Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). Amyotrophic lateral sclerosis is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. This disease is characterized by the coexistence of UMN and LMN signs and symptoms. The diagnosis is made clinically. Management is supportive and symptomatic, progressing to end-of-life care.

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Overview

Definition

  • Neurodegenerative disease involving both upper motor neurons (UMNs) and lower motor neurons (LMNs)
  • Also known as Lou Gehrig’s disease
  • Progressive disease leading eventually to paralysis and subsequently death
  • There is no cure.

Classification

  • Sporadic (aka acquired): no other known occurrences of the disease within a family
  • Familial ALS: multiple occurrences of the disease within a family

Epidemiology

  • Most common progressive motor neuron disease
  • 90%–95% of cases are sporadic
  • 10% of cases are inherited as an autosomal dominant trait.
  • Prevalence: 5.2 per 100,000 in the United States
  • Incidence: 1.6 per 100,000 in the United States
  • Age at onset: 40 years
  • Men > Women: 1.3–1.5
  • Caucasians more commonly affected

Risk factors

  • Age
  • Family history
  • Cigarette smoking 

Etiology

The cause of sporadic ALS is unknown. However, there are multiple contributing factors:

  • Inherent instability of the mutant protein superoxide dismutase type 1 (SOD1), leading to free radical toxicity
  • Gene mutations perturb RNA processing, transport, and metabolism:
    • C9orf73
    • TDP-43
    • Fused in sarcoma (FUS)
  • Cascading inflammatory responses
  • Accelerated cell death
  • Excessive concentrations of glutamate
  • Familial ALS associated with:
    • C9orf72 gene expansion
    • SOD1 gene mutation

Pathophysiology

The exact pathogenic mechanism of ALS is unknown. There appear to be both molecular and genetic pathways that combine to cause UMN and LMN apoptosis. 

  • Molecular pathways:
    • Reduced uptake of glutamate from the synaptic cleft causes glutamate excitotoxicity
    • Mediated by poorly functioning excitatory amino acid transporter 2 (EAAT2) on astrocyte cell membranes
    • Ca2+-dependent enzymatic pathways are activated, inducing neurodegeneration 
  • Genetic pathways:
    • Mutations in the following genes are pathogenic:
      • C9orf72
      • TDP-43
      • FUS
    • These mutations cause dysregulation in RNA metabolism:
      • Abnormal translation ensues
      • Intracellular neuronal aggregates form
    • Mutations in the SOD1 gene is pathogenic:
      • Causes dysfunction of the mitochondria
      • Increases free radical → cellular oxidative stress
      • Further accumulation of intracellular aggregates
      • Axonal transport becomes defective
  • Microglial activation:
    • Abnormal secretion of proinflammatory cytokines
    • Cytokines further contribute to neurotoxicity
Pathophysiologic mechanism of ALS

Theories of ALS cellular pathophysiology:
1. Excitotoxicity from glutamate induces intracellular neurodegenerative enzymatic processes.
2. Monocyte-mediated activation of microglia causes secretion of proinflammatory cytokines.
3. Specific gene mutations cause abnormal RNA translation, leading to intranuclear protein aggregation as well as cytoplasmic protein aggregation (4).
5. Mitochondrial dysfunction ensues, rendering neurons unable to adapt to oxidative stress.
6. Intracellular aggregates impair axonal transport.
7. Defective axonal transport leads to ineffective activation of the target neuromuscular junction.

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Clinical Presentation

History

  • Affected individuals report:
    • Limb weakness
    • Cramping in the early morning
    • Gait instability
    • Falling
    • Fatigue when walking
    • Stiffness of the affected limb(s)
    • Incoordination of the affected limb(s)
  • Pain:
    • Commonly due to muscle spasticity or decreased mobility
    • Traumatic injury from falls is also a common source of pain. 
  • Average time between onset of symptoms and diagnosis is roughly 1 year. 

Physical examination

During the usual natural course of the disease, more muscle groups are affected with time, starting with an asymmetrical distribution of weakness, later becoming symmetrical. 

Neurologic examination

  • Coexistence of UMN and LMN signs
  • In bulbar-onset ALS: 
    • Speech difficulties (e.g., dysarthria)
    • Dysphagia and sialorrhea due to progressive weakening of the muscles of mastication and swallowing
    • Exaggeration of the motor expressions of emotion
    • Excessive forced yawning
    • Pseudobulbar affect (e.g., episodes of uncontrollable laughter or crying)
  • Frontotemporal dementia (frontal lobe dysfunction): 
    • Early behavioral abnormalities and personality changes 
    • Weight loss (predictor of poor outcome)
    • Poor executive functioning
  • Constipation due to immobility 
  • Extrapyramidal symptoms and parkinsonism before or after motor neuron manifestations
  • Pearl: Weakness is followed by muscle atrophy as the disease progresses.
Table: Motor neuron findings in ALS
UMN signLMN signs
Asymmetrical weakness (earliest sign) can be attributed to either one.
  • Spasticity (occurs in wasted muscles)
  • Slowed rapid alternating movements
  • Spastic gait
  • Spontaneous clonus
  • Hyperreflexia
  • Muscle atrophy
  • Fasciculations (good specificity)
  • Proximal arm and leg weakness
  • Poor heel and/or toe walking
  • Poor rise from chair
  • Foot drop
  • Waddling gait
  • Hyporeflexia

Diagnosis

Diagnosis is made with clinical presentation alone, but laboratory tests and imaging are typically performed to rule out other illnesses. 

Diagnostic criteria

The specific criteria for the diagnosis of ALS are also known as the El Escorial World Federation of Neurology criteria.

Inclusion criteria:

  • Clinical, electrophysical, or neuropathologic evidence of LMN degeneration
  • Clinical, electrophysical, or neuropathologic evidence of UMN degeneration
  • Evidence of progressive spread of symptoms or signs within a region or to other regions

Exclusion criteria:

  • Electrophysiologic or pathologic evidence of other disease processes that might explain the patient’s motor neuron degeneration
  • Neuroimaging evidence of other diseases that might explain the observed clinical and electrophysiologic signs

Laboratory evaluation

Used to rule out other disorders and include:

  • CBC
  • Serum CK concentration
  • Electrolytes: 
    • Calcium
    • Phosphate
    • Magnesium
  • VDRL test 
  • HIV screening
  • ACE
  • HbA1c
  • Thyroid function studies
  • Serum parathyroid hormone
  • Vitamin B12 level

Electromyography (EMG)

Evidence of acute denervation, chronic denervation, and chronic reinnervation supports ALS diagnosis.

Neuroimaging (MRI)

  • Mainly used to rule out other illnesses
  • Findings associated with ALS (T2-weighted):
    • Decreased intensity of the motor cortex, known as the “motor band sign”
    • Hyperintense lesions of the corticospinal tracts 

Genetic testing

  • Reserved as screening tool for patients with family history, as only a small proportion of cases of ALS is familial
  • Available gene testing covers only a small fraction of causative genes for ALS. 
  • C9orf72 genotype, in particular, occurs in a high percentage of those with sporadic ALS.

Management

No definitive treatment. Current management is symptomatic and supportive.

Respiratory management

  • Noninvasive ventilation (NIV) is considered in the following scenarios:
    • Onset of dyspnea
    • Orthopnea
    • Nocturnal hypoxia
    • Forced vital capacity (FVC) < 50%
  • Invasive ventilation is considered when noninvasive measures are not tolerated:
    • Secure airway: tracheostomy
    • Chronic ventilatory support

Medical therapy

Medical therapy is based on underlying conditions and clinical presentation.

  • Disease-specific:
    • Riluzole has been associated with improved survival (2–3 months). 
    • Has several sites of action: 
      • Blockade of presynaptic release of glutamate
      • Partial blockade of postsynaptic N-methyl-D-aspartate (NMDA) receptors
      • Blockade of Na channels 
  • Muscle spasm:
    • Mexiletine is an oral Na⁺ channel blocker used to treat muscle spasms.
    • Baclofen is an oral GABA agonist used to treat muscle spasms.
    • Botulinum toxin causes neuromuscular junction blockade; IM injections may be used to treat muscle spasms when oral intake is no longer possible. 
  • Sialorrhea:
    • Atropine is an anticholinergic; drops are given sublingually to treat sialorrhea.
    • Amitriptyline is an oral tricyclic antidepressant with anticholinergic properties used to treat sialorrhea.
  • Thick bronchial/mucous secretions:
    • Guaifenesin is an oral mucolytic used to manage thick mucous secretions.
    • N-acetylcysteine is a nebulized mucolytic used to manage thick bronchial secretions, especially when respiratory support equipment is in use. 
  • Pain management:
    • 1st line: antiinflammatory agents (e.g., NSAIDs)
    • 2nd line: opioid analgesics
    • Special mattresses, pillows, and wheelchairs may prevent onset of pain.
  • Depression:
    • Amitriptyline is a tricyclic antidepressant shown to improve quality of life in ALS.
    • Can simultaneously treat insomnia, sialorrhea, and pseudobulbar affect

Nonmedical therapy

Nutrition:

  • Adequate supplementation with calorie-dense foods
  • Percutaneous gastrostomy should be considered to decrease effects of dysphagia (e.g., weight loss and aspiration)

Physical therapy, occupational therapy, and communication therapy:

The overall goal of these therapies is to improve the ability to carry out activities of daily living for as long as possible. Different tools are used to do so.

Table: Therapeutic methods/tools and their purposes used in nonmedical therapy for ALS
ToolPurpose
Physical therapy and
Occupational therapy
  • Walker
  • Wheelchair
  • Assist in ambulation
  • Assist in mobilization
  • Wrist splints
  • Ankle splints
  • Prevent wrist drop
  • Prevent ankle drop

Cervical collar

Prevent head drop

  • Special mattresses
  • Special pillows
  • Maximize comfort
  • Prevent pressure ulcers
Communication therapy

Writing

Alternative to speaking as vocal quality declines

Alphabet boards

Alternative to speaking as vocal quality declines and writing becomes impaired

Electronic assistive communication devices

Voice-assist device as vocal quality declines

End-of-life care

  • Advance directives on care and death should be obtained as soon as the diagnosis is made (e.g., when to withdraw ventilator support, when to discontinue gastrostomy feedings). 
  • Opioids (e.g., morphine) and benzodiazepines (e.g., diazepam) are used to treat dyspnea and anxiety. 
  • Care at home increases the likelihood of a peaceful death.

Complications 

  • Need for mechanical ventilatory support
  • Malnutrition
  • Functional decline 

Prognosis

  • Relentlessly progressive
  • Median survival: 3–5 years 
  • Weight gain, younger age, and limb symptoms have been associated with improved survival. 
  • At least 30% of patients develop cognitive impairment.
  • Affected individuals ultimately die from respiratory paralysis.

Differential Diagnosis

  • Spinal muscular atrophy (SMA): spectrum of autosomal recessive syndromes characterized by progressive proximal muscle weakness and atrophy due to degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brain stem. There are 5 clinical types of SMA, each with their distinctive clinical presentation. Initial diagnosis is made clinically and then definitively with genetic testing. Management is mostly supportive, and prognosis depends on the clinical type. 
  • Myasthenia gravis: autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. Myasthenia gravis presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Diagnosis is clinical but confirmed with electrodiagnostic studies. Treatment is with acetylcholinesterase inhibitors and immune therapies. 
  • Lambert-Eaton myasthenic syndrome: autoimmune disorder affecting the neuromuscular junction with strong association to small cell lung carcinoma. This syndrome affects the voltage-gated calcium channels at the presynaptic membrane and presents with proximal muscle weakness and symptoms of autonomic dysfunction such as dry mouth and sluggish pupillary reflexes. Diagnosis includes electrodiagnostics and detection of antibodies. Management is symptomatic, using potassium channel blockers and immunosuppressants. 
  • Poliomyelitis: infectious disease caused by the poliovirus. The majority of individuals with poliomyelitis will be asymptomatic or have a mild, abortive presentation with flu-like symptoms. A very minor proportion of individuals will progress to paralytic poliomyelitis, with neurologic progression (including asymmetric flaccid paralysis). The diagnosis is determined by the clinical presentation and can be supported by viral culture, PCR, and serology. Current antivirals are ineffective, and management is supportive. The 2 available vaccines have almost eradicated this disease worldwide. 
  • Thyrotoxicosis: classic physiologic manifestations of excess thyroid hormones. Thyrotoxicosis is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of the thyroid hormones triiodothyronine (T3) and thyroxine (T4). Clinical features of thyrotoxicosis are mostly due to an increase in the metabolic rate and overactivity of the sympathetic nervous system (i.e., an increase in the β-adrenergic “tone”). Treatment consists of beta blockade for symptomatic management while the underlying endocrine dysfunction is addressed.

References

  1. Brotman, R.G., Moreno-Escobar, M.C., Joseph, J., Pawar, G. (2021). Amyotrophic lateral sclerosis. StatPearls. http://www.ncbi.nlm.nih.gov/books/NBK556151/
  2. Huppert L.A., Dyster T.G. (Eds.). (2021). Diseases & pathophysiology in neurology. Chapter 12-04 of Huppert’s Notes: Pathophysiology and Clinical Pearls for Internal Medicine. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?sectionid=257403728&bookid=3072&Resultclick=2 
  3. Brown, R.H., Jr. (2018). Amyotrophic lateral sclerosis and other motor neuron diseases. Chapter 429 of Jameson J.L., et al. (Ed.), Harrison’s Principles of Internal Medicine, 20th ed. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192532519
  4. Fearon, C., Murray, B., Mitsumoto, H. (2022). Disorders of Upper and Lower Motor Neurons. In: Jankovic J., et al. (Ed.), Bradley’s Neurology in Clinical Practice. 5th ed., pp. 1535–1567. 
  5. Elman, L.B., McCluskey, L. (2021). Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease. UpToDate. https://www.uptodate.com/contents/clinical-features-of-amyotrophic-lateral-sclerosis-and-other-forms-of-motor-neuron-disease
  6. Ratti, E. (2015). Motor neuron diseases. DeckerMed Medicine. Retrieved August 8, 2021, from http://dx.doi.org/10.2310/PSYCH.6266
  7. Muscular Dystrophy Association. (2021). Amyotrophic lateral sclerosis (ALS). https://www.mda.org/disease/amyotrophic-lateral-sclerosis/diagnosis

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