BACKGROUND: Previous studies have indicated that progression independent of relapse activity (PIRA) is uncommon in patients with aquaporin- 4 antibody-positive (AQP4-IgG) neuromyelitis optica spectrum disorder (NMOSD). However, the patterns of disability accumulation in seronegative NMOSD are unknown. This study aimed to evaluate the prevalence of PIRA and relapse-associated worsening (RAW) in seronegative NMOSD. METHODS: We conducted a retrospective, multicentre cohort study of seronegative NMOSD patients from the MSBase registry. Inclusion criteria required at least three recorded expanded disability status scale (EDSS) scores: baseline, progression, and 6 months confirmed disability progression (CDP). For those with 6-month CDP, the presence or absence of relapse between baseline and progression determined the classification as RAW or PIRA, respectively. Descriptive statistics were employed to present the data. RESULTS: This study included 93 patients, with a median follow-up duration of 5.0 years (Q1 2.8, Q3 8.4). The cohort predominantly consisted of female patients (77.4%), with a median age of onset of 33.9 years (Q1 26.1, Q3 41.2). PIRA was observed in 1 case (1.1%), whilst RAW was documented in 7 cases (7.5%). CONCLUSION: This international cohort study confirms that CDP is uncommon in seronegative NMOSD. Given more than three quarters of CDP occur due to RAW, therapeutic strategies should focus primarily on preventing relapses.

College of Medicine and Health Sciences and Sultan Qaboos University Hospital Sultan Qaboos University Al Khodh Oman

CORe Department of Medicine University of Melbourne Melbourne VIC Australia

Department of Biotechnological and Applied Clinical Sciences University of L'Aquila L'Aquila Italy

Department of Medical and Surgical Sciences and Advanced Technologies GF Ingrassia Catania Italy

Department of Neurology Alfred Health Melbourne VIC Australia

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Czech Republic

Department of Neurology Antwerp University Hospital Drie Eikenstraat 655 2650 Edegem Belgium

Department of Neurology Faculty of Medicine University of Debrecen Debrecen Hungary

Department of Neurology Haydarpasa Numune Training and Research Hospital Istanbul Turkey

Department of Neurology Medical Faculty Karadeniz Technical University Trabzon Turkey

Department of Neurology Neuroimmunology Centre The Royal Melbourne Hospital Parkville VIC Australia

Department of Neurology Royal Brisbane Hospital Brisbane Australia

Department of Neurology School of Medicine Koc University Research Center for Translational Medicine Koc University Istanbul Turkey

Department of Neurology Universitary Hospital Ghent Ghent Belgium

Department of Neurology Walton Centre NHS Foundation Trust Liverpool UK

Department of Neuroscience Central Clinical School Monash University Melbourne VIC Australia

Department of Neuroscience Hospital Germans Trias 1 Pujol Badalona Spain

Faculty of Medicine Isfahan University of Medical Sciences Isfahan Iran

Hunter Medical Research Institute University of Newcastle NeurologyNewcastle Australia

Hunter New England Health John Hunter Hospital New Lambton Heights NSW Australia

Izmir University of Economics Medical Point Hospital Izmir Turkey

Multiple Sclerosis Research Association Izmir Turkey

Multiple Sclerosis Unit AOU Policlinico G Rodolico San Marco University of Catania Via Santa Sofia 78 95123 Catania Italy

Nehme and Therese Tohme Multiple Sclerosis Center American University of Beirut Medical Center Beirut Lebanon

Neurology Dr Etemadifar MS Institute Isfahan Iran

Royal Hobart Hospital Hobart TAS Australia

Translational Neurosciences Research Group Faculty of Medicine and Health Sciences University of Antwerp Universiteitsplein 1 2610 Wilrijk Belgium

University of Queensland Brisbane Australia

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