The goal of this observational study is to longitudinally investigating subjects with inaugural acute optic neuritis (ON).

The main questions it aims to answer are:

• Does the time to corticosteroid treatment affect the visual outcome at 6 months in subjects with acute multiple sclerosis (MS)-, aquaporin 4-IgG positive (AQP4-IgG+) and myelin-oligodendrocyte-glycoprotein-IgG positive (MOG-IgG+) ON?
• How differ clinical, structural, and laboratory biomarkers in subjects with acute ON, including clinical isolated syndrome (CIS), MS-ON, AQP4-IgG+ON, MOG-IgG+ON and seronegative non-MS-ON? Participants will undergo
• clinical examination, including clinical history, neurovisual and neurological tests
• serum and cerebrospinal fluid examination
• optical coherence tomography (OCT)
• magnetic resonance imaging (MRI)
• assessment of depression, pain, quality of life through validated questionnaires Researchers will compare subjects with MS-ON, AQP4-IgG+ON, MOG-IgG+ON and other ON (CIS, seronegative non-MS-ON) to detect diagnostic and predictive markers for the disease course.

The Acute Optic Neuritis Network (ACON) is a global cooperation of currently 26 academic centers longitudinally investigating subjects with inaugural acute optic neuritis (ON). ON often occurs at 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 ACON study is primarily designed to investigate the effect of time to high-dose corticosteroid treatment on 6-month visual outcomes in ON.

All patients presenting within 30 days of inaugural ON will be enrolled. For primary analysis, patients will subsequently be assigned either into the MS-ON, aquaporin-4-IgG positive ON (AQP4-IgG+ON) or MOG-IgG positive ON (MOG-IgG+ON) group and then further sub-stratified according to the number of days from onset of visual loss to high-dose corticosteroids. The primary outcome measure will be high-contrast best-corrected visual acuity (HC-BCVA) at 6 months. Additionally, 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: optical coherence tomography (OCT) and magnetic resonance imaging (MRI) measurements, serum and cerebrospinal fluid (CSF) biomarkers (AQP4- and MOG-IgG levels; neurofilament; glial fibrillary protein), questionnaires (headache, visual function in daily routine, depression, and quality of life) at presentation, at 6- and 12-months follow-up. Data will be collected from 22 academic hospitals from Africa, Asia, the Middle East, Europe, North America, South America, Australia and Europe. 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 accuracy of diagnostic stratification in acute demyelinating ON.

Inclusion Criteria:

• First-ever acute ON
• Onset of visual symptoms within maximum of 30 days
• Age ≥ 18 years
• Ability to give written informed consent
• Presence of written consent

Exclusion Criteria:

• MRI contraindication
• Prior demyelinating diagnosis
• Diagnosis of other forms of optic neuropathy (hereditary, granulomatous, infectious, infiltrative, toxic)
• Pregnancy at inclusion
• Relevant other diseases that conflict with study participation according to protocol
• Inability to cooperate

At least 300 patients with acute ON will be screened for study eligibility. We will include only inaugural ON patients. Subjects presenting for the first time with isolated ON or ON with additional demyelinating syndromes, e.g. myelitis or acute disseminated encephalomyelitis (ADEM) occurring within 30 days of the acute ON will be included. Patients with prior soft symptoms which can retrospectively be considered to be a demyelinating manifestation will be included, excluding patients with a prior demyelinating diagnosis. The prevalence of MS-, AQP4-IgG+ON and MOG-IgG+ON differs in each of the participating centers. For primary analysis, we collect data from subjects with MS-ON, AQP4-IgG+ON and MOG-IgG+ON. For secondary analysis, multimodal data will be collected in subjects with any demyelinating ON (CIS-ON, MS-ON, AQP4-IgG+ON or MOG-IgG+ON and seronegative non-MS-ON). We expect between 30-50% will be ineligible due to the rigorous exclusion criteria.

The datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author upon reasonable request