IT / EN
Close
IT / EN
Menu

Primary Lateral Sclerosis (PLS) (Ist. Auxologico)

Primary Lateral Sclerosis (PLS) is a neurodegenerative pathology involving the upper motor neuron (1st MN), which leads to the progressive onset of spasticity in both the limbs and the bulbar musculature. This results in the impairment of gait, hand motility, speech (eloquence), and swallowing (dysphagia). Essentially a sporadic disease, it is also characterized by cognitive and behavioral involvement. As a long-course disease, it must be carefully differentiated from the more severe Amyotrophic Lateral Sclerosis (ALS). The IRCCS Istituto Auxologico Italiano contributed to defining the latest guidelines for the disease (Turner et al., 2021) and provided a substantial contribution to the formulation of the new directives (Scirocco et al., 2025).

The etiology of Primary Lateral Sclerosis (PLS) is unknown, involving a combination of genetic and environmental factors. The primary pathological hallmark is the formation of TDP-43 protein aggregates in the motor cortex, resulting in neuronal loss.

The mechanisms responsible for the cytoplasmic translocation of TDP-43 and the subsequent formation of aggregates are multifaceted and have been variously identified as:

  • Excitotoxicity

  • Oxidative stress

  • Neuroinflammation

  • Mitochondrial dysfunction

PLS manifests with the onset of progressive spasticity and weakness (hyposthenia) in a limb or multiple limbs, and/or difficulty articulating speech and/or difficulty swallowing. Symptoms tend to spread, with progressive impairment of mobility due to spasticity, leading to difficulties in walking, grasping objects, articulating speech, and consuming food. The course of the disease is very prolonged but ultimately leads to a state of significant motor disability.

The diagnosis of PLS is achieved through clinical and anamnestic assessment, accompanied by:

  • Neuropsychological evaluation

  • Neuroimaging: MRI of the brain (and the entire spinal cord)

  • Electromyography (EMG)

  • Motor Evoked Potentials (MEP)

  • Genetic testing, if the medical history suggests a familial pattern

  • Biomarker acquisition: Light-chain neurofilaments (NfL) in the cerebrospinal fluid (CSF)

Available therapies

Available therapies are symptomatic for spasticity and include the use of baclofen, tizanidine hydrochloride, and dantrolene sodium. In selected cases, an intrathecal baclofen pump may be considered if oral medications are insufficient.

Research in progress

  • Definition of the genetic basis underlying the pathology.

  • Definition of cerebrospinal fluid (CSF) and serum biomarkers (such as NfL – Light-chain Neurofilaments).

  • Neuroimaging for an in-depth characterization of cortical involvement.

Contacts and informations

Referents: Vincenzo Silani, Nicola Ticozzi, Claudia Morelli, Barbara Poletti, Alberto Doretti, Luca Maderna, Antonia Ratti

Email / Ph neuro.nelli@auxologico.it / 02 61911 2937

Link: auxologico.it (Motor Neuron Diseases)