Natural History and Prognostic Factors of Primary Lateral Sclerosis: Insights from a Retrospective Study

This retrospective, single-center cohort study describes the natural history of Primary Lateral Sclerosis (PLS) in 34 patients followed at the AOU Modena Motor Neuron Disease Centre, integrating disease-specific functional assessment (PLS Functional Rating Scale, PLSFRS), neurophysiology, neuroimaging, and basic biofluid profiling. We systematically extracted demographics, onset site and timing, diagnostic delay, spread to multiple regions, respiratory function, emergence of lower motor neuron (LMN) signs, comorbidities, genetic testing, symptomatic treatments, and supportive procedures; survival was analyzed with Cox models. The cohort showed late-midlife onset (median 56.0 years) and diagnosis at 60.0 years, with a median diagnostic delay of 34 months and stable body habitus from premorbid to diagnostic assessments (BMI 26 kg/m²), underscoring a protracted but indolent course distinct from ALS. At first evaluation, functional autonomy was relatively preserved (median PLSFRS 58/68), and the longitudinal decline was modest (ΔPLSFRS 0.26 points months), consistent with slow progression. Clinically, bulbar onset was uncommon (17.7%), yet bulbar involvement accrued in most patients (79.4%; median 41.4 months), and three- region generalization was nearly universal (97.1%; median 45.2 months). A minority developed LMN signs (26.5%; median 26.6 months), while respiratory function at first measurement was largely preserved (median FVC 90.7%). Neurophysiology was highly sensitive to corticospinal dysfunction—MEPs were abnormal in all tested patients and SSEPs delayed in 60%—whereas conventional brain MRI detected corticospinal-tract hyperintensity in only 16.7%, highlighting the limited sensitivity of routine structural imaging and the complementary value of electrophysiology. Pharmacological care was symptom-directed: baclofen in 55.9% and off-label riluzole in 44.1%, without survival benefit attributable to riluzole. Supportive interventions were infrequent and typically late (NIV 17.6% at ~8.5 years; PEG 11.8% at ~8 years; invasive ventilation 5.9% at ~12.5 years), mirroring the indolent respiratory/bulbar trajectory of PLS. In multivariable survival analysis, age at onset emerged as the sole independent predictor of mortality (HR 1.09 per year; 95% CI 1.02–1.16; p=0.011), implying an ~8–9% hazard increase per additional year and offering an immediately actionable stratification lever for clinics and trials. Overall, this study adds contemporary evidence to the characterization of PLS as a distinct motor neuron disorder with a slow, regionally progressive UMN phenotype, prolonged life expectancy. Age at symptom onset represents the sole prognostic factor offering immediate applicability in clinical practice and trial stratification, providing a robust and quantifiable parameter to guide patient risk categorization and therapeutic decision-making. Moreover, our study confirms the diagnostic utility of electrophysiological and neuroradiological assessment and emphasizes the unmet need for disease-modifying treatments. These insights are pivotal for patient counseling, optimizing clinical trial design, and advancing translational research toward improved outcomes in PLS. Key Words: Motor neuron disease, Primary lateral sclerosis, Clinical management, PLS Functional rating scale, Disease progression.