Introduction

Amyotrophic lateral sclerosis is a devastating human disease of upper and lower motoneurons of unknown etiology. It is a neuromuscular disease progressively compromising arms, legs, speech, swallowing, and breathing. In the United States, the incidence of the disease is approximately 1.8 per 100,000 and its prevalence is between 5 and 7 per 100,000 (1). Males are affected more commonly than females. Approximately 5-10% of the cases are familial (1). Onset may occur at any age but it is most common in the later decades, and the incidence appears to increase with age. The mean age of onset is 55 years (14).

Clinical Features

Distal weakness and atrophy are the hallmarks of the disorder. Upper limb muscles are more frequently involved initially than lower limb muscles (13). Muscle cramps, parasthesias, and even pain are frequent complaints in ALS. Progression usually occurs over 12 to 30 months, and death ensues as a result of severe impairment of breathing functions (14). Sensory signs are usually absent, but occasionally are reported at sometime during the illness. The extraocular muscles are almost never symptomatically involved in ALS, although loss of occulomotor neurons from the brainstem has been reported (12). Control of bladder, bowel, and autonomic function is considered unimpaired, even late in the disease (14).

Electrophysiologic Studies

Standard nerve conduction studies and standard electromyography reflect the underlying pathophysiologic process. Features which indicate ALS include reduced numbers and increased amplitude and duration of motor unit action potentials. There are also fibrillation’s and fasciculations in many muscles not innervated by the same nerve or spinal cord segment. Fibrillation’s, positive sharp waves, and complex repetitive discharges are features of denervation. The increased amplitude and duration of the action potentials reflect increasing muscle fiber numbers in each motor unit, which is the result of successful reinnervation by surviving motor axons (20). The electrophysiologic features reflect the underlying pathophysiologic process and progress in the relative absence of clinical signs.

Pathophysiolic Features: Central Nervous System

In ALS, the brain may appear normal microscopically, although atrophy of the motor and premotor cortices is usually present. The most prominent changes are atrophy of the spinal cord and associated ventral roots and palpable firmness of the lateral columns.

The major pathological abnormality is degeneration and loss of large motor neurons of the motor cortex, brainstem, and spinal cord. The features of this process include shrinkage, chromatolysis, inclusions of lipofuscin, and gliosis (10). Corticospinal tract involvement is most readily observed in the anterior and lateral columns of the spinal cord. Degeneration is also present in these same fibers in the brainstem and cerebrum.

Neuronal changes are most prominent in the anterior horn of the spinal cord. The major changes are atrophy of the large spinal motor neurons and subsequent degeneration, loss, and glial replacement. Careful study of the motor neurons in Onufrowicz’s sacral nucleus, believed to innervate the anal and urethral external sphincters, confirms that they are uniformly preserved in ALS (11). This nucleus has also been thought to subserve some autonomic functions.

Cytoplasmic and Ultrastructural Features:

In remaining motor neurons there is chromatolysis and inclusions that are rich in ribonucleic acid. The whole neuron seems to be involved, and there is only minimal evidence of "dying back" of the peripheral axons. In addition, large proximal axonal swellings have been reported in motor neurons from patients with ALS (1). These "spheroids" represent abnormalities of neurofilaments and may be found in the cytoplasm as well as in the axon. The spheroids have been found in control patients, but are more numerous in the ALS patients (5). The swellings seem to be most numerous early in the course of the disease (19). Spheroid development and neuronal degeneration are thought to be complimentary processes.

Spheroids consist of bundles of neurofilaments with trapped cytoplasmic structures inside (9). Phosphorylated neurofilaments have been found to be increased in the soma and proximal axons of anterior horn cells from patients with ALS (15). This suggests that premature or excessive phosphorylation may be associated with impairment of neurofilament transport.

Etiologic Theories:

Abnormalities of axonal transport:

Because axonal transport is an essential neuronal function, a primary defect in this process could underlie the neuronal degeneration in ALS. Abnormalities of slow transport can cause changes in the density of cytoskeletal elements such as neurofilaments. Accumulation of neurofilaments causes axonal swelling, and depletion causes axonal atrophy (8). Both of these characteristics have been seen in association with ALS. Unfortunately, slow axonal transport is difficult to study in humans and nothing concrete has been found to determine the effects of the slow transport abnormalities.

Trophic Factors:

Appel postulated that neurodegenerative diseases are caused by a lack of a disorder-specific neurotrophic hormone (1). The best known neurotrophic factor is beta-nerve growth factor, synthesized predominantly in tissues innervated by sympathetic and sensory neurons. The growth factor is assimilated into specific neurons and retrogradely transported in the axon to exert its physiologic and specific biochemical effects at the level of the nucleus. Evidence indicates that beta-nerve growth factor is an important determinant of the developmental regulation and maintenance of specific neuronal sub-populations by the promotion of cell survival and neurite outgrowth (21). Although beta-nerve growth factor is the best characterized neurotrophic molecule, no human disease is yet known to be the result of absence or abnormal function of this molecule. Specific trophic factors from muscle that influence neuronal survival and neurite outgrowth have yet to be isolated (3). Although disruption of the neurotrophic function of muscle has ‘been postulated to be the etiologic mechanism in ALS, no specific motor system trophic molecule analogous to or even comparable to beta-nerve growth factor has yet been identified.

Immune Hypothesis:

A variety of evidence including immune complex deposition (7) and an increase in the incidence of thyroid disease and autoimmune disorders among patients with ALS and their blood relatives (2) has led some authors to postulate an immune cause of ALS.

Deposition of immune complexes have been found in the spinal cord and motor cortex of patients with ALS, but current evidence suggests that immune complexes in ALS are a phenomenon due to degeneration of cells in the central nervous system.

The possibility of an autoimmune mechanism of pathogenesis in ALS has long been considered. Antibodies that react in vitro with gangliosides have been found in sera of a large majority of patients with ALS and other motor neuron diseases (6). Gangliosides are present in high concentration in neuronal cell membrane terminals. It is proposed that the antibodies which bind to the nerve terminal might be internalized and conveyed to the cell bodies via retrograde axonal transport and produce their effect at the cell body.

The spinal cord and motor cortex of patients with ALS were found to stain positively for IgG, and no such reactivity was noted in control human tissues (7). Reactive microglia and/or macrophages were detected in the territory of degenerating pyramidal tracts and ventral horns.

Many studies have been carried out in an effort to determine the role of immunity in ALS. Considerable evidence, however, fails to support any conventional hypothesis of immune dysfunction in ALS.

Other Theories:

Various other theories have been postulated to explain the cause of ALS, but still nothing definite has been determined as to its etiology. Some of the other theories include a genetic hypothesis, an association with neoplasm, a DNA defect hypothesis, a viral hypothesis, and association with metallic toxins.

Treatment

Certain drugs, including quinine, phenytoin, and baclofen, diminish muscle cramps (18), and the anticholinesterase action of pyridostigmine bromide may help diminish symptomatic fatigability in some patients (16). Various other drugs can somewhat relieve specific symptoms. Also, discomfort and pain can be relieved with standard analgesics. Physical exercise is recommended for patients with ALS.

The inevitably fatal and progressive character of ALS create unique difficulties in achieving an ideal substance which alters the progress of the disorder. Studies have been done using thyrotropin releasing hormone. The most recent reports indicate that, with appropriate doses, patients have a definite early response to treatment (284). Patients had symptomatic improvement and temporarily increased muscular strength or diminished spasticity, although often in association with unpleasant side effects. The anti-viral agent guanidine was reported to have possible short-term benefits, but these results were not reproducible (17).

Although much effort has been put into finding answers to this puzzling disease, still it remains a progressive disorder for which there is no promising treatment.

References:

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3. Beach, R. L., Popiela, H.. Festoff, B. W. Trophic factors and neuromuscular function: implications for ALS. In Research Progress in Motor Neurone Disease. Edited by F.C. Rose. London, Pitman Books, 1984, pp. 228-248.

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19. Sasaki, S., Maruyama, S., Yamane, K., Sakuma, H., Lakeishi, M. Swellings of proximal axons in a case of motor neuron disease. Ann. Neurol., 25: 520 - 522, 1989.

20. Stalberg, E. Recent progress in ALS neurophysiology. Excerpta Medica International Congress Series No. 769, 1988, pp. 155-160.

21. Varon. S., Manthorpe, M., Davis, G. E., Williams, L. R., Skaper, S. D. Growth factors. Adv. Neurol. 47: 493-521, 1988.