Back to Basics: The Pathophysiology of Epileptic Seizures: A Primer For Pediatricians

Seizures are one of the most common neurologic disorders affecting children. As many as 5% of children experience a seizure during childhood. Although many epilepsies, especially refractory ones, are managed by specialists in pediatric neurology or epilepsy, general pediatricians often are called upon to manage children who have both acute and chronic seizures. Therefore, it is important to understand some of the basic pathophysiologic mechanisms underlying epileptic seizures. This understanding will allow the physician to choose the most appropriate medication for the given seizure type and clinical setting.Seizures can be a particular challenge to treat. Fortunately, in addition to the armamentarium of anticonvulsant agents previously available, a profusion of new antiepileptic drugs (AEDs) has appeared in the past 5 years. Some of these drugs are designed to address specific pathophysiologic defects in the sequence of events leading to the generation or spread of seizures. The purpose of this article is to review the principles of cellular neurophysiology as a foundation for understanding how normal neuronal function goes awry in epilepsy. First, normal synaptic transmission and neuronal firing are summarized. Next, the pathophysiology of acute and chronic seizures is discussed. Finally, the mechanisms by which AEDs control the hyperexcitability that underlies epilepsy are considered.A seizure is a temporary disruption of brain function due to the hypersynchronous, excessive discharge of cortical neurons. Sometimes the term epileptic seizure is used to distinguish from a nonepileptic seizure such as a pseudoseizure, which is not caused by hypersynchronous firing of neurons. The clinical manifestations of a seizure depend on the specific region and extent of brain involvement and may include an alteration in motor function, sensation, alertness, perception, autonomic function, or all of these. Any person can experience a seizure in the appropriate clinical setting (eg, meningitis, hypoglycemia, toxin ingestion),attesting to the innate capacity of even a “normal” brain to support hypersynchronous discharges, at least temporarily.Epilepsy is the condition of recurrent, unprovoked seizures (two or more), usually in a person who has a predisposition because of a chronic pathologic state (eg,brain tumor, cerebral dysgenesis, posttraumatic scar) or genetics. Approximately 1% to 2% of the population suffers from epilepsy,making it the second most common neurologic disorder (after stroke), affecting more than 2 million persons in the United States.An epilepsy syndrome refers to a group of clinical characteristics that consistently occur together,with seizures as a primary manifestation. Such features might include similar age of onset, electroencephalographic findings, precipitating factors, inheritance pattern, natural history, prognosis, and response to AEDs. Epilepsy syndromes in childhood include infantile spasms, febrile seizures, childhood absence epilepsy, benign rolandic epilepsy (BRE), and juvenile myoclonic epilepsy.The electroencephalogram (EEG)is the primary tool for recording electrical activity of the human brain. Small metal disk electrodes are attached to the scalp at specified locations. When sufficiently amplified, voltage changes generated in neocortical neurons are recorded on the EEG as waveforms of various frequencies,amplitudes, and morphology. EEG patterns vary according to the child’s age, state of alertness, and genetic background. The EEG records activity from near the brain’s surface, primarily from the neocortex. Electrical activity from deep in the brain (eg, brainstem,thalamus, deep temporal lobe) may not be recorded reliably by routine EEG. If surface recording is inadequate, special recording techniques might be required, such as surgical placement of electrodes directly on the brain or implanted into it.Epileptic seizures are broadly classified as partial (focal) or generalized, depending on their site of origin and pattern of spread (Fig. 1). Partial seizures originate in a localized area of the brain, with clinical manifestations based on the area of brain involved and how extensively discharges spread from this “focus”. For example, a focus in the left motor cortex may cause jerking of the right hand and arm. If the discharges spread to the motor area that controls the face and mouth, additional clinical ictal features would include facial twitching, drooling, and perhaps arrest of speech. This pattern of clinical and electrographic seizure is typical of the BRE syndrome.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, reflecting reciprocal excitation between the cortex and the thalamus (Fig. 1B). Generalized seizures also can spread and synchronize via the corpus callosum. Manifestations of a generalized seizure can range from brief impairment of consciousness (as in an absence seizure)to rhythmic jerking of all extremities accompanied by loss of posture and consciousness (a generalized tonic-clonic convulsion).A seizure that starts focally and then spreads widely throughout the brain is referred to as secondarily generalized. For example, in BRE, seizures sometimes begin focally in the face/hand motor cortex, then secondarily generalize into a generalized tonic-clonic (GTC) convulsion. Similarly, in a seizure of temporal lobe epilepsy (TLE), the first ictal symptom may be motor automatisms (eg, repetitive picking at the clothes) or affective changes(fear, distortion of time, déjà vu, or depersonalization)accompanied by discharges originating in the hippocampus or other temporal lobe structures. Such seizures commonly generalize, resulting in a GTC convulsion. Some partial seizures generalize secondarily so quickly that they appear, both clinically and on EEG, to be generalized from their onset.Although the mechanisms underlying partial seizures, partial seizures with secondary generalization, and primary generalized seizures differ somewhat, 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, including a network of interconnected neurons; the neuronal membrane with its ionic channels, neurotransmitters, and their receptors; or intracellular second messenger cascades. Examples of specific pathophysiologic defects occurring at different sites within the nervous system are listed in Table 1and are discussed more fully in subsequent sections. It is likely that specific genes modulate the excitability at each of these sites. In addition to intrinsic factors, acquired disorders also can express altered excitability at any of these levels. Just as epilepsy is not “one disease” but a broad category of conditions related to hyperexcitable neuronal function, there is no one mechanism of epilepsy;rather, several factors interact to create and sustain the hyperexcitable state.As a preface to considering the abnormal firing seen in epilepsy, we need to review normal synaptic transmission and neuronal firing. There are two basic types of neurons, depending on the neurotransmitter released from its terminals:excitatory or inhibitory (Fig. 2). When a neuron is activated, it releases a transmitter from prepackaged vesicles in presynaptic terminals, a process that requires calcium influx. The transmitter diffuses across the synaptic cleft and binds to its specific receptor on the postsynaptic membrane. Binding sets in motion a cascade of events that involves ion fluxes through the receptor and a subsequent change in excitability of the postsynaptic cell (depolarization or hyperpolarization, that is, movement of the membrane potential closer to or further away from the threshold voltage for generation of an action potential).The primary inhibitory transmitter in the brain is gamma-amino-butyric acid (GABA). GABA is synthesized from glutamate in the presynaptic terminal by action of the enzyme glutamic acid decarboxylase (GAD), which requires pyridoxine (vitamin B6) as a cofactor. Influx of Ca++ caused by depolarization of the terminal prompts vesicles to release GABA into the synaptic cleft. GABA diffuses across the cleft and binds to its receptors (GABAA), which opens a pore or channel through which chloride ions (Cl−) enter the neuron. This Cl− influx increases the negative charge inside the postsynaptic neuron, thereby hyperpolarizing it. The resultant change in membrane potential is called an inhibitory postsynaptic potential (IPSP) (Fig. 3). An IPSP reduces firing of the neuron by temporarily keeping the membrane potential away from firing threshold.1Obviously, a reduction of any component of the GABA-IPSP system favors excitation and predisposes to epileptic firing. Conversely, enhancing the GABA system is a logical approach for restraining neuronal hyperexcitability, and several AEDs act on various aspects of the GABA system (see section on AED mechanisms).Excitatory neurotransmission in the brain is mediated largely by the excitatory amino acid glutamate. Glutamate released from presynaptic terminals may bind to any of several glutamate receptor subtypes. For simplicity, we designate these as NMDA(N-methyl-D-aspartate) and non-NMDA (kainate and amino-3-hydroxy-5-methyl-isoxasole propionic acid or AMPA). This confusing nomenclature arose because experimentally, NMDA is a very selective agonist for one subtype of glutamate receptor (therefore, termed NMDA receptors),whereas AMPA and kainate prefer another type of glutamate receptor(therefore, named non-NMDA receptors). However, glutamate (not NMDA, AMPA, or kainate) actually is the naturally occurring neurotransmitter; it is a flexible molecule that can bind to both NMDA and non-NMDA receptors, with different physiologic consequences in each case. These receptor subtypes are of pivotal importance in the generation of epileptic firing.Non-NMDA receptors mediate the “fast” excitatory neurotransmission ordinarily associated with an excitatory postsynaptic potential (EPSP) (Fig. 3). Binding of glutamate to non-NMDA receptors causes influx of sodium ions (Na+)through the receptor’s pore, producing a “fast EPSP” (duration about 5 msec),often followed by an action potential if the threshold is reached.Glutamate binding to NMDA receptors sets into motion a somewhat different set of physiologic events. For activation of the NMDA receptor, the following must occur: 1) glutamate must bind to the NMDA receptor; 2) glycine, an essential co-agonist, must bind at another, nearby site on the NMDA receptor complex; and 3) magnesium ion (Mg++) blocking of the channel pore must be relieved (Fig. 2, inset). Mg++ ions play a unique role in the operation of the NMDA receptor. At resting potential, a Mg++ ion sits in the pore,preventing influx of any other ions. Once the membrane potential is depolarized by 10 to 20 mV (by a non-NMDA-mediated fast EPSP), the Mg++ is expelled out of the pore into the extracellular space, allowing Na+ and Ca++to flow into the neuron, giving rise to an NMDA-mediated prolonged EPSP. Much of the importance of NMDA receptors lies in their ability to allow influx of Ca++; once inside a neuron, Ca++ can participate in a number of crucial second messenger pathways. In the normal brain, NMDA receptors play important roles in learning, memory, and the neuronal plasticity that underlies many critical developmental processes. However, if NMDA receptors are overstimulated, the entry of excess Ca++ can wreak havoc, activating destructive intracellular enzymes (eg, endonucleases, proteases), which even may lead to cell death. The role of NMDA receptors in epileptic firing is described below.The depolarization caused by either the fast or slow EPSP also activates “voltage-gated” ionic channels (such as Na+ or Ca++) in the membrane; these channels, which are distinct from those opened directly by transmitter binding, become activated and open only at certain membrane potentials. If the sum of depolarizations caused by glutamate receptor activation and by voltage-gated channels is sufficient, firing threshold may be reached, and an action potential will occur. During the longer NMDA-evoked depolarization, several action potentials may fire. Below threshold, EPSPs and IPSPs are engaged in a dynamic, electrical “tug-of-war,” each affecting the membrane potential in the opposite direction. The final membrane potential is the sum of all excitatory and inhibitory inputs, which varies according to the magnitude and timing of each input.Action potentials are “all-or-none” events; once threshold is reached, an action potential will fire. The upstroke of the action potential is caused by a huge influx of Na+ through voltage-gated channels; the downstroke is due to efflux of potassium ions (K+) out of the cell through voltage-gated K+ channels. One epilepsy syndrome of relevance to pediatricians—benign familial neonatal convulsions—recently has been attributed to mutations of voltage-dependent K+ channels. Such mutations would prolong action potentials by reducing their repolarization rate, thus keeping the neuron depolarized longer.At the tail end of the action potential, the membrane potential is hyperpolarized briefly beyond its original resting level; this is called the afterhyperpolarization (AHP). The AHP is mediated by another type of K+ channel that differs from the one responsible for the action potential downstroke and does not depend on voltage. Rather, it depends on the intracellular calcium (Ca++) level. These “Ca++-dependent K+ channels”regulate the timing of neuronal firing by govening the neuron’s refractory period, the time during which the cell is recovering from the previous action potential and cannot yet generate another one. Therefore, if these channels, which can limit repetitive firing, become dysfunctional, epileptic discharges could result.Because the ionic balance inside and outside of the neuron is altered after neuronal firing(especially after epileptic a mechanism must to ionic neuronal firing, there is excess the cell and excess K+ in the extracellular A in the neuronal membrane this function by Na+ out and K+ into the In of ionic balance is by nearby which act and excess extracellular This role of is critical because extracellular K+ levels can the membrane directly and cause epileptic the involvement of ion fluxes through a of and channels 2) to the of normal neuronal firing. This for at a of sites if the system as in epilepsy.The pathophysiology of epilepsy has two distinct but related hyperexcitability and Hyperexcitability is the abnormal of a neuron to an excitatory the neuron to discharges of the one or refers to the of of neurons into an abnormal firing epilepsy is a network that requires of many neurons firing in the brain to cause it to and are mechanisms for excitation to inhibition to or a of and ictal a physiologic events at the of the brain and in a neuronal excitation and inhibition in the are are activated only when they are The EEG in the normal activity in which the neurons in the region the are not firing If or perhaps of neurons begin to in one area of the cortex, a EEG or discharge is recorded on the EEG The the area of cortex the the spread of such In the of neurons firing is 2, also some spread of the abnormal firing. Such are to in The the ictal with a of firing EEG which may for many or At this even more neurons are firing the of which would be a clinical seizure manifestations with the area of brain is on at the neuronal network when neurons from their normal firing pattern to the condition and then to the ictal The some of the physiologic features that these In this than recording electrical activity from the surface of the brain, we have electrodes inside excitatory cortical neurons and 2, thereby recording intracellular potentials. Much of understanding of epilepsy mechanisms from such an action potential in neuron when the membrane potential is depolarized to its threshold as discussed in neuron also may the activity of its neuron For example, a of several from an action potential in neuron may rise to an EPSP in neuron If cell an inhibitory is activated by a discharge from neuron then the activity in neuron 2 will be by an IPSP that in time with the EPSP. The recorded will be a If the IPSP perhaps with the the of the EPSP will be In this we can inhibition or If this is to of interconnected neurons, each the activity of many it is to how an in excitation or in inhibition in the system could lead to firing in a area of brain. neurons action or in and excitability is in by the of inhibitory intracellular of the EEG is called the depolarization It is termed because it from activity and because the membrane potential is depolarized for several of The is actually a a prolonged depolarization that causes the neuron to a of several action potentials on a of depolarization is an NMDA-mediated experimentally, NMDA receptor and seizures. The is by a non-NMDA-mediated EPSP and by a NMDA-mediated EPSP. with the NMDA-mediated slow EPSP of about 10 to 20 the is longer to and has many more action potentials the that the of the and EEG are similar they the is followed by a which the and least firing of action potentials. that a in neuron may a similar in neuron 2, which can the neuron so that an entire network of neurons can be into firing in If excitation excessive or inhibition is the can lead into an ictal discharge In the the is the neuron to generate a prolonged Such discharges in one neuron can spread to the inhibitory control on the system and leading to an electroencephalographic and clinical This may occur because the is due to of in to extracellular a in intracellular or a of other the brain can normal to generate and spread seizure activity if the system is in such a to excitation over In the of recurrent, unprovoked seizures function is This chronic hyperexcitability can from a number of mechanisms 2). For example, inhibition can from or of inhibitory conditions in which GABA is or GABA receptors have an abnormal or in when the of inhibitory excitatory excitation might occur if NMDA receptors are due to the of excessive glutamate or or if ionic channels that are responsible for repolarization are of the in is how the brain altered to create the for chronic epilepsy. Sometimes an or cause can be but often no is One type of epilepsy, can be a of to the one of the most of the brain. which can be caused by could hyperexcitability after the has This chronic hyperexcitability is due to the of several neuronal or temporal and the of abnormal how such might occur by producing excitatory neurons all activity the ordinarily only action potentials and neurons, which action potentials in response to causes of to of NMDA receptors and excessive as discussed but neurons. Therefore, of neuron are left a postsynaptic so they to their and those of neurons, an excitatory This in neuron 2 excessive excitatory and firing action neurons to the than unique only to the might a more general mechanism by which brain become brain is to seizures, with seizure during the first and especially during the first of physiologic features a hyperexcitable state in Ca++ and Na+ channels, which mediate neuronal to inhibitory NMDA receptors are in when they are for critical developmental processes. The pattern of in the brain is more the than in an network of excitatory The ability of to extracellular K+ also increases with Finally, perhaps may be an excitatory transmitter in the balance in the brain changes during The of these physiologic is that the brain is especially to hyperexcitability during a critical of these of brain the for producing the discussed we can some of the of various drugs (Fig. and other similar for these can be in AEDs aspects of the inhibitory and bind to different sites on the receptor. These drugs inhibition by allowing Cl− influx through the GABA by the of chloride channel and by the of is a new AED that be in the United it has in for the of infantile and other seizure is an of a that to a specific pathophysiologic the GABA GABA thereby the of GABA to in inhibitory new also increases GABA but it does so by GABA into the presynaptic The mechanism of action of it may the of GABA or AEDs aspects of neuronal and the new AED voltage-dependent sodium channels and the ability of neurons to used primarily for absence seizures, a unique calcium that is only in neurons, from firing in an and neocortical neurons into spike-wave new AEDs are to the function of NMDA receptors and or non-NMDA receptors The the ion pore of NMDA and agents have been in clinical because they cause excessive is to AEDs that other aspects of the NMDA system (Fig. 2, inset). In addition to blocking the ion activity might be by glutamate binding or blocking other sites on the receptor that must be activated for the receptor to function (such as the The voltage-dependent blocking of the NMDA receptor ion pore by Mg++ could be another site for anticonvulsant in magnesium has been used for by to control seizures in and as as the AED have excitatory and inhibitory of other epilepsy such as for infantile and the (a and used in seizure disorders refractory to largely AEDs are likely to ability to seizures according to specific pathophysiologic but it is essential to understand the underlying principles of normal and abnormal neuronal function to such agents most receptors also in the postsynaptic membrane; their activation causes a IPSP mediated by a that opens a potassium (K+) The role of in epilepsy is in Cl− is inside the neuron than when it in the extracellular Therefore, when GABA binds to its receptors and opens Cl− channels, the negative charge from inside to outside the neuron, its The loss of negative charge from inside the neuron it.