Primary Lateral Sclerosis: Difference between revisions

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== Definition / Description<br>  ==
== Definition / Description<br>  ==


Primary Lateral Sclerosis (PLS) is characterized as being a rare, non-hereditary, idiopathic, slow, and progressive degeneration of the upper motor neurons<ref name="statland et al.">Statland, JM, Barohn, RJ, Dimachkie, MM, Floeter, MK, Mitsumoto, H. Primary lateral sclerosis. Neurol Clin. 2015 Nov;33(4):749-60. [https://www.ncbi.nlm.nih.gov/pubmed/26515619 PMID: 26515619]</ref>. 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<ref name="gordon et al.">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. [http://dx.doi.org/10.1212/01.wnl.0000200962.94777.71 doi: 10.1212/01.wnl.0000200962.94777.71]</ref>.<br>  
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<ref name="statland et al.">Statland, JM, Barohn, RJ, Dimachkie, MM, Floeter, MK, Mitsumoto, H. Primary lateral sclerosis. Neurol Clin. 2015 Nov;33(4):749-60. [https://www.ncbi.nlm.nih.gov/pubmed/26515619 PMID: 26515619]</ref>. 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<ref name="gordon et al.">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. [http://dx.doi.org/10.1212/01.wnl.0000200962.94777.71 doi: 10.1212/01.wnl.0000200962.94777.71]</ref>.<br>  


== Clinically Relevant Anatomy  ==
== Clinically Relevant Anatomy  ==
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The exact cause of adult-onset PLS remains unknown<ref name="singer et al." />. 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 exact cause of adult-onset PLS remains unknown<ref name="singer et al." />. 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<ref name="singer et al." />. The effects of this mutation manifests with maturity.


== Mechanism of Injury / Pathological Process<br>  ==
== Mechanism of Injury / Pathological Process<br>  ==
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== Clinical Presentation  ==
== 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<ref name="statland et al." />. These include;
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<ref name="statland et al." />. These include:


*Spasticity  
*Spasticity  
Line 34: Line 36:
*Weakness
*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 to the lower cranial nerves<ref name="statland et al." />. Bulbar signs and symptoms include;
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<ref name="statland et al." />. Bulbar signs and symptoms include:


*Dysphagia  
*Dysphagia  
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*Pseudobulbar affect/ emotional lability
*Pseudobulbar affect/ emotional lability


PLS is classified as slowly progressive. The typical pattern of progression is spreading from side to side, region to region<ref name="statland et al." />. It may start in the bulbar region and descend down to the limbs, or it may start in the lower extremities, progress to arms, and then bulbar region. Symptoms spread slowly over many years before plateauing<ref name="statland et al." />. <br><br>  
PLS is classified as slowly progressive. The typical pattern of progression is spreading from side to side, region to region<ref name="statland et al." />. 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<ref name="statland et al." />. <br><br>  


== Prognosis  ==
== 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<ref name="singer et al." />. 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 EMG 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, misdiagnosis can occur. A detailed spectrum of PLS categories have been detailed<ref name="gordon et al." /><ref name="singer et al." /><span style="font-size: 13.28px;">.</span>  
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<ref name="singer et al." />. 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<ref name="gordon et al." /><ref name="singer et al." /><span style="font-size: 13.28px;">.</span>  


== Diagnostic Procedures  ==
== Diagnostic Procedures  ==
5 diagnostic categories of PLS-spectrum disorders has been suggested<ref name="gordon et al." /><ref name="singer et al." />. A more detail look of the conditions can be found in the study by Gordon et al. (2006).
<br>
{| width="700" border="1" cellpadding="1" cellspacing="1"
|+ '''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 &lt;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).
|}


<br>  
<br>  
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=== Physical Therapy  ===
=== Physical Therapy  ===


Physical therapist directed treatment for patients with Primary Lateral Sclerosis (PLS) should be symptom-directed as treatments, to date, have neither shown a cure nor a slowing down of the disease’s progression <ref name="singer et al." />. 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 <ref name="Stevenson">Stevenson VL. Rehabilitation in practice: spasticity management. Clin Rehabil. 2010 Apr;24(4):293-304. [http://dx.doi.org/10.1177/0269215509353254 doi: 10.1177/0269215509353254]</ref>. Fortunately, spasticity and muscle weakness are symptoms that are treatable by physical therapists through physical interventions that include active or passive movement (depending on which one the patient can tolerate) 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.  
Physical therapist directed treatment for patients with Primary Lateral Sclerosis (PLS) should be symptom-directed as treatments, to date, have neither shown a cure nor a slowing down of the disease’s progression<ref name="singer et al." />. 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<ref name="Stevenson">Stevenson VL. Rehabilitation in practice: spasticity management. Clin Rehabil. 2010 Apr;24(4):293-304. [http://dx.doi.org/10.1177/0269215509353254 doi: 10.1177/0269215509353254]</ref>. Fortunately, spasticity and muscle weakness are symptoms that are treatable by physical therapists through physical interventions that include active or passive movement (depending on which one the patient can tolerate) 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.  


<br>Swallowing therapy may also be used in patients experiencing symptoms of dysphagia to prevent the progression towards feeding-tube placement <ref name="singer et al." />. Studies have used techniques such as swallowing with resistance, improving larynx elevation, and progressive strengthening of the tongue and suprahyoid muscles as exercise-based swallowing interventions to improve functional swallowing and swallowing physiology <ref name="Madhavan">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. [https://www.ncbi.nlm.nih.gov/pubmed/22956864 PMID: 22956864]</ref>. The use of electrical stimulation to facilitate muscle contraction during swallowing has also been shown to reduce dependence on feeding tubes and aspirations, albeit in smaller sample sizes.  
<br>Swallowing therapy may also be used in patients experiencing symptoms of dysphagia to prevent the progression towards feeding-tube placement<ref name="singer et al." />. Studies have used techniques such as swallowing with resistance, improving larynx elevation, and progressive strengthening of the tongue and suprahyoid muscles as exercise-based swallowing interventions to improve functional swallowing and swallowing physiology<ref name="Madhavan">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. [https://www.ncbi.nlm.nih.gov/pubmed/22956864 PMID: 22956864]</ref>. The use of electrical stimulation to facilitate muscle contraction during swallowing has also been shown to reduce dependence on feeding tubes and aspirations, albeit in smaller sample sizes.  


=== Medical / Surgical  ===
=== Medical / Surgical  ===
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*Physical therapy
*Physical therapy


Ultimately, patients are best managed in a multidisciplinary motor neuron disease clinic where the various potential symptoms of primary lateral sclerosis could be comprehensively addressed <ref name="singer et al." />. <br>  
Ultimately, patients are best managed in a multidisciplinary motor neuron disease clinic where the various potential symptoms of primary lateral sclerosis could be comprehensively addressed<ref name="singer et al." />. <br>  


== Differential Diagnosis<br>  ==
== Differential Diagnosis<br>  ==
Line 79: Line 111:
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 that is associated with PLS are:  
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 that is associated with PLS are:  


1. Amyotrophic lateral sclerosis (ALS)&nbsp;<ref name="statland et al." /><ref name="Strong et al">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. [https://www.ncbi.nlm.nih.gov/pubmed/16036421 PMID: 16036421]</ref>  
1. Amyotrophic lateral sclerosis (ALS)<ref name="statland et al." /><ref name="Strong et al">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. [https://www.ncbi.nlm.nih.gov/pubmed/16036421 PMID: 16036421]</ref>  


*ALS presents with lower and/or upper motor deficits and has fast(er) progression; PLS is slower progression and typically only affects upper motor neurons&nbsp;<ref name="statland et al." />.  
*ALS presents with lower and/or upper motor deficits and has fast(er) progression; PLS is slower progression and typically only affects upper motor neurons.  
*ALS is more commonly associated with stiffness then PLS (47% vs 4%)<ref name="statland et al." />.  
*ALS is more commonly associated with stiffness then PLS (47% vs 4%).  
*Both ALS and PLS can be associated with cognitive issues but is not present in its ‘uncomplicated’ forms<ref name="Strong et al" />.
*Both ALS and PLS can be associated with cognitive issues but is not present in its ‘uncomplicated’ forms.


2. Hereditary spastic paraplegias (HSP)&nbsp;<ref name="Strong et al" />  
2. Hereditary spastic paraplegias (HSP)<ref name="Strong et al" />  


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


Other potential, but less specific, differential considerations include <ref name="statland et al." />:<br>  
Other potential, but less specific, differential considerations include<ref name="statland et al." />:<br>  


*Structural lesions, especially related to the spine (eg. cervical spondylmyelopathy)  
*Structural lesions, especially related to the spine (eg. cervical spondylmyelopathy)  

Revision as of 07:50, 7 May 2017

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

Lead Editors  

Definition / Description
[edit | edit source]

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[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. Many patients diagnosed with PLS continue to have high levels of independence for many years[2].

Clinically Relevant Anatomy[edit | edit source]


Epidemiology[3][edit | edit source]

  • 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[edit | edit source]

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, orALS2, gene[3]. The effects of this mutation manifests with maturity.

Mechanism of Injury / Pathological Process
[edit | edit source]


Clinical Presentation[edit | edit source]

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[1]. 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[1]. 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[edit | edit source]

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. 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[2][3].

Diagnostic Procedures[edit | edit source]

5 diagnostic categories of PLS-spectrum disorders has been suggested[2][3]. A more detail look of the conditions can be found in the study by Gordon et al. (2006).


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 <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[edit | edit source]


Management / Interventions
[edit | edit source]

Physical Therapy[edit | edit source]

Physical therapist directed treatment for patients with Primary Lateral Sclerosis (PLS) should be symptom-directed as treatments, to date, have neither shown a cure nor a slowing down of 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[4]. Fortunately, spasticity and muscle weakness are symptoms that are treatable by physical therapists through physical interventions that include active or passive movement (depending on which one the patient can tolerate) 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 techniques such as swallowing with resistance, improving larynx elevation, and progressive strengthening of the tongue and suprahyoid muscles as exercise-based swallowing interventions to improve functional swallowing and swallowing physiology[5]. The use of electrical stimulation to facilitate muscle contraction during swallowing has also been shown to reduce dependence on feeding tubes and aspirations, albeit in smaller sample sizes.

Medical / Surgical[edit | edit source]

Currently, there is no cure for primary lateral sclerosis. Therefore, treatment primarily focuses on relieving symptoms and preserving function. Depending on the patient’s presentation, treatments may include the following[1]:

  • 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

Ultimately, patients are best managed in a multidisciplinary motor neuron disease clinic where the various potential symptoms of primary lateral sclerosis could be comprehensively addressed[3].

Differential Diagnosis
[edit | edit source]

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 that is associated with PLS are:

1. Amyotrophic lateral sclerosis (ALS)[1][6]

  • ALS presents with lower and/or upper motor deficits and has fast(er) progression; PLS is slower progression and typically only affects upper motor neurons.
  • ALS is more commonly associated with stiffness then 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)[6]

  • HSP has spasticity of the lower limbs; PLS is associated with spasticity as well and slight weakness but spasticity can affect speech (spastic dysarthria).
  • Complicated cases of HSP can result in dementia & 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 related to the spine (eg. cervical spondylmyelopathy)
  • Infection (eg. HIV, syphilis)
  • Demyelinating disease (eg. MS)
  • Metabolic / toxic (eg. vitamin E deficiency)
  • Neurodegenerative (eg. Parkinson’s and parkinson's-plus syndromes)

Special care must be taken when diagnosing as PLS can be misdiagnosed as the above examples, and many more[7].

Key Evidence[edit | edit source]


Resources
[edit | edit source]

Interviews with individuals with PLS (videos and short biographies)

Clinical Trials for individuals with PLS

Case Studies[edit | edit source]


Recent Related Research (from Pubmed)[edit | edit source]

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References
[edit | edit source]

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Statland, JM, Barohn, RJ, Dimachkie, MM, Floeter, MK, Mitsumoto, H. Primary lateral sclerosis. Neurol Clin. 2015 Nov;33(4):749-60. PMID: 26515619
  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 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. ↑ Stevenson VL. Rehabilitation in practice: spasticity management. Clin Rehabil. 2010 Apr;24(4):293-304. doi: 10.1177/0269215509353254
  5. ↑ 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
  6. ↑ 6.0 6.1 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
  7. ↑ 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. PMID: 11606672


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