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 a rare, non-hereditary, idiopathic, slow, and progressive degeneration of the upper motor neurons[1]. 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. PLS itself is further subdivided into 5 diagnostic classifications, and these classifications arise from differences in both motor neuron signs and electromyogram (EMG) tests[2]. 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[1].

Clinically Relevant Anatomy


Epidemiology[3]

  • 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[3]. 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[3]. The effects of this mutation manifests with maturity.

Mechanism of Injury / Pathological Process


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[1]. 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[1]. 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[1]. 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[1].

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[3]. 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[2].

Diagnostic Procedures

In the case of diagnosing, the prognosis is the crucial differentiating factor between PLS and ALS[3]. 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 was proposed in 1992[3][4]. 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 needs to be further refined in order to reflect current clinical practice[5].

Pringle Criteria for PLS[4]
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 includes 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[2][3]

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[6][7]. 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[7].

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[3].

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[1]:

  • 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[8]. Considering the similarities in presentation between ALS and PLS, stem cells is a potential area of research for the treatment for 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[3]. 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[9]. 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[3]. 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[10]. 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[1]. Therefore, special consideration must be taken during the diagnosing process as PLS is often misdiagnosed[11]. 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)[1][12]

  • 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)[12]

  • 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[1]:

  • 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)

Key Evidence


Resources

Interviews (videos and short biographies)

Clinical Trials

Case Studies


Recent Related Research (from Pubmed)

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References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 Statland JM, Barohn RJ, Dimachkie MM, Floeter MK, Mitsumoto H. Primary lateral sclerosis. Neurol Clin. 2015 Nov;33(4):749-60. PMC: 4628724
  2. 2.0 2.1 2.2 Gordon PH, Cheng B, Katz IB, Pinto M, Hays AP, Mitsumoto H, Rowland LP. The natural history of primary lateral sclerosis. Neurology. 2006 Mar;66(5):647-53. doi: 10.1212/01.wnl.0000200962.94777.71
  3. 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 Singer MA, Statland JM, Wolfe GI, Barohn RJ. Primary lateral sclerosis. Muscle Nerve. 2007 Jan;35(3):291-302. doi: 10.1002/mus.20728
  4. 4.0 4.1 Pringle CE, Hudson AJ, Munoz DG, Kiernan JA, Brown WF, Ebers GC. Primary lateral scelrosis: clinical features, neuropathology and diagnostic criteria. Brain. 1992 Apr;115:495-520. PMID: 1606479
  5. Wais V, Rosenbohm A, Petri S, Kollewe K, Hermann A, Storch A, Hanisch F, Zierz S, Nagel G, Kassubek J, Weydt P, Brettschneider J, Weishaupt JH, Ludolph AC, Dorst J. The concept and diagnostic criteria of primary lateral sclerosis. Acta Neurol Scand. 2016 Nov;00:1-8. doi: 10.1111/ane.12713
  6. Floeter MK, Mills R. Progression in primary lateral sclerosis: a prospective analysis. Amyotroph Lateral Sc. 2009 Oct;10(5-6):339-46. PMC: 3434688
  7. 7.0 7.1 Fournier CN, Murphy A, Loci L, Mitsumoto H, Lomen-Hoerth C, Kisanuki Y, Simmons Z, Maragakis NJ, McVey AL, Al-Lahham T, Heiman-Patterson TD, Andrews J, McDonnell E, Cudkowicz M, Atassi N. Primary lateral sclerosis and early upper motor neuron disease: characteristics of a cross-sectional population. J Clin Neuromuscul Dis. 2016 Mar;17(3):99-105. doi: 10.1097/CND.0000000000000102
  8. Czarzasta J, Habich A, Siwek T, Czaplinski A, Maksymowicz W, Wojtkiewicz J. Stem cells for ALS: an overview of possible therapeutic approaches. Int J Dev Neurosci. 2017 Jan;57:46-55. PMID: 2808836
  9. Stevenson VL. Rehabilitation in practice: spasticity management. Clin Rehabil. 2010 Apr;24(4):293-304. doi: 10.1177/0269215509353254
  10. Sura L, Madhavan A, Carnaby G, Crary MA. Dysphagia in the elderly: management and nutritional considerations. Clin Interv Aging. 2012 Jan;7(7):287-98. PMID: 22956864
  11. Kuipers-Upmeijer J, de Jager A, Hew J, Snoek J, van Weerden T. Primary lateral sclerosis: clinical, neurophysiological, and magnetic resonance findings. J Neurol Neurosur Ps. 2001 Nov;71(5):615-20. PMC: 1737610
  12. 12.0 12.1 Strong MJ, Gordon PH. Primary lateral sclerosis, hereditary spastic paraplegia and amyotrophic lateral sclerosis: discrete entities or spectrum? Amyotroph Lateral Sc. 2005 Mar;6(1):8–16. PMID: 16036421