The new england journal of medicine
`
`review article
`
`mechanisms of disease
`Epilepsy
`
`Bernard S. Chang, M.D., and Daniel H. Lowenstein, M.D.
`
`e
`
`pilepsy is one of the most common neurologic problems
`worldwide. Approximately 2 million persons in the United States have epi-
`lepsy, and 3 percent of persons in the general population will have epilepsy at
`some point in their lives.1 In recent years, important advances have been made in the di-
`agnosis and treatment of seizure disorders.2 However, our understanding of the cellu-
`lar and molecular mechanisms by which epilepsy develops, or epileptogenesis, is still
`incomplete.
`In this overview, we highlight some of the prevailing ideas about epileptogenesis by
`presenting examples of epilepsy syndromes and theories of their mechanisms of origin.
`Several recent reviews offer more specialized and comprehensive discussions of this
`topic.3-5
`
`From the Comprehensive Epilepsy Center,
`Department of Neurology, Beth Israel Dea-
`coness Medical Center, and Harvard Med-
`ical School — both in Boston (B.S.C.); and
`the University of California San Francisco
`Epilepsy Center, Department of Neurology,
`University of California San Francisco, San
`Francisco (D.H.L.).
`
`N Engl J Med 2003;349:1257-66.
`Copyright © 2003 Massachusetts Medical Society.
`
`classification of epilepsy
`
`The term “epilepsy” encompasses a number of different syndromes whose cardinal
`feature is a predisposition to recurrent unprovoked seizures. Although specific seizures
`can be classified according to their clinical features (e.g., complex partial seizures and
`generalized tonic–clonic seizures),6 epilepsy syndromes can also be classified accord-
`ing to the type of seizure, the presence or absence of neurologic or developmental ab-
`normalities, and electroencephalographic (EEG) findings.7 For example, the syndrome
`of juvenile myoclonic epilepsy is characterized by the onset of myoclonic seizures, gen-
`eralized tonic–clonic seizures, and less frequently absence seizures in adolescents who
`have normal intellectual function, with EEG findings of rapid, generalized spike-wave
`and polyspike-wave discharges.8
`Epilepsy syndromes fall into two broad categories: generalized and partial (or local-
`ization-related) syndromes.7,8 In generalized epilepsies, the predominant type of sei-
`zures begins simultaneously in both cerebral hemispheres. Many forms of generalized
`epilepsy have a strong genetic component; in most, neurologic function is normal. In
`partial epilepsies, by contrast, seizures originate in one or more localized foci, although
`they can spread to involve the entire brain. Most partial epilepsies are believed to be the
`result of one or more central nervous system insults, but in many cases the nature of the
`insult is never identified.
`
`mechanisms of generalized epilepsies
`
`absence epilepsy
`Childhood absence epilepsy is a generalized epilepsy syndrome that begins between
`the ages of four and eight years with absence seizures and, more rarely, generalized ton-
`ic–clonic seizures.9 During absence seizures, patients stare and cease normal activity
`for a few seconds, then return immediately to normal and have no memory of the event.
`Since these seizures can occur tens or hundreds of times a day, an incorrect diagnosis of
`
`n engl j med 349;13 www.nejm.org september 25, 2003
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`1257
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`The New England Journal of Medicine
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`Downloaded from nejm.org by Joshua Scheufler on March 24, 2022. For personal use only. No other uses without permission.
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` Copyright © 2003 Massachusetts Medical Society. All rights reserved.
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` new england journal
`The
`
` medicine
`of
`
`attention-deficit disorder or daydreaming is fre-
`quently made. There is a classic EEG pattern of three-
`per-second, generalized spike-wave discharges in
`childhood absence epilepsy.
`For many years, the anatomical origin of absence
`seizures and the accompanying EEG pattern were
`debated. The results of some experiments support-
`ed the hypothesis that absence seizures originated
`in the thalamus. For example, electrical stimulation
`of the thalamus in cats produced bilaterally synchro-
`nous EEG discharges that resembled the classic ab-
`10
`sence pattern.
` Also, recordings from electrodes
`implanted in the thalamus of a child with absence
`epilepsy demonstrated three-per-second EEG dis-
`11
`charges during typical seizures.
` Other work, how-
`ever, suggested that the cerebral cortex itself was
`the primary origin of these seizures. For example,
`similar EEG discharges could be produced by ap-
`plying proconvulsant agents to the cortical surface
`12
`bilaterally.
`The mechanism that generates absence seizures
`is now believed to involve an alteration in the cir-
`cuitry between the thalamus and the cerebral cortex
`13-15
` Much has been learned from in vivo
`(Fig. 1).
`and in vitro electrophysiological recordings in an-
`imal models of absence epilepsy, both those that
`were experimentally induced and those that were
`16-18
`genetically determined.
` These and other stud-
`ies have shown that thalamocortical circuits gov-
`ern the rhythm of cortical excitation by the thala-
`mus and underlie normal physiologic patterns such
`19
` Three neuronal
`as those that occur during sleep.
`populations are involved in this circuitry: thalamic
`relay neurons, thalamic reticular neurons, and corti-
`cal pyramidal neurons. The thalamic relay neurons
`can activate the cortical pyramidal neurons either
`in a tonic mode, which occurs during wakefulness
`and rapid-eye-movement (REM) sleep, or in a burst
`mode, which occurs during non-REM sleep. The
`burst mode is made possible by T-type calcium
`channels, which allow for low-threshold depolar-
`izations on which bursts of action potentials (medi-
`ated by voltage-gated sodium channels) are super-
`20
`imposed.
` The mode of thalamocortical activation
`— tonic or burst — is controlled largely by input
`from the thalamic reticular neurons, which hyper-
`polarize the relay neurons, allowing them to fire in
`21
`bursts.
` The reticular neurons can themselves be
`inhibited through recurrent collaterals from neigh-
`22
` Both cortical pyramidal
`boring reticular neurons.
`neurons and thalamic relay neurons project to the
`reticular neurons to complete the circuitry. In ad-
`dition, ascending noradrenergic, serotonergic, and
`
`dopaminergic inputs to the thalamus modulate this
`23
`circuit and affect the likelihood of a burst mode.
`In normal non-REM sleep, thalamic relay neu-
`rons in the burst mode activate the cortex in a rhyth-
`mic, bilaterally synchronous way, creating visible
`19
`EEG patterns, such as sleep spindles.
` This “sleep
`state” of the thalamocortical circuit is in contrast to
`the normal “awake state,” in which the thalamic re-
`lay neurons are firing in the tonic mode and thal-
`amocortical projections are transferring sensory in-
`formation to the cortex in a nonrhythmic manner.
`In absence epilepsy, the abnormal circuit causes
`rhythmic activation of the cortex (typical of normal
`non-REM sleep) during wakefulness, which results
`in the characteristic EEG discharges and clinical
`15
`manifestations of an absence seizure.
` The precise
`abnormality of the circuit has yet to be determined,
`but there are multiple possibilities. Some data sug-
`gest that the T-type calcium channels may be the pri-
`24,25
`mary culprits.
` Other work has emphasized the
`importance of altered
`-aminobutyric acid (GABA)
`g
`26
` A combination of factors may
`receptor function.
`be involved, including changes in modulatory in-
`23
`put from the brain stem.
` The overriding concept,
`however, is that dysfunction of a neuronal circuit
`that produces a physiologic state of rhythmic corti-
`cal activation (sleep) can lead to abnormal paroxys-
`mal episodes of rhythmic cortical activation (absence
`seizures).
`This concept helps explain the unique pharma-
`cologic treatment of absence epilepsy. Ethosuxim-
`ide, a drug that suppresses absence seizures but
`not other types of seizures, appears to work by caus-
`ing voltage-dependent blockade of T-type calcium
`27
`currents.
` This mechanism, as might be expect-
`ed, is believed to inhibit the burst mode of thalamic-
`relay-neuron firing. Valproic acid, an antiepileptic
`drug used for absence seizures and other types of
`seizures, also acts on the T-type calcium channels,
`28
` Benzodiazepines that
`as well as other substrates.
`activate an inhibitory GABA
` receptor subtype on
`A
`thalamic reticular neurons can also be effective in
`suppressing absence seizures (although other types
`29
` Baclofen,
`of benzodiazepines can worsen them).
`an agonist of a GABA-receptor subtype that hy-
`perpolarizes thalamic relay neurons and makes the
`burst mode more likely, clearly exacerbates EEG
`30
`spike-wave discharges in animal models.
`
`generalized epilepsies associated
`with ion-channel mutations
`Although most generalized epilepsies have com-
`plex inheritance patterns, a few have a mendelian
`
`1258
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`n engl j med
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`349;13
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`www.nejm.org september
`
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`25
`
`2003
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org by Joshua Scheufler on March 24, 2022. For personal use only. No other uses without permission.
`
` Copyright © 2003 Massachusetts Medical Society. All rights reserved.
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`mechanisms of disease
`
`A
`
`+
`
`+
`
`–
`
`+
`
`–
`
`GABAB
`
`+
`
`–
`
`T-type Ca++
`channel
`
`–
`GABAA
`
`Thalamic relay
`
`Norepinephrine,
`dopamine,
`and serotonin
`
`B
`
`EEG Patterns
`
`Wakefulness
`
`Desynchronized
`
`Non-REM sleep
`
`Spindles
`
`Absence seizure
`
`Brain stem
`
`3-per-second
`spike wave
`
`Figure 1. The Normal Thalamocortical Circuit and EEG Patterns during Wakefulness, Non–Rapid-Eye-Movement
`(Non-REM) Sleep, and Absence Seizures.
`Panel A shows the normal thalamocortical circuit. Thalamic relay neurons can activate the cortical pyramidal neurons in
`either a tonic mode or a burst mode, the latter made possible by T-type calcium channels. The mode of thalamocortical
`activation is controlled largely by input from the thalamic reticular neurons, which hyperpolarize the relay neurons through
`-aminobutyric acid type B (GABA
`) receptors and are themselves inhibited by neighboring reticular neurons through
`g
`B
`activation of GABA type A (GABA
`) receptors. Cortical pyramidal neurons activate the thalamic reticular neurons in a
`A
`feed-forward loop. Ascending noradrenergic, serotonergic, and dopaminergic inputs from brain-stem structures appear
`to modulate this circuit.
`Panel B shows EEG patterns of wakefulness, non-REM sleep, and absence seizures. During wakefulness, the cortex is ac-
`tivated by the thalamus in a tonic mode, allowing for processing of external sensory inputs. This results in a desynchro-
`nized appearance of the EEG. During non-REM sleep, the cortex is activated in a burst mode, resulting in the EEG ap-
`pearance of rhythmic sleep spindles. During an absence seizure, the normal thalamocortical circuit becomes dysfunctional,
`allowing burst activation of the cortex to occur during wakefulness, which results in the EEG appearance of rhythmic
`spike-wave discharges and interrupts responsiveness to external stimuli.
`
`inheritance pattern and are associated with single-
`42-44
`gene mutations (Table 1).
` Almost all these mu-
`tations have been found in genes encoding ion-
`channel proteins (Fig. 2). Functional studies of the
`mutant channels have revealed potential mecha-
`nisms for some of these disorders.
`For example, “generalized epilepsy with febrile
`seizures plus” is a genetic syndrome consisting of
`febrile seizures plus at least one other type of seizure
`(absence, myoclonic, atonic, or afebrile generalized
`45
`tonic–clonic seizures).
` Pedigree analysis has sug-
`gested that the inheritance pattern is autosomal
`dominant with incomplete penetrance and linkage
`to chromosome 19q. In this disorder, there is a mu-
`
`tation in the gene for the voltage-gated sodium
`SCN1B
`channel
`1 subunit (
`), which modifies the
`b
`31
`gating and inactivation properties of the channel.
`The mutant channel protein, when expressed in oo-
`cytes of the frog genus xenopus, allows passage of
`an increased sodium current. In neurons, the muta-
`tion promotes depolarization and neuronal hyper-
`excitability. Since generalized epilepsy with febrile
`seizures plus was initially described, phenotypically
`similar families have been identified with mutations
`in sodium channel subunits SCN1A and SCN2A and
`32-34
` receptor subunit, GABRG2.
`the GABA
`A
`Another generalized epilepsy syndrome, benign
`familial neonatal convulsions, has also been linked
`
`n engl j med
`
`349;13
`
`www.nejm.org september
`
`25, 2003
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`1259
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`The New England Journal of Medicine
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`Downloaded from nejm.org by Joshua Scheufler on March 24, 2022. For personal use only. No other uses without permission.
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` Copyright © 2003 Massachusetts Medical Society. All rights reserved.
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` new england journal
`
` medicine
`of
`
`The
`
`Table 1. Epilepsy Syndromes Associated with Single-Gene Mutations.
`
`Epilepsy Syndrome
`
`Generalized epilepsy with febrile seizures plus
`
`Benign familial neonatal convulsions
`
`Autosomal dominant nocturnal frontal-lobe
`epilepsy
`
`Childhood absence epilepsy and febrile seizures
`Autosomal dominant partial epilepsy
`with auditory features
`
`*GABA
`
`A
`
` denotes
`g
`
`-aminobutyric acid type A.
`
`Gene
`
`SCN1B
`SCN1A
`SCN2A
`GABRG2
`KCNQ2
`
`KCNQ3
`CHRNA4
`
`CHRNB2
`
`GABRG2
`LGI1
`
`Gene Product*
`
`Study
`
`Sodium-channel subunit
`Sodium-channel subunit
`Sodium-channel subunit
`GABA
`-receptor subunit
`A
`Potassium channel
`
`Potassium channel
`Neuronal nicotinic acetylcholine–
`receptor subunit
`Neuronal nicotinic acetylcholine–
`receptor subunit
`GABA
`-receptor subunit
`A
`Leucine-rich transmembrane
`protein
`
`31
`
`33
`
`Wallace et al.
`32
`Escayg et al.
`Sugawara et al.
`34
`Baulac et al.
`35
`Biervert et al.,
`36
`Singh et al.
`37
`Charlier et al.
`Steinlein et al.
`
`38
`
`Fusco et al.
`
`39
`
`40
`
`Wallace et al.
`Kalachikov et al.
`
`41
`
`to single-gene mutations. In this autosomal dom-
`inant disorder, seizures that are not associated
`with neurologic or metabolic abnormalities begin
`in the first few days of life and usually remit with-
`46
`in a few weeks, with or without treatment.
` Mu-
`KCNQ2
`KCNQ3,
`tations have been identified in
` and
`the genes for potassium channels on chromosomes
`35-37
`20q and 8q.
` Functional studies have shown that
`the mutant channels allow passage of significantly
`35
`less potassium current than wild-type channels.
`Since potassium currents are the primary force be-
`hind repolarization of the neuronal membrane after
`depolarization, these mutations would be expected
`to prolong depolarization, thereby increasing neu-
`ronal hyperexcitability.
`In these pure epilepsy syndromes, then, muta-
`tions in genes encoding ion-channel proteins lead
`to hyperexcitability of cortical neurons through al-
`terations in channel function. Since these genes
`are expressed throughout the brain, it is plausible
`that the effect of the mutations is diffuse and there-
`fore confers a predisposition to a generalized sei-
`zure disorder. Similar ion-channel mutations have
`been identified in a variety of disorders now termed
`“channelopathies.” These conditions, which are
`characterized by paroxysmal episodes of neurologic
`or cardiac dysfunction, include episodic ataxia, pe-
`riodic paralysis, familial hemiplegic migraine, and
`47
`the long-QT syndrome.
` Two recent reports de-
`scribe calcium-channel mutations in patients with
`a combination of episodic ataxia and a mixed-sei-
`
`48,49
` These reports raise the prospect
`zure syndrome.
`that calcium-channel mutations will be found in
`pure epilepsy syndromes and emphasize the possi-
`bility that various paroxysmal neurologic disorders
`share common underlying mechanisms.
`
`unanswered questions
`Our understanding of generalized epileptogene-
`sis remains far from complete. Why, for example,
`do persistent alterations in neuronal circuits or ex-
`citability result in a paroxysmal disorder such as
`epilepsy? A better understanding of the molecular
`and cellular circumstances that predispose a per-
`son to a seizure at a particular time could have im-
`plications for the prevention of seizures. It is also
`unclear why many seizure syndromes have an age-
`dependent onset and why some remit spontane-
`ously. These features suggest that developmental
`changes in the nervous system have an important
`role in the clinical expression of generalized epi-
`50
`lepsy syndromes that are genetically determined.
`
`mechanisms of
`partial epilepsies
`
`mesial temporal-lobe epilepsy
`We know much less about the mechanisms un-
`derlying partial-seizure disorders than we do about
`generalized epileptogenesis, even though partial
`seizures are the most common seizure disorder in
`adults, often stemming from focal lesions such as
`
`1260
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`n engl j med
`
`349;13
`
`www.nejm.org september
`
`,
`
`25
`
`2003
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org by Joshua Scheufler on March 24, 2022. For personal use only. No other uses without permission.
`
` Copyright © 2003 Massachusetts Medical Society. All rights reserved.
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`mechanisms of disease
`
`A
`
`Normal ion-channel
`function
`
`B
`
`Mutation in SCN1B
`(generalized epilepsy with
`febrile seizures plus)
`
`C
`
`Mutation in KCNQ2, KCNQ3
`(benign familial neonatal
`convulsions)
`
`Na+
`
`Na+
`
`K+
`
`Na+
`
`K+
`
`Na+
`
`K+
`
`Na+
`
`K+
`
`K+
`
`Na+
`
`K+
`
`0 mV
`
`0 mV
`
`0 mV
`
`¡90 mV
`
`¡90 mV
`
`1 sec
`
`¡90 mV
`
`Figure 2. Examples of Ion-Channel Dysfunction Associated with Inherited Forms of Epilepsy.
`Panel A shows normal neuronal-ion-channel function and the action potential. Sodium and potassium channels are re-
`sponsible for the primary components of the action potential, which involve a depolarizing phase mediated by sodium-
`channel opening and a repolarizing phase due to potassium-channel opening and sodium-channel inactivation. Other
`potassium channels contribute to a longer-term repolarization that helps prevent repetitive firing of the neuron.
`
`
`Mutations in SCN1B, which encodes a voltage-gated sodium-channel subunit, are associated with generalized epilepsy with
`febrile seizures plus (Panel B). The apparent effect of these mutations is to allow passage of an increased sodium current,
`which would lead to a greater depolarization during the action potential and an increased tendency to fire repetitive bursts.
`
`Mutations in KCNQ2
`
` and KCNQ3,
` which both encode potassium channels, are associated with benign familial neonatal
`convulsions (Panel C). These mutations, which appear to decrease the potassium outflow underlying the longer-lasting
`“M current,” are likely to cause a loss of spike-firing adaptation and therefore an increase in neuronal firing frequency.
`
`1
`head trauma, strokes, and tumors.
` The most prev-
`alent of these syndromes features complex partial
`8,51
`seizures arising from the mesial temporal lobe.
`Recordings from intracranial depth electrodes have
`clearly demonstrated an ictal onset in mesial tempo-
`ral structures such as the hippocampus, amygdala,
`and adjacent parahippocampal cortex; surgical re-
`section of these areas in suitable patients usually
`52
`abolishes the seizures.
` These seizures can begin
`with olfactory or gustatory hallucinations, an epi-
`gastric sensation, or psychic symptoms such as déjà
`vu or depersonalization. Once the seizures progress
`to a loss of awareness, the patients may stare blank-
`ly, speak unintelligibly, or exhibit lip smacking, pick-
`53
`ing at clothing, or other automatisms.
`The most common lesion in surgically resected
`tissue from patients with mesial temporal-lobe epi-
`lepsy is hippocampal sclerosis, a well-described en-
`54-56
` In hippocam-
`tity whose cause remains elusive.
`pal sclerosis, there is selective loss of neurons in the
`
`dentate hilus and the hippocampal pyramidal-cell
`layer, with relative preservation of dentate granule
`cells and a small zone of pyramidal cells (in the cor-
`nu ammonis, field 2, of the hippocampus). The
`dense gliosis that accompanies the loss of neurons
`causes shrinkage and hardening of tissue. The term
`“mesial temporal sclerosis” has also been used for
`this lesion, because often there is neuronal loss in
`57
`the neighboring entorhinal cortex and amygdala.
`There is a vigorous debate about whether hip-
`pocampal sclerosis is a cause or an effect of sei-
`58,59
`zures.
` It has been seen in a wide variety of
`epileptic conditions, including cryptogenic tempo-
`60
`ral-lobe epilepsy
` and epilepsy that follows fe-
`61
` as
`brile seizures or other brain insults early in life,
`62
`well as in animal models of head injury
` and sei-
`63
`zures induced by chemicals.
` It is possible that
`hippocampal sclerosis represents a pathologic final
`common pathway to partial epilepsy from a num-
`ber of different causes.
`
`n engl j med
`
`349;13
`
`www.nejm.org september
`
`25, 2003
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`1261
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`The New England Journal of Medicine
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`Downloaded from nejm.org by Joshua Scheufler on March 24, 2022. For personal use only. No other uses without permission.
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` Copyright © 2003 Massachusetts Medical Society. All rights reserved.
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`
` new england journal
`The
`
` medicine
`of
`
`Detailed studies of the morphologic changes in
`hippocampal sclerosis have led to several hypothe-
`ses about the mechanism of epileptogenesis in this
`condition (Fig. 3). The best-described change is the
`sprouting of mossy-fiber axons from dentate gran-
`64
`ule cells.
` Normally, excitatory input to the hippo-
`campus comes directly to the hippocampal dentate
`granule cells from the neighboring entorhinal cor-
`tex, whereas inhibitory input arises locally from in-
`terneurons in the inner molecular layer. The den-
`tate granule cells sprout mossy-fiber axons, which
`extend to pyramidal neurons as part of the hippo-
`campal output pathway. Normal dentate granule
`cells appear to be relatively resistant to hypersyn-
`chronous activation and may actually serve to inhib-
`it the propagation of seizures from the entorhinal
`51
`cortex.
` In hippocampal sclerosis, however, these
`cells sprout mossy-fiber axons that are directed
`60,65,66
`back into the inner molecular layer,
` possibly
`because the neurons to which they usually extend
`have been lost. There is some evidence that these
`aberrant mossy fibers instigate a recurrent excita-
`tory circuit by forming synapses on the dendrites of
`67,68
` Although
`neighboring dentate granule cells.
`such a circuit is a plausible explanation for hyper-
`
`excitability, the causative role of mossy-fiber sprout-
`ing in epileptogenesis is still largely speculative.
`There is, for example, strong evidence that newly
`sprouted axons also form synapses on inhibitory in-
`terneurons as part of a feedback mechanism, rath-
`69-71
`er than simply increase excitation.
`Some investigators have suggested that the se-
`lective vulnerability of certain neurons may be a
`mechanism of epileptogenesis in hippocampal
`sclerosis. In animal models, excitatory interneurons
`located within the dentate gyrus, which normally
`activate inhibitory interneurons, appear to be selec-
`72
`tively lost.
` Loss of these excitatory cells would
`be expected to impair the inhibitory feedback and
`feed-forward mechanisms that act on dentate gran-
`73
` This expla-
`ule cells, resulting in hyperexcitability.
`nation is plausible, but the evidence that dentate
`granule cells can project directly onto inhibitory in-
`terneurons raises the possibility of a compensatory
`mechanism. For these reasons, the implications
`of selective cell loss in the hippocampus, although
`highly suggestive of a mechanism of epileptogene-
`sis, are still not completely understood.
`An intriguing hypothesis lies in the phenome-
`non of neurogenesis. Almost all neurons in the brain
`
`CA1 pyramidal
`cells
`Hippocampal
`output
`
`Perforant path input
`
`+
`
`+
`
`+
`
`Inhibitory
`interneuron
`
`ng+
`
`S prouti
`
`+
`
`–
`
`Sprouting
`
`Dentate
`granule cells
`
`CA3 pyramidal
`cells
`
`Inhibitory
`interneuron
`
`–
`
`Excitatory
`interneuron
`
`+
`
`Selectively
`vulnerable
`
`Neurogenesis
`
`Mossy fibers to CA3
`
`Subiculum
`
`Perforant
`pathway
`
`Dentate
`gyrus
`
`Entorhinal
`cortex
`
`Figure 3. Hippocampal Sclerosis.
`Hippocampal sclerosis is the most common identified pathological feature in cases of mesial temporal-lobe epilepsy. Normally, input to the hip-
`pocampus comes from the entorhinal cortex to the dentate granule cells through the perforant path. Dentate granule cells project to the CA3 sec-
`tor as the first step in the hippocampal output pathway. A close-up of the dentate granule-cell layer reveals several morphologic changes charac-
`teristic of hippocampal sclerosis that may play a part in epileptogenesis. Newly sprouted mossy fibers from dentate granule cells can synapse on
`dendrites of neighboring dentate granule cells, resulting in a recurrent excitatory circuit. They can also sprout onto inhibitory interneurons. Exci-
`tation interneurons, which normally activate inhibitory interneurons, may be selectively vulnerable to brain insults. Finally, neurogenesis of new
`dentate granule cells continues into adult life, and these neurons may integrate themselves into abnormal circuits.
`
`1262
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`n engl j med
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`25
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`2003
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`Downloaded from nejm.org by Joshua Scheufler on March 24, 2022. For personal use only. No other uses without permission.
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` Copyright © 2003 Massachusetts Medical Society. All rights reserved.
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`mechanisms of disease
`
`are postmitotic and do not divide in adults, but pro-
`genitor cells in the dentate gyrus of the hippocam-
`pus are known to divide. Postnatal neurogenesis in
`74
`the hippocampus can occur throughout life.
` In
`an animal model of temporal-lobe epilepsy induced
`with the use of pilocarpine, seizures can trigger in-
`creased mitotic activity in a proliferative area of
`the dentate gyrus, resulting in the differentiation
`75
`of new dentate granule cells.
` This process may be
`independent of mossy-fiber sprouting, which ap-
`pears to involve mature dentate granule cells rather
`76
` The functional
`than newly differentiated ones.
`significance of neuronal generation in the hippo-
`campus after a brain insult is uncertain, although
`some evidence suggests that new dentate granule
`cells become abnormally integrated into neuronal
`77
`circuits.
` The potential clearly exists for an imbal-
`ance between excitation and inhibition as new neu-
`rons differentiate and form synaptic connections.
`Since the genesis of dentate granule cells recapitu-
`lates similar processes early in the development of
`the nervous system, this mechanism could be rele-
`vant to epileptogenesis both early and later in life.
`In addition to these morphologic features,
`changes at the molecular level may also be impor-
`tant. The most prominent of these are alterations
`in the composition and expression of GABA
` recep-
`A
`tors on the surface of hippocampal dentate granule
`cells. Normally, GABA
` receptors in adults, which
`A
`consist of five subunits, serve as inhibitors, hyper-
`polarizing the neuron by allowing passage of chlo-
`ride ions when activated. In the pilocarpine model
`of temporal-lobe epilepsy, however, the expression
`A-receptor subunits in dentate gran-
`of various GABA
`ule cells is altered, and these altered receptors have
`heightened sensitivity to zinc, which is abundant
`in mossy-fiber terminals.78 Because this molecular
`change precedes the onset of spontaneous seizures,
`it is a plausible mechanism of epileptogenesis. Such
`findings have implications for treatment, since var-
`ious anticonvulsant drugs act through the GABAA
`receptor.
`In summary, hippocampal sclerosis, the most
`widely studied pathologic lesion underlying partial
`epilepsy, has features of structural reorganization,
`selective neuronal loss, and neurogenesis. The na-
`ture of these changes supports hypotheses that pre-
`dict the development of local hyperexcitability and a
`predisposition to partial seizures. However, the actu-
`al contributions of these factors, if any, to the de-
`velopment of an epileptic state have not been de-
`
`termined. Moreover, molecular alterations, such as
`changes in neurotransmitter receptors, are also like-
`ly to be important. What this research indicates is
`that changes in local circuits are compatible with the
`development of focal hyperexcitability, which may
`be the basis of some partial epilepsy syndromes.
`
`unanswered questions
`Although studies of mesial temporal-lobe epilepsy
`have yielded useful information, there are other
`plausible mechanisms of partial epileptogenesis
`that are not suggested by this syndrome. Some par-
`tial epilepsies, for example, are genetically deter-
`mined. Autosomal dominant nocturnal frontal-lobe
`epilepsy, in which single-gene mutations have been
`identified, has turned out to be a channelopathy that
`affects the neuronal nicotinic acetylcholine recep-
`tor, which serves as a ligand-gated sodium chan-
`nel.38 Why mutations in this receptor, which is wide-
`ly expressed throughout the brain, should cause
`partial seizures in the frontal lobe is just one of many
`mysteries. Some genetically determined partial ep-
`ilepsies, such as benign epilepsy with centrotempo-
`ral spikes (also called benign rolandic epilepsy), are
`age-limited syndromes, suggesting the importance
`of developmental influences.8,50,79 For many pa-
`tients with partial epilepsy, there may be an under-
`lying genetic predisposition that becomes manifest
`only after a sufficient environmental insult. Obvious-
`ly, understanding what molecular mechanisms are
`at work in patients with such a predisposition is of
`considerable clinical interest.
`
`newer areas of research
`
`cortical malformations
`A rapidly expanding area of investigation in epilep-
`togenesis is the study of malformations of cortical
`development, disorders in which the normal proc-
`ess of development in the cerebral cortex is disrupt-
`ed. These malformations range from microscopic
`dysplasias to global abnormalities such as lissen-
`cephaly (smooth brain) or subcortical band het-
`erotopia (double cortex)80 and can be classified as
`disorders of neuronal proliferation, neuronal migra-
`tion, or cortical organization.81 Many such malfor-
`mations are associated with refractory epilepsy and
`are increasingly recognized as a common cause of
`epilepsy that was previously believed to be crypto-
`genic.82 In numerous cases, magnetic resonance
`imaging with high resolution has identified small
`
`n engl j med
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`349;13
`
`www.nejm.org september
`
`25, 2003
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`1263
`
`The New England Journal of Medicine
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`Downloaded from nejm.org by Joshua Scheufler on March 24, 2022. For personal use only. No other uses without permission.
`
` Copyright © 2003 Massachusetts Medical Society. All rights reserved.
`
`AliveCor Ex. 2027 - Page 7
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`

`

`The new england journal of medicine
`
`cortical malformations in patients without any
`other obvious causes of epilepsy.
`Malformations of cortical architecture are useful
`for investigating the cellular and network changes
`that underlie the development of epilepsy.82-84 Al-
`though work in this area is still in its infancy, recent
`studies have provided us with a glimpse of what lies
`ahead. For example, in an animal model of hippo-
`campal heterotopias the heterotopic neurons lack
`a particular potassium channel that in normal hip-
`pocampal neurons subserves a voltage-activated fast
`potassium current.85 This defect would be expect-
`ed to lead to hyperexcitability. Other investigators
`have shown in a rat model that neurons within dys-
`plastic areas have impaired GABA-mediated inhibi-
`tory synaptic transmission, another defect that could
`lead to a predisposition to seizures.86
`
`the role of glial cells
`Decades of research in epileptogenesis, including
`much of the work highlighted in this review, have
`focused on the intrinsic properties and network
`connections of neurons. Glial cells, although long
`considered to be merely supporting cells in the cen-
`tral nervous system, may also have an important
`role.87 Glia perform key buffering functions that
`help to maintain the uptake of potassium and
`glutamate and other aspects of the extracellular
`milieu of neurons. Theoretically, disruption of these
`glial functions could cause neuronal hyperexcit-
`ability, since increased levels of extracellular po-
`tassium decrease the threshold for neuronal fir-
`ing and increased levels of glutamate could increase
`neuronal activation. Preliminary evidence from an
`animal model of cortical malform