Basic Mechanisms Of Epileptogenesis

To understand the mechanisms related to the development of epilepsy, some basic principles of normal neurophysiology must be reviewed. Electrical signals in neurons take two forms: the action potential, which propagates down the axon of the neuron from the soma to the axon terminal translocating information within a neuron; and transmission of information between neurons, which is accomplished primarily by chemical synapses.

A complex series of events underlie these electrical signals. Central to the understanding of these events is that the neuronal membrane is semipermeable to different ions carrying electrical current. The neuronal membrane's permeability

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exhibits rapid changes that can dramatically alter the voltage across it. At the resting membrane potential, sodium ions (Na + ), which are concentrated in the extracellular space, flow into the cell, and intracellular potassium ions (K + ) flow out. A Na+ -K+ pump, utilizing adenosine triphosphate (ATP), replaces the displaced ions. Influx of positively charged ions (Na+ and calcium ions [Ca2+ ]) raises the membrane potential in the direction of depolarization, whereas chloride ion (Cl - ) influx and K+ efflux hyperpolarizes the membrane. When a cell membrane is depolarized to threshold, Na + channels open, allowing the ions to flow intracellularly, which produces an action potential. Potassium efflux from the cell leads to repolarization of the membrane. The propagation of action potentials along axons transmits information throughout the nervous system. When the presynaptic axon terminal is stimulated by an action potential, there is an influx of Ca 2+ triggering the release of neurotransmitters that bind to postsynaptic membrane receptors. This process produces excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs) whose summation and synchronization comprise the electrical activity recorded from the surface electroencephalogram (EEG). Glutamate and aspartate are the primary excitatory neurotransmitters in the central nervous system (CNS). Gamma aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain.

A number of cortical cytoarchitectural and anatomical factors influence the propagation of electrical activity. The cerebral cortex is subdivided into neocortex, paleocortex, and archicortex. The archicortex includes the hippocampus and dentate gyrus, and the paleocortex consists of the piriform and olfactory cortices. The neocortex constitutes the remaining cortical regions characterized by the infolding of gyri and sulci. Epilepsy is a disorder that affects neocortical and archicortical neurons and their interconnections with brain stem and diencephalic structures.

The gray matter of the neocortex contains six types of neurons: pyramidal, stellate, horizontal, fusiform, basket, and Martinotti's cells ( .Fig, 5.2,-1).. The vertically aligned pyramidal cells are the main output neurons; they have extensive dendritic arborizations and excitatory synaptic endings that facilitate propagation of electrical activity. The granule, or stellate, cells are the major interneuronal pool. They are the second most numerous cells in the neocortex and are responsible for the propagation of both excitatory and inhibitory information. Axons of the horizontal and granule cells and collaterals of pyramidal and fusiform cells traverse parallel to the surface of the cortex. Pyramidal, fusiform, stellate, and Martinotti's cell axons form radial networks that travel vertically as projection or association fibers.

Projection fibers are afferent and efferent fibers conveying impulses to and from the cortex. Efferent fibers arise from the cortex and descend through the corona radiata and internal capsule. Afferent fibers arise primarily from the thalamus and project via the internal capsule to all regions of the cortex. Fibers interconnecting various cortical regions within the same hemisphere are known as association fibers. These include three main bundles: the uncinate fasciculus, connecting the orbital frontal gyri with anterior portions of the temporal lobe; the arcuate fasciculus, connecting the superior and middle frontal gyri with parts of the temporal lobe; and, the cingulum, connecting medial regions of the frontal and parietal lobes with parahippocampal and adjacent temporal cortical regions. Commissural fibers interconnect corresponding cortical regions of the two hemispheres and are represented by the corpus callosum and the anterior commissure. These pathways are important in the relay of information between hemispheres.

The pathophysiology of epilepsy involves alterations of normal physiological processes. An epileptic seizure is produced by synchronous and sustained firing of a population of neurons in the brain. The behavioral manifestations of a seizure reflect the function of the cortical neurons involved in the generation and spread of abnormal electrical activity. Epileptogenicity refers to the excitability and synchronization of neuronal networks that produce epileptiform activity in the brain. Both excitatory and inhibitory influences may be altered, creating a predisposition to excessive synchrony within neuronal populations.

Differences exist between patients who experience a single seizure and those with a tendency for recurrent seizures. Single seizures have various causes including electrolyte disturbances, drugs, and toxins. Increased extracellular K + leading to regenerative hyperexcitability underscores seizures that accompany metabolic aberrations. In hyponatremia, the extracellular space shrinks, leading to an increased concentration of extracellular K + and increased nonsynaptic or ephaptic coupling. This rise in K+ facilitates neuronal firing. Similarly, because membrane excitability varies inversely with the extracellular concentration of Ca 2+ , hypocalcemia can contribute to the synchronization and spread of abnormal electrical activity. Other metabolic disturbances such as hypomagnesemia, hyperglycemia, hypoxia, and ischemia can also produce seizures.

Alterations of neurotransmission, the ionic milieu, neuronal morphology, and neuronal networks are instrumental in the production of recurrent unprovoked seizures. Animal models using maximal electroshock and chemoconvulsants such as pentylenetetrazol have been used for decades to investigate the pathophysiology of generalized and focal seizures.

Experimentally induced focal epilepsies have been produced by the application of topical metals, such as cobalt, aluminum, and iron to the sensorimotor cortex. Pathological examination of these lesions reveals gliosis and neuronal loss. Neurons in the surrounding area may demonstrate abnormal dendritic morphology including denuded spines and reduced branching. Iron salts applied or injected into the cortex of experimental animals have been used in the investigation of post-traumatic epilepsy. Although the precise mechanisms of iron-induced epilepsy are unclear, iron is known to bind strongly with ATP and inhibit Na + -K+ -ATPase activity, leading to neuronal hyperexcitability. Additionally, iron reacts with the neuronal cell lipid membrane, producing free radicals and resulting in lipid peroxidation.

The kindling model is currently used in the study of partial epilepsy, particularly that involving the mesial temporal structures. Kindling refers to the processes that mediate long-lasting changes in brain function in response to repeated, gradually augmented stimulation of the brain. In the kindled animal, there is a permanent state of enhanced

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Figure 52-1 Types and orientation of neurons within the six-layer neocortl(From Pansky B, Allen DJ: Review of Neuroscience. New York, MacMillan, 1980, p 287.)

seizure susceptibility. These models are important not only in the understanding of the pathophysiological basis of epilepsy but also in the screening of new compounds that may have anticonvulsant activity.

The structures most susceptible to the development of recurrent seizures include the motor cortex and the hippocampal formation and amygdaloid complex of the limbic system. The motor cortex is comprised of three areas: primary motor cortex, premotor cortex, and supplementary motor area. The motor cortex exerts its control by way of descending corticospinal and corticobulbar tracts and pathways originating in the brain stem. The motor cortex receives input from the thalamus, parietal lobe, and prefrontal cortex. These afferents allow seizures arising in restricted areas to propagate diffusely.

The amygdaloid complex (see Chla.st.e.L3. is an aggregate of subcortical nuclei within the rostral pole of the mesial temporal lobe having reciprocal interconnections with the septal area, hypothalamus, and brain stem nuclei. The hippocampal formation extends along the floor of the temporal horn of the lateral ventricle and is comprised of the dentate gyrus, hippocampus proper (CA fields), and the subicular complex (see Cha.síeL4. ). Hippocampal or mesial temporal sclerosis is characterized by variable degrees of pyramidal cell loss and gliosis in the hippocampal subfields and dentate gyrus. This condition represents the most common pathological substrate of partial epilepsy in adolescents and adults.

The notion that epilepsy is an inherited disorder was suggested more than 2000 years ago. The prevalence of epilepsy in relatives of affected individuals ranges from 0.5 to 15 percent.[3] Rates are higher in idiopathic than symptomatic epilepsies. Studies of twins have demonstrated concordance rates as high as 70 percent in monozygotic and 10 percent in dizygotic pairs, [3] implying that factors other than genetics play a role in the occurrence of seizures in these groups. Thus far, three syndromes have been mapped to a single gene locus: juvenile myoclonic epilepsy to chromosome 6q, benign familial neonatal convulsions to 20p, and progressive myoclonic epilepsy of the Unverricht-Lundborg type to 21q. Several other epilepsies, including childhood/juvenile absence epilepsy, benign childhood epilepsy with centrotemporal spikes, childhood epilepsy with occipital paroxysms, and epilepsy with grand mal seizures on awakening appear to exhibit mendelian inheritance patterns and are likely to be mapped in the future. Additionally, as the result of various metabolic abnormalities, tumor formation, or impairment of normal brain growth or differentiation, seizures may occur in a large group of inherited neurological disorders. The investigation of these disorders may further elucidate the processes involved in epileptogenesis.

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Alcohol No More

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