Primary lateral sclerosis (PLS) is a rare, slowly progressive motor neuron disease that selectively affects the upper motor neurons in the brain and spinal cord. It produces a gradually worsening picture of stiffness and spasticity, mild voluntary muscle weakness, exaggerated reflexes, and impaired speech and swallowing, while sparing — at least early on — the lower motor neurons that ALS attacks. PLS is most often diagnosed in adults and is considered idiopathic and non-familial, though a separate juvenile-onset form and a designated adult subtype have been described and are managed as related but distinct entities. Some clinicians regard PLS as part of the broader ALS spectrum because a subset of individuals develop lower motor neuron involvement years after initial diagnosis.

Symptoms typically begin in the legs and ascend gradually over years, producing stiffness, slow movements, balance problems, and a spastic gait. Hand clumsiness and reduced dexterity may follow. Bulbar involvement causes slurred or strained speech, voice changes, and swallowing difficulty. Hyperreflexia, increased muscle tone, and pseudobulbar affect (involuntary laughing or crying) are common. Severe muscle wasting, prominent fasciculations, and rapid weakness are not characteristic of PLS and, when present, suggest an alternative diagnosis. Not all individuals experience all features, and the rate of progression varies considerably.

PLS is acquired and sporadic in the great majority of adults, and the underlying cause is not known. It is not inherited in classical Mendelian fashion. Research suggests selective degeneration of upper motor neuron pathways in the motor cortex and corticospinal tracts, but the trigger for that degeneration has not been identified. Distinct genetic forms — including juvenile primary lateral sclerosis and a designated adult subtype — exist as separate clinical entities and are evaluated independently when family history or early onset suggests them.

PLS is a clinical diagnosis made by a neurologist after a sustained period of observation, because the condition can only be distinguished from related disorders once its slow, upper motor neuron–predominant course has declared itself. Evaluation typically includes a detailed neurological exam, brain and spinal cord MRI to exclude structural lesions, and electromyography and nerve conduction studies, which by definition should not show widespread lower motor neuron denervation in PLS. The differential diagnosis is essential and includes amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia, multiple sclerosis, structural compressive lesions of the cervical cord, and other myelopathies; targeted testing — including, in selected patients, genetic studies for hereditary spastic paraplegia or juvenile motor neuron disorders — is used to rule these in or out. Many centers require several years of pure upper motor neuron features before assigning a definitive PLS diagnosis. Additional testing is often needed to confirm the diagnosis.

There is no FDA-approved disease-modifying therapy for primary lateral sclerosis, and care is supportive and multidisciplinary. Management focuses on reducing spasticity (with agents such as baclofen, tizanidine, or botulinum toxin injections under specialist supervision), maintaining mobility through physical therapy and assistive devices, and addressing speech and swallowing changes with speech-language pathology. Occupational therapy supports daily function, and psychosocial support helps with the emotional impact of a slowly progressive condition. Cramps, pseudobulbar affect, and sialorrhea are managed symptomatically. Patients should discuss treatment options with their healthcare team to determine which therapies may be appropriate, and care is best coordinated through a neuromuscular or motor neuron disease clinic.

PLS typically progresses slowly over many years, and overall life expectancy is generally longer than in ALS, often substantially so. Disability accumulates gradually, with mobility, communication, and swallowing affected over time. A subset of individuals initially diagnosed with PLS develop lower motor neuron involvement years later, at which point the diagnosis may be revised toward ALS; this is one reason long-term neurological follow-up is recommended.

Research in PLS is challenging because the condition is rare, slowly progressive, and clinically overlapping with ALS, and many motor neuron disease trials enroll PLS and ALS together. Active areas include biomarker development to distinguish PLS from ALS earlier, neuroimaging of the corticospinal tract, and evaluation of neuroprotective and symptomatic therapies. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility, recognizing that most listings under the broader "lateral sclerosis" search are ALS studies and that PLS-specific eligibility should be confirmed with the trial team.