Diagnostic Revision From Primary Lateral Sclerosis to Amyotrophic Lateral Sclerosis: A Cohort Study

BACKGROUND AND OBJECTIVES: Primary lateral sclerosis (PLS) is defined as a pure upper motor neuron syndrome and is a diagnosis of exclusion, amyotrophic lateral sclerosis (ALS) being the most likely alternative diagnostic consideration. A minimum disease duration of 2 years is required for the diagnosis of PLS, after which patients are classified as probable PLS (P-PLS) and subsequently as definite PLS (D-PLS) after 4 years. Our aim is to apply the current diagnostic criteria to a population-based cohort and investigate which clinical characteristics are associated with a diagnostic revision to ALS. METHODS: This cohort study included patients meeting the current diagnostic criteria for PLS retrospectively from the Dutch Motor Neuron Disease Registry. Diagnostic revision to ALS was based on clinical assessment, EMG findings according to the revised El Escorial Criteria, or if patients had died from disease progression within 4 years of disease onset. Clinical characteristics were compared for patients who underwent diagnostic revision with ALS vs true PLS. Subdistribution hazard ratios (SHRs) for characteristics associated with diagnostic revision were determined using Fine-Gray regression. RESULTS: We included 478 patients (median age of onset 59.3 years, interquartile range 50.8-67.0, 47.9% female), of whom 311 (65.1%) met criteria for P-PLS and 167 (34.9%) for D-PLS at diagnosis. Eighty-eight patients (18%) underwent diagnostic revision to ALS, 76 cases (86%) before 4 years of disease duration. Patients whose diagnosis was revised to ALS had higher median age at onset (63.4 vs 58.0 years, p = 5.20 × 10-4), more often had bulbar onset (38.6% vs 19.7%, p = 6.19 × 10-4), and faster progression (median ALS Functional Rating Scale-revised slope 0.43 vs 0.18, p = 6.05 × 10-11). The risk of diagnostic revision increased if progression rate was faster (SHR 3.08 95% CI 1.69-5.60, p = 2.35 × 10-4) and if diagnosis was P-PLS compared with D-PLS (SHR 3.08, 95% CI 1.65-5.74, p = 3.96 × 10-4). DISCUSSION: In our cohort, most diagnostic revisions from PLS to ALS were in patients with a disease duration of less than 4 years. Besides disease duration, a faster progression rate was associated with diagnostic revision from PLS to ALS. Adding progression rate to the current diagnostic criteria could increase accuracy and help identify patients at higher risk of developing ALS.