eMedicine Specialties > Physical Medicine and Rehabilitation > Disorders of the Motor Unit

Amyotrophic Lateral Sclerosis

Author: Patricia G Moyer Shannon, MD, MEd, Consulting Staff, Department of Physical Medicine and Rehabilitation, Carolinas Rehabilitation, Carolinas Medical Center
Coauthor(s): William L Bockenek, MD, Adjunct Clinical Professor, Department of Physical Medicine and Rehabilitation, University of North Carolina School of Medicine; Medical Director, Carolinas Rehabilitation; Coordinator of Post Polio Clinic; Chairman, Department of Physical Medicine and Rehabilitation, Carolinas Medical Center
Contributor Information and Disclosures

Updated: Mar 12, 2009

Introduction

Background

Amyotrophic lateral sclerosis (ALS) is the most common type of adult-onset motor neuron disease. Adult-onset motor neuron diseases are a group of neurologic disorders that present in adult life and are characterized primarily by progressive degeneration and loss of motor neurons. ALS involves upper and lower motor neurons and presents as an idiopathic, progressive degeneration of anterior horn cells and their associated neurons resulting in progressive muscle weakness, atrophy, and fasciculations. The disease was first described in 1869 and is commonly called Lou Gehrig disease after the professional baseball player who died of ALS in 1941.^1,2,3,4,5

Other diseases classified as adult-onset motor neuron diseases have more restricted presentations and can evolve into idiopathic ALS if the patient is tracked for a long period. These diseases include the following:

• Progressive bulbar palsy - Pure bulbar involvement
• Progressive muscular atrophy - Pure lower motor neuron degeneration
• Primary lateral sclerosis - Pure upper motor neuron degeneration
• Adult-onset spinal muscular atrophy - Includes a broad range of primary motor neuron diseases classified by pattern of inheritance, distribution of weakness, or age of onset

Pathophysiology

Amyotrophic lateral sclerosis (ALS) is named for its underlying pathophysiology. Amyotrophy refers to the atrophy of muscle fibers, which are denervated as their corresponding anterior horn cells degenerate. Lateral sclerosis refers to hardening of the anterior and lateral columns of the spinal cord as motor neurons in these areas degenerate and are replaced by fibrous astrocytes (gliosis).

Axonal Degeneration

Motor axons die by Wallerian degeneration, and large motor neurons are affected to a greater extent than smaller ones. This process occurs as a result of the death of the anterior horn cell body, leading to degeneration of the associated motor axon. As the axon breaks down, surrounding Schwann cells catabolize the axon's myelin sheath and engulf the axon, breaking it into fragments. This forms small ovoid compartments containing axonal debris and surrounding myelin, termed myelin ovoids. Ovoids then are phagocytized by macrophages recruited into the area to clean up debris.

This type of axonal degeneration can be seen in the brain on biopsy as atrophy and pallor of myelinated motor axons in the corticospinal tracts. In cases where the disease has been active for a long time, atrophy of the primary motor and premotor cortex may be seen as well. On biopsy of the spinal cord, degeneration of the myelinated motor axons with associated atrophy of the anterior motor roots of the spinal cord can be observed. Wallerian degeneration also occurs peripherally, and collateral branches of surviving axons in the surrounding area can be seen attempting to reinnervate denervated muscle fibers. On muscle biopsy, various stages of atrophy are noted from this pattern of denervation and subsequent reinnervation of muscle fibers.

In typical ALS, certain motor neurons are spared. In the brainstem, these include the oculomotor, trochlear, and abducens nerves. In the spinal cord, the posterior columns, spinocerebellar tracts, nucleus of Onuf (controls bowel and bladder function), and the Clarke column generally are spared, though the Clarke column can be affected in the familial form of the disease.

Frequency

United States

Currently, prevalence of amyotrophic lateral sclerosis (ALS) in the United States is estimated at 25,000-30,000 cases.

International

Annual incidence of amyotrophic lateral sclerosis (ALS) is 1-2 per 100,000 population with prevalence rate of 6 per 100,000 in the adult population. A geographic focus of the disease has been noted with increased incidence in the western Pacific where, in many cases, it is associated with Parkinsonism and dementia.

Mortality/Morbidity

Mean duration of amyotrophic lateral sclerosis (ALS) from onset to ventilator dependence or death is 2-4 years. Once ventilator use is initiated, mean survival generally is an additional 5 years, but frequently exceeds 10 years. Most patients who opt for ventilatory support die within 5 years of diagnosis, but a small percentage (8-22%) survive 10 years.

Sex

Male-to-female ratio for amyotrophic lateral sclerosis (ALS) is 1.5-2:1.

Age

Amyotrophic lateral sclerosis (ALS) may occur from the teenage years to the late 80s, but peak age at onset occurs from 55-75 years with mean age of 62 years at diagnosis.

Clinical

History

The clinical picture in all stages of amyotrophic lateral sclerosis (ALS) can vary and depends on the areas of the nervous system involved in each patient. Overall, the disease tends to be insidious and progressive with asymmetric weakness and atrophy. Fasciculations are seen from lower motor neuron involvement, and patients generally are hyperreflexic from upper motor neuron disease, though some reflexes may be diminished or absent because of excessive lower motor neuron degeneration.

In 75-80% of patients, symptoms begin with limb involvement, while 19-25% of patients present with bulbar symptoms. For those with limb involvement at presentation, incidence of upper limb versus lower limb involvement is approximately equal. Patients who have lower limb onset initially may complain of tripping, stumbling, or awkwardness when running. Those with upper limb onset may have difficulty with actions such as buttoning clothes, picking up small objects, or turning a key. With bulbar onset, patients note problems such as slurred speech, hoarseness, or decreased volume of speech.

Disease progression

As the disease progresses, muscle atrophy becomes more apparent, and spasticity may complicate gait and manual dexterity. Physicians usually recognize fasciculations first, but as patients become more aware of the involuntary twitching, they may become embarrassed by them. Immobility predisposes the patient to development of painful joint contractures. Muscle cramps are common, and, in some patients, persistent cramping of muscles and related joint stresses can cause diffuse and continuous aching of the limbs and back.

In patients with bulbar involvement, a mixture of spastic and flaccid components may characterize speech, resulting in a dysarthria with severe disintegration and slowness of articulation. Hypernasality occurs from palatal weakness, and patients eventually develop a strained, strangled vocal quality. With time, speech may be lost, and patients need to depend on other forms of communication such as writing, communication boards, or other assistive devices.

Patients with bulbar involvement also can develop swallowing difficulties (dysphagia) from progressive motor weakness. Swallowing liquids requires the greatest oropharyngeal muscle control; therefore, patients usually complain of more difficulty with liquids than with solids. Drooling is common and results from a combination of excessive salivation and poor labial control.

Some individuals may have pseudobulbar symptoms associated with their disease. These patients have an exaggerated emotional response, resulting in frequent and rapid alterations in emotions. Episodes of intense laughter may be followed immediately by tears, but the patient's response usually does not correspond to apparent social stimulus or the current psychosocial situation.

Preserved functions

Certain motor neurons usually are spared, and, as a result, patients have some functions that are preserved. Most retain extraocular movements and bowel and bladder control. Once patients become more affected, they may develop problems with urge incontinence and severe constipation because of weak abdominal musculature, but sphincter control generally is unaffected.

Since the disease primarily involves motor neurons, sensory function typically is preserved. Patients may complain of some numbness and paresthesias, but most do not have sensory symptoms. Sensory nerve conduction studies can be performed if indicated, but results generally are normal unless there is another identifiable condition to account for the patient's symptoms. Abnormalities have been reported on sensory nerve conduction studies in a small number of ALS patients. These findings, however, are varied, as they can be difficult to identify on routine nerve conduction studies.

In most patients, cognitive functioning is preserved. However, 3.5% of patients do exhibit clinical signs of dementia. These patients are usually found in the western Pacific, and may have associated symptoms of Parkinsonism.

Skin integrity usually is maintained, primarily from the combination of preserved sensory function along with continued control of bowel and bladder function. Some studies on these patients also have found morphologic changes in the skin that are complex and poorly understood but that may contribute to preservation of skin integrity.

Physical

Examination should correlate with the patient's clinical history and disease progression.

• Muscle weakness usually is asymmetric, and signs of upper and lower motor neuron involvement should be observed.
• In the initial stages, reflexes should be normal to increased, but as the disease becomes more advanced, reflexes may be diminished or absent. Pathologic long-tract signs of upper motor neuron involvement, such as the extensor plantar response and/or Hoffmann sign, may be present in patients with hyporeflexia or areflexia, depending upon the extent of the upper motor neuron involvement.
• In patients with bulbar involvement, speech may be impaired.
• Initially, a gag reflex should be present, and, if elicited, the physician should observe swallowing to check for signs of dysphagia. In advanced stages, the gag reflex may be absent; these patients probably have severe dysphagia and are at high risk for aspiration.

Causes

Amyotrophic lateral sclerosis (ALS) can be divided into familial and sporadic forms. Most are sporadic, accounting for 90-95% of cases. Remaining cases are familial. The clinical picture in the familial type of ALS is the same as in the sporadic form of the disease. Familial ALS nearly always is transmitted in an autosomal dominant pattern, and, in a subset of patients, a mutation for the gene Cu/Zn superoxide dismutase on chromosome 21 has been identified. Research points to involvement of deregulated cdk5 activity in the pathogenesis of the disease in individuals with this mutation. A second gene, ALS2, has also been found to be associated with the familial form of the disease. The role of these genes needs to be studied further.

Current research into the mechanisms resulting in sporadic and familial types of ALS has focused on excitotoxicity. This may occur secondary to overactivation of glutamate receptors, autoimmunity to calcium ion channels, oxidative stressors linked to free radical formation, or even cytoskeletal abnormalities such as intracellular accumulation of neurofilaments. Apoptosis has emerged as a significant pathogenic factor, and evidence suggests that insufficient vascular endothelial growth factor may also be a risk factor for ALS in humans. However, no direct mechanism has been identified and most researchers and clinicians agree that various factors, possibly a combination of some or all of the above processes, may lead to development of ALS. Current goals for therapies aim at studying combinations of agents that act by various mechanisms and evaluating stem cell therapy in combination with some of these agents.

Informing the patient

The American Academy of Neurology has established guidelines for breaking the news of a diagnosis of ALS to a patient. They include the following recommendations:

• Give the diagnosis to the patient and discuss its implications. Respect the cultural and social background of the patient in the communication process by asking whether the patient wishes to receive information or prefers that the information be communicated to a family member.
• Always give the diagnosis in person, never by telephone.
• Provide printed materials about the disease, contact information for advocacy associations, as well as a letter or audiotape summarizing what has been discussed.
• Avoid withholding the diagnosis, providing insufficient information, delivering information callously, or taking away or failing to provide hope.

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