The Acute Optic Neuritis Network (ACON): Study protocol of a non-interventional prospective multicenter study on diagnosis and treatment of acute optic neuritis

Susanna Asseyer; Nasrin Asgari; Jeffrey Bennett; Omer Bialer; Yolanda Blanco; Francesca Bosello; Anna Camos-Carreras; Edgar Carnero Contentti; Sara Carta; John Chen; Claudia Chien; Mashina Chomba; Russell C Dale; Josep Dalmau; Kristina Feldmann; Eoin P Flanagan; Caroline Froment Tilikete; Carolina Garcia-Alfonso; Joachim Havla; Mark Hellmann; Ho Jin Kim; Philipp Klyscz; Frank Konietschke; Chiara La Morgia; Marco Lana-Peixoto; Maria Isabel Leite; Netta Levin; Michael Levy; Sara Llufriu; Pablo Lopez; Itay Lotan; Alessandra Lugaresi; Romain Marignier; Sara Mariotto; Susan P Mollan; Cassandra Ocampo; Frederike Cosima Oertel; Maja Olszewska; Jacqueline Palace; Lekha Pandit; José Luis Peralta Uribe; Sean Pittock; Sudarshini Ramanathan; Natthapon Rattanathamsakul; Albert Saiz; Sara Samadzadeh; Bernardo Sanchez-Dalmau; Deanna Saylor; Michael Scheel; Tanja Schmitz-Hübsch; Jemal Shifa; Sasitorn Siritho; Pia S Sperber; Prem S Subramanian; Alon Tiosano; Adi Vaknin-Dembinsky; Alvaro Jose Mejia Vergara; Adi Wilf-Yarkoni; Luis Alfonso Zarco; Hanna G Zimmermann; Friedemann Paul; Hadas Stiebel-Kalish

doi:10.3389/fneur.2023.1102353

The Acute Optic Neuritis Network (ACON): Study protocol of a non-interventional prospective multicenter study on diagnosis and treatment of acute optic neuritis

Front Neurol. 2023 Feb 24:14:1102353. doi: 10.3389/fneur.2023.1102353. eCollection 2023.

Authors

Susanna Asseyer^{1

2

3

4}, Nasrin Asgari^{5

6}, Jeffrey Bennett⁷, Omer Bialer^{8

9}, Yolanda Blanco¹⁰, Francesca Bosello¹¹, Anna Camos-Carreras¹², Edgar Carnero Contentti¹³, Sara Carta¹¹, John Chen¹⁴, Claudia Chien^{1

2

3

4}, Mashina Chomba¹⁵, Russell C Dale^{16

17

18}, Josep Dalmau^{19

20}, Kristina Feldmann^{1

2

3}, Eoin P Flanagan²¹, Caroline Froment Tilikete²², Carolina Garcia-Alfonso²³, Joachim Havla²⁴, Mark Hellmann^{8

9}, Ho Jin Kim²⁵, Philipp Klyscz^{1

2

3

4}, Frank Konietschke², Chiara La Morgia^{26

27}, Marco Lana-Peixoto²⁸, Maria Isabel Leite²⁹, Netta Levin³⁰, Michael Levy³¹, Sara Llufriu^{32

33}, Pablo Lopez¹³, Itay Lotan^{8

9

31}, Alessandra Lugaresi^{34

35}, Romain Marignier²², Sara Mariotto¹¹, Susan P Mollan^{36

37}, Cassandra Ocampo³⁸, Frederike Cosima Oertel^{1

2

3

4}, Maja Olszewska⁴, Jacqueline Palace²⁹, Lekha Pandit³⁹, José Luis Peralta Uribe²³, Sean Pittock³¹, Sudarshini Ramanathan^{17

40

41}, Natthapon Rattanathamsakul⁴², Albert Saiz^{32

33}, Sara Samadzadeh^{1

2

3

4

5

6}, Bernardo Sanchez-Dalmau¹², Deanna Saylor^{15

43}, Michael Scheel^{1

2

3

4

44}, Tanja Schmitz-Hübsch^{1

2

3

4}, Jemal Shifa⁴⁵, Sasitorn Siritho^{42

46}, Pia S Sperber^{1

2

3

4

47}, Prem S Subramanian⁷, Alon Tiosano^{8

9}, Adi Vaknin-Dembinsky³⁰, Alvaro Jose Mejia Vergara⁴⁸, Adi Wilf-Yarkoni⁴⁹, Luis Alfonso Zarco²³, Hanna G Zimmermann^{1

2

3

50}, Friedemann Paul^{1

2

3

4}, Hadas Stiebel-Kalish^{8

9}

Affiliations

¹ Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité Universitätsmedizin Berlin, Berlin, Germany.
² Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental and Clinical Research Center, Berlin, Germany.
³ Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
⁴ NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
⁵ Department of Neurology, Slagelse Hospital, Slagelse, Denmark.
⁶ Institutes of Regional Health Research and Molecular Medicine, University of Southern Denmark, Odense, Denmark.
⁷ Programs in Neuroscience and Immunology, Departments of Neurology and Ophthalmology, Sue Anschutz-Rodgers Eye Center, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
⁸ Department of Neuro-Ophthalmology, Rabin Medical Center, Petah Tikva, Israel.
⁹ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
¹⁰ Neuroimmunology and Multiple Sclerosis Unit, Neurology Service, Hospital Clinic de Barcelona, and Institut d'Investigacions August Pi i Sunyer (IDIVAPS), University of Barcelona, Barcelona, Spain.
¹¹ Neurology Unit, Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Verona, Italy.
¹² Ophthalmology Department, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
¹³ Neuroimmunology Unit, Department of Neuroscience, Hospital Aleman, Buenos Aires, Argentina.
¹⁴ Department of Ophthalmology and Neurology, Mayo Clinic, Rochester, MN, United States.
¹⁵ Department of Internal Medicine, University Teaching Hospital, Lusaka, Zambia.
¹⁶ Clinical Neuroimmunology Group, Kids Neuroscience Centre, Sydney, NSW, Australia.
¹⁷ Faculty of Medicine and Health and Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
¹⁸ TY Nelson Department of Paediatric Neurology, Children's Hospital Westmead, Sydney, NSW, Australia.
¹⁹ ICREA-IDIBAPS, Service of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain.
²⁰ Department of Neurology, University of Pennsylvania, Philadelphia, PA, United States.
²¹ Laboratory Medicine and Pathology, Departments of Neurology, Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, MN, United States.
²² Neuro-Ophthalmology Unit, Pierre Wertheimer Neurological Hospital, Hospices Civils de Lyon, Lyon 1 University, Lyon Neuroscience Research Center, INSERM U1028, CNRS UMR5292, IMPACT Team, Lyon, France.
²³ Pontificia Universidad Javeriana and Hospital Unviersitario San Ignacio, Bogotá, Colombia.
²⁴ Institute of Clinical Neuroimmunology, LMU Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
²⁵ Department of Neurology, National Cancer Center, Goyang, Republic of Korea.
²⁶ Neurology Unit, IRCCS Institute of Neurological Sciences, Bologna, Italy.
²⁷ Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
²⁸ CIEM MS Center, Federal University of Minas Gerais Medical School, Belo Horizonte, Brazil.
²⁹ Department of Neurology, Oxford University Hospitals, National Health Service Trust, Oxford, United Kingdom.
³⁰ Department of Neurology, Hadassah Medical Center, Hebrew University, Jerusalem, Israel.
³¹ Neuromyelitis Optica Research Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
³² Neuroimmunology and Multiple Sclerosis Unit, Neurology Service, Hospital Clinic de Barcelona, Barcelona, Spain.
³³ Institut d'Investigacions August Pi i Sunyer (IDIVAPS), University of Barcelona, Barcelona, Spain.
³⁴ IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
³⁵ Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy.
³⁶ Birmingham Neuro-Ophthalmology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.
³⁷ Translational Brian Science, Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, United Kingdom.
³⁸ Faculty of Medicine, University of Botswana, Gaborone, Botswana.
³⁹ Center for Advanced Neurological Research, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, India.
⁴⁰ Translational Neuroimmunology Group, Kids Neuroscience Centre, Children's Hospital Westmead, Sydney, NSW, Australia.
⁴¹ Department of Neurology, Concord Hospital, Sydney, NSW, Australia.
⁴² Siriraj Neuroimmunology Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
⁴³ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
⁴⁴ Department of Neuroradiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
⁴⁵ Department of Surgery, University of Botswana, Gaborone, Botswana.
⁴⁶ Neuroscience Center, Bumrungrad International Hospital, Bangkok, Thailand.
⁴⁷ German Center for Cardiovascular Research (DZHK), Berlin, Germany.
⁴⁸ Department of Ophthalmology, Fundación Universitaria Sanitas Facultad de Medicina, Bogotá, Colombia.
⁴⁹ Department of Neurology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
⁵⁰ Einstein Center Digital Future, Berlin, Germany.

Abstract

Optic neuritis (ON) often occurs at the presentation of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD). The recommended treatment of high-dose corticosteroids for ON is based on a North American study population, which did not address treatment timing or antibody serostatus. The Acute Optic Neuritis Network (ACON) presents a global, prospective, observational study protocol primarily designed to investigate the effect of time to high-dose corticosteroid treatment on 6-month visual outcomes in ON. Patients presenting within 30 days of the inaugural ON will be enrolled. For the primary analysis, patients will subsequently be assigned into the MS-ON group, the aquapotin-4-IgG positive ON (AQP4-IgG+ON) group or the MOG-IgG positive ON (MOG-IgG+ON) group and then further sub-stratified according to the number of days from the onset of visual loss to high-dose corticosteroids (days-to-Rx). The primary outcome measure will be high-contrast best-corrected visual acuity (HC-BCVA) at 6 months. In addition, multimodal data will be collected in subjects with any ON (CIS-ON, MS-ON, AQP4-IgG+ON or MOG-IgG+ON, and seronegative non-MS-ON), excluding infectious and granulomatous ON. Secondary outcomes include low-contrast best-corrected visual acuity (LC-BCVA), optical coherence tomography (OCT), magnetic resonance imaging (MRI) measurements, serum and cerebrospinal fluid (CSF) biomarkers (AQP4-IgG and MOG-IgG levels, neurofilament, and glial fibrillary protein), and patient reported outcome measures (headache, visual function in daily routine, depression, and quality of life questionnaires) at presentation at 6-month and 12-month follow-up visits. Data will be collected from 28 academic hospitals from Africa, Asia, the Middle East, Europe, North America, South America, and Australia. Planned recruitment consists of 100 MS-ON, 50 AQP4-IgG+ON, and 50 MOG-IgG+ON. This prospective, multimodal data collection will assess the potential value of early high-dose corticosteroid treatment, investigate the interrelations between functional impairments and structural changes, and evaluate the diagnostic yield of laboratory biomarkers. This analysis has the ability to substantially improve treatment strategies and the accuracy of diagnostic stratification in acute demyelinating ON.

Trial registration: ClinicalTrials.gov, identifier: NCT05605951.

Keywords: Aquaporin-4-IgG (AQP4-IgG); MOG-IgG associated disorders (MOGAD); clinically isolated syndrome (CIS); multiple sclerosis (MS); neuromyelitis optica spectrum disorders (NMOSD); optic neuritis (ON).

Copyright © 2023 Asseyer, Asgari, Bennett, Bialer, Blanco, Bosello, Camos-Carreras, Carnero Contentti, Carta, Chen, Chien, Chomba, Dale, Dalmau, Feldmann, Flanagan, Froment Tilikete, Garcia-Alfonso, Havla, Hellmann, Kim, Klyscz, Konietschke, La Morgia, Lana-Peixoto, Leite, Levin, Levy, Llufriu, Lopez, Lotan, Lugaresi, Marignier, Mariotto, Mollan, Ocampo, Cosima Oertel, Olszewska, Palace, Pandit, Peralta Uribe, Pittock, Ramanathan, Rattanathamsakul, Saiz, Samadzadeh, Sanchez-Dalmau, Saylor, Scheel, Schmitz-Hübsch, Shifa, Siritho, Sperber, Subramanian, Tiosano, Vaknin-Dembinsky, Mejia Vergara, Wilf-Yarkoni, Zarco, Zimmermann, Paul and Stiebel-Kalish.

Associated data

ClinicalTrials.gov/NCT05605951