Primary Lateral Sclerosis

Original Editor - John-Carlo Caballes, David Castro, Alana Griffith, Joyce Tan, Joanne Van as part of the Queen's University Neuromotor Function Project Top Contributors - Joyce Tan, David Castro, John-Carlo Caballes, Kim Jackson, Alana Griffith, Joanne Van, Aminat Abolade, Rachael Lowe, WikiSysop, Claire Knott and Lucinda hampton

Definition / Description

Primary Lateral Sclerosis (PLS) is a neuromuscular disease characterized as a rare, non-hereditary, idiopathic, slow, and progressive degeneration of the upper motor neurons. PLS lies on a continuum of sporadic motor neurone diseases. 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. PLS itself is further subdivided into 5 diagnostic classifications, and these classifications arise from differences in both motor neuron signs and electromyogram (EMG) tests. Nonetheless, controversy continues to exist over whether PLS is a distinct pathological condition from ALS, but it is agreed upon that PLS is clinically distinct such that its prognosis is more benign and does not involve the lower motor neurons.

Epidemiology

• Approximately 2-5% of adults in neuromuscular clinics are diagnosed with PLS.
• The age of onset is approximately 50 years and older, though a juvenile-onset form of PLS has been identified 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, or ALS2, gene. The effects of this mutation manifest with maturity.

Clinical Presentation

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

• Spasticity
• Hyperreflexia
• Weakness

Other potential symptoms 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 from the time of diagnosis. 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. Many patients diagnosed with clinically pure PLS also continue to have high levels of independence for many years.

Diagnostic Procedures

In the case of diagnosing, the prognosis is the crucial differentiating factor between PLS and ALS. However, it is still common for patients to be diagnosed with PLS but later diagnosed with ALS instead, and vice versa. Due to the overlap in signs and symptoms, a misdiagnosis can occur.

The diagnostic criteria for PLS were proposed in 1992. Its use superseded the original criteria proposed in 1952 as it incorporated modern testing for diagnosis, and its use has continued since it was published. However, PLS is still not well defined and as such, the diagnostic criteria need to be further refined in order to reflect current clinical practice.

Pringle Criteria for PLS

Clinical	Insidious onset of spastic paresis beginning in the lower extremities but may appear in the bulbar or upper extremity first.
	Adult-onset, 50 years of age or later
	No family history of PLS
	Gradual progression of the disease
	Duration: 3 years or more.
	Clinical findings limited to those usually associated with corticospinal dysfunction
	Symmetrical distribution, ultimately developing severe spastic spinobulbar paresis
Laboratory (excludes other diagnoses)	Normal serum chemistries, which include normal vitamin B12 levels.
	Negative serologic tests for syphilis; in endemic areas, negative Lyme and human T-cell lymphocytotrophic virus-1 (HTLV-1) serologies.
	Normal cerebrospinal fluid parameters, including absence of oligoclonal bands.
	Absent denervation potentials on EMG or at most, occasional fibrillation and increased insertional activity in a few muscles (late and minor).
	Absence of compressive lesions of cervical spine or foramen magnum (spinal MRI scanning)
	Absence of high-signal lesions on MRI similar to those seen in multiple sclerosis.
Additional criteria suggestive of PLS	Normal bladder function
	Absent or very prolonged latency on cortical motor evoked responses in the presence of normal peripheral stimulus-evoked maximum compound muscle action potentials
	Focal atrophy of precentral gyrus on MRI
	Decreased glucose consumption in pericentral region on PET scan

5 diagnostic categories of PLS-spectrum disorders have also 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).

Outcome Measures

There are currently no standardized outcome measures for PLS. Instead, motor and respiratory measures have been used. This includes the following:

• Gait speed
• Finger tapping speed
• Vital capacity
• Non-invasive positive pressure ventilation (NIPPV)

In some studies, standardized measures designed for ALS have been used to study PLS.

• ALSFRS

Management / Interventions

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

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:

• Physical therapy
• 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
  

Currently, research has been done on the use of stem cells for treating ALS. Considering the similarities in presentation between ALS and PLS, stem cells areas a potential area of research for the treatment of PLS. Below is a testimonial video of an individual with PLS treated with stem cells. 

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 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.

Differential Diagnosis

As PLS is a condition that lies on a continuum of sporadic motor neuron disorders, there are several potential differential diagnoses. Therefore, special consideration must be taken during the diagnosing process as PLS is often misdiagnosed. The examples listed below are many of the misdiagnoses, but the two most likely upper motor neuron diseases associated with PLS are:

1. Amyotrophic lateral sclerosis (ALS)

• ALS presents with lower and upper motor neuron deficits and has a faster progression; PLS has a slower progression and typically affects only upper motor neurons.
• Individuals with ALS more commonly have stiffness (47% of patients) than those with PLS (4% of patients).
• Both ALS and PLS can be associated with cognitive issues, but deficits are not present in pure or 'uncomplicated' forms of PLS.

2. Hereditary spastic paraplegias (HSP)

• HSP results in spasticity of the lower limbs; PLS is associated with spasticity as well as 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 spondylomyelopathy)
• Infection (e.g. HIV, syphilis)
• Demyelinating disease (e.g. MS)
• Metabolic or toxic (e.g. vitamin E deficiency)
• Neurodegenerative (e.g. Parkinson’s Disease and Parkinson-plus syndromes)
  

Resources

• Interviews (videos and short biographies)
• Clinical Trials