Basic Mechanisms

Epileptic syndromes are characterized by a tendency to paroxysmal regional or generalized hyperexcitability of the cerebral cortex. Because of the phenomenolo-gical diversity and the etiological heterogeneity of epilepsies, it is likely that there are multiple underlying cellular and molecular mechanisms.

The mechanisms responsible for the occurrence of seizures (ictogenesis) and the development of epilepsy (epileptogenesis) have been studied in animal models and by in vitro studies of surgical human brain tissue. The exact mechanisms remain to be clarified. They represent complex changes of normal brain function on multiple levels, involving anatomy, physiology, and pharmacology. There are categorical differences in the pathophysiology of idiopathic generalized and symptomatic focal seizures. The latter are caused by a regional cortical hyperexcitation due to local disturbances in neuronal connectivity. Synaptic reorganization may be caused by any acquired injury or congenital abnormalities, such as in the many sub-forms of cortical dysplasia. Some areas of the brain seem more susceptible than others, the most vulnerable being mesial temporal lobe structures. The pathophy-siology of hippocampal sclerosis, the most common etiology of temporal lobe epilepsy, has been a topic of much controversy. It is most likely that the hippocam-pal structures are damaged by an early trauma, typically prolonged febrile seizures. The process of hippocampal sclerosis involves a synaptic reorganization with excitotoxic neuronal loss, loss of interneur-ons, and GABA deficit.

Epileptic neurons in an epileptogenic focus may produce bursts of action potentials that represent isolated spikes in the EEG as long as they remain locally restricted. Depending on the failure of local inhibitory mechanisms, these bursts may lead to ongoing and repetitive discharges. If larger neuronal networks are recruited in this hypersynchronous activity, this leads to an epileptic seizure that is either focal or secondary generalized depending on the extent of seizure spread. The local seizure threshold is regulated by influences on excitatory and inhibitory postsynaptic potentials. The membrane excitability is regulated by ion channels that are modulated by excitatory transmitters, particularly glutamate and aspartate, and the inhibitory transmitter GABA. These three levels are the major targets for antiepileptic drugs (Table III).

Primary generalized seizures are accompanied by a bilateral synchronous epileptic activity. Therefore, they cannot be explained by cortical dysfunction alone. They are caused by an imbalance of pathways between the thalamus and the cerebral cortex. These thalamocortical circuits are modulated by reticular nuclei. Excessive GABAergic inhibition and dysfunction of thalamic calcium channels also play a role in the pathogenesis, at least in the pathogenesis of absence seizures. These cortical-subcortical circuits are also responsible for circadian rhythms, which may explain the increased seizure risk after awakening and following sleep withdrawal in idiopathic generalized epilepsies. The appearance and disappearance of primary generalized seizures is strongly age dependent, a phenomenon that has been explained by disturbances in brain maturation processes.

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