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Mechanisms of initiation and propagation of seizures

Partial seizure activity can begin in a very discrete region of cortex and then spread to neighboring regions, i.e., there is a seizure initiation phase and a seizure propagation phase. Studies of experimental models of these phases suggest that the initiation phase is characterized by two concurrent events in an aggregate of neurons: (1) high-frequency bursts of action potentials, and (2) hypersynchronization. The bursting activity is caused by a relatively long-lasting depolarization of the neuronal membrane due to influx of extracellular calcium (Ca2+), which leads to the opening of voltage-dependent sodium (Na+) channels, influx of Na+, and generation of repetitive action potentials. This is followed by a hyperpolarizing afterpotential mediated by g-aminobutyric acid (GABA) receptors or potassium (K+) channels, depending on the cell type. The synchronized bursts from a sufficient number of neurons result in a so-called spike discharge on the EEG.

Normally, the spread of bursting activity is prevented by intact hyperpolarization and a region of surrounding inhibition created by inhibitory neurons. With sufficient activation there is a recruitment of surrounding neurons via a number of mechanisms. Repetitive discharges lead to the following: (1) an increase in extracellular K+, which blunts the extent of hyperpolarization and depolarizes neighboring neurons; (2) accumulation of Ca2+ in presynaptic terminals, leading to enhanced neurotransmitter release; and (3) depolarization-induced activation of the N-methyl-D-aspartate (NMDA) subtype of the excitatory amino acid receptor, which causes more Ca2+ influx and neuronal activation. The recruitment of a sufficient number of neurons leads to a loss of the surrounding inhibition and propagation of seizure activity into contiguous areas via local cortical connections, and to more distant areas via long commissural pathways such as the corpus callosum.

Many factors control neuronal excitability, and thus there are many potential mechanisms for altering a neuron's propensity to have bursting activity. Examples of mechanisms intrinsic to the neuron include changes in the conductance of ion channels, response characteristics of membrane receptors, cytoplasmic buffering, second-messenger systems, and protein expression as determined by gene transcription, translation, and posttranslational modification. Mechanisms extrinsic to the neuron include changes in the amount or type of neurotransmitters present at the synapse, modulation of receptors by extracellular ions and other molecules, and temporal and spatial properties of both synaptic and nonsynaptic input. Nonneural cells, such as astrocytes and oligodendrocytes, have an important role in many of these mechanisms as well.

Certain known causes of seizures are explained by these mechanisms. For example, accidental ingestion of domoic acid, which is an analogue of glutamate (the principal excitatory neurotransmitter in the brain), causes profound seizures via direct activation of excitatory amino acid receptors throughout the CNS. Penicillin, which can lower the seizure threshold in humans and is a potent convulsant in experimental models, reduces inhibition by antagonizing the effects of GABA at its receptor. The basic mechanisms of other precipitating factors of seizures, such as sleep deprivation, fever, alcohol withdrawal, hypoxia, and infection, are not as well understood but presumably involve analogous perturbations in neuronal excitability. Similarly, the endogenous factors that determine an individual's seizure threshold may relate to these properties as well.

Knowledge of the mechanisms responsible for the initiation and propagation of most generalized seizures (including tonic-clonic, myoclonic, and atonic types) remains rudimentary and reflects the limited understanding of the connectivity of the brain at a systems level. Much more is understood about the origin of generalized spike-and-wave discharges in absence seizures. These appear to be related to oscillatory rhythms that are normally generated during sleep by circuits connecting the thalamus and cortex. This oscillatory behavior involves an interaction between GABABreceptors, T-type Ca2+ channels, and K+ channels located within the thalamus. Pharmacologic studies indicate that modulation of these receptors and channels can induce absence seizures, and there is speculation that the genetic forms of absence epilepsy may be associated with mutations of components of this system.


Epileptogenesis refers to the transformation of a normal neuronal network into one that is chronically hyperexcitable. For example, there is often a delay of months to years between an initial CNS injury such as trauma, stroke, or infection and the first seizure. The injury appears to initiate a process that gradually lowers the seizure threshold in the affected region until a spontaneous seizure occurs. In many genetic and idiopathic forms of epilepsy, epileptogenesis is presumably determined by developmentally regulated events.

Pathologic studies of the hippocampus from patients with temporal lobe epilepsy have led to the suggestion that some forms of epileptogenesis are related to structural changes in neuronal networks. For example, many patients with MTLE syndrome have a highly selective loss of neurons that has been proposed to contribute to inhibition of the main excitatory neurons within the dentate gyrus. There is also evidence that, in response to the loss of neurons, there is reorganization or "sprouting" of surviving neurons in a way that affects the excitability of the network. Some of these changes can be seen in experimental models of prolonged electrical seizures or traumatic brain injury. Thus, an initial injury such as head injury may lead to a very focal, confined region of structural change that causes local hyperexcitability. The local hyperexcitability leads to further structural changes that evolve over time until the focal lesion produces clinically evident seizures. Similar models have also provided strong evidence for long-term alterations in intrinsic, biochemical properties of cells within the network, such as chronic changes in glutamate receptor function.


The most important recent progress in epilepsy research has been the identification of genetic mutations associated with a variety of epilepsy syndromes. Although all of the mutations identified to date cause rare forms of epilepsy, they have led to extremely important conceptual advances. For example, it appears that many of the inherited, idiopathic epilepsies (i.e., the relatively "pure" forms of epilepsy in which seizures are the phenotypic abnormality and brain structure and function are otherwise normal) are due to mutations affecting ion channel function. These syndromes are therefore part of the larger group of "channelopathies" causing paroxysmal disorders such as cardiac arrhythmias, episodic ataxia, periodic weakness, and familial hemiplegic migraine. In contrast, gene mutations observed in symptomatic epilepsies (i.e., disorders in which other neurologic abnormalities, such as cognitive impairment, coexist with seizures) are proving to be associated with pathways influencing CNS development or neuronal homeostasis. A current challenge is to identify the multiple susceptibility genes that underlie the more common forms of idiopathic epilepsies.

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