For Healthcare Professionals
 

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
 
ALS pathophysiology

Rethinking 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
ALS pathophysiology
Pathophysiology
 

ALS Pathophysiology:
A Degenerative CNS Disease

ALS Affects Motor Neurons
ALS is a devastating neurodegenerative disease 
primarily characterized by the degeneration 
of upper motor neurons and lower motor neurons.2
ALS motor neuron
ALS Disseminates Through the Motor System
ALS begins as a focal process, then spreads throughout the motor system, causing neuron loss at all levels of the motor system, from the cortex to the anterior horn of the spinal cord.2,3
ALS progression variability
Symptom Progression

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.4,5
Symptom Onset

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.4,6

Late Effects of Neurodegeneration

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.4
Possible Causes
of ALS
 

ALS Causes: Theorized Mechanisms
of Neurodegeneration1

Research suggests many factors may contribute to motor neuron cell deterioration, including7

ALS causes and mechanisms of neurodegeneration
  • Oxidative stress
  • Defective glutamate metabolism
  • Mitochondrial dysfunction
  • Genetic variations
  • Apoptosis
  • Cytoskeletal protein defects preventing normal cell movement and division
  • Autoimmune dysfunction
  • Inflammatory responses
ALS causes and mechanisms of neurodegeneration
  • Oxidative stress
  • Defective glutamate metabolism
  • Mitochondrial dysfunction
  • Genetic variations
  • Apoptosis
  • Cytoskeletal protein defects preventing normal cell movement and division
  • Autoimmune dysfunction
  • Inflammatory responses
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—when they may be more likely to benefit from potential treatments.8

Differentiating symptoms may help rule out similar diseases and expedite time to diagnosis.
  • Painless progressive weakness9
  • Changes in speech and swallowing9,10
  • Atrophy4,9
  • Weakness spreading from one mytome to another11
  • Trouble rolling over in bed4
  • Hand clenching that cannot be voluntarily released4,9
  • Lack of bowel or bladder involvement in a spinal diagnosis9

Arlie House Criteria

Clinically definite ALS has been defined by clinical or electrophysiological evidence, such as10:

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

Clinically probable ALS has been 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 above the lower motor neuron signs.10

Probable ALS–Laboratory Supported 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.10

Clinically possible ALS has been defined by clinical or electrophysiological evidence, such as10

  • 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
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 preservation of physical function should be the most important aim in treating ALS, as prolongation of survival with severe disability may not be meaningful.12

Moreover, measuring decline in functional ability is a valuable indicator of disease progression.
Research has demonstrated that a person's functional status correlates with quality of life and predicts survival time.1,13
References: 1. Beghi E, Mennini T, Bendotti C, et al. The heterogeneity of amyotrophic lateral sclerosis: a possible explanation of treatment failure. Curr Med Chem. 2007;14(30):3185-3200. 2. Sabatelli M, Conte A, Zollino M. Clinical and genetic heterogeneity of amyotrophic lateral sclerosis. Clin Genet. 2013;83(5):408-416. 3. Mitchell JD, Borasio GD. Amyotrophic lateral sclerosis. Lancet. 2007;369:2031-2041. 4. Amyotrophic lateral sclerosis (ALS) fact sheet. National Institute of Neurological Disorders and Stroke website. https://www.ninds.nih.gov/disorders/patient-caregiver-education/fact-sheets/amyotrophic-lateral-sclerosis-als-fact-sheet. Accessed April 13, 2017. 5. Walhout R, Verstraete E, Van Den Heuvel M, et al. Patterns of symptom development in patients with motor neuron disease. Amyotroph Lateral Scler Frontotemporal Degener. 2018;19(1-2):21-28. doi:10.1080/21678421.2017.1386688 6. Bae JS,  Simon NG, Menon P, et al. The puzzling case of hyperexcitability in amyotrophic lateral sclerosis. J Clin Neurol. 2013;9(2):65-74. 7. Outcome measures. European Network to Cure ALS website. https://www.encals.eu/outcome-measures/. Accessed October 1, 2018.  8. Paganoni S, Macklin E, Lee A, et al. Diagnostic timelines and delays in diagnosing amyotrophic lateral sclerosis (ALS). Amyotroph Lateral Scler Frontotemporal Degener. 2014;15(0):453-456. 9. Armon C. Amyotrophic lateral scelerosis clinical presentation. Medscape website. https://emedicine.medscape.com/article/1170097-clinical?pa=DwTiyVVRev3ILpiV. Accessed February 8, 2018. 10. Costa J, Swash M, de Carvalho M. Awaji criteria for the diagnosis of amyotrophic lateral sclerosis: a systematic review. Arch Neurol. 2012;69(11):1410-1416. 11. Kanouchi T, Ohkubo T, Yokota T. Can regional spreading of amyotrophic lateral sclerosis motor symptoms be explained by prion-like propagation? J Neurol Neurosurg Psychiatry. 2012;83(7):739-745. 12. 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(2):84-98. 13. Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. J Neurol Sci. 1999;169(1-2):13-21.