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Amyotrophic lateral sclerosis (ALS) was first described in 1869. It is frequently referred to as "Lou Gehrig's disease" in memory of the famous baseball player who died of ALS in 1941. ALS is defined as adult-onset, idiopathic, progressive degeneration of anterior horn cells and upper and lower motor neurons resulting in progressive muscle weakness, wasting and fasciculations. The clinical picture varies, depending on the location and progression of the pathologic changes. Diagnostic criteria of the World Federation of Neurology can help define and classify amyotrophic lateral sclerosis (Lou Gehrig's disease).
Atrophy of the anterior horn cells and replacement of the large motor neurons by fibrous astrocytes (gliosis) causes the affected anterior and lateral columns of the spinal cord to become hard, hence the term "lateral sclerosis."4 Large neurons tend to be affected before small ones,7 but the general distribution of pathologic findings within the spinal cord should correlate with the clinical findings. In the brain, atrophic changes may be found in the motor and premotor cortex.4,7 Peripheral nerves show secondary degeneration of axons and myelin.1 Surviving motor axons develop collateral branches to attempt reinnervation of muscles.
Cellular abnormalities and inclusion bodies have been described in the degenerating neurons, but none of these changes are pathognomonic.
ALS may have a multifactorial etiology or may result from a number of different neuronal insults. The major lines of investigation include genetic, viral, autoimmune.
Leading theories concern neurotoxicity relating to abnormalities of calcium and amino acids (especially glutamate) essential to neurotransmission. Excessive entry of these compounds into the neurons damages cell metabolism, resulting in pathologic changes. Neuronal damage could similarly result from oxidative processes that produce hydroxyl radicals. Clinical trials of medications that attempt to reverse these processes are under way. Other hypothetic causes of ALS include neurotoxicity from various metals, chemicals or foods,12 and, conversely, deficiency of neurotrophic agents (poorly understood proteins that enhance neuronal maintenance.
Clinical Features
The classic presentation of ALS is insidious, progressive, asymmetric muscular weakness and atrophy along with neurologic signs, particularly fasciculations and hyperreflexia.4 The clinical picture depends on the area of the nervous system that is damaged. The disease begins with equal frequency in upper and lower limbs (30 to 40 percent of cases each). Bulbar symptoms are the initial manifestations.
Patients with lower limb onset may complain of tripping, stumbling or awkwardness when walking or running. Those with upper limb onset may first notice difficulty in actions such as buttoning clothes, picking up small objects or turning keys. Speech problems, such as slurring, hoarseness or decreased volume, are the most common presentations.
As symptoms progressively worsen and spread, muscle atrophy becomes apparent and upper motor neuron symptoms such as spasticity complicate gait (in lower limb involvement) and manual dexterity (in upper limb involvement). Fasciculations in the affected limbs or the tongue cause "twitching," which may be embarrassing to the patient. Muscle pain may be caused by clonus.
Management
The management of ALS is a complex and demanding team effort requiring individualized therapy and continual adaptation of medications and therapies. In addition to conventional sources, World Wide Web sites such as those maintained by the American Academy of Neurology, the ALS Association, the World Federation of Neurology and the national ALS associations of several countries provide valuable information and support. However, the unregulated format of the Internet may also
Disease-Modifying Drugs
The only agent currently labeled for the treatment of ALS is riluzole (Rilutek). At least one other drug (mecasermin) is under consideration by the U.S. Food and Drug Administration. Clinical trials of other drugs are
Riluzole is believed to decrease glutamate release. One large study19 reported that 56.8 percent of patients treated with 100 mg of riluzole daily were alive without tracheostomy after 18 months, compared with 50.4 percent of patients who received a placebo, a clinically small but statistically significant difference. Previously, a
The monthly cost for riluzole is approximately $600. The manufacturer (Rhône-Poulenc Rorer; telephone, 1-800-340-7502) has established programs to assist patients in gaining access to this drug and other support services.
Symptomatic Treatments
Various symptomatic treatments may be helpful.5(pp321-8),15,24 Frequent, close contact with the patient and the family helps the physician gauge the significance of individual symptoms and the possible benefit of treatment compared with the risk of
Spasticity may be relieved by use of baclofen (Lioresal), in a dosage of 10 to 25 mg three times daily, diazepam (Valium), in a dosage of 2 to 15 mg three times daily, or dantrolene (Dantrium), gradually titrated to a dosage of 50 to 100 mg four times daily. Unfortunately, these
Pain may result from muscle contractures and secondary effects on joints. Muscle cramps occur in almost all patients and may cause severe pain and sleep disturbance. Physical therapy can ameliorate many of the painful symptoms of ALS. Nonsteroidal anti-inflammatory agents and anticonvulsive medications such as carbamazepine (Tegretol), in a dosage of 200 mg three times daily, or phenytoin (Dilantin), in a dosage of 300 mg at bedtime, may be useful. Early use of amitriptyline (Elavil), in a
Drooling may be one of the most distressing symptoms for patients with bulbar ALS. When excess saliva spills into the airway, bronchospasm can result. Mechanical suction devices are useful in preventing aspiration. Medications that suppress sialorrhea include anticholinergic drugs such as atropine, in a dosage of 0.4 mg four times daily, or scopolamine (Transderm-Scop), one 0.5-mg transdermal patch applied every three days. Some antihistamines, such as diphenhydramine (Benadryl), in
Tricyclic antidepressants are widely used in the treatment of ALS because of their multiple effects. Amitriptyline, in a dosage of 5 to 100 mg at bedtime, can provide antidepressant and antisialorrheic actions as well as nocturnal sedation, potentiation of analgesia and possible weight gain. Doxepin (Sinequan) and imipramine (Tofranil) have
Depression and anxiety are common in ALS and require individualized therapy. Supportive counseling is appropriate for all patients and their families, and antidepressant medication may also be helpful. An adequate dosage of a tricyclic agent may relieve the patient's depression, with the advantage that the
Supportive Therapies
Supportive therapies play a crucial role in the care of patients with ALS.5(pp360-463),15 Physical therapy should begin early and should be adapted to the patient's needs throughout the course of the disease. Exercises to promote strength, range of motion and endurance may dominate the early therapy program. Heat, massage or