Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS), formerly known as Lou Gehrig disease, is a neurodegenerative disease with upper and lower motor neuron dysfunction. The disease most commonly manifests between fifty and seventy years of age, often beginning with asymmetric weakness in the hands or feet. However, initial presentation is highly variable and some patients present with atypical/non-specific symptoms such as subtle vocal changes. As the disease progresses, most patients eventually develop one or both of the life-threatening symptoms: respiratory impairment and dysphagia. Riluzole and edaravone are currently the only drugs approved for the treatment of ALS. Multidisciplinary care is extremely important and includes nursing care, physiotherapy, and eventually assisted ventilation and enteral feeding. Most patients will die within 3–5 years, although approx. 30% have a chance of living longer.

• Prevalence: 5/100,000 population in the US ^[1]
• Incidence: 2–3 cases/100,000 population per year worldwide ^[2]
• Sex: ♂ > ♀
• Mean age of onset is 65 years.
• Familial history of ALS in 5–10% of cases ; 90–95% are sporadic

References:^[2][3]

Epidemiological data refers to the US, unless otherwise specified.

The Definitive cause of ALS is still unknown. Studies have suggested an interaction between genetic predisposition and environmental factors.

Genetics

Mutations of the following genes have been found in approx. 70% of familial clusters and some sporadic cases. ^[4]

• SOD1 ^[5]
  • Codes for superoxide dismutase
  • Mutations are associated with either a very aggressive or very slow disease progression
  • Account for 15–20% of familial ALS cases
• TARDBP
  • Сodes for the TDP-43 protein involved in DNA repair
  • In ALS, abnormally ubiquitylated TDP-43 forms inclusions within motor neurons.
  • Accounts for ∼ 5% of familial ALS cases
• C9orf72
  • Most common mutated gene in familial ALS (account for 30–40% of familial ALS cases)
  • Associated with a combination of ALS and frontotemporal dementia
• FUS
  • Mutations are associated with a young-onset rapidly-progressing ALS. ^[1]
  • Accounts for ∼ 5% of familial ALS cases

Environmental risk factors ^[6]

• Exposure to the following substances:
  • β-N-methylamino-L-alanine ^[7]
  • Pesticides (e.g., cis-chlordane, pentachlorobenzene) ^[8]
  • Lead
• Head trauma
• Individuals serving in US military ^[6][9]
• Smoking

• Classically affects the entire motor neuron system at two or more levels (both upper and lower motor neuron degeneration).
  • Upper motor neurons in the precentral gyrus and, frequently, prefrontal cortex
  • Lower motor neurons in the anterior horn of the spinal cord and brainstem
• Potential underlying mechanisms include abnormal RNA processing and protein aggregation, excitotoxicity, mitochondrial dysfunction, and defective neurofilaments.

References:^[10][11]

General disease characteristics

• Both upper motor neuron (UMN) and lower motor neuron (LMN) signs are present (see Upper motor neuron injury vs. lower motor neuron injury)
• Constant disease progression: it usually starts in one arm and/or leg then progresses to the contralateral side and eventually, after months or years, affects the respiratory system.

Early symptoms

• Symptoms are highly variable and potentially non-specific (e.g., subtle vocal changes or difficulties grasping objects)
• Asymmetric limb weakness, often beginning with weakness in the hands and feet
• Bulbar symptoms such as dysarthria, dysphagia, and tongue atrophy (20% of cases at disease onset)
• Pseudobulbar palsy with pseudobulbar affect may develop.
• Fasciculations, cramps, and muscle stiffness
• Weight loss
• Split hand sign: a wasting pattern in which the muscles of the thenar eminence atrophy due to degeneration of the lateral portion of the anterior horn of the spinal cord

Late symptoms

• Cognitive impairment (approx. 15% of ALS patients meet the criteria for frontotemporal dementia)
• Autonomic symptoms (e.g., constipation, bladder dysfunction) may develop; the mechanism of development is unclear. ^[1]
• Life-threatening symptoms
  • Respiratory failure due to paralysis of respiratory muscles
  • Dysphagia due to bulbar weakness or pseudobulbar palsy

References:^[11][12]

• Physical examination (including testing reflexes, Babinski sign, etc.) ^[1][11]
• Electromyography ^[13]
  • Denervation: fibrillations, positive sharp waves, and large amplitudes
  • Fasciculations
• Nerve conduction studies: usually normal
• Laboratory studies
  • Increased creatine kinase
  • Further testing of blood, urine, and CSF to exclude other causes (e.g., myasthenia gravis)
• Neuroimaging: MRI to exclude other causes (e.g., cervical spondylosis)
• Bedside swallowing test
  • A clinical assessment for swallowing abnormalities that involves the examination of the anatomy, function, and reflexes of the mouth, tongue, and mandible along with a trial of food and liquid
  • The test is considered positive if the patient is unable to drink continuously, coughs up after the swallowing attempt, and/or has a wet, gargling, or hoarse vocal quality.
  • Informs decisions on dietary modification (e.g., pureed food, thickened liquids, nasogastric tube, percutaneous endoscopic gastrostomy) and further investigations
  • If the test is positive, a formal swallowing study, such as a videofluoroscopic swallowing examination, should be performed to confirm the diagnosis.
  • Should be performed in all patients with ALS to screen for dysphagia.
  • Also performed in other neurological conditions that manifest with dysphagia, such as Parkinson disease, acute stroke, and Guillain-Barré syndrome.
• Pulmonary function testing
  • Spirometry: signs of restrictive lung disease
  • DLCO: normal
  • Respiratory muscle function testing: low maximal inspiratory pressure, maximal expiratory pressure, and sniff nasal inspiratory pressure

• Macroscopic features ^[14]
  • Atrophy of the precentral gyrus
  • Thinning of ventral spinal roots
  • Sclerosis and pallor of the corticospinal tract
  • Muscle atrophy
• Microscopic features ^[15]
  • Death of upper and lower motor neurons
  • Inclusion bodies in affected neurons, e.g.:
    • Lipofuscin
    • Bunina bodies
    • Ubiquitin-positive aggregates (associated with the protein TDP-43, which is also found in frontotemporal dementia)
  • Neuroinflammation (e.g., proliferation of astroglia and microglia)
  • Denervation, reinnervation, and atrophy of muscle fibers

• Multifocal motor neuropathy (MMN) ^[16][17]
  • A type of neuropathy that solely affects motor neurons
  • Slowly progressing asymmetrical paralysis and areflexia that typically affect the distal upper limbs
  • Muscle atrophy is rare.
  • EMG may reveal motor nerve conduction block.
  • Protein levels in CSF are usually normal.
  • Highly elevated anti-GM1-ganglioside antibody titers
• Myasthenia gravis
  • Weakness improves with acetylcholinesterase inhibitors
  • No UMN or LMN signs
• Lambert-Eaton myasthenic syndrome
  • Proximal muscle weakness that improves with repetitive stimulation (Lambert sign)
  • Symptoms of autonomic dysfunction (e.g., dry mouth)
  • Anti-VGCC antibodies
• Cervical spondylosis
  • Sensory symptoms
  • LMN confined to affected level of spinal compression
  • MRI shows spinal cord compression
• Thyrotoxicosis
  • Myopathy, fine tremor, and hyperreflexia resolve with treatment of hyperthyroidism
• Poliomyelitis
  • Asymmetric flaccid paralysis
  • Poliovirus RNA in CSF

The differential diagnoses listed here are not exhaustive.

• Riluzole
  • A sodium-channel blocker that inhibits glutamate release in the CNS and decreases glutamate excitotoxicity
  • Prolongs survival and slows functional decline in patients with ALS (on average, for 3 months) ^[1]
• Edaravone
  • A free radical scavenger
  • Has been shown to slow functional decline in some patients with ALS
• Sodium phenylbutyrate-taurursodiol ^[18][19]
  • A combination of sodium phenylbutyrate and taurursodiol (ursodeoxycholic acid conjugated with taurine)
  • Prolongs survival and slows functional decline in patients with ALS
• Multidisciplinary and symptomatic therapy

Rilouzole rilly helps treating Lou Gehrig disease

References:^[20][21]

• Most patients die within 3–5 years
• 5-year-survival: 30%
• 10-year-survival: 10–20%
• Early bulbar and/or respiratory symptoms are associated with a worse prognosis

References:^[1][22]