The Definition

Amyotrophic Lateral Sclerosis (ALS) is a degenerative motor neuron disease characterized by progressive dropout of motor neurons in the brain, brain stem, and spinal cord. Motor neuron death leads to increasing weakness of the limbs, facial muscles, and diaphragm, while sensory function remains intact.

ALS shares at least two important basic properties with other neurodegenerative diseases, like Alzheimer's disease, Parkinson's disease, and Huntington's disease. All are adult-onset disorders arising from neuronal death, and all target specific subsets of neurons in the brain or spinal cord.

The last decade has seen an explosion of new insights into the mechanisms of cell death in ALS. Motor neurons are especially sensitive to the toxic effects of glutamate, which is normally vital to brain function. Glutamate toxicity is very likely a contributing factor in the death of motor neurons in ALS. Several other cellular events have been implicated in the development of ALS. The motor neurons which are afflicted do not react normally to oxidative stress, and they also demonstrate mitochondrial dysfunction. Apoptosis may also play a role in ALS motor neuron death. Genetic studies demonstrate that abnormal functioning of the enzyme superoxide dismutase 1 (SOD1) plays a part in ALS pathogenesis.

Dysfunction in all of these different cell mechanisms suggests that ALS may be the result of a cascade of events. The drugs under evaluation for treatment of ALS play a role in one or more of these pathways.

 

Epidemiology

The prevalence of ALS is 4 to 7 cases per 100,000, with an incidence of about 1.5 per 100,000. This means that in the United States, approximately 5,000 people every year will be diagnosed with ALS, and about 25,000 people currently live with the disease.

The median age of onset is fifty-five years in most studies, although the distribution is so broad that ALS can be seen in teenagers and octogenarians.

Most cases of ALS occur in the absence of a family history of the disease (sporadic ALS). Ten percent of patients inherit the disease (familial ALS). In most cases of familial ALS, the disease is passed on in an autosomal dominant pattern. In some of these cases, the cause of the disease has been traced to a specific mutation in the gene that encodes the enzyme superoxide dismutase 1 (SOD1).

There are no proven environmental causes of ALS, such as exposure to toxins or radiation; several environmental agents, however, are under scrutiny. A few small geographic foci have reported higher than average numbers of ALS patients, namely the Kii peninsula of Japan, western New Guinea, and certain western Pacific islands, such as Guam. With the exception of those discrete areas, neither geography nor ethnicity seem to be a predisposing factor for developing the disease. However, recent studies have reported a rising incidence of ALS in veterans of the Gulf War.

 

Disease Symptoms

In approximately eighty percent of patients with ALS, the illness begins in the limbs, and in twenty percent the onset is in the muscles related to chewing and speaking (bulbar onset). With time, the weakness spreads to other areas of the body. Ultimately, patients become weak in all limbs, develop difficulty breathing, and develop impairments in their ability to speak and swallow. The muscles of eye movement remain relatively unaffected, as does smooth muscle function, including urinary and anal sphincters, digestive tract muscles and the bladder. The course is progressive with a linear decline in strength with time during the active phase of the disease.

 

Current Treatments

Current treatments available to patients with ALS fall into two categories: disease modifying treatments and symptom treatments.

Disease-Modifying Treatments

Currently, there is only one FDA-approved drug that alters the course of ALS. Riluzole is an oral medication that alters the effect of glutamate on motor neurons, although the extent of this effect is still being evaluated. Although riluzole does not cure ALS, it is the first drug available to patients with ALS.

It is the mission of the North East ALS Consortium to assess possible treatments in the laboratory and then to advance them to clinical trials in patients with ALS as rapidly as possible.

Symptom Treatment

Most of the treatments of ALS target its symptoms. Alleviation of symptoms improves a patient's quality of life and perhaps longevity.

Respiratory decline

Impaired respiratory function is a primary cause of disability in patients with ALS. Symptoms of respiratory decline include shortness of breath with exertion, inability to breath normally while lying flat, and disordered sleep with morning headaches and fatigue. Eventually, respiratory function can become so compromised that mechanical assistance is required to maintain sufficient breathing. A pulmonary function test can evaluate the state of a patient's respiratory system. Noninvasive intermittent positive pressure ventilation (NIPPV) assists the muscles of the respiratory system by blowing air through the nose and into the lungs while the patient breathes in. When the patient exhales, the air pressure slackens. This treatment is effective only if the patient's facial muscles are strong enough to keep the mouth closed so that air does not escape. With NIPPV, many patients sleep much more comfortably, and some also benefit from NIPPV during waking hours.

As respiratory function worsens, NIPPV may not provide adequate breathing support. Many patients must then consider the option of chronic assisted ventilation, which requires a tracheostomy (a tube surgically placed into the airway) and a permanent connection to a ventilator. Patients on mechanical ventilation do not need to exert any effort to breathe, but the equipment is costly, it requires extensive trained assistance, and it limits a patient's ability to speak, take nutrition by mouth, and ambulate freely. Given the vast impact that mechanical ventilation has on lifestyle, the choice to use it should be made with a lot of consideration.

Nutrition

Recent studies indicate that people with ALS have higher caloric intake requirements than healthy individuals of the same age, but meeting caloric needs can be a challenge when swallowing becomes difficult. Soft solids and nutritional supplements help maintain intake, but over time they may prove insufficient. Nutritional support through a gastrostomy (feeding) tube improves many patients' quality of life and energy level. Feeding through the tube is easy for patients and family to learn, and they are usually capable of its daily maintenance. Placement of a gastrostomy tube is usually a simple procedure, but it can be risky in patients with severely impaired breathing capacity. ALS clinicians often recommend early intervention with a gastrostomy tube.

Depression and emotional lability

People with ALS often suffer from depression, which can be treated with psychotherapy, support groups, and antidepressant medication. Anxiety, which is also common in people with ALS, can be treated with anxiolytic agents. Some ALS patients report extreme displays of laughing or crying, often at inappropriate stimuli. This emotional lability can be disabling, especially in patients still working. Antidepressant medication is an effective treatment for emotional lability. The combination of dextromethorphan and quinidine has also recently been demonstrated to alleviate symptoms of emotional lability.

Drooling

ALS patients do not produce more saliva, but drooling often occurs because of difficulties swallowing. Anticholinergic agents (which block acetylcholine) can reduce saliva production and drooling, but may have side effects, including difficulty urinating. Parotid gland radiation and botulinim toxin injected into the salivary glands have also been effective in some patients.

Stiffness and cramps

A component of the disease process in ALS is spasticity, or stiffness and reduced control of movements. There are several drugs that reduce spasticity, but these drugs do not improve control of movement to a significant degree. In very weak patients who suffer from stiffness, antispasticity medication can increase comfort and ease of transfers. Muscle cramps are also very common, and can disrupt sleep. Quinine sulphate is useful in reducing cramps.

Mobility

Mobility is often the key to independence. Ankle foot orthoses (AFOs) often improve gait in patients with foot drop. Lightweight wheeled walkers can make ambulation safer and faster if patients have enough arm strength to use them.