Primary Lateral Sclerosis : diagnostic boundaries and outcome

Abstract

Primary lateral sclerosis (PLS) is a diagnosis of exclusion in sporadic patients with an adult-onset gradually progressive upper motor neuron (UMN) syndrome. Differentiation between PLS, amyotrophic lateral sclerosis (ALS), and sporadic presentation of hereditary spastic paraparesis (HSP) is important for prognostication and genetic counseling of patients, but may be problematic. We studied a large cohort of Dutch patients with an sporadic adult-onset UMN syndrome in a 3-year prospective study. Some of our findings support the view that PLS may be a variant of ALS: we observed patients who converted from PLS to ALS, patients who had PLS as a phenotypic manifestation of familial ALS, and a patient who had clinical PLS up to the time of death, but who at autopsy showed ALS pathology. On the other hand, many patients retained a phenotype similar to HSP (UMN signs only in the legs, or at most also in the arms). In addition, we could genetically confirm the diagnosis of HSP in a proportion of the included patients. We found that spastin gene (SPG4) and paraplegin gene (SPG7) mutations are frequent cause of patients with UMN symptoms restricted to the legs (both in around 12% of the patients), but mutations were not found in patients with symptoms in the bulbar region (typical PLS phenotype). Differentiating (sporadic) HSP from PLS based on other clinical characteristics was unreliable and therefore depends on genetic testing. Based on our observations and recent studies by other groups, we designed new diagnostic criteria for PLS, incorporating levels of certainty of diagnosis of PLS instead of HSP based on the distribution of UMN symptoms over body region. Our 3-year prospective study validated that classifying patients with a disease duration ?4 years is able to differentiate PLS from HSP in levels of certainty: typical PLS (UMN signs in at least the bulbar region), probable PLS (UMN signs in arms and legs), and possible PLS (UMN signs only in the legs). A disease duration