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

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 and often nasal 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.

The bulbar muscles innervated by cranial nerves are predominantly affected, resulting from progressive degeneration of the motor neurons innervating bulbar musculature. This disorder causes progressive difficulty with chewing, swallowing, and talking; a nasal voice; reduced gag reflex; fasciculations and weak movement of the facial muscles and tongue; and weak palatal movement. Aspiration is a risk.

The upper motor neuron equivalent of this disorder is progressive pseudobulbar palsy. This disorder affects the corticobulbar tract, descending to bulbar lower motor neurons, but spares the lower motor neurons in the brain stem, causing upper motor neuron weakness of the bulbar muscles. and thus is called pseudobulbar. Speech is spastic, patients cannot rapidly repeat syllables, (kakaka, tatata, lalala, bababa); gag reflex and jaw jerk are brisk. A pseudobulbar affect with emotional lability may also occur.

Commonly, progressive bulbar palsy 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.

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.

In primary lateral sclerosis, progressive muscle stiffness in the arms and legs occurs with spasticity and hyperreflexia during examination. Fasciculations and muscle atrophy are atypical for this predominantly upper motor neuron disorder.

Survival is prolonged because risk of aspiration and pneumonia is low; several years must pass to result in total disability.

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.

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 that may be compressing the spinal cord.

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 Lumbar Puncture (Spinal Tap) Lumbar puncture is used to do the following: Evaluate intracranial pressure and cerebrospinal fluid (CSF) composition (see table Cerebrospinal Fluid Abnormalities in Various Disorders) Therapeutically... read more 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 for Tay-Sachs disease) should not be done unless patients are interested in genetic counseling; disorders detected by these tests have no known specific treatments.