinal optical coherence tomography in 539 patients withneuromyelitis optica spectrum disorders (CROCTINO) BMJ Open 202010(10)e035397

10 Motamedi S Gawlik K Ayadi N et al Normative data and minimally detectablechange for inner retinal layer thicknesses using a semi-automated OCT image seg-mentation pipeline Front Neurol 2019101117

11 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177-189

12 von Elm E Altman DG Egger M et al The strengthening the reporting of obser-vational studies in epidemiology (STROBE) statement guidelines for reportingobservational studies Int J Surg 201412(12)1495-1499

13 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PLoS One 20127(4)e34823

14 Schippling S Balk LJ Costello F et al Quality control for retinal OCT in multiplesclerosis validation of the OSCAR-IB criteria Mult Scler 201521(2)163-170

15 Lang A Carass A Hauser M et al Retinal layer segmentation of macular OCT imagesusing boundary classification Biomed Opt Express 20134(7)1133-1152

16 R Development Core Team R A Language and Environment for Statistical Computing[online] R Foundation for Statistical Computing 2008 R-projectorg

17 Akaishi T Kaneko K Himori N et al Subclinical retinal atrophy in the unaffectedfellow eyes of multiple sclerosis and neuromyelitis optica [online serial]J Neuroimmunol 201731310-15 Accessed October 8 2017 jni-journalcomarticleS0165-5728(17)30319-3fulltext

18 Alshowaeir D Yiannikas C Fraser C Klistorner A Mechanism of delayed con-duction of fellow eyes in patients with optic neuritis Int J Ophthalmol 201811(2)329-332

19 Manogaran P Traboulsee AL Lange AP Longitudinal study of retinal nerve fiberlayer thickness and macular volume in patients with neuromyelitis optica spectrumdisorder J Neuroophthalmol 201636(4)363-368

20 Kaufhold F ZimmermannH Schneider E et al Optic neuritis is associated with innernuclear layer thickening and microcystic macular edema independently of multiplesclerosis PLoS One 20138(8)e71145

21 Knier B Schmidt P Aly L et al Retinal inner nuclear layer volume reflects response toimmunotherapy in multiple sclerosis Brain 2016139(11)2855-2863

22 Petzold A Balcer LJ Calabresi PA et al Retinal layer segmentation in multiplesclerosis a systematic review and meta-analysis Lancet Neurol 201716(10)797-812

23 Pawlitzki M Horbrugger M Loewe K et al MS optic neuritis-induced long-termstructural changes within the visual pathway Neurol Neuroimmunol Neuroinflamm20207(2)e665

24 Pache F Zimmermann H Mikolajczak J et al MOG-IgG in NMO and relateddisorders a multicenter study of 50 patients Part 4 afferent visual system damageafter optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patientsJ Neuroinflammation 201613(1)282

25 Filippatou AG Vasileiou ES He Y et al Evidence of subclinical quantitative retinallayer abnormalities in AQP4-IgG seropositive NMOSD Mult Scler 2020 Dec 141352458520977771 doi 1011771352458520977771

26 Motamedi S Oertel FC Yadav SK et al Altered fovea in AQP4-IgGndashseropositiveneuromyelitis optica spectrum disorders Neurol Neuroimmunol Neuroinflamm 20207(5)e805

27 Roca-Fernandez A Oertel FC Yeo T et al Foveal changes in AQP4-Ab seropositiveNMOSD are independent of optic neuritis and not overtly progressive Eur J Neurol202128(7)2280-2293

28 Papadopoulou A Oertel FC Chien C et al Lateral geniculate nucleus volumechanges after optic neuritis in neuromyelitis optica a longitudinal study NeuroimageClin 202130102608

29 Ringelstein M Harmel J Zimmermann H et al Longitudinal optic neuritis-unrelatedvisual evoked potential changes in NMO spectrum disorders Neurology 202094(4)e407-e418

30 Pache F Zimmermann H Finke C et al Brain parenchymal damage in neuromyelitisoptica spectrum disorderndasha multimodal MRI study Eur Radiol 201626(12)4413-4422

31 Hokari M Yokoseki A Arakawa M et al Clinicopathological features in anteriorvisual pathway in neuromyelitis optica Ann Neurol 201679(4)605-624

32 You Y Zhu L Zhang T et al Evidence of muller glial dysfunction in patients withaquaporin-4 immunoglobulin Gndashpositive neuromyelitis optica spectrum disorderOphthalmology 2019126(6)801-810 Elsevier

33 Chien C Scheel M Schmitz-Hubsch T et al Spinal cord lesions and atrophy inNMOSD with AQP4-IgG and MOG-IgG associated autoimmunityMult Scler 201925(14)1926-1936

34 Felix CM Levin MH Verkman AS Complement-independent retinal pathologyproduced by intravitreal injection of neuromyelitis optica immunoglobulin GJ Neuroinflammation 201613(1)275

35 Balk LJ Coric D Knier B et al Retinal inner nuclear layer volume reflects in-flammatory disease activity in multiple sclerosis a longitudinal OCT studyMult SclerJ Exp Transl Clin 20195(3)2055217319871582

36 Gelfand JM Nolan R Schwartz DM Graves J Green AJ Microcystic macular oedemain multiple sclerosis is associated with disease severity Brain 2012135(pt 6)1786-1793

Appendix (continued)

Name Location Contribution

Uygur TanriverdiMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Anu Jacob MD The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Saif Huda MDPhD

The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Zoe Rimler BSc NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Allyson Reid MD NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Yang Mao-Draayer MD PhD

University of MichiganMedical School AnnArbor MI

Acquisition andanalysis of data

Ibis Soto deCastillo MD

Hospital Clınico deMaracaibo MaracaiboVenezuela

Acquisition andanalysis of data

Axel Petzold MDPhD

University College LondonLondon UK

Conception anddesign of the study

Ari J Green MD University of California SanFrancisco CA

Conception anddesign of the study

Michael RYeaman MD PhD

University of California LosAngeles CA

Conception anddesign of the study

Terry Smith MD University of MichiganMedical School AnnArbor MI

Conception anddesign of the study

Alexander UBrandt MD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinBerlin Berlin Germany

Acquisition andanalysis of dataconception and designof the study anddrafting a significantportion of themanuscript or figures

Friedemann PaulMD

CharitendashUniversitatsmedizinBerlin Corporate Member ofFreie Universitat Berlin andHumboldt-Universitat zuBerlin

Acquisition andanalysis of data andconception and designof the study

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

37 Gelfand JM Cree BA Nolan R Arnow S Green AJ Microcystic inner nuclear layerabnormalities and neuromyelitis optica JAMA Neurol 201370(5)629-633

38 Oberwahrenbrock T WeinholdMMikolajczak J et al Reliability of intra-retinal layerthickness estimates PLoS One 201510(9)e0137316

39 Borisow N Kleiter I Gahlen A et al Influence of female sex and fertile age onneuromyelitis optica spectrum disorders Mult Scler 201723(8)1092-1103

40 Mori M Kuwabara S Paul F Worldwide prevalence of neuromyelitis optica spectrumdisorders J Neurol Neurosurg Psychiatry 201889(6)555-556

41 Oertel FC Paul F Accelerating clinical research in neuromyelitis optica spectrumdisorders [online serial] Clin Exp Neuroimmunol 202112(2)89-91 AccessedMarch 28 2021 periclespericles-prodliteratumonlinecomdoiabs101111cen312637

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 13

DOI 101212NXI000000000000106820218 Neurol Neuroimmunol Neuroinflamm

Frederike Cosima Oertel Svenja Specovius Hanna G Zimmermann et al Retinal Optical Coherence Tomography in Neuromyelitis Optica

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Page 2: Retinal Optical Coherence Tomography in Neuromyelitis Optica

control and intraretinal segmentation The primary outcome was thickness of combined ganglion cell and inner plexiform(GCIP) layer secondary outcomes were thickness of peripapillary retinal nerve fiber layer (pRNFL) and visual acuity (VA)

ResultsEyes with ON (NMOSD-ON N = 260) or without ON (NMOSD-NON N = 241) were assessed compared with HCs (N =136) In NMOSD-ON GCIP layer (574 plusmn 122 μm) was reduced compared with HC (GCIP layer 814 plusmn 57 μm p lt 0001)GCIP layer loss (minus227 μm) after the first ON was higher than after the next (minus35 μm) and subsequent episodes pRNFLobservations were similar NMOSD-NON exhibited reduced GCIP layer but not pRNFL compared with HC VA was greatlyreduced in NMOSD-ON compared with HC eyes but did not differ between NMOSD-NON and HC

DiscussionOur results emphasize that attack prevention is key to avoid severe neuroaxonal damage and vision loss caused by ON inNMOSD Therapies ameliorating attack-related damage especially during a first attack are an unmet clinical need Mild signs ofneuroaxonal changes without apparent vision loss in ON-unaffected eyes might be solely due to contralateral ON attacks and donot suggest clinically relevant progression but need further investigation

Patients with neuromyelitis optica spectrum disorder (NMOSD)experience recurrent optic neuritis (ON)1 resulting in vision lossand decreased quality of life1-4 According to our understandingthere are at least 3 subtypes based on serostatus Up to 3 of 4patients manifest as antindashaquaporin-4 IgG (AQP4-IgG) sero-positive Approximately half of the AQP4-IgGndashseronegative pa-tients manifest as antindashmyelin oligodendrocyte glycoprotein IgG(MOG-IgG) seropositive and half are double seronegative5 Yetclinical correlates of serologic phenotypes including subclinical orclinical retinal degeneration and vision loss remain unclear67

Optical coherence tomography (OCT) is an interferometrictechnique producing high-resolution retinal images18 OCThas become a reliable tool for diagnosing and monitoringneurologic and neuro-ophthalmologic diseases especially forquantifying neurodegeneration after ON1 Because of limitedsamples and varying methods existing OCT studies inNMOSD are inconsistent regarding the amount of retinalneurodegeneration with and without ON Previous studies alsofailed to address the influence of retinal neurodegeneration onmicrocystic macular edema (MME) and function267 Theseissues together with heterogeneities and the often monocentriccharacter of previous cohorts limit the relevance of meta-analyses

To overcome these limitations we performed anOCT analysis ofAQP4-IgGndashseropositive patients with NMOSD in an in-ternational multicenter study termed Collaborative RetrospectiveStudy on retinal OCT in Neuromyelitis Optica (CROCTINO)9

It represents the largest NMOSD OCT data set and additionallyvalidated an OCT postprocessing approach to circumvent dif-ferences in acquisition and imaging processing protocols inherentto pooled analyses10 Outcomes include (1) distinguishing retinalneurodegeneration after ON from subtle damage in clinicallyunaffected eyes (2) defining frequency ofMME and (3) derivingstructure-function correlations

MethodsStudy DesignThis cross-sectional international multicenter study was per-formed under the aegis of the CROCTINO study which wasa collaborative effort within the Guthy-Jackson CharitableFoundation network9 Participating centers contributed OCTdata (acquired between 2008 and 2018) and clinical metadata(acquired between 2000 and 2018 eTable 1 linkslwwcomNXIA557)

Cohort SelectionInclusion criteria for this analysis were (1) patients diagnosedwith NMOSD per the 2015 International Panel of NMOSDdiagnosis criteria11 and (2) having confirmed serum AQP4-IgG Exclusion criteria were (1) comorbidities potentiallyconfounding interpretation of OCT results (eg maculardegeneration glaucoma and intracranial hypertension) (2) gt3months distance between clinical andOCT data acquisition(3) lt 6 months between OCT imaging and most recent ONor (4) an uncertain history of ON The inclusion and

GlossaryAQP4-IgG = aquaporin-4 IgG CROCTINO = Collaborative Retrospective Study on retinal OCT in Neuromyelitis OpticaEDSS = Expanded Disability Status Scale GCIP = ganglion cell and inner plexiform HC = healthy control HC-VA = high-contrast visual acuity INL = inner nuclear layer MME = microcystic macular edema MS = multiple sclerosis MOG-IgG =myelin oligodendrocyte glycoprotein IgG NMOSD = neuromyelitis optica spectrum disorder NMOSD-NON = NMOSDeyes without a history of ONOCT = optical coherence tomographyON = optic neuritis pRNFL = peripapillary retinal nervefiber layer SE = standard error VA = visual acuity VEP = visually evoked potential

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exclusion criteria are depicted in eFigure 1 linkslwwcomNXIA556 AQP4-IgG testing was performed at the discre-tion of each investigator

Standard Protocol Approvals Registrationsand Patient ConsentsAll participants gave written informed consent and the studywas approved by local ethics committees and conducted inaccordance with the applicable laws and the current version ofthe Declaration of Helsinki Data are reported according toSTROBE reporting guidelines12

OCTHigh-resolution imaging data were acquired using 3 differ-ent spectral domain OCT devices Spectralis SD-OCT(Heidelberg Engineering Heidelberg Germany) at 15 cen-ters (194 patients358 eyes 72 healthy controls [HCs]136eyes) Cirrus HD-OCT (Carl Zeiss Meditec Dublin CA) at6 centers (58 patients87 eyes) or Topcon 3D OCT-1(Topcon Tokyo Japan) at 1 center (31 patients56 eyes)All reading of OCT data was performed at CharitendashUniversitatsmedizin Berlin Translational Neuroimaging Groupby 5 graders Image quality was assessed using modifiedOSCAR-IB criteria by one of the graders respectively1314

OCT segmentation for the combined ganglion cell and innerplexiform (GCIP) layer and inner nuclear layer (INL) thick-nesses was corrected semi-automatically using an in-housesoftware1015 In brief GCIP layer and INL thicknesses werecalculated from a 5-mm diameter cylinder around the foveaexcluding the central 1-mm diameter cylinder from a macularvolume scan10 The peripapillary retinal nerve fiber layer(pRNFL) thickness was measured and corrected according tothe device protocol (Spectralis peripapillary ring scan with12deg or approximately 34 mm diameter around the optic discTopcon and Cirrus extraction from optic disc volume scan)For the current analysis eyes were excluded from the analysisif neither ring nor macular scan passed quality control Wefurther excluded data from the less common instrument for 1center The final cohort included 364 macular and 481 per-ipapillary scans of 501 eyes from 283 patients and 136 eyesfrom 72 HCs Lower numbers of macular scans comparedwith peripapillary scans were due to both lower submissionof macular data and more exclusions based on qualityconcerns

Visual and Global Function TestingHigh-contrast visual acuity (HC-VA) was available for 497(992) patient and 10 (139) HC eyes HC-VA was bestcorrected for 212 (423) patient and 56 (412) HC eyeshabitually corrected for 145 (289) patient and 2 (lt01)HC eyes and without correction for 140 (279) patient eyesand 17 (13) HC eyes All VA data are reported as logMARVA measurement method was decided on discretion of eachcenter Visually evoked potentials (VEPs) were available for167 (333) patient eyes and 40 (294) HC eyes with P100latency recorded as a binary value (normalprolonged) Ex-panded Disability Status Scale (EDSS) scores were de-termined at the discretion of each center with data availablefor 180 (636) patients

Statistical AnalysisStatistical analyses were performed with R version 361using RStudio and R Markdown (RStudio Inc BostonMA)16 p Values less than 005 were considered significantWe considered p values less than 010 a trend Groupmatching by age and sex for confirmatory analyses wasperformed using automatic matching by R package MatchIt(method exact) Group comparisons and correlations ofOCT and VA values were performed using linear mixed-

Table 1 Cohort Description for AQP4-IgGndashSeropositivePatients With NMOSD and HCs

AQP4-IgGndashseropositiveNMOSD HC

Subjects (N) 283 72

Eyes (N) 501 136

Sex (malefemale NN []) 28255 (99901) 2646 (361639)

Age (y mean plusmn SD) 441 plusmn 142 309 plusmn 77

Ethnicity (N [])

Asian 77 (272) 16 (222)

BlackAfrican American 13 (46) 0 (0)

White HispanicLatino 4 (14) 1 (14)

White Non-Hispanic 159 (562) 55 (764)

Othernonreported 30 (106) 0 (0)

Disease-modifying therapy (N[])

Rituximab 73 (258)

Azathioprine 67 (237)

Oral prednisolone 53 (187)

Mycophenolate mofetil 48 (170)

Methotrexate 8 (28)

Time since onset (y mean plusmn SD) 72 plusmn 67

EDSS score (median [IQR]) 35 (20ndash45)

Patients with a clinical history ofON (N [])

204 (721)

Eyes with a clinical history of ON(N [])

260 (52)

No of ON episodeseye (Nmedian [minndashmax])

1 (1ndash6)

Time since last ON (mo mean plusmnSD)

71 plusmn 57

Abbreviations AQP4-IgG = aquaporin-4 antibodies NMOSD = neuromyelitisoptica spectrum disorder HC = healthy control N = number OCT = opticalcoherence tomography ON = optic neuritis episodeAge (p lt 00001) and sex (p lt 00001) were not matched

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 3

effect models Intereye within-subject effects and effects ofthe center were included as random effects Sex ethnicityand age were included as fixed effects for the analyses in theentire cohort Age and sex were not included for thematched subset For OCT parameters the model was usedfor data from all devices separately and combined by Fishercombined probability test The marginal and conditionalcoefficients of determination of the linear models werecalculated with pseudo R-squared All results are reported

combined and individually for Spectralis SD-OCT theanalyses of data acquired by Cirrus HD-OCT or Topcon3D OCT-1 and for the matched subset are reported asonline-only supplement

Data AvailabilityThe data supporting the findings of this study are availablewithin the article and from the corresponding author byreasonable request

Figure 1 Group Comparisons of GCIP Layer Thickness

Boxplots of GCIP layer thicknesses (μm) acquired by Heidelberg SD-OCT with values of individual eyes (jitter) for (A) HC (grayleft) NMOSD-NON(dark bluemiddle) NMOSD-ON (dark redright) for (B) number of ON episodes (NMOSD-NON dark blueleft NMOSD-1-ON light redleft-middleNMOSD-2-ON medium-redright-middle NMOSD-ge3-ON medium-dark redright) and for (C) HC (grayleft) NMOSD-NONnon (light bluemiddle)NMOSD-NONcon (blueright) (D) Forest plots for results from different OCT devices for (Da) NMOSD-NON vs NMOSD-ON (Db) NMOSD-NON vsNMOSD-1-ON and (Dc) NMOSD-1-ON vs NMOSD-2-ON (eFigure 2 and eTable 2 linkslwwcomNXIA556 and linkslwwcomNXIA557) GCIP =ganglion cell and inner plexiform HC = eyes of HCs NMOSD-NON = eyes of patients with neuromyelitis optica without a history of ON NMOSD-NON-con =eyes of patients with neuromyelitis optica without a history of ON but a history of contralateral ON NMOSD-NONnon = eyes of patients withneuromyelitis optica without a history of ipsilateral or contralateral ON NMOSD-ON = eyes of patients with neuromyelitis optica with a history ofON NMOSD-1-ON = eyes of patients with neuromyelitis optica with a history of 1 ON episode NMOSD-2-ON = eyes of patients with neuromyelitisoptica with a history of 2 ON episodes ON = optic neuritis

4 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

ResultsFive hundred one eyes of 283 AQP4-IgGndashseropositive pa-tients and 136 eyes of 72 HCs were included in the analysis(Table 1)

Neuroaxonal Damage After ONGCIP layer and pRNFL were reduced in NMOSD-ONcompared with NMOSD eyes without a history of ON

(NMOSD-NON) and HC (GCIP layer 814 plusmn 57 μmpRNFL 1011 plusmn 90 μm) (Figures 1A and 2A Tables 2 and3) The absolute (GCIP layer minus227 μm pRNFL minus385 μm)and relative (GCIP layer minus388 pRNFL minus616) loss ineyes with 1 ON episode (NMOSD-1-ON) compared withNMOSD-NON was higher than in eyes with 2 ON episodes(NMOSD-2-ON) compared with NMOSD-1-ON (GCIPlayer absolute loss minus35 μm relative loss minus60 pRNFLabsolute loss minus91 μm relative loss minus145 ns) The loss in

Figure 2 Group Comparisons of pRNFL Thickness

Boxplots of pRNFL thicknesses acquired by Heidelberg SD-OCT [μm] with values of individual eyes (jitter) for (A) HC (grayleft) NMOSD-NON (dark bluemiddle) and NMOSD-ON (dark redright) for (B) number of ON episodes (NMOSD-NON dark blueleft NMOSD-1-ON light redleft-middle NMOSD-2-ONmedium-redright-middle and NMOSD-ge3-ON medium-dark redright) and for (C) HC (grayleft) NMOSD-NONnon (light bluemiddle) and NMOSD-NONcon

(blueright) (D) Forest plots for results from different OCT devices for (Da) NMOSD-NON vs NMOSD-ON (Db) NMOSD-NON vs NMOSD-1-ON and (Dc)NMOSD-1-ON vs NMOSD-2-ON (eFigure 3 and eTable 3 linkslwwcomNXIA556 and linkslwwcomNXIA557) HC = eyes of HCs NMOSD-NON = eyes ofpatients with neuromyelitis optica without a history of optic neuritis NMOSD-NON-con = eyes of patients with neuromyelitis optica without a history of opticneuritis but a history of contralateral optic neuritis NMOSD-NONnon = eyes of patients with neuromyelitis optica without a history of ipsilateral or contra-lateral optic neuritis NMOSD-ON = eyes of patients with neuromyelitis optica with a history of optic neuritis NMOSD-1-ON = eyes of patients withneuromyelitis optica with a history of 1 optic neuritis episode NMOSD-2-ON = eyes of patients with neuromyelitis optica with a history of 2 optic neuritisepisodes ON = optic neuritis pRNFL = peripapillary retinal nerve fiber layer

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eyes with ge3-ON episodes (NMOSD-3-ON) was lowercompared with NMOSD-2-ON (ns) (Figures 1B and 2B)Five NMOSD-NON eyes had pRNFL values lt 60 μm thesepatients had no relevant comorbidities but a history of con-tralateral ON1718 In sensitivity analyses to account for devicedifferences all significant analyses within the NMOSD cohortwere confirmed for data acquired by Cirrus and Topcon OCTdevices (eFigures 2 and 3 eTables 3 and 4 linkslwwcomNXIA556 linkslwwcomNXIA557)

Neuroaxonal Damage Without ONNMOSD-NON eyes had a reduced GCIP layer (759 plusmn 77 μmplt 0001) but not pRNFL (953 plusmn 144 μm) comparedwithHC(GCIP layer 814 plusmn 57 μm pRNFL 1011 plusmn 90 μm Figures 1Aand 2A Tables 2 and 3) By comparison only 28 NMOSD-NON eyes (51) had a GCIP layer le the 5th percentile of HCGCIP layer was also reduced inNMOSD-NONwith a history ofcontralateral ON (729 plusmn 102 μm) compared with NMOSD-NON without a history of contralateral ON (773 plusmn 59 μm p =0025 NMOSD-NONnon) This effect vanished when onlyconsidering NMOSD-NONcon with a history of 1 contralateralON (736 plusmn 94 μm) However only NMOSD-NONcon (p lt

0001) but not NMOSD-NONnon (p = 0061) had thinnedGCIP layer compared with HC (Figures 1C and 2C)

INL ChangesINL was thicker in NMOSD-ON compared with HC (394 plusmn26 μm) and NMOSD-NON (eTable 4 linkslwwcomNXIA557) Specifically INL was thicker in eyes with 1 ON episodecompared with NMOSD-NON but did not differ between eyeswith different numbers of ON episodes Also INL did not differbetween NMOSD-NONcon (389 plusmn 32 μm) and NMOSD-NONnon (385 plusmn 32 μm p = 0931) In all patients INLthickness (as the dependent variable in the linear mixed modeldescribed above) was correlated with thinner GCIP layer (B =minus011 standard error [SE] = 001 p lt 0001) and pRNFL (B =minus006 SE = 001 p lt 0001) This correlation existed inNMOSD-ON (GCIP layer B = minus 008 SE = 003 p = 0005pRNFL B = minus 006 SE = 001 p lt 0001) and not present inNMOSD-NON (eFigure 4 linkslwwcomNXIA556)

Scans of 363 NMOSD eyes were clearly suitable for MMEinvestigations (high quality eFigure 4C linkslwwcomNXIA556) MMEs were visible in 24 (66) eyes of 21 patients

Table 2 Group Comparisons of GCIP Layer Thickness for Heidelberg SD-OCT

No ofeyes

Thickness (μmmean plusmn SD)

Comparisonto

Absolutedifference (μmmean)

Relativedifference (mean) B SE p Value R2

marg R2cond

Combinedp value

NMOSD 268 673 plusmn 136 HCs minus140 minus208 156 20 lt00001 0143 0690 mdash

NMOSD-ON

124 574 plusmn 122 minus240 minus418 250 20 lt00001 0482 0839 mdash

NMOSD-NON

144 759 plusmn 77 minus54 minus72 58 14 lt00001 0088 0947 mdash

NMOSD-NONnon

99 773 plusmn 59 minus40 minus50 269 142 0061 0189 0924 mdash

NMOSD-NONcon

45 729 plusmn 102 minus85 minus104 844 177 lt00001 0260 0985 mdash

NMOSD-ON

124 574 plusmn 122 NMOSD-NON

minus185 minus244 minus158 11 lt00001 0430 0795 59e245

NMOSD-1-ON

76 586 plusmn 129 minus173 minus228 minus145 12 lt00001 0417 0803 14e233

NMOSD-2-ON

28 551 plusmn 94 NMOSD-1-ON

minus35 minus60 minus57 26 0028 0143 0729 0038

NMOSD-ge3-ON

20 559 plusmn 128 NMOSD-2-ON

08 14 49 26 0070 0311 0781 0222

NMOSD-NONcon

45 729 plusmn 102 NMOSD-NONnon

minus44 minus61 minus38 17 0025 0111 0701 0004

NMOSD-NON1-con

37 736 plusmn 94 minus37 minus51 minus35 16 0037 0149 0906 0154

Abbreviations AQP4-IgG = aquaporin-4 IgG B = estimate GCIP = ganglion cell and inner plexiformNMOSD=AQP4-IgGndashseropositiveNMOSD NMOSD-NON=AQP4-IgGndashseropositive NMOSD eyeswithout a history of ON NMOSD-NONnon = AQP4-IgGndashseropositive NMOSD eyeswithout a history ofONor contralateralON NMOSD-NONcon = AQP4-IgGndashseropositive NMOSD eyes without a history of ON but with a history of contralateral ON NMOSD-NON1-con = AQP4-IgGndashseropositive NMOSD eyes without a history of ON but with a history of 1 contralateral ON NMOSD-ON = AQP4-IgGndashseropositive NMOSD eyes with ahistory of ON NMOSD-1-ON =AQP4-IgGndashseropositive NMOSD eyeswith a history of 1ON NMO-2-ON =AQP4-IgGndashseropositive NMOSD eyeswith a history of2 ONs NMOSD-ge3-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 3 or more ONs NMOSD = neuromyelitis optica spectrum disorder NMOSD-NON = NMOSD eyes without a history of ON OCT = optical coherence tomography ON = optic neuritis episode Rcon = conditional R-squared Rmarg =marginal R-squared SE = standard error

6 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

Twenty-three eyes (131) of NMOSD-ON and 1 eye (05)of NMOSD-NON (with a history of contralateral ON) wereaffected The number of ON episodes did not influence theincidence of MMEs (NMOSD-1-ONN = 16 (14) NMOSD-2-ON N = 4 (114) NMOSD-ge3-ON N = 3 (111))

Including only the most frequent ethnicities in our data set(Asian and non-HispanicWhite) results did not differ and noethnicity was singled out regarding its pattern of injury (datanot shown)

OCT and Vision LossHC-VA was numerically reduced in NMOSD (025 plusmn 048)compared with HC (minus001 plusmn 008) and known healthy referencevalues NMOSD-ON also had reduced HC-VA (044 plusmn 058)compared with NMOSD-NON (004 plusmn 020 p lt 0001 p =0401) and HChealthy reference populations HC-VA wascorrelated with GCIP layer (B = minus0016 SE = 0002 p lt 0001)and pRNFL thicknesses (B = minus0010 SE = 0001 p lt 0001) inAQP4-IgGndashseropositive NMOSD AQP4-IgGndashseropositiveNMOSD eyes with prolonged VEP latency had a thinned GCIP

layer (B = minus11647 SE = 3628 p = 0002) and pRNFL (B =minus21965 SE = 3724 p lt 0001) EDSS score as ametric of globaldisability was inversely correlated with GCIP layer (B = minus1370SE= 0566 p= 0017) and pRNFL thicknesses (B= minus3148 SE=1080 p = 0004)

DiscussionOur study specifies a severe and functionally relevant decreaseof GCIP layer and pRNFL in NMOSD-ON compared withNMOSD-NON and HCs in AQP4-IgGndashseropositive pa-tients Neuroaxonal damage is particularly large from the firstepisode of ON where contribution to retinal damage insubsequent episodes of ON is still considerable but smaller Incontrast to previous smaller studies the current study ascer-tains GCIP layer but not pRNFL thinning in NMOSD-NONcompared with HC619 This effect was driven by eyes withcontralateral ON and not statistically significant in eyeswithout a history of ON INL was thicker in NMOSD-ONand was inversely correlated with GCIP layer Of note 131

Table 3 GroupComparisons of pRNFL ThicknessWith (A) Spectralis SD-OCTData for Comparisons vsHC (B) Data FromAllDevices for Intrapatient Cohort Comparisons

No ofeyes

Thickness (μmmean plusmn SD)

Comparisonto

Absolute difference(μm mean)

Relativedifference (mean) B SE p Value R2

marg R2cond

Combinedp value

NMOSD 344 763 plusmn 274 HCs minus140 minus326 242 43 lt00001 0143 0690 mdash

NMOSD-ON

170 569 plusmn 237 minus443 minus779 431 41 lt00001 0482 0839 mdash

NMOSD-NON

174 953 plusmn 144 minus59 minus62 46 30 0129 0088 0947 mdash

NMOSD-NONnon

116 974 plusmn 109 minus37 minus37 minus29 22 0204 0107 0893 mdash

NMOSD-NONcon

58 910 plusmn 191 minus47 minus46 71 42 0097 0100 0975 mdash

NMOSD-ON

170 569 plusmn 237 NMOSD-NON

minus384 minus403 minus338 21 lt00001 0436 0741 44e260

NMOSD-1-ON

97 626 plusmn 249 minus327 minus343 minus296 22 lt00001 0379 0712 46e240

NMOSD-2-ON

35 535 plusmn 213 NMOSD-1-ON

minus91 minus145 minus107 47 0024 0087 0528 0010

NMOSD-ge3-ON

38 452 plusmn 178 NMOSD-2-ON

minus83 minus155 minus04 43 0924 0087 0719 0838

NMOSD-NONcon

58 910 plusmn 191 NMOSD-NONnon

minus65 minus71 minus40 29 0173 0061 0939 0157

NMOSD-NON1-con

47 932 plusmn 181 minus42 minus46 minus32 29 0276 0056 0925 0616

Abbreviations AQP4-IgG = aquaporin-4 IgG NMOSD = AQP4-IgGndashseropositive NMOSD NMOSD-NON = AQP4-IgGndashseropositive NMOSD eyes without ahistory of ON NMOSD-NONnon = AQP4-IgGndashseropositive NMOSD eyes without a history of ON or contralateral ON NMOSD-NONcon = AQP4-IgGndashseropositive NMOSD eyes without a history of ON but with a history of contralateral ON NMOSD-NONcon = AQP4-IgGndashseropositive NMOSD eyes without ahistory of ON but with a history of 1 contralateral ON NMOSD-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of ON NMOSD-1-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 1 ON NMOSD-2-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 2 ONs NMOSD-ge3-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 3 or more ONs NMOSD = neuromyelitis optica spectrum disorder NMOSD-NON = NMOSD eyes without ahistory of ON OCT = optical coherence tomography ON = optic neuritis episode pRNFL = peripapillary retinal nerve fiber layer VEP = visually evokedpotential

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 7

of NMOSD-ON eyes showed MME indicative of secondaryinflammatory changes2021 This investigation overcame limitsof small samples and OCT data heterogeneity of earlierstudies through use of an international consortium ofNMOSD specialists This framework substantiated theCROCTINO studymdasha large multicenter retrospectiveevaluation of retinal pathology in NMOSD using OCT

The neuroaxonal degeneration in NMOSD-ON demon-strated here is substantially greater than reported changes inmultiple sclerosis (MS) a common differential diagnosis222

In a meta-analysis an average pRNFL loss of 20 μm wasestimated in MS after ON which is nearly 2-fold higher in ourNMOSD-ON cohort (minus384 μm)22 For GCIP layer our datasuggested approximately 15-fold higher loss in NMOSD(minus240 μm) compared with MS22 These differences not onlyresult from a higher ON frequency but may also be caused bymore severe retinal damage in NMOSD after a singular ON23

It is intriguing that the damage is particularly large after thefirst ON episode with smaller losses after subsequent epi-sodes which might be due to less neuroaxonal content insubsequent episodes224 Alternatively although the analysisof treatment effects exceeds the scope of this study it ispossible that the longer time to effective anti-inflammatorytherapy and the typical choice of less effective therapies (egsteroids instead of plasma exchange) at the first attack com-pared with following attacks may significantly contribute tothis difference Independent of the number of ONs the per-cent loss is smaller in GCIP layer compared with pRNFLndashpointing toward either (1) stronger loss of retinal nerve fibersthan retinal ganglion cells (2) impairment of ganglion cellsnot leading to extinction but axonal loss (3) a larger amountof non-neuronal tissue in GCIP layer or (4) RNFL loss in theperiphery beyond the macular area measured by GCIP layerThese hypotheses are not mutually exclusive and each mightcontribute to the effect Consistent with these concepts ex-cessive vision loss relative to neuroaxonal content and VEPlatency in AQP4-IgGndashseropositive patients compared withMOG-IgGndashseropositive and MS patients implies damage ofthe peripheral retina and optic nerve tissues which are notreflected in the macula and pattern VEP measurements4

Whether attack-independent neurodegeneration inAQP4-IgGndashseropositive NMOSD occurs has beencontroversial26725-28 The current study identifies de-creased GCIP layer in NMOSD-NON compared withHC but not pRNFL Such subclinical changes could becaused by contralateral involvement after unilateralON1718 Indeed our cohort suggests pronounced neu-rodegeneration in eyes with contralateral ON Howevereyes of patients without ON also exhibit a trend for thinnerGCIP layer compared with HCs Underscored by longitu-dinal studies showing ON-independent neurodegenerationand VEP latency prolongation729 such patterns suggest atleast 2 mechanisms of injury (1) a primary retinopathy oroptic neuropathy in context of an astrocytopathy or causedby direct damage to AQP4-expressing cells such as astrocytes

and Muller cells by either AQP4-IgG or AQP4-specificT cells or (2) a global or afferent visual system specificchronic or episodic neurodegenerative process Because le-sions often spare the brain and most studies outside ofpredisposed areas such as optic nerve and spinal cord failedto detect effects30 a constant global involvement seemsunlikely Several studies described changes affecting AQP4expression and astrocytic end feet31 parafoveal changes inagreement with an involvement of AQP4-expressing Mullercell6262732 and attack-independent spinal cord atrophy33

These findings are consistent with tissue infiltration byAQP4-IgGndashspecific T cells34 and the attack-independentloss of retinal ganglion cells7mdashfurther supporting the exis-tence of an ON-independent pathology which might berestricted to the main disease foci The latter hypothesescould be addressed by region-specific pathology or advancedimaging studies

INL changes have been suggested as a marker of neuro-inflammation and potential treatment response in MS213536

MME may develop as a consequence of neurodegenerationor othermdashnonndashdisease-specificmdashprocesses35 Patients withNMOSD were described to have INL thickening andMME2037 In our cohort 131 of NMOSD-ON eyes wereaffected byMME which is higher than the 2ndash5 described inMS but comparable to incidences in NMOSD described beforeby Gelfand and colleagues3537 However INL thickening itselfremained comparable to changes reported in MS35 This dis-parity could reflect a disrupted fluid homeostasis due to Mullercell involvement or loss of content of the INL with a parallelinflammatory reaction and development of MME The limitedaccessibility of MMEs especially in severely affected eyes due tolimited image quality has hindered their detailed assessmentsand most likely leads to underestimation of their incidence38

We demonstrate that the INL thickness is inversely correlatedwith neuroaxonal content and could be a valuable marker ofdisease severity also in NMOSD

Our study cohort was representative of patients with AQP4-IgGndashseropositive NMOSD with respect to a female pre-dominance and ON history1139 This OCT study includedmultiple ethnicity backgrounds although the distribution wasshifted toward CaucasianWhite patients and other ethnic-ities were underrepresented (eg Hispanic White and Black)limiting the generalizability of results40 Patients from differ-ent heritages presented similar findings

The current study was based on source data instead of a meta-analysis Using the Guthy-Jackson Charitable Foundation net-work this multicentric study was conducted without investigatorreimbursement and illustrated how collaboration integratinginternational perspectives can produce meaningful results Toovercome technical challenges of heterogeneous source data wedeveloped novel OCT postprocessing techniques allowing us toperform standardized analyses and enabling the uniform analysisof the largest OCT image data set in NMOSD to date10 Thusthe strengths of CROCTINO include its established

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

infrastructure large international network of experts represent-ing multiple ethnicities and geographic regions and the use ofstate-of-the-art OCT postprocessing techniques41

We recognize limitations of the current investigation Theretrospective and heterogeneous data acquisition might haveled to biases and impreciseness beyond the ability of ourquality control We addressed this by excluding uncertaincases HCs were only included from a limited number ofcenters The unbalanced data set limited some analyses suchas the influence of ethnicities or acute and disease-modifyingtreatments Case-control matching was impossible particu-larly with respect to subclinical progression dependent orindependent of ON and to ethnicity Similarly comparisonswith other NMOSD subtypes or MS were beyond the scopeof this study Longitudinal data acute ON data and AQP4-IgGndashseronegative and MOG-IgGndashseropositive patient dataare part of the CROCTINO data set and will be analyzed inthe future Also OCT data processing was performed bymultiple raters potentially introducing interrater variabilityMRI data and posterior visual pathway involvement were notinvestigated in this study However the current study ach-ieved an unprecedented worldwide assessment of retinaldamage in AQP4-IgGndashseropositive NMOSD

To conclude AQP4-IgGndashseropositive NMOSD is characterizedby a severe functionally relevant retinal neurodegeneration as aconsequence of ON Although the majority of damage occursduring the first episode there is cumulative loss with each suc-ceeding relapse TheON-associated damage is not limited to theneuroaxonal content but can also inducemdashlikely inflammation-mediatedmdashINL increase and occurrence ofMMEOur data alsosuggest attack-independent retinal damage in AQP4-IgGndashseropositive NMOSD Our study supports that at-tack prevention is key in avoiding neuroaxonal damage andvision loss in patients with NMOSD It further suggests thatthe first ON episode causes the most damage where onlysome patients with then established diagnosis will be on im-munosuppressive therapy This highlights the need for ef-fective therapies that can ameliorate an ongoing attack orregenerate attack-generated damage which is an unmet clin-ical need Last the study emphasizes the utility of OCT as asensitive structural metric and its potential for monitoringprogression and even treatment response in AQP4-IgGndashseropositive NMOSD The international CROCTINOprogram provides an unprecedented opportunity to applyOCT in a standardized manner to assess pathophysiologyclinical course and therapeutic efficacy in NMOSD

Study FundingGuthy-Jackson Charitable Foundation (GJCF) and GermanResearch Foundation (DFG)

DisclosureFC Oertel was employee of Nocturne GmbH and receivesresearch support by the American Academy of Neurology andthe National Multiple Sclerosis Society unrelated to this work

S Specovius reports no disclosures HG Zimmerman reportsresearch grants from Novartis and speaking honoraria fromBayer Healthcare unrelated to this study C Chien reportsspeaking honoraria from Bayer Healthcare unrelated to thiswork S Motamedi and C Bereuter report no disclosures LCook reports grants from Guthy Jackson Charitable Founda-tion during the conduct of the study EH Martinez-Lapiscinais employed by the European Medicines Agency (HumanMedicines) since 16 April 2019 This article is related with heractivity under Hospital Clinic of BarcelonaIDIBAPS affiliationand consequently as external activity it does not represent theviews of the Agency its Committees or working parties Beforeenrolling EMA Dr Martinez-Lapiscina reports grants fromInstituto de Salud Carlos III (Spain) amp Fondo Europeo deDesarrollo Regional grants from MS Innovation GMSI otherfromFundacio Privada Cellex and personal fees fromNovartisRoche Sanofi-Genzyme outside the submitted work MALana Peixoto and MA Fontanelle report no disclosures HJKim reports grants from the National Research Foundation ofKorea personal fees from Alexion Pharmaceuticals AprilbioBiogen Celltrion Eisai HanAll BioPharma MDimune MerckSerono Novartis Sanofi Genzyme Teva-Handok and VielaBio other from Viela Bio (formerly MedImmune) MultipleSclerosis Journal and Journal of Clinical Neurology outsidethe submitted work J-W Hyun reports grants from the Na-tional Research Foundation of Korea outside the submittedwork J Palace reports personal fees from Abide TherapeuticsAlexion Pharmaceuticals ARGENX Bayer Schering BiogenIdec Chugai Pharma EuroImmun Genzyme MedDayMedImmuneMerck Serono Novartis Roche Teva UCB andViela Bio grants from Abide Therapeutics Alexion Pharma-ceuticals Bayer Schering Biogen Idec Chugai Pharma Gen-zyme MedImmune Merck Serono Novartis and Teva grantsfrom Merck Serono Novartis Biogen Idec Teva AbideMedImmune Bayer Schering Genzyme Chugai and AlexionEugene Devic European Network the Grant for MultipleSclerosis Innovation the John Fell Fund the Medical ResearchCouncil the MS Society Myaware the UK National Institutefor Health Research Oxford Health Services Research Com-mittee and theGuthy-JacksonCharitable Foundation AMPLOand SPARKS Great Ormond Street for research studies out-side the submitted work MI Leite and S Sharma report nodisclosures A Roca-Fernandez is sponsored by Abide Thera-peutic outside of the submitted work and reports no potentialconflicts of interest R Kafieh A Dehghani M Pourazizi LPandit and A DrsquoCunha report no disclosures O Aktas reportsgrants from German Research Foundation (DFG) and Ger-man Ministry of Education and Research (BMBF) personalfees from Alexion and Almirall grants and personal fees fromBiogen personal fees from Merck grants and personal feesfrom Novartis grants and personal fees from Roche personalfees from Sanofi personal fees from Teva personal fees fromViela Bio outside the submitted work M Ringelstein receivedspeaker honoraria from Novartis Bayer Vital GmbH RocheAlexion and Ipsen and travel reimbursement from BayerSchering Biogen Idec Merz Genzyme Teva Roche andMerck none related to this study P Albrecht reports grants

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 9

personal fees and non-financial support from Allergan BiogenMerck Merz Pharmaceuticals Novartis Ipsen CelgeneRoche and personal fees and non-financial support from Tevaoutside the submitted work E May and C Tongco report nodisclosures L Leocani reports personal fees from RocheMerck Bristol Myers Squibb andMed-ex learning outside thesubmitted work M Pisa reports no disclosures M Radaellireports personal fees from Merck Serono Sanofi-GenzymeNovartis and Biogen outside the submitted work H Stiebel-Kalish reports no disclosures S Siritho reports personal feesfromNovartis Thailand Biogen Idec Eisai Thailandmarketingco ltd Merck Serono Teva Thailand and Menarini outsidethe submitted work J de Seze and T Senger report no dis-closures J Havla reports grants personal fees and non-financialsupport from Merck personal fees from Novartis CelgeneRoche Santhera Biogen Alexion Sanofi non-financial supportfrom Guthy-Jackson Charitable Foundation and grants fromFriedrich Baur Foundation outside the submitted work RMarignier AC Calvo D Bichuetti IM Tavares N Asgari KSoelberg A Altintas R Yildirim U Tanriverdi A Jacob SHuda Z Rimler and A Reid report no disclosures Y Mao-Draayer reports grants from NIH NIAID grants and personalfees from Genzyme grants from Chugai personal fees fromBiogen and EMD Serono grants and personal fees fromGenentech and Novartis during the conduct of the studygrants from NIH NIAID grants and personal fees from Gen-zyme grants fromChugai personal fees fromBiogen and EMDSerono grants and personal fees fromGenentech andNovartisoutside the submitted work I Soto de Castillo reports nodisclosures A Petzold reports personal fees and grants fromNovartis outside the submitted work and is part of the steeringcommittee of the OCTiMS study which is sponsored byNovartis He has not received honoraria for this activity AJGreen reports other from Bionure grants personal fees andother from Inception Sciences grants from Sherak Foundationpersonal fees and other from Pipeline Pharmaceuticals grantsfrom Hilton Foundation Adelson Foundation and NationalMS Society personal fees from JAMANeurology personal feesand other from MediimmuneViela outside the submittedwork In addition Dr Green has a patent Small Molecule drugfor Remyelination pending and has worked on testing off labelcompounds for remyelination MR Yeaman serves as an ad-visor to the Guthy-Jackson Charitable Foundation T Smithreports no disclosures AU Brandt reports grants from theGuthy Jackson Charitable Foundation during the conduct ofthe study shares from Motognosis GmbH and shares fromNocturne GmbH outside the submitted work In addition DrBrandt has a patent pending describing Foveal MorphometryF Paul reports grants from the Guthy Jackson CharitableFoundation during the conduct of the study grants from theGerman Research Foundation andGerman FederalMinistry ofEducation and research grants and other fromNovartis grantsand other from Bayer Novartis Biogen Idec Teva Sanofi-AventisGenzyme Merck Serono Chugai other from PLoSONE other from Neurologyreg Neuroimmunology amp Neuro-inflammation other from SanofiGenzyme Biogen Idec grantsfrom German Research Council Werth Stiftung of the City of

Cologne German Ministry of Education and Research ArthurArnstein Stiftung Berlin EU FP7 Framework Program ArthurArnstein Foundation Berlin National Multiple Sclerosis(USA) other from MedImmune Shire Alexion outside thesubmitted work In addition Dr Paul has a patent FovealMorphometry pending to Nocturne GmbH Go to NeurologyorgNN for full disclosures

Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationMarch 23 2021 Accepted in final form June 15 2021

Appendix Authors

Name Location Contribution

Frederike CosimaOertel MDPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data anddrafting a significantportion of themanuscript or figuresconception and designof the study

Svenja SpecoviusMSc

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of dataconception and designof the study

Hanna GZimmermannPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of dataconception and designof the study

Claudia ChienPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

SeyedamirhoseinMotamedi PhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

CharlotteBereuter BSc

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

Appendix (continued)

Name Location Contribution

Lawrence CookPhD

University of UtahSalt Lake City UT

Acquisition andanalysis of data andconception and designof the study

Marco AurelioLana Peixoto MDPhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Mariana AndradeFontanelle MD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Ho Jin Kim MDPhD

National Cancer CenterGoyang Republic of Korea

Acquisition andanalysis of data

Jae-Won HyunMD PhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

JacquelinePalace MD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Adriana Roca-Fernandez MSc

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Maria IsabelLeite MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

SrilakshmiSharma MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

FereshtehAshtari MD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Rahele KafiehPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Alireza DehghaniPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

MohsenPourazizi PhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Lekha PanditMD PhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Anitha DrsquoCunhaPhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Orhan Aktas MD Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

MariusRingelstein MD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Philipp AlbrechtMD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Eugene May MD Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Caryl Tongco Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Appendix (continued)

Name Location Contribution

Letizia LeocaniMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marco Pisa MD Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marta RadaelliMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Elena H Martinez-Lapiscina MDPhD

Hospital Clinic of Barcelona-Institut drsquoInvestigacionsBiomediques August PiSunyer Barcelona Spain

Acquisition andanalysis of data

Hadas Stiebel-Kalish MD

Sackler School of MedicineTel Aviv University Tel AvivIsrael

Acquisition andanalysis of data

Sasitorn SirithoMD

Siriraj Hospital andBumrungrad InternationalHospital Bangkok Thailand

Acquisition andanalysis of data

Jerome de SezeMD PhD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Thomas SengerMD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Joachim HavlaMD

Ludwig-MaximiliansUniversitat MuenchenMunich Germany

Acquisition andanalysis of data

RomainMarignier MDPhD

Pierre Wertheimer NeurologicalHospital Hospices Civils deLyon France

Acquisition andanalysis of data

Alvaro CoboCalvo MD PhD

Pierre WertheimerNeurological HospitalHospices Civils de LyonFrance Hospital UniversitariVall drsquoHebron UniversitatAutonoma de BarcelonaSpain

Acquisition andanalysis of data

Denis BichuettiMD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Ivan MaynartTavares MD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Nasrin AsgariMD PhD

University of SouthernDenmark OdenseDenmark

Acquisition andanalysis of data

Kerstin SoelbergMD

University of SouthernDenmark Odense Denmark

Acquisition andanalysis of data

Ayse Altintas MD Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Rengin YildirimMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 11

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9 Specovius S Zimmermann HG Oertel FC et al Cohort profile a collaborativemulticentre study of retinal optical coherence tomography in 539 patients withneuromyelitis optica spectrum disorders (CROCTINO) BMJ Open 202010(10)e035397

10 Motamedi S Gawlik K Ayadi N et al Normative data and minimally detectablechange for inner retinal layer thicknesses using a semi-automated OCT image seg-mentation pipeline Front Neurol 2019101117

11 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177-189

12 von Elm E Altman DG Egger M et al The strengthening the reporting of obser-vational studies in epidemiology (STROBE) statement guidelines for reportingobservational studies Int J Surg 201412(12)1495-1499

13 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PLoS One 20127(4)e34823

14 Schippling S Balk LJ Costello F et al Quality control for retinal OCT in multiplesclerosis validation of the OSCAR-IB criteria Mult Scler 201521(2)163-170

15 Lang A Carass A Hauser M et al Retinal layer segmentation of macular OCT imagesusing boundary classification Biomed Opt Express 20134(7)1133-1152

16 R Development Core Team R A Language and Environment for Statistical Computing[online] R Foundation for Statistical Computing 2008 R-projectorg

17 Akaishi T Kaneko K Himori N et al Subclinical retinal atrophy in the unaffectedfellow eyes of multiple sclerosis and neuromyelitis optica [online serial]J Neuroimmunol 201731310-15 Accessed October 8 2017 jni-journalcomarticleS0165-5728(17)30319-3fulltext

18 Alshowaeir D Yiannikas C Fraser C Klistorner A Mechanism of delayed con-duction of fellow eyes in patients with optic neuritis Int J Ophthalmol 201811(2)329-332

19 Manogaran P Traboulsee AL Lange AP Longitudinal study of retinal nerve fiberlayer thickness and macular volume in patients with neuromyelitis optica spectrumdisorder J Neuroophthalmol 201636(4)363-368

20 Kaufhold F ZimmermannH Schneider E et al Optic neuritis is associated with innernuclear layer thickening and microcystic macular edema independently of multiplesclerosis PLoS One 20138(8)e71145

21 Knier B Schmidt P Aly L et al Retinal inner nuclear layer volume reflects response toimmunotherapy in multiple sclerosis Brain 2016139(11)2855-2863

22 Petzold A Balcer LJ Calabresi PA et al Retinal layer segmentation in multiplesclerosis a systematic review and meta-analysis Lancet Neurol 201716(10)797-812

23 Pawlitzki M Horbrugger M Loewe K et al MS optic neuritis-induced long-termstructural changes within the visual pathway Neurol Neuroimmunol Neuroinflamm20207(2)e665

24 Pache F Zimmermann H Mikolajczak J et al MOG-IgG in NMO and relateddisorders a multicenter study of 50 patients Part 4 afferent visual system damageafter optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patientsJ Neuroinflammation 201613(1)282

25 Filippatou AG Vasileiou ES He Y et al Evidence of subclinical quantitative retinallayer abnormalities in AQP4-IgG seropositive NMOSD Mult Scler 2020 Dec 141352458520977771 doi 1011771352458520977771

26 Motamedi S Oertel FC Yadav SK et al Altered fovea in AQP4-IgGndashseropositiveneuromyelitis optica spectrum disorders Neurol Neuroimmunol Neuroinflamm 20207(5)e805

27 Roca-Fernandez A Oertel FC Yeo T et al Foveal changes in AQP4-Ab seropositiveNMOSD are independent of optic neuritis and not overtly progressive Eur J Neurol202128(7)2280-2293

28 Papadopoulou A Oertel FC Chien C et al Lateral geniculate nucleus volumechanges after optic neuritis in neuromyelitis optica a longitudinal study NeuroimageClin 202130102608

29 Ringelstein M Harmel J Zimmermann H et al Longitudinal optic neuritis-unrelatedvisual evoked potential changes in NMO spectrum disorders Neurology 202094(4)e407-e418

30 Pache F Zimmermann H Finke C et al Brain parenchymal damage in neuromyelitisoptica spectrum disorderndasha multimodal MRI study Eur Radiol 201626(12)4413-4422

31 Hokari M Yokoseki A Arakawa M et al Clinicopathological features in anteriorvisual pathway in neuromyelitis optica Ann Neurol 201679(4)605-624

32 You Y Zhu L Zhang T et al Evidence of muller glial dysfunction in patients withaquaporin-4 immunoglobulin Gndashpositive neuromyelitis optica spectrum disorderOphthalmology 2019126(6)801-810 Elsevier

33 Chien C Scheel M Schmitz-Hubsch T et al Spinal cord lesions and atrophy inNMOSD with AQP4-IgG and MOG-IgG associated autoimmunityMult Scler 201925(14)1926-1936

34 Felix CM Levin MH Verkman AS Complement-independent retinal pathologyproduced by intravitreal injection of neuromyelitis optica immunoglobulin GJ Neuroinflammation 201613(1)275

35 Balk LJ Coric D Knier B et al Retinal inner nuclear layer volume reflects in-flammatory disease activity in multiple sclerosis a longitudinal OCT studyMult SclerJ Exp Transl Clin 20195(3)2055217319871582

36 Gelfand JM Nolan R Schwartz DM Graves J Green AJ Microcystic macular oedemain multiple sclerosis is associated with disease severity Brain 2012135(pt 6)1786-1793

Appendix (continued)

Name Location Contribution

Uygur TanriverdiMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Anu Jacob MD The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Saif Huda MDPhD

The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Zoe Rimler BSc NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Allyson Reid MD NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Yang Mao-Draayer MD PhD

University of MichiganMedical School AnnArbor MI

Acquisition andanalysis of data

Ibis Soto deCastillo MD

Hospital Clınico deMaracaibo MaracaiboVenezuela

Acquisition andanalysis of data

Axel Petzold MDPhD

University College LondonLondon UK

Conception anddesign of the study

Ari J Green MD University of California SanFrancisco CA

Conception anddesign of the study

Michael RYeaman MD PhD

University of California LosAngeles CA

Conception anddesign of the study

Terry Smith MD University of MichiganMedical School AnnArbor MI

Conception anddesign of the study

Alexander UBrandt MD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinBerlin Berlin Germany

Acquisition andanalysis of dataconception and designof the study anddrafting a significantportion of themanuscript or figures

Friedemann PaulMD

CharitendashUniversitatsmedizinBerlin Corporate Member ofFreie Universitat Berlin andHumboldt-Universitat zuBerlin

Acquisition andanalysis of data andconception and designof the study

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

37 Gelfand JM Cree BA Nolan R Arnow S Green AJ Microcystic inner nuclear layerabnormalities and neuromyelitis optica JAMA Neurol 201370(5)629-633

38 Oberwahrenbrock T WeinholdMMikolajczak J et al Reliability of intra-retinal layerthickness estimates PLoS One 201510(9)e0137316

39 Borisow N Kleiter I Gahlen A et al Influence of female sex and fertile age onneuromyelitis optica spectrum disorders Mult Scler 201723(8)1092-1103

40 Mori M Kuwabara S Paul F Worldwide prevalence of neuromyelitis optica spectrumdisorders J Neurol Neurosurg Psychiatry 201889(6)555-556

41 Oertel FC Paul F Accelerating clinical research in neuromyelitis optica spectrumdisorders [online serial] Clin Exp Neuroimmunol 202112(2)89-91 AccessedMarch 28 2021 periclespericles-prodliteratumonlinecomdoiabs101111cen312637

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 13

DOI 101212NXI000000000000106820218 Neurol Neuroimmunol Neuroinflamm

Frederike Cosima Oertel Svenja Specovius Hanna G Zimmermann et al Retinal Optical Coherence Tomography in Neuromyelitis Optica

This information is current as of September 15 2021

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Page 3: Retinal Optical Coherence Tomography in Neuromyelitis Optica

exclusion criteria are depicted in eFigure 1 linkslwwcomNXIA556 AQP4-IgG testing was performed at the discre-tion of each investigator

Standard Protocol Approvals Registrationsand Patient ConsentsAll participants gave written informed consent and the studywas approved by local ethics committees and conducted inaccordance with the applicable laws and the current version ofthe Declaration of Helsinki Data are reported according toSTROBE reporting guidelines12

OCTHigh-resolution imaging data were acquired using 3 differ-ent spectral domain OCT devices Spectralis SD-OCT(Heidelberg Engineering Heidelberg Germany) at 15 cen-ters (194 patients358 eyes 72 healthy controls [HCs]136eyes) Cirrus HD-OCT (Carl Zeiss Meditec Dublin CA) at6 centers (58 patients87 eyes) or Topcon 3D OCT-1(Topcon Tokyo Japan) at 1 center (31 patients56 eyes)All reading of OCT data was performed at CharitendashUniversitatsmedizin Berlin Translational Neuroimaging Groupby 5 graders Image quality was assessed using modifiedOSCAR-IB criteria by one of the graders respectively1314

OCT segmentation for the combined ganglion cell and innerplexiform (GCIP) layer and inner nuclear layer (INL) thick-nesses was corrected semi-automatically using an in-housesoftware1015 In brief GCIP layer and INL thicknesses werecalculated from a 5-mm diameter cylinder around the foveaexcluding the central 1-mm diameter cylinder from a macularvolume scan10 The peripapillary retinal nerve fiber layer(pRNFL) thickness was measured and corrected according tothe device protocol (Spectralis peripapillary ring scan with12deg or approximately 34 mm diameter around the optic discTopcon and Cirrus extraction from optic disc volume scan)For the current analysis eyes were excluded from the analysisif neither ring nor macular scan passed quality control Wefurther excluded data from the less common instrument for 1center The final cohort included 364 macular and 481 per-ipapillary scans of 501 eyes from 283 patients and 136 eyesfrom 72 HCs Lower numbers of macular scans comparedwith peripapillary scans were due to both lower submissionof macular data and more exclusions based on qualityconcerns

Visual and Global Function TestingHigh-contrast visual acuity (HC-VA) was available for 497(992) patient and 10 (139) HC eyes HC-VA was bestcorrected for 212 (423) patient and 56 (412) HC eyeshabitually corrected for 145 (289) patient and 2 (lt01)HC eyes and without correction for 140 (279) patient eyesand 17 (13) HC eyes All VA data are reported as logMARVA measurement method was decided on discretion of eachcenter Visually evoked potentials (VEPs) were available for167 (333) patient eyes and 40 (294) HC eyes with P100latency recorded as a binary value (normalprolonged) Ex-panded Disability Status Scale (EDSS) scores were de-termined at the discretion of each center with data availablefor 180 (636) patients

Statistical AnalysisStatistical analyses were performed with R version 361using RStudio and R Markdown (RStudio Inc BostonMA)16 p Values less than 005 were considered significantWe considered p values less than 010 a trend Groupmatching by age and sex for confirmatory analyses wasperformed using automatic matching by R package MatchIt(method exact) Group comparisons and correlations ofOCT and VA values were performed using linear mixed-

Table 1 Cohort Description for AQP4-IgGndashSeropositivePatients With NMOSD and HCs

AQP4-IgGndashseropositiveNMOSD HC

Subjects (N) 283 72

Eyes (N) 501 136

Sex (malefemale NN []) 28255 (99901) 2646 (361639)

Age (y mean plusmn SD) 441 plusmn 142 309 plusmn 77

Ethnicity (N [])

Asian 77 (272) 16 (222)

BlackAfrican American 13 (46) 0 (0)

White HispanicLatino 4 (14) 1 (14)

White Non-Hispanic 159 (562) 55 (764)

Othernonreported 30 (106) 0 (0)

Disease-modifying therapy (N[])

Rituximab 73 (258)

Azathioprine 67 (237)

Oral prednisolone 53 (187)

Mycophenolate mofetil 48 (170)

Methotrexate 8 (28)

Time since onset (y mean plusmn SD) 72 plusmn 67

EDSS score (median [IQR]) 35 (20ndash45)

Patients with a clinical history ofON (N [])

204 (721)

Eyes with a clinical history of ON(N [])

260 (52)

No of ON episodeseye (Nmedian [minndashmax])

1 (1ndash6)

Time since last ON (mo mean plusmnSD)

71 plusmn 57

Abbreviations AQP4-IgG = aquaporin-4 antibodies NMOSD = neuromyelitisoptica spectrum disorder HC = healthy control N = number OCT = opticalcoherence tomography ON = optic neuritis episodeAge (p lt 00001) and sex (p lt 00001) were not matched

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 3

effect models Intereye within-subject effects and effects ofthe center were included as random effects Sex ethnicityand age were included as fixed effects for the analyses in theentire cohort Age and sex were not included for thematched subset For OCT parameters the model was usedfor data from all devices separately and combined by Fishercombined probability test The marginal and conditionalcoefficients of determination of the linear models werecalculated with pseudo R-squared All results are reported

combined and individually for Spectralis SD-OCT theanalyses of data acquired by Cirrus HD-OCT or Topcon3D OCT-1 and for the matched subset are reported asonline-only supplement

Data AvailabilityThe data supporting the findings of this study are availablewithin the article and from the corresponding author byreasonable request

Figure 1 Group Comparisons of GCIP Layer Thickness

Boxplots of GCIP layer thicknesses (μm) acquired by Heidelberg SD-OCT with values of individual eyes (jitter) for (A) HC (grayleft) NMOSD-NON(dark bluemiddle) NMOSD-ON (dark redright) for (B) number of ON episodes (NMOSD-NON dark blueleft NMOSD-1-ON light redleft-middleNMOSD-2-ON medium-redright-middle NMOSD-ge3-ON medium-dark redright) and for (C) HC (grayleft) NMOSD-NONnon (light bluemiddle)NMOSD-NONcon (blueright) (D) Forest plots for results from different OCT devices for (Da) NMOSD-NON vs NMOSD-ON (Db) NMOSD-NON vsNMOSD-1-ON and (Dc) NMOSD-1-ON vs NMOSD-2-ON (eFigure 2 and eTable 2 linkslwwcomNXIA556 and linkslwwcomNXIA557) GCIP =ganglion cell and inner plexiform HC = eyes of HCs NMOSD-NON = eyes of patients with neuromyelitis optica without a history of ON NMOSD-NON-con =eyes of patients with neuromyelitis optica without a history of ON but a history of contralateral ON NMOSD-NONnon = eyes of patients withneuromyelitis optica without a history of ipsilateral or contralateral ON NMOSD-ON = eyes of patients with neuromyelitis optica with a history ofON NMOSD-1-ON = eyes of patients with neuromyelitis optica with a history of 1 ON episode NMOSD-2-ON = eyes of patients with neuromyelitisoptica with a history of 2 ON episodes ON = optic neuritis

4 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

ResultsFive hundred one eyes of 283 AQP4-IgGndashseropositive pa-tients and 136 eyes of 72 HCs were included in the analysis(Table 1)

Neuroaxonal Damage After ONGCIP layer and pRNFL were reduced in NMOSD-ONcompared with NMOSD eyes without a history of ON

(NMOSD-NON) and HC (GCIP layer 814 plusmn 57 μmpRNFL 1011 plusmn 90 μm) (Figures 1A and 2A Tables 2 and3) The absolute (GCIP layer minus227 μm pRNFL minus385 μm)and relative (GCIP layer minus388 pRNFL minus616) loss ineyes with 1 ON episode (NMOSD-1-ON) compared withNMOSD-NON was higher than in eyes with 2 ON episodes(NMOSD-2-ON) compared with NMOSD-1-ON (GCIPlayer absolute loss minus35 μm relative loss minus60 pRNFLabsolute loss minus91 μm relative loss minus145 ns) The loss in

Figure 2 Group Comparisons of pRNFL Thickness

Boxplots of pRNFL thicknesses acquired by Heidelberg SD-OCT [μm] with values of individual eyes (jitter) for (A) HC (grayleft) NMOSD-NON (dark bluemiddle) and NMOSD-ON (dark redright) for (B) number of ON episodes (NMOSD-NON dark blueleft NMOSD-1-ON light redleft-middle NMOSD-2-ONmedium-redright-middle and NMOSD-ge3-ON medium-dark redright) and for (C) HC (grayleft) NMOSD-NONnon (light bluemiddle) and NMOSD-NONcon

(blueright) (D) Forest plots for results from different OCT devices for (Da) NMOSD-NON vs NMOSD-ON (Db) NMOSD-NON vs NMOSD-1-ON and (Dc)NMOSD-1-ON vs NMOSD-2-ON (eFigure 3 and eTable 3 linkslwwcomNXIA556 and linkslwwcomNXIA557) HC = eyes of HCs NMOSD-NON = eyes ofpatients with neuromyelitis optica without a history of optic neuritis NMOSD-NON-con = eyes of patients with neuromyelitis optica without a history of opticneuritis but a history of contralateral optic neuritis NMOSD-NONnon = eyes of patients with neuromyelitis optica without a history of ipsilateral or contra-lateral optic neuritis NMOSD-ON = eyes of patients with neuromyelitis optica with a history of optic neuritis NMOSD-1-ON = eyes of patients withneuromyelitis optica with a history of 1 optic neuritis episode NMOSD-2-ON = eyes of patients with neuromyelitis optica with a history of 2 optic neuritisepisodes ON = optic neuritis pRNFL = peripapillary retinal nerve fiber layer

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 5

eyes with ge3-ON episodes (NMOSD-3-ON) was lowercompared with NMOSD-2-ON (ns) (Figures 1B and 2B)Five NMOSD-NON eyes had pRNFL values lt 60 μm thesepatients had no relevant comorbidities but a history of con-tralateral ON1718 In sensitivity analyses to account for devicedifferences all significant analyses within the NMOSD cohortwere confirmed for data acquired by Cirrus and Topcon OCTdevices (eFigures 2 and 3 eTables 3 and 4 linkslwwcomNXIA556 linkslwwcomNXIA557)

Neuroaxonal Damage Without ONNMOSD-NON eyes had a reduced GCIP layer (759 plusmn 77 μmplt 0001) but not pRNFL (953 plusmn 144 μm) comparedwithHC(GCIP layer 814 plusmn 57 μm pRNFL 1011 plusmn 90 μm Figures 1Aand 2A Tables 2 and 3) By comparison only 28 NMOSD-NON eyes (51) had a GCIP layer le the 5th percentile of HCGCIP layer was also reduced inNMOSD-NONwith a history ofcontralateral ON (729 plusmn 102 μm) compared with NMOSD-NON without a history of contralateral ON (773 plusmn 59 μm p =0025 NMOSD-NONnon) This effect vanished when onlyconsidering NMOSD-NONcon with a history of 1 contralateralON (736 plusmn 94 μm) However only NMOSD-NONcon (p lt

0001) but not NMOSD-NONnon (p = 0061) had thinnedGCIP layer compared with HC (Figures 1C and 2C)

INL ChangesINL was thicker in NMOSD-ON compared with HC (394 plusmn26 μm) and NMOSD-NON (eTable 4 linkslwwcomNXIA557) Specifically INL was thicker in eyes with 1 ON episodecompared with NMOSD-NON but did not differ between eyeswith different numbers of ON episodes Also INL did not differbetween NMOSD-NONcon (389 plusmn 32 μm) and NMOSD-NONnon (385 plusmn 32 μm p = 0931) In all patients INLthickness (as the dependent variable in the linear mixed modeldescribed above) was correlated with thinner GCIP layer (B =minus011 standard error [SE] = 001 p lt 0001) and pRNFL (B =minus006 SE = 001 p lt 0001) This correlation existed inNMOSD-ON (GCIP layer B = minus 008 SE = 003 p = 0005pRNFL B = minus 006 SE = 001 p lt 0001) and not present inNMOSD-NON (eFigure 4 linkslwwcomNXIA556)

Scans of 363 NMOSD eyes were clearly suitable for MMEinvestigations (high quality eFigure 4C linkslwwcomNXIA556) MMEs were visible in 24 (66) eyes of 21 patients

Table 2 Group Comparisons of GCIP Layer Thickness for Heidelberg SD-OCT

No ofeyes

Thickness (μmmean plusmn SD)

Comparisonto

Absolutedifference (μmmean)

Relativedifference (mean) B SE p Value R2

marg R2cond

Combinedp value

NMOSD 268 673 plusmn 136 HCs minus140 minus208 156 20 lt00001 0143 0690 mdash

NMOSD-ON

124 574 plusmn 122 minus240 minus418 250 20 lt00001 0482 0839 mdash

NMOSD-NON

144 759 plusmn 77 minus54 minus72 58 14 lt00001 0088 0947 mdash

NMOSD-NONnon

99 773 plusmn 59 minus40 minus50 269 142 0061 0189 0924 mdash

NMOSD-NONcon

45 729 plusmn 102 minus85 minus104 844 177 lt00001 0260 0985 mdash

NMOSD-ON

124 574 plusmn 122 NMOSD-NON

minus185 minus244 minus158 11 lt00001 0430 0795 59e245

NMOSD-1-ON

76 586 plusmn 129 minus173 minus228 minus145 12 lt00001 0417 0803 14e233

NMOSD-2-ON

28 551 plusmn 94 NMOSD-1-ON

minus35 minus60 minus57 26 0028 0143 0729 0038

NMOSD-ge3-ON

20 559 plusmn 128 NMOSD-2-ON

08 14 49 26 0070 0311 0781 0222

NMOSD-NONcon

45 729 plusmn 102 NMOSD-NONnon

minus44 minus61 minus38 17 0025 0111 0701 0004

NMOSD-NON1-con

37 736 plusmn 94 minus37 minus51 minus35 16 0037 0149 0906 0154

Abbreviations AQP4-IgG = aquaporin-4 IgG B = estimate GCIP = ganglion cell and inner plexiformNMOSD=AQP4-IgGndashseropositiveNMOSD NMOSD-NON=AQP4-IgGndashseropositive NMOSD eyeswithout a history of ON NMOSD-NONnon = AQP4-IgGndashseropositive NMOSD eyeswithout a history ofONor contralateralON NMOSD-NONcon = AQP4-IgGndashseropositive NMOSD eyes without a history of ON but with a history of contralateral ON NMOSD-NON1-con = AQP4-IgGndashseropositive NMOSD eyes without a history of ON but with a history of 1 contralateral ON NMOSD-ON = AQP4-IgGndashseropositive NMOSD eyes with ahistory of ON NMOSD-1-ON =AQP4-IgGndashseropositive NMOSD eyeswith a history of 1ON NMO-2-ON =AQP4-IgGndashseropositive NMOSD eyeswith a history of2 ONs NMOSD-ge3-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 3 or more ONs NMOSD = neuromyelitis optica spectrum disorder NMOSD-NON = NMOSD eyes without a history of ON OCT = optical coherence tomography ON = optic neuritis episode Rcon = conditional R-squared Rmarg =marginal R-squared SE = standard error

6 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

Twenty-three eyes (131) of NMOSD-ON and 1 eye (05)of NMOSD-NON (with a history of contralateral ON) wereaffected The number of ON episodes did not influence theincidence of MMEs (NMOSD-1-ONN = 16 (14) NMOSD-2-ON N = 4 (114) NMOSD-ge3-ON N = 3 (111))

Including only the most frequent ethnicities in our data set(Asian and non-HispanicWhite) results did not differ and noethnicity was singled out regarding its pattern of injury (datanot shown)

OCT and Vision LossHC-VA was numerically reduced in NMOSD (025 plusmn 048)compared with HC (minus001 plusmn 008) and known healthy referencevalues NMOSD-ON also had reduced HC-VA (044 plusmn 058)compared with NMOSD-NON (004 plusmn 020 p lt 0001 p =0401) and HChealthy reference populations HC-VA wascorrelated with GCIP layer (B = minus0016 SE = 0002 p lt 0001)and pRNFL thicknesses (B = minus0010 SE = 0001 p lt 0001) inAQP4-IgGndashseropositive NMOSD AQP4-IgGndashseropositiveNMOSD eyes with prolonged VEP latency had a thinned GCIP

layer (B = minus11647 SE = 3628 p = 0002) and pRNFL (B =minus21965 SE = 3724 p lt 0001) EDSS score as ametric of globaldisability was inversely correlated with GCIP layer (B = minus1370SE= 0566 p= 0017) and pRNFL thicknesses (B= minus3148 SE=1080 p = 0004)

DiscussionOur study specifies a severe and functionally relevant decreaseof GCIP layer and pRNFL in NMOSD-ON compared withNMOSD-NON and HCs in AQP4-IgGndashseropositive pa-tients Neuroaxonal damage is particularly large from the firstepisode of ON where contribution to retinal damage insubsequent episodes of ON is still considerable but smaller Incontrast to previous smaller studies the current study ascer-tains GCIP layer but not pRNFL thinning in NMOSD-NONcompared with HC619 This effect was driven by eyes withcontralateral ON and not statistically significant in eyeswithout a history of ON INL was thicker in NMOSD-ONand was inversely correlated with GCIP layer Of note 131

Table 3 GroupComparisons of pRNFL ThicknessWith (A) Spectralis SD-OCTData for Comparisons vsHC (B) Data FromAllDevices for Intrapatient Cohort Comparisons

No ofeyes

Thickness (μmmean plusmn SD)

Comparisonto

Absolute difference(μm mean)

Relativedifference (mean) B SE p Value R2

marg R2cond

Combinedp value

NMOSD 344 763 plusmn 274 HCs minus140 minus326 242 43 lt00001 0143 0690 mdash

NMOSD-ON

170 569 plusmn 237 minus443 minus779 431 41 lt00001 0482 0839 mdash

NMOSD-NON

174 953 plusmn 144 minus59 minus62 46 30 0129 0088 0947 mdash

NMOSD-NONnon

116 974 plusmn 109 minus37 minus37 minus29 22 0204 0107 0893 mdash

NMOSD-NONcon

58 910 plusmn 191 minus47 minus46 71 42 0097 0100 0975 mdash

NMOSD-ON

170 569 plusmn 237 NMOSD-NON

minus384 minus403 minus338 21 lt00001 0436 0741 44e260

NMOSD-1-ON

97 626 plusmn 249 minus327 minus343 minus296 22 lt00001 0379 0712 46e240

NMOSD-2-ON

35 535 plusmn 213 NMOSD-1-ON

minus91 minus145 minus107 47 0024 0087 0528 0010

NMOSD-ge3-ON

38 452 plusmn 178 NMOSD-2-ON

minus83 minus155 minus04 43 0924 0087 0719 0838

NMOSD-NONcon

58 910 plusmn 191 NMOSD-NONnon

minus65 minus71 minus40 29 0173 0061 0939 0157

NMOSD-NON1-con

47 932 plusmn 181 minus42 minus46 minus32 29 0276 0056 0925 0616

Abbreviations AQP4-IgG = aquaporin-4 IgG NMOSD = AQP4-IgGndashseropositive NMOSD NMOSD-NON = AQP4-IgGndashseropositive NMOSD eyes without ahistory of ON NMOSD-NONnon = AQP4-IgGndashseropositive NMOSD eyes without a history of ON or contralateral ON NMOSD-NONcon = AQP4-IgGndashseropositive NMOSD eyes without a history of ON but with a history of contralateral ON NMOSD-NONcon = AQP4-IgGndashseropositive NMOSD eyes without ahistory of ON but with a history of 1 contralateral ON NMOSD-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of ON NMOSD-1-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 1 ON NMOSD-2-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 2 ONs NMOSD-ge3-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 3 or more ONs NMOSD = neuromyelitis optica spectrum disorder NMOSD-NON = NMOSD eyes without ahistory of ON OCT = optical coherence tomography ON = optic neuritis episode pRNFL = peripapillary retinal nerve fiber layer VEP = visually evokedpotential

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 7

of NMOSD-ON eyes showed MME indicative of secondaryinflammatory changes2021 This investigation overcame limitsof small samples and OCT data heterogeneity of earlierstudies through use of an international consortium ofNMOSD specialists This framework substantiated theCROCTINO studymdasha large multicenter retrospectiveevaluation of retinal pathology in NMOSD using OCT

The neuroaxonal degeneration in NMOSD-ON demon-strated here is substantially greater than reported changes inmultiple sclerosis (MS) a common differential diagnosis222

In a meta-analysis an average pRNFL loss of 20 μm wasestimated in MS after ON which is nearly 2-fold higher in ourNMOSD-ON cohort (minus384 μm)22 For GCIP layer our datasuggested approximately 15-fold higher loss in NMOSD(minus240 μm) compared with MS22 These differences not onlyresult from a higher ON frequency but may also be caused bymore severe retinal damage in NMOSD after a singular ON23

It is intriguing that the damage is particularly large after thefirst ON episode with smaller losses after subsequent epi-sodes which might be due to less neuroaxonal content insubsequent episodes224 Alternatively although the analysisof treatment effects exceeds the scope of this study it ispossible that the longer time to effective anti-inflammatorytherapy and the typical choice of less effective therapies (egsteroids instead of plasma exchange) at the first attack com-pared with following attacks may significantly contribute tothis difference Independent of the number of ONs the per-cent loss is smaller in GCIP layer compared with pRNFLndashpointing toward either (1) stronger loss of retinal nerve fibersthan retinal ganglion cells (2) impairment of ganglion cellsnot leading to extinction but axonal loss (3) a larger amountof non-neuronal tissue in GCIP layer or (4) RNFL loss in theperiphery beyond the macular area measured by GCIP layerThese hypotheses are not mutually exclusive and each mightcontribute to the effect Consistent with these concepts ex-cessive vision loss relative to neuroaxonal content and VEPlatency in AQP4-IgGndashseropositive patients compared withMOG-IgGndashseropositive and MS patients implies damage ofthe peripheral retina and optic nerve tissues which are notreflected in the macula and pattern VEP measurements4

Whether attack-independent neurodegeneration inAQP4-IgGndashseropositive NMOSD occurs has beencontroversial26725-28 The current study identifies de-creased GCIP layer in NMOSD-NON compared withHC but not pRNFL Such subclinical changes could becaused by contralateral involvement after unilateralON1718 Indeed our cohort suggests pronounced neu-rodegeneration in eyes with contralateral ON Howevereyes of patients without ON also exhibit a trend for thinnerGCIP layer compared with HCs Underscored by longitu-dinal studies showing ON-independent neurodegenerationand VEP latency prolongation729 such patterns suggest atleast 2 mechanisms of injury (1) a primary retinopathy oroptic neuropathy in context of an astrocytopathy or causedby direct damage to AQP4-expressing cells such as astrocytes

and Muller cells by either AQP4-IgG or AQP4-specificT cells or (2) a global or afferent visual system specificchronic or episodic neurodegenerative process Because le-sions often spare the brain and most studies outside ofpredisposed areas such as optic nerve and spinal cord failedto detect effects30 a constant global involvement seemsunlikely Several studies described changes affecting AQP4expression and astrocytic end feet31 parafoveal changes inagreement with an involvement of AQP4-expressing Mullercell6262732 and attack-independent spinal cord atrophy33

These findings are consistent with tissue infiltration byAQP4-IgGndashspecific T cells34 and the attack-independentloss of retinal ganglion cells7mdashfurther supporting the exis-tence of an ON-independent pathology which might berestricted to the main disease foci The latter hypothesescould be addressed by region-specific pathology or advancedimaging studies

INL changes have been suggested as a marker of neuro-inflammation and potential treatment response in MS213536

MME may develop as a consequence of neurodegenerationor othermdashnonndashdisease-specificmdashprocesses35 Patients withNMOSD were described to have INL thickening andMME2037 In our cohort 131 of NMOSD-ON eyes wereaffected byMME which is higher than the 2ndash5 described inMS but comparable to incidences in NMOSD described beforeby Gelfand and colleagues3537 However INL thickening itselfremained comparable to changes reported in MS35 This dis-parity could reflect a disrupted fluid homeostasis due to Mullercell involvement or loss of content of the INL with a parallelinflammatory reaction and development of MME The limitedaccessibility of MMEs especially in severely affected eyes due tolimited image quality has hindered their detailed assessmentsand most likely leads to underestimation of their incidence38

We demonstrate that the INL thickness is inversely correlatedwith neuroaxonal content and could be a valuable marker ofdisease severity also in NMOSD

Our study cohort was representative of patients with AQP4-IgGndashseropositive NMOSD with respect to a female pre-dominance and ON history1139 This OCT study includedmultiple ethnicity backgrounds although the distribution wasshifted toward CaucasianWhite patients and other ethnic-ities were underrepresented (eg Hispanic White and Black)limiting the generalizability of results40 Patients from differ-ent heritages presented similar findings

The current study was based on source data instead of a meta-analysis Using the Guthy-Jackson Charitable Foundation net-work this multicentric study was conducted without investigatorreimbursement and illustrated how collaboration integratinginternational perspectives can produce meaningful results Toovercome technical challenges of heterogeneous source data wedeveloped novel OCT postprocessing techniques allowing us toperform standardized analyses and enabling the uniform analysisof the largest OCT image data set in NMOSD to date10 Thusthe strengths of CROCTINO include its established

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

infrastructure large international network of experts represent-ing multiple ethnicities and geographic regions and the use ofstate-of-the-art OCT postprocessing techniques41

We recognize limitations of the current investigation Theretrospective and heterogeneous data acquisition might haveled to biases and impreciseness beyond the ability of ourquality control We addressed this by excluding uncertaincases HCs were only included from a limited number ofcenters The unbalanced data set limited some analyses suchas the influence of ethnicities or acute and disease-modifyingtreatments Case-control matching was impossible particu-larly with respect to subclinical progression dependent orindependent of ON and to ethnicity Similarly comparisonswith other NMOSD subtypes or MS were beyond the scopeof this study Longitudinal data acute ON data and AQP4-IgGndashseronegative and MOG-IgGndashseropositive patient dataare part of the CROCTINO data set and will be analyzed inthe future Also OCT data processing was performed bymultiple raters potentially introducing interrater variabilityMRI data and posterior visual pathway involvement were notinvestigated in this study However the current study ach-ieved an unprecedented worldwide assessment of retinaldamage in AQP4-IgGndashseropositive NMOSD

To conclude AQP4-IgGndashseropositive NMOSD is characterizedby a severe functionally relevant retinal neurodegeneration as aconsequence of ON Although the majority of damage occursduring the first episode there is cumulative loss with each suc-ceeding relapse TheON-associated damage is not limited to theneuroaxonal content but can also inducemdashlikely inflammation-mediatedmdashINL increase and occurrence ofMMEOur data alsosuggest attack-independent retinal damage in AQP4-IgGndashseropositive NMOSD Our study supports that at-tack prevention is key in avoiding neuroaxonal damage andvision loss in patients with NMOSD It further suggests thatthe first ON episode causes the most damage where onlysome patients with then established diagnosis will be on im-munosuppressive therapy This highlights the need for ef-fective therapies that can ameliorate an ongoing attack orregenerate attack-generated damage which is an unmet clin-ical need Last the study emphasizes the utility of OCT as asensitive structural metric and its potential for monitoringprogression and even treatment response in AQP4-IgGndashseropositive NMOSD The international CROCTINOprogram provides an unprecedented opportunity to applyOCT in a standardized manner to assess pathophysiologyclinical course and therapeutic efficacy in NMOSD

Study FundingGuthy-Jackson Charitable Foundation (GJCF) and GermanResearch Foundation (DFG)

DisclosureFC Oertel was employee of Nocturne GmbH and receivesresearch support by the American Academy of Neurology andthe National Multiple Sclerosis Society unrelated to this work

S Specovius reports no disclosures HG Zimmerman reportsresearch grants from Novartis and speaking honoraria fromBayer Healthcare unrelated to this study C Chien reportsspeaking honoraria from Bayer Healthcare unrelated to thiswork S Motamedi and C Bereuter report no disclosures LCook reports grants from Guthy Jackson Charitable Founda-tion during the conduct of the study EH Martinez-Lapiscinais employed by the European Medicines Agency (HumanMedicines) since 16 April 2019 This article is related with heractivity under Hospital Clinic of BarcelonaIDIBAPS affiliationand consequently as external activity it does not represent theviews of the Agency its Committees or working parties Beforeenrolling EMA Dr Martinez-Lapiscina reports grants fromInstituto de Salud Carlos III (Spain) amp Fondo Europeo deDesarrollo Regional grants from MS Innovation GMSI otherfromFundacio Privada Cellex and personal fees fromNovartisRoche Sanofi-Genzyme outside the submitted work MALana Peixoto and MA Fontanelle report no disclosures HJKim reports grants from the National Research Foundation ofKorea personal fees from Alexion Pharmaceuticals AprilbioBiogen Celltrion Eisai HanAll BioPharma MDimune MerckSerono Novartis Sanofi Genzyme Teva-Handok and VielaBio other from Viela Bio (formerly MedImmune) MultipleSclerosis Journal and Journal of Clinical Neurology outsidethe submitted work J-W Hyun reports grants from the Na-tional Research Foundation of Korea outside the submittedwork J Palace reports personal fees from Abide TherapeuticsAlexion Pharmaceuticals ARGENX Bayer Schering BiogenIdec Chugai Pharma EuroImmun Genzyme MedDayMedImmuneMerck Serono Novartis Roche Teva UCB andViela Bio grants from Abide Therapeutics Alexion Pharma-ceuticals Bayer Schering Biogen Idec Chugai Pharma Gen-zyme MedImmune Merck Serono Novartis and Teva grantsfrom Merck Serono Novartis Biogen Idec Teva AbideMedImmune Bayer Schering Genzyme Chugai and AlexionEugene Devic European Network the Grant for MultipleSclerosis Innovation the John Fell Fund the Medical ResearchCouncil the MS Society Myaware the UK National Institutefor Health Research Oxford Health Services Research Com-mittee and theGuthy-JacksonCharitable Foundation AMPLOand SPARKS Great Ormond Street for research studies out-side the submitted work MI Leite and S Sharma report nodisclosures A Roca-Fernandez is sponsored by Abide Thera-peutic outside of the submitted work and reports no potentialconflicts of interest R Kafieh A Dehghani M Pourazizi LPandit and A DrsquoCunha report no disclosures O Aktas reportsgrants from German Research Foundation (DFG) and Ger-man Ministry of Education and Research (BMBF) personalfees from Alexion and Almirall grants and personal fees fromBiogen personal fees from Merck grants and personal feesfrom Novartis grants and personal fees from Roche personalfees from Sanofi personal fees from Teva personal fees fromViela Bio outside the submitted work M Ringelstein receivedspeaker honoraria from Novartis Bayer Vital GmbH RocheAlexion and Ipsen and travel reimbursement from BayerSchering Biogen Idec Merz Genzyme Teva Roche andMerck none related to this study P Albrecht reports grants

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 9

personal fees and non-financial support from Allergan BiogenMerck Merz Pharmaceuticals Novartis Ipsen CelgeneRoche and personal fees and non-financial support from Tevaoutside the submitted work E May and C Tongco report nodisclosures L Leocani reports personal fees from RocheMerck Bristol Myers Squibb andMed-ex learning outside thesubmitted work M Pisa reports no disclosures M Radaellireports personal fees from Merck Serono Sanofi-GenzymeNovartis and Biogen outside the submitted work H Stiebel-Kalish reports no disclosures S Siritho reports personal feesfromNovartis Thailand Biogen Idec Eisai Thailandmarketingco ltd Merck Serono Teva Thailand and Menarini outsidethe submitted work J de Seze and T Senger report no dis-closures J Havla reports grants personal fees and non-financialsupport from Merck personal fees from Novartis CelgeneRoche Santhera Biogen Alexion Sanofi non-financial supportfrom Guthy-Jackson Charitable Foundation and grants fromFriedrich Baur Foundation outside the submitted work RMarignier AC Calvo D Bichuetti IM Tavares N Asgari KSoelberg A Altintas R Yildirim U Tanriverdi A Jacob SHuda Z Rimler and A Reid report no disclosures Y Mao-Draayer reports grants from NIH NIAID grants and personalfees from Genzyme grants from Chugai personal fees fromBiogen and EMD Serono grants and personal fees fromGenentech and Novartis during the conduct of the studygrants from NIH NIAID grants and personal fees from Gen-zyme grants fromChugai personal fees fromBiogen and EMDSerono grants and personal fees fromGenentech andNovartisoutside the submitted work I Soto de Castillo reports nodisclosures A Petzold reports personal fees and grants fromNovartis outside the submitted work and is part of the steeringcommittee of the OCTiMS study which is sponsored byNovartis He has not received honoraria for this activity AJGreen reports other from Bionure grants personal fees andother from Inception Sciences grants from Sherak Foundationpersonal fees and other from Pipeline Pharmaceuticals grantsfrom Hilton Foundation Adelson Foundation and NationalMS Society personal fees from JAMANeurology personal feesand other from MediimmuneViela outside the submittedwork In addition Dr Green has a patent Small Molecule drugfor Remyelination pending and has worked on testing off labelcompounds for remyelination MR Yeaman serves as an ad-visor to the Guthy-Jackson Charitable Foundation T Smithreports no disclosures AU Brandt reports grants from theGuthy Jackson Charitable Foundation during the conduct ofthe study shares from Motognosis GmbH and shares fromNocturne GmbH outside the submitted work In addition DrBrandt has a patent pending describing Foveal MorphometryF Paul reports grants from the Guthy Jackson CharitableFoundation during the conduct of the study grants from theGerman Research Foundation andGerman FederalMinistry ofEducation and research grants and other fromNovartis grantsand other from Bayer Novartis Biogen Idec Teva Sanofi-AventisGenzyme Merck Serono Chugai other from PLoSONE other from Neurologyreg Neuroimmunology amp Neuro-inflammation other from SanofiGenzyme Biogen Idec grantsfrom German Research Council Werth Stiftung of the City of

Cologne German Ministry of Education and Research ArthurArnstein Stiftung Berlin EU FP7 Framework Program ArthurArnstein Foundation Berlin National Multiple Sclerosis(USA) other from MedImmune Shire Alexion outside thesubmitted work In addition Dr Paul has a patent FovealMorphometry pending to Nocturne GmbH Go to NeurologyorgNN for full disclosures

Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationMarch 23 2021 Accepted in final form June 15 2021

Appendix Authors

Name Location Contribution

Frederike CosimaOertel MDPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data anddrafting a significantportion of themanuscript or figuresconception and designof the study

Svenja SpecoviusMSc

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of dataconception and designof the study

Hanna GZimmermannPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of dataconception and designof the study

Claudia ChienPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

SeyedamirhoseinMotamedi PhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

CharlotteBereuter BSc

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

Appendix (continued)

Name Location Contribution

Lawrence CookPhD

University of UtahSalt Lake City UT

Acquisition andanalysis of data andconception and designof the study

Marco AurelioLana Peixoto MDPhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Mariana AndradeFontanelle MD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Ho Jin Kim MDPhD

National Cancer CenterGoyang Republic of Korea

Acquisition andanalysis of data

Jae-Won HyunMD PhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

JacquelinePalace MD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Adriana Roca-Fernandez MSc

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Maria IsabelLeite MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

SrilakshmiSharma MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

FereshtehAshtari MD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Rahele KafiehPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Alireza DehghaniPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

MohsenPourazizi PhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Lekha PanditMD PhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Anitha DrsquoCunhaPhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Orhan Aktas MD Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

MariusRingelstein MD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Philipp AlbrechtMD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Eugene May MD Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Caryl Tongco Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Appendix (continued)

Name Location Contribution

Letizia LeocaniMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marco Pisa MD Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marta RadaelliMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Elena H Martinez-Lapiscina MDPhD

Hospital Clinic of Barcelona-Institut drsquoInvestigacionsBiomediques August PiSunyer Barcelona Spain

Acquisition andanalysis of data

Hadas Stiebel-Kalish MD

Sackler School of MedicineTel Aviv University Tel AvivIsrael

Acquisition andanalysis of data

Sasitorn SirithoMD

Siriraj Hospital andBumrungrad InternationalHospital Bangkok Thailand

Acquisition andanalysis of data

Jerome de SezeMD PhD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Thomas SengerMD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Joachim HavlaMD

Ludwig-MaximiliansUniversitat MuenchenMunich Germany

Acquisition andanalysis of data

RomainMarignier MDPhD

Pierre Wertheimer NeurologicalHospital Hospices Civils deLyon France

Acquisition andanalysis of data

Alvaro CoboCalvo MD PhD

Pierre WertheimerNeurological HospitalHospices Civils de LyonFrance Hospital UniversitariVall drsquoHebron UniversitatAutonoma de BarcelonaSpain

Acquisition andanalysis of data

Denis BichuettiMD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Ivan MaynartTavares MD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Nasrin AsgariMD PhD

University of SouthernDenmark OdenseDenmark

Acquisition andanalysis of data

Kerstin SoelbergMD

University of SouthernDenmark Odense Denmark

Acquisition andanalysis of data

Ayse Altintas MD Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Rengin YildirimMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 11

References1 Oertel FC Zimmermann H Paul F Brandt AU Optical coherence tomog-

raphy in neuromyelitis optica spectrum disorders potential advantages forindividualized monitoring of progression and therapy EPMA J 20189(1)21-33

2 Schneider E Zimmermann H Oberwahrenbrock T et al Optical coherence to-mography reveals distinct patterns of retinal damage in neuromyelitis optica andmultiple sclerosis PLoS One 20138(6)e66151

3 Bouyon M Collongues N Zephir H et al Longitudinal follow-up of vision in aneuromyelitis optica cohort Mult Scler 201319(10)1320-1322

4 Sotirchos ES Filippatou A Fitzgerald KC et al Aquaporin-4 IgG seropositivity isassociated with worse visual outcomes after optic neuritis than MOG-IgG seroposi-tivity and multiple sclerosis independent of macular ganglion cell layer thinningMultScler 201926(11)1360-1371

5 Hamid SHM Whittam D Mutch K et al What proportion of AQP4-IgG-negativeNMO spectrum disorder patients are MOG-IgG positive A cross sectional study of132 patients J Neurol 2017264(10)2088-2094

6 Oertel FC Kuchling J ZimmermannH et al Microstructural visual system changes inAQP4-antibody-seropositive NMOSD Neurol Neuroimmunol Neuroinflamm 20174(3)e334

7 Oertel FC Havla J Roca-Fernandez A et al Retinal ganglion cell loss in neuromyelitisoptica a longitudinal study J Neurol Neurosurg Psychiatry 201889(12)1259-1265

8 Huang D Swanson EA Lin CP et al Optical coherence tomography Science 1991254(5035)1178-1181

9 Specovius S Zimmermann HG Oertel FC et al Cohort profile a collaborativemulticentre study of retinal optical coherence tomography in 539 patients withneuromyelitis optica spectrum disorders (CROCTINO) BMJ Open 202010(10)e035397

10 Motamedi S Gawlik K Ayadi N et al Normative data and minimally detectablechange for inner retinal layer thicknesses using a semi-automated OCT image seg-mentation pipeline Front Neurol 2019101117

11 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177-189

12 von Elm E Altman DG Egger M et al The strengthening the reporting of obser-vational studies in epidemiology (STROBE) statement guidelines for reportingobservational studies Int J Surg 201412(12)1495-1499

13 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PLoS One 20127(4)e34823

14 Schippling S Balk LJ Costello F et al Quality control for retinal OCT in multiplesclerosis validation of the OSCAR-IB criteria Mult Scler 201521(2)163-170

15 Lang A Carass A Hauser M et al Retinal layer segmentation of macular OCT imagesusing boundary classification Biomed Opt Express 20134(7)1133-1152

16 R Development Core Team R A Language and Environment for Statistical Computing[online] R Foundation for Statistical Computing 2008 R-projectorg

17 Akaishi T Kaneko K Himori N et al Subclinical retinal atrophy in the unaffectedfellow eyes of multiple sclerosis and neuromyelitis optica [online serial]J Neuroimmunol 201731310-15 Accessed October 8 2017 jni-journalcomarticleS0165-5728(17)30319-3fulltext

18 Alshowaeir D Yiannikas C Fraser C Klistorner A Mechanism of delayed con-duction of fellow eyes in patients with optic neuritis Int J Ophthalmol 201811(2)329-332

19 Manogaran P Traboulsee AL Lange AP Longitudinal study of retinal nerve fiberlayer thickness and macular volume in patients with neuromyelitis optica spectrumdisorder J Neuroophthalmol 201636(4)363-368

20 Kaufhold F ZimmermannH Schneider E et al Optic neuritis is associated with innernuclear layer thickening and microcystic macular edema independently of multiplesclerosis PLoS One 20138(8)e71145

21 Knier B Schmidt P Aly L et al Retinal inner nuclear layer volume reflects response toimmunotherapy in multiple sclerosis Brain 2016139(11)2855-2863

22 Petzold A Balcer LJ Calabresi PA et al Retinal layer segmentation in multiplesclerosis a systematic review and meta-analysis Lancet Neurol 201716(10)797-812

23 Pawlitzki M Horbrugger M Loewe K et al MS optic neuritis-induced long-termstructural changes within the visual pathway Neurol Neuroimmunol Neuroinflamm20207(2)e665

24 Pache F Zimmermann H Mikolajczak J et al MOG-IgG in NMO and relateddisorders a multicenter study of 50 patients Part 4 afferent visual system damageafter optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patientsJ Neuroinflammation 201613(1)282

25 Filippatou AG Vasileiou ES He Y et al Evidence of subclinical quantitative retinallayer abnormalities in AQP4-IgG seropositive NMOSD Mult Scler 2020 Dec 141352458520977771 doi 1011771352458520977771

26 Motamedi S Oertel FC Yadav SK et al Altered fovea in AQP4-IgGndashseropositiveneuromyelitis optica spectrum disorders Neurol Neuroimmunol Neuroinflamm 20207(5)e805

27 Roca-Fernandez A Oertel FC Yeo T et al Foveal changes in AQP4-Ab seropositiveNMOSD are independent of optic neuritis and not overtly progressive Eur J Neurol202128(7)2280-2293

28 Papadopoulou A Oertel FC Chien C et al Lateral geniculate nucleus volumechanges after optic neuritis in neuromyelitis optica a longitudinal study NeuroimageClin 202130102608

29 Ringelstein M Harmel J Zimmermann H et al Longitudinal optic neuritis-unrelatedvisual evoked potential changes in NMO spectrum disorders Neurology 202094(4)e407-e418

30 Pache F Zimmermann H Finke C et al Brain parenchymal damage in neuromyelitisoptica spectrum disorderndasha multimodal MRI study Eur Radiol 201626(12)4413-4422

31 Hokari M Yokoseki A Arakawa M et al Clinicopathological features in anteriorvisual pathway in neuromyelitis optica Ann Neurol 201679(4)605-624

32 You Y Zhu L Zhang T et al Evidence of muller glial dysfunction in patients withaquaporin-4 immunoglobulin Gndashpositive neuromyelitis optica spectrum disorderOphthalmology 2019126(6)801-810 Elsevier

33 Chien C Scheel M Schmitz-Hubsch T et al Spinal cord lesions and atrophy inNMOSD with AQP4-IgG and MOG-IgG associated autoimmunityMult Scler 201925(14)1926-1936

34 Felix CM Levin MH Verkman AS Complement-independent retinal pathologyproduced by intravitreal injection of neuromyelitis optica immunoglobulin GJ Neuroinflammation 201613(1)275

35 Balk LJ Coric D Knier B et al Retinal inner nuclear layer volume reflects in-flammatory disease activity in multiple sclerosis a longitudinal OCT studyMult SclerJ Exp Transl Clin 20195(3)2055217319871582

36 Gelfand JM Nolan R Schwartz DM Graves J Green AJ Microcystic macular oedemain multiple sclerosis is associated with disease severity Brain 2012135(pt 6)1786-1793

Appendix (continued)

Name Location Contribution

Uygur TanriverdiMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Anu Jacob MD The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Saif Huda MDPhD

The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Zoe Rimler BSc NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Allyson Reid MD NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Yang Mao-Draayer MD PhD

University of MichiganMedical School AnnArbor MI

Acquisition andanalysis of data

Ibis Soto deCastillo MD

Hospital Clınico deMaracaibo MaracaiboVenezuela

Acquisition andanalysis of data

Axel Petzold MDPhD

University College LondonLondon UK

Conception anddesign of the study

Ari J Green MD University of California SanFrancisco CA

Conception anddesign of the study

Michael RYeaman MD PhD

University of California LosAngeles CA

Conception anddesign of the study

Terry Smith MD University of MichiganMedical School AnnArbor MI

Conception anddesign of the study

Alexander UBrandt MD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinBerlin Berlin Germany

Acquisition andanalysis of dataconception and designof the study anddrafting a significantportion of themanuscript or figures

Friedemann PaulMD

CharitendashUniversitatsmedizinBerlin Corporate Member ofFreie Universitat Berlin andHumboldt-Universitat zuBerlin

Acquisition andanalysis of data andconception and designof the study

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

37 Gelfand JM Cree BA Nolan R Arnow S Green AJ Microcystic inner nuclear layerabnormalities and neuromyelitis optica JAMA Neurol 201370(5)629-633

38 Oberwahrenbrock T WeinholdMMikolajczak J et al Reliability of intra-retinal layerthickness estimates PLoS One 201510(9)e0137316

39 Borisow N Kleiter I Gahlen A et al Influence of female sex and fertile age onneuromyelitis optica spectrum disorders Mult Scler 201723(8)1092-1103

40 Mori M Kuwabara S Paul F Worldwide prevalence of neuromyelitis optica spectrumdisorders J Neurol Neurosurg Psychiatry 201889(6)555-556

41 Oertel FC Paul F Accelerating clinical research in neuromyelitis optica spectrumdisorders [online serial] Clin Exp Neuroimmunol 202112(2)89-91 AccessedMarch 28 2021 periclespericles-prodliteratumonlinecomdoiabs101111cen312637

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 13

DOI 101212NXI000000000000106820218 Neurol Neuroimmunol Neuroinflamm

Frederike Cosima Oertel Svenja Specovius Hanna G Zimmermann et al Retinal Optical Coherence Tomography in Neuromyelitis Optica

This information is current as of September 15 2021

ServicesUpdated Information amp

httpnnneurologyorgcontent86e1068fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent86e1068fullhtmlref-list-1

This article cites 40 articles 7 of which you can access for free at

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Page 4: Retinal Optical Coherence Tomography in Neuromyelitis Optica

effect models Intereye within-subject effects and effects ofthe center were included as random effects Sex ethnicityand age were included as fixed effects for the analyses in theentire cohort Age and sex were not included for thematched subset For OCT parameters the model was usedfor data from all devices separately and combined by Fishercombined probability test The marginal and conditionalcoefficients of determination of the linear models werecalculated with pseudo R-squared All results are reported

combined and individually for Spectralis SD-OCT theanalyses of data acquired by Cirrus HD-OCT or Topcon3D OCT-1 and for the matched subset are reported asonline-only supplement

Data AvailabilityThe data supporting the findings of this study are availablewithin the article and from the corresponding author byreasonable request

Figure 1 Group Comparisons of GCIP Layer Thickness

Boxplots of GCIP layer thicknesses (μm) acquired by Heidelberg SD-OCT with values of individual eyes (jitter) for (A) HC (grayleft) NMOSD-NON(dark bluemiddle) NMOSD-ON (dark redright) for (B) number of ON episodes (NMOSD-NON dark blueleft NMOSD-1-ON light redleft-middleNMOSD-2-ON medium-redright-middle NMOSD-ge3-ON medium-dark redright) and for (C) HC (grayleft) NMOSD-NONnon (light bluemiddle)NMOSD-NONcon (blueright) (D) Forest plots for results from different OCT devices for (Da) NMOSD-NON vs NMOSD-ON (Db) NMOSD-NON vsNMOSD-1-ON and (Dc) NMOSD-1-ON vs NMOSD-2-ON (eFigure 2 and eTable 2 linkslwwcomNXIA556 and linkslwwcomNXIA557) GCIP =ganglion cell and inner plexiform HC = eyes of HCs NMOSD-NON = eyes of patients with neuromyelitis optica without a history of ON NMOSD-NON-con =eyes of patients with neuromyelitis optica without a history of ON but a history of contralateral ON NMOSD-NONnon = eyes of patients withneuromyelitis optica without a history of ipsilateral or contralateral ON NMOSD-ON = eyes of patients with neuromyelitis optica with a history ofON NMOSD-1-ON = eyes of patients with neuromyelitis optica with a history of 1 ON episode NMOSD-2-ON = eyes of patients with neuromyelitisoptica with a history of 2 ON episodes ON = optic neuritis

4 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

ResultsFive hundred one eyes of 283 AQP4-IgGndashseropositive pa-tients and 136 eyes of 72 HCs were included in the analysis(Table 1)

Neuroaxonal Damage After ONGCIP layer and pRNFL were reduced in NMOSD-ONcompared with NMOSD eyes without a history of ON

(NMOSD-NON) and HC (GCIP layer 814 plusmn 57 μmpRNFL 1011 plusmn 90 μm) (Figures 1A and 2A Tables 2 and3) The absolute (GCIP layer minus227 μm pRNFL minus385 μm)and relative (GCIP layer minus388 pRNFL minus616) loss ineyes with 1 ON episode (NMOSD-1-ON) compared withNMOSD-NON was higher than in eyes with 2 ON episodes(NMOSD-2-ON) compared with NMOSD-1-ON (GCIPlayer absolute loss minus35 μm relative loss minus60 pRNFLabsolute loss minus91 μm relative loss minus145 ns) The loss in

Figure 2 Group Comparisons of pRNFL Thickness

Boxplots of pRNFL thicknesses acquired by Heidelberg SD-OCT [μm] with values of individual eyes (jitter) for (A) HC (grayleft) NMOSD-NON (dark bluemiddle) and NMOSD-ON (dark redright) for (B) number of ON episodes (NMOSD-NON dark blueleft NMOSD-1-ON light redleft-middle NMOSD-2-ONmedium-redright-middle and NMOSD-ge3-ON medium-dark redright) and for (C) HC (grayleft) NMOSD-NONnon (light bluemiddle) and NMOSD-NONcon

(blueright) (D) Forest plots for results from different OCT devices for (Da) NMOSD-NON vs NMOSD-ON (Db) NMOSD-NON vs NMOSD-1-ON and (Dc)NMOSD-1-ON vs NMOSD-2-ON (eFigure 3 and eTable 3 linkslwwcomNXIA556 and linkslwwcomNXIA557) HC = eyes of HCs NMOSD-NON = eyes ofpatients with neuromyelitis optica without a history of optic neuritis NMOSD-NON-con = eyes of patients with neuromyelitis optica without a history of opticneuritis but a history of contralateral optic neuritis NMOSD-NONnon = eyes of patients with neuromyelitis optica without a history of ipsilateral or contra-lateral optic neuritis NMOSD-ON = eyes of patients with neuromyelitis optica with a history of optic neuritis NMOSD-1-ON = eyes of patients withneuromyelitis optica with a history of 1 optic neuritis episode NMOSD-2-ON = eyes of patients with neuromyelitis optica with a history of 2 optic neuritisepisodes ON = optic neuritis pRNFL = peripapillary retinal nerve fiber layer

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 5

eyes with ge3-ON episodes (NMOSD-3-ON) was lowercompared with NMOSD-2-ON (ns) (Figures 1B and 2B)Five NMOSD-NON eyes had pRNFL values lt 60 μm thesepatients had no relevant comorbidities but a history of con-tralateral ON1718 In sensitivity analyses to account for devicedifferences all significant analyses within the NMOSD cohortwere confirmed for data acquired by Cirrus and Topcon OCTdevices (eFigures 2 and 3 eTables 3 and 4 linkslwwcomNXIA556 linkslwwcomNXIA557)

Neuroaxonal Damage Without ONNMOSD-NON eyes had a reduced GCIP layer (759 plusmn 77 μmplt 0001) but not pRNFL (953 plusmn 144 μm) comparedwithHC(GCIP layer 814 plusmn 57 μm pRNFL 1011 plusmn 90 μm Figures 1Aand 2A Tables 2 and 3) By comparison only 28 NMOSD-NON eyes (51) had a GCIP layer le the 5th percentile of HCGCIP layer was also reduced inNMOSD-NONwith a history ofcontralateral ON (729 plusmn 102 μm) compared with NMOSD-NON without a history of contralateral ON (773 plusmn 59 μm p =0025 NMOSD-NONnon) This effect vanished when onlyconsidering NMOSD-NONcon with a history of 1 contralateralON (736 plusmn 94 μm) However only NMOSD-NONcon (p lt

0001) but not NMOSD-NONnon (p = 0061) had thinnedGCIP layer compared with HC (Figures 1C and 2C)

INL ChangesINL was thicker in NMOSD-ON compared with HC (394 plusmn26 μm) and NMOSD-NON (eTable 4 linkslwwcomNXIA557) Specifically INL was thicker in eyes with 1 ON episodecompared with NMOSD-NON but did not differ between eyeswith different numbers of ON episodes Also INL did not differbetween NMOSD-NONcon (389 plusmn 32 μm) and NMOSD-NONnon (385 plusmn 32 μm p = 0931) In all patients INLthickness (as the dependent variable in the linear mixed modeldescribed above) was correlated with thinner GCIP layer (B =minus011 standard error [SE] = 001 p lt 0001) and pRNFL (B =minus006 SE = 001 p lt 0001) This correlation existed inNMOSD-ON (GCIP layer B = minus 008 SE = 003 p = 0005pRNFL B = minus 006 SE = 001 p lt 0001) and not present inNMOSD-NON (eFigure 4 linkslwwcomNXIA556)

Scans of 363 NMOSD eyes were clearly suitable for MMEinvestigations (high quality eFigure 4C linkslwwcomNXIA556) MMEs were visible in 24 (66) eyes of 21 patients

Table 2 Group Comparisons of GCIP Layer Thickness for Heidelberg SD-OCT

No ofeyes

Thickness (μmmean plusmn SD)

Comparisonto

Absolutedifference (μmmean)

Relativedifference (mean) B SE p Value R2

marg R2cond

Combinedp value

NMOSD 268 673 plusmn 136 HCs minus140 minus208 156 20 lt00001 0143 0690 mdash

NMOSD-ON

124 574 plusmn 122 minus240 minus418 250 20 lt00001 0482 0839 mdash

NMOSD-NON

144 759 plusmn 77 minus54 minus72 58 14 lt00001 0088 0947 mdash

NMOSD-NONnon

99 773 plusmn 59 minus40 minus50 269 142 0061 0189 0924 mdash

NMOSD-NONcon

45 729 plusmn 102 minus85 minus104 844 177 lt00001 0260 0985 mdash

NMOSD-ON

124 574 plusmn 122 NMOSD-NON

minus185 minus244 minus158 11 lt00001 0430 0795 59e245

NMOSD-1-ON

76 586 plusmn 129 minus173 minus228 minus145 12 lt00001 0417 0803 14e233

NMOSD-2-ON

28 551 plusmn 94 NMOSD-1-ON

minus35 minus60 minus57 26 0028 0143 0729 0038

NMOSD-ge3-ON

20 559 plusmn 128 NMOSD-2-ON

08 14 49 26 0070 0311 0781 0222

NMOSD-NONcon

45 729 plusmn 102 NMOSD-NONnon

minus44 minus61 minus38 17 0025 0111 0701 0004

NMOSD-NON1-con

37 736 plusmn 94 minus37 minus51 minus35 16 0037 0149 0906 0154

Abbreviations AQP4-IgG = aquaporin-4 IgG B = estimate GCIP = ganglion cell and inner plexiformNMOSD=AQP4-IgGndashseropositiveNMOSD NMOSD-NON=AQP4-IgGndashseropositive NMOSD eyeswithout a history of ON NMOSD-NONnon = AQP4-IgGndashseropositive NMOSD eyeswithout a history ofONor contralateralON NMOSD-NONcon = AQP4-IgGndashseropositive NMOSD eyes without a history of ON but with a history of contralateral ON NMOSD-NON1-con = AQP4-IgGndashseropositive NMOSD eyes without a history of ON but with a history of 1 contralateral ON NMOSD-ON = AQP4-IgGndashseropositive NMOSD eyes with ahistory of ON NMOSD-1-ON =AQP4-IgGndashseropositive NMOSD eyeswith a history of 1ON NMO-2-ON =AQP4-IgGndashseropositive NMOSD eyeswith a history of2 ONs NMOSD-ge3-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 3 or more ONs NMOSD = neuromyelitis optica spectrum disorder NMOSD-NON = NMOSD eyes without a history of ON OCT = optical coherence tomography ON = optic neuritis episode Rcon = conditional R-squared Rmarg =marginal R-squared SE = standard error

6 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

Twenty-three eyes (131) of NMOSD-ON and 1 eye (05)of NMOSD-NON (with a history of contralateral ON) wereaffected The number of ON episodes did not influence theincidence of MMEs (NMOSD-1-ONN = 16 (14) NMOSD-2-ON N = 4 (114) NMOSD-ge3-ON N = 3 (111))

Including only the most frequent ethnicities in our data set(Asian and non-HispanicWhite) results did not differ and noethnicity was singled out regarding its pattern of injury (datanot shown)

OCT and Vision LossHC-VA was numerically reduced in NMOSD (025 plusmn 048)compared with HC (minus001 plusmn 008) and known healthy referencevalues NMOSD-ON also had reduced HC-VA (044 plusmn 058)compared with NMOSD-NON (004 plusmn 020 p lt 0001 p =0401) and HChealthy reference populations HC-VA wascorrelated with GCIP layer (B = minus0016 SE = 0002 p lt 0001)and pRNFL thicknesses (B = minus0010 SE = 0001 p lt 0001) inAQP4-IgGndashseropositive NMOSD AQP4-IgGndashseropositiveNMOSD eyes with prolonged VEP latency had a thinned GCIP

layer (B = minus11647 SE = 3628 p = 0002) and pRNFL (B =minus21965 SE = 3724 p lt 0001) EDSS score as ametric of globaldisability was inversely correlated with GCIP layer (B = minus1370SE= 0566 p= 0017) and pRNFL thicknesses (B= minus3148 SE=1080 p = 0004)

DiscussionOur study specifies a severe and functionally relevant decreaseof GCIP layer and pRNFL in NMOSD-ON compared withNMOSD-NON and HCs in AQP4-IgGndashseropositive pa-tients Neuroaxonal damage is particularly large from the firstepisode of ON where contribution to retinal damage insubsequent episodes of ON is still considerable but smaller Incontrast to previous smaller studies the current study ascer-tains GCIP layer but not pRNFL thinning in NMOSD-NONcompared with HC619 This effect was driven by eyes withcontralateral ON and not statistically significant in eyeswithout a history of ON INL was thicker in NMOSD-ONand was inversely correlated with GCIP layer Of note 131

Table 3 GroupComparisons of pRNFL ThicknessWith (A) Spectralis SD-OCTData for Comparisons vsHC (B) Data FromAllDevices for Intrapatient Cohort Comparisons

No ofeyes

Thickness (μmmean plusmn SD)

Comparisonto

Absolute difference(μm mean)

Relativedifference (mean) B SE p Value R2

marg R2cond

Combinedp value

NMOSD 344 763 plusmn 274 HCs minus140 minus326 242 43 lt00001 0143 0690 mdash

NMOSD-ON

170 569 plusmn 237 minus443 minus779 431 41 lt00001 0482 0839 mdash

NMOSD-NON

174 953 plusmn 144 minus59 minus62 46 30 0129 0088 0947 mdash

NMOSD-NONnon

116 974 plusmn 109 minus37 minus37 minus29 22 0204 0107 0893 mdash

NMOSD-NONcon

58 910 plusmn 191 minus47 minus46 71 42 0097 0100 0975 mdash

NMOSD-ON

170 569 plusmn 237 NMOSD-NON

minus384 minus403 minus338 21 lt00001 0436 0741 44e260

NMOSD-1-ON

97 626 plusmn 249 minus327 minus343 minus296 22 lt00001 0379 0712 46e240

NMOSD-2-ON

35 535 plusmn 213 NMOSD-1-ON

minus91 minus145 minus107 47 0024 0087 0528 0010

NMOSD-ge3-ON

38 452 plusmn 178 NMOSD-2-ON

minus83 minus155 minus04 43 0924 0087 0719 0838

NMOSD-NONcon

58 910 plusmn 191 NMOSD-NONnon

minus65 minus71 minus40 29 0173 0061 0939 0157

NMOSD-NON1-con

47 932 plusmn 181 minus42 minus46 minus32 29 0276 0056 0925 0616

Abbreviations AQP4-IgG = aquaporin-4 IgG NMOSD = AQP4-IgGndashseropositive NMOSD NMOSD-NON = AQP4-IgGndashseropositive NMOSD eyes without ahistory of ON NMOSD-NONnon = AQP4-IgGndashseropositive NMOSD eyes without a history of ON or contralateral ON NMOSD-NONcon = AQP4-IgGndashseropositive NMOSD eyes without a history of ON but with a history of contralateral ON NMOSD-NONcon = AQP4-IgGndashseropositive NMOSD eyes without ahistory of ON but with a history of 1 contralateral ON NMOSD-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of ON NMOSD-1-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 1 ON NMOSD-2-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 2 ONs NMOSD-ge3-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 3 or more ONs NMOSD = neuromyelitis optica spectrum disorder NMOSD-NON = NMOSD eyes without ahistory of ON OCT = optical coherence tomography ON = optic neuritis episode pRNFL = peripapillary retinal nerve fiber layer VEP = visually evokedpotential

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of NMOSD-ON eyes showed MME indicative of secondaryinflammatory changes2021 This investigation overcame limitsof small samples and OCT data heterogeneity of earlierstudies through use of an international consortium ofNMOSD specialists This framework substantiated theCROCTINO studymdasha large multicenter retrospectiveevaluation of retinal pathology in NMOSD using OCT

The neuroaxonal degeneration in NMOSD-ON demon-strated here is substantially greater than reported changes inmultiple sclerosis (MS) a common differential diagnosis222

In a meta-analysis an average pRNFL loss of 20 μm wasestimated in MS after ON which is nearly 2-fold higher in ourNMOSD-ON cohort (minus384 μm)22 For GCIP layer our datasuggested approximately 15-fold higher loss in NMOSD(minus240 μm) compared with MS22 These differences not onlyresult from a higher ON frequency but may also be caused bymore severe retinal damage in NMOSD after a singular ON23

It is intriguing that the damage is particularly large after thefirst ON episode with smaller losses after subsequent epi-sodes which might be due to less neuroaxonal content insubsequent episodes224 Alternatively although the analysisof treatment effects exceeds the scope of this study it ispossible that the longer time to effective anti-inflammatorytherapy and the typical choice of less effective therapies (egsteroids instead of plasma exchange) at the first attack com-pared with following attacks may significantly contribute tothis difference Independent of the number of ONs the per-cent loss is smaller in GCIP layer compared with pRNFLndashpointing toward either (1) stronger loss of retinal nerve fibersthan retinal ganglion cells (2) impairment of ganglion cellsnot leading to extinction but axonal loss (3) a larger amountof non-neuronal tissue in GCIP layer or (4) RNFL loss in theperiphery beyond the macular area measured by GCIP layerThese hypotheses are not mutually exclusive and each mightcontribute to the effect Consistent with these concepts ex-cessive vision loss relative to neuroaxonal content and VEPlatency in AQP4-IgGndashseropositive patients compared withMOG-IgGndashseropositive and MS patients implies damage ofthe peripheral retina and optic nerve tissues which are notreflected in the macula and pattern VEP measurements4

Whether attack-independent neurodegeneration inAQP4-IgGndashseropositive NMOSD occurs has beencontroversial26725-28 The current study identifies de-creased GCIP layer in NMOSD-NON compared withHC but not pRNFL Such subclinical changes could becaused by contralateral involvement after unilateralON1718 Indeed our cohort suggests pronounced neu-rodegeneration in eyes with contralateral ON Howevereyes of patients without ON also exhibit a trend for thinnerGCIP layer compared with HCs Underscored by longitu-dinal studies showing ON-independent neurodegenerationand VEP latency prolongation729 such patterns suggest atleast 2 mechanisms of injury (1) a primary retinopathy oroptic neuropathy in context of an astrocytopathy or causedby direct damage to AQP4-expressing cells such as astrocytes

and Muller cells by either AQP4-IgG or AQP4-specificT cells or (2) a global or afferent visual system specificchronic or episodic neurodegenerative process Because le-sions often spare the brain and most studies outside ofpredisposed areas such as optic nerve and spinal cord failedto detect effects30 a constant global involvement seemsunlikely Several studies described changes affecting AQP4expression and astrocytic end feet31 parafoveal changes inagreement with an involvement of AQP4-expressing Mullercell6262732 and attack-independent spinal cord atrophy33

These findings are consistent with tissue infiltration byAQP4-IgGndashspecific T cells34 and the attack-independentloss of retinal ganglion cells7mdashfurther supporting the exis-tence of an ON-independent pathology which might berestricted to the main disease foci The latter hypothesescould be addressed by region-specific pathology or advancedimaging studies

INL changes have been suggested as a marker of neuro-inflammation and potential treatment response in MS213536

MME may develop as a consequence of neurodegenerationor othermdashnonndashdisease-specificmdashprocesses35 Patients withNMOSD were described to have INL thickening andMME2037 In our cohort 131 of NMOSD-ON eyes wereaffected byMME which is higher than the 2ndash5 described inMS but comparable to incidences in NMOSD described beforeby Gelfand and colleagues3537 However INL thickening itselfremained comparable to changes reported in MS35 This dis-parity could reflect a disrupted fluid homeostasis due to Mullercell involvement or loss of content of the INL with a parallelinflammatory reaction and development of MME The limitedaccessibility of MMEs especially in severely affected eyes due tolimited image quality has hindered their detailed assessmentsand most likely leads to underestimation of their incidence38

We demonstrate that the INL thickness is inversely correlatedwith neuroaxonal content and could be a valuable marker ofdisease severity also in NMOSD

Our study cohort was representative of patients with AQP4-IgGndashseropositive NMOSD with respect to a female pre-dominance and ON history1139 This OCT study includedmultiple ethnicity backgrounds although the distribution wasshifted toward CaucasianWhite patients and other ethnic-ities were underrepresented (eg Hispanic White and Black)limiting the generalizability of results40 Patients from differ-ent heritages presented similar findings

The current study was based on source data instead of a meta-analysis Using the Guthy-Jackson Charitable Foundation net-work this multicentric study was conducted without investigatorreimbursement and illustrated how collaboration integratinginternational perspectives can produce meaningful results Toovercome technical challenges of heterogeneous source data wedeveloped novel OCT postprocessing techniques allowing us toperform standardized analyses and enabling the uniform analysisof the largest OCT image data set in NMOSD to date10 Thusthe strengths of CROCTINO include its established

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

infrastructure large international network of experts represent-ing multiple ethnicities and geographic regions and the use ofstate-of-the-art OCT postprocessing techniques41

We recognize limitations of the current investigation Theretrospective and heterogeneous data acquisition might haveled to biases and impreciseness beyond the ability of ourquality control We addressed this by excluding uncertaincases HCs were only included from a limited number ofcenters The unbalanced data set limited some analyses suchas the influence of ethnicities or acute and disease-modifyingtreatments Case-control matching was impossible particu-larly with respect to subclinical progression dependent orindependent of ON and to ethnicity Similarly comparisonswith other NMOSD subtypes or MS were beyond the scopeof this study Longitudinal data acute ON data and AQP4-IgGndashseronegative and MOG-IgGndashseropositive patient dataare part of the CROCTINO data set and will be analyzed inthe future Also OCT data processing was performed bymultiple raters potentially introducing interrater variabilityMRI data and posterior visual pathway involvement were notinvestigated in this study However the current study ach-ieved an unprecedented worldwide assessment of retinaldamage in AQP4-IgGndashseropositive NMOSD

To conclude AQP4-IgGndashseropositive NMOSD is characterizedby a severe functionally relevant retinal neurodegeneration as aconsequence of ON Although the majority of damage occursduring the first episode there is cumulative loss with each suc-ceeding relapse TheON-associated damage is not limited to theneuroaxonal content but can also inducemdashlikely inflammation-mediatedmdashINL increase and occurrence ofMMEOur data alsosuggest attack-independent retinal damage in AQP4-IgGndashseropositive NMOSD Our study supports that at-tack prevention is key in avoiding neuroaxonal damage andvision loss in patients with NMOSD It further suggests thatthe first ON episode causes the most damage where onlysome patients with then established diagnosis will be on im-munosuppressive therapy This highlights the need for ef-fective therapies that can ameliorate an ongoing attack orregenerate attack-generated damage which is an unmet clin-ical need Last the study emphasizes the utility of OCT as asensitive structural metric and its potential for monitoringprogression and even treatment response in AQP4-IgGndashseropositive NMOSD The international CROCTINOprogram provides an unprecedented opportunity to applyOCT in a standardized manner to assess pathophysiologyclinical course and therapeutic efficacy in NMOSD

Study FundingGuthy-Jackson Charitable Foundation (GJCF) and GermanResearch Foundation (DFG)

DisclosureFC Oertel was employee of Nocturne GmbH and receivesresearch support by the American Academy of Neurology andthe National Multiple Sclerosis Society unrelated to this work

S Specovius reports no disclosures HG Zimmerman reportsresearch grants from Novartis and speaking honoraria fromBayer Healthcare unrelated to this study C Chien reportsspeaking honoraria from Bayer Healthcare unrelated to thiswork S Motamedi and C Bereuter report no disclosures LCook reports grants from Guthy Jackson Charitable Founda-tion during the conduct of the study EH Martinez-Lapiscinais employed by the European Medicines Agency (HumanMedicines) since 16 April 2019 This article is related with heractivity under Hospital Clinic of BarcelonaIDIBAPS affiliationand consequently as external activity it does not represent theviews of the Agency its Committees or working parties Beforeenrolling EMA Dr Martinez-Lapiscina reports grants fromInstituto de Salud Carlos III (Spain) amp Fondo Europeo deDesarrollo Regional grants from MS Innovation GMSI otherfromFundacio Privada Cellex and personal fees fromNovartisRoche Sanofi-Genzyme outside the submitted work MALana Peixoto and MA Fontanelle report no disclosures HJKim reports grants from the National Research Foundation ofKorea personal fees from Alexion Pharmaceuticals AprilbioBiogen Celltrion Eisai HanAll BioPharma MDimune MerckSerono Novartis Sanofi Genzyme Teva-Handok and VielaBio other from Viela Bio (formerly MedImmune) MultipleSclerosis Journal and Journal of Clinical Neurology outsidethe submitted work J-W Hyun reports grants from the Na-tional Research Foundation of Korea outside the submittedwork J Palace reports personal fees from Abide TherapeuticsAlexion Pharmaceuticals ARGENX Bayer Schering BiogenIdec Chugai Pharma EuroImmun Genzyme MedDayMedImmuneMerck Serono Novartis Roche Teva UCB andViela Bio grants from Abide Therapeutics Alexion Pharma-ceuticals Bayer Schering Biogen Idec Chugai Pharma Gen-zyme MedImmune Merck Serono Novartis and Teva grantsfrom Merck Serono Novartis Biogen Idec Teva AbideMedImmune Bayer Schering Genzyme Chugai and AlexionEugene Devic European Network the Grant for MultipleSclerosis Innovation the John Fell Fund the Medical ResearchCouncil the MS Society Myaware the UK National Institutefor Health Research Oxford Health Services Research Com-mittee and theGuthy-JacksonCharitable Foundation AMPLOand SPARKS Great Ormond Street for research studies out-side the submitted work MI Leite and S Sharma report nodisclosures A Roca-Fernandez is sponsored by Abide Thera-peutic outside of the submitted work and reports no potentialconflicts of interest R Kafieh A Dehghani M Pourazizi LPandit and A DrsquoCunha report no disclosures O Aktas reportsgrants from German Research Foundation (DFG) and Ger-man Ministry of Education and Research (BMBF) personalfees from Alexion and Almirall grants and personal fees fromBiogen personal fees from Merck grants and personal feesfrom Novartis grants and personal fees from Roche personalfees from Sanofi personal fees from Teva personal fees fromViela Bio outside the submitted work M Ringelstein receivedspeaker honoraria from Novartis Bayer Vital GmbH RocheAlexion and Ipsen and travel reimbursement from BayerSchering Biogen Idec Merz Genzyme Teva Roche andMerck none related to this study P Albrecht reports grants

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 9

personal fees and non-financial support from Allergan BiogenMerck Merz Pharmaceuticals Novartis Ipsen CelgeneRoche and personal fees and non-financial support from Tevaoutside the submitted work E May and C Tongco report nodisclosures L Leocani reports personal fees from RocheMerck Bristol Myers Squibb andMed-ex learning outside thesubmitted work M Pisa reports no disclosures M Radaellireports personal fees from Merck Serono Sanofi-GenzymeNovartis and Biogen outside the submitted work H Stiebel-Kalish reports no disclosures S Siritho reports personal feesfromNovartis Thailand Biogen Idec Eisai Thailandmarketingco ltd Merck Serono Teva Thailand and Menarini outsidethe submitted work J de Seze and T Senger report no dis-closures J Havla reports grants personal fees and non-financialsupport from Merck personal fees from Novartis CelgeneRoche Santhera Biogen Alexion Sanofi non-financial supportfrom Guthy-Jackson Charitable Foundation and grants fromFriedrich Baur Foundation outside the submitted work RMarignier AC Calvo D Bichuetti IM Tavares N Asgari KSoelberg A Altintas R Yildirim U Tanriverdi A Jacob SHuda Z Rimler and A Reid report no disclosures Y Mao-Draayer reports grants from NIH NIAID grants and personalfees from Genzyme grants from Chugai personal fees fromBiogen and EMD Serono grants and personal fees fromGenentech and Novartis during the conduct of the studygrants from NIH NIAID grants and personal fees from Gen-zyme grants fromChugai personal fees fromBiogen and EMDSerono grants and personal fees fromGenentech andNovartisoutside the submitted work I Soto de Castillo reports nodisclosures A Petzold reports personal fees and grants fromNovartis outside the submitted work and is part of the steeringcommittee of the OCTiMS study which is sponsored byNovartis He has not received honoraria for this activity AJGreen reports other from Bionure grants personal fees andother from Inception Sciences grants from Sherak Foundationpersonal fees and other from Pipeline Pharmaceuticals grantsfrom Hilton Foundation Adelson Foundation and NationalMS Society personal fees from JAMANeurology personal feesand other from MediimmuneViela outside the submittedwork In addition Dr Green has a patent Small Molecule drugfor Remyelination pending and has worked on testing off labelcompounds for remyelination MR Yeaman serves as an ad-visor to the Guthy-Jackson Charitable Foundation T Smithreports no disclosures AU Brandt reports grants from theGuthy Jackson Charitable Foundation during the conduct ofthe study shares from Motognosis GmbH and shares fromNocturne GmbH outside the submitted work In addition DrBrandt has a patent pending describing Foveal MorphometryF Paul reports grants from the Guthy Jackson CharitableFoundation during the conduct of the study grants from theGerman Research Foundation andGerman FederalMinistry ofEducation and research grants and other fromNovartis grantsand other from Bayer Novartis Biogen Idec Teva Sanofi-AventisGenzyme Merck Serono Chugai other from PLoSONE other from Neurologyreg Neuroimmunology amp Neuro-inflammation other from SanofiGenzyme Biogen Idec grantsfrom German Research Council Werth Stiftung of the City of

Cologne German Ministry of Education and Research ArthurArnstein Stiftung Berlin EU FP7 Framework Program ArthurArnstein Foundation Berlin National Multiple Sclerosis(USA) other from MedImmune Shire Alexion outside thesubmitted work In addition Dr Paul has a patent FovealMorphometry pending to Nocturne GmbH Go to NeurologyorgNN for full disclosures

Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationMarch 23 2021 Accepted in final form June 15 2021

Appendix Authors

Name Location Contribution

Frederike CosimaOertel MDPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data anddrafting a significantportion of themanuscript or figuresconception and designof the study

Svenja SpecoviusMSc

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of dataconception and designof the study

Hanna GZimmermannPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of dataconception and designof the study

Claudia ChienPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

SeyedamirhoseinMotamedi PhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

CharlotteBereuter BSc

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

Appendix (continued)

Name Location Contribution

Lawrence CookPhD

University of UtahSalt Lake City UT

Acquisition andanalysis of data andconception and designof the study

Marco AurelioLana Peixoto MDPhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Mariana AndradeFontanelle MD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Ho Jin Kim MDPhD

National Cancer CenterGoyang Republic of Korea

Acquisition andanalysis of data

Jae-Won HyunMD PhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

JacquelinePalace MD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Adriana Roca-Fernandez MSc

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Maria IsabelLeite MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

SrilakshmiSharma MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

FereshtehAshtari MD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Rahele KafiehPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Alireza DehghaniPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

MohsenPourazizi PhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Lekha PanditMD PhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Anitha DrsquoCunhaPhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Orhan Aktas MD Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

MariusRingelstein MD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Philipp AlbrechtMD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Eugene May MD Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Caryl Tongco Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Appendix (continued)

Name Location Contribution

Letizia LeocaniMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marco Pisa MD Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marta RadaelliMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Elena H Martinez-Lapiscina MDPhD

Hospital Clinic of Barcelona-Institut drsquoInvestigacionsBiomediques August PiSunyer Barcelona Spain

Acquisition andanalysis of data

Hadas Stiebel-Kalish MD

Sackler School of MedicineTel Aviv University Tel AvivIsrael

Acquisition andanalysis of data

Sasitorn SirithoMD

Siriraj Hospital andBumrungrad InternationalHospital Bangkok Thailand

Acquisition andanalysis of data

Jerome de SezeMD PhD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Thomas SengerMD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Joachim HavlaMD

Ludwig-MaximiliansUniversitat MuenchenMunich Germany

Acquisition andanalysis of data

RomainMarignier MDPhD

Pierre Wertheimer NeurologicalHospital Hospices Civils deLyon France

Acquisition andanalysis of data

Alvaro CoboCalvo MD PhD

Pierre WertheimerNeurological HospitalHospices Civils de LyonFrance Hospital UniversitariVall drsquoHebron UniversitatAutonoma de BarcelonaSpain

Acquisition andanalysis of data

Denis BichuettiMD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Ivan MaynartTavares MD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Nasrin AsgariMD PhD

University of SouthernDenmark OdenseDenmark

Acquisition andanalysis of data

Kerstin SoelbergMD

University of SouthernDenmark Odense Denmark

Acquisition andanalysis of data

Ayse Altintas MD Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Rengin YildirimMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 11

References1 Oertel FC Zimmermann H Paul F Brandt AU Optical coherence tomog-

raphy in neuromyelitis optica spectrum disorders potential advantages forindividualized monitoring of progression and therapy EPMA J 20189(1)21-33

2 Schneider E Zimmermann H Oberwahrenbrock T et al Optical coherence to-mography reveals distinct patterns of retinal damage in neuromyelitis optica andmultiple sclerosis PLoS One 20138(6)e66151

3 Bouyon M Collongues N Zephir H et al Longitudinal follow-up of vision in aneuromyelitis optica cohort Mult Scler 201319(10)1320-1322

4 Sotirchos ES Filippatou A Fitzgerald KC et al Aquaporin-4 IgG seropositivity isassociated with worse visual outcomes after optic neuritis than MOG-IgG seroposi-tivity and multiple sclerosis independent of macular ganglion cell layer thinningMultScler 201926(11)1360-1371

5 Hamid SHM Whittam D Mutch K et al What proportion of AQP4-IgG-negativeNMO spectrum disorder patients are MOG-IgG positive A cross sectional study of132 patients J Neurol 2017264(10)2088-2094

6 Oertel FC Kuchling J ZimmermannH et al Microstructural visual system changes inAQP4-antibody-seropositive NMOSD Neurol Neuroimmunol Neuroinflamm 20174(3)e334

7 Oertel FC Havla J Roca-Fernandez A et al Retinal ganglion cell loss in neuromyelitisoptica a longitudinal study J Neurol Neurosurg Psychiatry 201889(12)1259-1265

8 Huang D Swanson EA Lin CP et al Optical coherence tomography Science 1991254(5035)1178-1181

9 Specovius S Zimmermann HG Oertel FC et al Cohort profile a collaborativemulticentre study of retinal optical coherence tomography in 539 patients withneuromyelitis optica spectrum disorders (CROCTINO) BMJ Open 202010(10)e035397

10 Motamedi S Gawlik K Ayadi N et al Normative data and minimally detectablechange for inner retinal layer thicknesses using a semi-automated OCT image seg-mentation pipeline Front Neurol 2019101117

11 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177-189

12 von Elm E Altman DG Egger M et al The strengthening the reporting of obser-vational studies in epidemiology (STROBE) statement guidelines for reportingobservational studies Int J Surg 201412(12)1495-1499

13 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PLoS One 20127(4)e34823

14 Schippling S Balk LJ Costello F et al Quality control for retinal OCT in multiplesclerosis validation of the OSCAR-IB criteria Mult Scler 201521(2)163-170

15 Lang A Carass A Hauser M et al Retinal layer segmentation of macular OCT imagesusing boundary classification Biomed Opt Express 20134(7)1133-1152

16 R Development Core Team R A Language and Environment for Statistical Computing[online] R Foundation for Statistical Computing 2008 R-projectorg

17 Akaishi T Kaneko K Himori N et al Subclinical retinal atrophy in the unaffectedfellow eyes of multiple sclerosis and neuromyelitis optica [online serial]J Neuroimmunol 201731310-15 Accessed October 8 2017 jni-journalcomarticleS0165-5728(17)30319-3fulltext

18 Alshowaeir D Yiannikas C Fraser C Klistorner A Mechanism of delayed con-duction of fellow eyes in patients with optic neuritis Int J Ophthalmol 201811(2)329-332

19 Manogaran P Traboulsee AL Lange AP Longitudinal study of retinal nerve fiberlayer thickness and macular volume in patients with neuromyelitis optica spectrumdisorder J Neuroophthalmol 201636(4)363-368

20 Kaufhold F ZimmermannH Schneider E et al Optic neuritis is associated with innernuclear layer thickening and microcystic macular edema independently of multiplesclerosis PLoS One 20138(8)e71145

21 Knier B Schmidt P Aly L et al Retinal inner nuclear layer volume reflects response toimmunotherapy in multiple sclerosis Brain 2016139(11)2855-2863

22 Petzold A Balcer LJ Calabresi PA et al Retinal layer segmentation in multiplesclerosis a systematic review and meta-analysis Lancet Neurol 201716(10)797-812

23 Pawlitzki M Horbrugger M Loewe K et al MS optic neuritis-induced long-termstructural changes within the visual pathway Neurol Neuroimmunol Neuroinflamm20207(2)e665

24 Pache F Zimmermann H Mikolajczak J et al MOG-IgG in NMO and relateddisorders a multicenter study of 50 patients Part 4 afferent visual system damageafter optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patientsJ Neuroinflammation 201613(1)282

25 Filippatou AG Vasileiou ES He Y et al Evidence of subclinical quantitative retinallayer abnormalities in AQP4-IgG seropositive NMOSD Mult Scler 2020 Dec 141352458520977771 doi 1011771352458520977771

26 Motamedi S Oertel FC Yadav SK et al Altered fovea in AQP4-IgGndashseropositiveneuromyelitis optica spectrum disorders Neurol Neuroimmunol Neuroinflamm 20207(5)e805

27 Roca-Fernandez A Oertel FC Yeo T et al Foveal changes in AQP4-Ab seropositiveNMOSD are independent of optic neuritis and not overtly progressive Eur J Neurol202128(7)2280-2293

28 Papadopoulou A Oertel FC Chien C et al Lateral geniculate nucleus volumechanges after optic neuritis in neuromyelitis optica a longitudinal study NeuroimageClin 202130102608

29 Ringelstein M Harmel J Zimmermann H et al Longitudinal optic neuritis-unrelatedvisual evoked potential changes in NMO spectrum disorders Neurology 202094(4)e407-e418

30 Pache F Zimmermann H Finke C et al Brain parenchymal damage in neuromyelitisoptica spectrum disorderndasha multimodal MRI study Eur Radiol 201626(12)4413-4422

31 Hokari M Yokoseki A Arakawa M et al Clinicopathological features in anteriorvisual pathway in neuromyelitis optica Ann Neurol 201679(4)605-624

32 You Y Zhu L Zhang T et al Evidence of muller glial dysfunction in patients withaquaporin-4 immunoglobulin Gndashpositive neuromyelitis optica spectrum disorderOphthalmology 2019126(6)801-810 Elsevier

33 Chien C Scheel M Schmitz-Hubsch T et al Spinal cord lesions and atrophy inNMOSD with AQP4-IgG and MOG-IgG associated autoimmunityMult Scler 201925(14)1926-1936

34 Felix CM Levin MH Verkman AS Complement-independent retinal pathologyproduced by intravitreal injection of neuromyelitis optica immunoglobulin GJ Neuroinflammation 201613(1)275

35 Balk LJ Coric D Knier B et al Retinal inner nuclear layer volume reflects in-flammatory disease activity in multiple sclerosis a longitudinal OCT studyMult SclerJ Exp Transl Clin 20195(3)2055217319871582

36 Gelfand JM Nolan R Schwartz DM Graves J Green AJ Microcystic macular oedemain multiple sclerosis is associated with disease severity Brain 2012135(pt 6)1786-1793

Appendix (continued)

Name Location Contribution

Uygur TanriverdiMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Anu Jacob MD The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Saif Huda MDPhD

The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Zoe Rimler BSc NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Allyson Reid MD NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Yang Mao-Draayer MD PhD

University of MichiganMedical School AnnArbor MI

Acquisition andanalysis of data

Ibis Soto deCastillo MD

Hospital Clınico deMaracaibo MaracaiboVenezuela

Acquisition andanalysis of data

Axel Petzold MDPhD

University College LondonLondon UK

Conception anddesign of the study

Ari J Green MD University of California SanFrancisco CA

Conception anddesign of the study

Michael RYeaman MD PhD

University of California LosAngeles CA

Conception anddesign of the study

Terry Smith MD University of MichiganMedical School AnnArbor MI

Conception anddesign of the study

Alexander UBrandt MD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinBerlin Berlin Germany

Acquisition andanalysis of dataconception and designof the study anddrafting a significantportion of themanuscript or figures

Friedemann PaulMD

CharitendashUniversitatsmedizinBerlin Corporate Member ofFreie Universitat Berlin andHumboldt-Universitat zuBerlin

Acquisition andanalysis of data andconception and designof the study

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

37 Gelfand JM Cree BA Nolan R Arnow S Green AJ Microcystic inner nuclear layerabnormalities and neuromyelitis optica JAMA Neurol 201370(5)629-633

38 Oberwahrenbrock T WeinholdMMikolajczak J et al Reliability of intra-retinal layerthickness estimates PLoS One 201510(9)e0137316

39 Borisow N Kleiter I Gahlen A et al Influence of female sex and fertile age onneuromyelitis optica spectrum disorders Mult Scler 201723(8)1092-1103

40 Mori M Kuwabara S Paul F Worldwide prevalence of neuromyelitis optica spectrumdisorders J Neurol Neurosurg Psychiatry 201889(6)555-556

41 Oertel FC Paul F Accelerating clinical research in neuromyelitis optica spectrumdisorders [online serial] Clin Exp Neuroimmunol 202112(2)89-91 AccessedMarch 28 2021 periclespericles-prodliteratumonlinecomdoiabs101111cen312637

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 13

DOI 101212NXI000000000000106820218 Neurol Neuroimmunol Neuroinflamm

Frederike Cosima Oertel Svenja Specovius Hanna G Zimmermann et al Retinal Optical Coherence Tomography in Neuromyelitis Optica

This information is current as of September 15 2021

ServicesUpdated Information amp

httpnnneurologyorgcontent86e1068fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent86e1068fullhtmlref-list-1

This article cites 40 articles 7 of which you can access for free at

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Page 5: Retinal Optical Coherence Tomography in Neuromyelitis Optica

ResultsFive hundred one eyes of 283 AQP4-IgGndashseropositive pa-tients and 136 eyes of 72 HCs were included in the analysis(Table 1)

Neuroaxonal Damage After ONGCIP layer and pRNFL were reduced in NMOSD-ONcompared with NMOSD eyes without a history of ON

(NMOSD-NON) and HC (GCIP layer 814 plusmn 57 μmpRNFL 1011 plusmn 90 μm) (Figures 1A and 2A Tables 2 and3) The absolute (GCIP layer minus227 μm pRNFL minus385 μm)and relative (GCIP layer minus388 pRNFL minus616) loss ineyes with 1 ON episode (NMOSD-1-ON) compared withNMOSD-NON was higher than in eyes with 2 ON episodes(NMOSD-2-ON) compared with NMOSD-1-ON (GCIPlayer absolute loss minus35 μm relative loss minus60 pRNFLabsolute loss minus91 μm relative loss minus145 ns) The loss in

Figure 2 Group Comparisons of pRNFL Thickness

Boxplots of pRNFL thicknesses acquired by Heidelberg SD-OCT [μm] with values of individual eyes (jitter) for (A) HC (grayleft) NMOSD-NON (dark bluemiddle) and NMOSD-ON (dark redright) for (B) number of ON episodes (NMOSD-NON dark blueleft NMOSD-1-ON light redleft-middle NMOSD-2-ONmedium-redright-middle and NMOSD-ge3-ON medium-dark redright) and for (C) HC (grayleft) NMOSD-NONnon (light bluemiddle) and NMOSD-NONcon

(blueright) (D) Forest plots for results from different OCT devices for (Da) NMOSD-NON vs NMOSD-ON (Db) NMOSD-NON vs NMOSD-1-ON and (Dc)NMOSD-1-ON vs NMOSD-2-ON (eFigure 3 and eTable 3 linkslwwcomNXIA556 and linkslwwcomNXIA557) HC = eyes of HCs NMOSD-NON = eyes ofpatients with neuromyelitis optica without a history of optic neuritis NMOSD-NON-con = eyes of patients with neuromyelitis optica without a history of opticneuritis but a history of contralateral optic neuritis NMOSD-NONnon = eyes of patients with neuromyelitis optica without a history of ipsilateral or contra-lateral optic neuritis NMOSD-ON = eyes of patients with neuromyelitis optica with a history of optic neuritis NMOSD-1-ON = eyes of patients withneuromyelitis optica with a history of 1 optic neuritis episode NMOSD-2-ON = eyes of patients with neuromyelitis optica with a history of 2 optic neuritisepisodes ON = optic neuritis pRNFL = peripapillary retinal nerve fiber layer

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 5

eyes with ge3-ON episodes (NMOSD-3-ON) was lowercompared with NMOSD-2-ON (ns) (Figures 1B and 2B)Five NMOSD-NON eyes had pRNFL values lt 60 μm thesepatients had no relevant comorbidities but a history of con-tralateral ON1718 In sensitivity analyses to account for devicedifferences all significant analyses within the NMOSD cohortwere confirmed for data acquired by Cirrus and Topcon OCTdevices (eFigures 2 and 3 eTables 3 and 4 linkslwwcomNXIA556 linkslwwcomNXIA557)

Neuroaxonal Damage Without ONNMOSD-NON eyes had a reduced GCIP layer (759 plusmn 77 μmplt 0001) but not pRNFL (953 plusmn 144 μm) comparedwithHC(GCIP layer 814 plusmn 57 μm pRNFL 1011 plusmn 90 μm Figures 1Aand 2A Tables 2 and 3) By comparison only 28 NMOSD-NON eyes (51) had a GCIP layer le the 5th percentile of HCGCIP layer was also reduced inNMOSD-NONwith a history ofcontralateral ON (729 plusmn 102 μm) compared with NMOSD-NON without a history of contralateral ON (773 plusmn 59 μm p =0025 NMOSD-NONnon) This effect vanished when onlyconsidering NMOSD-NONcon with a history of 1 contralateralON (736 plusmn 94 μm) However only NMOSD-NONcon (p lt

0001) but not NMOSD-NONnon (p = 0061) had thinnedGCIP layer compared with HC (Figures 1C and 2C)

INL ChangesINL was thicker in NMOSD-ON compared with HC (394 plusmn26 μm) and NMOSD-NON (eTable 4 linkslwwcomNXIA557) Specifically INL was thicker in eyes with 1 ON episodecompared with NMOSD-NON but did not differ between eyeswith different numbers of ON episodes Also INL did not differbetween NMOSD-NONcon (389 plusmn 32 μm) and NMOSD-NONnon (385 plusmn 32 μm p = 0931) In all patients INLthickness (as the dependent variable in the linear mixed modeldescribed above) was correlated with thinner GCIP layer (B =minus011 standard error [SE] = 001 p lt 0001) and pRNFL (B =minus006 SE = 001 p lt 0001) This correlation existed inNMOSD-ON (GCIP layer B = minus 008 SE = 003 p = 0005pRNFL B = minus 006 SE = 001 p lt 0001) and not present inNMOSD-NON (eFigure 4 linkslwwcomNXIA556)

Scans of 363 NMOSD eyes were clearly suitable for MMEinvestigations (high quality eFigure 4C linkslwwcomNXIA556) MMEs were visible in 24 (66) eyes of 21 patients

Table 2 Group Comparisons of GCIP Layer Thickness for Heidelberg SD-OCT

No ofeyes

Thickness (μmmean plusmn SD)

Comparisonto

Absolutedifference (μmmean)

Relativedifference (mean) B SE p Value R2

marg R2cond

Combinedp value

NMOSD 268 673 plusmn 136 HCs minus140 minus208 156 20 lt00001 0143 0690 mdash

NMOSD-ON

124 574 plusmn 122 minus240 minus418 250 20 lt00001 0482 0839 mdash

NMOSD-NON

144 759 plusmn 77 minus54 minus72 58 14 lt00001 0088 0947 mdash

NMOSD-NONnon

99 773 plusmn 59 minus40 minus50 269 142 0061 0189 0924 mdash

NMOSD-NONcon

45 729 plusmn 102 minus85 minus104 844 177 lt00001 0260 0985 mdash

NMOSD-ON

124 574 plusmn 122 NMOSD-NON

minus185 minus244 minus158 11 lt00001 0430 0795 59e245

NMOSD-1-ON

76 586 plusmn 129 minus173 minus228 minus145 12 lt00001 0417 0803 14e233

NMOSD-2-ON

28 551 plusmn 94 NMOSD-1-ON

minus35 minus60 minus57 26 0028 0143 0729 0038

NMOSD-ge3-ON

20 559 plusmn 128 NMOSD-2-ON

08 14 49 26 0070 0311 0781 0222

NMOSD-NONcon

45 729 plusmn 102 NMOSD-NONnon

minus44 minus61 minus38 17 0025 0111 0701 0004

NMOSD-NON1-con

37 736 plusmn 94 minus37 minus51 minus35 16 0037 0149 0906 0154

Abbreviations AQP4-IgG = aquaporin-4 IgG B = estimate GCIP = ganglion cell and inner plexiformNMOSD=AQP4-IgGndashseropositiveNMOSD NMOSD-NON=AQP4-IgGndashseropositive NMOSD eyeswithout a history of ON NMOSD-NONnon = AQP4-IgGndashseropositive NMOSD eyeswithout a history ofONor contralateralON NMOSD-NONcon = AQP4-IgGndashseropositive NMOSD eyes without a history of ON but with a history of contralateral ON NMOSD-NON1-con = AQP4-IgGndashseropositive NMOSD eyes without a history of ON but with a history of 1 contralateral ON NMOSD-ON = AQP4-IgGndashseropositive NMOSD eyes with ahistory of ON NMOSD-1-ON =AQP4-IgGndashseropositive NMOSD eyeswith a history of 1ON NMO-2-ON =AQP4-IgGndashseropositive NMOSD eyeswith a history of2 ONs NMOSD-ge3-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 3 or more ONs NMOSD = neuromyelitis optica spectrum disorder NMOSD-NON = NMOSD eyes without a history of ON OCT = optical coherence tomography ON = optic neuritis episode Rcon = conditional R-squared Rmarg =marginal R-squared SE = standard error

6 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

Twenty-three eyes (131) of NMOSD-ON and 1 eye (05)of NMOSD-NON (with a history of contralateral ON) wereaffected The number of ON episodes did not influence theincidence of MMEs (NMOSD-1-ONN = 16 (14) NMOSD-2-ON N = 4 (114) NMOSD-ge3-ON N = 3 (111))

Including only the most frequent ethnicities in our data set(Asian and non-HispanicWhite) results did not differ and noethnicity was singled out regarding its pattern of injury (datanot shown)

OCT and Vision LossHC-VA was numerically reduced in NMOSD (025 plusmn 048)compared with HC (minus001 plusmn 008) and known healthy referencevalues NMOSD-ON also had reduced HC-VA (044 plusmn 058)compared with NMOSD-NON (004 plusmn 020 p lt 0001 p =0401) and HChealthy reference populations HC-VA wascorrelated with GCIP layer (B = minus0016 SE = 0002 p lt 0001)and pRNFL thicknesses (B = minus0010 SE = 0001 p lt 0001) inAQP4-IgGndashseropositive NMOSD AQP4-IgGndashseropositiveNMOSD eyes with prolonged VEP latency had a thinned GCIP

layer (B = minus11647 SE = 3628 p = 0002) and pRNFL (B =minus21965 SE = 3724 p lt 0001) EDSS score as ametric of globaldisability was inversely correlated with GCIP layer (B = minus1370SE= 0566 p= 0017) and pRNFL thicknesses (B= minus3148 SE=1080 p = 0004)

DiscussionOur study specifies a severe and functionally relevant decreaseof GCIP layer and pRNFL in NMOSD-ON compared withNMOSD-NON and HCs in AQP4-IgGndashseropositive pa-tients Neuroaxonal damage is particularly large from the firstepisode of ON where contribution to retinal damage insubsequent episodes of ON is still considerable but smaller Incontrast to previous smaller studies the current study ascer-tains GCIP layer but not pRNFL thinning in NMOSD-NONcompared with HC619 This effect was driven by eyes withcontralateral ON and not statistically significant in eyeswithout a history of ON INL was thicker in NMOSD-ONand was inversely correlated with GCIP layer Of note 131

Table 3 GroupComparisons of pRNFL ThicknessWith (A) Spectralis SD-OCTData for Comparisons vsHC (B) Data FromAllDevices for Intrapatient Cohort Comparisons

No ofeyes

Thickness (μmmean plusmn SD)

Comparisonto

Absolute difference(μm mean)

Relativedifference (mean) B SE p Value R2

marg R2cond

Combinedp value

NMOSD 344 763 plusmn 274 HCs minus140 minus326 242 43 lt00001 0143 0690 mdash

NMOSD-ON

170 569 plusmn 237 minus443 minus779 431 41 lt00001 0482 0839 mdash

NMOSD-NON

174 953 plusmn 144 minus59 minus62 46 30 0129 0088 0947 mdash

NMOSD-NONnon

116 974 plusmn 109 minus37 minus37 minus29 22 0204 0107 0893 mdash

NMOSD-NONcon

58 910 plusmn 191 minus47 minus46 71 42 0097 0100 0975 mdash

NMOSD-ON

170 569 plusmn 237 NMOSD-NON

minus384 minus403 minus338 21 lt00001 0436 0741 44e260

NMOSD-1-ON

97 626 plusmn 249 minus327 minus343 minus296 22 lt00001 0379 0712 46e240

NMOSD-2-ON

35 535 plusmn 213 NMOSD-1-ON

minus91 minus145 minus107 47 0024 0087 0528 0010

NMOSD-ge3-ON

38 452 plusmn 178 NMOSD-2-ON

minus83 minus155 minus04 43 0924 0087 0719 0838

NMOSD-NONcon

58 910 plusmn 191 NMOSD-NONnon

minus65 minus71 minus40 29 0173 0061 0939 0157

NMOSD-NON1-con

47 932 plusmn 181 minus42 minus46 minus32 29 0276 0056 0925 0616

Abbreviations AQP4-IgG = aquaporin-4 IgG NMOSD = AQP4-IgGndashseropositive NMOSD NMOSD-NON = AQP4-IgGndashseropositive NMOSD eyes without ahistory of ON NMOSD-NONnon = AQP4-IgGndashseropositive NMOSD eyes without a history of ON or contralateral ON NMOSD-NONcon = AQP4-IgGndashseropositive NMOSD eyes without a history of ON but with a history of contralateral ON NMOSD-NONcon = AQP4-IgGndashseropositive NMOSD eyes without ahistory of ON but with a history of 1 contralateral ON NMOSD-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of ON NMOSD-1-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 1 ON NMOSD-2-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 2 ONs NMOSD-ge3-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 3 or more ONs NMOSD = neuromyelitis optica spectrum disorder NMOSD-NON = NMOSD eyes without ahistory of ON OCT = optical coherence tomography ON = optic neuritis episode pRNFL = peripapillary retinal nerve fiber layer VEP = visually evokedpotential

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 7

of NMOSD-ON eyes showed MME indicative of secondaryinflammatory changes2021 This investigation overcame limitsof small samples and OCT data heterogeneity of earlierstudies through use of an international consortium ofNMOSD specialists This framework substantiated theCROCTINO studymdasha large multicenter retrospectiveevaluation of retinal pathology in NMOSD using OCT

The neuroaxonal degeneration in NMOSD-ON demon-strated here is substantially greater than reported changes inmultiple sclerosis (MS) a common differential diagnosis222

In a meta-analysis an average pRNFL loss of 20 μm wasestimated in MS after ON which is nearly 2-fold higher in ourNMOSD-ON cohort (minus384 μm)22 For GCIP layer our datasuggested approximately 15-fold higher loss in NMOSD(minus240 μm) compared with MS22 These differences not onlyresult from a higher ON frequency but may also be caused bymore severe retinal damage in NMOSD after a singular ON23

It is intriguing that the damage is particularly large after thefirst ON episode with smaller losses after subsequent epi-sodes which might be due to less neuroaxonal content insubsequent episodes224 Alternatively although the analysisof treatment effects exceeds the scope of this study it ispossible that the longer time to effective anti-inflammatorytherapy and the typical choice of less effective therapies (egsteroids instead of plasma exchange) at the first attack com-pared with following attacks may significantly contribute tothis difference Independent of the number of ONs the per-cent loss is smaller in GCIP layer compared with pRNFLndashpointing toward either (1) stronger loss of retinal nerve fibersthan retinal ganglion cells (2) impairment of ganglion cellsnot leading to extinction but axonal loss (3) a larger amountof non-neuronal tissue in GCIP layer or (4) RNFL loss in theperiphery beyond the macular area measured by GCIP layerThese hypotheses are not mutually exclusive and each mightcontribute to the effect Consistent with these concepts ex-cessive vision loss relative to neuroaxonal content and VEPlatency in AQP4-IgGndashseropositive patients compared withMOG-IgGndashseropositive and MS patients implies damage ofthe peripheral retina and optic nerve tissues which are notreflected in the macula and pattern VEP measurements4

Whether attack-independent neurodegeneration inAQP4-IgGndashseropositive NMOSD occurs has beencontroversial26725-28 The current study identifies de-creased GCIP layer in NMOSD-NON compared withHC but not pRNFL Such subclinical changes could becaused by contralateral involvement after unilateralON1718 Indeed our cohort suggests pronounced neu-rodegeneration in eyes with contralateral ON Howevereyes of patients without ON also exhibit a trend for thinnerGCIP layer compared with HCs Underscored by longitu-dinal studies showing ON-independent neurodegenerationand VEP latency prolongation729 such patterns suggest atleast 2 mechanisms of injury (1) a primary retinopathy oroptic neuropathy in context of an astrocytopathy or causedby direct damage to AQP4-expressing cells such as astrocytes

and Muller cells by either AQP4-IgG or AQP4-specificT cells or (2) a global or afferent visual system specificchronic or episodic neurodegenerative process Because le-sions often spare the brain and most studies outside ofpredisposed areas such as optic nerve and spinal cord failedto detect effects30 a constant global involvement seemsunlikely Several studies described changes affecting AQP4expression and astrocytic end feet31 parafoveal changes inagreement with an involvement of AQP4-expressing Mullercell6262732 and attack-independent spinal cord atrophy33

These findings are consistent with tissue infiltration byAQP4-IgGndashspecific T cells34 and the attack-independentloss of retinal ganglion cells7mdashfurther supporting the exis-tence of an ON-independent pathology which might berestricted to the main disease foci The latter hypothesescould be addressed by region-specific pathology or advancedimaging studies

INL changes have been suggested as a marker of neuro-inflammation and potential treatment response in MS213536

MME may develop as a consequence of neurodegenerationor othermdashnonndashdisease-specificmdashprocesses35 Patients withNMOSD were described to have INL thickening andMME2037 In our cohort 131 of NMOSD-ON eyes wereaffected byMME which is higher than the 2ndash5 described inMS but comparable to incidences in NMOSD described beforeby Gelfand and colleagues3537 However INL thickening itselfremained comparable to changes reported in MS35 This dis-parity could reflect a disrupted fluid homeostasis due to Mullercell involvement or loss of content of the INL with a parallelinflammatory reaction and development of MME The limitedaccessibility of MMEs especially in severely affected eyes due tolimited image quality has hindered their detailed assessmentsand most likely leads to underestimation of their incidence38

We demonstrate that the INL thickness is inversely correlatedwith neuroaxonal content and could be a valuable marker ofdisease severity also in NMOSD

Our study cohort was representative of patients with AQP4-IgGndashseropositive NMOSD with respect to a female pre-dominance and ON history1139 This OCT study includedmultiple ethnicity backgrounds although the distribution wasshifted toward CaucasianWhite patients and other ethnic-ities were underrepresented (eg Hispanic White and Black)limiting the generalizability of results40 Patients from differ-ent heritages presented similar findings

The current study was based on source data instead of a meta-analysis Using the Guthy-Jackson Charitable Foundation net-work this multicentric study was conducted without investigatorreimbursement and illustrated how collaboration integratinginternational perspectives can produce meaningful results Toovercome technical challenges of heterogeneous source data wedeveloped novel OCT postprocessing techniques allowing us toperform standardized analyses and enabling the uniform analysisof the largest OCT image data set in NMOSD to date10 Thusthe strengths of CROCTINO include its established

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

infrastructure large international network of experts represent-ing multiple ethnicities and geographic regions and the use ofstate-of-the-art OCT postprocessing techniques41

We recognize limitations of the current investigation Theretrospective and heterogeneous data acquisition might haveled to biases and impreciseness beyond the ability of ourquality control We addressed this by excluding uncertaincases HCs were only included from a limited number ofcenters The unbalanced data set limited some analyses suchas the influence of ethnicities or acute and disease-modifyingtreatments Case-control matching was impossible particu-larly with respect to subclinical progression dependent orindependent of ON and to ethnicity Similarly comparisonswith other NMOSD subtypes or MS were beyond the scopeof this study Longitudinal data acute ON data and AQP4-IgGndashseronegative and MOG-IgGndashseropositive patient dataare part of the CROCTINO data set and will be analyzed inthe future Also OCT data processing was performed bymultiple raters potentially introducing interrater variabilityMRI data and posterior visual pathway involvement were notinvestigated in this study However the current study ach-ieved an unprecedented worldwide assessment of retinaldamage in AQP4-IgGndashseropositive NMOSD

To conclude AQP4-IgGndashseropositive NMOSD is characterizedby a severe functionally relevant retinal neurodegeneration as aconsequence of ON Although the majority of damage occursduring the first episode there is cumulative loss with each suc-ceeding relapse TheON-associated damage is not limited to theneuroaxonal content but can also inducemdashlikely inflammation-mediatedmdashINL increase and occurrence ofMMEOur data alsosuggest attack-independent retinal damage in AQP4-IgGndashseropositive NMOSD Our study supports that at-tack prevention is key in avoiding neuroaxonal damage andvision loss in patients with NMOSD It further suggests thatthe first ON episode causes the most damage where onlysome patients with then established diagnosis will be on im-munosuppressive therapy This highlights the need for ef-fective therapies that can ameliorate an ongoing attack orregenerate attack-generated damage which is an unmet clin-ical need Last the study emphasizes the utility of OCT as asensitive structural metric and its potential for monitoringprogression and even treatment response in AQP4-IgGndashseropositive NMOSD The international CROCTINOprogram provides an unprecedented opportunity to applyOCT in a standardized manner to assess pathophysiologyclinical course and therapeutic efficacy in NMOSD

Study FundingGuthy-Jackson Charitable Foundation (GJCF) and GermanResearch Foundation (DFG)

DisclosureFC Oertel was employee of Nocturne GmbH and receivesresearch support by the American Academy of Neurology andthe National Multiple Sclerosis Society unrelated to this work

S Specovius reports no disclosures HG Zimmerman reportsresearch grants from Novartis and speaking honoraria fromBayer Healthcare unrelated to this study C Chien reportsspeaking honoraria from Bayer Healthcare unrelated to thiswork S Motamedi and C Bereuter report no disclosures LCook reports grants from Guthy Jackson Charitable Founda-tion during the conduct of the study EH Martinez-Lapiscinais employed by the European Medicines Agency (HumanMedicines) since 16 April 2019 This article is related with heractivity under Hospital Clinic of BarcelonaIDIBAPS affiliationand consequently as external activity it does not represent theviews of the Agency its Committees or working parties Beforeenrolling EMA Dr Martinez-Lapiscina reports grants fromInstituto de Salud Carlos III (Spain) amp Fondo Europeo deDesarrollo Regional grants from MS Innovation GMSI otherfromFundacio Privada Cellex and personal fees fromNovartisRoche Sanofi-Genzyme outside the submitted work MALana Peixoto and MA Fontanelle report no disclosures HJKim reports grants from the National Research Foundation ofKorea personal fees from Alexion Pharmaceuticals AprilbioBiogen Celltrion Eisai HanAll BioPharma MDimune MerckSerono Novartis Sanofi Genzyme Teva-Handok and VielaBio other from Viela Bio (formerly MedImmune) MultipleSclerosis Journal and Journal of Clinical Neurology outsidethe submitted work J-W Hyun reports grants from the Na-tional Research Foundation of Korea outside the submittedwork J Palace reports personal fees from Abide TherapeuticsAlexion Pharmaceuticals ARGENX Bayer Schering BiogenIdec Chugai Pharma EuroImmun Genzyme MedDayMedImmuneMerck Serono Novartis Roche Teva UCB andViela Bio grants from Abide Therapeutics Alexion Pharma-ceuticals Bayer Schering Biogen Idec Chugai Pharma Gen-zyme MedImmune Merck Serono Novartis and Teva grantsfrom Merck Serono Novartis Biogen Idec Teva AbideMedImmune Bayer Schering Genzyme Chugai and AlexionEugene Devic European Network the Grant for MultipleSclerosis Innovation the John Fell Fund the Medical ResearchCouncil the MS Society Myaware the UK National Institutefor Health Research Oxford Health Services Research Com-mittee and theGuthy-JacksonCharitable Foundation AMPLOand SPARKS Great Ormond Street for research studies out-side the submitted work MI Leite and S Sharma report nodisclosures A Roca-Fernandez is sponsored by Abide Thera-peutic outside of the submitted work and reports no potentialconflicts of interest R Kafieh A Dehghani M Pourazizi LPandit and A DrsquoCunha report no disclosures O Aktas reportsgrants from German Research Foundation (DFG) and Ger-man Ministry of Education and Research (BMBF) personalfees from Alexion and Almirall grants and personal fees fromBiogen personal fees from Merck grants and personal feesfrom Novartis grants and personal fees from Roche personalfees from Sanofi personal fees from Teva personal fees fromViela Bio outside the submitted work M Ringelstein receivedspeaker honoraria from Novartis Bayer Vital GmbH RocheAlexion and Ipsen and travel reimbursement from BayerSchering Biogen Idec Merz Genzyme Teva Roche andMerck none related to this study P Albrecht reports grants

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 9

personal fees and non-financial support from Allergan BiogenMerck Merz Pharmaceuticals Novartis Ipsen CelgeneRoche and personal fees and non-financial support from Tevaoutside the submitted work E May and C Tongco report nodisclosures L Leocani reports personal fees from RocheMerck Bristol Myers Squibb andMed-ex learning outside thesubmitted work M Pisa reports no disclosures M Radaellireports personal fees from Merck Serono Sanofi-GenzymeNovartis and Biogen outside the submitted work H Stiebel-Kalish reports no disclosures S Siritho reports personal feesfromNovartis Thailand Biogen Idec Eisai Thailandmarketingco ltd Merck Serono Teva Thailand and Menarini outsidethe submitted work J de Seze and T Senger report no dis-closures J Havla reports grants personal fees and non-financialsupport from Merck personal fees from Novartis CelgeneRoche Santhera Biogen Alexion Sanofi non-financial supportfrom Guthy-Jackson Charitable Foundation and grants fromFriedrich Baur Foundation outside the submitted work RMarignier AC Calvo D Bichuetti IM Tavares N Asgari KSoelberg A Altintas R Yildirim U Tanriverdi A Jacob SHuda Z Rimler and A Reid report no disclosures Y Mao-Draayer reports grants from NIH NIAID grants and personalfees from Genzyme grants from Chugai personal fees fromBiogen and EMD Serono grants and personal fees fromGenentech and Novartis during the conduct of the studygrants from NIH NIAID grants and personal fees from Gen-zyme grants fromChugai personal fees fromBiogen and EMDSerono grants and personal fees fromGenentech andNovartisoutside the submitted work I Soto de Castillo reports nodisclosures A Petzold reports personal fees and grants fromNovartis outside the submitted work and is part of the steeringcommittee of the OCTiMS study which is sponsored byNovartis He has not received honoraria for this activity AJGreen reports other from Bionure grants personal fees andother from Inception Sciences grants from Sherak Foundationpersonal fees and other from Pipeline Pharmaceuticals grantsfrom Hilton Foundation Adelson Foundation and NationalMS Society personal fees from JAMANeurology personal feesand other from MediimmuneViela outside the submittedwork In addition Dr Green has a patent Small Molecule drugfor Remyelination pending and has worked on testing off labelcompounds for remyelination MR Yeaman serves as an ad-visor to the Guthy-Jackson Charitable Foundation T Smithreports no disclosures AU Brandt reports grants from theGuthy Jackson Charitable Foundation during the conduct ofthe study shares from Motognosis GmbH and shares fromNocturne GmbH outside the submitted work In addition DrBrandt has a patent pending describing Foveal MorphometryF Paul reports grants from the Guthy Jackson CharitableFoundation during the conduct of the study grants from theGerman Research Foundation andGerman FederalMinistry ofEducation and research grants and other fromNovartis grantsand other from Bayer Novartis Biogen Idec Teva Sanofi-AventisGenzyme Merck Serono Chugai other from PLoSONE other from Neurologyreg Neuroimmunology amp Neuro-inflammation other from SanofiGenzyme Biogen Idec grantsfrom German Research Council Werth Stiftung of the City of

Cologne German Ministry of Education and Research ArthurArnstein Stiftung Berlin EU FP7 Framework Program ArthurArnstein Foundation Berlin National Multiple Sclerosis(USA) other from MedImmune Shire Alexion outside thesubmitted work In addition Dr Paul has a patent FovealMorphometry pending to Nocturne GmbH Go to NeurologyorgNN for full disclosures

Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationMarch 23 2021 Accepted in final form June 15 2021

Appendix Authors

Name Location Contribution

Frederike CosimaOertel MDPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data anddrafting a significantportion of themanuscript or figuresconception and designof the study

Svenja SpecoviusMSc

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of dataconception and designof the study

Hanna GZimmermannPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of dataconception and designof the study

Claudia ChienPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

SeyedamirhoseinMotamedi PhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

CharlotteBereuter BSc

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

Appendix (continued)

Name Location Contribution

Lawrence CookPhD

University of UtahSalt Lake City UT

Acquisition andanalysis of data andconception and designof the study

Marco AurelioLana Peixoto MDPhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Mariana AndradeFontanelle MD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Ho Jin Kim MDPhD

National Cancer CenterGoyang Republic of Korea

Acquisition andanalysis of data

Jae-Won HyunMD PhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

JacquelinePalace MD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Adriana Roca-Fernandez MSc

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Maria IsabelLeite MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

SrilakshmiSharma MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

FereshtehAshtari MD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Rahele KafiehPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Alireza DehghaniPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

MohsenPourazizi PhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Lekha PanditMD PhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Anitha DrsquoCunhaPhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Orhan Aktas MD Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

MariusRingelstein MD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Philipp AlbrechtMD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Eugene May MD Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Caryl Tongco Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Appendix (continued)

Name Location Contribution

Letizia LeocaniMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marco Pisa MD Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marta RadaelliMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Elena H Martinez-Lapiscina MDPhD

Hospital Clinic of Barcelona-Institut drsquoInvestigacionsBiomediques August PiSunyer Barcelona Spain

Acquisition andanalysis of data

Hadas Stiebel-Kalish MD

Sackler School of MedicineTel Aviv University Tel AvivIsrael

Acquisition andanalysis of data

Sasitorn SirithoMD

Siriraj Hospital andBumrungrad InternationalHospital Bangkok Thailand

Acquisition andanalysis of data

Jerome de SezeMD PhD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Thomas SengerMD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Joachim HavlaMD

Ludwig-MaximiliansUniversitat MuenchenMunich Germany

Acquisition andanalysis of data

RomainMarignier MDPhD

Pierre Wertheimer NeurologicalHospital Hospices Civils deLyon France

Acquisition andanalysis of data

Alvaro CoboCalvo MD PhD

Pierre WertheimerNeurological HospitalHospices Civils de LyonFrance Hospital UniversitariVall drsquoHebron UniversitatAutonoma de BarcelonaSpain

Acquisition andanalysis of data

Denis BichuettiMD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Ivan MaynartTavares MD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Nasrin AsgariMD PhD

University of SouthernDenmark OdenseDenmark

Acquisition andanalysis of data

Kerstin SoelbergMD

University of SouthernDenmark Odense Denmark

Acquisition andanalysis of data

Ayse Altintas MD Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Rengin YildirimMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 11

References1 Oertel FC Zimmermann H Paul F Brandt AU Optical coherence tomog-

raphy in neuromyelitis optica spectrum disorders potential advantages forindividualized monitoring of progression and therapy EPMA J 20189(1)21-33

2 Schneider E Zimmermann H Oberwahrenbrock T et al Optical coherence to-mography reveals distinct patterns of retinal damage in neuromyelitis optica andmultiple sclerosis PLoS One 20138(6)e66151

3 Bouyon M Collongues N Zephir H et al Longitudinal follow-up of vision in aneuromyelitis optica cohort Mult Scler 201319(10)1320-1322

4 Sotirchos ES Filippatou A Fitzgerald KC et al Aquaporin-4 IgG seropositivity isassociated with worse visual outcomes after optic neuritis than MOG-IgG seroposi-tivity and multiple sclerosis independent of macular ganglion cell layer thinningMultScler 201926(11)1360-1371

5 Hamid SHM Whittam D Mutch K et al What proportion of AQP4-IgG-negativeNMO spectrum disorder patients are MOG-IgG positive A cross sectional study of132 patients J Neurol 2017264(10)2088-2094

6 Oertel FC Kuchling J ZimmermannH et al Microstructural visual system changes inAQP4-antibody-seropositive NMOSD Neurol Neuroimmunol Neuroinflamm 20174(3)e334

7 Oertel FC Havla J Roca-Fernandez A et al Retinal ganglion cell loss in neuromyelitisoptica a longitudinal study J Neurol Neurosurg Psychiatry 201889(12)1259-1265

8 Huang D Swanson EA Lin CP et al Optical coherence tomography Science 1991254(5035)1178-1181

9 Specovius S Zimmermann HG Oertel FC et al Cohort profile a collaborativemulticentre study of retinal optical coherence tomography in 539 patients withneuromyelitis optica spectrum disorders (CROCTINO) BMJ Open 202010(10)e035397

10 Motamedi S Gawlik K Ayadi N et al Normative data and minimally detectablechange for inner retinal layer thicknesses using a semi-automated OCT image seg-mentation pipeline Front Neurol 2019101117

11 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177-189

12 von Elm E Altman DG Egger M et al The strengthening the reporting of obser-vational studies in epidemiology (STROBE) statement guidelines for reportingobservational studies Int J Surg 201412(12)1495-1499

13 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PLoS One 20127(4)e34823

14 Schippling S Balk LJ Costello F et al Quality control for retinal OCT in multiplesclerosis validation of the OSCAR-IB criteria Mult Scler 201521(2)163-170

15 Lang A Carass A Hauser M et al Retinal layer segmentation of macular OCT imagesusing boundary classification Biomed Opt Express 20134(7)1133-1152

16 R Development Core Team R A Language and Environment for Statistical Computing[online] R Foundation for Statistical Computing 2008 R-projectorg

17 Akaishi T Kaneko K Himori N et al Subclinical retinal atrophy in the unaffectedfellow eyes of multiple sclerosis and neuromyelitis optica [online serial]J Neuroimmunol 201731310-15 Accessed October 8 2017 jni-journalcomarticleS0165-5728(17)30319-3fulltext

18 Alshowaeir D Yiannikas C Fraser C Klistorner A Mechanism of delayed con-duction of fellow eyes in patients with optic neuritis Int J Ophthalmol 201811(2)329-332

19 Manogaran P Traboulsee AL Lange AP Longitudinal study of retinal nerve fiberlayer thickness and macular volume in patients with neuromyelitis optica spectrumdisorder J Neuroophthalmol 201636(4)363-368

20 Kaufhold F ZimmermannH Schneider E et al Optic neuritis is associated with innernuclear layer thickening and microcystic macular edema independently of multiplesclerosis PLoS One 20138(8)e71145

21 Knier B Schmidt P Aly L et al Retinal inner nuclear layer volume reflects response toimmunotherapy in multiple sclerosis Brain 2016139(11)2855-2863

22 Petzold A Balcer LJ Calabresi PA et al Retinal layer segmentation in multiplesclerosis a systematic review and meta-analysis Lancet Neurol 201716(10)797-812

23 Pawlitzki M Horbrugger M Loewe K et al MS optic neuritis-induced long-termstructural changes within the visual pathway Neurol Neuroimmunol Neuroinflamm20207(2)e665

24 Pache F Zimmermann H Mikolajczak J et al MOG-IgG in NMO and relateddisorders a multicenter study of 50 patients Part 4 afferent visual system damageafter optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patientsJ Neuroinflammation 201613(1)282

25 Filippatou AG Vasileiou ES He Y et al Evidence of subclinical quantitative retinallayer abnormalities in AQP4-IgG seropositive NMOSD Mult Scler 2020 Dec 141352458520977771 doi 1011771352458520977771

26 Motamedi S Oertel FC Yadav SK et al Altered fovea in AQP4-IgGndashseropositiveneuromyelitis optica spectrum disorders Neurol Neuroimmunol Neuroinflamm 20207(5)e805

27 Roca-Fernandez A Oertel FC Yeo T et al Foveal changes in AQP4-Ab seropositiveNMOSD are independent of optic neuritis and not overtly progressive Eur J Neurol202128(7)2280-2293

28 Papadopoulou A Oertel FC Chien C et al Lateral geniculate nucleus volumechanges after optic neuritis in neuromyelitis optica a longitudinal study NeuroimageClin 202130102608

29 Ringelstein M Harmel J Zimmermann H et al Longitudinal optic neuritis-unrelatedvisual evoked potential changes in NMO spectrum disorders Neurology 202094(4)e407-e418

30 Pache F Zimmermann H Finke C et al Brain parenchymal damage in neuromyelitisoptica spectrum disorderndasha multimodal MRI study Eur Radiol 201626(12)4413-4422

31 Hokari M Yokoseki A Arakawa M et al Clinicopathological features in anteriorvisual pathway in neuromyelitis optica Ann Neurol 201679(4)605-624

32 You Y Zhu L Zhang T et al Evidence of muller glial dysfunction in patients withaquaporin-4 immunoglobulin Gndashpositive neuromyelitis optica spectrum disorderOphthalmology 2019126(6)801-810 Elsevier

33 Chien C Scheel M Schmitz-Hubsch T et al Spinal cord lesions and atrophy inNMOSD with AQP4-IgG and MOG-IgG associated autoimmunityMult Scler 201925(14)1926-1936

34 Felix CM Levin MH Verkman AS Complement-independent retinal pathologyproduced by intravitreal injection of neuromyelitis optica immunoglobulin GJ Neuroinflammation 201613(1)275

35 Balk LJ Coric D Knier B et al Retinal inner nuclear layer volume reflects in-flammatory disease activity in multiple sclerosis a longitudinal OCT studyMult SclerJ Exp Transl Clin 20195(3)2055217319871582

36 Gelfand JM Nolan R Schwartz DM Graves J Green AJ Microcystic macular oedemain multiple sclerosis is associated with disease severity Brain 2012135(pt 6)1786-1793

Appendix (continued)

Name Location Contribution

Uygur TanriverdiMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Anu Jacob MD The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Saif Huda MDPhD

The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Zoe Rimler BSc NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Allyson Reid MD NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Yang Mao-Draayer MD PhD

University of MichiganMedical School AnnArbor MI

Acquisition andanalysis of data

Ibis Soto deCastillo MD

Hospital Clınico deMaracaibo MaracaiboVenezuela

Acquisition andanalysis of data

Axel Petzold MDPhD

University College LondonLondon UK

Conception anddesign of the study

Ari J Green MD University of California SanFrancisco CA

Conception anddesign of the study

Michael RYeaman MD PhD

University of California LosAngeles CA

Conception anddesign of the study

Terry Smith MD University of MichiganMedical School AnnArbor MI

Conception anddesign of the study

Alexander UBrandt MD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinBerlin Berlin Germany

Acquisition andanalysis of dataconception and designof the study anddrafting a significantportion of themanuscript or figures

Friedemann PaulMD

CharitendashUniversitatsmedizinBerlin Corporate Member ofFreie Universitat Berlin andHumboldt-Universitat zuBerlin

Acquisition andanalysis of data andconception and designof the study

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

37 Gelfand JM Cree BA Nolan R Arnow S Green AJ Microcystic inner nuclear layerabnormalities and neuromyelitis optica JAMA Neurol 201370(5)629-633

38 Oberwahrenbrock T WeinholdMMikolajczak J et al Reliability of intra-retinal layerthickness estimates PLoS One 201510(9)e0137316

39 Borisow N Kleiter I Gahlen A et al Influence of female sex and fertile age onneuromyelitis optica spectrum disorders Mult Scler 201723(8)1092-1103

40 Mori M Kuwabara S Paul F Worldwide prevalence of neuromyelitis optica spectrumdisorders J Neurol Neurosurg Psychiatry 201889(6)555-556

41 Oertel FC Paul F Accelerating clinical research in neuromyelitis optica spectrumdisorders [online serial] Clin Exp Neuroimmunol 202112(2)89-91 AccessedMarch 28 2021 periclespericles-prodliteratumonlinecomdoiabs101111cen312637

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 13

DOI 101212NXI000000000000106820218 Neurol Neuroimmunol Neuroinflamm

Frederike Cosima Oertel Svenja Specovius Hanna G Zimmermann et al Retinal Optical Coherence Tomography in Neuromyelitis Optica

This information is current as of September 15 2021

ServicesUpdated Information amp

httpnnneurologyorgcontent86e1068fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent86e1068fullhtmlref-list-1

This article cites 40 articles 7 of which you can access for free at

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Page 6: Retinal Optical Coherence Tomography in Neuromyelitis Optica

eyes with ge3-ON episodes (NMOSD-3-ON) was lowercompared with NMOSD-2-ON (ns) (Figures 1B and 2B)Five NMOSD-NON eyes had pRNFL values lt 60 μm thesepatients had no relevant comorbidities but a history of con-tralateral ON1718 In sensitivity analyses to account for devicedifferences all significant analyses within the NMOSD cohortwere confirmed for data acquired by Cirrus and Topcon OCTdevices (eFigures 2 and 3 eTables 3 and 4 linkslwwcomNXIA556 linkslwwcomNXIA557)

Neuroaxonal Damage Without ONNMOSD-NON eyes had a reduced GCIP layer (759 plusmn 77 μmplt 0001) but not pRNFL (953 plusmn 144 μm) comparedwithHC(GCIP layer 814 plusmn 57 μm pRNFL 1011 plusmn 90 μm Figures 1Aand 2A Tables 2 and 3) By comparison only 28 NMOSD-NON eyes (51) had a GCIP layer le the 5th percentile of HCGCIP layer was also reduced inNMOSD-NONwith a history ofcontralateral ON (729 plusmn 102 μm) compared with NMOSD-NON without a history of contralateral ON (773 plusmn 59 μm p =0025 NMOSD-NONnon) This effect vanished when onlyconsidering NMOSD-NONcon with a history of 1 contralateralON (736 plusmn 94 μm) However only NMOSD-NONcon (p lt

0001) but not NMOSD-NONnon (p = 0061) had thinnedGCIP layer compared with HC (Figures 1C and 2C)

INL ChangesINL was thicker in NMOSD-ON compared with HC (394 plusmn26 μm) and NMOSD-NON (eTable 4 linkslwwcomNXIA557) Specifically INL was thicker in eyes with 1 ON episodecompared with NMOSD-NON but did not differ between eyeswith different numbers of ON episodes Also INL did not differbetween NMOSD-NONcon (389 plusmn 32 μm) and NMOSD-NONnon (385 plusmn 32 μm p = 0931) In all patients INLthickness (as the dependent variable in the linear mixed modeldescribed above) was correlated with thinner GCIP layer (B =minus011 standard error [SE] = 001 p lt 0001) and pRNFL (B =minus006 SE = 001 p lt 0001) This correlation existed inNMOSD-ON (GCIP layer B = minus 008 SE = 003 p = 0005pRNFL B = minus 006 SE = 001 p lt 0001) and not present inNMOSD-NON (eFigure 4 linkslwwcomNXIA556)

Scans of 363 NMOSD eyes were clearly suitable for MMEinvestigations (high quality eFigure 4C linkslwwcomNXIA556) MMEs were visible in 24 (66) eyes of 21 patients

Table 2 Group Comparisons of GCIP Layer Thickness for Heidelberg SD-OCT

No ofeyes

Thickness (μmmean plusmn SD)

Comparisonto

Absolutedifference (μmmean)

Relativedifference (mean) B SE p Value R2

marg R2cond

Combinedp value

NMOSD 268 673 plusmn 136 HCs minus140 minus208 156 20 lt00001 0143 0690 mdash

NMOSD-ON

124 574 plusmn 122 minus240 minus418 250 20 lt00001 0482 0839 mdash

NMOSD-NON

144 759 plusmn 77 minus54 minus72 58 14 lt00001 0088 0947 mdash

NMOSD-NONnon

99 773 plusmn 59 minus40 minus50 269 142 0061 0189 0924 mdash

NMOSD-NONcon

45 729 plusmn 102 minus85 minus104 844 177 lt00001 0260 0985 mdash

NMOSD-ON

124 574 plusmn 122 NMOSD-NON

minus185 minus244 minus158 11 lt00001 0430 0795 59e245

NMOSD-1-ON

76 586 plusmn 129 minus173 minus228 minus145 12 lt00001 0417 0803 14e233

NMOSD-2-ON

28 551 plusmn 94 NMOSD-1-ON

minus35 minus60 minus57 26 0028 0143 0729 0038

NMOSD-ge3-ON

20 559 plusmn 128 NMOSD-2-ON

08 14 49 26 0070 0311 0781 0222

NMOSD-NONcon

45 729 plusmn 102 NMOSD-NONnon

minus44 minus61 minus38 17 0025 0111 0701 0004

NMOSD-NON1-con

37 736 plusmn 94 minus37 minus51 minus35 16 0037 0149 0906 0154

Abbreviations AQP4-IgG = aquaporin-4 IgG B = estimate GCIP = ganglion cell and inner plexiformNMOSD=AQP4-IgGndashseropositiveNMOSD NMOSD-NON=AQP4-IgGndashseropositive NMOSD eyeswithout a history of ON NMOSD-NONnon = AQP4-IgGndashseropositive NMOSD eyeswithout a history ofONor contralateralON NMOSD-NONcon = AQP4-IgGndashseropositive NMOSD eyes without a history of ON but with a history of contralateral ON NMOSD-NON1-con = AQP4-IgGndashseropositive NMOSD eyes without a history of ON but with a history of 1 contralateral ON NMOSD-ON = AQP4-IgGndashseropositive NMOSD eyes with ahistory of ON NMOSD-1-ON =AQP4-IgGndashseropositive NMOSD eyeswith a history of 1ON NMO-2-ON =AQP4-IgGndashseropositive NMOSD eyeswith a history of2 ONs NMOSD-ge3-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 3 or more ONs NMOSD = neuromyelitis optica spectrum disorder NMOSD-NON = NMOSD eyes without a history of ON OCT = optical coherence tomography ON = optic neuritis episode Rcon = conditional R-squared Rmarg =marginal R-squared SE = standard error

6 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

Twenty-three eyes (131) of NMOSD-ON and 1 eye (05)of NMOSD-NON (with a history of contralateral ON) wereaffected The number of ON episodes did not influence theincidence of MMEs (NMOSD-1-ONN = 16 (14) NMOSD-2-ON N = 4 (114) NMOSD-ge3-ON N = 3 (111))

Including only the most frequent ethnicities in our data set(Asian and non-HispanicWhite) results did not differ and noethnicity was singled out regarding its pattern of injury (datanot shown)

OCT and Vision LossHC-VA was numerically reduced in NMOSD (025 plusmn 048)compared with HC (minus001 plusmn 008) and known healthy referencevalues NMOSD-ON also had reduced HC-VA (044 plusmn 058)compared with NMOSD-NON (004 plusmn 020 p lt 0001 p =0401) and HChealthy reference populations HC-VA wascorrelated with GCIP layer (B = minus0016 SE = 0002 p lt 0001)and pRNFL thicknesses (B = minus0010 SE = 0001 p lt 0001) inAQP4-IgGndashseropositive NMOSD AQP4-IgGndashseropositiveNMOSD eyes with prolonged VEP latency had a thinned GCIP

layer (B = minus11647 SE = 3628 p = 0002) and pRNFL (B =minus21965 SE = 3724 p lt 0001) EDSS score as ametric of globaldisability was inversely correlated with GCIP layer (B = minus1370SE= 0566 p= 0017) and pRNFL thicknesses (B= minus3148 SE=1080 p = 0004)

DiscussionOur study specifies a severe and functionally relevant decreaseof GCIP layer and pRNFL in NMOSD-ON compared withNMOSD-NON and HCs in AQP4-IgGndashseropositive pa-tients Neuroaxonal damage is particularly large from the firstepisode of ON where contribution to retinal damage insubsequent episodes of ON is still considerable but smaller Incontrast to previous smaller studies the current study ascer-tains GCIP layer but not pRNFL thinning in NMOSD-NONcompared with HC619 This effect was driven by eyes withcontralateral ON and not statistically significant in eyeswithout a history of ON INL was thicker in NMOSD-ONand was inversely correlated with GCIP layer Of note 131

Table 3 GroupComparisons of pRNFL ThicknessWith (A) Spectralis SD-OCTData for Comparisons vsHC (B) Data FromAllDevices for Intrapatient Cohort Comparisons

No ofeyes

Thickness (μmmean plusmn SD)

Comparisonto

Absolute difference(μm mean)

Relativedifference (mean) B SE p Value R2

marg R2cond

Combinedp value

NMOSD 344 763 plusmn 274 HCs minus140 minus326 242 43 lt00001 0143 0690 mdash

NMOSD-ON

170 569 plusmn 237 minus443 minus779 431 41 lt00001 0482 0839 mdash

NMOSD-NON

174 953 plusmn 144 minus59 minus62 46 30 0129 0088 0947 mdash

NMOSD-NONnon

116 974 plusmn 109 minus37 minus37 minus29 22 0204 0107 0893 mdash

NMOSD-NONcon

58 910 plusmn 191 minus47 minus46 71 42 0097 0100 0975 mdash

NMOSD-ON

170 569 plusmn 237 NMOSD-NON

minus384 minus403 minus338 21 lt00001 0436 0741 44e260

NMOSD-1-ON

97 626 plusmn 249 minus327 minus343 minus296 22 lt00001 0379 0712 46e240

NMOSD-2-ON

35 535 plusmn 213 NMOSD-1-ON

minus91 minus145 minus107 47 0024 0087 0528 0010

NMOSD-ge3-ON

38 452 plusmn 178 NMOSD-2-ON

minus83 minus155 minus04 43 0924 0087 0719 0838

NMOSD-NONcon

58 910 plusmn 191 NMOSD-NONnon

minus65 minus71 minus40 29 0173 0061 0939 0157

NMOSD-NON1-con

47 932 plusmn 181 minus42 minus46 minus32 29 0276 0056 0925 0616

Abbreviations AQP4-IgG = aquaporin-4 IgG NMOSD = AQP4-IgGndashseropositive NMOSD NMOSD-NON = AQP4-IgGndashseropositive NMOSD eyes without ahistory of ON NMOSD-NONnon = AQP4-IgGndashseropositive NMOSD eyes without a history of ON or contralateral ON NMOSD-NONcon = AQP4-IgGndashseropositive NMOSD eyes without a history of ON but with a history of contralateral ON NMOSD-NONcon = AQP4-IgGndashseropositive NMOSD eyes without ahistory of ON but with a history of 1 contralateral ON NMOSD-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of ON NMOSD-1-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 1 ON NMOSD-2-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 2 ONs NMOSD-ge3-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 3 or more ONs NMOSD = neuromyelitis optica spectrum disorder NMOSD-NON = NMOSD eyes without ahistory of ON OCT = optical coherence tomography ON = optic neuritis episode pRNFL = peripapillary retinal nerve fiber layer VEP = visually evokedpotential

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 7

of NMOSD-ON eyes showed MME indicative of secondaryinflammatory changes2021 This investigation overcame limitsof small samples and OCT data heterogeneity of earlierstudies through use of an international consortium ofNMOSD specialists This framework substantiated theCROCTINO studymdasha large multicenter retrospectiveevaluation of retinal pathology in NMOSD using OCT

The neuroaxonal degeneration in NMOSD-ON demon-strated here is substantially greater than reported changes inmultiple sclerosis (MS) a common differential diagnosis222

In a meta-analysis an average pRNFL loss of 20 μm wasestimated in MS after ON which is nearly 2-fold higher in ourNMOSD-ON cohort (minus384 μm)22 For GCIP layer our datasuggested approximately 15-fold higher loss in NMOSD(minus240 μm) compared with MS22 These differences not onlyresult from a higher ON frequency but may also be caused bymore severe retinal damage in NMOSD after a singular ON23

It is intriguing that the damage is particularly large after thefirst ON episode with smaller losses after subsequent epi-sodes which might be due to less neuroaxonal content insubsequent episodes224 Alternatively although the analysisof treatment effects exceeds the scope of this study it ispossible that the longer time to effective anti-inflammatorytherapy and the typical choice of less effective therapies (egsteroids instead of plasma exchange) at the first attack com-pared with following attacks may significantly contribute tothis difference Independent of the number of ONs the per-cent loss is smaller in GCIP layer compared with pRNFLndashpointing toward either (1) stronger loss of retinal nerve fibersthan retinal ganglion cells (2) impairment of ganglion cellsnot leading to extinction but axonal loss (3) a larger amountof non-neuronal tissue in GCIP layer or (4) RNFL loss in theperiphery beyond the macular area measured by GCIP layerThese hypotheses are not mutually exclusive and each mightcontribute to the effect Consistent with these concepts ex-cessive vision loss relative to neuroaxonal content and VEPlatency in AQP4-IgGndashseropositive patients compared withMOG-IgGndashseropositive and MS patients implies damage ofthe peripheral retina and optic nerve tissues which are notreflected in the macula and pattern VEP measurements4

Whether attack-independent neurodegeneration inAQP4-IgGndashseropositive NMOSD occurs has beencontroversial26725-28 The current study identifies de-creased GCIP layer in NMOSD-NON compared withHC but not pRNFL Such subclinical changes could becaused by contralateral involvement after unilateralON1718 Indeed our cohort suggests pronounced neu-rodegeneration in eyes with contralateral ON Howevereyes of patients without ON also exhibit a trend for thinnerGCIP layer compared with HCs Underscored by longitu-dinal studies showing ON-independent neurodegenerationand VEP latency prolongation729 such patterns suggest atleast 2 mechanisms of injury (1) a primary retinopathy oroptic neuropathy in context of an astrocytopathy or causedby direct damage to AQP4-expressing cells such as astrocytes

and Muller cells by either AQP4-IgG or AQP4-specificT cells or (2) a global or afferent visual system specificchronic or episodic neurodegenerative process Because le-sions often spare the brain and most studies outside ofpredisposed areas such as optic nerve and spinal cord failedto detect effects30 a constant global involvement seemsunlikely Several studies described changes affecting AQP4expression and astrocytic end feet31 parafoveal changes inagreement with an involvement of AQP4-expressing Mullercell6262732 and attack-independent spinal cord atrophy33

These findings are consistent with tissue infiltration byAQP4-IgGndashspecific T cells34 and the attack-independentloss of retinal ganglion cells7mdashfurther supporting the exis-tence of an ON-independent pathology which might berestricted to the main disease foci The latter hypothesescould be addressed by region-specific pathology or advancedimaging studies

INL changes have been suggested as a marker of neuro-inflammation and potential treatment response in MS213536

MME may develop as a consequence of neurodegenerationor othermdashnonndashdisease-specificmdashprocesses35 Patients withNMOSD were described to have INL thickening andMME2037 In our cohort 131 of NMOSD-ON eyes wereaffected byMME which is higher than the 2ndash5 described inMS but comparable to incidences in NMOSD described beforeby Gelfand and colleagues3537 However INL thickening itselfremained comparable to changes reported in MS35 This dis-parity could reflect a disrupted fluid homeostasis due to Mullercell involvement or loss of content of the INL with a parallelinflammatory reaction and development of MME The limitedaccessibility of MMEs especially in severely affected eyes due tolimited image quality has hindered their detailed assessmentsand most likely leads to underestimation of their incidence38

We demonstrate that the INL thickness is inversely correlatedwith neuroaxonal content and could be a valuable marker ofdisease severity also in NMOSD

Our study cohort was representative of patients with AQP4-IgGndashseropositive NMOSD with respect to a female pre-dominance and ON history1139 This OCT study includedmultiple ethnicity backgrounds although the distribution wasshifted toward CaucasianWhite patients and other ethnic-ities were underrepresented (eg Hispanic White and Black)limiting the generalizability of results40 Patients from differ-ent heritages presented similar findings

The current study was based on source data instead of a meta-analysis Using the Guthy-Jackson Charitable Foundation net-work this multicentric study was conducted without investigatorreimbursement and illustrated how collaboration integratinginternational perspectives can produce meaningful results Toovercome technical challenges of heterogeneous source data wedeveloped novel OCT postprocessing techniques allowing us toperform standardized analyses and enabling the uniform analysisof the largest OCT image data set in NMOSD to date10 Thusthe strengths of CROCTINO include its established

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

infrastructure large international network of experts represent-ing multiple ethnicities and geographic regions and the use ofstate-of-the-art OCT postprocessing techniques41

We recognize limitations of the current investigation Theretrospective and heterogeneous data acquisition might haveled to biases and impreciseness beyond the ability of ourquality control We addressed this by excluding uncertaincases HCs were only included from a limited number ofcenters The unbalanced data set limited some analyses suchas the influence of ethnicities or acute and disease-modifyingtreatments Case-control matching was impossible particu-larly with respect to subclinical progression dependent orindependent of ON and to ethnicity Similarly comparisonswith other NMOSD subtypes or MS were beyond the scopeof this study Longitudinal data acute ON data and AQP4-IgGndashseronegative and MOG-IgGndashseropositive patient dataare part of the CROCTINO data set and will be analyzed inthe future Also OCT data processing was performed bymultiple raters potentially introducing interrater variabilityMRI data and posterior visual pathway involvement were notinvestigated in this study However the current study ach-ieved an unprecedented worldwide assessment of retinaldamage in AQP4-IgGndashseropositive NMOSD

To conclude AQP4-IgGndashseropositive NMOSD is characterizedby a severe functionally relevant retinal neurodegeneration as aconsequence of ON Although the majority of damage occursduring the first episode there is cumulative loss with each suc-ceeding relapse TheON-associated damage is not limited to theneuroaxonal content but can also inducemdashlikely inflammation-mediatedmdashINL increase and occurrence ofMMEOur data alsosuggest attack-independent retinal damage in AQP4-IgGndashseropositive NMOSD Our study supports that at-tack prevention is key in avoiding neuroaxonal damage andvision loss in patients with NMOSD It further suggests thatthe first ON episode causes the most damage where onlysome patients with then established diagnosis will be on im-munosuppressive therapy This highlights the need for ef-fective therapies that can ameliorate an ongoing attack orregenerate attack-generated damage which is an unmet clin-ical need Last the study emphasizes the utility of OCT as asensitive structural metric and its potential for monitoringprogression and even treatment response in AQP4-IgGndashseropositive NMOSD The international CROCTINOprogram provides an unprecedented opportunity to applyOCT in a standardized manner to assess pathophysiologyclinical course and therapeutic efficacy in NMOSD

Study FundingGuthy-Jackson Charitable Foundation (GJCF) and GermanResearch Foundation (DFG)

DisclosureFC Oertel was employee of Nocturne GmbH and receivesresearch support by the American Academy of Neurology andthe National Multiple Sclerosis Society unrelated to this work

S Specovius reports no disclosures HG Zimmerman reportsresearch grants from Novartis and speaking honoraria fromBayer Healthcare unrelated to this study C Chien reportsspeaking honoraria from Bayer Healthcare unrelated to thiswork S Motamedi and C Bereuter report no disclosures LCook reports grants from Guthy Jackson Charitable Founda-tion during the conduct of the study EH Martinez-Lapiscinais employed by the European Medicines Agency (HumanMedicines) since 16 April 2019 This article is related with heractivity under Hospital Clinic of BarcelonaIDIBAPS affiliationand consequently as external activity it does not represent theviews of the Agency its Committees or working parties Beforeenrolling EMA Dr Martinez-Lapiscina reports grants fromInstituto de Salud Carlos III (Spain) amp Fondo Europeo deDesarrollo Regional grants from MS Innovation GMSI otherfromFundacio Privada Cellex and personal fees fromNovartisRoche Sanofi-Genzyme outside the submitted work MALana Peixoto and MA Fontanelle report no disclosures HJKim reports grants from the National Research Foundation ofKorea personal fees from Alexion Pharmaceuticals AprilbioBiogen Celltrion Eisai HanAll BioPharma MDimune MerckSerono Novartis Sanofi Genzyme Teva-Handok and VielaBio other from Viela Bio (formerly MedImmune) MultipleSclerosis Journal and Journal of Clinical Neurology outsidethe submitted work J-W Hyun reports grants from the Na-tional Research Foundation of Korea outside the submittedwork J Palace reports personal fees from Abide TherapeuticsAlexion Pharmaceuticals ARGENX Bayer Schering BiogenIdec Chugai Pharma EuroImmun Genzyme MedDayMedImmuneMerck Serono Novartis Roche Teva UCB andViela Bio grants from Abide Therapeutics Alexion Pharma-ceuticals Bayer Schering Biogen Idec Chugai Pharma Gen-zyme MedImmune Merck Serono Novartis and Teva grantsfrom Merck Serono Novartis Biogen Idec Teva AbideMedImmune Bayer Schering Genzyme Chugai and AlexionEugene Devic European Network the Grant for MultipleSclerosis Innovation the John Fell Fund the Medical ResearchCouncil the MS Society Myaware the UK National Institutefor Health Research Oxford Health Services Research Com-mittee and theGuthy-JacksonCharitable Foundation AMPLOand SPARKS Great Ormond Street for research studies out-side the submitted work MI Leite and S Sharma report nodisclosures A Roca-Fernandez is sponsored by Abide Thera-peutic outside of the submitted work and reports no potentialconflicts of interest R Kafieh A Dehghani M Pourazizi LPandit and A DrsquoCunha report no disclosures O Aktas reportsgrants from German Research Foundation (DFG) and Ger-man Ministry of Education and Research (BMBF) personalfees from Alexion and Almirall grants and personal fees fromBiogen personal fees from Merck grants and personal feesfrom Novartis grants and personal fees from Roche personalfees from Sanofi personal fees from Teva personal fees fromViela Bio outside the submitted work M Ringelstein receivedspeaker honoraria from Novartis Bayer Vital GmbH RocheAlexion and Ipsen and travel reimbursement from BayerSchering Biogen Idec Merz Genzyme Teva Roche andMerck none related to this study P Albrecht reports grants

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 9

personal fees and non-financial support from Allergan BiogenMerck Merz Pharmaceuticals Novartis Ipsen CelgeneRoche and personal fees and non-financial support from Tevaoutside the submitted work E May and C Tongco report nodisclosures L Leocani reports personal fees from RocheMerck Bristol Myers Squibb andMed-ex learning outside thesubmitted work M Pisa reports no disclosures M Radaellireports personal fees from Merck Serono Sanofi-GenzymeNovartis and Biogen outside the submitted work H Stiebel-Kalish reports no disclosures S Siritho reports personal feesfromNovartis Thailand Biogen Idec Eisai Thailandmarketingco ltd Merck Serono Teva Thailand and Menarini outsidethe submitted work J de Seze and T Senger report no dis-closures J Havla reports grants personal fees and non-financialsupport from Merck personal fees from Novartis CelgeneRoche Santhera Biogen Alexion Sanofi non-financial supportfrom Guthy-Jackson Charitable Foundation and grants fromFriedrich Baur Foundation outside the submitted work RMarignier AC Calvo D Bichuetti IM Tavares N Asgari KSoelberg A Altintas R Yildirim U Tanriverdi A Jacob SHuda Z Rimler and A Reid report no disclosures Y Mao-Draayer reports grants from NIH NIAID grants and personalfees from Genzyme grants from Chugai personal fees fromBiogen and EMD Serono grants and personal fees fromGenentech and Novartis during the conduct of the studygrants from NIH NIAID grants and personal fees from Gen-zyme grants fromChugai personal fees fromBiogen and EMDSerono grants and personal fees fromGenentech andNovartisoutside the submitted work I Soto de Castillo reports nodisclosures A Petzold reports personal fees and grants fromNovartis outside the submitted work and is part of the steeringcommittee of the OCTiMS study which is sponsored byNovartis He has not received honoraria for this activity AJGreen reports other from Bionure grants personal fees andother from Inception Sciences grants from Sherak Foundationpersonal fees and other from Pipeline Pharmaceuticals grantsfrom Hilton Foundation Adelson Foundation and NationalMS Society personal fees from JAMANeurology personal feesand other from MediimmuneViela outside the submittedwork In addition Dr Green has a patent Small Molecule drugfor Remyelination pending and has worked on testing off labelcompounds for remyelination MR Yeaman serves as an ad-visor to the Guthy-Jackson Charitable Foundation T Smithreports no disclosures AU Brandt reports grants from theGuthy Jackson Charitable Foundation during the conduct ofthe study shares from Motognosis GmbH and shares fromNocturne GmbH outside the submitted work In addition DrBrandt has a patent pending describing Foveal MorphometryF Paul reports grants from the Guthy Jackson CharitableFoundation during the conduct of the study grants from theGerman Research Foundation andGerman FederalMinistry ofEducation and research grants and other fromNovartis grantsand other from Bayer Novartis Biogen Idec Teva Sanofi-AventisGenzyme Merck Serono Chugai other from PLoSONE other from Neurologyreg Neuroimmunology amp Neuro-inflammation other from SanofiGenzyme Biogen Idec grantsfrom German Research Council Werth Stiftung of the City of

Cologne German Ministry of Education and Research ArthurArnstein Stiftung Berlin EU FP7 Framework Program ArthurArnstein Foundation Berlin National Multiple Sclerosis(USA) other from MedImmune Shire Alexion outside thesubmitted work In addition Dr Paul has a patent FovealMorphometry pending to Nocturne GmbH Go to NeurologyorgNN for full disclosures

Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationMarch 23 2021 Accepted in final form June 15 2021

Appendix Authors

Name Location Contribution

Frederike CosimaOertel MDPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data anddrafting a significantportion of themanuscript or figuresconception and designof the study

Svenja SpecoviusMSc

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of dataconception and designof the study

Hanna GZimmermannPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of dataconception and designof the study

Claudia ChienPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

SeyedamirhoseinMotamedi PhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

CharlotteBereuter BSc

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

Appendix (continued)

Name Location Contribution

Lawrence CookPhD

University of UtahSalt Lake City UT

Acquisition andanalysis of data andconception and designof the study

Marco AurelioLana Peixoto MDPhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Mariana AndradeFontanelle MD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Ho Jin Kim MDPhD

National Cancer CenterGoyang Republic of Korea

Acquisition andanalysis of data

Jae-Won HyunMD PhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

JacquelinePalace MD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Adriana Roca-Fernandez MSc

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Maria IsabelLeite MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

SrilakshmiSharma MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

FereshtehAshtari MD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Rahele KafiehPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Alireza DehghaniPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

MohsenPourazizi PhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Lekha PanditMD PhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Anitha DrsquoCunhaPhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Orhan Aktas MD Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

MariusRingelstein MD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Philipp AlbrechtMD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Eugene May MD Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Caryl Tongco Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Appendix (continued)

Name Location Contribution

Letizia LeocaniMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marco Pisa MD Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marta RadaelliMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Elena H Martinez-Lapiscina MDPhD

Hospital Clinic of Barcelona-Institut drsquoInvestigacionsBiomediques August PiSunyer Barcelona Spain

Acquisition andanalysis of data

Hadas Stiebel-Kalish MD

Sackler School of MedicineTel Aviv University Tel AvivIsrael

Acquisition andanalysis of data

Sasitorn SirithoMD

Siriraj Hospital andBumrungrad InternationalHospital Bangkok Thailand

Acquisition andanalysis of data

Jerome de SezeMD PhD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Thomas SengerMD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Joachim HavlaMD

Ludwig-MaximiliansUniversitat MuenchenMunich Germany

Acquisition andanalysis of data

RomainMarignier MDPhD

Pierre Wertheimer NeurologicalHospital Hospices Civils deLyon France

Acquisition andanalysis of data

Alvaro CoboCalvo MD PhD

Pierre WertheimerNeurological HospitalHospices Civils de LyonFrance Hospital UniversitariVall drsquoHebron UniversitatAutonoma de BarcelonaSpain

Acquisition andanalysis of data

Denis BichuettiMD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Ivan MaynartTavares MD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Nasrin AsgariMD PhD

University of SouthernDenmark OdenseDenmark

Acquisition andanalysis of data

Kerstin SoelbergMD

University of SouthernDenmark Odense Denmark

Acquisition andanalysis of data

Ayse Altintas MD Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Rengin YildirimMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 11

References1 Oertel FC Zimmermann H Paul F Brandt AU Optical coherence tomog-

raphy in neuromyelitis optica spectrum disorders potential advantages forindividualized monitoring of progression and therapy EPMA J 20189(1)21-33

2 Schneider E Zimmermann H Oberwahrenbrock T et al Optical coherence to-mography reveals distinct patterns of retinal damage in neuromyelitis optica andmultiple sclerosis PLoS One 20138(6)e66151

3 Bouyon M Collongues N Zephir H et al Longitudinal follow-up of vision in aneuromyelitis optica cohort Mult Scler 201319(10)1320-1322

4 Sotirchos ES Filippatou A Fitzgerald KC et al Aquaporin-4 IgG seropositivity isassociated with worse visual outcomes after optic neuritis than MOG-IgG seroposi-tivity and multiple sclerosis independent of macular ganglion cell layer thinningMultScler 201926(11)1360-1371

5 Hamid SHM Whittam D Mutch K et al What proportion of AQP4-IgG-negativeNMO spectrum disorder patients are MOG-IgG positive A cross sectional study of132 patients J Neurol 2017264(10)2088-2094

6 Oertel FC Kuchling J ZimmermannH et al Microstructural visual system changes inAQP4-antibody-seropositive NMOSD Neurol Neuroimmunol Neuroinflamm 20174(3)e334

7 Oertel FC Havla J Roca-Fernandez A et al Retinal ganglion cell loss in neuromyelitisoptica a longitudinal study J Neurol Neurosurg Psychiatry 201889(12)1259-1265

8 Huang D Swanson EA Lin CP et al Optical coherence tomography Science 1991254(5035)1178-1181

9 Specovius S Zimmermann HG Oertel FC et al Cohort profile a collaborativemulticentre study of retinal optical coherence tomography in 539 patients withneuromyelitis optica spectrum disorders (CROCTINO) BMJ Open 202010(10)e035397

10 Motamedi S Gawlik K Ayadi N et al Normative data and minimally detectablechange for inner retinal layer thicknesses using a semi-automated OCT image seg-mentation pipeline Front Neurol 2019101117

11 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177-189

12 von Elm E Altman DG Egger M et al The strengthening the reporting of obser-vational studies in epidemiology (STROBE) statement guidelines for reportingobservational studies Int J Surg 201412(12)1495-1499

13 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PLoS One 20127(4)e34823

14 Schippling S Balk LJ Costello F et al Quality control for retinal OCT in multiplesclerosis validation of the OSCAR-IB criteria Mult Scler 201521(2)163-170

15 Lang A Carass A Hauser M et al Retinal layer segmentation of macular OCT imagesusing boundary classification Biomed Opt Express 20134(7)1133-1152

16 R Development Core Team R A Language and Environment for Statistical Computing[online] R Foundation for Statistical Computing 2008 R-projectorg

17 Akaishi T Kaneko K Himori N et al Subclinical retinal atrophy in the unaffectedfellow eyes of multiple sclerosis and neuromyelitis optica [online serial]J Neuroimmunol 201731310-15 Accessed October 8 2017 jni-journalcomarticleS0165-5728(17)30319-3fulltext

18 Alshowaeir D Yiannikas C Fraser C Klistorner A Mechanism of delayed con-duction of fellow eyes in patients with optic neuritis Int J Ophthalmol 201811(2)329-332

19 Manogaran P Traboulsee AL Lange AP Longitudinal study of retinal nerve fiberlayer thickness and macular volume in patients with neuromyelitis optica spectrumdisorder J Neuroophthalmol 201636(4)363-368

20 Kaufhold F ZimmermannH Schneider E et al Optic neuritis is associated with innernuclear layer thickening and microcystic macular edema independently of multiplesclerosis PLoS One 20138(8)e71145

21 Knier B Schmidt P Aly L et al Retinal inner nuclear layer volume reflects response toimmunotherapy in multiple sclerosis Brain 2016139(11)2855-2863

22 Petzold A Balcer LJ Calabresi PA et al Retinal layer segmentation in multiplesclerosis a systematic review and meta-analysis Lancet Neurol 201716(10)797-812

23 Pawlitzki M Horbrugger M Loewe K et al MS optic neuritis-induced long-termstructural changes within the visual pathway Neurol Neuroimmunol Neuroinflamm20207(2)e665

24 Pache F Zimmermann H Mikolajczak J et al MOG-IgG in NMO and relateddisorders a multicenter study of 50 patients Part 4 afferent visual system damageafter optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patientsJ Neuroinflammation 201613(1)282

25 Filippatou AG Vasileiou ES He Y et al Evidence of subclinical quantitative retinallayer abnormalities in AQP4-IgG seropositive NMOSD Mult Scler 2020 Dec 141352458520977771 doi 1011771352458520977771

26 Motamedi S Oertel FC Yadav SK et al Altered fovea in AQP4-IgGndashseropositiveneuromyelitis optica spectrum disorders Neurol Neuroimmunol Neuroinflamm 20207(5)e805

27 Roca-Fernandez A Oertel FC Yeo T et al Foveal changes in AQP4-Ab seropositiveNMOSD are independent of optic neuritis and not overtly progressive Eur J Neurol202128(7)2280-2293

28 Papadopoulou A Oertel FC Chien C et al Lateral geniculate nucleus volumechanges after optic neuritis in neuromyelitis optica a longitudinal study NeuroimageClin 202130102608

29 Ringelstein M Harmel J Zimmermann H et al Longitudinal optic neuritis-unrelatedvisual evoked potential changes in NMO spectrum disorders Neurology 202094(4)e407-e418

30 Pache F Zimmermann H Finke C et al Brain parenchymal damage in neuromyelitisoptica spectrum disorderndasha multimodal MRI study Eur Radiol 201626(12)4413-4422

31 Hokari M Yokoseki A Arakawa M et al Clinicopathological features in anteriorvisual pathway in neuromyelitis optica Ann Neurol 201679(4)605-624

32 You Y Zhu L Zhang T et al Evidence of muller glial dysfunction in patients withaquaporin-4 immunoglobulin Gndashpositive neuromyelitis optica spectrum disorderOphthalmology 2019126(6)801-810 Elsevier

33 Chien C Scheel M Schmitz-Hubsch T et al Spinal cord lesions and atrophy inNMOSD with AQP4-IgG and MOG-IgG associated autoimmunityMult Scler 201925(14)1926-1936

34 Felix CM Levin MH Verkman AS Complement-independent retinal pathologyproduced by intravitreal injection of neuromyelitis optica immunoglobulin GJ Neuroinflammation 201613(1)275

35 Balk LJ Coric D Knier B et al Retinal inner nuclear layer volume reflects in-flammatory disease activity in multiple sclerosis a longitudinal OCT studyMult SclerJ Exp Transl Clin 20195(3)2055217319871582

36 Gelfand JM Nolan R Schwartz DM Graves J Green AJ Microcystic macular oedemain multiple sclerosis is associated with disease severity Brain 2012135(pt 6)1786-1793

Appendix (continued)

Name Location Contribution

Uygur TanriverdiMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Anu Jacob MD The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Saif Huda MDPhD

The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Zoe Rimler BSc NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Allyson Reid MD NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Yang Mao-Draayer MD PhD

University of MichiganMedical School AnnArbor MI

Acquisition andanalysis of data

Ibis Soto deCastillo MD

Hospital Clınico deMaracaibo MaracaiboVenezuela

Acquisition andanalysis of data

Axel Petzold MDPhD

University College LondonLondon UK

Conception anddesign of the study

Ari J Green MD University of California SanFrancisco CA

Conception anddesign of the study

Michael RYeaman MD PhD

University of California LosAngeles CA

Conception anddesign of the study

Terry Smith MD University of MichiganMedical School AnnArbor MI

Conception anddesign of the study

Alexander UBrandt MD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinBerlin Berlin Germany

Acquisition andanalysis of dataconception and designof the study anddrafting a significantportion of themanuscript or figures

Friedemann PaulMD

CharitendashUniversitatsmedizinBerlin Corporate Member ofFreie Universitat Berlin andHumboldt-Universitat zuBerlin

Acquisition andanalysis of data andconception and designof the study

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

37 Gelfand JM Cree BA Nolan R Arnow S Green AJ Microcystic inner nuclear layerabnormalities and neuromyelitis optica JAMA Neurol 201370(5)629-633

38 Oberwahrenbrock T WeinholdMMikolajczak J et al Reliability of intra-retinal layerthickness estimates PLoS One 201510(9)e0137316

39 Borisow N Kleiter I Gahlen A et al Influence of female sex and fertile age onneuromyelitis optica spectrum disorders Mult Scler 201723(8)1092-1103

40 Mori M Kuwabara S Paul F Worldwide prevalence of neuromyelitis optica spectrumdisorders J Neurol Neurosurg Psychiatry 201889(6)555-556

41 Oertel FC Paul F Accelerating clinical research in neuromyelitis optica spectrumdisorders [online serial] Clin Exp Neuroimmunol 202112(2)89-91 AccessedMarch 28 2021 periclespericles-prodliteratumonlinecomdoiabs101111cen312637

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 13

DOI 101212NXI000000000000106820218 Neurol Neuroimmunol Neuroinflamm

Frederike Cosima Oertel Svenja Specovius Hanna G Zimmermann et al Retinal Optical Coherence Tomography in Neuromyelitis Optica

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Page 7: Retinal Optical Coherence Tomography in Neuromyelitis Optica

Twenty-three eyes (131) of NMOSD-ON and 1 eye (05)of NMOSD-NON (with a history of contralateral ON) wereaffected The number of ON episodes did not influence theincidence of MMEs (NMOSD-1-ONN = 16 (14) NMOSD-2-ON N = 4 (114) NMOSD-ge3-ON N = 3 (111))

Including only the most frequent ethnicities in our data set(Asian and non-HispanicWhite) results did not differ and noethnicity was singled out regarding its pattern of injury (datanot shown)

OCT and Vision LossHC-VA was numerically reduced in NMOSD (025 plusmn 048)compared with HC (minus001 plusmn 008) and known healthy referencevalues NMOSD-ON also had reduced HC-VA (044 plusmn 058)compared with NMOSD-NON (004 plusmn 020 p lt 0001 p =0401) and HChealthy reference populations HC-VA wascorrelated with GCIP layer (B = minus0016 SE = 0002 p lt 0001)and pRNFL thicknesses (B = minus0010 SE = 0001 p lt 0001) inAQP4-IgGndashseropositive NMOSD AQP4-IgGndashseropositiveNMOSD eyes with prolonged VEP latency had a thinned GCIP

layer (B = minus11647 SE = 3628 p = 0002) and pRNFL (B =minus21965 SE = 3724 p lt 0001) EDSS score as ametric of globaldisability was inversely correlated with GCIP layer (B = minus1370SE= 0566 p= 0017) and pRNFL thicknesses (B= minus3148 SE=1080 p = 0004)

DiscussionOur study specifies a severe and functionally relevant decreaseof GCIP layer and pRNFL in NMOSD-ON compared withNMOSD-NON and HCs in AQP4-IgGndashseropositive pa-tients Neuroaxonal damage is particularly large from the firstepisode of ON where contribution to retinal damage insubsequent episodes of ON is still considerable but smaller Incontrast to previous smaller studies the current study ascer-tains GCIP layer but not pRNFL thinning in NMOSD-NONcompared with HC619 This effect was driven by eyes withcontralateral ON and not statistically significant in eyeswithout a history of ON INL was thicker in NMOSD-ONand was inversely correlated with GCIP layer Of note 131

Table 3 GroupComparisons of pRNFL ThicknessWith (A) Spectralis SD-OCTData for Comparisons vsHC (B) Data FromAllDevices for Intrapatient Cohort Comparisons

No ofeyes

Thickness (μmmean plusmn SD)

Comparisonto

Absolute difference(μm mean)

Relativedifference (mean) B SE p Value R2

marg R2cond

Combinedp value

NMOSD 344 763 plusmn 274 HCs minus140 minus326 242 43 lt00001 0143 0690 mdash

NMOSD-ON

170 569 plusmn 237 minus443 minus779 431 41 lt00001 0482 0839 mdash

NMOSD-NON

174 953 plusmn 144 minus59 minus62 46 30 0129 0088 0947 mdash

NMOSD-NONnon

116 974 plusmn 109 minus37 minus37 minus29 22 0204 0107 0893 mdash

NMOSD-NONcon

58 910 plusmn 191 minus47 minus46 71 42 0097 0100 0975 mdash

NMOSD-ON

170 569 plusmn 237 NMOSD-NON

minus384 minus403 minus338 21 lt00001 0436 0741 44e260

NMOSD-1-ON

97 626 plusmn 249 minus327 minus343 minus296 22 lt00001 0379 0712 46e240

NMOSD-2-ON

35 535 plusmn 213 NMOSD-1-ON

minus91 minus145 minus107 47 0024 0087 0528 0010

NMOSD-ge3-ON

38 452 plusmn 178 NMOSD-2-ON

minus83 minus155 minus04 43 0924 0087 0719 0838

NMOSD-NONcon

58 910 plusmn 191 NMOSD-NONnon

minus65 minus71 minus40 29 0173 0061 0939 0157

NMOSD-NON1-con

47 932 plusmn 181 minus42 minus46 minus32 29 0276 0056 0925 0616

Abbreviations AQP4-IgG = aquaporin-4 IgG NMOSD = AQP4-IgGndashseropositive NMOSD NMOSD-NON = AQP4-IgGndashseropositive NMOSD eyes without ahistory of ON NMOSD-NONnon = AQP4-IgGndashseropositive NMOSD eyes without a history of ON or contralateral ON NMOSD-NONcon = AQP4-IgGndashseropositive NMOSD eyes without a history of ON but with a history of contralateral ON NMOSD-NONcon = AQP4-IgGndashseropositive NMOSD eyes without ahistory of ON but with a history of 1 contralateral ON NMOSD-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of ON NMOSD-1-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 1 ON NMOSD-2-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 2 ONs NMOSD-ge3-ON = AQP4-IgGndashseropositive NMOSD eyes with a history of 3 or more ONs NMOSD = neuromyelitis optica spectrum disorder NMOSD-NON = NMOSD eyes without ahistory of ON OCT = optical coherence tomography ON = optic neuritis episode pRNFL = peripapillary retinal nerve fiber layer VEP = visually evokedpotential

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 7

of NMOSD-ON eyes showed MME indicative of secondaryinflammatory changes2021 This investigation overcame limitsof small samples and OCT data heterogeneity of earlierstudies through use of an international consortium ofNMOSD specialists This framework substantiated theCROCTINO studymdasha large multicenter retrospectiveevaluation of retinal pathology in NMOSD using OCT

The neuroaxonal degeneration in NMOSD-ON demon-strated here is substantially greater than reported changes inmultiple sclerosis (MS) a common differential diagnosis222

In a meta-analysis an average pRNFL loss of 20 μm wasestimated in MS after ON which is nearly 2-fold higher in ourNMOSD-ON cohort (minus384 μm)22 For GCIP layer our datasuggested approximately 15-fold higher loss in NMOSD(minus240 μm) compared with MS22 These differences not onlyresult from a higher ON frequency but may also be caused bymore severe retinal damage in NMOSD after a singular ON23

It is intriguing that the damage is particularly large after thefirst ON episode with smaller losses after subsequent epi-sodes which might be due to less neuroaxonal content insubsequent episodes224 Alternatively although the analysisof treatment effects exceeds the scope of this study it ispossible that the longer time to effective anti-inflammatorytherapy and the typical choice of less effective therapies (egsteroids instead of plasma exchange) at the first attack com-pared with following attacks may significantly contribute tothis difference Independent of the number of ONs the per-cent loss is smaller in GCIP layer compared with pRNFLndashpointing toward either (1) stronger loss of retinal nerve fibersthan retinal ganglion cells (2) impairment of ganglion cellsnot leading to extinction but axonal loss (3) a larger amountof non-neuronal tissue in GCIP layer or (4) RNFL loss in theperiphery beyond the macular area measured by GCIP layerThese hypotheses are not mutually exclusive and each mightcontribute to the effect Consistent with these concepts ex-cessive vision loss relative to neuroaxonal content and VEPlatency in AQP4-IgGndashseropositive patients compared withMOG-IgGndashseropositive and MS patients implies damage ofthe peripheral retina and optic nerve tissues which are notreflected in the macula and pattern VEP measurements4

Whether attack-independent neurodegeneration inAQP4-IgGndashseropositive NMOSD occurs has beencontroversial26725-28 The current study identifies de-creased GCIP layer in NMOSD-NON compared withHC but not pRNFL Such subclinical changes could becaused by contralateral involvement after unilateralON1718 Indeed our cohort suggests pronounced neu-rodegeneration in eyes with contralateral ON Howevereyes of patients without ON also exhibit a trend for thinnerGCIP layer compared with HCs Underscored by longitu-dinal studies showing ON-independent neurodegenerationand VEP latency prolongation729 such patterns suggest atleast 2 mechanisms of injury (1) a primary retinopathy oroptic neuropathy in context of an astrocytopathy or causedby direct damage to AQP4-expressing cells such as astrocytes

and Muller cells by either AQP4-IgG or AQP4-specificT cells or (2) a global or afferent visual system specificchronic or episodic neurodegenerative process Because le-sions often spare the brain and most studies outside ofpredisposed areas such as optic nerve and spinal cord failedto detect effects30 a constant global involvement seemsunlikely Several studies described changes affecting AQP4expression and astrocytic end feet31 parafoveal changes inagreement with an involvement of AQP4-expressing Mullercell6262732 and attack-independent spinal cord atrophy33

These findings are consistent with tissue infiltration byAQP4-IgGndashspecific T cells34 and the attack-independentloss of retinal ganglion cells7mdashfurther supporting the exis-tence of an ON-independent pathology which might berestricted to the main disease foci The latter hypothesescould be addressed by region-specific pathology or advancedimaging studies

INL changes have been suggested as a marker of neuro-inflammation and potential treatment response in MS213536

MME may develop as a consequence of neurodegenerationor othermdashnonndashdisease-specificmdashprocesses35 Patients withNMOSD were described to have INL thickening andMME2037 In our cohort 131 of NMOSD-ON eyes wereaffected byMME which is higher than the 2ndash5 described inMS but comparable to incidences in NMOSD described beforeby Gelfand and colleagues3537 However INL thickening itselfremained comparable to changes reported in MS35 This dis-parity could reflect a disrupted fluid homeostasis due to Mullercell involvement or loss of content of the INL with a parallelinflammatory reaction and development of MME The limitedaccessibility of MMEs especially in severely affected eyes due tolimited image quality has hindered their detailed assessmentsand most likely leads to underestimation of their incidence38

We demonstrate that the INL thickness is inversely correlatedwith neuroaxonal content and could be a valuable marker ofdisease severity also in NMOSD

Our study cohort was representative of patients with AQP4-IgGndashseropositive NMOSD with respect to a female pre-dominance and ON history1139 This OCT study includedmultiple ethnicity backgrounds although the distribution wasshifted toward CaucasianWhite patients and other ethnic-ities were underrepresented (eg Hispanic White and Black)limiting the generalizability of results40 Patients from differ-ent heritages presented similar findings

The current study was based on source data instead of a meta-analysis Using the Guthy-Jackson Charitable Foundation net-work this multicentric study was conducted without investigatorreimbursement and illustrated how collaboration integratinginternational perspectives can produce meaningful results Toovercome technical challenges of heterogeneous source data wedeveloped novel OCT postprocessing techniques allowing us toperform standardized analyses and enabling the uniform analysisof the largest OCT image data set in NMOSD to date10 Thusthe strengths of CROCTINO include its established

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

infrastructure large international network of experts represent-ing multiple ethnicities and geographic regions and the use ofstate-of-the-art OCT postprocessing techniques41

We recognize limitations of the current investigation Theretrospective and heterogeneous data acquisition might haveled to biases and impreciseness beyond the ability of ourquality control We addressed this by excluding uncertaincases HCs were only included from a limited number ofcenters The unbalanced data set limited some analyses suchas the influence of ethnicities or acute and disease-modifyingtreatments Case-control matching was impossible particu-larly with respect to subclinical progression dependent orindependent of ON and to ethnicity Similarly comparisonswith other NMOSD subtypes or MS were beyond the scopeof this study Longitudinal data acute ON data and AQP4-IgGndashseronegative and MOG-IgGndashseropositive patient dataare part of the CROCTINO data set and will be analyzed inthe future Also OCT data processing was performed bymultiple raters potentially introducing interrater variabilityMRI data and posterior visual pathway involvement were notinvestigated in this study However the current study ach-ieved an unprecedented worldwide assessment of retinaldamage in AQP4-IgGndashseropositive NMOSD

To conclude AQP4-IgGndashseropositive NMOSD is characterizedby a severe functionally relevant retinal neurodegeneration as aconsequence of ON Although the majority of damage occursduring the first episode there is cumulative loss with each suc-ceeding relapse TheON-associated damage is not limited to theneuroaxonal content but can also inducemdashlikely inflammation-mediatedmdashINL increase and occurrence ofMMEOur data alsosuggest attack-independent retinal damage in AQP4-IgGndashseropositive NMOSD Our study supports that at-tack prevention is key in avoiding neuroaxonal damage andvision loss in patients with NMOSD It further suggests thatthe first ON episode causes the most damage where onlysome patients with then established diagnosis will be on im-munosuppressive therapy This highlights the need for ef-fective therapies that can ameliorate an ongoing attack orregenerate attack-generated damage which is an unmet clin-ical need Last the study emphasizes the utility of OCT as asensitive structural metric and its potential for monitoringprogression and even treatment response in AQP4-IgGndashseropositive NMOSD The international CROCTINOprogram provides an unprecedented opportunity to applyOCT in a standardized manner to assess pathophysiologyclinical course and therapeutic efficacy in NMOSD

Study FundingGuthy-Jackson Charitable Foundation (GJCF) and GermanResearch Foundation (DFG)

DisclosureFC Oertel was employee of Nocturne GmbH and receivesresearch support by the American Academy of Neurology andthe National Multiple Sclerosis Society unrelated to this work

S Specovius reports no disclosures HG Zimmerman reportsresearch grants from Novartis and speaking honoraria fromBayer Healthcare unrelated to this study C Chien reportsspeaking honoraria from Bayer Healthcare unrelated to thiswork S Motamedi and C Bereuter report no disclosures LCook reports grants from Guthy Jackson Charitable Founda-tion during the conduct of the study EH Martinez-Lapiscinais employed by the European Medicines Agency (HumanMedicines) since 16 April 2019 This article is related with heractivity under Hospital Clinic of BarcelonaIDIBAPS affiliationand consequently as external activity it does not represent theviews of the Agency its Committees or working parties Beforeenrolling EMA Dr Martinez-Lapiscina reports grants fromInstituto de Salud Carlos III (Spain) amp Fondo Europeo deDesarrollo Regional grants from MS Innovation GMSI otherfromFundacio Privada Cellex and personal fees fromNovartisRoche Sanofi-Genzyme outside the submitted work MALana Peixoto and MA Fontanelle report no disclosures HJKim reports grants from the National Research Foundation ofKorea personal fees from Alexion Pharmaceuticals AprilbioBiogen Celltrion Eisai HanAll BioPharma MDimune MerckSerono Novartis Sanofi Genzyme Teva-Handok and VielaBio other from Viela Bio (formerly MedImmune) MultipleSclerosis Journal and Journal of Clinical Neurology outsidethe submitted work J-W Hyun reports grants from the Na-tional Research Foundation of Korea outside the submittedwork J Palace reports personal fees from Abide TherapeuticsAlexion Pharmaceuticals ARGENX Bayer Schering BiogenIdec Chugai Pharma EuroImmun Genzyme MedDayMedImmuneMerck Serono Novartis Roche Teva UCB andViela Bio grants from Abide Therapeutics Alexion Pharma-ceuticals Bayer Schering Biogen Idec Chugai Pharma Gen-zyme MedImmune Merck Serono Novartis and Teva grantsfrom Merck Serono Novartis Biogen Idec Teva AbideMedImmune Bayer Schering Genzyme Chugai and AlexionEugene Devic European Network the Grant for MultipleSclerosis Innovation the John Fell Fund the Medical ResearchCouncil the MS Society Myaware the UK National Institutefor Health Research Oxford Health Services Research Com-mittee and theGuthy-JacksonCharitable Foundation AMPLOand SPARKS Great Ormond Street for research studies out-side the submitted work MI Leite and S Sharma report nodisclosures A Roca-Fernandez is sponsored by Abide Thera-peutic outside of the submitted work and reports no potentialconflicts of interest R Kafieh A Dehghani M Pourazizi LPandit and A DrsquoCunha report no disclosures O Aktas reportsgrants from German Research Foundation (DFG) and Ger-man Ministry of Education and Research (BMBF) personalfees from Alexion and Almirall grants and personal fees fromBiogen personal fees from Merck grants and personal feesfrom Novartis grants and personal fees from Roche personalfees from Sanofi personal fees from Teva personal fees fromViela Bio outside the submitted work M Ringelstein receivedspeaker honoraria from Novartis Bayer Vital GmbH RocheAlexion and Ipsen and travel reimbursement from BayerSchering Biogen Idec Merz Genzyme Teva Roche andMerck none related to this study P Albrecht reports grants

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 9

personal fees and non-financial support from Allergan BiogenMerck Merz Pharmaceuticals Novartis Ipsen CelgeneRoche and personal fees and non-financial support from Tevaoutside the submitted work E May and C Tongco report nodisclosures L Leocani reports personal fees from RocheMerck Bristol Myers Squibb andMed-ex learning outside thesubmitted work M Pisa reports no disclosures M Radaellireports personal fees from Merck Serono Sanofi-GenzymeNovartis and Biogen outside the submitted work H Stiebel-Kalish reports no disclosures S Siritho reports personal feesfromNovartis Thailand Biogen Idec Eisai Thailandmarketingco ltd Merck Serono Teva Thailand and Menarini outsidethe submitted work J de Seze and T Senger report no dis-closures J Havla reports grants personal fees and non-financialsupport from Merck personal fees from Novartis CelgeneRoche Santhera Biogen Alexion Sanofi non-financial supportfrom Guthy-Jackson Charitable Foundation and grants fromFriedrich Baur Foundation outside the submitted work RMarignier AC Calvo D Bichuetti IM Tavares N Asgari KSoelberg A Altintas R Yildirim U Tanriverdi A Jacob SHuda Z Rimler and A Reid report no disclosures Y Mao-Draayer reports grants from NIH NIAID grants and personalfees from Genzyme grants from Chugai personal fees fromBiogen and EMD Serono grants and personal fees fromGenentech and Novartis during the conduct of the studygrants from NIH NIAID grants and personal fees from Gen-zyme grants fromChugai personal fees fromBiogen and EMDSerono grants and personal fees fromGenentech andNovartisoutside the submitted work I Soto de Castillo reports nodisclosures A Petzold reports personal fees and grants fromNovartis outside the submitted work and is part of the steeringcommittee of the OCTiMS study which is sponsored byNovartis He has not received honoraria for this activity AJGreen reports other from Bionure grants personal fees andother from Inception Sciences grants from Sherak Foundationpersonal fees and other from Pipeline Pharmaceuticals grantsfrom Hilton Foundation Adelson Foundation and NationalMS Society personal fees from JAMANeurology personal feesand other from MediimmuneViela outside the submittedwork In addition Dr Green has a patent Small Molecule drugfor Remyelination pending and has worked on testing off labelcompounds for remyelination MR Yeaman serves as an ad-visor to the Guthy-Jackson Charitable Foundation T Smithreports no disclosures AU Brandt reports grants from theGuthy Jackson Charitable Foundation during the conduct ofthe study shares from Motognosis GmbH and shares fromNocturne GmbH outside the submitted work In addition DrBrandt has a patent pending describing Foveal MorphometryF Paul reports grants from the Guthy Jackson CharitableFoundation during the conduct of the study grants from theGerman Research Foundation andGerman FederalMinistry ofEducation and research grants and other fromNovartis grantsand other from Bayer Novartis Biogen Idec Teva Sanofi-AventisGenzyme Merck Serono Chugai other from PLoSONE other from Neurologyreg Neuroimmunology amp Neuro-inflammation other from SanofiGenzyme Biogen Idec grantsfrom German Research Council Werth Stiftung of the City of

Cologne German Ministry of Education and Research ArthurArnstein Stiftung Berlin EU FP7 Framework Program ArthurArnstein Foundation Berlin National Multiple Sclerosis(USA) other from MedImmune Shire Alexion outside thesubmitted work In addition Dr Paul has a patent FovealMorphometry pending to Nocturne GmbH Go to NeurologyorgNN for full disclosures

Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationMarch 23 2021 Accepted in final form June 15 2021

Appendix Authors

Name Location Contribution

Frederike CosimaOertel MDPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data anddrafting a significantportion of themanuscript or figuresconception and designof the study

Svenja SpecoviusMSc

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of dataconception and designof the study

Hanna GZimmermannPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of dataconception and designof the study

Claudia ChienPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

SeyedamirhoseinMotamedi PhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

CharlotteBereuter BSc

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

Appendix (continued)

Name Location Contribution

Lawrence CookPhD

University of UtahSalt Lake City UT

Acquisition andanalysis of data andconception and designof the study

Marco AurelioLana Peixoto MDPhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Mariana AndradeFontanelle MD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Ho Jin Kim MDPhD

National Cancer CenterGoyang Republic of Korea

Acquisition andanalysis of data

Jae-Won HyunMD PhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

JacquelinePalace MD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Adriana Roca-Fernandez MSc

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Maria IsabelLeite MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

SrilakshmiSharma MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

FereshtehAshtari MD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Rahele KafiehPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Alireza DehghaniPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

MohsenPourazizi PhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Lekha PanditMD PhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Anitha DrsquoCunhaPhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Orhan Aktas MD Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

MariusRingelstein MD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Philipp AlbrechtMD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Eugene May MD Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Caryl Tongco Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Appendix (continued)

Name Location Contribution

Letizia LeocaniMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marco Pisa MD Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marta RadaelliMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Elena H Martinez-Lapiscina MDPhD

Hospital Clinic of Barcelona-Institut drsquoInvestigacionsBiomediques August PiSunyer Barcelona Spain

Acquisition andanalysis of data

Hadas Stiebel-Kalish MD

Sackler School of MedicineTel Aviv University Tel AvivIsrael

Acquisition andanalysis of data

Sasitorn SirithoMD

Siriraj Hospital andBumrungrad InternationalHospital Bangkok Thailand

Acquisition andanalysis of data

Jerome de SezeMD PhD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Thomas SengerMD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Joachim HavlaMD

Ludwig-MaximiliansUniversitat MuenchenMunich Germany

Acquisition andanalysis of data

RomainMarignier MDPhD

Pierre Wertheimer NeurologicalHospital Hospices Civils deLyon France

Acquisition andanalysis of data

Alvaro CoboCalvo MD PhD

Pierre WertheimerNeurological HospitalHospices Civils de LyonFrance Hospital UniversitariVall drsquoHebron UniversitatAutonoma de BarcelonaSpain

Acquisition andanalysis of data

Denis BichuettiMD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Ivan MaynartTavares MD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Nasrin AsgariMD PhD

University of SouthernDenmark OdenseDenmark

Acquisition andanalysis of data

Kerstin SoelbergMD

University of SouthernDenmark Odense Denmark

Acquisition andanalysis of data

Ayse Altintas MD Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Rengin YildirimMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 11

References1 Oertel FC Zimmermann H Paul F Brandt AU Optical coherence tomog-

raphy in neuromyelitis optica spectrum disorders potential advantages forindividualized monitoring of progression and therapy EPMA J 20189(1)21-33

2 Schneider E Zimmermann H Oberwahrenbrock T et al Optical coherence to-mography reveals distinct patterns of retinal damage in neuromyelitis optica andmultiple sclerosis PLoS One 20138(6)e66151

3 Bouyon M Collongues N Zephir H et al Longitudinal follow-up of vision in aneuromyelitis optica cohort Mult Scler 201319(10)1320-1322

4 Sotirchos ES Filippatou A Fitzgerald KC et al Aquaporin-4 IgG seropositivity isassociated with worse visual outcomes after optic neuritis than MOG-IgG seroposi-tivity and multiple sclerosis independent of macular ganglion cell layer thinningMultScler 201926(11)1360-1371

5 Hamid SHM Whittam D Mutch K et al What proportion of AQP4-IgG-negativeNMO spectrum disorder patients are MOG-IgG positive A cross sectional study of132 patients J Neurol 2017264(10)2088-2094

6 Oertel FC Kuchling J ZimmermannH et al Microstructural visual system changes inAQP4-antibody-seropositive NMOSD Neurol Neuroimmunol Neuroinflamm 20174(3)e334

7 Oertel FC Havla J Roca-Fernandez A et al Retinal ganglion cell loss in neuromyelitisoptica a longitudinal study J Neurol Neurosurg Psychiatry 201889(12)1259-1265

8 Huang D Swanson EA Lin CP et al Optical coherence tomography Science 1991254(5035)1178-1181

9 Specovius S Zimmermann HG Oertel FC et al Cohort profile a collaborativemulticentre study of retinal optical coherence tomography in 539 patients withneuromyelitis optica spectrum disorders (CROCTINO) BMJ Open 202010(10)e035397

10 Motamedi S Gawlik K Ayadi N et al Normative data and minimally detectablechange for inner retinal layer thicknesses using a semi-automated OCT image seg-mentation pipeline Front Neurol 2019101117

11 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177-189

12 von Elm E Altman DG Egger M et al The strengthening the reporting of obser-vational studies in epidemiology (STROBE) statement guidelines for reportingobservational studies Int J Surg 201412(12)1495-1499

13 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PLoS One 20127(4)e34823

14 Schippling S Balk LJ Costello F et al Quality control for retinal OCT in multiplesclerosis validation of the OSCAR-IB criteria Mult Scler 201521(2)163-170

15 Lang A Carass A Hauser M et al Retinal layer segmentation of macular OCT imagesusing boundary classification Biomed Opt Express 20134(7)1133-1152

16 R Development Core Team R A Language and Environment for Statistical Computing[online] R Foundation for Statistical Computing 2008 R-projectorg

17 Akaishi T Kaneko K Himori N et al Subclinical retinal atrophy in the unaffectedfellow eyes of multiple sclerosis and neuromyelitis optica [online serial]J Neuroimmunol 201731310-15 Accessed October 8 2017 jni-journalcomarticleS0165-5728(17)30319-3fulltext

18 Alshowaeir D Yiannikas C Fraser C Klistorner A Mechanism of delayed con-duction of fellow eyes in patients with optic neuritis Int J Ophthalmol 201811(2)329-332

19 Manogaran P Traboulsee AL Lange AP Longitudinal study of retinal nerve fiberlayer thickness and macular volume in patients with neuromyelitis optica spectrumdisorder J Neuroophthalmol 201636(4)363-368

20 Kaufhold F ZimmermannH Schneider E et al Optic neuritis is associated with innernuclear layer thickening and microcystic macular edema independently of multiplesclerosis PLoS One 20138(8)e71145

21 Knier B Schmidt P Aly L et al Retinal inner nuclear layer volume reflects response toimmunotherapy in multiple sclerosis Brain 2016139(11)2855-2863

22 Petzold A Balcer LJ Calabresi PA et al Retinal layer segmentation in multiplesclerosis a systematic review and meta-analysis Lancet Neurol 201716(10)797-812

23 Pawlitzki M Horbrugger M Loewe K et al MS optic neuritis-induced long-termstructural changes within the visual pathway Neurol Neuroimmunol Neuroinflamm20207(2)e665

24 Pache F Zimmermann H Mikolajczak J et al MOG-IgG in NMO and relateddisorders a multicenter study of 50 patients Part 4 afferent visual system damageafter optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patientsJ Neuroinflammation 201613(1)282

25 Filippatou AG Vasileiou ES He Y et al Evidence of subclinical quantitative retinallayer abnormalities in AQP4-IgG seropositive NMOSD Mult Scler 2020 Dec 141352458520977771 doi 1011771352458520977771

26 Motamedi S Oertel FC Yadav SK et al Altered fovea in AQP4-IgGndashseropositiveneuromyelitis optica spectrum disorders Neurol Neuroimmunol Neuroinflamm 20207(5)e805

27 Roca-Fernandez A Oertel FC Yeo T et al Foveal changes in AQP4-Ab seropositiveNMOSD are independent of optic neuritis and not overtly progressive Eur J Neurol202128(7)2280-2293

28 Papadopoulou A Oertel FC Chien C et al Lateral geniculate nucleus volumechanges after optic neuritis in neuromyelitis optica a longitudinal study NeuroimageClin 202130102608

29 Ringelstein M Harmel J Zimmermann H et al Longitudinal optic neuritis-unrelatedvisual evoked potential changes in NMO spectrum disorders Neurology 202094(4)e407-e418

30 Pache F Zimmermann H Finke C et al Brain parenchymal damage in neuromyelitisoptica spectrum disorderndasha multimodal MRI study Eur Radiol 201626(12)4413-4422

31 Hokari M Yokoseki A Arakawa M et al Clinicopathological features in anteriorvisual pathway in neuromyelitis optica Ann Neurol 201679(4)605-624

32 You Y Zhu L Zhang T et al Evidence of muller glial dysfunction in patients withaquaporin-4 immunoglobulin Gndashpositive neuromyelitis optica spectrum disorderOphthalmology 2019126(6)801-810 Elsevier

33 Chien C Scheel M Schmitz-Hubsch T et al Spinal cord lesions and atrophy inNMOSD with AQP4-IgG and MOG-IgG associated autoimmunityMult Scler 201925(14)1926-1936

34 Felix CM Levin MH Verkman AS Complement-independent retinal pathologyproduced by intravitreal injection of neuromyelitis optica immunoglobulin GJ Neuroinflammation 201613(1)275

35 Balk LJ Coric D Knier B et al Retinal inner nuclear layer volume reflects in-flammatory disease activity in multiple sclerosis a longitudinal OCT studyMult SclerJ Exp Transl Clin 20195(3)2055217319871582

36 Gelfand JM Nolan R Schwartz DM Graves J Green AJ Microcystic macular oedemain multiple sclerosis is associated with disease severity Brain 2012135(pt 6)1786-1793

Appendix (continued)

Name Location Contribution

Uygur TanriverdiMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Anu Jacob MD The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Saif Huda MDPhD

The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Zoe Rimler BSc NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Allyson Reid MD NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Yang Mao-Draayer MD PhD

University of MichiganMedical School AnnArbor MI

Acquisition andanalysis of data

Ibis Soto deCastillo MD

Hospital Clınico deMaracaibo MaracaiboVenezuela

Acquisition andanalysis of data

Axel Petzold MDPhD

University College LondonLondon UK

Conception anddesign of the study

Ari J Green MD University of California SanFrancisco CA

Conception anddesign of the study

Michael RYeaman MD PhD

University of California LosAngeles CA

Conception anddesign of the study

Terry Smith MD University of MichiganMedical School AnnArbor MI

Conception anddesign of the study

Alexander UBrandt MD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinBerlin Berlin Germany

Acquisition andanalysis of dataconception and designof the study anddrafting a significantportion of themanuscript or figures

Friedemann PaulMD

CharitendashUniversitatsmedizinBerlin Corporate Member ofFreie Universitat Berlin andHumboldt-Universitat zuBerlin

Acquisition andanalysis of data andconception and designof the study

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

37 Gelfand JM Cree BA Nolan R Arnow S Green AJ Microcystic inner nuclear layerabnormalities and neuromyelitis optica JAMA Neurol 201370(5)629-633

38 Oberwahrenbrock T WeinholdMMikolajczak J et al Reliability of intra-retinal layerthickness estimates PLoS One 201510(9)e0137316

39 Borisow N Kleiter I Gahlen A et al Influence of female sex and fertile age onneuromyelitis optica spectrum disorders Mult Scler 201723(8)1092-1103

40 Mori M Kuwabara S Paul F Worldwide prevalence of neuromyelitis optica spectrumdisorders J Neurol Neurosurg Psychiatry 201889(6)555-556

41 Oertel FC Paul F Accelerating clinical research in neuromyelitis optica spectrumdisorders [online serial] Clin Exp Neuroimmunol 202112(2)89-91 AccessedMarch 28 2021 periclespericles-prodliteratumonlinecomdoiabs101111cen312637

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 13

DOI 101212NXI000000000000106820218 Neurol Neuroimmunol Neuroinflamm

Frederike Cosima Oertel Svenja Specovius Hanna G Zimmermann et al Retinal Optical Coherence Tomography in Neuromyelitis Optica

This information is current as of September 15 2021

ServicesUpdated Information amp

httpnnneurologyorgcontent86e1068fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent86e1068fullhtmlref-list-1

This article cites 40 articles 7 of which you can access for free at

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Page 8: Retinal Optical Coherence Tomography in Neuromyelitis Optica

of NMOSD-ON eyes showed MME indicative of secondaryinflammatory changes2021 This investigation overcame limitsof small samples and OCT data heterogeneity of earlierstudies through use of an international consortium ofNMOSD specialists This framework substantiated theCROCTINO studymdasha large multicenter retrospectiveevaluation of retinal pathology in NMOSD using OCT

The neuroaxonal degeneration in NMOSD-ON demon-strated here is substantially greater than reported changes inmultiple sclerosis (MS) a common differential diagnosis222

In a meta-analysis an average pRNFL loss of 20 μm wasestimated in MS after ON which is nearly 2-fold higher in ourNMOSD-ON cohort (minus384 μm)22 For GCIP layer our datasuggested approximately 15-fold higher loss in NMOSD(minus240 μm) compared with MS22 These differences not onlyresult from a higher ON frequency but may also be caused bymore severe retinal damage in NMOSD after a singular ON23

It is intriguing that the damage is particularly large after thefirst ON episode with smaller losses after subsequent epi-sodes which might be due to less neuroaxonal content insubsequent episodes224 Alternatively although the analysisof treatment effects exceeds the scope of this study it ispossible that the longer time to effective anti-inflammatorytherapy and the typical choice of less effective therapies (egsteroids instead of plasma exchange) at the first attack com-pared with following attacks may significantly contribute tothis difference Independent of the number of ONs the per-cent loss is smaller in GCIP layer compared with pRNFLndashpointing toward either (1) stronger loss of retinal nerve fibersthan retinal ganglion cells (2) impairment of ganglion cellsnot leading to extinction but axonal loss (3) a larger amountof non-neuronal tissue in GCIP layer or (4) RNFL loss in theperiphery beyond the macular area measured by GCIP layerThese hypotheses are not mutually exclusive and each mightcontribute to the effect Consistent with these concepts ex-cessive vision loss relative to neuroaxonal content and VEPlatency in AQP4-IgGndashseropositive patients compared withMOG-IgGndashseropositive and MS patients implies damage ofthe peripheral retina and optic nerve tissues which are notreflected in the macula and pattern VEP measurements4

Whether attack-independent neurodegeneration inAQP4-IgGndashseropositive NMOSD occurs has beencontroversial26725-28 The current study identifies de-creased GCIP layer in NMOSD-NON compared withHC but not pRNFL Such subclinical changes could becaused by contralateral involvement after unilateralON1718 Indeed our cohort suggests pronounced neu-rodegeneration in eyes with contralateral ON Howevereyes of patients without ON also exhibit a trend for thinnerGCIP layer compared with HCs Underscored by longitu-dinal studies showing ON-independent neurodegenerationand VEP latency prolongation729 such patterns suggest atleast 2 mechanisms of injury (1) a primary retinopathy oroptic neuropathy in context of an astrocytopathy or causedby direct damage to AQP4-expressing cells such as astrocytes

and Muller cells by either AQP4-IgG or AQP4-specificT cells or (2) a global or afferent visual system specificchronic or episodic neurodegenerative process Because le-sions often spare the brain and most studies outside ofpredisposed areas such as optic nerve and spinal cord failedto detect effects30 a constant global involvement seemsunlikely Several studies described changes affecting AQP4expression and astrocytic end feet31 parafoveal changes inagreement with an involvement of AQP4-expressing Mullercell6262732 and attack-independent spinal cord atrophy33

These findings are consistent with tissue infiltration byAQP4-IgGndashspecific T cells34 and the attack-independentloss of retinal ganglion cells7mdashfurther supporting the exis-tence of an ON-independent pathology which might berestricted to the main disease foci The latter hypothesescould be addressed by region-specific pathology or advancedimaging studies

INL changes have been suggested as a marker of neuro-inflammation and potential treatment response in MS213536

MME may develop as a consequence of neurodegenerationor othermdashnonndashdisease-specificmdashprocesses35 Patients withNMOSD were described to have INL thickening andMME2037 In our cohort 131 of NMOSD-ON eyes wereaffected byMME which is higher than the 2ndash5 described inMS but comparable to incidences in NMOSD described beforeby Gelfand and colleagues3537 However INL thickening itselfremained comparable to changes reported in MS35 This dis-parity could reflect a disrupted fluid homeostasis due to Mullercell involvement or loss of content of the INL with a parallelinflammatory reaction and development of MME The limitedaccessibility of MMEs especially in severely affected eyes due tolimited image quality has hindered their detailed assessmentsand most likely leads to underestimation of their incidence38

We demonstrate that the INL thickness is inversely correlatedwith neuroaxonal content and could be a valuable marker ofdisease severity also in NMOSD

Our study cohort was representative of patients with AQP4-IgGndashseropositive NMOSD with respect to a female pre-dominance and ON history1139 This OCT study includedmultiple ethnicity backgrounds although the distribution wasshifted toward CaucasianWhite patients and other ethnic-ities were underrepresented (eg Hispanic White and Black)limiting the generalizability of results40 Patients from differ-ent heritages presented similar findings

The current study was based on source data instead of a meta-analysis Using the Guthy-Jackson Charitable Foundation net-work this multicentric study was conducted without investigatorreimbursement and illustrated how collaboration integratinginternational perspectives can produce meaningful results Toovercome technical challenges of heterogeneous source data wedeveloped novel OCT postprocessing techniques allowing us toperform standardized analyses and enabling the uniform analysisof the largest OCT image data set in NMOSD to date10 Thusthe strengths of CROCTINO include its established

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

infrastructure large international network of experts represent-ing multiple ethnicities and geographic regions and the use ofstate-of-the-art OCT postprocessing techniques41

We recognize limitations of the current investigation Theretrospective and heterogeneous data acquisition might haveled to biases and impreciseness beyond the ability of ourquality control We addressed this by excluding uncertaincases HCs were only included from a limited number ofcenters The unbalanced data set limited some analyses suchas the influence of ethnicities or acute and disease-modifyingtreatments Case-control matching was impossible particu-larly with respect to subclinical progression dependent orindependent of ON and to ethnicity Similarly comparisonswith other NMOSD subtypes or MS were beyond the scopeof this study Longitudinal data acute ON data and AQP4-IgGndashseronegative and MOG-IgGndashseropositive patient dataare part of the CROCTINO data set and will be analyzed inthe future Also OCT data processing was performed bymultiple raters potentially introducing interrater variabilityMRI data and posterior visual pathway involvement were notinvestigated in this study However the current study ach-ieved an unprecedented worldwide assessment of retinaldamage in AQP4-IgGndashseropositive NMOSD

To conclude AQP4-IgGndashseropositive NMOSD is characterizedby a severe functionally relevant retinal neurodegeneration as aconsequence of ON Although the majority of damage occursduring the first episode there is cumulative loss with each suc-ceeding relapse TheON-associated damage is not limited to theneuroaxonal content but can also inducemdashlikely inflammation-mediatedmdashINL increase and occurrence ofMMEOur data alsosuggest attack-independent retinal damage in AQP4-IgGndashseropositive NMOSD Our study supports that at-tack prevention is key in avoiding neuroaxonal damage andvision loss in patients with NMOSD It further suggests thatthe first ON episode causes the most damage where onlysome patients with then established diagnosis will be on im-munosuppressive therapy This highlights the need for ef-fective therapies that can ameliorate an ongoing attack orregenerate attack-generated damage which is an unmet clin-ical need Last the study emphasizes the utility of OCT as asensitive structural metric and its potential for monitoringprogression and even treatment response in AQP4-IgGndashseropositive NMOSD The international CROCTINOprogram provides an unprecedented opportunity to applyOCT in a standardized manner to assess pathophysiologyclinical course and therapeutic efficacy in NMOSD

Study FundingGuthy-Jackson Charitable Foundation (GJCF) and GermanResearch Foundation (DFG)

DisclosureFC Oertel was employee of Nocturne GmbH and receivesresearch support by the American Academy of Neurology andthe National Multiple Sclerosis Society unrelated to this work

S Specovius reports no disclosures HG Zimmerman reportsresearch grants from Novartis and speaking honoraria fromBayer Healthcare unrelated to this study C Chien reportsspeaking honoraria from Bayer Healthcare unrelated to thiswork S Motamedi and C Bereuter report no disclosures LCook reports grants from Guthy Jackson Charitable Founda-tion during the conduct of the study EH Martinez-Lapiscinais employed by the European Medicines Agency (HumanMedicines) since 16 April 2019 This article is related with heractivity under Hospital Clinic of BarcelonaIDIBAPS affiliationand consequently as external activity it does not represent theviews of the Agency its Committees or working parties Beforeenrolling EMA Dr Martinez-Lapiscina reports grants fromInstituto de Salud Carlos III (Spain) amp Fondo Europeo deDesarrollo Regional grants from MS Innovation GMSI otherfromFundacio Privada Cellex and personal fees fromNovartisRoche Sanofi-Genzyme outside the submitted work MALana Peixoto and MA Fontanelle report no disclosures HJKim reports grants from the National Research Foundation ofKorea personal fees from Alexion Pharmaceuticals AprilbioBiogen Celltrion Eisai HanAll BioPharma MDimune MerckSerono Novartis Sanofi Genzyme Teva-Handok and VielaBio other from Viela Bio (formerly MedImmune) MultipleSclerosis Journal and Journal of Clinical Neurology outsidethe submitted work J-W Hyun reports grants from the Na-tional Research Foundation of Korea outside the submittedwork J Palace reports personal fees from Abide TherapeuticsAlexion Pharmaceuticals ARGENX Bayer Schering BiogenIdec Chugai Pharma EuroImmun Genzyme MedDayMedImmuneMerck Serono Novartis Roche Teva UCB andViela Bio grants from Abide Therapeutics Alexion Pharma-ceuticals Bayer Schering Biogen Idec Chugai Pharma Gen-zyme MedImmune Merck Serono Novartis and Teva grantsfrom Merck Serono Novartis Biogen Idec Teva AbideMedImmune Bayer Schering Genzyme Chugai and AlexionEugene Devic European Network the Grant for MultipleSclerosis Innovation the John Fell Fund the Medical ResearchCouncil the MS Society Myaware the UK National Institutefor Health Research Oxford Health Services Research Com-mittee and theGuthy-JacksonCharitable Foundation AMPLOand SPARKS Great Ormond Street for research studies out-side the submitted work MI Leite and S Sharma report nodisclosures A Roca-Fernandez is sponsored by Abide Thera-peutic outside of the submitted work and reports no potentialconflicts of interest R Kafieh A Dehghani M Pourazizi LPandit and A DrsquoCunha report no disclosures O Aktas reportsgrants from German Research Foundation (DFG) and Ger-man Ministry of Education and Research (BMBF) personalfees from Alexion and Almirall grants and personal fees fromBiogen personal fees from Merck grants and personal feesfrom Novartis grants and personal fees from Roche personalfees from Sanofi personal fees from Teva personal fees fromViela Bio outside the submitted work M Ringelstein receivedspeaker honoraria from Novartis Bayer Vital GmbH RocheAlexion and Ipsen and travel reimbursement from BayerSchering Biogen Idec Merz Genzyme Teva Roche andMerck none related to this study P Albrecht reports grants

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 9

personal fees and non-financial support from Allergan BiogenMerck Merz Pharmaceuticals Novartis Ipsen CelgeneRoche and personal fees and non-financial support from Tevaoutside the submitted work E May and C Tongco report nodisclosures L Leocani reports personal fees from RocheMerck Bristol Myers Squibb andMed-ex learning outside thesubmitted work M Pisa reports no disclosures M Radaellireports personal fees from Merck Serono Sanofi-GenzymeNovartis and Biogen outside the submitted work H Stiebel-Kalish reports no disclosures S Siritho reports personal feesfromNovartis Thailand Biogen Idec Eisai Thailandmarketingco ltd Merck Serono Teva Thailand and Menarini outsidethe submitted work J de Seze and T Senger report no dis-closures J Havla reports grants personal fees and non-financialsupport from Merck personal fees from Novartis CelgeneRoche Santhera Biogen Alexion Sanofi non-financial supportfrom Guthy-Jackson Charitable Foundation and grants fromFriedrich Baur Foundation outside the submitted work RMarignier AC Calvo D Bichuetti IM Tavares N Asgari KSoelberg A Altintas R Yildirim U Tanriverdi A Jacob SHuda Z Rimler and A Reid report no disclosures Y Mao-Draayer reports grants from NIH NIAID grants and personalfees from Genzyme grants from Chugai personal fees fromBiogen and EMD Serono grants and personal fees fromGenentech and Novartis during the conduct of the studygrants from NIH NIAID grants and personal fees from Gen-zyme grants fromChugai personal fees fromBiogen and EMDSerono grants and personal fees fromGenentech andNovartisoutside the submitted work I Soto de Castillo reports nodisclosures A Petzold reports personal fees and grants fromNovartis outside the submitted work and is part of the steeringcommittee of the OCTiMS study which is sponsored byNovartis He has not received honoraria for this activity AJGreen reports other from Bionure grants personal fees andother from Inception Sciences grants from Sherak Foundationpersonal fees and other from Pipeline Pharmaceuticals grantsfrom Hilton Foundation Adelson Foundation and NationalMS Society personal fees from JAMANeurology personal feesand other from MediimmuneViela outside the submittedwork In addition Dr Green has a patent Small Molecule drugfor Remyelination pending and has worked on testing off labelcompounds for remyelination MR Yeaman serves as an ad-visor to the Guthy-Jackson Charitable Foundation T Smithreports no disclosures AU Brandt reports grants from theGuthy Jackson Charitable Foundation during the conduct ofthe study shares from Motognosis GmbH and shares fromNocturne GmbH outside the submitted work In addition DrBrandt has a patent pending describing Foveal MorphometryF Paul reports grants from the Guthy Jackson CharitableFoundation during the conduct of the study grants from theGerman Research Foundation andGerman FederalMinistry ofEducation and research grants and other fromNovartis grantsand other from Bayer Novartis Biogen Idec Teva Sanofi-AventisGenzyme Merck Serono Chugai other from PLoSONE other from Neurologyreg Neuroimmunology amp Neuro-inflammation other from SanofiGenzyme Biogen Idec grantsfrom German Research Council Werth Stiftung of the City of

Cologne German Ministry of Education and Research ArthurArnstein Stiftung Berlin EU FP7 Framework Program ArthurArnstein Foundation Berlin National Multiple Sclerosis(USA) other from MedImmune Shire Alexion outside thesubmitted work In addition Dr Paul has a patent FovealMorphometry pending to Nocturne GmbH Go to NeurologyorgNN for full disclosures

Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationMarch 23 2021 Accepted in final form June 15 2021

Appendix Authors

Name Location Contribution

Frederike CosimaOertel MDPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data anddrafting a significantportion of themanuscript or figuresconception and designof the study

Svenja SpecoviusMSc

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of dataconception and designof the study

Hanna GZimmermannPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of dataconception and designof the study

Claudia ChienPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

SeyedamirhoseinMotamedi PhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

CharlotteBereuter BSc

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

Appendix (continued)

Name Location Contribution

Lawrence CookPhD

University of UtahSalt Lake City UT

Acquisition andanalysis of data andconception and designof the study

Marco AurelioLana Peixoto MDPhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Mariana AndradeFontanelle MD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Ho Jin Kim MDPhD

National Cancer CenterGoyang Republic of Korea

Acquisition andanalysis of data

Jae-Won HyunMD PhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

JacquelinePalace MD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Adriana Roca-Fernandez MSc

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Maria IsabelLeite MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

SrilakshmiSharma MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

FereshtehAshtari MD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Rahele KafiehPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Alireza DehghaniPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

MohsenPourazizi PhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Lekha PanditMD PhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Anitha DrsquoCunhaPhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Orhan Aktas MD Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

MariusRingelstein MD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Philipp AlbrechtMD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Eugene May MD Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Caryl Tongco Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Appendix (continued)

Name Location Contribution

Letizia LeocaniMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marco Pisa MD Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marta RadaelliMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Elena H Martinez-Lapiscina MDPhD

Hospital Clinic of Barcelona-Institut drsquoInvestigacionsBiomediques August PiSunyer Barcelona Spain

Acquisition andanalysis of data

Hadas Stiebel-Kalish MD

Sackler School of MedicineTel Aviv University Tel AvivIsrael

Acquisition andanalysis of data

Sasitorn SirithoMD

Siriraj Hospital andBumrungrad InternationalHospital Bangkok Thailand

Acquisition andanalysis of data

Jerome de SezeMD PhD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Thomas SengerMD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Joachim HavlaMD

Ludwig-MaximiliansUniversitat MuenchenMunich Germany

Acquisition andanalysis of data

RomainMarignier MDPhD

Pierre Wertheimer NeurologicalHospital Hospices Civils deLyon France

Acquisition andanalysis of data

Alvaro CoboCalvo MD PhD

Pierre WertheimerNeurological HospitalHospices Civils de LyonFrance Hospital UniversitariVall drsquoHebron UniversitatAutonoma de BarcelonaSpain

Acquisition andanalysis of data

Denis BichuettiMD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Ivan MaynartTavares MD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Nasrin AsgariMD PhD

University of SouthernDenmark OdenseDenmark

Acquisition andanalysis of data

Kerstin SoelbergMD

University of SouthernDenmark Odense Denmark

Acquisition andanalysis of data

Ayse Altintas MD Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Rengin YildirimMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 11

References1 Oertel FC Zimmermann H Paul F Brandt AU Optical coherence tomog-

raphy in neuromyelitis optica spectrum disorders potential advantages forindividualized monitoring of progression and therapy EPMA J 20189(1)21-33

2 Schneider E Zimmermann H Oberwahrenbrock T et al Optical coherence to-mography reveals distinct patterns of retinal damage in neuromyelitis optica andmultiple sclerosis PLoS One 20138(6)e66151

3 Bouyon M Collongues N Zephir H et al Longitudinal follow-up of vision in aneuromyelitis optica cohort Mult Scler 201319(10)1320-1322

4 Sotirchos ES Filippatou A Fitzgerald KC et al Aquaporin-4 IgG seropositivity isassociated with worse visual outcomes after optic neuritis than MOG-IgG seroposi-tivity and multiple sclerosis independent of macular ganglion cell layer thinningMultScler 201926(11)1360-1371

5 Hamid SHM Whittam D Mutch K et al What proportion of AQP4-IgG-negativeNMO spectrum disorder patients are MOG-IgG positive A cross sectional study of132 patients J Neurol 2017264(10)2088-2094

6 Oertel FC Kuchling J ZimmermannH et al Microstructural visual system changes inAQP4-antibody-seropositive NMOSD Neurol Neuroimmunol Neuroinflamm 20174(3)e334

7 Oertel FC Havla J Roca-Fernandez A et al Retinal ganglion cell loss in neuromyelitisoptica a longitudinal study J Neurol Neurosurg Psychiatry 201889(12)1259-1265

8 Huang D Swanson EA Lin CP et al Optical coherence tomography Science 1991254(5035)1178-1181

9 Specovius S Zimmermann HG Oertel FC et al Cohort profile a collaborativemulticentre study of retinal optical coherence tomography in 539 patients withneuromyelitis optica spectrum disorders (CROCTINO) BMJ Open 202010(10)e035397

10 Motamedi S Gawlik K Ayadi N et al Normative data and minimally detectablechange for inner retinal layer thicknesses using a semi-automated OCT image seg-mentation pipeline Front Neurol 2019101117

11 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177-189

12 von Elm E Altman DG Egger M et al The strengthening the reporting of obser-vational studies in epidemiology (STROBE) statement guidelines for reportingobservational studies Int J Surg 201412(12)1495-1499

13 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PLoS One 20127(4)e34823

14 Schippling S Balk LJ Costello F et al Quality control for retinal OCT in multiplesclerosis validation of the OSCAR-IB criteria Mult Scler 201521(2)163-170

15 Lang A Carass A Hauser M et al Retinal layer segmentation of macular OCT imagesusing boundary classification Biomed Opt Express 20134(7)1133-1152

16 R Development Core Team R A Language and Environment for Statistical Computing[online] R Foundation for Statistical Computing 2008 R-projectorg

17 Akaishi T Kaneko K Himori N et al Subclinical retinal atrophy in the unaffectedfellow eyes of multiple sclerosis and neuromyelitis optica [online serial]J Neuroimmunol 201731310-15 Accessed October 8 2017 jni-journalcomarticleS0165-5728(17)30319-3fulltext

18 Alshowaeir D Yiannikas C Fraser C Klistorner A Mechanism of delayed con-duction of fellow eyes in patients with optic neuritis Int J Ophthalmol 201811(2)329-332

19 Manogaran P Traboulsee AL Lange AP Longitudinal study of retinal nerve fiberlayer thickness and macular volume in patients with neuromyelitis optica spectrumdisorder J Neuroophthalmol 201636(4)363-368

20 Kaufhold F ZimmermannH Schneider E et al Optic neuritis is associated with innernuclear layer thickening and microcystic macular edema independently of multiplesclerosis PLoS One 20138(8)e71145

21 Knier B Schmidt P Aly L et al Retinal inner nuclear layer volume reflects response toimmunotherapy in multiple sclerosis Brain 2016139(11)2855-2863

22 Petzold A Balcer LJ Calabresi PA et al Retinal layer segmentation in multiplesclerosis a systematic review and meta-analysis Lancet Neurol 201716(10)797-812

23 Pawlitzki M Horbrugger M Loewe K et al MS optic neuritis-induced long-termstructural changes within the visual pathway Neurol Neuroimmunol Neuroinflamm20207(2)e665

24 Pache F Zimmermann H Mikolajczak J et al MOG-IgG in NMO and relateddisorders a multicenter study of 50 patients Part 4 afferent visual system damageafter optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patientsJ Neuroinflammation 201613(1)282

25 Filippatou AG Vasileiou ES He Y et al Evidence of subclinical quantitative retinallayer abnormalities in AQP4-IgG seropositive NMOSD Mult Scler 2020 Dec 141352458520977771 doi 1011771352458520977771

26 Motamedi S Oertel FC Yadav SK et al Altered fovea in AQP4-IgGndashseropositiveneuromyelitis optica spectrum disorders Neurol Neuroimmunol Neuroinflamm 20207(5)e805

27 Roca-Fernandez A Oertel FC Yeo T et al Foveal changes in AQP4-Ab seropositiveNMOSD are independent of optic neuritis and not overtly progressive Eur J Neurol202128(7)2280-2293

28 Papadopoulou A Oertel FC Chien C et al Lateral geniculate nucleus volumechanges after optic neuritis in neuromyelitis optica a longitudinal study NeuroimageClin 202130102608

29 Ringelstein M Harmel J Zimmermann H et al Longitudinal optic neuritis-unrelatedvisual evoked potential changes in NMO spectrum disorders Neurology 202094(4)e407-e418

30 Pache F Zimmermann H Finke C et al Brain parenchymal damage in neuromyelitisoptica spectrum disorderndasha multimodal MRI study Eur Radiol 201626(12)4413-4422

31 Hokari M Yokoseki A Arakawa M et al Clinicopathological features in anteriorvisual pathway in neuromyelitis optica Ann Neurol 201679(4)605-624

32 You Y Zhu L Zhang T et al Evidence of muller glial dysfunction in patients withaquaporin-4 immunoglobulin Gndashpositive neuromyelitis optica spectrum disorderOphthalmology 2019126(6)801-810 Elsevier

33 Chien C Scheel M Schmitz-Hubsch T et al Spinal cord lesions and atrophy inNMOSD with AQP4-IgG and MOG-IgG associated autoimmunityMult Scler 201925(14)1926-1936

34 Felix CM Levin MH Verkman AS Complement-independent retinal pathologyproduced by intravitreal injection of neuromyelitis optica immunoglobulin GJ Neuroinflammation 201613(1)275

35 Balk LJ Coric D Knier B et al Retinal inner nuclear layer volume reflects in-flammatory disease activity in multiple sclerosis a longitudinal OCT studyMult SclerJ Exp Transl Clin 20195(3)2055217319871582

36 Gelfand JM Nolan R Schwartz DM Graves J Green AJ Microcystic macular oedemain multiple sclerosis is associated with disease severity Brain 2012135(pt 6)1786-1793

Appendix (continued)

Name Location Contribution

Uygur TanriverdiMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Anu Jacob MD The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Saif Huda MDPhD

The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Zoe Rimler BSc NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Allyson Reid MD NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Yang Mao-Draayer MD PhD

University of MichiganMedical School AnnArbor MI

Acquisition andanalysis of data

Ibis Soto deCastillo MD

Hospital Clınico deMaracaibo MaracaiboVenezuela

Acquisition andanalysis of data

Axel Petzold MDPhD

University College LondonLondon UK

Conception anddesign of the study

Ari J Green MD University of California SanFrancisco CA

Conception anddesign of the study

Michael RYeaman MD PhD

University of California LosAngeles CA

Conception anddesign of the study

Terry Smith MD University of MichiganMedical School AnnArbor MI

Conception anddesign of the study

Alexander UBrandt MD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinBerlin Berlin Germany

Acquisition andanalysis of dataconception and designof the study anddrafting a significantportion of themanuscript or figures

Friedemann PaulMD

CharitendashUniversitatsmedizinBerlin Corporate Member ofFreie Universitat Berlin andHumboldt-Universitat zuBerlin

Acquisition andanalysis of data andconception and designof the study

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

37 Gelfand JM Cree BA Nolan R Arnow S Green AJ Microcystic inner nuclear layerabnormalities and neuromyelitis optica JAMA Neurol 201370(5)629-633

38 Oberwahrenbrock T WeinholdMMikolajczak J et al Reliability of intra-retinal layerthickness estimates PLoS One 201510(9)e0137316

39 Borisow N Kleiter I Gahlen A et al Influence of female sex and fertile age onneuromyelitis optica spectrum disorders Mult Scler 201723(8)1092-1103

40 Mori M Kuwabara S Paul F Worldwide prevalence of neuromyelitis optica spectrumdisorders J Neurol Neurosurg Psychiatry 201889(6)555-556

41 Oertel FC Paul F Accelerating clinical research in neuromyelitis optica spectrumdisorders [online serial] Clin Exp Neuroimmunol 202112(2)89-91 AccessedMarch 28 2021 periclespericles-prodliteratumonlinecomdoiabs101111cen312637

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 13

DOI 101212NXI000000000000106820218 Neurol Neuroimmunol Neuroinflamm

Frederike Cosima Oertel Svenja Specovius Hanna G Zimmermann et al Retinal Optical Coherence Tomography in Neuromyelitis Optica

This information is current as of September 15 2021

ServicesUpdated Information amp

httpnnneurologyorgcontent86e1068fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent86e1068fullhtmlref-list-1

This article cites 40 articles 7 of which you can access for free at

Subspecialty Collections

httpnnneurologyorgcgicollectionvisual_lossVisual loss

httpnnneurologyorgcgicollectionretinaRetina

httpnnneurologyorgcgicollectionoptic_neuritisOptic neuritis see Neuro-ophthalmologyOptic Nerve

httpnnneurologyorgcgicollectiondevics_syndromeDevics syndrome

httpnnneurologyorgcgicollectionall_imagingAll Imagingfollowing collection(s) This article along with others on similar topics appears in the

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Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm

Page 9: Retinal Optical Coherence Tomography in Neuromyelitis Optica

infrastructure large international network of experts represent-ing multiple ethnicities and geographic regions and the use ofstate-of-the-art OCT postprocessing techniques41

We recognize limitations of the current investigation Theretrospective and heterogeneous data acquisition might haveled to biases and impreciseness beyond the ability of ourquality control We addressed this by excluding uncertaincases HCs were only included from a limited number ofcenters The unbalanced data set limited some analyses suchas the influence of ethnicities or acute and disease-modifyingtreatments Case-control matching was impossible particu-larly with respect to subclinical progression dependent orindependent of ON and to ethnicity Similarly comparisonswith other NMOSD subtypes or MS were beyond the scopeof this study Longitudinal data acute ON data and AQP4-IgGndashseronegative and MOG-IgGndashseropositive patient dataare part of the CROCTINO data set and will be analyzed inthe future Also OCT data processing was performed bymultiple raters potentially introducing interrater variabilityMRI data and posterior visual pathway involvement were notinvestigated in this study However the current study ach-ieved an unprecedented worldwide assessment of retinaldamage in AQP4-IgGndashseropositive NMOSD

To conclude AQP4-IgGndashseropositive NMOSD is characterizedby a severe functionally relevant retinal neurodegeneration as aconsequence of ON Although the majority of damage occursduring the first episode there is cumulative loss with each suc-ceeding relapse TheON-associated damage is not limited to theneuroaxonal content but can also inducemdashlikely inflammation-mediatedmdashINL increase and occurrence ofMMEOur data alsosuggest attack-independent retinal damage in AQP4-IgGndashseropositive NMOSD Our study supports that at-tack prevention is key in avoiding neuroaxonal damage andvision loss in patients with NMOSD It further suggests thatthe first ON episode causes the most damage where onlysome patients with then established diagnosis will be on im-munosuppressive therapy This highlights the need for ef-fective therapies that can ameliorate an ongoing attack orregenerate attack-generated damage which is an unmet clin-ical need Last the study emphasizes the utility of OCT as asensitive structural metric and its potential for monitoringprogression and even treatment response in AQP4-IgGndashseropositive NMOSD The international CROCTINOprogram provides an unprecedented opportunity to applyOCT in a standardized manner to assess pathophysiologyclinical course and therapeutic efficacy in NMOSD

Study FundingGuthy-Jackson Charitable Foundation (GJCF) and GermanResearch Foundation (DFG)

DisclosureFC Oertel was employee of Nocturne GmbH and receivesresearch support by the American Academy of Neurology andthe National Multiple Sclerosis Society unrelated to this work

S Specovius reports no disclosures HG Zimmerman reportsresearch grants from Novartis and speaking honoraria fromBayer Healthcare unrelated to this study C Chien reportsspeaking honoraria from Bayer Healthcare unrelated to thiswork S Motamedi and C Bereuter report no disclosures LCook reports grants from Guthy Jackson Charitable Founda-tion during the conduct of the study EH Martinez-Lapiscinais employed by the European Medicines Agency (HumanMedicines) since 16 April 2019 This article is related with heractivity under Hospital Clinic of BarcelonaIDIBAPS affiliationand consequently as external activity it does not represent theviews of the Agency its Committees or working parties Beforeenrolling EMA Dr Martinez-Lapiscina reports grants fromInstituto de Salud Carlos III (Spain) amp Fondo Europeo deDesarrollo Regional grants from MS Innovation GMSI otherfromFundacio Privada Cellex and personal fees fromNovartisRoche Sanofi-Genzyme outside the submitted work MALana Peixoto and MA Fontanelle report no disclosures HJKim reports grants from the National Research Foundation ofKorea personal fees from Alexion Pharmaceuticals AprilbioBiogen Celltrion Eisai HanAll BioPharma MDimune MerckSerono Novartis Sanofi Genzyme Teva-Handok and VielaBio other from Viela Bio (formerly MedImmune) MultipleSclerosis Journal and Journal of Clinical Neurology outsidethe submitted work J-W Hyun reports grants from the Na-tional Research Foundation of Korea outside the submittedwork J Palace reports personal fees from Abide TherapeuticsAlexion Pharmaceuticals ARGENX Bayer Schering BiogenIdec Chugai Pharma EuroImmun Genzyme MedDayMedImmuneMerck Serono Novartis Roche Teva UCB andViela Bio grants from Abide Therapeutics Alexion Pharma-ceuticals Bayer Schering Biogen Idec Chugai Pharma Gen-zyme MedImmune Merck Serono Novartis and Teva grantsfrom Merck Serono Novartis Biogen Idec Teva AbideMedImmune Bayer Schering Genzyme Chugai and AlexionEugene Devic European Network the Grant for MultipleSclerosis Innovation the John Fell Fund the Medical ResearchCouncil the MS Society Myaware the UK National Institutefor Health Research Oxford Health Services Research Com-mittee and theGuthy-JacksonCharitable Foundation AMPLOand SPARKS Great Ormond Street for research studies out-side the submitted work MI Leite and S Sharma report nodisclosures A Roca-Fernandez is sponsored by Abide Thera-peutic outside of the submitted work and reports no potentialconflicts of interest R Kafieh A Dehghani M Pourazizi LPandit and A DrsquoCunha report no disclosures O Aktas reportsgrants from German Research Foundation (DFG) and Ger-man Ministry of Education and Research (BMBF) personalfees from Alexion and Almirall grants and personal fees fromBiogen personal fees from Merck grants and personal feesfrom Novartis grants and personal fees from Roche personalfees from Sanofi personal fees from Teva personal fees fromViela Bio outside the submitted work M Ringelstein receivedspeaker honoraria from Novartis Bayer Vital GmbH RocheAlexion and Ipsen and travel reimbursement from BayerSchering Biogen Idec Merz Genzyme Teva Roche andMerck none related to this study P Albrecht reports grants

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 9

personal fees and non-financial support from Allergan BiogenMerck Merz Pharmaceuticals Novartis Ipsen CelgeneRoche and personal fees and non-financial support from Tevaoutside the submitted work E May and C Tongco report nodisclosures L Leocani reports personal fees from RocheMerck Bristol Myers Squibb andMed-ex learning outside thesubmitted work M Pisa reports no disclosures M Radaellireports personal fees from Merck Serono Sanofi-GenzymeNovartis and Biogen outside the submitted work H Stiebel-Kalish reports no disclosures S Siritho reports personal feesfromNovartis Thailand Biogen Idec Eisai Thailandmarketingco ltd Merck Serono Teva Thailand and Menarini outsidethe submitted work J de Seze and T Senger report no dis-closures J Havla reports grants personal fees and non-financialsupport from Merck personal fees from Novartis CelgeneRoche Santhera Biogen Alexion Sanofi non-financial supportfrom Guthy-Jackson Charitable Foundation and grants fromFriedrich Baur Foundation outside the submitted work RMarignier AC Calvo D Bichuetti IM Tavares N Asgari KSoelberg A Altintas R Yildirim U Tanriverdi A Jacob SHuda Z Rimler and A Reid report no disclosures Y Mao-Draayer reports grants from NIH NIAID grants and personalfees from Genzyme grants from Chugai personal fees fromBiogen and EMD Serono grants and personal fees fromGenentech and Novartis during the conduct of the studygrants from NIH NIAID grants and personal fees from Gen-zyme grants fromChugai personal fees fromBiogen and EMDSerono grants and personal fees fromGenentech andNovartisoutside the submitted work I Soto de Castillo reports nodisclosures A Petzold reports personal fees and grants fromNovartis outside the submitted work and is part of the steeringcommittee of the OCTiMS study which is sponsored byNovartis He has not received honoraria for this activity AJGreen reports other from Bionure grants personal fees andother from Inception Sciences grants from Sherak Foundationpersonal fees and other from Pipeline Pharmaceuticals grantsfrom Hilton Foundation Adelson Foundation and NationalMS Society personal fees from JAMANeurology personal feesand other from MediimmuneViela outside the submittedwork In addition Dr Green has a patent Small Molecule drugfor Remyelination pending and has worked on testing off labelcompounds for remyelination MR Yeaman serves as an ad-visor to the Guthy-Jackson Charitable Foundation T Smithreports no disclosures AU Brandt reports grants from theGuthy Jackson Charitable Foundation during the conduct ofthe study shares from Motognosis GmbH and shares fromNocturne GmbH outside the submitted work In addition DrBrandt has a patent pending describing Foveal MorphometryF Paul reports grants from the Guthy Jackson CharitableFoundation during the conduct of the study grants from theGerman Research Foundation andGerman FederalMinistry ofEducation and research grants and other fromNovartis grantsand other from Bayer Novartis Biogen Idec Teva Sanofi-AventisGenzyme Merck Serono Chugai other from PLoSONE other from Neurologyreg Neuroimmunology amp Neuro-inflammation other from SanofiGenzyme Biogen Idec grantsfrom German Research Council Werth Stiftung of the City of

Cologne German Ministry of Education and Research ArthurArnstein Stiftung Berlin EU FP7 Framework Program ArthurArnstein Foundation Berlin National Multiple Sclerosis(USA) other from MedImmune Shire Alexion outside thesubmitted work In addition Dr Paul has a patent FovealMorphometry pending to Nocturne GmbH Go to NeurologyorgNN for full disclosures

Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationMarch 23 2021 Accepted in final form June 15 2021

Appendix Authors

Name Location Contribution

Frederike CosimaOertel MDPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data anddrafting a significantportion of themanuscript or figuresconception and designof the study

Svenja SpecoviusMSc

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of dataconception and designof the study

Hanna GZimmermannPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of dataconception and designof the study

Claudia ChienPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

SeyedamirhoseinMotamedi PhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

CharlotteBereuter BSc

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

Appendix (continued)

Name Location Contribution

Lawrence CookPhD

University of UtahSalt Lake City UT

Acquisition andanalysis of data andconception and designof the study

Marco AurelioLana Peixoto MDPhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Mariana AndradeFontanelle MD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Ho Jin Kim MDPhD

National Cancer CenterGoyang Republic of Korea

Acquisition andanalysis of data

Jae-Won HyunMD PhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

JacquelinePalace MD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Adriana Roca-Fernandez MSc

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Maria IsabelLeite MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

SrilakshmiSharma MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

FereshtehAshtari MD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Rahele KafiehPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Alireza DehghaniPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

MohsenPourazizi PhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Lekha PanditMD PhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Anitha DrsquoCunhaPhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Orhan Aktas MD Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

MariusRingelstein MD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Philipp AlbrechtMD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Eugene May MD Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Caryl Tongco Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Appendix (continued)

Name Location Contribution

Letizia LeocaniMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marco Pisa MD Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marta RadaelliMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Elena H Martinez-Lapiscina MDPhD

Hospital Clinic of Barcelona-Institut drsquoInvestigacionsBiomediques August PiSunyer Barcelona Spain

Acquisition andanalysis of data

Hadas Stiebel-Kalish MD

Sackler School of MedicineTel Aviv University Tel AvivIsrael

Acquisition andanalysis of data

Sasitorn SirithoMD

Siriraj Hospital andBumrungrad InternationalHospital Bangkok Thailand

Acquisition andanalysis of data

Jerome de SezeMD PhD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Thomas SengerMD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Joachim HavlaMD

Ludwig-MaximiliansUniversitat MuenchenMunich Germany

Acquisition andanalysis of data

RomainMarignier MDPhD

Pierre Wertheimer NeurologicalHospital Hospices Civils deLyon France

Acquisition andanalysis of data

Alvaro CoboCalvo MD PhD

Pierre WertheimerNeurological HospitalHospices Civils de LyonFrance Hospital UniversitariVall drsquoHebron UniversitatAutonoma de BarcelonaSpain

Acquisition andanalysis of data

Denis BichuettiMD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Ivan MaynartTavares MD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Nasrin AsgariMD PhD

University of SouthernDenmark OdenseDenmark

Acquisition andanalysis of data

Kerstin SoelbergMD

University of SouthernDenmark Odense Denmark

Acquisition andanalysis of data

Ayse Altintas MD Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Rengin YildirimMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 11

References1 Oertel FC Zimmermann H Paul F Brandt AU Optical coherence tomog-

raphy in neuromyelitis optica spectrum disorders potential advantages forindividualized monitoring of progression and therapy EPMA J 20189(1)21-33

2 Schneider E Zimmermann H Oberwahrenbrock T et al Optical coherence to-mography reveals distinct patterns of retinal damage in neuromyelitis optica andmultiple sclerosis PLoS One 20138(6)e66151

3 Bouyon M Collongues N Zephir H et al Longitudinal follow-up of vision in aneuromyelitis optica cohort Mult Scler 201319(10)1320-1322

4 Sotirchos ES Filippatou A Fitzgerald KC et al Aquaporin-4 IgG seropositivity isassociated with worse visual outcomes after optic neuritis than MOG-IgG seroposi-tivity and multiple sclerosis independent of macular ganglion cell layer thinningMultScler 201926(11)1360-1371

5 Hamid SHM Whittam D Mutch K et al What proportion of AQP4-IgG-negativeNMO spectrum disorder patients are MOG-IgG positive A cross sectional study of132 patients J Neurol 2017264(10)2088-2094

6 Oertel FC Kuchling J ZimmermannH et al Microstructural visual system changes inAQP4-antibody-seropositive NMOSD Neurol Neuroimmunol Neuroinflamm 20174(3)e334

7 Oertel FC Havla J Roca-Fernandez A et al Retinal ganglion cell loss in neuromyelitisoptica a longitudinal study J Neurol Neurosurg Psychiatry 201889(12)1259-1265

8 Huang D Swanson EA Lin CP et al Optical coherence tomography Science 1991254(5035)1178-1181

9 Specovius S Zimmermann HG Oertel FC et al Cohort profile a collaborativemulticentre study of retinal optical coherence tomography in 539 patients withneuromyelitis optica spectrum disorders (CROCTINO) BMJ Open 202010(10)e035397

10 Motamedi S Gawlik K Ayadi N et al Normative data and minimally detectablechange for inner retinal layer thicknesses using a semi-automated OCT image seg-mentation pipeline Front Neurol 2019101117

11 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177-189

12 von Elm E Altman DG Egger M et al The strengthening the reporting of obser-vational studies in epidemiology (STROBE) statement guidelines for reportingobservational studies Int J Surg 201412(12)1495-1499

13 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PLoS One 20127(4)e34823

14 Schippling S Balk LJ Costello F et al Quality control for retinal OCT in multiplesclerosis validation of the OSCAR-IB criteria Mult Scler 201521(2)163-170

15 Lang A Carass A Hauser M et al Retinal layer segmentation of macular OCT imagesusing boundary classification Biomed Opt Express 20134(7)1133-1152

16 R Development Core Team R A Language and Environment for Statistical Computing[online] R Foundation for Statistical Computing 2008 R-projectorg

17 Akaishi T Kaneko K Himori N et al Subclinical retinal atrophy in the unaffectedfellow eyes of multiple sclerosis and neuromyelitis optica [online serial]J Neuroimmunol 201731310-15 Accessed October 8 2017 jni-journalcomarticleS0165-5728(17)30319-3fulltext

18 Alshowaeir D Yiannikas C Fraser C Klistorner A Mechanism of delayed con-duction of fellow eyes in patients with optic neuritis Int J Ophthalmol 201811(2)329-332

19 Manogaran P Traboulsee AL Lange AP Longitudinal study of retinal nerve fiberlayer thickness and macular volume in patients with neuromyelitis optica spectrumdisorder J Neuroophthalmol 201636(4)363-368

20 Kaufhold F ZimmermannH Schneider E et al Optic neuritis is associated with innernuclear layer thickening and microcystic macular edema independently of multiplesclerosis PLoS One 20138(8)e71145

21 Knier B Schmidt P Aly L et al Retinal inner nuclear layer volume reflects response toimmunotherapy in multiple sclerosis Brain 2016139(11)2855-2863

22 Petzold A Balcer LJ Calabresi PA et al Retinal layer segmentation in multiplesclerosis a systematic review and meta-analysis Lancet Neurol 201716(10)797-812

23 Pawlitzki M Horbrugger M Loewe K et al MS optic neuritis-induced long-termstructural changes within the visual pathway Neurol Neuroimmunol Neuroinflamm20207(2)e665

24 Pache F Zimmermann H Mikolajczak J et al MOG-IgG in NMO and relateddisorders a multicenter study of 50 patients Part 4 afferent visual system damageafter optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patientsJ Neuroinflammation 201613(1)282

25 Filippatou AG Vasileiou ES He Y et al Evidence of subclinical quantitative retinallayer abnormalities in AQP4-IgG seropositive NMOSD Mult Scler 2020 Dec 141352458520977771 doi 1011771352458520977771

26 Motamedi S Oertel FC Yadav SK et al Altered fovea in AQP4-IgGndashseropositiveneuromyelitis optica spectrum disorders Neurol Neuroimmunol Neuroinflamm 20207(5)e805

27 Roca-Fernandez A Oertel FC Yeo T et al Foveal changes in AQP4-Ab seropositiveNMOSD are independent of optic neuritis and not overtly progressive Eur J Neurol202128(7)2280-2293

28 Papadopoulou A Oertel FC Chien C et al Lateral geniculate nucleus volumechanges after optic neuritis in neuromyelitis optica a longitudinal study NeuroimageClin 202130102608

29 Ringelstein M Harmel J Zimmermann H et al Longitudinal optic neuritis-unrelatedvisual evoked potential changes in NMO spectrum disorders Neurology 202094(4)e407-e418

30 Pache F Zimmermann H Finke C et al Brain parenchymal damage in neuromyelitisoptica spectrum disorderndasha multimodal MRI study Eur Radiol 201626(12)4413-4422

31 Hokari M Yokoseki A Arakawa M et al Clinicopathological features in anteriorvisual pathway in neuromyelitis optica Ann Neurol 201679(4)605-624

32 You Y Zhu L Zhang T et al Evidence of muller glial dysfunction in patients withaquaporin-4 immunoglobulin Gndashpositive neuromyelitis optica spectrum disorderOphthalmology 2019126(6)801-810 Elsevier

33 Chien C Scheel M Schmitz-Hubsch T et al Spinal cord lesions and atrophy inNMOSD with AQP4-IgG and MOG-IgG associated autoimmunityMult Scler 201925(14)1926-1936

34 Felix CM Levin MH Verkman AS Complement-independent retinal pathologyproduced by intravitreal injection of neuromyelitis optica immunoglobulin GJ Neuroinflammation 201613(1)275

35 Balk LJ Coric D Knier B et al Retinal inner nuclear layer volume reflects in-flammatory disease activity in multiple sclerosis a longitudinal OCT studyMult SclerJ Exp Transl Clin 20195(3)2055217319871582

36 Gelfand JM Nolan R Schwartz DM Graves J Green AJ Microcystic macular oedemain multiple sclerosis is associated with disease severity Brain 2012135(pt 6)1786-1793

Appendix (continued)

Name Location Contribution

Uygur TanriverdiMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Anu Jacob MD The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Saif Huda MDPhD

The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Zoe Rimler BSc NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Allyson Reid MD NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Yang Mao-Draayer MD PhD

University of MichiganMedical School AnnArbor MI

Acquisition andanalysis of data

Ibis Soto deCastillo MD

Hospital Clınico deMaracaibo MaracaiboVenezuela

Acquisition andanalysis of data

Axel Petzold MDPhD

University College LondonLondon UK

Conception anddesign of the study

Ari J Green MD University of California SanFrancisco CA

Conception anddesign of the study

Michael RYeaman MD PhD

University of California LosAngeles CA

Conception anddesign of the study

Terry Smith MD University of MichiganMedical School AnnArbor MI

Conception anddesign of the study

Alexander UBrandt MD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinBerlin Berlin Germany

Acquisition andanalysis of dataconception and designof the study anddrafting a significantportion of themanuscript or figures

Friedemann PaulMD

CharitendashUniversitatsmedizinBerlin Corporate Member ofFreie Universitat Berlin andHumboldt-Universitat zuBerlin

Acquisition andanalysis of data andconception and designof the study

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

37 Gelfand JM Cree BA Nolan R Arnow S Green AJ Microcystic inner nuclear layerabnormalities and neuromyelitis optica JAMA Neurol 201370(5)629-633

38 Oberwahrenbrock T WeinholdMMikolajczak J et al Reliability of intra-retinal layerthickness estimates PLoS One 201510(9)e0137316

39 Borisow N Kleiter I Gahlen A et al Influence of female sex and fertile age onneuromyelitis optica spectrum disorders Mult Scler 201723(8)1092-1103

40 Mori M Kuwabara S Paul F Worldwide prevalence of neuromyelitis optica spectrumdisorders J Neurol Neurosurg Psychiatry 201889(6)555-556

41 Oertel FC Paul F Accelerating clinical research in neuromyelitis optica spectrumdisorders [online serial] Clin Exp Neuroimmunol 202112(2)89-91 AccessedMarch 28 2021 periclespericles-prodliteratumonlinecomdoiabs101111cen312637

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 13

DOI 101212NXI000000000000106820218 Neurol Neuroimmunol Neuroinflamm

Frederike Cosima Oertel Svenja Specovius Hanna G Zimmermann et al Retinal Optical Coherence Tomography in Neuromyelitis Optica

This information is current as of September 15 2021

ServicesUpdated Information amp

httpnnneurologyorgcontent86e1068fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent86e1068fullhtmlref-list-1

This article cites 40 articles 7 of which you can access for free at

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httpnnneurologyorgcgicollectionoptic_neuritisOptic neuritis see Neuro-ophthalmologyOptic Nerve

httpnnneurologyorgcgicollectiondevics_syndromeDevics syndrome

httpnnneurologyorgcgicollectionall_imagingAll Imagingfollowing collection(s) This article along with others on similar topics appears in the

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httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

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Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

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Page 10: Retinal Optical Coherence Tomography in Neuromyelitis Optica

personal fees and non-financial support from Allergan BiogenMerck Merz Pharmaceuticals Novartis Ipsen CelgeneRoche and personal fees and non-financial support from Tevaoutside the submitted work E May and C Tongco report nodisclosures L Leocani reports personal fees from RocheMerck Bristol Myers Squibb andMed-ex learning outside thesubmitted work M Pisa reports no disclosures M Radaellireports personal fees from Merck Serono Sanofi-GenzymeNovartis and Biogen outside the submitted work H Stiebel-Kalish reports no disclosures S Siritho reports personal feesfromNovartis Thailand Biogen Idec Eisai Thailandmarketingco ltd Merck Serono Teva Thailand and Menarini outsidethe submitted work J de Seze and T Senger report no dis-closures J Havla reports grants personal fees and non-financialsupport from Merck personal fees from Novartis CelgeneRoche Santhera Biogen Alexion Sanofi non-financial supportfrom Guthy-Jackson Charitable Foundation and grants fromFriedrich Baur Foundation outside the submitted work RMarignier AC Calvo D Bichuetti IM Tavares N Asgari KSoelberg A Altintas R Yildirim U Tanriverdi A Jacob SHuda Z Rimler and A Reid report no disclosures Y Mao-Draayer reports grants from NIH NIAID grants and personalfees from Genzyme grants from Chugai personal fees fromBiogen and EMD Serono grants and personal fees fromGenentech and Novartis during the conduct of the studygrants from NIH NIAID grants and personal fees from Gen-zyme grants fromChugai personal fees fromBiogen and EMDSerono grants and personal fees fromGenentech andNovartisoutside the submitted work I Soto de Castillo reports nodisclosures A Petzold reports personal fees and grants fromNovartis outside the submitted work and is part of the steeringcommittee of the OCTiMS study which is sponsored byNovartis He has not received honoraria for this activity AJGreen reports other from Bionure grants personal fees andother from Inception Sciences grants from Sherak Foundationpersonal fees and other from Pipeline Pharmaceuticals grantsfrom Hilton Foundation Adelson Foundation and NationalMS Society personal fees from JAMANeurology personal feesand other from MediimmuneViela outside the submittedwork In addition Dr Green has a patent Small Molecule drugfor Remyelination pending and has worked on testing off labelcompounds for remyelination MR Yeaman serves as an ad-visor to the Guthy-Jackson Charitable Foundation T Smithreports no disclosures AU Brandt reports grants from theGuthy Jackson Charitable Foundation during the conduct ofthe study shares from Motognosis GmbH and shares fromNocturne GmbH outside the submitted work In addition DrBrandt has a patent pending describing Foveal MorphometryF Paul reports grants from the Guthy Jackson CharitableFoundation during the conduct of the study grants from theGerman Research Foundation andGerman FederalMinistry ofEducation and research grants and other fromNovartis grantsand other from Bayer Novartis Biogen Idec Teva Sanofi-AventisGenzyme Merck Serono Chugai other from PLoSONE other from Neurologyreg Neuroimmunology amp Neuro-inflammation other from SanofiGenzyme Biogen Idec grantsfrom German Research Council Werth Stiftung of the City of

Cologne German Ministry of Education and Research ArthurArnstein Stiftung Berlin EU FP7 Framework Program ArthurArnstein Foundation Berlin National Multiple Sclerosis(USA) other from MedImmune Shire Alexion outside thesubmitted work In addition Dr Paul has a patent FovealMorphometry pending to Nocturne GmbH Go to NeurologyorgNN for full disclosures

Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationMarch 23 2021 Accepted in final form June 15 2021

Appendix Authors

Name Location Contribution

Frederike CosimaOertel MDPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data anddrafting a significantportion of themanuscript or figuresconception and designof the study

Svenja SpecoviusMSc

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of dataconception and designof the study

Hanna GZimmermannPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of dataconception and designof the study

Claudia ChienPhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

SeyedamirhoseinMotamedi PhD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

CharlotteBereuter BSc

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinCorporate Member of FreieUniversitat Berlin andHumboldt-Universitat zuBerlin Germany

Acquisition andanalysis of data

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

Appendix (continued)

Name Location Contribution

Lawrence CookPhD

University of UtahSalt Lake City UT

Acquisition andanalysis of data andconception and designof the study

Marco AurelioLana Peixoto MDPhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Mariana AndradeFontanelle MD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Ho Jin Kim MDPhD

National Cancer CenterGoyang Republic of Korea

Acquisition andanalysis of data

Jae-Won HyunMD PhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

JacquelinePalace MD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Adriana Roca-Fernandez MSc

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Maria IsabelLeite MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

SrilakshmiSharma MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

FereshtehAshtari MD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Rahele KafiehPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Alireza DehghaniPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

MohsenPourazizi PhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Lekha PanditMD PhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Anitha DrsquoCunhaPhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Orhan Aktas MD Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

MariusRingelstein MD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Philipp AlbrechtMD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Eugene May MD Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Caryl Tongco Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Appendix (continued)

Name Location Contribution

Letizia LeocaniMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marco Pisa MD Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marta RadaelliMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Elena H Martinez-Lapiscina MDPhD

Hospital Clinic of Barcelona-Institut drsquoInvestigacionsBiomediques August PiSunyer Barcelona Spain

Acquisition andanalysis of data

Hadas Stiebel-Kalish MD

Sackler School of MedicineTel Aviv University Tel AvivIsrael

Acquisition andanalysis of data

Sasitorn SirithoMD

Siriraj Hospital andBumrungrad InternationalHospital Bangkok Thailand

Acquisition andanalysis of data

Jerome de SezeMD PhD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Thomas SengerMD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Joachim HavlaMD

Ludwig-MaximiliansUniversitat MuenchenMunich Germany

Acquisition andanalysis of data

RomainMarignier MDPhD

Pierre Wertheimer NeurologicalHospital Hospices Civils deLyon France

Acquisition andanalysis of data

Alvaro CoboCalvo MD PhD

Pierre WertheimerNeurological HospitalHospices Civils de LyonFrance Hospital UniversitariVall drsquoHebron UniversitatAutonoma de BarcelonaSpain

Acquisition andanalysis of data

Denis BichuettiMD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Ivan MaynartTavares MD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Nasrin AsgariMD PhD

University of SouthernDenmark OdenseDenmark

Acquisition andanalysis of data

Kerstin SoelbergMD

University of SouthernDenmark Odense Denmark

Acquisition andanalysis of data

Ayse Altintas MD Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Rengin YildirimMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 11

References1 Oertel FC Zimmermann H Paul F Brandt AU Optical coherence tomog-

raphy in neuromyelitis optica spectrum disorders potential advantages forindividualized monitoring of progression and therapy EPMA J 20189(1)21-33

2 Schneider E Zimmermann H Oberwahrenbrock T et al Optical coherence to-mography reveals distinct patterns of retinal damage in neuromyelitis optica andmultiple sclerosis PLoS One 20138(6)e66151

3 Bouyon M Collongues N Zephir H et al Longitudinal follow-up of vision in aneuromyelitis optica cohort Mult Scler 201319(10)1320-1322

4 Sotirchos ES Filippatou A Fitzgerald KC et al Aquaporin-4 IgG seropositivity isassociated with worse visual outcomes after optic neuritis than MOG-IgG seroposi-tivity and multiple sclerosis independent of macular ganglion cell layer thinningMultScler 201926(11)1360-1371

5 Hamid SHM Whittam D Mutch K et al What proportion of AQP4-IgG-negativeNMO spectrum disorder patients are MOG-IgG positive A cross sectional study of132 patients J Neurol 2017264(10)2088-2094

6 Oertel FC Kuchling J ZimmermannH et al Microstructural visual system changes inAQP4-antibody-seropositive NMOSD Neurol Neuroimmunol Neuroinflamm 20174(3)e334

7 Oertel FC Havla J Roca-Fernandez A et al Retinal ganglion cell loss in neuromyelitisoptica a longitudinal study J Neurol Neurosurg Psychiatry 201889(12)1259-1265

8 Huang D Swanson EA Lin CP et al Optical coherence tomography Science 1991254(5035)1178-1181

9 Specovius S Zimmermann HG Oertel FC et al Cohort profile a collaborativemulticentre study of retinal optical coherence tomography in 539 patients withneuromyelitis optica spectrum disorders (CROCTINO) BMJ Open 202010(10)e035397

10 Motamedi S Gawlik K Ayadi N et al Normative data and minimally detectablechange for inner retinal layer thicknesses using a semi-automated OCT image seg-mentation pipeline Front Neurol 2019101117

11 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177-189

12 von Elm E Altman DG Egger M et al The strengthening the reporting of obser-vational studies in epidemiology (STROBE) statement guidelines for reportingobservational studies Int J Surg 201412(12)1495-1499

13 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PLoS One 20127(4)e34823

14 Schippling S Balk LJ Costello F et al Quality control for retinal OCT in multiplesclerosis validation of the OSCAR-IB criteria Mult Scler 201521(2)163-170

15 Lang A Carass A Hauser M et al Retinal layer segmentation of macular OCT imagesusing boundary classification Biomed Opt Express 20134(7)1133-1152

16 R Development Core Team R A Language and Environment for Statistical Computing[online] R Foundation for Statistical Computing 2008 R-projectorg

17 Akaishi T Kaneko K Himori N et al Subclinical retinal atrophy in the unaffectedfellow eyes of multiple sclerosis and neuromyelitis optica [online serial]J Neuroimmunol 201731310-15 Accessed October 8 2017 jni-journalcomarticleS0165-5728(17)30319-3fulltext

18 Alshowaeir D Yiannikas C Fraser C Klistorner A Mechanism of delayed con-duction of fellow eyes in patients with optic neuritis Int J Ophthalmol 201811(2)329-332

19 Manogaran P Traboulsee AL Lange AP Longitudinal study of retinal nerve fiberlayer thickness and macular volume in patients with neuromyelitis optica spectrumdisorder J Neuroophthalmol 201636(4)363-368

20 Kaufhold F ZimmermannH Schneider E et al Optic neuritis is associated with innernuclear layer thickening and microcystic macular edema independently of multiplesclerosis PLoS One 20138(8)e71145

21 Knier B Schmidt P Aly L et al Retinal inner nuclear layer volume reflects response toimmunotherapy in multiple sclerosis Brain 2016139(11)2855-2863

22 Petzold A Balcer LJ Calabresi PA et al Retinal layer segmentation in multiplesclerosis a systematic review and meta-analysis Lancet Neurol 201716(10)797-812

23 Pawlitzki M Horbrugger M Loewe K et al MS optic neuritis-induced long-termstructural changes within the visual pathway Neurol Neuroimmunol Neuroinflamm20207(2)e665

24 Pache F Zimmermann H Mikolajczak J et al MOG-IgG in NMO and relateddisorders a multicenter study of 50 patients Part 4 afferent visual system damageafter optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patientsJ Neuroinflammation 201613(1)282

25 Filippatou AG Vasileiou ES He Y et al Evidence of subclinical quantitative retinallayer abnormalities in AQP4-IgG seropositive NMOSD Mult Scler 2020 Dec 141352458520977771 doi 1011771352458520977771

26 Motamedi S Oertel FC Yadav SK et al Altered fovea in AQP4-IgGndashseropositiveneuromyelitis optica spectrum disorders Neurol Neuroimmunol Neuroinflamm 20207(5)e805

27 Roca-Fernandez A Oertel FC Yeo T et al Foveal changes in AQP4-Ab seropositiveNMOSD are independent of optic neuritis and not overtly progressive Eur J Neurol202128(7)2280-2293

28 Papadopoulou A Oertel FC Chien C et al Lateral geniculate nucleus volumechanges after optic neuritis in neuromyelitis optica a longitudinal study NeuroimageClin 202130102608

29 Ringelstein M Harmel J Zimmermann H et al Longitudinal optic neuritis-unrelatedvisual evoked potential changes in NMO spectrum disorders Neurology 202094(4)e407-e418

30 Pache F Zimmermann H Finke C et al Brain parenchymal damage in neuromyelitisoptica spectrum disorderndasha multimodal MRI study Eur Radiol 201626(12)4413-4422

31 Hokari M Yokoseki A Arakawa M et al Clinicopathological features in anteriorvisual pathway in neuromyelitis optica Ann Neurol 201679(4)605-624

32 You Y Zhu L Zhang T et al Evidence of muller glial dysfunction in patients withaquaporin-4 immunoglobulin Gndashpositive neuromyelitis optica spectrum disorderOphthalmology 2019126(6)801-810 Elsevier

33 Chien C Scheel M Schmitz-Hubsch T et al Spinal cord lesions and atrophy inNMOSD with AQP4-IgG and MOG-IgG associated autoimmunityMult Scler 201925(14)1926-1936

34 Felix CM Levin MH Verkman AS Complement-independent retinal pathologyproduced by intravitreal injection of neuromyelitis optica immunoglobulin GJ Neuroinflammation 201613(1)275

35 Balk LJ Coric D Knier B et al Retinal inner nuclear layer volume reflects in-flammatory disease activity in multiple sclerosis a longitudinal OCT studyMult SclerJ Exp Transl Clin 20195(3)2055217319871582

36 Gelfand JM Nolan R Schwartz DM Graves J Green AJ Microcystic macular oedemain multiple sclerosis is associated with disease severity Brain 2012135(pt 6)1786-1793

Appendix (continued)

Name Location Contribution

Uygur TanriverdiMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Anu Jacob MD The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Saif Huda MDPhD

The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Zoe Rimler BSc NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Allyson Reid MD NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Yang Mao-Draayer MD PhD

University of MichiganMedical School AnnArbor MI

Acquisition andanalysis of data

Ibis Soto deCastillo MD

Hospital Clınico deMaracaibo MaracaiboVenezuela

Acquisition andanalysis of data

Axel Petzold MDPhD

University College LondonLondon UK

Conception anddesign of the study

Ari J Green MD University of California SanFrancisco CA

Conception anddesign of the study

Michael RYeaman MD PhD

University of California LosAngeles CA

Conception anddesign of the study

Terry Smith MD University of MichiganMedical School AnnArbor MI

Conception anddesign of the study

Alexander UBrandt MD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinBerlin Berlin Germany

Acquisition andanalysis of dataconception and designof the study anddrafting a significantportion of themanuscript or figures

Friedemann PaulMD

CharitendashUniversitatsmedizinBerlin Corporate Member ofFreie Universitat Berlin andHumboldt-Universitat zuBerlin

Acquisition andanalysis of data andconception and designof the study

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

37 Gelfand JM Cree BA Nolan R Arnow S Green AJ Microcystic inner nuclear layerabnormalities and neuromyelitis optica JAMA Neurol 201370(5)629-633

38 Oberwahrenbrock T WeinholdMMikolajczak J et al Reliability of intra-retinal layerthickness estimates PLoS One 201510(9)e0137316

39 Borisow N Kleiter I Gahlen A et al Influence of female sex and fertile age onneuromyelitis optica spectrum disorders Mult Scler 201723(8)1092-1103

40 Mori M Kuwabara S Paul F Worldwide prevalence of neuromyelitis optica spectrumdisorders J Neurol Neurosurg Psychiatry 201889(6)555-556

41 Oertel FC Paul F Accelerating clinical research in neuromyelitis optica spectrumdisorders [online serial] Clin Exp Neuroimmunol 202112(2)89-91 AccessedMarch 28 2021 periclespericles-prodliteratumonlinecomdoiabs101111cen312637

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 13

DOI 101212NXI000000000000106820218 Neurol Neuroimmunol Neuroinflamm

Frederike Cosima Oertel Svenja Specovius Hanna G Zimmermann et al Retinal Optical Coherence Tomography in Neuromyelitis Optica

This information is current as of September 15 2021

ServicesUpdated Information amp

httpnnneurologyorgcontent86e1068fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent86e1068fullhtmlref-list-1

This article cites 40 articles 7 of which you can access for free at

Subspecialty Collections

httpnnneurologyorgcgicollectionvisual_lossVisual loss

httpnnneurologyorgcgicollectionretinaRetina

httpnnneurologyorgcgicollectionoptic_neuritisOptic neuritis see Neuro-ophthalmologyOptic Nerve

httpnnneurologyorgcgicollectiondevics_syndromeDevics syndrome

httpnnneurologyorgcgicollectionall_imagingAll Imagingfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm

Page 11: Retinal Optical Coherence Tomography in Neuromyelitis Optica

Appendix (continued)

Name Location Contribution

Lawrence CookPhD

University of UtahSalt Lake City UT

Acquisition andanalysis of data andconception and designof the study

Marco AurelioLana Peixoto MDPhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Mariana AndradeFontanelle MD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

Ho Jin Kim MDPhD

National Cancer CenterGoyang Republic of Korea

Acquisition andanalysis of data

Jae-Won HyunMD PhD

University of Minas GeraisMedical School BeloHorizonte Brazil

Acquisition andanalysis of data

JacquelinePalace MD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Adriana Roca-Fernandez MSc

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

Maria IsabelLeite MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

SrilakshmiSharma MD PhD

Oxford University HospitalsNational Health Service TrustOxford United Kingdom

Acquisition andanalysis of data

FereshtehAshtari MD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Rahele KafiehPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Alireza DehghaniPhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

MohsenPourazizi PhD

Isfahan University of MedicalSciences Isfahan Iran

Acquisition andanalysis of data

Lekha PanditMD PhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Anitha DrsquoCunhaPhD

KS Hegde Medical AcademyNitte University MangaloreIndia

Acquisition andanalysis of data

Orhan Aktas MD Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

MariusRingelstein MD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Philipp AlbrechtMD

Heinrich Heine UniversityDusseldorf DusseldorfGermany

Acquisition andanalysis of data

Eugene May MD Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Caryl Tongco Swedish Neuroscience InstituteNeuro-Ophthalmology SeattleWA

Acquisition andanalysis of data

Appendix (continued)

Name Location Contribution

Letizia LeocaniMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marco Pisa MD Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Marta RadaelliMD PhD

Institute of ExperimentalNeurology Scientific InstituteHospital San Raffaele andUniversity Vita-Salute SanRaffaele Milan Italy

Acquisition andanalysis of data

Elena H Martinez-Lapiscina MDPhD

Hospital Clinic of Barcelona-Institut drsquoInvestigacionsBiomediques August PiSunyer Barcelona Spain

Acquisition andanalysis of data

Hadas Stiebel-Kalish MD

Sackler School of MedicineTel Aviv University Tel AvivIsrael

Acquisition andanalysis of data

Sasitorn SirithoMD

Siriraj Hospital andBumrungrad InternationalHospital Bangkok Thailand

Acquisition andanalysis of data

Jerome de SezeMD PhD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Thomas SengerMD

University Hospital ofStrasbourg France

Acquisition andanalysis of data

Joachim HavlaMD

Ludwig-MaximiliansUniversitat MuenchenMunich Germany

Acquisition andanalysis of data

RomainMarignier MDPhD

Pierre Wertheimer NeurologicalHospital Hospices Civils deLyon France

Acquisition andanalysis of data

Alvaro CoboCalvo MD PhD

Pierre WertheimerNeurological HospitalHospices Civils de LyonFrance Hospital UniversitariVall drsquoHebron UniversitatAutonoma de BarcelonaSpain

Acquisition andanalysis of data

Denis BichuettiMD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Ivan MaynartTavares MD PhD

Escola Paulista de MedicinaUniversidade Federal de SatildeoPaulo Satildeo Paulo Brazil

Acquisition andanalysis of data

Nasrin AsgariMD PhD

University of SouthernDenmark OdenseDenmark

Acquisition andanalysis of data

Kerstin SoelbergMD

University of SouthernDenmark Odense Denmark

Acquisition andanalysis of data

Ayse Altintas MD Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Rengin YildirimMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 11

References1 Oertel FC Zimmermann H Paul F Brandt AU Optical coherence tomog-

raphy in neuromyelitis optica spectrum disorders potential advantages forindividualized monitoring of progression and therapy EPMA J 20189(1)21-33

2 Schneider E Zimmermann H Oberwahrenbrock T et al Optical coherence to-mography reveals distinct patterns of retinal damage in neuromyelitis optica andmultiple sclerosis PLoS One 20138(6)e66151

3 Bouyon M Collongues N Zephir H et al Longitudinal follow-up of vision in aneuromyelitis optica cohort Mult Scler 201319(10)1320-1322

4 Sotirchos ES Filippatou A Fitzgerald KC et al Aquaporin-4 IgG seropositivity isassociated with worse visual outcomes after optic neuritis than MOG-IgG seroposi-tivity and multiple sclerosis independent of macular ganglion cell layer thinningMultScler 201926(11)1360-1371

5 Hamid SHM Whittam D Mutch K et al What proportion of AQP4-IgG-negativeNMO spectrum disorder patients are MOG-IgG positive A cross sectional study of132 patients J Neurol 2017264(10)2088-2094

6 Oertel FC Kuchling J ZimmermannH et al Microstructural visual system changes inAQP4-antibody-seropositive NMOSD Neurol Neuroimmunol Neuroinflamm 20174(3)e334

7 Oertel FC Havla J Roca-Fernandez A et al Retinal ganglion cell loss in neuromyelitisoptica a longitudinal study J Neurol Neurosurg Psychiatry 201889(12)1259-1265

8 Huang D Swanson EA Lin CP et al Optical coherence tomography Science 1991254(5035)1178-1181

9 Specovius S Zimmermann HG Oertel FC et al Cohort profile a collaborativemulticentre study of retinal optical coherence tomography in 539 patients withneuromyelitis optica spectrum disorders (CROCTINO) BMJ Open 202010(10)e035397

10 Motamedi S Gawlik K Ayadi N et al Normative data and minimally detectablechange for inner retinal layer thicknesses using a semi-automated OCT image seg-mentation pipeline Front Neurol 2019101117

11 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177-189

12 von Elm E Altman DG Egger M et al The strengthening the reporting of obser-vational studies in epidemiology (STROBE) statement guidelines for reportingobservational studies Int J Surg 201412(12)1495-1499

13 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PLoS One 20127(4)e34823

14 Schippling S Balk LJ Costello F et al Quality control for retinal OCT in multiplesclerosis validation of the OSCAR-IB criteria Mult Scler 201521(2)163-170

15 Lang A Carass A Hauser M et al Retinal layer segmentation of macular OCT imagesusing boundary classification Biomed Opt Express 20134(7)1133-1152

16 R Development Core Team R A Language and Environment for Statistical Computing[online] R Foundation for Statistical Computing 2008 R-projectorg

17 Akaishi T Kaneko K Himori N et al Subclinical retinal atrophy in the unaffectedfellow eyes of multiple sclerosis and neuromyelitis optica [online serial]J Neuroimmunol 201731310-15 Accessed October 8 2017 jni-journalcomarticleS0165-5728(17)30319-3fulltext

18 Alshowaeir D Yiannikas C Fraser C Klistorner A Mechanism of delayed con-duction of fellow eyes in patients with optic neuritis Int J Ophthalmol 201811(2)329-332

19 Manogaran P Traboulsee AL Lange AP Longitudinal study of retinal nerve fiberlayer thickness and macular volume in patients with neuromyelitis optica spectrumdisorder J Neuroophthalmol 201636(4)363-368

20 Kaufhold F ZimmermannH Schneider E et al Optic neuritis is associated with innernuclear layer thickening and microcystic macular edema independently of multiplesclerosis PLoS One 20138(8)e71145

21 Knier B Schmidt P Aly L et al Retinal inner nuclear layer volume reflects response toimmunotherapy in multiple sclerosis Brain 2016139(11)2855-2863

22 Petzold A Balcer LJ Calabresi PA et al Retinal layer segmentation in multiplesclerosis a systematic review and meta-analysis Lancet Neurol 201716(10)797-812

23 Pawlitzki M Horbrugger M Loewe K et al MS optic neuritis-induced long-termstructural changes within the visual pathway Neurol Neuroimmunol Neuroinflamm20207(2)e665

24 Pache F Zimmermann H Mikolajczak J et al MOG-IgG in NMO and relateddisorders a multicenter study of 50 patients Part 4 afferent visual system damageafter optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patientsJ Neuroinflammation 201613(1)282

25 Filippatou AG Vasileiou ES He Y et al Evidence of subclinical quantitative retinallayer abnormalities in AQP4-IgG seropositive NMOSD Mult Scler 2020 Dec 141352458520977771 doi 1011771352458520977771

26 Motamedi S Oertel FC Yadav SK et al Altered fovea in AQP4-IgGndashseropositiveneuromyelitis optica spectrum disorders Neurol Neuroimmunol Neuroinflamm 20207(5)e805

27 Roca-Fernandez A Oertel FC Yeo T et al Foveal changes in AQP4-Ab seropositiveNMOSD are independent of optic neuritis and not overtly progressive Eur J Neurol202128(7)2280-2293

28 Papadopoulou A Oertel FC Chien C et al Lateral geniculate nucleus volumechanges after optic neuritis in neuromyelitis optica a longitudinal study NeuroimageClin 202130102608

29 Ringelstein M Harmel J Zimmermann H et al Longitudinal optic neuritis-unrelatedvisual evoked potential changes in NMO spectrum disorders Neurology 202094(4)e407-e418

30 Pache F Zimmermann H Finke C et al Brain parenchymal damage in neuromyelitisoptica spectrum disorderndasha multimodal MRI study Eur Radiol 201626(12)4413-4422

31 Hokari M Yokoseki A Arakawa M et al Clinicopathological features in anteriorvisual pathway in neuromyelitis optica Ann Neurol 201679(4)605-624

32 You Y Zhu L Zhang T et al Evidence of muller glial dysfunction in patients withaquaporin-4 immunoglobulin Gndashpositive neuromyelitis optica spectrum disorderOphthalmology 2019126(6)801-810 Elsevier

33 Chien C Scheel M Schmitz-Hubsch T et al Spinal cord lesions and atrophy inNMOSD with AQP4-IgG and MOG-IgG associated autoimmunityMult Scler 201925(14)1926-1936

34 Felix CM Levin MH Verkman AS Complement-independent retinal pathologyproduced by intravitreal injection of neuromyelitis optica immunoglobulin GJ Neuroinflammation 201613(1)275

35 Balk LJ Coric D Knier B et al Retinal inner nuclear layer volume reflects in-flammatory disease activity in multiple sclerosis a longitudinal OCT studyMult SclerJ Exp Transl Clin 20195(3)2055217319871582

36 Gelfand JM Nolan R Schwartz DM Graves J Green AJ Microcystic macular oedemain multiple sclerosis is associated with disease severity Brain 2012135(pt 6)1786-1793

Appendix (continued)

Name Location Contribution

Uygur TanriverdiMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Anu Jacob MD The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Saif Huda MDPhD

The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Zoe Rimler BSc NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Allyson Reid MD NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Yang Mao-Draayer MD PhD

University of MichiganMedical School AnnArbor MI

Acquisition andanalysis of data

Ibis Soto deCastillo MD

Hospital Clınico deMaracaibo MaracaiboVenezuela

Acquisition andanalysis of data

Axel Petzold MDPhD

University College LondonLondon UK

Conception anddesign of the study

Ari J Green MD University of California SanFrancisco CA

Conception anddesign of the study

Michael RYeaman MD PhD

University of California LosAngeles CA

Conception anddesign of the study

Terry Smith MD University of MichiganMedical School AnnArbor MI

Conception anddesign of the study

Alexander UBrandt MD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinBerlin Berlin Germany

Acquisition andanalysis of dataconception and designof the study anddrafting a significantportion of themanuscript or figures

Friedemann PaulMD

CharitendashUniversitatsmedizinBerlin Corporate Member ofFreie Universitat Berlin andHumboldt-Universitat zuBerlin

Acquisition andanalysis of data andconception and designof the study

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

37 Gelfand JM Cree BA Nolan R Arnow S Green AJ Microcystic inner nuclear layerabnormalities and neuromyelitis optica JAMA Neurol 201370(5)629-633

38 Oberwahrenbrock T WeinholdMMikolajczak J et al Reliability of intra-retinal layerthickness estimates PLoS One 201510(9)e0137316

39 Borisow N Kleiter I Gahlen A et al Influence of female sex and fertile age onneuromyelitis optica spectrum disorders Mult Scler 201723(8)1092-1103

40 Mori M Kuwabara S Paul F Worldwide prevalence of neuromyelitis optica spectrumdisorders J Neurol Neurosurg Psychiatry 201889(6)555-556

41 Oertel FC Paul F Accelerating clinical research in neuromyelitis optica spectrumdisorders [online serial] Clin Exp Neuroimmunol 202112(2)89-91 AccessedMarch 28 2021 periclespericles-prodliteratumonlinecomdoiabs101111cen312637

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 13

DOI 101212NXI000000000000106820218 Neurol Neuroimmunol Neuroinflamm

Frederike Cosima Oertel Svenja Specovius Hanna G Zimmermann et al Retinal Optical Coherence Tomography in Neuromyelitis Optica

This information is current as of September 15 2021

ServicesUpdated Information amp

httpnnneurologyorgcontent86e1068fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent86e1068fullhtmlref-list-1

This article cites 40 articles 7 of which you can access for free at

Subspecialty Collections

httpnnneurologyorgcgicollectionvisual_lossVisual loss

httpnnneurologyorgcgicollectionretinaRetina

httpnnneurologyorgcgicollectionoptic_neuritisOptic neuritis see Neuro-ophthalmologyOptic Nerve

httpnnneurologyorgcgicollectiondevics_syndromeDevics syndrome

httpnnneurologyorgcgicollectionall_imagingAll Imagingfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm

Page 12: Retinal Optical Coherence Tomography in Neuromyelitis Optica

References1 Oertel FC Zimmermann H Paul F Brandt AU Optical coherence tomog-

raphy in neuromyelitis optica spectrum disorders potential advantages forindividualized monitoring of progression and therapy EPMA J 20189(1)21-33

2 Schneider E Zimmermann H Oberwahrenbrock T et al Optical coherence to-mography reveals distinct patterns of retinal damage in neuromyelitis optica andmultiple sclerosis PLoS One 20138(6)e66151

3 Bouyon M Collongues N Zephir H et al Longitudinal follow-up of vision in aneuromyelitis optica cohort Mult Scler 201319(10)1320-1322

4 Sotirchos ES Filippatou A Fitzgerald KC et al Aquaporin-4 IgG seropositivity isassociated with worse visual outcomes after optic neuritis than MOG-IgG seroposi-tivity and multiple sclerosis independent of macular ganglion cell layer thinningMultScler 201926(11)1360-1371

5 Hamid SHM Whittam D Mutch K et al What proportion of AQP4-IgG-negativeNMO spectrum disorder patients are MOG-IgG positive A cross sectional study of132 patients J Neurol 2017264(10)2088-2094

6 Oertel FC Kuchling J ZimmermannH et al Microstructural visual system changes inAQP4-antibody-seropositive NMOSD Neurol Neuroimmunol Neuroinflamm 20174(3)e334

7 Oertel FC Havla J Roca-Fernandez A et al Retinal ganglion cell loss in neuromyelitisoptica a longitudinal study J Neurol Neurosurg Psychiatry 201889(12)1259-1265

8 Huang D Swanson EA Lin CP et al Optical coherence tomography Science 1991254(5035)1178-1181

9 Specovius S Zimmermann HG Oertel FC et al Cohort profile a collaborativemulticentre study of retinal optical coherence tomography in 539 patients withneuromyelitis optica spectrum disorders (CROCTINO) BMJ Open 202010(10)e035397

10 Motamedi S Gawlik K Ayadi N et al Normative data and minimally detectablechange for inner retinal layer thicknesses using a semi-automated OCT image seg-mentation pipeline Front Neurol 2019101117

11 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177-189

12 von Elm E Altman DG Egger M et al The strengthening the reporting of obser-vational studies in epidemiology (STROBE) statement guidelines for reportingobservational studies Int J Surg 201412(12)1495-1499

13 Tewarie P Balk L Costello F et al TheOSCAR-IB consensus criteria for retinal OCTquality assessment PLoS One 20127(4)e34823

14 Schippling S Balk LJ Costello F et al Quality control for retinal OCT in multiplesclerosis validation of the OSCAR-IB criteria Mult Scler 201521(2)163-170

15 Lang A Carass A Hauser M et al Retinal layer segmentation of macular OCT imagesusing boundary classification Biomed Opt Express 20134(7)1133-1152

16 R Development Core Team R A Language and Environment for Statistical Computing[online] R Foundation for Statistical Computing 2008 R-projectorg

17 Akaishi T Kaneko K Himori N et al Subclinical retinal atrophy in the unaffectedfellow eyes of multiple sclerosis and neuromyelitis optica [online serial]J Neuroimmunol 201731310-15 Accessed October 8 2017 jni-journalcomarticleS0165-5728(17)30319-3fulltext

18 Alshowaeir D Yiannikas C Fraser C Klistorner A Mechanism of delayed con-duction of fellow eyes in patients with optic neuritis Int J Ophthalmol 201811(2)329-332

19 Manogaran P Traboulsee AL Lange AP Longitudinal study of retinal nerve fiberlayer thickness and macular volume in patients with neuromyelitis optica spectrumdisorder J Neuroophthalmol 201636(4)363-368

20 Kaufhold F ZimmermannH Schneider E et al Optic neuritis is associated with innernuclear layer thickening and microcystic macular edema independently of multiplesclerosis PLoS One 20138(8)e71145

21 Knier B Schmidt P Aly L et al Retinal inner nuclear layer volume reflects response toimmunotherapy in multiple sclerosis Brain 2016139(11)2855-2863

22 Petzold A Balcer LJ Calabresi PA et al Retinal layer segmentation in multiplesclerosis a systematic review and meta-analysis Lancet Neurol 201716(10)797-812

23 Pawlitzki M Horbrugger M Loewe K et al MS optic neuritis-induced long-termstructural changes within the visual pathway Neurol Neuroimmunol Neuroinflamm20207(2)e665

24 Pache F Zimmermann H Mikolajczak J et al MOG-IgG in NMO and relateddisorders a multicenter study of 50 patients Part 4 afferent visual system damageafter optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patientsJ Neuroinflammation 201613(1)282

25 Filippatou AG Vasileiou ES He Y et al Evidence of subclinical quantitative retinallayer abnormalities in AQP4-IgG seropositive NMOSD Mult Scler 2020 Dec 141352458520977771 doi 1011771352458520977771

26 Motamedi S Oertel FC Yadav SK et al Altered fovea in AQP4-IgGndashseropositiveneuromyelitis optica spectrum disorders Neurol Neuroimmunol Neuroinflamm 20207(5)e805

27 Roca-Fernandez A Oertel FC Yeo T et al Foveal changes in AQP4-Ab seropositiveNMOSD are independent of optic neuritis and not overtly progressive Eur J Neurol202128(7)2280-2293

28 Papadopoulou A Oertel FC Chien C et al Lateral geniculate nucleus volumechanges after optic neuritis in neuromyelitis optica a longitudinal study NeuroimageClin 202130102608

29 Ringelstein M Harmel J Zimmermann H et al Longitudinal optic neuritis-unrelatedvisual evoked potential changes in NMO spectrum disorders Neurology 202094(4)e407-e418

30 Pache F Zimmermann H Finke C et al Brain parenchymal damage in neuromyelitisoptica spectrum disorderndasha multimodal MRI study Eur Radiol 201626(12)4413-4422

31 Hokari M Yokoseki A Arakawa M et al Clinicopathological features in anteriorvisual pathway in neuromyelitis optica Ann Neurol 201679(4)605-624

32 You Y Zhu L Zhang T et al Evidence of muller glial dysfunction in patients withaquaporin-4 immunoglobulin Gndashpositive neuromyelitis optica spectrum disorderOphthalmology 2019126(6)801-810 Elsevier

33 Chien C Scheel M Schmitz-Hubsch T et al Spinal cord lesions and atrophy inNMOSD with AQP4-IgG and MOG-IgG associated autoimmunityMult Scler 201925(14)1926-1936

34 Felix CM Levin MH Verkman AS Complement-independent retinal pathologyproduced by intravitreal injection of neuromyelitis optica immunoglobulin GJ Neuroinflammation 201613(1)275

35 Balk LJ Coric D Knier B et al Retinal inner nuclear layer volume reflects in-flammatory disease activity in multiple sclerosis a longitudinal OCT studyMult SclerJ Exp Transl Clin 20195(3)2055217319871582

36 Gelfand JM Nolan R Schwartz DM Graves J Green AJ Microcystic macular oedemain multiple sclerosis is associated with disease severity Brain 2012135(pt 6)1786-1793

Appendix (continued)

Name Location Contribution

Uygur TanriverdiMD

Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Turkey

Acquisition andanalysis of data

Anu Jacob MD The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Saif Huda MDPhD

The Walton Centre forNeurology andNeurosurgery LiverpoolUnited Kingdom

Acquisition andanalysis of data

Zoe Rimler BSc NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Allyson Reid MD NYU School of Medicine NewYork NY

Acquisition andanalysis of data

Yang Mao-Draayer MD PhD

University of MichiganMedical School AnnArbor MI

Acquisition andanalysis of data

Ibis Soto deCastillo MD

Hospital Clınico deMaracaibo MaracaiboVenezuela

Acquisition andanalysis of data

Axel Petzold MDPhD

University College LondonLondon UK

Conception anddesign of the study

Ari J Green MD University of California SanFrancisco CA

Conception anddesign of the study

Michael RYeaman MD PhD

University of California LosAngeles CA

Conception anddesign of the study

Terry Smith MD University of MichiganMedical School AnnArbor MI

Conception anddesign of the study

Alexander UBrandt MD

Experimental and ClinicalResearch Center MaxDelbruck Center forMolecular Medicine andCharitendashUniversitatsmedizinBerlin Berlin Germany

Acquisition andanalysis of dataconception and designof the study anddrafting a significantportion of themanuscript or figures

Friedemann PaulMD

CharitendashUniversitatsmedizinBerlin Corporate Member ofFreie Universitat Berlin andHumboldt-Universitat zuBerlin

Acquisition andanalysis of data andconception and designof the study

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

37 Gelfand JM Cree BA Nolan R Arnow S Green AJ Microcystic inner nuclear layerabnormalities and neuromyelitis optica JAMA Neurol 201370(5)629-633

38 Oberwahrenbrock T WeinholdMMikolajczak J et al Reliability of intra-retinal layerthickness estimates PLoS One 201510(9)e0137316

39 Borisow N Kleiter I Gahlen A et al Influence of female sex and fertile age onneuromyelitis optica spectrum disorders Mult Scler 201723(8)1092-1103

40 Mori M Kuwabara S Paul F Worldwide prevalence of neuromyelitis optica spectrumdisorders J Neurol Neurosurg Psychiatry 201889(6)555-556

41 Oertel FC Paul F Accelerating clinical research in neuromyelitis optica spectrumdisorders [online serial] Clin Exp Neuroimmunol 202112(2)89-91 AccessedMarch 28 2021 periclespericles-prodliteratumonlinecomdoiabs101111cen312637

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 13

DOI 101212NXI000000000000106820218 Neurol Neuroimmunol Neuroinflamm

Frederike Cosima Oertel Svenja Specovius Hanna G Zimmermann et al Retinal Optical Coherence Tomography in Neuromyelitis Optica

This information is current as of September 15 2021

ServicesUpdated Information amp

httpnnneurologyorgcontent86e1068fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent86e1068fullhtmlref-list-1

This article cites 40 articles 7 of which you can access for free at

Subspecialty Collections

httpnnneurologyorgcgicollectionvisual_lossVisual loss

httpnnneurologyorgcgicollectionretinaRetina

httpnnneurologyorgcgicollectionoptic_neuritisOptic neuritis see Neuro-ophthalmologyOptic Nerve

httpnnneurologyorgcgicollectiondevics_syndromeDevics syndrome

httpnnneurologyorgcgicollectionall_imagingAll Imagingfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

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37 Gelfand JM Cree BA Nolan R Arnow S Green AJ Microcystic inner nuclear layerabnormalities and neuromyelitis optica JAMA Neurol 201370(5)629-633

38 Oberwahrenbrock T WeinholdMMikolajczak J et al Reliability of intra-retinal layerthickness estimates PLoS One 201510(9)e0137316

39 Borisow N Kleiter I Gahlen A et al Influence of female sex and fertile age onneuromyelitis optica spectrum disorders Mult Scler 201723(8)1092-1103

40 Mori M Kuwabara S Paul F Worldwide prevalence of neuromyelitis optica spectrumdisorders J Neurol Neurosurg Psychiatry 201889(6)555-556

41 Oertel FC Paul F Accelerating clinical research in neuromyelitis optica spectrumdisorders [online serial] Clin Exp Neuroimmunol 202112(2)89-91 AccessedMarch 28 2021 periclespericles-prodliteratumonlinecomdoiabs101111cen312637

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 13

DOI 101212NXI000000000000106820218 Neurol Neuroimmunol Neuroinflamm

Frederike Cosima Oertel Svenja Specovius Hanna G Zimmermann et al Retinal Optical Coherence Tomography in Neuromyelitis Optica

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httpnnneurologyorgcgicollectionvisual_lossVisual loss

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httpnnneurologyorgcgicollectionoptic_neuritisOptic neuritis see Neuro-ophthalmologyOptic Nerve

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Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm

Page 14: Retinal Optical Coherence Tomography in Neuromyelitis Optica

DOI 101212NXI000000000000106820218 Neurol Neuroimmunol Neuroinflamm

Frederike Cosima Oertel Svenja Specovius Hanna G Zimmermann et al Retinal Optical Coherence Tomography in Neuromyelitis Optica

This information is current as of September 15 2021

ServicesUpdated Information amp

httpnnneurologyorgcontent86e1068fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent86e1068fullhtmlref-list-1

This article cites 40 articles 7 of which you can access for free at

Subspecialty Collections

httpnnneurologyorgcgicollectionvisual_lossVisual loss

httpnnneurologyorgcgicollectionretinaRetina

httpnnneurologyorgcgicollectionoptic_neuritisOptic neuritis see Neuro-ophthalmologyOptic Nerve

httpnnneurologyorgcgicollectiondevics_syndromeDevics syndrome

httpnnneurologyorgcgicollectionall_imagingAll Imagingfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm


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