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ice bucket challenge

Image: “Mission Accomplished – ALS Ice Bucket Challenge” by Anthony Quintano. License: CC BY 2.0


What is Amyotrophic Lateral Sclerosis (ALS)?

Amyotrophic Lateral Sclerosis (also known as ALS or Lou-Gehrig’s disease) is a degenerative disease of the central nervous system.

ALS

Image: Amyotrophic lateral sclerosis. MRI (parasagittal FLAIR) demonstrates an increased T2 signal within the posterior part of the internal capsule and can be tracked to the subcortical white matter of the motor cortex, outlining the corticospinal tract, consistent with the clinical diagnosis of ALS. By Frank Gaillard, License: CC BY-SA 3.0

ALS leads to progressive damage to upper and lower motor neurons.

The death of affected motor neurons leads to denervation and atrophy of the corresponding muscles (or amyotrophy). The loss of motor neurons results in the thinning of the corticospinal tracts in the lateral columns of the spinal cord. The resulting gliosis imparts a particular firmness to the lateral columns (or lateral sclerosis).

Reminder: The motor system in the CNS is represented by the primary motor cortex located in the precentral gyrus (upper motor neurons), which sends efferent nerve fibers through the corticospinal tract to the alpha motor neurons (lower motor neurons) in the anterior horns of the spinal cord.

Epidemiology

With a global incidence of 2–3/100,000, ALS is a relatively rare disease. The peak incidence occurs in the 5th to 7th decade of life, with men more often affected than women.

Causes of ALS

Mostly sporadic occurrence

Most cases of the disease (90%) are sporadic. The remaining 10% are so-called familial cases of ALS (autosomal dominant inheritance), caused by a variety of genetic mutations. The mutations are associated with the gene coding cytosolic Cu-Zn superoxide dismutase (SOD1) located on the q arm of chromosome 21 (SOD1 mutation). This enzyme is responsible for the detoxification of free superoxide radicals.

Other proteins that have been the focus of interest include the RNA-binding proteins FUS and TDP-43, elevated levels of which are found in the cytosol of affected neurons.

Usually, the distal extremities are affected first and the patients present with asymmetric weakness.

Toxic over-stimulation of the affected neurons (excitotoxicity) by the neurotransmitter glutamate is also a potential causative factor. This theory is corroborated by reports suggesting the mechanism of action of riluzole, the only authorized and demonstrably effective medication for ALS, which inhibits the release of glutamate from the synapses.

Note: Nearly 90% of cases occur sporadically, and the remaining 10% are of genetic origin, with mutations mainly affecting the cytosolic Cu-Zn superoxide dismutase (SOD1), which is responsible for detoxifying free superoxide radicals. Furthermore, glutamate excitotoxicity is considered as a potential causative factor of ALS.

Symptoms of ALS

ALS affects muscle functions

The clinical presentation of ALS is characterized by concurrent symptoms triggered by the upper or lower motor neurons.

Affected patients complain of muscle cramps and muscle weakness of the upper and lower extremities (usually starting at the distal end) and of the trunk, muscle atrophies (usually starting with the small muscles of the hand), and involuntary and occasionally painful muscular contractions (fasciculations). During the course of the disease, bulbar symptoms such as fasciculations and weakness of the lingual muscles, weakness of mimic muscles, dysphagia with (pseudo)ptyalism, dysarthria, and pathological laughing and crying can occur.

Furthermore, cognitive deficits such as frontotemporal dementia have been observed. However, respiratory insufficiency develops at a progressive stage of the disease and is a life-threatening aspect of the condition. It involves dyspnea and an increased risk of bronchopulmonary infections.

Note: Damage to the cortical motor neurons (upper motor neurons) leads to spastic paresis, pyramidal signs, and overresponsive reflexes (hyperreflexia). The destruction of alpha motor neurons (lower motor neurons) results in flaccid paralysis, fasciculations, and muscle atrophies.

Diagnosis of ALS

Diagnosis of exclusion for ALS

The diagnosis of amyotrophic lateral sclerosis is established by exclusion. In accordance with the so-called El Escorial criteria postulated by the World Federation of Neurology (WFN) in 1998, a diagnosis is only confirmed when at least 3 body regions (out of bulbar, cervical, thoracic, and lumbosacral motor neurons) show clinical and electrophysiological signs of motor neuronal damage (upper and lower motor neurons). However, the practical value of these criteria is disputed since a definitive diagnosis is only possible in an already progressive stage of the disease.

Extensive neurological examination of the aforementioned findings is essential together with a comprehensive electrophysiological evaluation:

  • Electromyogram (EMG): Muscular denervation caused by the destruction of the lower motor neurons manifests as an increase in spontaneous activity of the affected muscle fibers, which translates to fasciculation potentials and positive sharp waves on EMG.
  • Electromyoneurography (ENG): A sign of axonal damage with reduced amplitudes of the compound motor action potentials can be found. Initially, the nerve conduction velocity (NCV) is not impaired but is diminished with disease progression.
ALS

Image: Amyotrophic lateral sclerosis. MRI (axial FLAIR) demonstrates an increased T2 signal within the posterior part of the internal capsule, consistent with the clinical diagnosis of ALS. By Frank Gaillard, License: CC BY-SA 3.0

In accordance with standard recommendations, further differential diagnosis should be based on an MRI in order to rule out spinal causes (e.g., myelopathy, radiculopathy). Extensive laboratory testing based on the following parameters is also needed:

  • Inflammation marker (ESR, CRP)
  • Electrolyte panel, blood glucose
  • Differential blood count
  • Liver function tests (GOT, GPT)
  • Thyroid levels (TSH, T3, T4)
  • Vitamin B12 (methylmalonic acid, homocysteine)
  • Total serum protein and immunoelectrophoresis-serum test
  • CK, creatinine

During the follow-up care, lung function (vital capacity) and body mass index (BMI) should be assessed. In case of high incidence of ALS within a family, genetic testing should be performed to screen for mutations (SOD1, TDP-43, FUS).

Note: ALS is a diagnosis of exclusion. Essential examinations include comprehensive neurological testing, electromyogram, electromyoneurography, and genetic testing of cases of patients with familial ALS.

Treatment of ALS

Medication and symptom management

No causal treatment for ALS exists currently. The only medication that has been proven effective is the glutamate antagonist riluzole, which has been shown by several studies to prolong survival time. Edaravone is the second drug approved for ALS treatment. Edaverone acts as an antioxidant, and is administered as a recurring monthly series of daily intravenous infusions over 10 days. Further, the treatment strategies are focused on symptom management as follows.

  • Physical therapy and ergotherapy to strengthen the muscles, reduce spasms, improve ventilation, and maintain the remaining muscle functions
  • Speech therapy for dysphagia and dysarthria. Cases of severe dysphagia may be treated via the insertion of PEG.
  • Treatment of muscle cramps with magnesium, quinine sulfate, and carbamazepine
  • Effective pneumonia prophylaxis with mucolytics, tapping massage, beta-blocker (propranolol), ipratropium bromide, and possibly antibiotic treatment
  • Treatment of respiratory insufficiency using oxygen, non-invasive and invasive ventilation, and tracheostomy (only with patient’s consent)
  • Treatment of hypersalivation with anticholinergic drugs (scopolamine patches and atropine drops) and botulinum injection into the parotid gland
  • Treatment of dyspnea with morphine and benzodiazepine (lorazepam and midazolam)
  • Treatment of depressive symptoms/labile affect with amitriptyline and SSRI
  • Pain treatment according to the WHO pain ladder
  • Effective thrombosis prophylaxis with low-molecular-weight heparin
  • Provision of aids as needed (such as foot drop splints and cough assist devices)
Note: As of 2014, no causal treatment for ALS is available. The only authorized medication is riluzole (a glutamate antagonist), which has been shown to prolong survival time.

Prognosis of ALS

ALS is a progressive and fatal disease. The median survival is 3–4 years from the time of diagnosis. However, a slower progression with longer survival is possible.

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