Primary Lateral Sclerosis

Original Editors - John-Carlo Caballes, David Castro, Alana Griffith, Joyce Tan, Joanne Van

Lead Editors  

Definition / Description

Primary Lateral Sclerosis (PLS) is a neuromuscular disease characterized as being a rare, non-hereditary, idiopathic, slow, and progressive degeneration of the upper motor neurons. PLS lies on a continuum of sporadic motor neuron disorders. This spectrum includes other disorders such as progressive muscular atrophy, which involves only lower motor neurons, as well as amyotrophic lateral sclerosis (ALS), characterized by both upper and lower motor neuron involvement. Many patients diagnosed with PLS continue to have high levels of independence for many years.

Epidemiology

• Approximately 2-5% of adults in neuromuscular clinics will be diagnosed with PLS.
• The age of onset is approximately 50 years and older, though a juvenile form of PLS has been described as well.
• Although the difference is not pronounced, there is a slight male predominance over females in being diagnosed with PLS.

Etiology

The exact cause of adult-onset PLS remains unknown. PLS is a diagnosis of exclusion, meaning that individuals are diagnosed with the condition when their progressive upper motor neuron dysfunctions cannot be explained by any other possible cause.

The juvenile form of PLS is thought to occur due to mutations in the alsin, orALS2, gene. The effects of this mutation manifests with maturity.

Clinical Presentation

PLS is due to upper motor neuron (UMN) degeneration, and therefore clinical presentation is consistent with signs and symptoms of an UMN disorder in the absence of lower motor neuron (LMN) symptoms. These include:

• Spasticity
• Hyperreflexia
• Weakness

Other key features include stiffness and increasing difficulty maintaining balance with the progression of the disorder. PLS may affect the bulbar region in the medulla, causing degeneration of the lower cranial nerves. Bulbar signs and symptoms include:

• Dysphagia
• Dysarthria
• Pseudobulbar affect/ emotional lability

PLS is classified as slowly progressive. The typical pattern of progression is spreading from side to side, region to region. It may start in the bulbar region and descend down to the limbs, or it may start in the lower extremities, progress to the arms, and then the bulbar region. Symptoms spread slowly over many years before plateauing.

Prognosis

A distinctive clinical feature of PLS is that it has a very slow progression, leading it to be considered to have a more benign prognosis in comparison to ALS. The longevity of individuals with PLS is unclear, but it has been estimated to be 7.9 years or longer. Individuals with PLS and minimal electromyogram (EMG) test changes appear to have a decreased ability to ambulate independently in comparison to those without EMG changes. Nonetheless, patients may still be able to ambulate without aids after several years of being diagnosed.

It is common for patients to be diagnosed with PLS but later diagnosed with ALS instead. Due to their similar course of progression, a misdiagnosis can occur. A detailed spectrum of PLS categories have been described below.

Diagnostic Procedures

5 diagnostic categories of PLS-spectrum disorders has been suggested.

Diagnostic Categories of PLS

Diagnostic Category	Description
Autopsy-proven PLS	Clinically diagnosed PLS with motor cortex and corticospinal tract degeneration. No motor neuron loss, no anterior horn cell gliolosis, and absence of Bunina bodies or ubiquitinated inclusions.
Clinically pure PLS	UMN signs without focal muscle atrophy or visible fasciculations. No evidence of EMG denervation at 4 or more years from the onset of symptoms. Age of onset is after 40 years.
UMN-dominant ALS	Symptoms lasting less than 4 years, or disability resulting mainly from UMN signs with minor EMG denervation or LMN signs that do not meet diagnostic criteria for ALS.
PLS plus	Dominant UMN signs with clinical, laboratory, or pathological evidence of dementia, parkinsonism, or sensory tract abnormalities.
Symptomatic lateral sclerosis	Clinically diagnosed PLS with an identifiable probable cause (e.g. HIV infection).

Management / Interventions

Ultimately, patients are best managed in a multidisciplinary motor neuron disease clinic where the various potential symptoms of PLS could be comprehensively addressed.

Physical Therapy

Physical therapy treatment for patients with PLS should be symptom-directed as treatments to date have neither shown to cure nor slow down the disease’s progression. The common symptoms of PLS include leg weakness, spasticity, spastic bulbar weakness, dysarthria, dysphagia, urinary urgency, and incontinence. Poorly managed spasticity, for example, can lead to soft tissue contractures, immobility, and a decrease in function. Fortunately, spasticity and muscle weakness are symptoms that can be treated by physical therapists through physical interventions, including active or passive movement (dependent on patient tolerance) and muscle strengthening. These types of interventions will help minimize changes by maintaining the range of movement and preventing the formation of contractures. Alternatively, physical therapists may also consider splinting if the patient experiences frequent spasms.

Swallowing therapy may also be used in patients experiencing symptoms of dysphagia to prevent the progression towards feeding-tube placement. Studies have used exercise-based swallowing intervention techniques such as swallowing with resistance, improving larynx elevation, and progressive strengthening of the tongue and suprahyoid muscles to improve functional swallowing and swallowing physiology. The use of electrical stimulation to facilitate muscle contraction during swallowing has additionally been shown to reduce dependence on feeding tubes and aspirations, albeit in smaller sample sizes.

Medical / Surgical

Currently, there is no cure for PLS. Therefore, treatment primarily focuses on relieving symptoms and preserving function. Depending on the patient’s presentation, treatments may include the following:

• Oral medications such as balcofen, dantrolene, and tizanadine for muscle spasticity
• Surgically implanted balcofen pump
• Anticholinergic medication or botulism toxin injections for drooling
• Feeding tube for dysphagia
• Assistive devices such as walkers or wheelchairs for gait impairments
• Physical therapy
  

Differential Diagnosis

As PLS is a condition that lies on a continuum of sporadic motor neuron disorders, there are several potential differential diagnosis. The 2 most likely upper motor neuron diseases associated with PLS are:

1. Amyotrophic lateral sclerosis (ALS)

• ALS presents with lower and/or upper motor neuron deficits and has a faster progression; PLS has a slower progression and typically affects only upper motor neurons.
• ALS is more commonly associated with stiffness than PLS (47% vs. 4%).
• Both ALS and PLS can be associated with cognitive issues but is not present in its ‘uncomplicated’ forms.

2. Hereditary spastic paraplegias (HSP)

• HSP results in spasticity of the lower limbs; PLS is associated with spasticity as well and slight weakness, but spasticity can additionally affect speech (spastic dysarthria).
• Complicated cases of HSP can result in dementia and mental retardation which may mimic cognitive issues possibly present in complicated cases of PLS.

Other potential, but less specific, differential considerations include:

• Structural lesions, especially those related to the spine (e.g. cervical spondylmyelopathy)
• Infection (e.g. HIV, syphilis)
• Demyelinating disease (e.g. MS)
• Metabolic / toxic (e.g. vitamin E deficiency)
• Neurodegenerative (e.g. Parkinson’s Disease and Parkinson-plus syndromes)

Special care must be taken when diagnosing due to the possibility of PLS being misdiagnosed as one of the above examples.

Resources

Interviews with individuals with PLS (videos and short biographies)

• http://www.healthtalk.org/peoples-experiences/nerves-brain/motor-neurone-disease-mnd/peoples-profiles/rarer-forms-pls-primary-lateral-sclerosis

Clinical Trials for individuals with PLS

• https://clinicaltrials.gov/ct2/results?term=Primary+Lateral+Sclerosis&Search=Search