Determinants and prognostic value of onset symptoms in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) has heterogeneous clinical presentations at onset. We aimed to investigate determinants of MS onset-symptom type, and the prognostic relevance of onset categories for long-term disability outcomes. METHODS: We analyzed 1385 incident MS cases from a Swedish population-based case-control study. Onset symptoms were hierarchically categorized as pyramidal/motor, brainstem/cerebellar, visual, or sensory, with sensory used as the reference. Associations with sex, ancestry, age at onset, smoking and body mass index were assessed using multinomial logistic regression. Disability progression was analyzed with Kaplan-Meier curves and Cox proportional hazards models for time to EDSS 3, 4, and 6. RESULTS: Male sex was associated with higher odds of motor (OR 1.54, 95% CI 1.07-2.20) and brainstem/cerebellar onset (OR 1.36, 95% CI 1.00-1.84). Non-Nordic ancestry was linked to motor onset (OR 1.75, 95% CI 1.21-2.51). Obesity was strongly associated with visual onset (OR 2.22, 95% CI 1.41-3.40), and smoking with motor and brainstem/cerebellar onset. Motor onset consistently predicted shorter times to EDSS milestones. Brainstem/cerebellar onset conferred increased risk of reaching EDSS 4. In supplementary analyses, multifocal onset was associated with faster progression, but this effect was largely driven by concomitant motor involvement. CONCLUSIONS: The first clinical manifestation of MS varies by demographic and lifestyle characteristics and carries prognostic value for subsequent disability progression.