Amyotrophic Lateral Sclerosis

Taylor Harrison, M.D.
Joseph S. Kass, M.D., J.D.

Basic Information

Definition

Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative neuromuscular condition of undetermined etiology affecting corticospinal tracts and anterior horn cells, thereby resulting in dysfunction of both upper motor neurons (UMN) and lower motor neurons (LMN).

Synonyms

Lou Gehrig’s disease
ALS

ICD-10CM CODES
G12.21	Amyotrophic lateral sclerosis

Epidemiology & Demographics

Incidence

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Two new cases per 100,000 persons per year.
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Onset is usually between the ages of 50 and 70 yr.
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Male/female ratio is 1.8:1.

Prevalence

4.2 in 100,000 white persons

2 in 100,000 black persons

Physical Findings & Clinical Presentation

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LMN signs (weakness, hypotonia, muscle wasting, fasciculations, hyporeflexia or areflexia).
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UMN signs (loss of fine motor dexterity, spasticity, extensor plantar responses, hyperreflexia, clonus).
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Preservation of extraocular movements, sensation, bowel and bladder function.
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Dysarthria, dysphagia, pseudobulbar affect, frontal lobe dysfunction.
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Respiratory insufficiency progressing to respiratory failure typically occurs late in the disease.
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ALS comprises approximately 90% of adult-onset motor neuron diseases. Other presentations of motor neuron disease include progressive muscular atrophy, primary lateral sclerosis, progressive bulbar palsy, progressive pseudobulbar palsy, and ALS-parkinsonism-dementia complex.

Etiology

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90% to 95% of all cases are sporadic.
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5% to 10% cases are familial; known genetic mutations include copper-zinc superoxide dismutase enzyme mutations (10%–20% of familial cases), TAR DNA-binding protein mutations (3%–10% of familial cases), FUS (5% of familial cases), ANG (which encodes angiogenin, ribonuclease, RNase A family, 5; 1% of familial cases), and C9ORF72.
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C9ORF72 hexanucleotide repeat expansion recently identified genetic cause, although the frequency is geographically variable; in the U.S., reported in up to 23% of familial ALS and 4% of sporadic ALS.
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TDP-43 and FUS mutations also associated with ALS and frontotemporal dementia.
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Increased risk factors in whites, non-Hispanics, age >60 years. Family history of ALS, previous exposure to heavy metals, pesticides, BMAA.¹

Diagnosis

Differential Diagnosis

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Multifocal motor neuropathy with conduction block
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Cervical spondylotic myelopathy with polyradiculopathy
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Spinal stenosis with compression of lumbosacral nerve roots
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Chronic inflammatory demyelinating polyneuropathy with central nervous system lesions
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Syringomyelia
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Syringobulbia
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Foramen magnum tumor
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Meningeal carcinomatosis
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Spinal muscular atrophy
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Polyglucosan body disease
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Bulbospinal muscular atrophy (Kennedy disease)
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Monomelic amyotrophy
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Lyme disease
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ALS-like syndromes have been reported in the setting of lead intoxication, HIV, hyperparathyroidism, hyperthyroidism, lymphoma, and vitamin B₁₂ deficiency.

Workup

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Diagnosis is based on clinical findings, EMG results, and exclusion of alternative causes.
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MRI of brain and spine without contrast to exclude alternative causes

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Electromyography and nerve conduction studies (El Escorial criteria; see Table 1)

TABLE1 Revised EL Escorial Diagnostic Criteria for Amyotrophic Lateral SclerosisFrom Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, Saunders.

The diagnosis of ALS requires:

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[A:1] Evidence of LMN degeneration by clinical, electrophysiologic, or neuropathologic examination
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[A:2] Evidence of UMN degeneration by clinical examination and
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[A:3] Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination

Together with the absence of:

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[B:1] Electrophysiologic and pathologic evidence of another disease that might explain the signs of LMN and/or UMN degeneration and
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[B:2] Neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiologic signs

Levels of diagnostic certainty:

Definite ALS

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UMN signs and LMN signs in 3 regions

Probable ALS

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UMN signs and LMN signs in 2 regions with UMN signs rostral to LMN signs

Probable ALS—laboratory supported

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UMN signs in 1 or more regions and LMN signs defined by EMG in at least 2 regions

Possible ALS

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UMN signs and LMN signs in 1 region (together) or
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UMN signs in 2 or more regions
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UMN and LMN signs in 2 regions with no UMN signs rostral to LMN signs

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Assessment of respiratory function (forced vital capacity [FVC], negative inspiratory force)

Laboratory Tests

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Vitamin B₁₂, thyroid function, parathyroid hormone, HIV may be considered
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Serum protein electrophoresis with immunofixation
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DNA studies for SMA or bulbospinal atrophy (Kennedy’s disease), hexosaminidase levels in a pure LMN syndrome
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24-hour urine for heavy metals if indicated

Imaging Studies

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Craniospinal neuroimaging contingent on clinical scenario. MRI of the brain and spinal cord are useful to help exclude stroke and cervical cord compression.
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Modified barium swallow to evaluate aspiration risk

Treatment

Nonpharmacologic Therapy

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Bilevel positive airway pressure (BiPAP) ventilation may improve quality of life and may increase tracheostomy-free survival in patients with respiratory difficulty (defined by orthopnea or FVC 50% of predicted).
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Percutaneous endoscopic gastrostomy (PEG) tube placement improves nutritional intake, promotes weight stabilization, and eases medication administration. Some studies suggest PEG placement may prolong life 1 to 4 mo, particularly when placed before FVC falls to ≤50% of predicted value.
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Nutrition, speech therapy, physical and occupational therapy services.
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Suction device for sialorrhea.
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Cough assist device for ineffective coughing and maintaining a clear airway.
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Communication may be eased with computerized assistive devices.
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Early discussion of living will, resuscitation orders, desire for PEG and tracheostomy, potential long-term care options.
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Encourage contact with local support groups.

Acute General Rx

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Riluzole, a glutamate antagonist, is the first FDA-approved medication known to extend tracheostomy-free survival in patients with ALS. Dosage is 50 mg q12h, at least 1 hr before or 2 hr after meals. It is shown to prolong survival by 2 to 3 months. Manufacturer recommends checking alanine aminotransferase (ALT) once a month for 3 months initially, followed by once every 3 months until the first year of therapy is completed. ALT should be checked periodically thereafter.
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Edaravone was FDA approved in 2017 and was found to slow down physical decline by 33% compared with placebo in a phase III trial lasting 6 months. It is administered intravenously, requiring an initial cycle of daily infusions for 14 consecutive days, followed by 14 days without infusion. Subsequent treatment cycles require ten infusions over 14 days, followed by 14 days without infusions. Cost is a factor, and insurance coverage is variable.

Chronic Rx

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Sialorrhea may respond to either glycopyrrolate or amitriptyline (consider either propranolol or metoprolol if secretions are thick).Botulinum toxin may be effective in medically refractory cases.
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Spasticity may be treated pharmacologically with baclofen, tizanidine, clonazepam.
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Pseudobulbar affect may improve with amitriptyline, sertraline, or dextromethorphan/quinine.

Disposition

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Currently there is no cure for ALS.
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Mean duration of symptoms is 3 to 5 yr.
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Approximately 20% of patients survive >5 yr.

Referral

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Referral to a neurologist experienced in neuromuscular disease is recommended to confirm the diagnosis. One prospective, population-based study suggested improved survival in subjects treated in a multidisciplinary ALS clinic.
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Gastroenterology referral for PEG placement is recommended while FVC remains >50% to minimize morbidity attributable to risks inherent to the procedure.
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Pulmonology referral for bilevel positive pressure airway ventilation (BiPAP)

Pearls & Considerations

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Patient-physician communication is an integral and essential part in both the initial diagnosis and subsequent treatment of ALS.
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A multidisciplinary approach to supportive care may lead to an improved level of daily functioning and foster an increased sense of independence.

Ferri – Amyotrophic Lateral Sclerosis