Pediatrics in Review 1998 Stafstrom 342 51

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DOI: 10.1542/pir.19-10-3421998;19;342Pediatrics in Review

Carl E. StafstromBack to Basics: The Pathophysiology of Epileptic Seizures: A Primer For Pediatricians

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342 Pediatrics in Review Vol. 19 No. 10 October 1998

BACK TO BASICS

A review of

the scientific

foundations

of current

clinical practice

Introduction

Seizures are one of the most com-mon neurologic disorders affectingchildren. As many as 5% of childrenexperience a seizure during child-hood. Although many epilepsies,especially refractory ones, aremanaged by specialists in pediatricneurology or epilepsy, generalpediatricians often are called uponto manage children who have bothacute and chronic seizures. There-

fore, it is important to understandsome of the basic pathophysiologicmechanisms underlying epilepticseizures. This understanding willallow the physician to choose themost appropriate medication forthe given seizure type and clinicalsetting.

Seizures can be a particularchallenge to treat. Fortunately, inaddition to the armamentarium ofanticonvulsant agents previouslyavailable, a profusion of newantiepileptic drugs (AEDs) hasappeared in the past 5 years. Some

of these drugs are designed toaddress specific pathophysiologicdefects in the sequence of eventsleading to the generation or spreadof seizures. The purpose of thisarticle is to review the principlesof cellular neurophysiology as a

foundation for understanding hownormal neuronal function goes awryin epilepsy. First, normal synaptictransmission and neuronal firingare summarized. Next, the patho-physiology of acute and chronicseizures is discussed. Finally, themechanisms by which AEDs controlthe hyperexcitability that underliesepilepsy are considered.

Seizures and Epilepsy

DEFINITIONS

A seizure is a temporary disruptionof brain function due to the hyper-synchronous, excessive dischargeof cortical neurons. Sometimes theterm epileptic seizure is used to dis-tinguish from a nonepileptic seizuresuch as a pseudoseizure, which isnot caused by hypersynchronousfiring of neurons. The clinical mani-festations of a seizure depend on thespecific region and extent of braininvolvement and may include an

alteration in motor function, sen-sation, alertness, perception, auto-nomic function, or all of these.Any person can experience a seizurein the appropriate clinical setting(eg, meningitis, hypoglycemia, toxiningestion), attesting to the innatecapacity of even a normal brainto support hypersynchronous dis-charges, at least temporarily.

Epilepsy is the condition ofrecurrent, unprovoked seizures (twoor more), usually in a person who

has a predisposition because of achronic pathologic state (eg, braintumor, cerebral dysgenesis, post-traumatic scar) or genetics. Approxi-mately 1% to 2% of the populationsuffers from epilepsy, making it thesecond most common neurologicdisorder (after stroke), affectingmore than 2 million persons in theUnited States.

An epilepsy syndrome refers to agroup of clinical characteristics thatconsistently occur together, with

seizures as a primary manifestation.Such features might include similarage of onset, electroencephalo-graphic findings, precipitatingfactors, inheritance pattern, naturalhistory, prognosis, and response toAEDs. Epilepsy syndromes in child-hood include infantile spasms,febrile seizures, childhood absenceepilepsy, benign rolandic epilepsy(BRE), and juvenile myoclonicepilepsy.

MEASURING SEIZURES

The electroencephalogram (EEG) isthe primary tool for recording elec-trical activity of the human brain.Small metal disk electrodes areattached to the scalp at specifiedlocations. When sufficiently ampli-fied, voltage changes generated inneocortical neurons are recorded onthe EEG as waveforms of variousfrequencies, amplitudes, and mor-phology. EEG patterns vary accord-ing to the childs age, state of alert-ness, and genetic background. The

The Pathophysiology of Epileptic Seizures:A Primer For Pediatricians

Carl E. Stafstrom, MD, PhD*

*Associate Professor of Pediatrics and Neu-rology, Tufts University School of Medicine;Director, Epilepsy Center for Children,The Floating Hospital for Children at NewEngland Medical Center, Boston, MA.

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Pediatrics in Review Vol. 19 No. 10 October 1998 343

EEG records activity from near thebrains surface, primarily from theneocortex. Electrical activity fromdeep in the brain (eg, brainstem,thalamus, deep temporal lobe) maynot be recorded reliably by routine

EEG. If surface recording is inade-quate, special recording techniquesmight be required, such as surgicalplacement of electrodes directly onthe brain or implanted into it.

CLASSIFICATION OF SEIZURES

Epileptic seizures are broadly classi-fied as partial (focal) or generalized,depending on their site of origin andpattern of spread (Fig. 1). Partialseizures originate in a localizedarea of the brain, with clinicalmanifestations based on the area

of brain involved and how exten-sively discharges spread from thisfocus. For example, a focus inthe left motor cortex may cause

jerking of the right hand and arm.If the discharges spread to the motorarea that controls the face andmouth, additional clinical ictalfeatures would include facialtwitching, drooling, and perhapsarrest of speech. This pattern ofclinical and electrographic seizureis typical of the BRE syndrome.

Generalized seizures begin withabnormal electrical discharges

occurring in both hemispheressimultaneously. The EEG signatureof a primary generalized seizure isbilaterally synchronous spike-wavedischarges recorded over the entirebrain at once, reflecting reciprocalexcitation between the cortex andthe thalamus (Fig. 1B). Generalizedseizures also can spread and syn-chronize via the corpus callosum.Manifestations of a generalizedseizure can range from brief impair-ment of consciousness (as in anabsence seizure) to rhythmic jerk-ing of all extremities accompaniedby loss of posture and conscious-ness (a generalized tonic-clonicconvulsion).

A seizure that starts focally andthen spreads widely throughout thebrain is referred to as secondarilygeneralized. For example, in BRE,seizures sometimes begin focally inthe face/hand motor cortex, thensecondarily generalize into a general-ized tonic-clonic (GTC) convulsion.Similarly, in a seizure of temporal

lobe epilepsy (TLE), the first ictalsymptom may be motor automatisms(eg, repetitive picking at the clothes)or affective changes (fear, distortionof time, dj vu, or depersonaliza-tion) accompanied by dischargesoriginating in the hippocampusor other temporal lobe structures.Such seizures commonly generalize,resulting in a GTC convulsion.Some partial seizures generalizesecondarily so quickly that they

appear, both clinically and on EEG,to be generalized from their onset.

Although the mechanisms under-lying partial seizures, partial seizureswith secondary generalization, andprimary generalized seizures differsomewhat, it is useful to think aboutany seizure as a disruption in thenormal balance between excitationand inhibition in part or all of thebrain. A seizure can occur whenexcitation increases, inhibition

FIGURE 1. Coronal brain sections depicting seizure types and potential routes ofseizure spread. A. Focal area of hyperexcitability (yellow) and spread to nearby neo-cortex (red arrow) via corpus callosum or other commissures to the contralateralcerebral hemisphere (solid green arrow) or via subcortical pathways (eg, thalamus,

brainstem) in secondary generalization (dashed green lines). Accompanying EEGpatterns show brain electrical activity under numbered electrodes. Focal epileptiformactivity (spikes) is maximal at 3 and is also seen at 4 (left traces). If a seizure secon-darily generalizes, activity may be seen synchronously at all electrodes, after a delay(right traces). B. Primary generalized seizure begins simultaneously in both hemi-spheres. The characteristic bilateral synchronous spike-wave pattern on EEG isgenerated by interactions between cortex and thalamus, with rapid spread via corpuscallosum (CC) contributing to the rapid bilateral synchrony. One type of thalamicneuron (in blue) is a GABAergic inhibitory cell that has intrinsic oscillatory proper-ties. It can fire in bursts of action potentials due to a specific type of calcium chan-nel, allowing these cells to modulate ongoing excitatory corticothalamic activity,which gives rise to the spike-waves on EEG. Cortical neurons send impulses to bothexcitatory thalamic neurons (red) and to inhibitory neurons (blue), setting up oscilla-tions of excitatory and inhibitory activity, which gives rise to the rhythmic spike-waves on EEG. Illustration by Marcia Smith and Alan Michaels.



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decreases, or both. Hyperexcitabilitycan occur at one or more levels ofbrain function, including a networkof interconnected neurons; the

neuronal membrane with its ionicchannels, neurotransmitters, andtheir receptors; or intracellular sec-ond messenger cascades. Examplesof specific pathophysiologic defectsoccurring at different sites within thenervous system are listed in Table 1and are discussed more fully in sub-sequent sections. It is likely thatspecific genes modulate the excita-bility at each of these sites. In addi-tion to intrinsic factors, acquireddisorders also can express alteredexcitability at any of these levels.

Just as epilepsy is not one diseasebut a broad category of conditionsrelated to hyperexcitable neuronalfunction, there is no one mechanismof epilepsy; rather, several factorsinteract to create and sustain thehyperexcitable state.

Normal Synaptic Functionand Neuronal Firing

As a preface to considering theabnormal firing seen in epilepsy,

we need to review normal synaptictransmission and neuronal firing.There are two basic types of neu-rons, depending on the neurotrans-

mitter released from its terminals:excitatory or inhibitory (Fig. 2).When a neuron is activated, itreleases a transmitter from prepack-aged vesicles in presynaptic termi-nals, a process that requires calciuminflux. The transmitter diffusesacross the synaptic cleft and bindsto its specific receptor on the post-synaptic membrane. Binding setsin motion a cascade of events thatinvolves ion fluxes through thereceptor and a subsequent change inexcitability of the postsynaptic cell

(depolarization or hyperpolarization,that is, movement of the membranepotential closer to or further awayfrom the threshold voltage for gen-eration of an action potential).

INHIBITORY NEURO-TRANSMISSION

The primary inhibitory transmitterin the brain is gamma-amino-butyricacid (GABA). GABA is synthesizedfrom glutamate in the presynapticterminal by action of the enzyme

glutamic acid decarboxylase (GAD),which requires pyridoxine (vitaminB6) as a cofactor. Influx of Ca

++

caused by depolarization of the

terminal prompts vesicles to releaseGABA into the synaptic cleft.GABA diffuses across the cleft andbinds to its receptors (GABAA),which opens a pore or channelthrough which chloride ions (Cl

)

enter the neuron. This Cl

influxincreases the negative charge insidethe postsynaptic neuron, therebyhyperpolarizing it. The resultantchange in membrane potential iscalled an inhibitory postsynapticpotential (IPSP) (Fig. 3). An IPSPreduces firing of the neuron by

temporarily keeping the membranepotential away from firing thresh-old.* Obviously, a reduction ofany component of the GABA-IPSPsystem favors excitation and predis-poses to epileptic firing. Conversely,enhancing the GABA system is a

TABLE 1. Examples of Specific Pathophysiologic Defects Leading to Epilepsy

LEVEL OFBRAIN FUNCTION CONDITION PATHOPHYSIOLOGIC MECHANISM

Neuronal network Cerebral dysgenesis, posttraumatic Altered neuronal circuits: formation of

scar, mesial temporal sclerosis aberrant excitatory connections(in TLE) (sprouting)

Neuronal structure Down syndrome and possibly other Abnormal structure of dendrites andsyndromes with mental retardation dendritic spines: altered currentand seizures flow in neuron

Neurotransmitter synthesis Pyridoxine (vitamin B6) dependency Decreased GABA synthesis; B6 isa cofactor of glutamic aciddecarboxylase (GAD)

Neurotransmitter receptors: Angelman syndrome Abnormal GABA receptor subunitsInhibitory

Neurotransmitter receptors: Nonketotic hyperglycinemia Excess glycine leads to overactivationExcitatory of NMDA receptors

Synapse development Neonatal seizures Many possible mechanisms, includingearlier development of excitatorysynapses and a lag in developmentof inhibitory synapses

Ionic channels Benign familial neonatal Potassium channel mutations: impairedconvulsions repolarization

TLE = temporal lobe epilepsyNMDA = N-methyl-D-aspartate

*For completeness, GABAB receptors also

exist in the postsynaptic membrane; their acti-vation causes a longer-lasting IPSP mediated

by a G-protein that opens a potassium (K+)

channel. The role of GABAB receptors inepilepsy currently is being explored.



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logical approach for restraining neu-ronal hyperexcitability, and severalAEDs act on various aspects of theGABA system (see section on AEDmechanisms).

EXCITATORY NEURO-TRANSMISSION

Excitatory neurotransmission inthe brain is mediated largely by theexcitatory amino acid glutamate.Glutamate released from presynapticterminals may bind to any of severalglutamate receptor subtypes. Forsimplicity, we designate these asNMDA (N-methyl-D-aspartate) andnon-NMDA (kainate and amino-3-hydroxy-5-methyl-isoxasole propi-onic acid or AMPA). This confusingnomenclature arose because experi-

mentally, NMDA is a very selectiveagonist for one subtype of glutamatereceptor (therefore, termed NMDAreceptors), whereas AMPA andkainate prefer another type of gluta-mate receptor (therefore, namednon-NMDA receptors). However,glutamate (not NMDA, AMPA, orkainate) actually is the naturallyoccurring neurotransmitter; it isa flexible molecule that can bindto both NMDA and non-NMDAreceptors, with different physiologicconsequences in each case. Thesereceptor subtypes are of pivotal

importance in the generation ofepileptic firing.

Non-NMDA receptors mediatethe fast excitatory neurotrans-mission ordinarily associated withan excitatory postsynaptic potential(EPSP) (Fig. 3). Binding of gluta-mate to non-NMDA receptorscauses influx of sodium ions (Na

+

)through the receptors pore, produc-ing a fast EPSP (duration about5 msec), often followed by an actionpotential if the threshold is reached.

Glutamate binding to NMDAreceptors sets into motion a some-what different set of physiologicevents. For activation of the NMDAreceptor, the following must occur:1) glutamate must bind to theNMDA receptor; 2) glycine, anessential co-agonist, must bind atanother, nearby site on the NMDAreceptor complex; and 3) magne-sium ion (Mg

++

) blocking of thechannel pore must be relieved(Fig. 2, inset). Mg

++ions play a

unique role in the operation of the

FIGURE 2. Normal synaptic transmission. Representative inhibitory and excitatorypresynaptic terminals and postsynaptic neurons are shown. A. Inhibitory synapse.

GABA binding to its postsynaptic GABAA receptors allows influx of Cl

ions, whichhyperpolarizes the postsynaptic neuron (inhibitory postsynaptic potential; see text).GAD=glutamic acid decarboxylase. B. Excitatory synapse. Glutamate released fromthe terminal crosses the synaptic cleft and binds to one of several glutamate receptorsubtypes (NMDA or non-NMDA; see text). Binding to non-NMDA receptors causes afast excitatory postsynaptic potential; binding to NMDA receptors produces alonger, slow excitatory postsynaptic potential. If the postsynaptic neuron is depolar-ized sufficiently to reach firing threshold, an action potential will occur. Inset showsdetails of the NMDA receptor-ion pore complex. For the NMDA-ion pore to open,several events must occur: glutamate (circle) must bind to the receptor, glycine (trian-gle) must bind to its own receptor site on the NMDA receptor complex, and when thecell is sufficiently depolarized, Mg

++

must leave the channel pore. Only then can Na+

and Ca++

flow into the neuron and produce a prolonged NMDA-mediated excitatorypostsynaptic potential. Illustration by Marcia Smith and Alan Michaels.



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NMDA receptor. At resting poten-tial, a Mg

++ion sits in the pore,

preventing influx of any other ions.Once the membrane potential isdepolarized by 10 to 20 mV (by anon-NMDA-mediated fast EPSP),the Mg

++is expelled out of the pore

into the extracellular space, allowingNa

+

and Ca++

to flow into the neu-ron, giving rise to an NMDA-medi-ated prolonged EPSP. Much of theimportance of NMDA receptors liesin their ability to allow influx ofCa

++; once inside a neuron, Ca

++

can participate in a number of cru-cial second messenger pathways.In the normal brain, NMDA recep-tors play important roles in learning,memory, and the neuronal plasticitythat underlies many critical devel-opmental processes. However, ifNMDA receptors are overstimulated,the entry of excess Ca

++can wreak

havoc, activating destructive intra-cellular enzymes (eg, endonucleases,proteases), which even may leadto cell death. The role of NMDA

receptors in epileptic firing isdescribed below.

The depolarization caused byeither the fast or slow EPSP alsoactivates voltage-gated ionic chan-nels (such as Na

+or Ca

++) in the

membrane; these channels, whichare distinct from those openeddirectly by transmitter binding,become activated and open only atcertain membrane potentials. If thesum of depolarizations caused byglutamate receptor activation and byvoltage-gated channels is sufficient,firing threshold may be reached,and an action potential will occur.During the longer NMDA-evokeddepolarization, several action poten-tials may fire. Below threshold,EPSPs and IPSPs are engaged in adynamic, electrical tug-of-war,each affecting the membrane poten-tial in the opposite direction. Thefinal membrane potential is thesum of all excitatory and inhibitoryinputs, which varies according to themagnitude and timing of each input.

ACTION POTENTIALS

Action potentials are all-or-noneevents; once threshold is reached,an action potential will fire. Theupstroke of the action potential iscaused by a huge influx of Na

+

through voltage-gated channels;the downstroke is due to efflux ofpotassium ions (K

+) out of the cell

through voltage-gated K+

channels.One epilepsy syndrome of relevanceto pediatriciansbenign familialneonatal convulsionsrecently hasbeen attributed to mutations of volt-age-dependent K

+

channels. Suchmutations would prolong actionpotentials by reducing their repolar-ization rate, thus keeping the neurondepolarized longer.

At the tail end of the action poten-tial, the membrane potential is hyper-polarized briefly beyond its originalresting level; this is called the after-hyperpolarization (AHP). The AHPis mediated by another type of K

+

channel that differs from the oneresponsible for the action potential

FIGURE 3. Normal neuronal firing. Schematic of neuron with one excitatory (E, green) and one inhibitory (I, red) input. Rightside shows membrane potential (in mV), beginning at resting potential (70 mV). Activation of E leads to graded excitatory post-synaptic potentials, the larger of which reaches threshold (about 40 mV) for an action potential. The action potential is followedby an afterhyperpolarization (AHP), the magnitude and duration of which determine when the next action potential can occur.

Activation of I causes an inhibitory postsynaptic potential. Inset shows magnified portion of the neuronal membrane as a lipidbilayer with interposed voltage-gated Na

+

and K+

channels; the direction of ion fluxes during excitatory activation is shown. Afterfiring, the membrane-bound Na-K pump and star-shaped astroglial cells restore ionic balance. Illustration by Marcia Smith andAlan Michaels.



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downstroke and does not depend onvoltage. Rather, it depends on theintracellular calcium (Ca

++) level.

These Ca++

-dependent K+

channelsregulate the timing of neuronal firingby govening the neurons refractory

period, the time during which thecell is recovering from the previousaction potential and cannot yet gener-ate another one. Therefore, if thesechannels, which can limit repetitivefiring, become dysfunctional, epilep-tic discharges could result.

RESTORATION OF IONICHOMEOSTASIS

Because the ionic balance insideand outside of the neuron is alteredafter neuronal firing (especiallyafter repetitive, epileptic discharges),a mechanism must exist to restoreionic homeostasis. After neuronalfiring, there is excess Na

+inside

the cell and excess K+

in the extra-cellular space. A Na-K ATPase(energy-dependent pump) in theneuronal membrane provides thisrestorative function by pumpingNa

+

back out and K+

back into thecell. In addition, normalization ofionic balance is aided by nearbyglial cells, which act as ionicsponges and soak up excessextracellular K

+. This role of glial

cells is critical because elevated

extracellular K+

levels can depolar-ize the membrane directly andcause epileptic firing.

In summary, the involvement ofmultiple ion fluxes through a widevariety of voltage- and transmitter-dependent channels (Table 2) speaksto the complexity of normal neu-ronal firing. This complexity pro-vides numerous opportunities forpharmacologic interventions at avariety of sites if the system becomespathologically hyperexcitable, asin epilepsy.

Abnormal NeuronalFiring: Epilepsy

The pathophysiology of epilepsy

has two distinct but related hall-marks: hyperexcitability and hyper-synchrony. Hyperexcitability is theabnormal responsiveness of a neuronto an excitatory input; the neurontends to fire multiple discharges in-stead of the usual one or two. Hyper-synchrony refers to the recruitmentof large numbers of neighboringneurons into an abnormal firingmode. Ultimately, epilepsy is anetwork phenomenon that requiresparticipation of many neurons firingsynchronously. What happens in thenormally functioning brain to cause

it to fire hypersynchronously, andwhat are possible mechanisms forexcitation to increase, inhibition todiminish, or both?

PHYSIOLOGIC EVENTS

IN THE BRAIN

Figure 4 is a schematic overview ofnormal, interictal (between seizures),and ictal (during a seizure) physio-logic events at the level of the wholebrain and in a simplified neuronalcircuit. Normally, excitation andinhibition in the neocortex are rela-tively balanced. Neurons are acti-vated only when needed; otherwise,they are quiescent. The EEG in thenormal situation (left column) showslow-voltage desynchronized activ-ity in which the neurons in the

region under the electrode are notfiring synchronously. If hundreds orperhaps thousands of neurons beginto fire synchronously in one area ofthe cortex, a so-called EEG spikeor interictal discharge is recordedon the EEG (middle column). Thelarger the area of cortex involved,the greater the spread of such inter-ictal discharge. In Figure 4, thelargest concentration of neurons fir-ing synchronously is under electrode2, although electrode 1 also detectssome spread of the abnormal firing.Such interictal spikes are typically

TABLE 2. Roles of Channels and Receptors in Normal and Epileptic Firing

ROLE IN NORMALCHANNEL OR RECEPTOR NEURONAL FUNCTION POSSIBLE ROLE IN EPILEPSY

Voltage-gated Na+

channel Subthreshold EPSP; action potential Repetitive action potential firingupstroke

Voltage-gated K+

channel Action potential downstroke Action potential repolarization

Ca++

-dependent K+

channel AHP following action potential; sets Limits repetitive firingrefractory period

Voltage-gated Ca++

channel Transmitter release; carries depolarizing Excess transmitter release; activates

charge from dendrites to soma pathologic intracellular processesNon-NMDA receptor Fast EPSP Initiates PDS

NMDA receptor Prolonged, slow EPSP Maintains PDS; Ca++

activatespathologic intracellular processes

GABAA receptor IPSP Limits excitation

GABAB receptor Prolonged IPSP Limits excitation

Na-K pump Restores ionic balance Prevents K+

-induced depolarization

K = potassium, Na = sodium, Ca = calcium, EPSP = excitatory postsynaptic potential, AHP = afterhyperpolarization, NMDA = N-methyl-

D-asparatate, PDS = paroxysmal depolarization shift, IPSP = inhibitory postsynaptic potential.



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30 to 50 msec in duration. The thirdcolumn depicts the ictal state, with abarrage of rapidly firing EEGspikes, which may continue formany seconds or minutes. At thispoint, even more neurons are firingsynchronously, the result of whichwould be a clinical seizure whosemanifestations correlate with thearea of brain involved.

PHYSIOLOGIC EVENTS INTHE NEURONAL NETWORK

What is going on at the neuronalnetwork level when neuronsprogress from their normal firingpattern to the interictal conditionand then to the ictal state? Thelower panel depicts some of thephysiologic features that accompany

these transitions. In this illustration,rather than recording electrical activ-ity from the surface of the brain,we have placed single electrodesinside individual excitatory corticalneurons 1 and 2, thereby recordingintracellular potentials. Much of ourunderstanding of epilepsy mecha-nisms comes from such experimentsusing animal models.

Normally, an action potentialoccurs in neuron 1 when the mem-brane potential is depolarized to itsthreshold level, as discussed previ-ously. Discharges in neuron 1 alsomay influence the activity of itsneighbor, neuron 2. For example, adelay of several milliseconds froman action potential in neuron 1 maygive rise to an EPSP in neuron 2.

If cell 3, an inhibitory interneuron,also is activated by a discharge fromneuron 1, then the activity in neuron2 will be modified by an IPSP thatoverlaps in time with the EPSP. Therecorded event will be a summedEPSP-IPSP sequence. If the IPSPoccurs earlier, perhaps coincidentwith the EPSP, the depolarizingeffect of the EPSP will be dimin-ished. In this way, we can envisioninhibition as sculpting or modi-fying ongoing excitation. If thisconcept is extrapolated to thou-sands of interconnected neurons,each influencing the activity ofmany neighbors, it is easy to seehow an increase in excitation ordecrease in inhibition in the systemcould lead to hypersynchronous,

Figure 4. Abnormal neuronal firing at the levels of A) the brain and B) a simplified neuronal network, consisting of two excitatoryneurons (1 and 2) and an inhibitory interneuron (3). EEG (top set of traces) and intracellular recordings (bottom set of traces) areshown for the normal (left column), interictal (middle column), and ictal conditions (right column). Numbered traces refer to like-numbered recording sites. Note time scale differences in different traces. A. Three EEG electrodes record activity from superficialneocortical neurons. In the normal case, activity is low voltage and desynchronized (neurons are not firing together in syn-chrony). In the interictal condition, large spikes are seen focally at electrode 2 (and to a lesser extent at electrode 1, where theymight be termed sharp waves), representing synchronized firing of a large population of hyperexcitable neurons (expanded intime below). The ictal state is characterized by a long run of spikes. B. At the neuronal network level, the intracellular correlate ofthe interictal EEG spike is called the paroxysmal depolarization shift (PDS). The PDS is initiated by a non-NMDA-mediated

fast EPSP (blue) but is maintained by a longer, larger NMDA-mediated EPSP (red). The post-PDS hyperpolarization (*) tem-

porarily stabilizes the neuron. If this post-PDS hyperpolarization fails (right column, thick arrow), ictal discharge can occur. Thelowermost traces, recordings from neuron 2, show activity similar to that recorded in neuron 1, with some delay (double-headedarrow). Activation of inhibitory neuron 3 by firing of neuron 1 prevents neuron 2 from generating an action potential (the IPSPcounters the depolarization caused by the EPSP). If it does reach firing threshold, neuron 2 then can recruit additional neurons,leading to an entire network firing in synchrony (seizure). Illustration by Marcia Smith and Alan Michaels.



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epileptic firing in a large area ofbrain. Normally, neurons fire singleaction potentials, alone or in runs,and excitability is kept in checkby the presence of powerful inhibi-tory influences.

The intracellular correlate of theinterictal EEG spike is called theparoxysmal depolarization shift(PDS). It is termed paroxysmalbecause it arises suddenly frombaseline activity and depolariza-tion shift because the membranepotential is depolarized (less nega-tive) for several tens of millisec-onds. The PDS is actually a giantEPSP, a prolonged depolarizationthat causes the neuron to fire aburst of several action potentialsriding on a large envelope of depo-larization (Figure 4, middle column).Importantly, the PDS is an NMDA-mediated event; experimentally,NMDA receptor blockers preventPDSs and seizures. The PDS isinitiated by a fast, non-NMDA-mediated EPSP and sustained by aprolonged, NMDA-mediated EPSP.Compared with the usual NMDA-mediated slow EPSP of about 10 to20 msec, the PDS is longer (30 to50 msec) and has many more actionpotentials riding atop the depolariza-tion. Note that the durations of thePDS and interictal EEG spike are

similar (because they represent thesame event).

The PDS is followed by a largepost-PDS hyperpolarization, whichterminates the PDS and stops, atleast temporarily, rampant firing ofaction potentials. Note that a PDSin neuron 1 may activate a similarPDS in neuron 2, which can activatethe next neuron so that an entirenetwork of neurons can be recruitedrapidly into firing in synchrony.If excitation becomes excessiveor inhibition is curtailed severely,the PDS can lead into an ictaldischarge (right column). In thetop tracing, the post-PDS hyper-polarization is lost (thick arrow),allowing the neuron to generate aprolonged paroxysmal discharge.Such discharges in one neuron canspread easily to others, overwhelm-ing the inhibitory control on thesystem and leading to an electro-encephalographic and clinicalseizure. This interictal-to-ictal tran-sition may occur because the post-

PDS hyperpolarization is diminisheddue to potentiation of EPSPs, decre-ment in IPSPs, inability to clearextracellular K

+, a large increase

in intracellular calcium, or a varietyof other mechanisms.

In summary, the brain can useexisting, normal circuitry to generateand spread seizure activity if thesystem is perturbed in such a wayto favor excitation over inhibition.In the case of recurrent, unprovokedseizures (epilepsy), neuronal func-tion is persistently abnormal. Thischronic hyperexcitability can resultfrom a number of mechanisms(Tables 1, 2). For example, reducedinhibition can result from death ordysfunction of inhibitory neurons,genetic conditions in which GABAsynthesis is impaired or GABAreceptors have an abnormal subunitcomposition, or early in life whenthe development of inhibitory con-nections lags behind excitatory

ones. Enhanced excitation mightoccur if NMDA receptors are over-

activated due to the presence ofexcessive glutamate or glycineor if ionic channels that are respon-sible for repolarization are geneti-cally aberrant.

STRUCTURAL ALTERATIONS

One of the great mysteries in neuro-science is how the brain becomespermanently altered to create thesubstrate for chronic epilepsy. Some-times an etiology or structural causecan be determined, but often noexplanation is found. One type ofepilepsy, TLE, can be a consequenceof structural alterations to the hippo-campus, one of the most epilepto-genic areas of the brain. Hippocam-pal injury, which can be caused bystatus epilepticus, could producepersistent hyperexcitability longafter the status episode has ceased.This chronic hyperexcitability isdue to the combined effects ofseveral structural alterations: neu-ronal death, gliosis or mesial tem-poral sclerosis, and the growth of

new, abnormal axonal connections(sprouting).

Figure 5 depicts how such sprout-ing might occur by producing aber-rant excitatory connections. Dentategranule neurons receive all incoming

activity entering the hippocampus.They ordinarily fire only singleaction potentials and innervatehippocampal pyramidal neurons,which fire single action potentialsin response to dentate input. Statusepilepticus typically causes death ofpyramidal cells (due to overactiva-tion of NMDA receptors and exces-sive Ca

++entry, as discussed previ-

ously) but spares dentate neurons.Therefore, axons of dentate neuron1 are left without a postsynaptictarget, so they wind back to inner-vate their own dendrites and thoseof neighboring dentate neurons,forming an autoexcitatory, rever-berating excitatory circuit. Thisresults in dentate neuron 2 receiving

excessive excitatory input and firingmultiple action potentials, causing

surviving pyramidal neurons to dothe same. Rather than being uniqueonly to the hippocampus, sproutingmight comprise a more generalmechanism by which brain circuitsbecome hyperexcitable.

Enhanced Excitabilityin the Immature Brain

The immature brain is particularlypredisposed to seizures, with seizureincidence being highest during thefirst decade and especially duringthe first year of life. Several physio-logic features favor a relative hyper-excitable state early in life. Ca

++and

Na+

channels, which mediate neu-ronal excitation, develop relativelyearly. Excitatory synapses tend toform before inhibitory synapses.NMDA receptors are overexpressedtransiently early in postnatal devel-opment, when they are needed forcritical developmental processes.The branching pattern of axons inthe immature brain is markedly more

Ultimately, epilepsy is a network phenomenon that requires

participation of many neurons firing synchronously.



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complex than later in life, formingan exuberant network of excitatoryconnections. The ability of glialcells to clear extracellular K

+also

increases with age. Finally, GABA,perhaps paradoxically, may be anexcitatory transmitter early in devel-opment.* Therefore, the excitatory/inhibitory balance in the brainchanges dramatically during devel-opment. The disadvantage of thesephysiologic adaptations is that thebrain is especially vulnerable tohyperexcitability during a criticalwindow of development. Neverthe-

less, these neurophysiologic idiosyn-crasies of early brain developmentprovide the opportunity for produc-ing novel, age-specific therapies.

Antiepileptic DrugMechanisms

Using the concepts discussed previ-ously, we now can examine some ofthe actions of various antiseizuredrugs (Fig. 6). Clinical indications,doses, side effects, and other similarinformation for these medicationscan be found in standard textbooks.

Several AEDs target aspects ofthe inhibitory system. Phenobarbital(PHB) and benzodiazepines (BZD)bind to different sites on the GABAAreceptor. These drugs enhance inhibi-tion by allowing increased Cl

influx

through the GABA receptorPHBby increasing the duration of chlo-ride channel openings and BZD byincreasing the frequency of open-ings. Vigabatrin (VGB) is a newAED that should be available in theUnited States soon; it has shownmuch promise in Europe for thetreatment of infantile spasms andother seizure types. VGB is anexample of a designer drug thatwas created to target a specific

pathophysiologic mechanism. VGBinhibits the GABA degradatoryenzyme, GABA transaminase,thereby increasing the amount ofGABA available to partake ininhibitory neurotransmission.

Another new AED, tiagabine (TGB),also increases GABA availability,but it does so by preventing GABAreuptake into the presynaptic termi-nal. The mechanism of action ofgabapentin (GBP) remains unre-solved; it may increase the rate ofGABA synthesis or release.

Other AEDs affect aspects ofneuronal excitation. Phenytoin,carbamazepine, and the new AEDlamotrigine block voltage-dependentsodium channels and reduce theability of neurons to fire repetitively.Ethosuximide, used primarily forabsence seizures, blocks a uniquecalcium current that is present onlyin thalamic neurons, preventingthem from firing in an oscillatoryfashion and recruiting neocorticalneurons into spike-wave patterns.Several new AEDs are said to alterthe function of NMDA receptors(lamotrigine and felbamate) or non-NMDA receptors (topiramate). Thedissociative anesthetic ketamineblocks the ion pore of NMDA re-ceptors, although ketamine and simi-larly acting agents have been disap-

pointing in clinical trials becausethey cause excessive sedation.

Much effort is being expended todesign novel AEDs that selectivelytarget other aspects of the NMDAsystem (Fig. 2, inset). In addition toblocking the ion pore, antiseizureactivity might be produced by antag-onizing glutamate binding or block-ing other sites on the receptor com-plex that must be activated for thereceptor complex to function (suchas the glycine coactivator site). Thevoltage-dependent blocking of theNMDA receptor ion pore by Mg

++

could be another site for novelanticonvulsant action; in fact,magnesium sulfate has been usedfor years by obstetricians to controlseizures in eclampsia.

Topiramate, felbamate, andgabapentin, as well as the estab-lished AED valproic acid, probablyhave mixed excitatory and inhibi-tory actions. Mechanisms of otherepilepsy treatments, such as adreno-corticotrophic hormone (ACTH,

FIGURE 5. Simplified depiction of sprouting in the hippocampus. A. Normal situa-tion. Left: Dentate granule neurons (1, 2) make excitatory synapses (E) onto den-drites of hippocampal pyramidal neurons (3, 4). Right: Activation of dentate neuron2 causes single action potential in pyramidal neuron 3. B) Following status epilepti-cus, which causes many pyramidal neurons to die (4, dashed lines), axons of dentateneuron 1 are left without a target. Those axons then sprout and innervate the den-drites of granule neurons (thick arrow), creating the substrate for a hyperexcitablecircuit. Now, when neuron 2 is activated, it fires multiple action potentials, causing

pyramidal neuron 3 to fire repetitively as well (right tracings). Illustration by MarciaSmith and Alan Michaels.

*Early in development, Cl concentration isgreater inside the neuron than later, whenit predominates in the extracellular space.Therefore, when GABA binds to its receptorsand opens Cl channels, the negative charge

flows from inside to outside the neuron, downits concentration gradient. The loss of nega-tive charge from inside the neuron depolar-izes it.



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used for infantile spasms) and theketogenic diet (a high-fat, low-car-bohydrate and -protein diet usedin seizure disorders refractory toAEDs), remain largely unknown.Future AEDs are likely to increase

our ability to treat seizures selec-tively according to specific patho-physiologic mechanisms, but it isessential to understand the underly-ing principles of normal and abnor-mal neuronal function to use suchagents most effectively.

SUGGESTED READING

Avoli M. Molecular mechanisms of antiepi-leptic drugs. Science & Medicine. 1997;July/August:5463

Clark S, Wilson W. Mechanisms of epilepto-genesis and the expression of epileptiformactivity. In: Wyllie E, ed. The Treatment of

Epilepsy: Principles and Practice. 2nd ed.Baltimore, Md: Williams & Wilkins; 1996:5381

Holmes GL. Epilepsy in the developing brain:lessons from the laboratory and clinic.

Epilepsia. 1997;38:1230Levy RH, Mattson RH, Meldrum BS, eds.

Antiepileptic Drugs. 4th ed. New York,NY: Raven Press; 1995

Schwartzkroin PA, Moshe SL, Noebels JL,Swann JW, eds.Brain Development and

Epilepsy. New York, NY: Oxford Univer-sity Press; 1995

FIGURE 6. Actions of antiepileptic drugs on inhibitory (A) and excitatory (B) mech-anisms. Drugs that enhance inhibition have been developed to act at both pre- and

postsynaptic sites to enhance GABAergic inhibition. AEDs targeting excitation affectprimarily postsynaptic mechanisms. Ketamine and Mg

++

are not strictly AEDs, butare shown here to illustrate their actions at a specific site (the ion pore) on the

NMDA receptor. Several of the newer AEDs (gabapentin, lamotrigine, felbamate,topinamate) probably have multiple mechanisms of action. Illustration by MarciaSmith and Alan Michaels.



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DOI: 10.1542/pir.19-10-3421998;19;342Pediatrics in Review

Carl E. StafstromBack to Basics: The Pathophysiology of Epileptic Seizures: A Primer For Pediatricians

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