Amyotrophic Lateral Sclerosis is an insidiously developing, adult-onset, progressive anterior horn cell degeneration with associated degeneration of descending motor pathways. Despite increasing clinical and research interest, its cause remains obscure. Although many theories as to its cause have been proposed, no intervention has yet been shown to modify biologically determined motor system degeneration.
There is no clear cut neuropathological diagnosis for Amyotrophic Lateral Sclerosis (ALS). Instead, clinicians must rely on both the topographic distribution of the neuronal loss and the finding of some characteristic cytological changes. The precise pattern of these changes, however, varies to
some extent, depending on whether the disease is of the classical sporadic type, one of the less common familial types, or the Chamorro form in Guam (1).
The primary feature of ALS is anterior horn neuronal cell degeneration and loss. The pathologic features of this process include shrinkage and pyknosis of the large spinal motor neurons (with consequent prominence of lipofuscin), the presence of ghost cells, neuronophagia, and gliosis (2). There is a massive loss of Betz cells and other pyramidal cells from the precentral cortex. Along with the loss of cortical cells, the corticospinal tracts are preferentially depleted of large myelinated fibers (3). Corticospinal tract involvement is most readily observed in the anterior and lateral columns of the spinal cord, particularly caudally. Degeneration of the spinocerebellar tracts may be seen. The posterior columns are affected (but not always) as well (4).
Cell loss can be difficult to judge in the brainstem nuclei. Associated findings such as intracellular degenerative changes and denervation of target muscles may be necessary to confirm pathologic involvement in this region. Lower brain stem nuclei are almost always more consistently and extensively involved than the upper brain-stem nuclei (2). However, changes in the occulomotor nuclei are rarely associated with clinical signs.
In recent studies, it has been shown that the occulomotor and sacral nuclei have been associated with patients whose course of illness has been extended over a longer period of time with the help of respirators and other medical equipment. This finding suggests that these neuronal phenotypes are vulnerable to the pathophysiologic process but are inexplicably more resistant to it than are lower cranial and spinal motor neurons (4).
Standard nerve conduction studies and electromyography have long been used in the diagnosis of ALS. The characteristics of standard nerve conduction studies and standard electromyography reflect the underlying pathophysiologic process. Features that support a diagnosis of ALS include reduced numbers and increased amplitude and duration of motor unit action potentials, in addition to 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. As the number of functional motor units in a muscle diminishes in ALS, the mean motor unit amplitude and motor unit potential area increase. Increased duration and amplitude of motor unit action potentials reflect increasing muscle fiber numbers in each motor unit, which is the result of successful reinnervation by surviving motor axons (4).
Swash and Schwartz (5) defined four stages in ALS on the basis of clinical and electromyographic criteria. In the first two stages, muscle strength is unimpaired, and fiber density progresses from mildly to markedly increased levels. Fiber densities may be up to five times their normal levels, and maximum electromyographic motor unit action potential amplitudes may increase as much as forty times. These changes indicate successful, continuous reinnervation of denervated fibers. In the third stage, clinical weakness and fatigability develop. Fiber densities are high, and impulse blocking is detected as increased jitter ("jitter" refers to instability in sub-components of the motor unit action potentials when measured by single fiber electromyography). This stage may represent exhaustion of physiologically successful reinnervation. Finally, the muscle becomes profoundly weak and atrophic, and fiber densities, when still measurable, may be decreased (4).
Many different cytoplasmic and ultrastructural abnormalities have been identified in ALS. Although some are typical of the disease and others are commonly associated with it, none of them is pathognomic (4).
Spheroids are irregular swellings of material that is faintly eosinophilic and strongly argentophilic with a whirled, fibrillary pattern found associated with anterior horn cells. Although these are found in patients with ALS, they are also found in normal control subjects, but are much less frequently encountered. Spheroids may take on various shapes and arise in either dendrites or axons. They seem to be most numerous early in the course of the disease. When they are large, they are seen associated with atrophy of the process in which they arose. Spheroid volume also seems to increase along with atrophy of the cell some and chromatolysis or increasing lipofuscin. These findings suggest that spheroid development and neuronal degeneration are complementary processes (4).
At the ultrastructural level, spheroids consist of interwoven bundles of 10 nm. neurofilaments. Within them, apparently trapped during spheroid development, may be found cytoplasmic structures such as mitochondria, smooth endoplasmic reticulum, and even nuclei (6).
Another feature seen commonly in patients with ALS is Buinina bodies. These are small (2-3 microns), round, eosinophilic structures found in the neural cytoplasm. When present in a neuron, four to six of them are typically found. These may fuse into chains. They may be autophagic, but their precise origin is unknown.
There are many different theories as to the cause of ALS, each with its good points and its drawbacks. There is no general consensus as of yet as to what specifically causes ALS.
Genetic theories on ALS were postulated soon after the disease was discovered, but no consensus about the relative contribution of genetic and environmental factors has yet been reached. No genetic marker linked to ALS has ever been discovered (4), but familial aggregation of the disease does actually occur (7). Whether this is a genetic predisposition or some other factor is yet to be seen.
In a number of patients with ALS, it was noted that they had a coexisting carcinoma. It has been proposed that this is what is causing ALS. However, no definitely increased incidence of carcinoma has been found in patients with the disease (8).
A defect in DNA repair enzymes which results in the formation of abnormal neuronal proteins causing premature cell death has been another proposal. Evidence for this theory is reduced levels of cytoplasmic RNA in the anterior horn cells of ALS patients. Disproving this notion, is the fact that cell survival after irradiation of cell lines derived from patients with ALS is no different from that in control subjects (4).
The role of metallic toxins in ALS is another theory being offered. Elemental lead has become a universal pollutant. High doses are neurotoxic and can cause an encephalopathy or a lower motor neuron disorder (or both). The search for abnormal accumulations of lead in specific tissues of ALS patients remains largely inconclusive. Treatment with chelating agents has yielded no benefit in most patients. Other metals being considered in the cause of this disease include mercury, aluminum, manganese, and selenium (4).
A variety of evidence, including immune complex deposition and increased autoimmune disorders among patients with ALS, has led some to believe ALS has an immune cause. Considerable evidence, however, fails to support any conventional hypothesis of immune dysfunction in ALS. Proposed unconventional autoimmune processes remain to be, tested.
Other theories as to the cause of the disease include abnormal carbohydrate metabolism, viral causes, thyroid disease, defects in calcium metabolism, and other toxic factors (4). Each of these by themselves fail to fully explain the cause of ALS.
There is no treatment for ALS as of yet. However, despite the unavailability of therapy that can alter the prognosis for ALS patients, a strong consensus on the need for active management of the disease has recently been developed. This management focuses on symptomatic care no matter how small the problem may be. This includes splints for wrist-drop, Teflon prostheses for palatal weakness and surgical collars for neck weakness, to name a few. Physical exercise, particularly aerobic exercise is recommended for these patients as well.
rude annual death rates for ALS have risen rather steadily in the United States. Several studies have shown that males are more likely to get this disease than females. Geographical location was shown to have very little significance on the incidence of ALS. Finally, some studies have shown that there is a higher incidence among people involved in agriculture or heavy labor (9). However, these studies have a rather small sample size so there validity remains questionable.
The nature of ALS, with the fear and hopelessness it engenders in its victims, makes it imperative that claims of successful therapeutic intervention be based on objective scientific assessment. The inevitably fatal, sometimes variable, and often rapidly progressive character of ALS may create unique difficulties in achieving this ideal. In spite of extensive research, attractive hypotheses, and new treatment strategies, Amyotrophic Lateral Sclerosis remains an enigmatic and incurable disease.
Bibliography:
1. Hirano, A. Cytopathology of amyotrophic lateral sclerosis. Adv. Neurol., 1991; 56:91-101.
2. Hughes, J. T. Pathology of amyotrophic lateral sclerosis. Adv. Neurol., 1982; 36:61-73.
3. Sobue, G., Hashizume, Y., Mitsuma, T. ,Takahashi, A. Size- dependent myelinated fiber loss in the corticospinal tract in Shy-Drager syndrome and amyotrophic lateral sclerosis. Neurology, 1987; 37:529-532.
4. Williams, D. B., Windebank, A. J. Motor neuron disease (amyotrophic lateral sclerosis). Mayo Clin. Proc., 1991; 66(1): 54-92.
5. Swash, M., Schwartz. Staging motor neurone disease: single fiber EMG studies of asymmetry, progression and compensatory reinnervation. In Research Progress in Motor Neurone Disease, 1984; 123-140.
6. Hirano, A., et. al. Fine structural observations of neurofilamentous changes in amyotrophic lateral sclerosis. J. Neuropathol. Exp. Neurol., 1984; 43:461-470.
7. Kurland, L. T., Mulder, D. W. Epidemiologic investigations of amyotrophic lateral sclerosis. Neurology, 1989; 5:182-196.
8. Barron, K. D., Rodichok, L. D. Cancer and disorders of motor neurons. Adv. Neurol., 1982; 36:267-272.
9. Kurtzke, J. F. Risk factors in amyotrophic lateral sclerosis. Adv. Neurol., 1991; 56:245-70.