Primary Lateral Sclerosis: An Overview

Abstract

Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder which causes the selective deterioration of the upper motor neurons (UMNs), sparing the lower motor neuron (LMN) system. The clinical course is defined by a progressive motor disability due to muscle spasticity which typically involves lower extremities and bulbar muscles. Although classically considered a sporadic disease, some familiar cases and possible causative genes have been reported. Despite it having been recognized as a rare but distinct entity, whether it actually represents an extreme end of the motor neuron diseases continuum is still an open issue. The main knowledge gap is the lack of specific biomarkers to improve the clinical diagnostic accuracy. Indeed, the diagnostic imprecision, together with some uncertainty about overlap with UMN-predominant ALS and Hereditary Spastic Paraplegia (HSP), has become an obstacle to the development of specific therapeutic trials. In this study, we provided a comprehensive analysis of the existing literature, including neuropathological, clinical, neuroimaging, and neurophysiological features of the disease, and highlighting the controversies still unsolved in the differential diagnoses and the current diagnostic criteria. We also discussed the current knowledge gaps still present in both diagnostic and therapeutic fields when approaching this rare condition.

Keywords: ALS; hereditary spastic paraplegia; motor neuron disease; primary lateral sclerosis; review.

Figure 1

Diagram showing the possible genetic work-up in PLS (only genes for which pathogenic variants have been reported are mentioned).

Figure 2

Current diagnostic criteria for PLS [7]. UMN: upper motor neuron; LMN: lower motor neuron. * Minimally increased insertional activity and positive sharp waves or fibrillation potentials in extremity muscles are allowed.

Figure 3

MRI in a PLS patient. (A) Sagittal T1 sequence showing atrophy of primary motor cortex with enlargement of central sulcus (white arrow). (B) Coronal flair sequence showing bilateral corticospinal tract hyperintensities (black arrows).