Abstract

BACKGROUND: Neurodegenerative diseases often feature a prolonged phase of subtle changes preceding diagnosis. In amyotrophic lateral sclerosis (ALS), defining this prodromal period is critical for identifying early disease features and intervention windows.

METHODS: In this case-control study, 475 patients with ALS and 285 controls from 20 centres in Germany and Switzerland completed a digital questionnaire on prodromal symptoms and health-related factors. Logistic regression included subgroup analyses by sex and clinical strata.

FINDINGS: Patients with ALS reported a higher burden of prodromal complaints (OR 7.50, 95% CI 4.27-13.17; P < 0.001), particularly neuro-motor, sensory, and pain-related symptoms. Before symptom onset, patients consulted neurologists more often (OR 1.26, 1.10-1.44; P < 0.001) and females more often received speech therapy (OR 2.35, 1.05-5.28; P = 0.038). Prodromal herniated discs were more common in males (OR 2.21, 1.04-4.68; P = 0.038) and spinal-onset patients (OR 2.14, 1.25-3.67; P = 0.006). Patients more often had lower secondary education (OR 1.93, 1.24-3.01; P = 0.004), physically demanding occupations (OR 2.21, 1.42-3.43; P < 0.001), and higher consumption habits (P < 0.005). Weight trajectories differed by sex (P = 0.009), with pre-onset weight loss in male patients (P < 0.001).

INTERPRETATION: Patients with ALS retrospectively reported subtle motor impairment before recognised symptom onset, alongside altered healthcare use and sex- and subgroup-specific patterns. These findings suggest that sporadic ALS may be preceded by a prodromal period and identify mild motor impairment as a potential marker, pending prospective validation.

FUNDING: DGM e. V.