Observational Study

. 2024 Sep;11(9):2473-2484.

doi: 10.1002/acn3.52166. Epub 2024 Aug 4.

Application of the international criteria for optic neuritis in the Acute Optic Neuritis Network

Philipp Klyscz^#^{1

2

3

4}, Susanna Asseyer^#^{1

2

3

4}, Ricardo Alonso⁵, Charlotte Bereuter^{1

4}, Omer Bialer^{6

7}, Atira Bick⁸, Sara Carta⁹, John J Chen^{10

11

12}, Leila Cohen⁵, Yamit Cohen-Tayar^{6

7

13}, Edgar Carnero Contentti¹⁴, Russell C Dale^{15

16

17}, Eoin P Flanagan^{10

11

18}, Jonathan A Gernert¹⁹, Julian Haas^{1

3

4}, Joachim Havla¹⁹, Christoph Heesen²⁰, Mark Hellmann^{6

7}, Netta Levin⁸, Pablo Lopez¹⁴, Itay Lotan^{7

21

22}, Maria Belen Luis⁵, Sara Mariotto⁹, Christina Mayer²⁰, Alvaro Jose Mejia Vergara²³, Cassandra Ocampo²⁴, Susana Ochoa⁵, Frederike C Oertel^{1

2

4}, Maja Olszewska⁴, José Luis Peralta Uribe²⁵, Jaume Sastre-Garriga²⁶, Dario Scocco⁵, Sudarshini Ramanathan^{16

27

28}, Natthapon Rattanathamsakul²⁹, Fu-Dong Shi³⁰, Jemal Shifa³¹, Ilya Simantov^{6

7

13}, Sasitorn Siritho^{29

32}, Alon Tiosano^{6

7}, Nanthaya Tisavipat^{10

11}, Isabel Torres²⁵, Adi Vaknin Dembinsky⁸, Angela Vidal-Jordana²⁶, Adi Wilf-Yarkoni^{21

33}, Ti Wu³⁰, Sol Zamir⁸, Luis Alfonso Zarco²⁵, Hanna G Zimmermann^{1

3

34}, Axel Petzold^{35

36

37}, Friedemann Paul^{1

2

3

4}, Hadas Stiebel-Kalish^{6

7

13}

Affiliations

¹ Experimental and Clinical Research Center, A Cooperation between Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité - Universitätsmedizin Berlin, Berlin, Germany.
² Department of Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
³ Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
⁴ Neuroscience Clinical Research Center (NCRC), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
⁵ University Center of MS and NMOSD, Neurology Department, Ramos Mejia Hospital, Buenos Aires, Argentina.
⁶ Department of Neuro-Ophthalmology, Rabin Medical Center, Petah Tikva, Israel.
⁷ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
⁸ Department of Neurology, Hadassah Medical Center, Hebrew University, Jerusalem, Israel.
⁹ Neurology Unit, Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Verona, Italy.
¹⁰ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
¹¹ Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota, USA.
¹² Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA.
¹³ Eye Laboratory, Felsenstein Medical Research Center, Tel Aviv University, Tel Aviv, Israel.
¹⁴ Neuroimmunology Unit, Department of Neuroscience, Hospital Aleman, Buenos Aires, Argentina.
¹⁵ TY Nelson Department of Paediatric Neurology, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
¹⁶ Faculty of Medicine and Health and Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.
¹⁷ Clinical Neuroimmunology Group, Kids Neuroscience Centre, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
¹⁸ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁹ Institute of Clinical Neuroimmunology, LMU Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany.
²⁰ Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
²¹ Neuroimmunology Service, Department of Neurology, Rabin Medical Center, Petah Tikva, Israel.
²² Neuromyelitis Optica Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
²³ Ophthalmology Department, University of Florida, Gainesville, Florida, USA.
²⁴ Faculty of Medicine, University of Botswana, Gaborone, Botswana.
²⁵ Pontificia Universidad Javeriana and Hospital Universitario San Ignacio, Bogotá, Colombia.
²⁶ Neurology Department, Multiple Sclerosis Centre of Catalonia (Cemcat), Vall d'Hebron University Hospital, Barcelona, Spain.
²⁷ Department of Neurology, Concord Hospital, Sydney, New South Wales, Australia.
²⁸ Translational Neuroimmunology Group, Kids Neuroscience Centre, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
²⁹ Faculty of Medicine Siriraj Hospital, Mahidol University Bangkok, Bangkok, Thailand.
³⁰ Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China.
³¹ Department of Surgery, University of Botswana, Gaborone, Botswana.
³² Neuroscience Center, Bumrungrad International Hospital, Bangkok, Thailand.
³³ Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
³⁴ Einstein Center Digital Future, Berlin, Germany.
³⁵ The National Hospital for Neurology and Neurosurgery, University College London, London, UK.
³⁶ Moorfields Eye Hospital, London, UK.
³⁷ Neuro-ophthalmology Expert Centre, Amsterdam, Netherlands.

^# Contributed equally.

PMID: 39099240
PMCID: PMC11537134
DOI: 10.1002/acn3.52166

Observational Study

Application of the international criteria for optic neuritis in the Acute Optic Neuritis Network

Philipp Klyscz et al. Ann Clin Transl Neurol. 2024 Sep.

. 2024 Sep;11(9):2473-2484.

doi: 10.1002/acn3.52166. Epub 2024 Aug 4.

Authors

Affiliations

¹ Experimental and Clinical Research Center, A Cooperation between Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité - Universitätsmedizin Berlin, Berlin, Germany.
² Department of Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
³ Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
⁴ Neuroscience Clinical Research Center (NCRC), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
⁵ University Center of MS and NMOSD, Neurology Department, Ramos Mejia Hospital, Buenos Aires, Argentina.
⁶ Department of Neuro-Ophthalmology, Rabin Medical Center, Petah Tikva, Israel.
⁷ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
⁸ Department of Neurology, Hadassah Medical Center, Hebrew University, Jerusalem, Israel.
⁹ Neurology Unit, Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Verona, Italy.
¹⁰ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
¹¹ Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota, USA.
¹² Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA.
¹³ Eye Laboratory, Felsenstein Medical Research Center, Tel Aviv University, Tel Aviv, Israel.
¹⁴ Neuroimmunology Unit, Department of Neuroscience, Hospital Aleman, Buenos Aires, Argentina.
¹⁵ TY Nelson Department of Paediatric Neurology, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
¹⁶ Faculty of Medicine and Health and Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.
¹⁷ Clinical Neuroimmunology Group, Kids Neuroscience Centre, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
¹⁸ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁹ Institute of Clinical Neuroimmunology, LMU Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany.
²⁰ Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
²¹ Neuroimmunology Service, Department of Neurology, Rabin Medical Center, Petah Tikva, Israel.
²² Neuromyelitis Optica Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
²³ Ophthalmology Department, University of Florida, Gainesville, Florida, USA.
²⁴ Faculty of Medicine, University of Botswana, Gaborone, Botswana.
²⁵ Pontificia Universidad Javeriana and Hospital Universitario San Ignacio, Bogotá, Colombia.
²⁶ Neurology Department, Multiple Sclerosis Centre of Catalonia (Cemcat), Vall d'Hebron University Hospital, Barcelona, Spain.
²⁷ Department of Neurology, Concord Hospital, Sydney, New South Wales, Australia.
²⁸ Translational Neuroimmunology Group, Kids Neuroscience Centre, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
²⁹ Faculty of Medicine Siriraj Hospital, Mahidol University Bangkok, Bangkok, Thailand.
³⁰ Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China.
³¹ Department of Surgery, University of Botswana, Gaborone, Botswana.
³² Neuroscience Center, Bumrungrad International Hospital, Bangkok, Thailand.
³³ Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
³⁴ Einstein Center Digital Future, Berlin, Germany.
³⁵ The National Hospital for Neurology and Neurosurgery, University College London, London, UK.
³⁶ Moorfields Eye Hospital, London, UK.
³⁷ Neuro-ophthalmology Expert Centre, Amsterdam, Netherlands.

^# Contributed equally.

PMID: 39099240
PMCID: PMC11537134
DOI: 10.1002/acn3.52166

Abstract

Objective: The first international consensus criteria for optic neuritis (ICON) were published in 2022. We applied these criteria to a prospective, global observational study of acute optic neuritis (ON).

Methods: We included 160 patients with a first-ever acute ON suggestive of a demyelinating CNS disease from the Acute Optic Neuritis Network (ACON). We applied the 2022 ICON to all participants and subsequently adjusted the ICON by replacing a missing relative afferent pupillary defect (RAPD) or dyschromatopsia if magnetic resonance imaging pathology of the optical nerve plus optical coherence tomography abnormalities or certain biomarkers are present.

Results: According to the 2022 ICON, 80 (50%) patients were classified as definite ON, 12 (7%) patients were classified as possible ON, and 68 (43%) as not ON (NON). The main reasons for classification as NON were absent RAPD (52 patients, 76%) or dyschromatopsia (49 patients, 72%). Distribution of underlying ON etiologies was as follows: 78 (49%) patients had a single isolated ON, 41 (26%) patients were diagnosed with multiple sclerosis, 25 (16%) patients with myelin oligodendrocyte glycoprotein antibody-associated disease, and 15 (9%) with neuromyelitis optica spectrum disorder. The application of the adjusted ON criteria yielded a higher proportion of patients classified as ON (126 patients, 79%).

Interpretation: According to the 2022 ICON, almost half of the included patients in ACON did not fulfill the requirements for classification of definite or possible ON, particularly due to missing RAPD and dyschromatopsia. Thorough RAPD examination and formal color vision testing are critical to the application of the 2022 ICON.

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Conflict of interest statement

PK, RA, CB, OB, AB, SC, LC, YC‐T, JH, MH, NL, PL, IL, MBL, CM, AJMV, CO, SO, MO, JLPU, JS‐G, DS, NR, F‐DS, JS, IS, SS, AT, NT, IT, AVD, AW‐Y, TW, SZ, and LAZ did not report any disclosures. SA received speaker's honoraria from Bayer, Alexion, Roche, and research grants from Stiftung Charité, Fritz‐Thyssen‐Stiftung, HEAD Genuit Stiftung, Rahel Hirsch Program, Novartis, and Roche. JJC is a consultant to UCB and Horizon, unrelated to this study. ECC has received reimbursement for developing educational presentations, educational and research grants, consultation fees and/or travel stipends from Biogen Argentina y LATAM, Genzyme Argentina, Merck Argentina y LATAM, Roche Argentina y LATAM, Raffo, Novartis Argentina, MERZ Argentina, Biosidus, Astrazeneca Argentina, Horizon Global, Amgen Argentina, the Guthy‐Jackson Charitable Foundation (Los Angeles, CA, USA), The Sumaira Foundation (Boston, MA, USA) and LACTRIMS. RCD received research funding from the Star Scientific Foundation, The Trish Multiple Sclerosis Research Foundation, Multiple Sclerosis Research Australia, the Petre Foundation, and the NHMRC (Australia; Investigator Grant). He has also received honoraria from Biogen Idec as an invited speaker and is on the IDMC for a Roche RCT in pediatric MS. He is on the medical advisory board (nonremunerated position). EPF served on advisory boards for Alexion, Genentech, Horizon Therapeutics, and UCB. He has received research support from UCB. He has received speaker honoraria from Pharmacy Times. He received royalties from UpToDate. He is a site principal investigator in a randomized clinical trial of Rozanolixizumab for relapsing myelin oligodendrocyte glycoprotein antibody‐associated disease run by UCB. He is a site principal investigator and a member of the steering committee for a clinical trial of satralizumab for relapsing myelin oligodendrocyte glycoprotein antibody‐associated disease run by Roche/Genentech. He has received funding from the NIH (R01NS113828). Dr Flanagan is a member of the medical advisory board of the MOG project. He is an editorial board member of Neurology, Neuroimmunology and Neuroinflammation, The Journal of the Neurological Sciences and Neuroimmunology Reports. A patent has been submitted on DACH1‐IgG as a biomarker of paraneoplastic autoimmunity. JAG reports travel expenses and nonfinancial support from Merck, outside the submitted work. JH reports grants from Friedrich‐Baur‐Stiftung, Merck, and Horizon; personal fees and nonfinancial support from Alexion, Horizon, Roche, Merck, Novartis, Biogen, B.M.S., and Janssen; and nonfinancial support from the Guthy‐Jackson Charitable Foundation and The Sumaira Foundation. CH received research grants from Merck, Novartis, and speaker honoraria from Merck and Roche. SM received speakers' honoraria from Alexion, Novartis, Biogen, Sanofi, and Horizon unrelated to this study. FCO currently receives research funding from the Hertie Foundation for Excellence in Clinical Neurosciences and Novartis, both unrelated to this project. She also received fellowship support by the American Academy of Neurology (until 2023) and the National Multiple Sclerosis Society (until 2023), both unrelated to this project.

JS‐G serves as a co‐editor for Europe for the Multiple Sclerosis Journal and as an Editor‐in‐Chief of Revista de Neurología, receives research support from Fondo de Investigaciones Sanitarias (19/950 and 22/750), and in the last, 12 months has served as a consultant/speaker for BMS, Roche, Sanofi, Janssen, and Merck. SR received research funding from the National Health and Medical Research Council (NHMRC, Australia), the Petre Foundation, the Brain Foundation, the Royal Australasian College of Physicians, and the University of Sydney. She is supported by an NHMRC Investigator Grant (GNT2008339). She serves as a consultant on an advisory board for UCB and Limbic Neurology and has been an invited speaker for educational/research sessions coordinated by Biogen, Alexion, Novartis, Excemed, and Limbic Neurology. She is on the medical advisory board (nonremunerated positions) of The MOG Project and the Sumaira Foundation. AV‐J has received support from contracts Juan Rodes (JR16/00024) and from Fondo de Investigación en Salud (PI17/02162 and PI22/01589) from Instituto de Salud Carlos III, Spain, and in the last 2 years, she has engaged in consulting and/or participated as speaker in events organized by Roche, Novartis, Merck, and Sanofi. HGZ reports research grants and speaker honoraria from Novartis. AP reports personal fees from Novartis, Heidelberg Engineering, and Zeiss, grants from Novartis, outside the submitted work; and AP is part of the steering committee of the OCTiMS study which is sponsored by Novartis. AP is part of the steering committee of Angio‐OCT which is sponsored by Zeiss. He does not receive honorary as part of these activities. The NIHR BRC at Moorfields Eye Hospital supported AP. FP served on the scientific advisory boards of Novartis and MedImmune; received travel funding and/or speaker honoraria from Bayer, Novartis, Biogen, Teva, Sanofi‐Aventis/Genzyme, Merck Serono, Alexion, Chugai, MedImmune, and Shire; is an associate editor of Neurology: Neuroimmunology & Neuroinflammation; is an academic editor of PLoS ONE; consulted for Sanofi Genzyme, Biogen, MedImmune, Shire, and Alexion; received research support from Bayer, Novartis, Biogen, Teva, Sanofi‐Aventis/Geynzme, Alexion, and Merck Serono; and received research support from the German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, Arthur Arnstein Stiftung Berlin, EU FP7 Framework Program, Arthur Arnstein Foundation Berlin, Guthy‐Jackson Charitable Foundation, and NMSS. HS‐K reports consulting fees and nonfinancial support from Roche, and Quark, consulting fees from the Israel Ministry of Health, and research grants from the Maratier Foundation for Vision Research and the Israel Motor Vehicle accident‐prevention authority, unrelated to this study.

Figures

**Figure 1**
Availability of OCT, MRI, and biomarker (AQP4‐/MOG‐IgG, OCB) testing for all patients. Each row represents an individual patient. If any diagnostic procedure is not available, the respective tile is left blank. OCT was the least available paraclinical test in our cohort. AQP4‐IgG, aquaporin‐4‐IgG; MOG‐IgG, myelin oligodendrocyte glycoprotein‐IgG; MRI, magnetic resonance imaging; OCB, oligoclonal bands; OCT, optical coherence tomography.

**Figure 2**
Bar plots showing distribution among 160 ACON patients meeting the 2022 ICON (A), the number of patients with documented dyschromatopsia (B), and the percentage of patients in whom RAPD was documented (C). ACON, Acute Optic Neuritis Network; ICON, international consensus criteria for optic neuritis; ON, optic neuritis; RAPD, relative afferent pupillary defect.

**Figure 3**
Comparative bar plot shows that substituting clinical symptoms with paraclinical signs of the 2022 ICON results in a higher proportion of patients classified as ON. First, original ON criteria were dichotomized by joining definite and possible ON. For the adjusted criteria, all patients that were initially classified as NON (due to missing RAPD or dyschromatopsia), were reclassified as ON if they had MRI pathology of the affected optic nerve and were positive for at least one additional paraclinical criteria (i.e., OCT pathology or presence of AQP‐/MOG‐IgG/OCB). AQP4‐IgG, aquaporin 4‐IgG; ICON, international consensus criteria for optic neuritis; MOG‐IgG, myelin oligodendrocyte glycoprotein‐IgG; MRI, magnetic resonance imaging; NON, no ON; OCB, oligoclonal bands; OCT, optical coherence tomography; ON, optic neuritis; RAPD, relative afferent pupillary defect.

See this image and copyright information in PMC

References

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Application of the international criteria for optic neuritis in the Acute Optic Neuritis Network

Affiliations

Application of the international criteria for optic neuritis in the Acute Optic Neuritis Network

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous