Epilepsy - Pathophysiology

Pathophysiology

Mutations in several genes have been linked to several types of epilepsy. Some genes that code for protein sub units of voltage-gated and ligand-gated ion channels have been associated with forms of generalized epilepsy and infantile seizure syndromes.

One speculated mechanism for some forms of inherited epilepsy are mutations of the genes that code for sodium channel proteins; these defective sodium channels stay open for too long, thus making the neuron hyper-excitable. Glutamate, an excitatory neurotransmitter, may, therefore, be released from these neurons in large amounts, which — by binding with nearby glutamatergic neurons — triggers excessive calcium (Ca2+) release in these post-synaptic cells. Such excessive calcium release can be neurotoxic to the affected cell. The hippocampus, which contains a large volume of just such glutamatergic neurons (and NMDA receptors, which are permeable to Ca2+ entry after binding of both glutamate and glycine), is especially vulnerable to epileptic seizure, subsequent spread of excitation, and possible neuronal death. Another possible mechanism involves mutations leading to ineffective GABA (the brain's most common inhibitory neurotransmitter) action. Epilepsy-related mutations in some non-ion channel genes have also been identified.

Much like the channelopathies in voltage-gated ion channels, several ligand-gated ion channels have been linked to some types of frontal and generalized epilepsies.

Epileptogenesis is the process by which a normal brain develops epilepsy after trauma, such as a lesion on the brain. One interesting finding in animals is that repeated low-level electrical stimulation to some brain sites can lead to permanent increases in seizure susceptibility: in other words, a permanent decrease in seizure "threshold." This phenomenon, known as kindling (by analogy with the use of burning twigs to start a larger fire) was discovered by Dr. Graham Goddard in 1967. It is important to note that these "kindled" animals do not experience spontaneous seizures. Chemical stimulation can also induce seizures; repeated exposures to some pesticides have been shown to induce seizures in both humans and animals. One mechanism proposed for this is called excitotoxicity. The roles of kindling and excitotoxicity, if any, in human epilepsy are currently hotly debated.

Other causes of epilepsy are brain lesions, where there is scar tissue or another abnormal mass of tissue in an area of the brain.

The complexity of understanding what seizures are have led to considerable efforts to use computational models of epilepsy to both interpret experimental and clinical data, as well as guide strategies for therapy.

Physical, emotional, and social functioning of youth are interfered specifically if seizures are uncontrolled. Some other noted consequences on repeated seizures are neuronal loss, gliosis, parenchymal microhemorrhages, excess of starch bodies, leptomeningeal thickening, subpial gliosis, perivascular gliosis and periavascular atrophy.

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