Epileptogenesis is the gradual process by which a typical brain develops epilepsy. Epilepsy is a chronic condition in which seizures occur. These changes to the brain occasionally cause neurons to fire in an abnormal, hypersynchronous manner, known as a seizure.
Causes
The causes of epilepsy are broadly classified as genetic, structural/metabolic, or unknown. Anything that causes epilepsy causes epileptogenesis, because epileptogenesis is the process of developing epilepsy. Structural causes of epilepsy include neurodegenerative diseases, traumatic brain injury, stroke, brain tumor, infections of the central nervous system, and status epilepticus (a prolonged seizure or a series of seizures occurring in quick succession).
Latent period
After a brain injury occurs, there is frequently a "silent" or "latent period" lasting months or years in which seizures do not occur; Canadian neurosurgeon Wilder Penfield called this time between injury and seizure "a silent period of strange ripening". During this latent period, changes in the physiology of the brain result in the development of epilepsy. This process, during which hyperexcitable neural networks form, is referred to as epileptogenesis. If researchers come to better understand epileptogenesis, the latent period may allow healthcare providers to interfere with the development of epilepsy or to reduce its severity.
Pathophysiology
Changes that occur during epileptogenesis are poorly understood but are thought to include cell death, axonal sprouting, reorganization of neural networks, alterations in the release of neurotransmitters, and neurogenesis. These changes cause neurons to become hyperexcitable and can lead to spontaneous seizures.
Brain regions that are highly sensitive to insults and can cause epileptogenesis include temporal lobe structures such as the hippocampus, the amygdala, and the piriform cortex.
Neural reorganization
In addition to chemical processes, the physical structure of neurons in the brain may be altered. In acquired epilepsy in both humans and animal models, pyramidal neurons are lost, and new synapses are formed.
Hyperexcitability, a characteristic feature of epileptogenesis in which the likelihood that neural networks will be activated is increased, may be due to loss of inhibitory neurons, such as GABAergic interneurons, that would normally balance out the excitability of other neurons. Neuronal circuits that are epileptic are known for being hyperexcitable and for lacking the normal balance of glutamatergic neurons (those that usually increase excitation) and GABAergic ones (those that decrease it). In addition, the levels of GABA and the sensitivity of GABAA receptors to the neurotransmitter may decrease, resulting in less inhibition.
Another proposed mechanism for epileptogenesis in TBI is that damage to white matter causes hyperexcitability by effectively undercutting the cerebral cortex.
Glutamate receptor activation
It is believed that activation of biochemical receptors on the surfaces of neurons is involved in epileptogenesis; these include the TrkB neurotrophin receptor and both ionotropic glutamate receptors and metabotropic glutamate receptors (those that are directly linked to an ion channel and those that are not, respectively). Each of these types of receptor may, when activated, cause an increase in the concentration of calcium ions (Ca2+) within the area of the cell on which the receptors are located, and this Ca2+ can activate enzymes such as Src and Fyn that may lead to epileptogenesis.
Excessive release of the neurotransmitter glutamate is widely recognized as an important part of epileptogenesis early after a brain injury, including in humans. Excessive release of glutamate results in excitotoxicity, in which neurons are excessively depolarized, intracellular Ca2+ concentrations increase sharply, and cellular damage or death results. Excessive glutamatergic activity is also a feature of neuronal circuits after epilepsy has developed, but glutamate does not appear to play an important role in epileptogenesis during the latent period. Another factor in hyperexcitability may include a decrease in the concentration of Ca2+ outside cells (i.e. in the extracellular space) and a decrease in the activity of ATPase in glial cells.