Every 90 minutes, an American dies from amyotrophic lateral sclerosis (ALS). It also is called Lou Gehrig's disease, because it forced that National Baseball Hall of Fame honoree's 1939 retirement and caused his death 2 years later at age 37.
Rapidly progressive and fatal, ALS causes devastating weakness, muscle wasting, fasciculations (twitching), and hyperreflexia (which may cause pain and muscle cramps).1 ALS affects all muscles under voluntary control; patients lose strength and the ability to move their arms, legs, and body. Ultimately, stilled respiratory muscles prevent breathing without ventilatory support. This sequela kills 80% of ALS patients, usually within 5 years of diagnosis.
The disease affects approximately 30,000 Americans, and nearly 5000 new cases occur annually. Prevention or reversal is impossible at this time. Lou Gehrig was unusually young when he contracted the disorder—it generally occurs in people between the ages of 50 and 70, and rarely before age 45.1,2
ALS affects men more often than women (1.5:1). Depending on the area of the nervous system that is damaged, the insidious presentation of the disease begins with dexterity or gait problems. It appears in either the upper or lower limbs (30% to 40% of cases each).3,4 Patients with lower-limb onset may trip or may walk or run awkwardly. Buttoning clothes, picking up small objects, or turning keys becomes a nightmare due to upper-limb involvement.
In the bulbar form of the disease (19% to 25% of cases), the first symptom is difficulty speaking or swallowing.3,4 Slurring (dysarthria), hoarseness, and decreased voice volume (dysphonia) are the most common presentations of bulbar ALS. Excessive salivation (sialorrhea) and swallowing difficulty lead to drooling. Swallowing of saliva tends to be more difficult than swallowing of solids. Exaggerated emotional response (pseudobulbar affect; frequent, brief episodes of laughter or tears that alternate rapidly) also is common.
As function declines in both upper and lower motor neurons over months to years, patients become completely disabled, often need ventilatory support, and may require a gastrostomy for feeding. Primary neuropathic pain does not occur in ALS. Immobility predisposes patients to painful joint complications. Death usually occurs from respiratory failure or cachexia. Yet, sphincter control, sensory function, and skin integrity remain intact. Cachectic, bedridden ALS patients rarely develop pressure ulcers, probably due to collagen changes.5,6 Intellectual abilities usually remain strong, but cognitive impairment occurs in up to 30% of patients.6
The etiology of ALS is unknown. Some hyperendemic areas have been identified in the Mariana Islands, New Guinea, and southern Japan. Less than 10% of ALS is hereditary.6 Viral infection, cicad nuts, and pesticides have been suspected. After the 1991 Gulf War, an increased incidence of ALS in veterans suggested a war-related environmental trigger. Through 1998 in veterans younger than age 45, the expected incidence was approximately 1.57 cases per year, but the observed incidence was 5 cases per year.7 Current research is focused on neuronal glutamate abnormalities and the role of potential neurotoxins and neurotrophic factors.
Riluzole is the sole agent currently labeled for the treatment of ALS. Its mechanism of action is probably decreased glutamate release. A recent meta-analysis found only 4 controlled studies of riluzole. The researchers concluded that more studies are needed, especially to clarify the effect of the drugs in patients over 75 years old and in those with more advanced disease. They found riluzole 100 mg daily to be reasonably safe; it probably prolongs survival by about 2 months in patients with ALS. The effects of riluzole on functional abilities are unclear, and the drug does not halt the disease process.8
Adverse effects include elevated liver enzymes, asthenia, nausea, dizziness, diarrhea, and granulocytopenia.8-11 A recent study demonstrated that serum levels vary significantly among individuals, although riluzole usually is prescribed in a fixed dose. The researchers observed serum levels and the area under the curve per kilogram of body weight (AUC/kg) in 169 patients. Patients with high serum levels and AUC/kg experienced diarrhea more often but reported fewer fasciculations and less muscle stiffness. The investigators suggested raising the riluzole dose in patients with low riluzole serum concentrations, because the risk of serious side effects is low.11,12
Antioxidants, such as vitamin E, have been used for decades. No evidence indicates that they help, but they do not complicate matters either. In 2003, the FDA granted orphan drug status to the manufacturer of a catalytic antioxidant compound, AEOL 10150. It has demonstrated efficacy in a transgenic mouse model of ALS. Survival time after symptom onset for the AEOL 10150?treated group was 2.5 times the survival period of the control group.13
Many patients complain of a characteristic set of symptoms: spasticity, pain, drooling, depression/anxiety, and wasting. Individualized therapy and constant adaptation of medications are crucial (Table).
Muscle contractures, cramps, and secondary effects on joints may cause pain and disturb sleep. Physical therapy can help. Concurrent amitriptyline or nortriptyline given at bedtime may potentiate analgesic medications. Lorazepam may relieve severe fasciculations.
Drooling distresses patients with bulbar ALS and is socially disabling. When excess saliva spills into the airway, bronchospasm can follow. Mechanical suction devices are used to prevent aspiration. In addition to anticholinergic drugs, antihistamines such as diphenhydramine also may suppress sialorrhea.6
Depression and Anxiety
These symptoms are common in ALS. Antidepressant medication with supportive counseling should be tailored to the individual's needs. The very side-effect profile that makes tricyclic antidepressants (TCAs) problematic for others can be exploited in ALS patients. TCAs may relieve depression while producing dry mouth, sedation, and weight gain. They also may potentiate analgesia. Selective serotonin reuptake inhibitors can be effective but may cause insomnia and agitation. Benzodiazepines may relieve anxiety and insomnia but can cause daytime sedation.2,6
Weight loss is characteristic of the disease, and often the extent of cachexia is disproportionate to muscle atrophy or nutritional difficulties. Patients with dysphagia require frequent, high-energy, soft, moist meals. Finding the correct food consistency for the patient is important; otherwise, meals frustrate rather than satisfy the patient.2,6
European studies are being conducted to evaluate the safety and efficacy of EHT 0201 (pentoxifylline) in patients suffering from ALS. EHT 0201 may potentially be added to riluzole therapy. A large study to determine whether tamoxifen, a protein kinase C inhibitor, can decrease glutamate is underway in Wisconsin. Also, animal studies of cyclooxygenase-2 inhibition have had promising results; it may relieve ALS because cyclooxygenase is the rate-limiting enzyme of prostaglandins that rapidly stimulate glutamate release. Oral administration of either celecoxib or rofecoxib has significantly improved motor performance, attenuated weight loss, and extended survival.14,15
Lou Gehrig took his last swing at a baseball in Kansas City on June 12, 1939. The next day he was admitted to the Mayo Clinic and was told that he had ALS, a "form of polio." (The latter theory has been rejected.) Over the next 2 years, he was treated with therapy and vitamin E, but nothing helped. Sixty-five years later, Lou Gehrig is unforgettable, and the disease that bears his name still instills fear. More is known about ALS on a cellular level, and better symptomatic treatment is available. For now, the use of multiple agents affecting multiple pathways in a palliative way is the best that clinicians can do.
Ms. Yeznach Wick is a senior clinical research pharmacist at the National Institutes of Health. The opinions expressed herein are the author's and are not necessarily those of any government agency.
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