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At a glance

A degenerative and progressive motor neuron disease primarily involving motor neurons in the cerebral cortex, brainstem, and spinal cord and manifesting initially with fasciculations that will eventually progress to muscle weakness and paralysis.

Synonyms

ALS; Lou Gehrig Disease (named after the famous American baseball player for the New York Yankees who succumbed to amyotrophic lateral sclerosis in 1941).

History

First described in 1869 by Jean-Martin Charcot, a French neurologist.

Incidence

Annually, approximately 4 to 8 new cases per 100,000 are diagnosed in the general population with a male-to-female ratio of 1.5:1 and an age at onset of typically between 40 and 60 years.

Genetic inheritance

The etiology is not known. Amyotrophic Lateral Sclerosis (ALS) can be inherited in an autosomal dominant (in about 10% of cases), autosomal recessive, or X-linked fashion. The remaining cases are believed to be either environmental (eg, manganese, mercury, fertilizers, insecticides, herbicides) or caused by an unknown slow-virus infection. However, despite extensive searches for infectious causative agents, no viral or bacterial etiology has been identified. The hypothesis that glutamate excitotoxicity, oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction are involved in the process of neuronal cell death has been at least in part supported by the discovery of superoxide dismutase-1 (SOD1) mutations in approximately 10% of patients with familial ALS.

Pathophysiology

This degenerative motor neuron disease affects upper and lower motor neurons (LMNs). The upper motor neuron (UMN) axons descend mainly through the great corticofugal tracts to the brainstem and the spinal cord to modify the activity of the LMNs. Signs of UMN degeneration include increased muscle tone, hyperreflexia, clonus, pathologic spread of reflexes, extensor plantar response, and weakness. The LMNs are located in the brainstem and spinal cord and innervate the skeletal muscles. LMN involvement in ALS presents as hyporeflexia, muscle cramps, fasciculations, weakness, and muscle atrophy. Depending on the initial presentation, different types of ALS can be distinguished that include primarily cortical neuron degeneration (primary lateral sclerosis), degeneration of central nuclei (pseudobulbar palsy), and/or motor neurons (progressive spinal amyotrophia). Independent of the initial symptoms, the disease will eventually spread to other muscle groups. Patients may present with progressive bulbar palsy or (commonly symmetrical and distal) weakness of single or multiple muscle groups of the limbs. The primarily bulbar form of ALS is associated with a worse prognosis with regard to severity and overall survival time. Fasciculations of the intrinsic hand muscles, which are an early and characteristic sign, later progress to weakness (poor handgrip), and atrophy and eventually spread proximally to the forearms and shoulder girdle muscles. Typically, both upper and LMNs are affected. Clinically, limb or tongue fasciculations, hyperreflexia, clonus, and spasticity are found. An inflammatory response with activated microglia, reactive astrocytes, and IgG antibodies can be found in ...

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