https://doi.org/10.1177/13524585211066598 https://doi.org/10.1177/13524585211066598 MULTIPLE SCLEROSIS MSJ JOURNAL journals.sagepub.com/home/msj 1 Multiple Sclerosis Journal 1–10 DOI: 10.1177/ 13524585211066598 © The Author(s), 2021. Article reuse guidelines: sagepub.com/journals- permissions Introduction Multiple sclerosis (MS) is a chronic disease of the central nervous system, specifically featured by inflammation, widespread primary demyelination, and progressive neurodegeneration. 1 Cognitive impair- ment in MS is now recognized as a core disease fea- ture, which can occur early in the course of the disease, and is more frequent and severe among patients with progressive MS. 2,3 MS patients with cognitive dys- function have lower employment rates, experience limitations in social and family functions, and report lower quality of life. 4,5 Furthermore, longitudinal stud- ies have demonstrated that cognitive impairment is a predictor of conversion of clinically isolated syndrome to MS 5,6 and of future disease progression namely degree of physical disability, transition to secondary progressive MS (SPMS), and functional handicap. 5,7–9 The North American Research Committee on Multiple Sclerosis (NARCOMS) registry reported an increased mortality risk in patients with self-reported cognitive impairment, independent of the effect of physical dis- ability. 10 Although, it has been shown that subjective cognitive complaints in MS are closely related to psy- chopathology symptoms and often do not reflect objective cognitive deficits. 11 Two studies have explored whether objective cognitive deficits (using screening measures) are predictive of survival in MS. 12,13 These studies have produced inconsistent findings. This study aims to explore the prognostic value of cognitive dysfunction, documented with a compre- hensive neuropsychological assessment. 14 We hypoth- esized that cognitive dysfunction is predictive of Cognitive dysfunction and mortality in multiple sclerosis: Long-term retrospective review Sara Cavaco , Inês Ferreira, Inês Moreira, Ernestina Santos, Raquel Samões, Ana Paula Sousa , Joaquim Pinheiro, Armando Teixeira-Pinto and Ana Martins da Silva Abstract Background: Cognitive dysfunction as a predictor of clinical progression and mortality in multiple scle- rosis (MS) is still a matter of debate. Objective: The aim of this study was to explore the long-term outcome associated with neuropsychologi- cal performance in a cohort of patients with MS. Methods: A series of 408 MS patients had previously undergone a comprehensive neuropsychological assessment and a contemporaneous neurological evaluation (T1). A retrospective review of the clinical records was conducted 102–192 months after T1. Demographic and clinical data regarding the last clini- cal appointment with EDSS measurement (T2) were collected and the date of the last clinical contact or death (TS) was recorded. Results: This review revealed that cognitive dysfunction (T1) was associated with higher odds of transi- tioning from relapsing–remitting course to a progressive disease course (adjusted odds ratio (OR) = 2.29, p = 0.043) and higher hazard of death in the total sample (adjusted hazard ratio (HR) = 3.07, p = 0.006) and the progressive disease course subgroup (adjusted HR = 3.68, p = 0.007), even when adjusting for other covariates. Discussion: The study results demonstrate that cognitive dysfunction in MS is predictive of poorer prog- nosis and mortality. Keywords: Multiple sclerosis, neuropsychology, cognitive dysfunction, prognosis, mortality, survival Date received: 12 August 2021; revised: 17 November 2021; accepted: 28 November 2021 Correspondence to: S Cavaco Neurology Department Centro Hospitalar Universitário do Porto, 4099- 001 Porto, Portugal. sara.cavaco@chporto.min- saude.pt Sara Cavaco Inês Ferreira Inês Moreira Neurology Department, Centro Hospitalar Universitário do Porto, Porto, Portugal/Neuropsychology Unit, Centro Hospitalar Universitário do Porto, Porto, Portugal Ernestina Santos Raquel Samões Ana Martins da Silva Neurology Department, Centro Hospitalar Universitário do Porto, Porto, Portugal Ana Paula Sousa Neurophysiology Department, Centro Hospitalar Universitário do Porto, Porto, Portugal Joaquim Pinheiro Neurology Department, Centro Hospitalar de Vila Nova de Gaia, Vila Nova de Gaia, Portugal Armando Teixeira-Pinto Sydney School of Public Health, The University of Sydney, Sydney, NSW, Australia 1066598MSJ 0 0 10.1177/13524585211066598Multiple Sclerosis JournalS Cavaco, I Ferreira research-article2021 2021 Original Research Paper