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Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases

by Michael Rubin, MDCM

Amyotrophic lateral sclerosis (ALS) and other motor neuron diseases (MNDs) are characterized by steady, relentless, progressive degeneration of corticospinal tracts, anterior horn cells, bulbar motor nuclei, or a combination. Symptoms vary in severity and may include muscle weakness and atrophy, fasciculations, emotional lability, and respiratory muscle weakness. Diagnosis involves nerve conduction studies, electromyography, and exclusion of other disorders via MRI and laboratory tests. Treatment is supportive.

ALS (Lou Gehrig disease, Charcot syndrome) is the most common MND. MNDs may involve the CNS as well as the peripheral nervous system. Usually, etiology is unknown. Nomenclature and symptoms vary according to the part of the motor system most affected. Myopathies have similar features but are disorders of the muscle membrane, contractile apparatus, or organelles (see Congenital Myopathies).

MNDs can be classified as upper and lower; some disorders (eg, ALS) have features of both. MNDs are more common among men, most often appearing during their 50s.

Symptoms and Signs

Upper MNDs (eg, primary lateral sclerosis) affect neurons of the motor cortex, which extend to the brain stem (corticobulbar tracts) or spinal cord (corticospinal tracts). Generally, symptoms consist of stiffness, clumsiness, and awkward movements, usually affecting first the mouth, throat, or both, then spreading to the limbs.

Lower MNDs affect the anterior horn cells or cranial nerve motor nuclei or their efferent axons to the skeletal muscles. In bulbar palsies, only the cranial nerve motor nuclei in the brain stem (bulbar nuclei) are affected. Patients usually present with facial weakness, dysphagia, and dysarthria. When anterior horn cells of spinal (not cranial) nerves are affected, as in spinal muscular atrophies (see Spinal Muscular Atrophies), symptoms usually include muscle weakness and atrophy, fasciculations (visible muscle twitches), and muscle cramps, initially in a hand, a foot, or the tongue. Poliomyelitis, an enteroviral infection that attacks anterior horn cells, and postpolio syndrome are also lower MNDs (see Poliomyelitis).

Physical findings help differentiate upper from lower MNDs (see Table: Distinguishing Upper From Lower Motor Neuron Lesions) and weakness due to lower MNDs from that due to myopathy (see Table: Distinguishing the Cause of Muscle Weakness: Lower Motor Neuron Dysfunction vs Myopathy*).

Distinguishing Upper From Lower Motor Neuron Lesions

Feature

Upper Lesion

Lower Lesion

Reflexes

Hyperactive

Diminished or absent

Atrophy

Absent*

Present

Fasciculations

Absent

Present

Tone

Increased

Decreased or absent

*May appear with prolonged disuse of limbs.

Distinguishing the Cause of Muscle Weakness: Lower Motor Neuron Dysfunction vs Myopathy*

Feature

Lower Motor Neuron Dysfunction

Myopathy*

Distribution of weakness

Distal > proximal

Proximal > distal

Fasciculations

May be present

Absent

Reflexes

Diminished

Often preserved

*Nerve function intact.

>= more affected than.

Amyotrophic lateral sclerosis (ALS)

Most patients with ALS present with random, asymmetric symptoms, consisting of cramps, weakness, and muscle atrophy of the hands (most commonly) or feet. Weakness progresses to the forearms, shoulders, and lower limbs. Fasciculations, spasticity, hyperactive deep tendon reflexes, extensor plantar reflexes, clumsiness, stiffness of movement, weight loss, fatigue, and difficulty controlling facial expression and tongue movements soon follow. Other symptoms include hoarseness, dysphagia, and slurred speech; because swallowing is difficult, salivation appears to increase, and patients tend to choke on liquids.

Late in the disorder, a pseudobulbar affect occurs, with inappropriate, involuntary, and uncontrollable excesses of laughter or crying. Sensory systems, consciousness, cognition, voluntary eye movements, sexual function, and urinary and anal sphincters are usually spared.

Death is usually caused by failure of the respiratory muscles; 50% of patients die within 3 yr of onset, 20% live 5 yr, and 10% live 10 yr. Survival for > 30 yr is rare. In progressive bulbar palsy with ALS (bulbar-variant ALS), deterioration and death occur more rapidly.

Progressive bulbar palsy

The muscles innervated by cranial nerves and corticobulbar tracts are predominantly affected, causing progressive difficulty with chewing, swallowing, and talking; nasal voice; reduced gag reflex; fasciculations and weak movement of the facial muscles and tongue; and weak palatal movement. Aspiration is a risk. A pseudobulbar affect with emotional lability may occur if the corticobulbar tract is affected. Commonly, the disorder spreads, affecting extrabulbar segments; then it is called bulbar-variant ALS.

Patients with dysphagia have a very poor prognosis; respiratory complications due to aspiration frequently result in death within 1 to 3 yr.

Progressive muscular atrophy

In many cases, especially those with childhood onset, inheritance is autosomal recessive. Other cases are sporadic. The disorder can develop at any age. Anterior horn cell involvement occurs alone or is more prominent than corticospinal involvement, and progression tends to be more benign than that of other MNDs.

Fasciculations may be the earliest manifestation. Muscle wasting and marked weakness begin in the hands and progress to the arms, shoulders, and legs, eventually becoming generalized. Patients may survive 25 yr.

Pearls & Pitfalls

  • Suspect ALS or another motor neuron disease in patients who have features of upper and/or lower neuron weakness (eg, extensor plantar responses plus atrophy and fasciculations).

Primary lateral sclerosis and progressive pseudobulbar palsy

Muscle stiffness and signs of distal motor weakness gradually increase, affecting the limbs in primary lateral sclerosis and the lower cranial nerves in progressive pseudobulbar palsy. Fasciculations and muscle atrophy may follow many years later. These disorders usually take several years to result in total disability.

Diagnosis

  • Electrodiagnostic tests

  • MRI of the brain and, if no cranial nerve involvement, cervical spine

  • Laboratory tests to check for other, treatable causes

Diagnosis is suggested by progressive, generalized motor weakness without significant sensory abnormalities. Other disorders that cause pure muscle weakness should be ruled out:

  • Disorders of neuromuscular transmission

  • Various myopathies (including noninflammatory and drug-induced)

  • Spinal muscular atrophies (mostly in children)

  • Polymyositis

  • Dermatomyositis

  • Thyroid and adrenal disorders

  • Electrolyte abnormalities (eg, hypokalemia, hypercalcemia, hypophosphatemia)

  • Various infections (eg, syphilis, Lyme disease, hepatitis C)

  • Autoimmune-mediated motor neuropathies

When cranial nerves are affected, a treatable cause is less likely. Upper and lower motor neuron signs plus weakness in facial muscles strongly suggest ALS.

Pearls & Pitfalls

  • If cranial nerves are affected and findings are compatible with ALS, a treatable alternative cause is less likely.

Electrodiagnostic tests should be done to check for evidence of disorders of neuromuscular transmission or demyelination. Such evidence is not present in MNDs; nerve conduction velocities are usually normal until late in the disease. Needle electromyography (EMG) is the most useful test, showing fibrillations, positive waves, fasciculations, and sometimes giant motor units, even in unaffected limbs.

Brain MRI is required. When there is no clinical or EMG evidence of cranial nerve motor weakness, MRI of the cervical spine is indicated to exclude structural lesions.

Laboratory tests are done to check for treatable causes. Tests include CBC, electrolytes, creatine kinase, and thyroid function tests. Serum and urine protein electrophoresis with immunofixation is done to check for a paraprotein that is rarely associated with MNDs. Discovering an underlying paraproteinemia may indicate that the MND is paraneoplastic, and treatment of the paraproteinemia may ameliorate the MND. Antimyelin-associated glycoprotein (MAG) antibodies are associated with a demyelinating motor neuropathy, which may mimic ALS. A 24-h urine collection is done to check for heavy metals in patients who may have been exposed to them. Lumbar puncture (see Lumbar puncture (spinal tap)) may be done to exclude other clinically suspected disorders; if WBCs or the protein level is elevated, an alternative diagnosis is likely.

Serum Venereal Disease Research Laboratories (VDRL) tests, ESR, and measurement of certain antibodies (rheumatoid factor, Lyme titer, HIV, hepatitis C virus, antinuclear [ANA], anti-Hu [to check for anti-Hu paraneoplastic syndrome]) are indicated only if suggested by risk factors or history. Genetic testing (eg, for superoxide dismutase gene mutation or genetic abnormalities that cause spinal muscular atrophies) and enzyme measurements (eg, hexosaminidase A) should not be done unless patients are interested in genetic counseling; disorders detected by these tests have no known specific treatments.

Treatment

  • Supportive care

  • Riluzole for bulbar variant ALS

There is no specific treatment for MNDs. However, an antiglutamate drug, riluzole 50 mg po bid, prolongs life by 2 to 3 mo in patients with bulbar variant ALS. A multidisciplinary team approach helps patients cope with progressive neurologic disability.

The following drugs may help reduce symptoms:

  • For spasticity, baclofen

  • For cramps, quinine or phenytoin

  • To decrease saliva production, a strong anticholinergic drug (eg, glycopyrrolate, amitriptyline, benztropine, trihexyphenidyl, transdermal hyoscine, atropine)

  • For pseudobulbar affect, amitriptyline and fluvoxamine

In patients with progressive bulbar palsy, surgery to improve swallowing has had limited success.

Key Points

  • Consider an MND in patients who have diffuse upper and/or lower motor weakness without sensory abnormalities.

  • Suspect ALS in patients with upper and lower motor neuron signs plus weakness in facial muscles.

  • Do MRI of the brain and electrodiagnostic and laboratory testing to exclude other disorders.

  • The mainstay of treatment is supportive measures (eg, multidisciplinary support to help cope with disability; drug treatment for symptoms such as spasticity, cramps, and pseudobulbar affect).

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • LIORESAL
  • ATROPEN
  • RILUTEK
  • No US brand name
  • COGENTIN
  • ROBINUL FORTE, ROBINUL
  • QUALAQUIN
  • DILANTIN
  • LUVOX

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