INTRODUCTION	Section 2 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Background: Amyotrophic lateral sclerosis (ALS) is a devastating disorder of the anterior horn cells of the spinal cord and the motor cranial nuclei that leads to progressive muscle weakness and atrophy. Although major recent advances have shed light on its etiology, the key mechanisms in both familial and sporadic ALS remain unknown. No cure is known. This article reviews the major breakthroughs in ALS research, the clinical aspects of the disease, and current therapeutic options. An outline of new and promising technology and its application to the understanding of ALS is presented.

Pathophysiology: ALS primarily involves anterior horn cells in the spinal cord and cranial motor nerves. Patients may have weakness of bulbar muscles or of single or multiple limb muscle groups. Presentation is not always bilateral or symmetrical. A predominantly bulbar form usually leads to more rapid deterioration and death. Limb weakness is predominantly distal. Weakness and atrophy of the intrinsic hand muscles are prominent. Weakness progresses to involve the forearms and shoulder girdle muscles and the lower extremities.

Involvement of both upper and lower motor neurons is characteristic. Patients develop variable hyperreflexia, clonus, spasticity, extensor plantar responses, and limb or tongue fasciculations. Wallerian degeneration of corticospinal and corticobulbar tracts may be demonstrated by MRI (high-intensity T2 lesions in frontal lobes) or in postmortem examination. Extraocular muscles and bladder and anal sphincter muscles typically are spared.

ALS rarely affects cognitive functions. Electromyogram (EMG) shows signs of diffuse denervation with generally preserved nerve conduction velocities. Although an inflammatory process may be present, new evidence points toward multiple mechanisms that promote neuronal cell death in the CNS as the underlying basis for ALS. The recent demonstration of superoxide dismutase 1 (SOD1) mutations in human familial ALS and in murine ALS models supports the view that oxidative stress, mitochondrial dysfunction, and excitotoxicity pathways may be involved in the process of neuronal cell death.

A lack of trophic factor support has been hypothesized, as some authors have reported decreased insulin-like growth factor 1 (IGF-1) in patients with ALS. Aberrant RNA processing in sporadic ALS is thought to lead to abnormal expression of glutamate transporter (EAAT2) variants in the spinal cord. Despite multiple searches for infectious causative agents, no definitive viral or bacterial etiology has been identified.

ALS can be part of a complex with parkinsonism and dementia (ALS/PDC complex). This variant can be seen in patients from southern Guam. An ALS-like motor neuron disease also can be seen as a paraneoplastic syndrome in patients with cancer.

The complexity of ALS pathogenesis is highlighted by the recent discovery that alsin, a molecule putatively involved in cell-signaling, may be affected in a subset of familial ALS cases.

Autoimmunity may play a role in ALS. T cells, activated microglia, and immunoglobulin G (IgG) within the spinal cord lesions may be the primary event that leads to tissue destruction. Supporting this hypothesis, IgG derived from ALS patient sera may affect the conductance of neuronal voltage-activated calcium channels and may induce an excessive release of glutamate from nerve endings. The presence of immune complex formation in spinal cords of patients with ALS also has been demonstrated.

The El Escorial World Federation of Neurology criteria are helpful in diagnosis. Careful clinical history-taking is essential in making the correct diagnosis. For instance, Lyme neuroborreliosis on rare occasions may mimic an ALS-like syndrome.

Intravenous cyclophosphamide treatment has resulted in only temporary and mild amelioration of symptoms.

Patients with ALS may benefit from riluzole, a glutamate antagonist medication that modestly prolongs tracheostomy-free survival. Techniques that aim to elucidate altered pathways of gene expression (ie, gene chip technology) or protein expression (proteomics) may give clues to ALS pathogenesis in animal models. These may also expedite the identification of abnormal pathway-modifying pharmaceutical agents.

Frequency:

• In the US: Taking into account the most comprehensive studies (by Kurtzke), the frequency is approximately 5 cases per 100,000 population.

Mortality/Morbidity:

• ALS leads to death within a decade. In most cases, death occurs within 5 years.

• Some patients with familial, juvenile-onset ALS have been reported to survive for longer periods (2-3 decades).

Race: In the United States, ALS affects whites more often than nonwhites; the white-to-nonwhite ratio is 1.6:1.

Sex: The ratio of ALS-affected males to females is 1.5:1.

Age: Onset occurs in the fourth to seventh decades of life. However, exceptions to this do exist.

	CLINICAL	Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

History:

• ALS begins insidiously as weakness, atrophy, or fasciculations in 1 or more limbs.

• The manifestations are usually distal but gradually progress to involve the more proximal muscles.

• Fasciculations and atrophy of the tongue may be noted.

• Respiratory insufficiency is usually a late event.

Physical:

• Physical examination reveals weakness and atrophy of the intrinsic hand muscles, hyperreflexia with extensor plantar responses, and clonus.

• Thigh fasciculations are common.

• Hyperreflexia can be variable and in some cases may be absent.

• Sensory involvement, if any, is minimal.

• Patients may present with an inability to write due to weakness. Gait function may be preserved until later stages.

Causes:

• Nearly 10% of ALS cases are familial; the disease is transmitted in an autosomal dominant fashion.

• The copper/zinc SOD1 gene is mutated in 10-20% of these familial cases. Alsin is mutated in fewer cases of familial ALS.

• Although the primary mechanism of SOD1-mediated neural injury is currently unknown, apoptosis, excitotoxicity, and oxidative stress are thought to play major roles in pathogenesis.

• Sporadic ALS shares clinical features with familial ALS. However, no SOD1 mutations or polymorphisms have been identified in these patients. Common pathways of disease pathogenesis may play a role, with different molecular abnormalities that lead to similar phenotypes.

• Several studies have shown an inflammatory component to the affected spinal cord regions, with the presence of activated microglia, reactive astrocytes, and IgG deposition. Whether this reaction precedes or accompanies the molecular events that promote neuronal cell death is unknown.

• ALS animal models

• The SOD1 transgenic model of ALS has provided important insights into potential pathogenetic mechanisms in human ALS. Experimental animals with the alsin mutation have also been generated.

• Recent investigations suggest that SOD1 mutations act through a gain of function and involve free radical generation.

• Disease onset in these animals correlates with a massive increase in degenerating mitochondria.

• The murine SOD1 mutant also shows a proliferation of astrocytes and microglia within the brain and spinal cord, suggesting the presence of a reactive inflammatory component.

• Knockout mice for SOD1 exhibit typical progressive muscle atrophy and weakness with selective damage to motor neurons that closely resembles human ALS.

• In the wobbler mouse (a motor neuron disease model), administration of recombinant IGF-1 delays the deterioration of grip strength.

• Mice that overexpress the human neurofilament (NF) heavy gene accumulate neurofilaments in the spinal cord, leading to an ALS-like disease. Disruption of normal axonal transport in motor neurons is believed to trigger the phenotype of this ALS model.

• A motor neuron disease that resembles ALS can be generated in rabbits by sciatic subperineural administration of aluminum. Retrograde transport of aluminum results in anterior horn cell neurofilament accumulation and fragmentation of endoplasmic reticulum.