Evolving diagnostic criteria in primary lateral sclerosis: The clinical and radiological basis of "probable PLS".

ABSTRACT

INTRODUCTION: Primary lateral sclerosis is a rare neurodegenerative disorder of the upper motor neurons. Diagnostic criteria have changed considerably over the years, and the recent consensus criteria introduced 'probable PLS' for patients with a symptom duration of 2-4 years. The objective of this study is the systematic evaluation of clinical and neuroimaging characteristics in early PLS by studying a group of 'probable PLS patients' in comparison to a cohort of established PLS patients. METHODS: In a prospective neuroimaging study, thirty-nine patients were stratified by the new consensus criteria into 'probable' (symptom duration 2-4 years) or 'definite' PLS (symptom duration >4 years). Patients were evaluated with a standardised battery of clinical instruments (ALSFRS-r, Penn upper motor neuron score, the modified Ashworth spasticity scale), whole genome sequencing, and underwent structural and diffusion MRI. The imaging profile of the two PLS cohorts were contrasted to a dataset of 100 healthy controls. All 'probable PLS' patients subsequently fulfilled criteria for 'definite' PLS on longitudinal follow-up and none transitioned to develop ALS. RESULTS: PLS patients tested negative for known ALS- or HSP-associated mutations on whole genome sequencing. Despite their shorter symptom duration, 'probable PLS' patients already exhibited considerable functional disability, upper motor neuron disease burden and the majority of them required walking aids for safe ambulation. Their ALSFRS-r, UMN and modified Ashworth score means were 83%, 98% and 85% of the 'definite' group respectively. Motor cortex thickness was significantly reduced in both PLS groups in comparison to controls, but cortical changes were less widespread in 'probable' PLS on morphometric analyses. Corticospinal tract and corpus callosum metrics were relatively well preserved in the 'probable' group in contrast to the widespread white matter degeneration observed in the 'definite' group. CONCLUSIONS: Our clinical and radiological analyses support the recent introduction of the 'probable' PLS category, as this cohort already exhibits considerable disability and cerebral changes consistent with established PLS. Before the publication of the new consensus criteria, these patients would have not been diagnosed with PLS on the basis of their symptom duration despite their significant functional impairment and motor cortex atrophy. The introduction of this new category will facilitate earlier recruitment into clinical trials, and shorten the protracted diagnostic uncertainty the majority of PLS patients face.