The Epidemiology of Primary Lateral Sclerosis: Results from a Population-Based Cohort

Objective: In this population-based study, we described the epidemiology of primary lateral sclerosis (PLS) in northern Italy and compared the clinical characteristics of patients with PLS to those with predominant upper motor neuron (PUMN) involvement and classic amyotrophic lateral sclerosis (ALS). Methods: Patients from the PARALS registry diagnosed with probable or definite PLS between 2007 and 2021 were included. Crude annual incidence rates were calculated, along with age- and sex-specific rates. A survival analysis was performed to identify prognostic factors at diagnosis. Covariates included sex, age at onset, site of onset, diagnostic delay, forced vital capacity (FVC), change in ALS Functional Rating Scale (ΔFRS), and change in body mass index (ΔBMI). Results: A total of 57 PLS patients (2.7%) were included, with a crude incidence rate of 0.084 per 100,000 person-years. Compared to PUMN and classic ALS, PLS patients were younger (median onset age 63.5 years, interquartile range [IQR] 54.9–70.4) and predominantly female (male-to-female ratio 0.58). Bulbar onset occurred in 11 cases (19.3%), all of whom later developed spinal symptoms. At censoring, 38 patients (66.7%) were still alive (median survival 8.3 years, IQR 5.7–12.3), corresponding to a point prevalence of 0.89 per 100,000. Survival was significantly associated with age at onset (hazard ratio [HR] 1.17, 95% confidence interval [CI]: 1.05–1.33, p = 0.001), male sex (HR 4.41, 95% CI: 1.24–15.6, p = 0.02), and FVC at diagnosis (HR 0.95, 95% CI: 0.93–0.98, p = 0.006). Interpretation: PLS was confirmed to be rarer than other ALS phenotypes. Patients had a higher age at onset than previously reported and a female predominance. Sex, age at onset, and respiratory function were key prognostic factors. ANN NEUROL 2026;99:606–613.