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Understanding ALS

While our knowledge of the pathogenesis of ALS remains incomplete, new and exciting research continues to uncover information about the pathophysiology and underlying causes of ALS. As this understanding evolves, it’s imperative that we refine how we monitor, manage, and even define disease progression.1,2
 
ALS pathophysiology

Understanding ALS

While our knowledge of the pathogenesis of ALS remains incomplete, new and exciting research continues to uncover information about the pathophysiology and underlying causes of ALS. As this understanding evolves, it’s imperative that we refine how we monitor, manage, and even define disease progression.1,2
ALS pathophysiology
Pathophysiology
 

ALS Pathophysiology:
A Degenerative CNS Disease

ALS Affects Motor Neurons1

ALS is a devastating neurodegenerative disease primarily characterized by the degeneration of upper and lower motor neurons.
ALS motor neuron
ALS Disseminates Through the Motor System1,3

ALS begins as a focal process then spreads throughout the motor system, causing neuron loss – from the cortex, to the anterior horn of the spinal cord.
ALS progression variability
Symptom Progression1

The process of neurodegeneration may vary from patient to patient. However, symptom progression in different parts of the body can occur in an organized manner.
Symptom Onset3

The onset of ALS may be so subtle that the symptoms are overlooked. By the time the first symptoms of ALS are noticeable, the underlying pathophysiology has already resulted in neuronal damage.


Late Effects of Neurodegeneration1,2

Motor neurodegeneration eventually causes weakness of all voluntary muscles and progressive paralysis. ALS gradually spreads to muscles involved in speaking, swallowing, and breathing. The leading cause of death in ALS is respiratory failure.
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Possible Causes
of ALS
 

ALS Causes: Theorized Mechanisms
of Neurodegeneration1,2

Research suggests many factors may contribute to motor neuron cell deterioration, including:

ALS causes and mechanisms of neurodegeneration
  • Oxidative stress
  • Defective glutamate metabolism
  • Mitochondrial dysfunction
  • Genetic variations
  • Apoptosis
  • Altered protein and neurofilament metabolism
  • Autoimmune dysfunction
  • Inflammatory responses
ALS causes and mechanisms of neurodegeneration
  • Oxidative stress
  • Defective glutamate metabolism
  • Mitochondrial dysfunction
  • Genetic variations
  • Apoptosis
  • Altered protein and neurofilament metabolism
  • Autoimmune dysfunction
  • Inflammatory responses
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Signs of Differentiating
Diagnosis in ALS
 

Signs of Differentiating Diagnosis in ALS

The symptomatic onset and clinical presentation of ALS can resemble some forms of other neurological diseases, often leading to delayed diagnosis. This delay may result in patients missing the opportunity to begin addressing ALS-related symptoms earlier in their disease course.

Differentiating symptoms may help rule out similar diseases and expedite time to diagnosis.2,3

These include:
  • Painless progressive weakness
  • Changes in speech and swallowing
  • Atrophy
  • Weakness spreading from one myotome to another
  • Trouble rolling over in bed
  • Hand clenching that cannot be voluntarily released
  • Lack of bowel or bladder involvement in a spinal diagnosis3

Airlie House Criteria4

Clinically definite ALS has been defined by clinical or electrophysiological evidence, such as:


Clinically Definite ALS

Clinically Probable ALS

Probable ALS–Laboratory Supported

Clinically Possible ALS

Defined by clinical or electrophysiological evidence, such as:

  • The presence of lower motor neuron symptoms and upper motor neuron symptoms in the bulbar region and in at least 2 spinal regions
  • The presence of lower motor neuron symptoms and upper motor neuron symptoms in 3 spinal regions
    		•

    Defined by clinical or electrophysiological evidence of lower motor neuron symptoms and upper motor neuron symptoms in at least 2 regions with some upper motor neuron signs rostral to (or above) the lower motor neuron signs.

    Exists when clinical signs of upper motor neuron and lower motor neuron dysfunction are found in only 1 region, but electrophysiological signs of lower motor neuron are observed in at least 2 regions.

    Defined by clinical or electrophysiological evidence, as follows:

  • The presence of upper motor neuron and lower motor neuron dysfunction in only 1 region
  • The presence of upper motor neuron signs alone in at least 2 regions
  • The presence of signs above the upper motor neuron signs
    		•
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    Preserving
    Function
     

    The Importance of Maintaining Function

    There are several reasons why preserving functional status has emerged as a widely used clinical outcome. For one, according to patient surveys, the desire for preserving physical function should be the most important aim in treating ALS, as prolongation of survival with severe disability may not be meaningful.5

    Moreover, a decline in functional ability is a valuable indicator of disease progression.1,2
    Research has demonstrated that a person's functional status correlates with quality of life and can aid in predicting survival time.2
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    NEXT: ASSESSING ALS FUNCTION
    REFERENCES: 1. ALS Society of Canada. A guide to ALS patient care for primary care physicians. Accessed August 2020 at: https://als.ca/wp-content/uploads/2017/02/A-Guide-to-ALS-Patient-Care-For-Primary-Care-Physicians-English.pdf 2. Zarei S, Carr K, Reiley L, et al. A comprehensive review of amyotrophic lateral sclerosis. Surg Neurol Int 2015;6:171. 3. ALS Society of Canada. A manual for people living with ALS. Accessed August 2020 at: https://als.ca/wp-content/uploads/2017/02/2012-Manual-People-Living-With-ALS-English.pdf 4. Brooks BR, Miller RG, Swash M, et al. El escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1(5):293-299. 5. Leigh PN, Swash M, Iwasaki Y, et al. Amyotrophic lateral sclerosis: a consensus viewpoint on designing and implementing a clinical trial. Amyotroph Lateral Scler Other Motor Neuron Disord 2004;5:84-98.