Classification of Seizures and Epilepsy

The International League Against Epilepsy (ILAE) has derived two classification schemes, one for epileptic seizures (1) and another for epileptic syndromes (2). The seizure classification scheme uses clinical criteria only: what the event looked like to an observer and the interictal (and sometimes ictal) EEG pattern. Seizures are divided into those that begin focally (partial seizures) and those that simultaneously begin in both cerebral hemispheres (generalized seizures). The epilepsy syndrome classification utilizes additional information to permit a two-tiered categorization. First, as with the seizure classification, the seizures within a syndrome are divided into generalized or localization-related, i.e., focal onset, events. Second, the syndromes are organized into those that have a known etiology (symptomatic or secondary) and those that are idiopathic (primary) or cryptogenic. The reader is referred to refs. 1 and 2 for further details. These classifications allow the clinician to choose appropriate therapy, tailored to the specific seizure type or epilepsy. Some seizure/epilepsy types respond better to one form of therapy or another. However, these schemes are not definitive and will require ongoing revision as more knowledge is gained about epilepsy genetics and pathophysiology. The ILAE is currently working on another revised classification that takes into consideration recent advances in our understanding of epilepsy, its causes, and its manifestations (3).

Figure 1 utilizes this broad classification of seizures as partial (focal) or generalized, to illustrate the site of origin and spread of seizure activity. Partial seizures originate in a localized area of brain, with clinical manifestations based on the area of brain involved and how extensively discharges spread from this "focus" (Fig. 1A). For example, discharges from a focus in the left motor cortex may cause jerking of the right hand and arm. If the discharges spread to the motor area controlling the face and mouth, additional clinical ictal features would include facial twitching, drooling, and perhaps speech arrest. This pattern of clinical and electrographic seizure is typically seen in BRE, in which epileptic discharges are seen over the central-temporal area around the rolandic fissure.

On the other hand, generalized seizures begin with abnormal electrical discharges occurring in both hemispheres simultaneously. The EEG signature of a primary generalized seizure is "bilaterally synchronous spike-wave discharges" recorded over the entire brain at once. These generalized discharges reflect reciprocal excitation between the cortex and the thalamus (Fig. 1B). Generalized seizures can also spread and synchronize via the corpus callosum. A generalized seizure can manifest as anything from brief impairment of consciousness (as in an absence seizure) to rhythmic jerking of all extremities with loss of posture and consciousness (a generalized tonic-clonic [GTC] convulsion). A seizure that starts focally, then spreads widely throughout the brain is referred to as secondarily generalized (Fig. 1A, far right panel). For example, in BRE, seizures sometimes begin focally in face/hand motor cortex, then secondarily generalize to cause a GTC convulsion. Similarly, in a seizure of temporal lobe epilepsy (TLE), the first ictal symptom may be an aura, e.g., unusual taste or smell, motor automatism, e.g., repetitive picking at the clothes, or affective change, e.g., fear, distortion of time, déjà vu, or depersonaliza-tion, accompanied by discharges originating in the hippocampus or other temporal lobe structure; such seizures commonly generalize, resulting in a GTC convulsion. Some partial seizures secondarily generalize so quickly that they appear, both clinically and elec-trographically, to be generalized from the onset.

Although the mechanisms underlying partial seizures, partial seizures with secondary generalization, and primary generalized seizures differ somewhat (4), it is useful to think about any seizure as a disruption in the normal balance between excitation and inhibition in part or all of the brain. A seizure can occur when excitation increases, inhibition decreases, or both. Hyperexcitability can occur at one or more levels of brain function, such as a network of interconnected neurons, the neuronal membrane

Fig. 1. Coronal brain sections depicting seizure types and potential routes of seizure spread. (A) Focal area of hyperexcitability (star) and spread to nearby neocortex (solid arrow), via corpus callo-sum or other commissures to the contralateral cerebral hemisphere (dotted arrow), or via subcortical pathways, e.g., thalamus, brainstem (downward dashed arrow), resulting in secondary generalization (upward dashed arrows). Accompanying EEGs show brain electrical activity under numbered electrodes. Focal epileptiform activity (spikes) is maximal at electrode 3 and is also seen nearby at electrode 4 (left traces). If a seizure secondarily generalizes, spike activity may be seen synchronously at all electrodes, after a delay (right-most traces). (B) A primary generalized seizure begins simultaneously in both hemispheres. The characteristic bilateral synchronous "spike-wave" pattern on EEG is generated by interactions between cortex and thalamus, with rapid spread via corpus callosum (CC) contributing to the rapid bilateral synchrony. One type of thalamic neuron (solid circle) is a GABAer-gic inhibitory cell with intrinsic oscillatory properties; this neuron has a specific type of calcium channel, which enables it to fire in bursts of action potentials, allowing the GABAergic cells to modulate ongoing excitatory corticothalamic activity. Cortical neurons send impulses to both inhibitory thalamic neurons (solid circle) and excitatory thalamic relay neurons (diamond), setting up oscillations of excitatory and inhibitory activity, which in turn give rise to the rhythmic spike waves on EEG. (Modified with permission of the American Academy of Pediatrics from ref. 58.)

with its ionic channels, neurotransmitters and their receptors, or intracellular second-messenger cascades, and so on. Examples of specific pathophysiologic defects occurring at different sites within the nervous system are listed in Table 1 and are discussed more fully in subsequent sections. It is likely that specific genes modulate the excitability at each of these sites (5). Similarly, in addition to intrinsic factors, acquired disorders can express altered excitability at any of these levels. Just as epilepsy is not "one disease" but a broad spectrum of conditions associated with hyperexcitable neuronal function, there is no "one mechanism" of epilepsy; rather, several factors interact to create and sustain the hyperexcitable state.

Table 1

Examples of Specific Pathophysiologic Defects Leading to Epilepsy

Level of brain function Neuronal network

Neuron structure

Neurotransmitter synthesis

Neurotransmitter receptors:

inhibitory Neurotransmitter receptors:

excitatory Synapse development

Ionic channels


Cerebral dysgenesis, posttraumatic scar, mesial temporal sclerosis (in TLE) Downs syndrome and possibly other syndromes with mental retardation and seizures Pyridoxine (vitamin B6)

dependency Angelman syndrome

Nonketotic hyperglycinemia

Neonatal seizures

Benign familial neonatal convulsions

Pathophysiologic mechanism

Altered neuronal circuits: formation of aberrant excitatory connections ("sprouting") Abnormal structure of dendrites and dendritic spines: altered current flow in neuron Decreased GABA synthesis:

B6, a cofactor of GAD Abnormal GABA receptor subunits Excess glycine leads to of

NMDA receptors Many possible mechanisms, including the depolarizing action of GABA early in development Potassium channel mutations: impaired repolarization

TLE, temporal lobe epilepsy; NMDA, N-methyl-D-aspartate; GABA, y-aminobutyric acid; GAD, glutamic acid decarboxylase.

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