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Amyotrophic Lateral Sclerosis (ALS) and Other Motor Neuron Diseases (MNDs)

(Lou Gehrig Disease; Charcot Syndrome)


Michael Rubin

, MDCM, New York Presbyterian Hospital-Cornell Medical Center

Last full review/revision Sep 2019| Content last modified Sep 2019
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Amyotrophic lateral sclerosis and other motor neuron diseases 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.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease (MND). MNDs may involve the central nervous system (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.

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, 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.

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


Upper Lesion

Lower Lesion



Diminished or absent









Decreased or absent

* May appear with prolonged disuse of limbs.


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


Lower Motor Neuron Dysfunction


Distribution of weakness

Distal > proximal

Proximal > distal


May be present




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 years of onset, 20% live 5 years, and 10% live 10 years. Survival for > 30 years 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 years.

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. Deep tendon reflexes are hypoactive. Patients may survive 25 years.

Pearls & Pitfalls

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

Primary lateral sclerosis and progressive pseudobulbar palsy

In both disorders, muscle stiffness and signs of distal motor weakness gradually increase. Primary lateral sclerosis affects the limbs, and progressive pseudobulbar palsy affects the lower cranial nerves. Fasciculations and muscle atrophy may follow many years later.

These disorders usually take several years to result in total disability.


  • Electrodiagnostic tests

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

  • Laboratory tests to check for other, treatable causes

Diagnosis of motor neuron diseases is suggested by progressive, generalized motor weakness without significant sensory abnormalities.

Differential diagnosis

Other disorders that cause pure muscle weakness should be ruled out:

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

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 complete blood count, 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-hour urine collection is done to check for heavy metals in patients who may have been exposed to them.

Lumbar puncture may be done to exclude other clinically suspected disorders; if white blood cells or the protein level is elevated, an alternative diagnosis is likely.

The serum Venereal Disease Research Laboratories (VDRL) test, erythrocyte sedimentation rate, 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.


  • Supportive care

  • Riluzole

  • Edaravone

The mainstay of care for patients with amyotrophic lateral sclerosis is timely intervention to manage symptoms.

A multidisciplinary team approach helps patients cope with progressive neurologic disability.

No drug offers a substantial clinical benefit for patients with ALS. However, riluzole may provide limited improvement in survival (by 2 to 3 months), and edaravone may slow the decline in function to some degree.

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, fluvoxamine, or a combination of dextromethorphan and quinidine

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

Key Points

  • Consider motor neuron disease 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).

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NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version

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