Early onset sleep disorders predict severity, progression and death in multiple system atrophy

Background: Early stridor onset (≤ 3 years from disease onset) is a predictor of shorter survival in Multiple System Atrophy (MSA), but its role on disease progression is not yet established. In MSA, previous studies on trajectories of disease did not include stridor and REM sleep behavior disorder (RBD) as clinical variable. The aims of the study were: (1) to investigate disease progression in MSA patients with early stridor onset and with early stridor and/or RBD onset; (2) to assess cerebrospinal fluid (CSF) levels of neurofilament light chain protein (NfL) in MSA patients with early onset sleep disorders. Methods: This is a retrospective and prospective cohort study including 208 (120 males) MSA patients. Occurrence of symptoms/signs, milestones of disease progression, and their latency from disease onset were collected. RBD and stridor were video-polysomnography (VPSG)-confirmed. CSF NfL levels were analyzed. Survival data and predictors of mortality were calculated. Results: Out of 208 MSA patients (157 deceased), 91 were diagnosed with stridor and 160 with VPSG-confirmed RBD. Patients with early stridor onset (n = 41) and with early stridor and/or RBD onset (n = 132) showed an early autonomic involvement, developed a more progressive and severe disease and presented higher CSF NfL than those with late stridor and RBD onset. Early stridor and early RBD were independent risk factors on MSA survival. Conclusions: The evidence of a more rapid and severe disease progression and of high CSF NfL levels in patients who early developed sleep disorders could define a different MSA phenotype with a widespread impairment of central-brainstem circuits.