Essentials

• ALS is the most common of motor neurone diseases which typically involve atrophy and weakness of voluntary muscles resulting from nerve destruction in the motor pathway.
• Weakness and atrophy of the voluntary muscles without sensory symptoms.
• The functions of the autonomic nervous system and the sphincters remain intact.
• Mild cognitive impairment is found in 40% of the patients.

Aetiology

• The aetiology of ALS remains unknown.
• The disease is not contagious.
• Some patients have the disease in the family. The term familial amyotrophic lateral sclerosis (FALS) is used in these cases. This condition, however, does not have a generally adopted definition. If one of the family members has a verified mutation that causes the disease, the term is justified. In an isolated case of ALS, the risk of the descendants or siblings falling ill with the disease is in a class of one percent only.
  • In Finland, approximately 20% of ALS patients have the disease in the family.
• The dominantly inherited C9ORF72 mutation is the most common one. This mutation also causes frontotemporal lobar degeneration (FTLD) (Frontotemporal lobar degeneration). Whether the presence of the mutation is examined should be carefully considered.
• The demonstration of the recessively inherited SOD1 p.D91A mutation is meaningful considering the prognosis and the genetic counselling.
• Either of these mutations can be found in up to 30% of patients, including those who are not known to have the disease in their family.

Epidemiology

• Annual incidence about 1–3/100,000 (population-based and regional variation exists) https://pubmed.ncbi.nlm.nih.gov/28980624/
• Median age of onset about 60 years

Symptoms

• The most common primary symptom is weakness of one upper or lower extremity in functions requiring normal muscle strength.
• Cramps especially in legs are typical.
• In bulbar involvement, the initial symptom is deterioration of speech and swallowing. Atrophy and fasciculations of the tongue may be seen. Inability to push out the tongue and difficulty in forming the sound ’r’ (in languages where ’r’ is pronounced with alveolar trill) are typical first symptoms.
• 10–25% of patients may complain of slight distal numbness, paraesthesiae or mild pain.

Clinical course

• Muscle weakness and atrophy progress proximally starting in the distal parts and spread to other limbs, respiratory muscles and to the bulbar area. The weakness can also begin in the bulbar area and progress distally.
• Upper motor neurone damage leads to spasticity (not always detected) and to accelerated tendon reflexes. Babinski's sign is positive in about 50%.
• Lower motor neurone damage weakens muscle tonus and reflexes, which is why the tonus can vary between individuals.
• When upper motor neurone damage is dominant, the term primary lateral sclerosis (PLS) is used.
• As the disease progresses, muscle atrophy and poor muscle tone become dominant.
• The cardiac muscle is not involved.
• Ocular muscle functions are spared until the final stage of the disease.

Findings

• Atrophy of the small thenar and palmar muscles is the most prominent finding (picture (Muscle atrophy of the hand in a patient with ALS)).
• Muscular atrophy leads to weight loss.
• Fasciculations mainly in the muscles of the limbs and in the tongue. Fasciculations alone are not a sign of a disease.
• Sensory deficits suggest some other aetiology than ALS.
• Frontal type dementia may be the first symptom.

Investigations

• There are no specific findings in laboratory tests. Plasma CK and CSF protein concentrations may be somewhat increased.
• ENMG (usually requested by a neurologist)
  • Fasciculations, polyphasia
  • Fibrillations in the denervated muscles
  • Normal motor nerve conduction velocity
  • Changes also in symptomless muscles
  • A control ENMG is often required.
• CT or MRI imaging of the head is required to exclude other CNS disorders, cervical spondylotic myelopathy and neoplasms.

Prognosis

• Refrain from communicating a specific predicted survival time to the patient.
  • Median survival is about 3.5 years from onset of symptoms, but 10% live over 10 years.
  • The prognosis is somewhat poorer in the bulbar form of the disease.
  • Disease form involving respiratory muscles at the onset of the disease has the poorest prognosis, often less than 2 years.
  • The basic cause of death is ALS, but in most cases the immediate cause is pneumonia.

Treatment

• Therapy is symptomatic.
• Riluzole (50 mg twice daily) has been shown to prolong survival or postpone the start of mechanical ventilation, but only by a mean of 3 months [Evidence Level: B]. It does not affect the clinical symptoms.
  • Paradoxically, it may cause muscle weakness but this will subside to the natural level when the drug is discontinued. Also nausea may occur.
  • Basic blood count with platelet count and plasma ALT concentration should be monitored during the pharmacotherapy. Treatment should be discontinued if ALT levels increase to higher than five times the upper limit of normal.
  • Treatment is initiated by a specialist in motor neurone diseases.
  • Edaravone is used in many countries but it is not approved for use in the EU.

Muscle weakness

Cramps and spasticity

Salivation and mucus production

Difficulty with speech

Nutrition and dysphagia

Respiratory difficulties