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WORKSHOP REPORT

9th Workshop on the Neurobiology of

Epilepsy (WONOEP IX): The transition

from the interictal to the ictal state (Teluk

Nibong, Langkawi Island, Malaysia, July

4–7, 2007)

The Workshop on the Neurobiology of Epilepsy(WONOEP) is a satellite meeting of the InternationalEpilepsy Congress organized since 1989 by the Commis-sion on Neurobiology of the International League AgainstEpilepsy (ILAE), devoted to the discussion of the ba-sic neuroscience of epilepsies in an informal setting (seereports of previous WONOEPs in the References). Thetheme for the 9th edition of WONOEP (Langkawi Island,Malaysia, July 4–7, 2007) was “The transition from the in-terictal to the ictal state.” The identification of the mecha-nisms that control the transition into the ictal state is crucialfor the understanding of seizure genesis (ictogenesis) and,ultimately, for developing new strategies to cure epilepsy.Several recent technological advances in the diagnosis ofhuman epilepsies have provided an opportunity to improveour understanding of ictogenesis. Intracranial EEG record-ings performed in patients with drug-resistant epilepsies,and selected for surgical ablation of the epileptogenic re-gion, has allowed investigators to study human brain ac-tivity during seizures. The most important outcome fromthe analysis of presurgical and intraoperative intracerebralrecordings is the identification of interictal and ictal EEGpatterns generated in the region of seizure onset. Presur-gical recordings also provide an experimental window inwhich to study micro- and macrocircuits in supposedlynormal human brain structures, explored en passage whileaiming at nearby epileptic areas. Another area of researchthat has promoted and reinforced the need to understandictal and interictal patterns is the expanding field of seizureprediction and detection. Anticipation of seizure occur-rence relies on the analysis of the temporal evolution ofEEG signal changes that precede the ictal discharge. Devel-oping a precise and possibly automated protocol for identi-fication of ictal and interictal patterns in different forms ofepilepsies is crucial for detecting preictal states. Finally, therecent use of functional imaging in epilepsy has provided anovel approach to the study of ictogenesis, and uncoveredthe role of the interactions between neuronal and vascularbrain compartments in the generation of interictal and ictaldischarge patterns.

Several controversial issues on ictal transition arestill open for discussion, including (1) the definition of“ictal” and “interictal” states, (2) the characterization of ic-tal onset patterns and the correlation between a particularseizure pattern and a specific brain region, (3) the iden-tification of peculiar ictal patterns for given experimentalmodels/conditions. Several elements contribute to confu-sion in the dialogue between basic and clinical scientistsworking in the epilepsy field, because the terminology uti-lized in the clinical setting to define activity patterns maydiffer from that in use among basic neuroscientists. To en-hance interactions between clinical and basic sciences, alarger participation of scientists with clinical expertise waspromoted in WONOEP IX.

The meeting was opened by two lectures, by GyorgyBuzsaki and by Jean Gotman, on the role of fast oscil-lations in neuronal synchronization during physiologicalprocesses and in epileptogenesis. During a panel session,the features of focal ictal patterns in different epilepticexperimental conditions and in human epilepsy were dis-cussed, in an attempt to draw a correlation between the ex-perimental data and the intracranial EEG findings observedin humans. Ictal patterns in mesial temporal lobe and neo-cortical human epilepsies were reviewed by Anatol Braginand Stefano Francione, respectively, based on intracranialpresurgical recordings performed in drug-resistant patients.Experimental ictal patterns observed in animal models offocal epilepsy in vivo and in vitro were reviewed by EdBertram and Marco de Curtis. A definition of the interic-tal and ictal patterns and the prevalent ictal onset featuresin different forms of focal epilepsies were discussed. Theexistence of a correlation between a specific region/brainalteration and a particular seizure pattern was stressed forboth experimental and human findings.

Paroxysmal high-frequency activity (HFA) is one of thecommon interictal patterns observed in focal epilepsy. HFAon the scalp electroencephalogram (EEG) colocalizes withseizure onset in children and were proposed as predictivesurrogate marker of epileptogenesis by Joyce Wu, sincetheir presence showed a strong correlation with seizureexacerbation in sequential video-EEG recordings. HiroshiOtsubo confirmed that in pediatric patients, interictal HFAcorrelates with the ictal onset zone, identified by intracra-nial video-EEG recordings, and can be detected duringinterictal spikes with event-related analysis performedwith magnetoencephalography. In an in vitro experimen-tal model of seizure, preictal strengthening in power and

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synchronization of HFA generated by the collective, asyn-chronous firing of multiple mini-aggregates of CA1 neu-rons (extending over ∼150 μm) was reported by JohnJefferys. These observations suggest that the generationand propagation of seizures could be mediated by a pro-gressive preictal synaptic synchronization of HFA acrossneuronal assemblies. Michel Le Van Quyen showed, usingan intact immature septohippocampal formation in vitro,that hippocamposeptal long-range gamma aminobutyricacid (GABA)ergic interneurons are necessary to synchro-nize local hippocampal interneurons into coherent high-frequency firing. These long-range neurons, by providingfast synchronization among distantly functional networks,may also participate in the construction of hippocampalnetworks during development.

The existence of a preictal state in patients with in-tractable focal epilepsy was discussed by Bela Weiss, whoshowed dramatic changes in brain electrical activity ana-lyzed by estimation of a self-similarity pattern, the Hurstexponent, before the onset of epileptic seizures. PaoloFederico proposed that a preictal state could be detectedat the site of presumed seizure focus as well as in remotebrain regions up to 20 min prior to seizure onset by analyz-ing BOLD signal changes during functional MRI analysis.Kevin Staley described the correlation between interictalspikes and seizures, with the view that seizures were theconsequence of a relatively improbable spike ignition path-way. Optical recordings of interictal activity in slices andcomputer modeling demonstrated that seizures may ariseas a consequence of the looping/regenerative activation ofinterictal spikes.

Anatol Bragin described two seizure onset patterns inpatients with mesial temporal lobe epilepsy: hypersyn-chronous and low-voltage fast pattern. The hypersyn-chronous pattern could be reproduced experimentally infreely moving animals by injection of bicuculline intothe hippocampal CA3 area. The low-voltage fast pat-tern was not observed in acute experiments, suggestingthat it may result from chronic structural abnormalitiesin neuronal and glial networks. Igor Timofeev presenteddata suggesting that cortical ictogenesis and epileptoge-nesis are based on mechanisms independent from theproepileptic trigger. He demonstrated the presence of long-lasting hyperpolarizing potentials in both trauma and kin-dling models of epileptogenesis, during all states of vig-ilance that induce homeostatic upregulation of neuronalexcitability, eventually leading to seizure generation. JohnSwann presented an animal model of infantile spasms in-duced by chronic infusion of the sodium channel blocker,TTX, in which frequent clusters of spasms correlate tohigh-voltage slow transients followed by an electrodecre-mental episode of fast activity. Between “spasms” EEGrecordings showed a hypsarrhythmic pattern consisting ofasynchronous high-amplitude slow waves intermixed withmultifocal spikes. Regional or generalized EEG alterations

may predict transition from hypsarrhythmia to the elec-trodecremental events correlated with spasms. Luiz Mellodescribed the ictal patterns in the marmoset pilocarpinemodel of epilepsy, characterized by recurrent spontaneousepileptic seizures not associated with intense degenera-tive process often seen in rodents. Jeff Noebels discussedgene-specific epilepsy syndromes observed in mice withtargeted deficiencies in ion channel subunit genes. Video-EEG seizure recordings from transgenic mice that exhibitelevated thalamic T-type currents revealed a stereotypedpattern of abrupt, generalized thalamocortical seizureswith no evidence of interictal abnormalities. In contrast,potassium channel subunit knockout mice showed tran-sition patterns of partial-onset seizures with subsequentgeneralization.

The role of GABAergic function in interictal-ictal transi-tion was discussed by Gary Mathern, who examined tissuechanges in human and rodent models of cortical dyspla-sia. By comparing the number of GABAergic neurons inhuman tissue, he showed that the expression of GAD67mRNA and GAD protein is not reduced in pediatric corti-cal dysplasia cases. These results are consistent with cellu-lar electrophysiology studies presented by Carlos Cepedathat support the concept that GABA is an important neu-rotransmitter in pediatric cortical dysplasia. In slices fromcortical dysplasia pediatric patients, ictal discharges wereobserved only when the proconvulsant 4-aminopyridine (4-AP) was coperfused with the GABAB receptor antagonist,phaclofen, but not in the presence of GABAA receptorantagonists. These findings indicate a permissive role ofGABAB receptors in pediatric dysplastic tissue in vitro.Rene Pumain presented evidence showing a reduced ef-ficacy of glycolysis-dependent GABAAR phosphorylationand of GABAergic inhibition in postsurgical cortical tis-sue samples from epileptic patients, favoring seizure ini-tiation and propagation. These findings suggest a func-tional link between the epileptic pathology and the regionalcerebral glucose hypometabolism observed in patients withpartial epilepsies. Gilles Huberfeld showed that in humanpostoperative epileptogenic subiculum, ictal dischargescan be induced by increasing cellular excitability or bychanging external pH. The transition period is character-ized by the emergence of large population preictal eventsthat are dependent on glutamatergic transmission. Once es-tablished, preictal discharges trigger ictal events through aGABAergic mechanism. Ed Dudek showed that repetitiveactivation of synaptic inputs in minislices of the dentategyrus obtained from kainate-treated epileptic rats, causesdepression of GABA-mediated inhibition and facilitationof intracellular EPSPs in granule cells, thus unmaskingnew recurrent excitatory circuits and triggering seizures.To examine neural dynamics of the seizure transition, PeterCarlen presented an in vitro model of recurrent seizures in-duced by perfusing the isolated mouse hippocampus withlow magnesium solution. Spontaneous seizure transitions

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recorded in pyramidal neurons and interneurons in theCA1 and CA3 regions were preceded by an initial “sub-state” wherein inhibitory synaptic input dominated, fol-lowed by a phase in which inhibition was maintained andincreasing, which in turn entrained “overpowering” excita-tion prevailed. Paul Rutecki showed that transient group Imetabotropic glutamate receptor activation in the rat hip-pocampal slice causes a long-lasting suppression of theslow afterhyperpolarization (sAHP) activated by neuronalactivity, that converts the interictal pattern into ictal activ-ity. These results suggest that enhancement of the sAHPmay be target for antiepileptic drugs. Jeffrey Loeb reportedon the molecular analysis of human neocortical tissue re-moved from the focal seizure onset zone. Using microar-rays, a core group of induced genes—referred to as thehuman “epileptic transcriptome”—was identified. Many ofthese genes and associated signaling pathways are inducedin pyramidal neurons and have sharply demarcated bor-ders that may relate to the gyral pattern of the cortex. Thepresentations of Albert Becker and Heinz Beck focusedthe contribution of increases of the potassium M-current(KCNQ2 and 3) and persistent sodium current (Nav1.6)in CA1 neurons of chronically epileptic animals to en-hanced propensity for seizures. The voltage-dependence ofactivation of M-currents was shifted in a depolarizing di-rection, rendering the channel less available at subthresh-old potentials. Intriguingly, these findings are similar tothe functional consequences of KCNQ channel mutationsthat give rise to some hereditary forms of epilepsy. FengRu Tang showed that voltage-dependent calcium channels,Cav1.2, Cav1.3 or Cav2.1, up- or down-regulate in func-tionally different groups of CA1 interneurons during andafter pilocarpine-induced SE. The induced expression ofCav1.3 or Cav2.1 in reactive astrocytes 7 and 60 days af-ter SE suggests that calcium signaling in these cells maybe involved in initiation, maintenance, or spread of seizureactivity.

During experimental status epilepticus (SE), synapticGABAA receptors become internalized in hippocampalgranule cells, while extrasynaptic delta-subunit-containingGABAA receptors that mediate the tonic current increase.David Naylor demonstrated that a decrease in amplitudeof IPSCs coupled with an increase in GABAA tonic cur-rent was also observed following exogenous extracellularGABA application, suggesting that an activity-dependentincrease in extracellular GABA occurs during SE, and maybe sufficient to erode synaptic inhibition and favor the tran-sition from an interictal to an ictal state. Moreover, simu-lation experiments showed that high-frequency GABA re-lease approximating “fast ripples” (100–200 ms potentialsat 40–160 Hz) can temporarily degrade synaptic inhibi-tion. Claude Wasterlain reported that 30–60 min of SE in-creases N-methyl-D-aspartate (NMDA)- and alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA)-receptor-mediated miniature postsynaptic currents in gran-

ule cells, due to a migration of NR1 subunits of NMDAreceptors from cytoplasm to synapses. These changes inreceptor trafficking enhance excitation, and may play arole in the transition from single seizures to SE. Niko-laus Sucher demonstrated that pyramidal neurons in layerV of the developing rodent somatosensory cortex expressMg2+-insensitive NMDA receptors that induce excitatorypostsynaptic currents directly without the need for coinci-dent membrane depolarization. These noncanonical NM-DARs are upregulated in a mouse model of tuberous scle-rosis and could promote long-lasting plasticity changes thatoccur during epileptogenesis.

The role of neurosteroids in determining whether ornot a seizure occurs during different behavioral conditionswas discussed by Michael Rogawski. Neurosteroids syn-thesized in the periphery and in the brain are powerful reg-ulators of brain excitability as positive allosteric modula-tors of extrasynaptic GABAA receptors. Endogenous neu-rosteroids play a role in regulating seizure susceptibilityduring the menstrual cycle (catamenial epilepsy), in stress-ful conditions, and in the hypoandrogenic state that is com-mon in the setting of uncontrolled temporal lobe epilepsy.Filiz Onat reported on the temporary (3 months) suppres-sion of spike-and-wave discharges (SWD) after kainic acidinjections in genetic absence epilepsy rats from Strasbourg(GAERS). These data demonstrate a transient breakdownof mechanisms underlying corticothalamocortical oscilla-tory circuits involved in SWD generation and suggest aninteraction between the limbic circuits and corticothalam-ocortical networks in epileptogenesis. The generation ofrhythmic SWDs in absence epilepsy may be due to an in-crease in cortical firing synchronization. By using a newmethod for calculation of extracellular field potentials,based on a single pyramidal cell compartmental model,Gilles van Luijtelaar showed that weak population syn-chronization of cortical pyramidal neurons generates fieldresponses similar to a sleep spindle, while stronger syn-chronization clearly correlated with SWD. These simula-tion studies suggest that changes in the degree of firingsynchronization in large population of pyramidal cells re-flect changes in synaptic strength. In a mathematical modelof the nonsynaptic mechanisms of epileptiform activity,Antonio-Carlos Almeida hypothesized that (1) the sodium-potassium pump activity is responsible for the duration ofthe interictal and ictal states; (2) the interictal-ictal transi-tion is characterized by an increasing excitability mediatedby the chloride Nernst potential “overcoming” the mem-brane potential (as in immature neurons).

Intrahippocampal pathways may also play a role inpromoting ictogenesis in temporal lobe epilepsy. Byperforming simultaneous voltage-sensitive dye imagingand patch-clamp recordings in hipopcampal slices fromepileptic pilocarpine-treated rats, Douglas Coulter showedthat the temporoammonic pathway exhibits a large in-crease in effectiveness that was stronger in animals with

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a high seizure frequency, suggesting that this pathway me-diates the generation and/or propagation of seizure activ-ity in the hippocampus. Another structure that may beimportantly involved in epileptogenesis is the subiculum.By immunohistochemistry and in situ hybridization in thekainic acid model, Guenther Sperk demonstrated degener-ation of parvalbumin-containing GABAergic neurons andafferent (calretinin-positive) thalamic neurons, coupled tosprouting of somatostatin/NPY/GABAergic interneurons(OML cells) and over-expression of NPY in pyramidalcells of the subiculum, 1–3 months after the initial SE.Aristea Galanopoulou showed that the switch of GABAA

receptor signaling from depolarizing to hyperpolarizingin CA1 pyramidal neurons of the rat hippocampus ap-pears earlier in female than in male animals. Furthermore,early life kainic acid-induced SE, show sex-specific effectson GABAA receptor signaling, which may have potentialrepercussions for subsequent brain development. MicheleSimonato demonstrated that overexpression of FGF-2 intransgenic mice exerts two different, apparently contrastingeffects: it favors ictogenesis and prevents seizure-inducedcell death. The mechanisms underlying these contrastingeffects are critical to control seizures and their deleteri-ous consequences through modulation of the FGF-2 sys-tem. The endocannabinoid (2AG)-synthesizing enzyme,colocalizes with mGluR5 in the perisynaptic annulus ondendritic spines, and is supposed to induce retrograde in-hibition of glutamate release via presynaptic cannabiniodreceptors CB1. Tamas Freund demonstrated that CB1 re-ceptors are selectively reduced in the epileptic human hip-pocampus, even when cell death is minimal. This reduc-tion may result in a loss of negative feedback on glutamaterelease, and thereby could contribute to ictogenesis in theepileptic temporal lobe. Yoshiya Murashima showed thatin the brain of EL mice, proinflammatory cytokines are in-creased progressively with both development and seizureactivity. A periodic increase of cytokines prior to the nextseizure episode may work together with neuronal factorsduring epileptogenesis and in the transition from interictalto ictal state. Luisa Rocha showed that 24 h after electricalamygdala kindling in rats, the after-discharge threshold andsusceptibility to subsequent seizures were reduced by ad-ministration of nociceptin, a peptide activated by seizureactivity, while seizure parameters at threshold were notmodified. In fully kindled rats, nociceptin enhanced after-discharge threshold and decreased susceptibility to subse-quent seizures. The data suggest that nociceptin induces in-hibitory effects on after-discharge threshold and enhancesthe postictal period.

In several animal models of temporal lobe epilepsy, thechronic phase is preceded by a seizure-free latent period.Interestingly, interictal-like activity appears soon after theinitial insult, suggesting that it could play a role in buildingan epileptogenic network and could be causally linked tocognitive deficits. Christophe Bernard reported that epilep-

tic animals begin to display spatial memory deficits dur-ing the latent period. These deficits were not correlated tointerictal-like activity, but to modifications in the endoge-nous theta rhythm. When present, interictal-like activitydisrupted theta activity. Pavel Mares discussed the onto-genetic development of interictal-ictal transition in corti-cal foci elicited by epidural application of bicuculline infreely moving 7-, 12-, 18- and 25-day-old rats. All the agegroups studied exhibited transition of interictal activity ofunilateral foci into ictal phases. Surprisingly, ictal activ-ity that started focally and irregularly spread over the cor-tex of the two hemispheres was recorded in 7-day-old ratpups. Raman Sankar described the application of rapid kin-dling as a method for studying the antiepileptogenic po-tential of candidate drugs, such as topiramate, in rat pupsat different developmental stages. This method has alsobeen effectively utilized to develop an animal model ofepilepsy-associated depression, an important comorbidityof epilepsy. Increases in ATP turnover with elevation ofadenosine may be very important in causing postictal de-pression of brain activity. Maria-Jose Fernandes demon-strated an increase in the expression of P2 × 7 receptorsin glial cells during acute SE, while in the interictal pe-riod there was a reduction in the concentration of all anti-convulsant purines that may contribute to the triggering ofspontaneous seizures. ATP may reduce glutamate releaseby activating P2 × 7 receptors, and form adenosine throughits breakdown by ecto-5-nucleotidase. These two mech-anisms inhibit hyperexcitability and spontaneous seizuresoccurrence.

ACKNOWLEDGMENTS

The workshop was sponsored by ILAE and by the generous sup-port of UCB Pharma International, UCB Pharma Japan, Janssen PharmaJapan, Valeant Pharmaceutical International, Ortho-McNeill Neurologics,Teikoku Pharmaceutical Co. Ltd, Cyberonics and Kyouwahakkou Phar-maceutical Co. Ltd. We are grateful to Pascale Quilichini for the admin-istrative organization of the meeting.

Marco de Curtis1,4

decurtis@istituto-besta.itYoshiya Murashima2,4

Raman Sankar3,4

1Fondazione Istituto Neurologico Carlo BestaMilano, Italy

2Division of PsychobiologyTokyo Institute of Psychiatry

Setagaya-Ku, Japan3David Geffen School of Medicine, UCLA

Los Angeles, California, U.S.A.4Commission on Neurobiology of the International

League Against Epilepsy (ILAE)

REFERENCES

Proceedings of the 3rd WONOEP Symposium. Tromso, Norway, June1993. (1996) Epilepsy Res Suppl 12:S1–385.

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Fourth Workshop on the Neurobiology of Epilepsy (WONOEP IV).Adare, Ireland, 26-28 June 1997. (1998) Epilepsy Res Suppl 32:S1–S332

Brain plasticity and epilepsy. Papers presented at the 5th Workshop onthe Neurobiology of Epilepsy (WONOEP V). Cesky Krumlov, CzechRepublic. September 8-10, 1999. (2004) Epilepsia 41(Suppl 6):S1–S205.

Proceedings and abstracts from the 7th Workshop on the Neu-robiology of Epilepsy (WONOEP VII). Ericeira, Portu-gal, October 7-11, 2003. (2005) Epilepsia. 46(Suppl 5):S1–S207.

Proceedings of the 8th Workshop on the Neurobiology of Epilepsy (WO-NOEP VIII), Villiers-le-Mahieu, France, August 24-26, 2005. (2007)Epilepsia. 48(Suppl 5):S1–S167.

LETTERS/COMMENTARY

Clinical relevance of patients with epilepsy

included in clinical trials

To the Editors:Although randomized clinical trials provide useful infor-

mation about efficacy and tolerability of new antiepilepticdrugs (AEDs), the external validity or generalizability oftheir results can be limited as they are usually conductedin protocol-restricted patient populations using fixed studydesigns and dosing schedules for short treatment periods(Walker & Sander, 1997; Ben-Menachem, 2005; Gilliam,2005).

We aimed to assess how many patients with epilepsyin clinical practice would qualify for a standard efficacyAED trial after application of common exclusion crite-ria. We examined all efficacy studies with AEDs pub-lished in the period from 2002 to May 2007 and foundthe following common exclusion criteria: (1) pregnancyor breast-feeding; (2) insufficient seizure frequency (<1seizure per month); (3) clinically relevant systemic illness(e.g., heart, renal, or hepatic disease); (4) concomitant useof three or more AEDs; (5) progressive neurological orcerebral disease, neoplasia, or structural lesion; (6) pres-ence of a psychiatric disorder; and (7) alcohol or drugabuse.

A total of 432 adult patients with epilepsy attending twoneurology clinics in the Czech Republic represented theclinical practice cohort. Information was retrieved frommedical records. Three-quarters (76%) of patients had a toolow seizure frequency (less than one seizure per month) tobe eligible for inclusion in a clinical trial. Half of the studypopulation (51%) was evaluated as having clinically rele-vant comorbidity for exclusion from a clinical trial; 21% ofpatients had a neurological comorbidity, 19% had a psychi-atric disorder, and 23% suffered from relevant systemic ill-nesses (many patients had a combination of comorbidities).Twenty-three percent of the patients used a combination ofthree or more AEDs. When the exclusion criteria were sub-

sequently applied to the whole group of patients, only 9%of patients would qualify for a standard AED trial. Whenwe applied the criteria to the subgroup of patients with oneor more seizures per month (n = 106), still only 36% ofthese patients would be eligible for entering a clinical effi-cacy study.

As the prevalence of many common psychiatric and so-matic conditions is high in adults with epilepsy (Gaitatziset al., 2004; Strine et al., 2005; Tellez-Zenteno et al., 2005),exclusion of patients with comorbidity limits the possibil-ity to extrapolate the results of clinical trials to real-worldclinical practice. A history or presence of comorbidityalone would already render half of the patients in our to-tal cohort not eligible for inclusion in a trial. Furthermore,this criterion would exclude 65% of patients with recurrentpartial seizures.

In conclusion, our findings show that the efficacy tri-als in epilepsy tend to evaluate only a small subset ofpatients with a specific clinical profile that is not repre-sentative for day-to-day clinical practice. Evidence fromclinical trials provides only partial information on the ef-fectiveness of AEDs in real clinical practice and thereforeobservational research within the setting of daily clinicalpractice is necessary to complement the results of clinicaltrials.

Eva Tlusta1,2

eva.tlusta@faf.cuni.czKim B. Handoko2

Marian Majoie3

Toine C.G. Egberts2,4

Jiri Vlcek1

Eibert R. Heerdink2

1Department of Social and Clinical PharmacyFaculty of Pharmacy, Charles University in Prague

Prague, Czech Republic2Division of Pharmacoepidemiology

and PharmacotherapyUtrecht Institute for Pharmaceutical SciencesUtrecht University, Utrecht, The Netherlands

3Department of NeurologyEpilepsy Centre Kempenhaeghe

Heeze, The Netherlands4Department of Clinical PharmacyUniversity Medical Center Utrecht

Utrecht, The Netherlands

REFERENCES

Ben-Menachem E. (2005). Data from regulatory studies: what do theytell? What don’t they tell? Acta Neurol Scand 112(Suppl. 181):21–25.

Gaitatzis A, Carroll K, Majeed A, Sander JW. (2004). The epidemiologyof the comorbidity of epilepsy in the general population. Epilepsia45:1613–1622.

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Gilliam FG. (2005). Epilepsy–success in clinical practice: translating tri-als to practice. Eur J Neurol 12(Suppl. 4):22–29.

Strine TW, Kobau R, Chapman DP, Thurman DJ, Price P, Balluz LS.(2005). Psychological distress, comorbidities, and health behaviorsamong U.S. adults with seizures: results from the 2002 NationalHealth Interview Survey. Epilepsia 46:1133–1139.

Tellez-Zenteno JF, Matijevic S, Wiebe S. (2005). Somatic comorbidityof epilepsy in the general population in Canada. Epilepsia 46:1955–1962.

Walker MC, Sander JW. (1997). Difficulties in extrapolating from clinicaltrial data to clinical practice: the case of antiepileptic drugs. Neurology49:333–337.

Is epilepsy surgery utilized to its full extent?

To the Editors:In 2001, Engel stated that surgery in patients with

drug-resistant focal epilepsy is one of the most neglectedsuccessful treatments worldwide (Engel, 2001). Guide-lines advise screening for epilepsy surgery in patientswith persistent seizures after 2 years of medical treat-ment, when two or three first-line antiepileptic drugs havefailed (Engel et al., 2003; Karceski et al., 2005; Van Don-selaar & Carpay, 2006). Six years later, we investigatedwhether epilepsy surgery is still underutilized and, if so,why.

From a general, nonacademic hospital and a tertiaryepilepsy clinic in The Netherlands, we collected a ran-dom sample of all adult patients who were not seizurefree despite medical treatment (Fig. 1). The files of thepatients not referred for presurgical work-up were evalu-ated by a panel of two independent experienced epileptolo-

Figure 1.Flow chart of evaluated patients.Epilepsia C© ILAE

gists who determined whether the patients were correctlynot referred, whether they were potential candidates forwork-up but additional diagnostic tests (e.g., MRI accord-ing to special epilepsy protocol or video EEG monitoring)were indicated, or whether they were straightforward truecandidates.

Results are presented in Fig. 1. In the general hospi-tal, 31 of the 427 evaluated patients were not referred forpresurgical work-up, although they should have been ac-cording to the guidelines, while seven patients were cor-rectly referred. In tertiary care, this distribution was 42 of160 patients not referred and 15 referred. The expert panelconcluded that of the 73 (31 + 42) nonreferred intractablepatients, four (two from secondary and two from tertiarycare) were true candidates for presurgical work-up and 12(eight from secondary and four from tertiary care) werepotential candidates pending further testing. In total, therewere 16 incorrectly nonreferred patients.

In secondary care, 10 additional (two true and eightpotential) candidates were incorrectly not referred, whichmeans that the referral rate should have been 1.3 ([7 + 2]/7)to 2.4 ([7 + 2 + 8]/7) times higher than currently. In ter-tiary care, six additional (two true and four potential) can-didates were eligible for referral, leading to a 1.1 ([15 +2]/15) to 1.4 ([15 + 2 + 4]/15) times higher referral rate.Overall, instead of 22 patients, at least 26 (22 + 4) andat the most 38 (22 + 4 + 12) of 587 evaluated patientsshould have been referred—that is, 4–6% of the outpatientepilepsy patients. This rate is slightly higher than the 3%Lathoo et al. estimated for the United Kingdom (Lhatooet al., 2003).

In the 16 nonreferred patients, mean time since failureof a third drug was 5.7 years (median = 4.3; range = 0.3–19.6). When asked, caring neurologists gave as a main rea-son for not referring that they considered the seizure burdenas low. Some secondary care patients had been referred toa tertiary care clinic, but in tertiary care the possibility forpresurgical work-up was not raised.

In conclusion, physicians in secondary and tertiary caredo not sufficiently adhere to guidelines for referral topresurgical work-up. We believe that better use of avail-able noninvasive diagnostic facilities should be encour-aged, so as to facilitate appropriate referral to presurgicalwork-up.

ACKNOWLEDGMENT

This study was supported by a grant from the Dutch College of HealthInsurers (CVZ). The study sponsor had no involvement in the study de-sign; in the collection, analysis, and interpretation of the data; in the writ-ing of the report; and in the decision to submit the paper for publication.

Conflict of interest: The authors confirm that they have read the Journal’sposition on issues involved in ethical publication and affirm that this re-port is consistent with those guidelines. In addition, the authors report noconflicts of interest.

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Sabine G. Uijl1

s.g.uijl@umcutrecht.nlKarel G.M. Moons2

Frans S.S. Leijten1

Ellen P.H.M. Veltman3

Anneke Budde1

Cees A. van Donselaar4

1Department of Neurology and NeurosurgeryRudolf Magnus Institute of Neuroscience

and University Medical Center UtrechtUtrecht, The Netherlands

2Julius Center for Health Sciences and Primary CareUniversity Medical Center Utrecht

Utrecht, The Netherlands3Epilepsy Center Kempenhaeghe, Heeze

The Netherlands4Medical Center Rijnmond Zuid

Rotterdam, The Netherlands

REFERENCES

Engel J Jr. (2001) Finally, a randomized, controlled trial of epilepsysurgery. N Engl J Med 345:365–367.

Engel J Jr, Wiebe S, French J, Sperling M, Williamson P, Spencer D,Gumnit R, Zahn C, Westbrook E, Enos B. (2003) Practice parame-ter: temporal lobe and localized neocortical resections for epilepsy:Report of the Quality Standards Subcommittee of the AmericanAcademy of Neurology, in Association with the American EpilepsySociety and the American Association of Neurological Surgeons.Neurology 60:538–547.

Karceski S, Morrell MJ, Carpenter D. (2005) Treatment of epilepsyin adults: expert opinion. Epilepsy Behav 7(Suppl. 1):S1–S64.

Lhatoo SD, Solomon JK, McEvoy AW, Kitchen ND, Shorvon SD, SanderJW. (2003) A prospective study of the requirement for and the provi-sion of epilepsy surgery in the United Kingdom. Epilepsia 44:673–676.

Van Donselaar CA, Carpay JA. (2006) Epilepsy; guidelines for diagno-sis and treatment: Dutch Neurological Society (NVN). Roto SmeetsGrafiservices, Utrecht.

More on the history of temporal lobe surgery

To the Editors:I appreciated Dr. Moran’s letter to the editor (Moran,

2008) providing a more balanced background to the histor-ical paper by De Almeida et al. (2007), which discussedPenfield’s role in the decision to include mesial struc-tures in temporal lobe resections. I agree that it is unclearwhether Morris (1950, 1956) took the initial bold step toremove normal-appearing hippocampus, and that there isa tendency toward hagiography when Penfield’s discipleswrite about his contributions. Given the rapidly develop-ing field throughout the Americas and Europe at the time(see Gastaut, 1954; Baldwin & Bailey, 1958), it is equallylikely that the approach evolved simultaneously at many

centers, for reasons that have not been documented. In de-fense of the Montreal Neurologic Institute (MNI), how-ever, Dr Moran is incorrect when he attributes Gibbs withthe first EEG evidence that psychomotor seizures were oftemporal lobe origin (Gibbs et al., 1948). I was taught byMurray Falconer to always say that Bailey & Gibbs (1951)were the first to perform temporal lobe resections on thebasis of EEG evidence alone, but not because Gibbs wasthe first electroencephalographer to recognize the localiz-ing value of anterior temporal EEG spikes, but becauseBailey was the first neurosurgeon willing to operate onthis evidence alone. Jasper & Kershman (1941) fully de-scribed temporal interictal EEG correlates of masticatory,olfactory, and visual auras, motor automatisms, and ictal“dreamy states” 7 years before Gibbs. Interestingly, Jasperrepublished this information in the 1941 textbook byPenfield & Erickson (1941), while Penfield concluded, inthe same textbook (page 462), that “when an encephalo-graph (meaning pneumoencephalogram) shows no evi-dence of a lesion, either atrophic or expanding, in that areaof brain in which the seizures are arising, as indicated byseizure classification, any operative procedure is probablydoomed to turn out to be a negative exploration.” As Moranpoints out, the classic paper of Penfield & Flanigin (1950),on 68 temporal lobe operations, contained only three inwhich mesial temporal structures were removed, althoughthe following year Jasper et al. (1951), the same year thatthe Bailey and Gibbs surgical paper appeared, publishedthe EEG findings on these patients, including intraopera-tive electrocorticography, which captured a seizure orig-inating in the mesial temporal lobe. My own conclusionwhen I was preparing a history of epilepsy surgery (Engel,1993) was that Jasper fully understood the importance ofmesial temporal structures in the generation of what wenow call complex partial seizures, but that Penfield paid lit-tle attention to the EEG and directed his surgical resectionsentirely to removal of structural lesions. Before publishingthis history, I sent the manuscript to Herman Flanigin, whowas coauthor on both of the MNI papers, and his responsewas, “That’s exactly what happened.”

Conflict of interest: I confirm that I have read the Journal’s position on is-sues involved in ethical publication and affirm that this letter is consistentwith those guidelines. I have no conflicts of interest with respect to thisletter.

Jerome Engel Jr.engel@ucla.edu

Reed Neurological Research CenterDavid Geffen School of Medicine at UCLA

Los Angeles, California

REFERENCES

Bailey P, Gibbs FA. (1951) The surgical treatment of psychomotorepilepsy. J Am Med Assoc 145:365–370.

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Baldwin M, Bailey P (Eds). (1958) Temporal lobe epilepsy. Charles C.Thomas, Chicago.

De Almeida AN, Teixeira MJ, Feindelo WH. (2007) From lateral tomesial: the quest for a surgical cure for temporal lobe epilepsy.Epilepsia 49:98–107.

Engel J Jr. (1993) Historical perspectives and future directions. In Wyl-lie E (Ed) The treatment of epilepsy: principles and practice. Lea &Febiger, Malvern, PA, pp. 989–998.

Gastaut H. (1954) Colloque sur les problemes d’anatomie normale etpathologique poses par les decharges epileptiques. Acta Medica Bel-gica, Bruxelles.

Gibbs EL, Gibbs FA, Fuster B. (1948) Psychomotor epilepsy. Arch NeurolPsychiatry 60:331–339.

Jasper H, Kershman J. (1941) Electroencephalographic classification ofthe epilepsies. Arch Neurol Psychiatry 45:903–943.

Jasper H, Pertuisset B, Flanigin H. (1951) EEG and cortical electro-grams in patients with temporal lobe seizures. Arch Neurol Psychiatry65:272–290.

Jasper HH. (1941) Electroencephalography. In Penfield W, Erickson TC(Eds) Epilepsy and cerebral localization. Charles C. Thomas, Spring-field, IL, pp. 380–454.

Moran NF. (2008) A more balanced and inclusive view of the history oftemporal lobectomy. Epilepsia 49:543–544.

Morris AA. (1950) The surgical treatment of psychomotor epilepsy. MedAnn Dist Columbia 19, 121–131.

Morris AA. (1956) Temporal lobectomy with removal of uncus,hippocampus and amygdala. Arch Neurol Psychiatry 76:479–496.

Penfield W, Erickson TC. (1941) Epilepsy and cerebral localization.Charles C. Thomas, Springfield, IL.

Penfield W, Flanigin H. (1950) Surgical therapy of temporal lobeseizures. Arch Neurol Psychiatry 64:491–500.

NEXT MONTH IN EpilepsiaThe September issue of Epilepsia opens with an histor-

ical view on “Psychoses of epilepsy in Babylon” by Drs.Wilson and Reynolds. This article is followed by a reviewof “The epilepsy treatment gap in developing countries”by Dr. Mbuba and colleagues. The theme of epilepsy carein developing countries is taken up again in Gray Matters,including a letter on the potential use of modified Atkinsdiet, and commentaries on traditional healers and on nurse-led care in Africa. Full-length research reports focus onpediatric and genetic studies, such as: treatment of infan-tile spasms, SCNA1 mutations in SMEI, NaV1.2 functionin benign familial neonatal infantile seizures, and simplefebrile seizure history associated with hippocampal abnor-malities in adults. Other papers deal with electrical stimula-tion treatment protocols, hormonal changes and catamenialpatterns, and ictal spread.

ONLINE EARLYAladdin & Gross, “Refractory status epilepticus during

pregnancy secondary to cavernous angioma”Aouam et al., “Carbamazepine-induced DRESS and

HHV6 primary infection: The importance of skin tests”

Asadi-Pooya et al., “Nutritional supplements, foods, andepilepsy: Is there a relationship?

Auer et al., “History of simple febrile seizures is associ-ated with hippocampal abnormalities in adults”

Bidmon et al., “Glutamine synthetase becomes nitratedand its activity is reduced during repetitive seizure activityin the pentylenetetrazole model of epilepsy”

Chu et al., “Erythropoietin reduces epileptogenic pro-cesses following status epilepticus”

Derry et al., “Severe autosomal dominant nocturnalfrontal lobe epilepsy associated with psychiatric disordersand intellectual disability”

Deshpande et al., “Carisbamate prevents the develop-ment and expression of spontaneous recurrent epileptiformdischarges and is neuroprotective in cultured hippocampalneurons”

Gastens et al., “Predictors of pharmacoresistantepilepsy: Pharmacoresistant rats differ from pharmacore-sponsive rats in behavioral and cognitive abnormalitiesassociated with experimentally induced epilepsy”

Gong et al., “Insights into the sequence of structural con-sequences of convulsive status epilepticus: A longitudinalMRI study”

Grabenstatter & Dudek, “A new potential AED, carisba-mate, substantially reduces spontaneous motor seizures inrats with kainate-induced epilepsy”

Jacobs et al., “Interictal high-frequency oscillations (80–500 Hz) are an indicator of seizure onset areas independentof spikes in the human epileptic brain”

Kurz et al., “A cellular mechanism for dendritic spineloss in the pilocarpine model of status epilepticus”

Lado & Moshe, “How do seizures stop?”Mazarati et al., “Antiepileptogenic and antiictogenic ef-

fects of retigabine under conditions of rapid kindling: Anontogenic study”

Misra et al., “Impaired Nav1.2 function and reducedcell surface expression in benign familial neonatal-infantileseizures”

Mosyagin et al., “Association of ABCB1 genetic vari-ants 3435C>T and 2677G>T to ABCB1 mRNA and pro-tein expression in brain tissue from refractory epilepsypatients”

Reynolds & Wilson, “Psychoses of epilepsy in Babylon:The oldest account of the disorder”

Rheims et al., “Analysis of clinical patterns and under-lying epileptogenic zones of hypermotor seizures”

Roulet-Perez et al., “Glut-1 deficiency syndrome mas-querading as idiopathic generalized epilepsy”

Sahota et al., “Seizure type, antiepileptic drugs, and re-productive endocrine dysfunction in Indian women withepilepsy: A cross-sectional study”

Spencer et al., “Interictal spikes on intracranial record-ing: Behavior, physiology, and implications”

Tsiropoulos et al., “Exposure to antiepileptic drugs andthe risk of hip fracture: A case-control study”

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Tuan et al., “The prevalence of epilepsy in a rural districtof Vietnam: A population-based study from the EPIBAVIproject”

Vinogradova, “Audiogenic kindling in Wistar andWAG/Rij rats: Kindling-prone and kindling-resistant sub-populations”

Wang et al., “Microchromosomal deletions involvingSCN1A and adjacent genes in severe myoclonic epilepsyin infancy”

Weber et al., “A BFIS-like syndrome with late onsetand febrile seizures: Suggestive linkage to chromosome16p11.2–16q12.1”

Winkler et al., “The head nodding syndrome: Classifica-tion and possible causes”

Zangaladze et al., “Characteristics and clinical signifi-cance of subclinical seizures”

ANNOUNCEMENTS

Early Career Physician-Scientist Award

The Milken Family Foundation and the AmericanEpilepsy Society announce the call for applications for theEarly Career Physician-Scientists awards, open to inves-tigators from around the world. This award is designedto assist physician-scientists embarking on early academiccareers devoted to epilepsy research. Preference is givento innovative studies leading to new treatments or othernovel translational research. $50,000 USD is awarded fora 12 month period beginning in January 2009. Applica-tions are due by Monday, September 8, 2008. Eligibil-ity requirements and application information are availableat http://www.aesnet.org/go/research/aes-sponsored-grant-program.

2nd Baltic Sea Summer School on Epilepsy

The 2nd Baltic Sea Summer School on Epilepsy willtake place from August 31–September 4, 2008, closeto Copenhagen, Denmark. Please see the EUREPA web-site http://www.epilepsy-academy.org for further infor-mation, or contact Petra Novotny at petra@epilepsy-academy.org.

8th European Congress on Epileptology

The 8th European Congress on Epileptology will takeplace in Berlin, Germany, September 21–25, 2008. Itis presented under the auspices of the German andIsraeli ILAE chapters. For more information go to:http://www.epilepsyberlin2008.org/.

VIREPA Distance Learning Courses

2008/2009

Four VIREPA e-moderated distance learning courseswill start again in October 2008. The courses are: “Geneticsof Epilepsy,” “EEG in the diagnosis and management ofepilepsy,” “Neuroimaging” and “Clinical Pharmacologyand Pharmacotherapy.” An introductory meeting for par-ticipants of all courses (not mandatory) will take place dur-ing the 8th European Congress on Epileptology in Berlinin September 2008. The deadline for application to allcourses is August 1, 2008. For detailed information and ap-plication, please see http://www.epilepsy–academy.org orcontact the Epilepsy Academy Office at office@epilepsy-academy.org.

11th European Conference on Epilepsy &

Society

The 11th European Conference on Epilepsy and Soci-ety, sponsored by the International Bureau for Epilepsy(IBE) will take place October 15–17 in the WorldTrade Center Marseille Provence, located at the heartof Marseille, France. For more information, go tohttp://www.epilepsyandsociety.org/.

Epilepsy at the Cutting Edge

This international meeting, celebrating the ongoing con-tributions of Fred and Eva Andermann, will address thegenetics of epilepsy and epilepsy surgery. The meeting willbe held at the Montreal Neurological Institute and Hospital,Montreal, Canada on October 23–25, 2008. Information isavailable at http://www.mni.mcgill.ca.

5th Latin American Epilepsy Congress

The 5th Congreso Latinoamericano de Epilepsia willtake place in Montevideo, Uruguay on November 5–8,2008. Jointly sponsored by the ILAE and IBE, the orga-nizing committee is headed by A. Scaramelli (Uruguay),L. Nunez Orozco (Mexico), and S. Moshe (USA). Ab-stracts are due by May 31, 2008; pre-meeting registrationdeadline is September 5, 2008. For more informa-tion, contact: montevideo@epilepsycongress.org or go tohttp://www.epilepsymontevideo2008.org/committees.html.

2nd Biennial North American Regional

Epilepsy Congress

The American Epilepsy Society will host the 2ndBiennial North American Regional Epilepsy Congress

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at their 62nd Annual Meeting, 5–9 December, 2008,in Seattle, WA, USA. For more information goto http://www.aesnet.org/go/meetings-and-events/annual-meeting.

Michael Prize

The Michael Prize is awarded biannually for the bestcontribution to scientific and clinical research promotingfurther developments in epileptology. It designed to attractapplications from younger scientists (under 45 years ofage), and is associated with a monetary award of 15,000Euros. Application for the 2009 Prize is based on pub-lications that have appeared in 2007/2008; papers of thesame period, and not yet published, will also be consid-ered. Publications/papers, together with a curriculum vitaeand a photo, should be submitted in triplicate to StiftungMichael by December 31, 2008.

Since 2006, the Michael Prize has been sponsored byUCB International. Members of the jury for the 2009 Prizeare: Uwe Heinemann (Berlin, Germany), Brian Meldrum(London, UK), and Solomon Moshe (New York, USA).

For applications and/or further information, contact:Stiftung Michael, Muenzkamp 5, D-22339 Hamburg, Ger-many. tel: +49-(0)40 5388540; fax: +49-(0)40 5381559;e-mail: stiftungmichael@t-online.de

Innsbruck Colloquium on Status Epilepticus

2009

The Innsbruck Colloquium on Status Epilepticus willtake place April 2–4, 2009. The conference (chaired byS. Shorvon and E. Trinka) will focus on the follow-

ing topics: bridging the gap from experimental mod-els to clinical practice; infectious causes and inflam-matory mechanisms in status epilepticus (SE); SE inthe developing brain; and new treatment options. Reg-istration opens September 1, 2008. For further infor-mation, contact the conference secretariat: PCO TyrolCongress, Rennweg 3, A-6020 Innsbruck, Austria, e-mail:se2009@come-innsbruck.at or visit the conference web-site: http://www.innsbruck-se2009.eu.

12th Annual Meeting of the Infantile Seizure

Society

The 12th Annual Meeting of the Infantile SeizureSociety (Y. Fukuyama, chair) will take place in Ku-rume, Japan on May 9–10, 2009. This meeting (T.Matsuishi, president) will be devoted to an Interna-tional Symposium on Epilepsy in Autistic SpectrumDisorders and Related Conditions. For further informa-tion, e-mail to: iss2009@med.kurume-u.ac.jp or visithttp://www.med.kurume-u.ac.jp/med/ped/iss2009/index.html or http://www.iss-jpn.info/.

28th International Epilepsy Congress

The 28th International Epilepsy Congress, sponsoredjointly by the International League Against Epilepsy(ILAE) and the International Bureau for Epilepsy (IBE)will take place in Budapest, Hungary on June 28ththrough July 2nd, 2009. This Congress will be the Cen-tenary celebration of ILAE. For further information, visithttp://www.epilepsybudapest2009.org.

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CALENDAR OF MEETINGS

2008

July 2008

❑ Venice Epilepsy Summer School, 7thInternational Course: Bridging Basic withClinical Epileptology – 3

28 July–8 AugustVenice, Italyemail: epilepsysummercourse@univiu.orghttp://www.epilearn.eu/summer course/third/index.html

August 2008

❑ 2nd Baltic Sea Summer School on Epilepsy31 August–4 SeptemberCopenhagen, Denmarkhttp://www.epilepsy-academy.org

September 2008

❑ 8th European Congress on Epileptology21–25 SeptemberBerlin, Germanyhttp://www.epilepsyberlin2008.org

October 2008

❑ 11th European Conference on Epilepsy & Society(IBE)

15–17 OctoberMarseille, Francehttp://www.epilepsyandsociety.org/conferenceprogramme/conference programme.html

❑ The Fred and Eva Andermann Meeting: Epilepsyat the Cutting Edge

23–25 OctoberMontreal, Canadahttp://www.mni.mcgill.ca

❑ 19th International Symposium on the AutonomicNervous System

29 October–1 NovemberKauai, Hawaii, U.S.Ahttp://www.americanautonomicsociety.org

November 2008

❑ 5th Latin American Epilepsy Congress (ILAE &IBE)

5–8 NovemberMontevideo, Uruguayhttp://www.epilepsymontevideo2008.org

❑ Journees Francaises de l’Epilepsie13–15 NovemberLyon, Francehttp://www.lfce-epilepsies.fr/

December 2008

❑ 2008 American Epilepsy Society Annual Meeting5–9 DecemberSeattle, Washington, U.S.Ahttp://www.aesnet.org/go/meetings-and-events/annual-meeting

2009

April 2009

❑ The Innsbruck Colloquium on Status Epilepticus2–4 AprilInnsbruck, Austriahttp://www.innsbruck-se2009.eu

May 2009

❑ The 12th Annual Meeting of the Infantile SeizureSociety (ISS): International Symposium onEpilepsy in Autistic Spectrum Disorders andRelated Conditions (ISEASD)

9–10 MayKurume, Japanhttp://www.med.kurume-u.ac.jp/med/ped/iss2009/index.html

June 2009

❑ 28th International Epilepsy Congress (ILAE &IBE)

28 June–2 JulyBudapest, Hungaryhttp://www.epilepsybudapest2009.org

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