Recent studies of the problem of ictogenesis, or the ways that seizures develop in an

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1 NEUROLOGICAL REVIEW Emerging Concepts in the Pthogenesis of Epilepsy nd Epileptogenesis Mrc A. Dichter, MD, PhD Recent studies of the problem of ictogenesis, or the wys tht s develop in n lredy hyperexcitble brin, re leding to prdigm-shifting concepts tht my led to exciting new therpies for s. Reserch on the eqully importnt re of epileptogenesis, or the wys tht norml brin becomes epileptic, is lso expnding, but comprble reserch into trnsltion of lbortory findings into successful clinicl interventions for those t high risk needs to be developed. Arch Neurol. 2009;66(4): Two new res of reserch hve the potentil to hve mjor effect on the current understnding of the physiologic mechnisms underlying genertion nd on possible new tretment strtegies for preventing epilepsy fter brin injury. These developments my seem to be seprte nd unconnected, but they represent 2 of the most fundmentl questions in epilepsy reserch: how do s develop in the brin nd how does norml brin develop epilepsy fter injury? The first section of this rticle introduces wht could be considered prdigm shift in the understnding nd conceptuliztion of wht is occurring in the brin of someone with epilepsy during bseline interictl periods, when no overt clinicl s re occurring, nd then during the development of s. The second section focuses on old nd new informtion bout how the norml brin cn be ltered to develop the propensity for these hyperexcitble phenomen nd emphsizes criticl gps in our understnding of this process. It lso ddresses wht is needed to trnslte the informtion bout epileptogenesis into cliniclly meningful prevention strtegies for individuls who re identified s being t high risk. Author Affilition: Deprtment of Neurology, University of Pennsylvni, Phildelphi. ICTOGENESIS, THE DISTRIBUTED NATURE OF SEIZURE FOCI, AND SEIZURE PREDICTION For more thn century, the concept of the epileptic focus, nd of the s tht rise from such brin regions, consisted of vgue notion of one re of the brin tht ws injured, or t lest bnormlly excitble, tht ws reltively discrete, nd tht, if removed, would render the ptient free. In ddition, it ws thought tht the ws n brupt nd sudden event, either confined to the bnorml region or spreding throughout the brin. It is becoming more pprent from reserch in severl lbortories, prtly bsed on new technologies, tht n epileptic region of the brin more likely consists of multiple smll distributed hyperexcitble networks. More interesting, perhps, is tht vriety of electrophysiologic chnges my be occurring frequently in these regions tht move the brin into different probbility sttes tht my wx nd wne before clinicl s develop. These bnorml electricl events my include micros, or like electrophysiologic events, which occur frequently in these smll regions; clinicl s my result when these micros slowly enlrge, begin to colesce, nd engge more nd more of the norml brin in surrounding regions. The implictions of this new hy Americn Medicl Assocition. All rights reserved. Downloded From: on 11/05/2016

2 A B b Figure 1. Norml humn hippocmpus (A) nd hippocmpl sclerosis (B). Indictes neuronl loss nd gliosis; nd b, grnule cell dispersion. Not illustrted in this Nissl stin is extensive xon sprouting by surviving neurons in the grnule cell lyer nd elsewhere nd mjor chnges in gene expression in surviving neurons nd gli in the injured regions. 1-3 Originl imges used with permission from Robert Sloviter, PhD. pothesis re enormous nd re discussed lter in this rticle. Wht might these microdomins look like? These possibilities cn be exmined for the humn hippocmpus nd surrounding regions, prts of the brin tht re very epileptogenic nd trditionlly hve been deemed responsible for intrctble complex prtil s. In ptients with temporl lobe epilepsy, the hippocmpus is smll nd sclerotic. At the microscopic level, there is extensive cell loss, with smll ptches of surviving (lthough injured) neurons, dispersl of surviving neurons, gliosis, xonl sprouting, nd the formtion of new synptic connections, especilly locl connections in smll networks (Figure 1). At the moleculr level, the surviving neurons nd gli express mny different genes tht encode ion chnnels nd receptors, s well s other proteins, compred with their norml counterprts. 1-3 These chnges in gene expression ptterns ffect the physiologic nd phrmcologic fetures of the injured regions. Severl yers go, UCLA-bsed epilepsy reserch group, nd others, using new electrophysiologic techniques tht focused on high-bndwidth (highfrequency) recording, begn noting highly loclized bursts of high-frequency ctivity riding on interictl spike dischrges in deep limbic res. 4,5 In some respects, these findings could be considered nlogous to old findings of fterdischrges nd high-frequency oscilltions occurring fter interictl spikes in discrete res of epileptogenic neocortex nd hippocmpus observed in experimentl niml models 6,7 nd in humn ptients. 8 These oscilltions seemed to be ssocited with the regions from which s emnted nd were generlly not seen on spikes in more distnt regions. The UCLA group clled these fst ripples, nd others used the term highfrequency epileptiform dischrges. They proposed tht one could differentite red spikes from green spikes, with red spikes indicting the most ictogenic res. They lso demonstrted tht the fst ripples occurred more frequently in prhippocmpl regions, such s the subiculr cortex. 9 Bsed on their observtions in humn ptients nd epileptic niml models, they proposed hypothesis tht chronic epileptogenesis requires development of network of pthologiclly interconnected neuron clusters. 10(pS144) Although not rdicl deprture from some previous thinking, this work focused the ttention of the field on the concept of more distributed network rther thn on more homogeneous epileptic re. At the neocorticl level, in ptients with injuries or dysplsis, similr phenomen cn be found t the ntomicl nd electrophysiologic levels. 11 Often, these re more difficult to loclize or identify becuse the cellulr structure of the neocortex is more complex thn tht of the hippocmpus, nd the lesions tend to be more distributed. These concepts hve now been tken to new level by studies using microelectrode recordings from humn epileptic regions. This cn be done using surfce grids nd specilized electrodes in the neocortex or using microwire recordings from deep structures. In work originting from the Myo Clinic, performed by Worrell nd Sted in collbortion with Litt 12 t the University of Pennsylvni, brief like dischrges were recorded frequently from severl microelectrodes within loclized epileptic regions of the cortex, but in only 1 microelectrode t time. These dischrges re never seen with mcroelectroencephlogrphic electrodes, nd they seem to occur in very discrete regions. They re often seen in only 1 of series of closely spced microelectrodes, result tht indictes very limited sptil distribution. Although much more dt re needed, hypothesis emerging from these discoveries is tht micros occur frequently in hyperexcitble regions of the neocortex or hippocmpus nd tht these events re often brief nd self-limited. A hypothesis in development bsed on these observtions suggests tht full-blown, cliniclly detectble develops when these micros begin to enlrge, colesce, nd eventully rech criticl mss. Whether there re behviorl consequences of these smll loclized events remins to be seen, but it is n intriguing issue regrding so mny of the problems tht ptients with epilepsy hve tht seem distinct from the s they experience. Wht fctors re likely to be responsible for these events nd their expnsion? Undoubtedly, inhibition plys role in confining the like events, both in time nd spce, ccording to hypothesis first presented in the 1960s. 13 Experiments performed by the UCLA group illustrte how Americn Medicl Assocition. All rights reserved. Downloded From: on 11/05/2016

3 fst ripple dischrges in hippocmpl slice tken from n epileptic rt re loclized (red) t bseline, but, when synptic, -minobutyric cid medited inhibition is reduced, the fst ripples spred throughout the slice nd the interictl dischrges increse in size. 14 These dt support some long-stnding hypotheses bout ictogenesis lso bsed on the blnce between excittion nd inhibition in smll loclized corticl circuits. 13,15 How does this phenomenon occur physiologiclly, without the ddition of receptor ntgonists? In n epileptic region, there is n excittory center where some of the principl cells tend to fire in bnorml highfrequency bursts. These bursts re likely due, t lest in prt, to enhnced recurrent excittory connections. These neurons lso typiclly synpse onto inhibitory interneurons, which hve widely distributed locl connections nd inhibit surrounding regions. When the excittory neurons fire too ggressively, interesting phenomen occur, ll of which re prt of the norml functioning of the vertebrte brin. Excittory synpses re fcilitted with repetitive stimultion, producing stronger ctivtion of recurrent excittory circuits. Simultneously, repetitive stimultion of inhibitory synpses produces decline in synptic strength This combintion of enhnced positive feedbck nd diminished negtive feedbck results in n explosive sitution, nd ctivity is produced. This cn occur in smll, highly loclized regions, such s those smpled by 1 microwire s discussed previously herein; in lrger surrounding regions; or even t distnces from the hyperexcitble region. This is the likely mechnism by which s develop nd spred rpidly throughout the brin. Wht re the implictions of ll this informtion? First, t purely clinicl level, the recording of these events my permit enhnced focus locliztion for resective surgery. Second, s newer, innovtive tretments re developed, locliztion for brin stimultion or locl drug delivery cn be performed. Third, if s re not beginning bruptly but re developing by the increses nd regressions of these micros, it is possible tht s cn be predicted, sfe periods cn be identified, nd therpy cn be directed to ptients during high-risk times, possibly by using intelligent closedloop feedbck devices. These therpies cn be directed towrd disrupting incipient hypersynchrony. Other recent reserch 19 indictes tht s do not strt bruptly but my develop with predictble series of chnges in brin electricl ctivity. One exmple, from Litt s lbortory, is tht multiple dimensions of informtion cn be extrcted from intrcrnil electroencephlogrms (without microwire recordings) in vrious time domins preceding s. 20 In more recent study, 21 this lbortory, using sophisticted sttisticl techniques, demonstrted the occurrence of more probbilistic series of events, with focus on n incresing probbility of occurrence rther thn on purely liner mrch towrd. Regions of the brin oscillte between periods of reltive quiescence nd periods of incresingly higher probbilities, suggesting tht my be imminent. 21 All this work is focused on the design of new therpies tht will be tied directly to the prediction of occurrence online nd the delivery of some form of therpy to disrupt the developing hypersynchrony. The first genertion of such devices is currently undergoing clinicl testing s both n open-loop stimultion 22 nd closed-loop stimultion coupled with erly detection. 23 As more is lerned bout loclized chnges in brin excitbility sttes, it is hoped tht closed-loop devices could be ctivted by the impending increse in excitbility rther thn the ptient hving to wit for to ctully begin. PREVENTION OF EPILEPSY At this time, ttention cn be turned from predicting nd preventing s to predicting nd preventing epilepsy. How does the norml humn brin develop epilepsy, or hyperexcitbility? This is fundmentl scientific nd clinicl issue. However, unlike the drmtic nd prdigm-chnging dvnces discussed so fr, the issue of prevention of epilepsy remins problemtic. For this reson, it is pproprite to propose the recognition of new syndrome: the risk of epilepsy development (RED) syndrome. The RED syndrome recognizes tht fter vriety of brin injuries (eg, trum, sttus epilepticus, ischemi, centrl nervous system infection, nd some forms of chronic neurodegenertion), process hs begun tht leds to the development of epilepsy, t lest in substntil frction of individuls. Why is it necessry to invent new syndrome? Epilepsy seems to be either the only disese known to humnkind, or one of very few, in which physicins wit until the disorder develops nd then only try to tret the symptoms. Reserch nd tretment strtegies for virtully every other disese focus on either prevention or cure, especilly prevention. Smokers re not encourged to continue smoking nd then treted for cough only fter they develop lung cncer. Very high cholesterol levels or blood pressure redings re not ignored until hert ttcks or strokes occur. When possible, medicl therpy focuses on risk reduction nd prevention. Epilepsy prevention hs not been mjor focus of reserch despite the fct tht epilepsy is mjor medicl problem. It develops over time, so there is opportunity to intervene, nd risk fctors cn often be identified. So one my sk why the neurology community hs not focused more on this issue. Prt of the reson is becuse there is insufficient bsic scientific informtion bout intervention strtegies. However, there hs been recent drmtic increse in reserch focusing on the mechnisms of epileptogenesis tht prllels the studies described erlier on the mechnisms of ictogenesis. It is clerly possible to identify ptients who re t reltively high risk for epilepsy. 24,25 These include individuls with moderte to severe hed injury (such s we re seeing in veterns returning from Irq nd Afghnistn); individuls with intrcerebrl hemorrhge, brin tumors, sttus epilepticus, nd vriety of chronic neurodegenertive diseses; nd children with prolonged febrile s, dysplstic brins, nd who hve certin genetic forms of epilepsy but hve not yet become symptomtic. However, t the present time, nothing cn be done to reduce the risk of epilepsy in these individuls. One cn get sense of the stte of clinicl investig Americn Medicl Assocition. All rights reserved. Downloded From: on 11/05/2016

4 tion in this re by exmining the CliniclTrils.gov Web site (Figure 2). Most of the mjor neurologic disorders list mny clinicl trils in progress, most of which re focused on prevention or direct tretment. The figure includes more thn 150 clinicl trils in epilepsy, but lmost ll of them re devoted to symptomtic therpy. There re only 2 clinicl trils listed tht re trying to prevent epilepsy in high-risk individuls. Both re pilot trils nd focus on individuls with trumtic brin injury. It is cler tht more work needs to be done in this re. To develop strtegies for the prevention of epilepsy, it is necessry to understnd the process of epileptogenesis. Initilly, norml brin experiences some form of injury. The injury cn result from trum, infection, ischemi, bout of prolonged s (sttus epilepticus), or the presence of mlformtion or mss lesion. Depending on the ptient s ge nd genetic bckground, some cute dmge occurs, nd then, progressive dmge often continues. The brin tries to repir itself, but fter ltent period of dys, weeks, months, or even yers, condition of hyperexcitbility develops nd s begin. The s themselves my produce progressive dmge, depending on where in the brin they occur nd how intense they re. We do not know whether this is 1-shot event or whether multiple hits re necessry for full expression of the epileptic phenotype (Figure 3). The end product of the epileptogenic process hs been nlyzed using humn brin tissue, mostly vi electrophysiologic studies or postmortem or surgicl pthologicl exmintions. The process of epileptogenesis hs lso Clinicl Trils, No Stroke PD AD Epilepsy MS TBI MD Antiepileptogenesis Figure 2. Number of clinicl trils listed on the CliniclTrils.gov Web site for vrious neurologic disorders. AD indictes Alzheimer disese; MD, musculr dystrophy; MS, multiple sclerosis; PD, Prkinson disese; nd TBI, trumtic brin injury. been exmined in vriety of niml models. 26 The mjor findings of these studies cn be distilled to the types tht were discussed erlier: cell loss, xonl sprouting, synptic reorgniztion, ltertions in the neuronl phenotype, neurogenesis, circuit reorgniztion, nd ltered glil function. Ech of these cn be therpeutic trget, but it must be pprecited tht mny of these processes my be involved in the ttempt of the brin to repir the dmge nd recover lost function. This is significnt issue for ny clinicl tril becuse it is importnt not to prevent epilepsy t the cost of impiring recovery of function. In fct, severl nti gents hve been shown to retrd recovery of function in models of ischemi nd trumtic brin injury There re severl current hypotheses bout pproches to prevention of epilepsy, but there re very few dt in this field on which to build significnt clinicl progrm. One prominent ide is tht by protecting the brin from the injury, one cn prevent epilepsy. At gross level this is true: tht is, if ll dmge is prevented, epilepsy is unlikely to occur. However, there re lso dt from experimentl studies 30,31 tht indicte tht some forms of prtil protection do not, in fct, prevent subsequent epilepsy. Thus, even logicl nd sensible hypothesis needs creful experimentl nd clinicl verifiction. Exmintion of the current sttus of ntiepileptogenesis t the clinicl level produces disppointing results. 32 This cn led to nihilistic conclusion tht nothing should be done until bsic reserch in niml models indictes more promising pthwys. However, if the clinicl reserch in this field is put on hold until tht time, without suitble preprtion nd pilot studies, it will tke t lest 5 or 10 yers to determine whether ny lbortory brekthrough is effective in clinicl setting with humn ptients. An lterntive pln would be to begin the process now so tht when the lbortory brekthrough becomes vilble, it will be cler how best to evlute its effectiveness s therpy. 33 It is importnt to continue to improve the bility to identify those t risk, to begin thinking bout tretment before s develop, to tret with sfe therpies, nd to exmine the outcome. In the process of developing truly ntiepileptogenic therpy, it will be importnt to distinguish the dely of the onset of symptoms ccomplished by using symptomtic tretment (eg, n nti drug) from the true reduction of the occurrence of the disorder. However, it must lso be recognized tht effective suppres- A B C Clinicl Clinicl Clinicl Figure 3. Hypotheticl epileptogenic events tht led to chronic epilepsy. The dotted line designtes the threshold t which clinicl s become pprent. A, One hit. B, Two hits. C, Multiple hits Americn Medicl Assocition. All rights reserved. Downloded From: on 11/05/2016

5 sion of ll erly s, even smll ones tht re not esily identified using current technologies, my be interfering with the process of epileptogenesis; so, in this cse, symptomtic nti drug therpy my lso be ntiepileptogenic. As mentioned, there re currently 2 ongoing pilot studies designed to explore these issues, nd there re pioneering studies by Temkin nd collegues 34,35 t the University of Wshington tht hve led the wy in this field. As these pilot studies re undertken, it will be useful to exmine biomrkers in severl domins tht might identify those in the high-risk groups who re developing hyperexcitble brins nd who might require more ggressive monitoring nd intervention. These biomrkers would include electrophysiologic mrkers, from sclp nd, likely, intrcrnil recordings, where one might look for the ppernce ofinterictlspikes, 36 fstripples, 37 ndmicros. 12 They would lso include imging biomrkers nd, possibly, biochemicl biomrkers in serum or cerebrospinl fluid. The long-term gol in this effort is to cure epilepsy by preventing its development in t-risk individuls. To ccomplish this, it will be necessry to recognize the RED syndrome, to develop consensus for the need for clinicl trils in ntiepileptogenesis, to develop the clinicl infrstructure for performing such trils in network of centers, to develop better clinicl tril prdigms, nd to prtner with those who perform bsic reserch in ntiepileptogenesis. In summry, prdigm-shifting reserch is ltering how we understnd the processes by which s develop in n lredy hyperexcitble brin. These new discoveries hve gret promise to led to new forms of therpy with long-term intrcrnil electroencephlogrphic monitoring, prediction, brin stimultion, locl drug delivery, nd intelligent implnted closed-loop feedbck devices. These re therpies tht would hve been in the relm of science fiction just few yers go. In ddition to lerning how to predict s, it is lso possible to predict epilepsy, t lest with some level of probbility. However, just s the field is trying to cpitlize on newly developed bility to predict s, strong focus of bsic nd clinicl reserch on the importnt topic of preventing epilepsy in those who re known to be t high risk is needed. In this endevor, it would be pproprite to rise RED flg for epilepsy! Accepted for Publiction: My 4, Correspondence: Mrc A. Dichter, MD, PhD, Deprtment of Neurology, University of Pennsylvni, 3 Gtes Building, 3400 Spruce St, Phildelphi, PA (dichter@mil.med.upenn.edu). Finncil Disclosure: None reported. REFERENCES 1. Bernrd C, Anderson A, Becker A, Poolos NP, Beck H, Johnston D. Acquired dendritic chnnelopthy in temporl lobe epilepsy. Science. 2004;305(5683): Ellerkmnn RK, Remy S, Chen J, et l. Moleculr nd functionl chnges in voltgedependent N chnnels following pilocrpine-induced sttus epilepticus in rt dentte grnule cells. 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Do interictl spikes drive epileptogenesis? Neuroscientist. 2005;11(4): Brgin A, Wilson CL, Almjno J, Mody I, Engel J Jr. High-frequency oscilltions fter sttus epilepticus: epileptogenesis nd genesis. Epilepsi. 2004; 45(9): Americn Medicl Assocition. All rights reserved. Downloded From: on 11/05/2016