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• Intrinsic problems with immune system - probably common to all autoimmune diseases, probably genetic.
• Problems with the blood-brain barrier, allowing T cells to enter the CNS and promote production of antibodies against myelin
• A specific Infectious agent – Some have proposed that a virus triggers the autoimmune response that leads to demyelinization. No specific agent has been found
• Vitamin D deficiency – the geographic distribution supports this. Vitamin D is involved in regulating the immune system, as well as neural function.
Grigoriadis and Hadjigeorgiou Journal of Autoimmune Diseases 2006 3:1 doi:10.1186/1740-2557-3-1
Proposed scheme for virus-mediated autoimmunity in multiple sclerosis.
• Anti-inflammatory agents – corticosteroids, chemotherapeutic agents, etc. as used to treat lupus. – Drawbacks: These drugs have many side effects. In addition,
they generally increase the risk of infection, and viral and bacterial infections have been shown to speed the progression of MS.
• Supplemental vitamin D has been shown to slow the progression of MS
• Tysabri – A monoclonal antibody against T cells, which blocks their entry into the CNS. – Drawback: cripples brain defenses against infection. Patients
are at risk of deadly brain infections.
ALS affects both upper (within the CNS) and lower (those that directly innervate muscle)
• 5-10% of cases are strictly genetic (Familial ALS).
• Of these about 10% are due to a defect in an enzyme called superoxide dismutase 1 (SOD1), which scavenges free radicals.
• This finding has led some to speculate that free radical damage may be involved in other forms of the disease.
Possible environmental risk factors
• Exposure to a dietary toxin called BMAA may account for high incidence in Guam and other places in the western Pacific.
• US military veterans from both the Pacific and the Gulf War.
• Exposure to herbicides has long been suspected, as clusters have been seen in athletes and farmers.
Possible Mechanisms of ALS Pathogenesis
• Oxidant injury, perhaps due to some abnormality in antioxidant systems
• Glutamate toxicity, perhaps due to a defect in astroglial cells which normally remove this neurotransmitter from the synapse. The resulting “excitotoxicity” leads to neuronal death, causing further release of glutamate.
Treatments for ALS
• Riluzole, a drug that decreases glutamate release is the only FDA-approved drug for ALS. It is only moderately effective suggesting that other mechanisms are involved in the pathogenesis of ALS.
• Other drugs are used to treat symptoms of the disease, including muscle cramps, spasms, fatigue, etc.