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pilepsy Research (2009) 86, 82—88

journa l homepage: www.e lsev ier .com/ locate /ep i lepsyres

tiology and site of temporal lobe epilepsy influenceostictal cytokine release

ebastian Bauera,∗, Sabine Cepokb, Anelia Todorova-Rudolphc,areike Nowaka, Martina Köllera, Rüdiger Lorenzd, Wolfgang H. Oertel a,elix Rosenowa, Bernhard Hemmerb, Hajo M. Hamera

Department of Neurology, University of Marburg, Rudolf-Bultmann-Str. 8, 35033 Marburg, GermanyDepartment of Neurology, Technische Universität München, Ismaninger Str. 22, München, GermanyKlinikum Weilmünster, Weilstr. 10, Weilmünster, GermanyNeuropediatric and epileptological office, Brunnenstr. 54, Bad Wildungen, Germany

eceived 1 March 2009; received in revised form 25 April 2009; accepted 11 May 2009vailable online 10 June 2009

KEYWORDSTemporal lobeepilepsy;IL-1;IL-6;TNF-alpha;Cytokines;Seizure

Summary Inflammatory mechanisms are involved in the pathogenesis of epilepsy. Vice versa,immune functions are regulated by the brain. We measured postictal changes in serum levels ofthe immuno-modulating cytokines IL-1�, IL-6 and TNF� in patients with well-defined temporallobe epilepsy (TLE) and determined modifying factors. Serum levels of IL-1�, IL-6 and TNF�

were quantified by ELISA at baseline as well as immediately, 1 h and 24 h after a complex partial(CPS) or secondary generalized tonic—clonic seizure (GTCS) during video-EEG monitoring in 25patients suffering from temporal epilepsy. IL-6 increased by 51% immediately after the seizure(p < 0.01) and remained elevated for 24 h. This increase lacked in patients with hippocampal

sclerosis (HS; n = 16, mean increase 28%, p > 0.5, vs. 112%, p < 0.01 in patients without HS).IL-6 levels were higher after right-sided seizures as compared to left-sided seizures 24 h afterthe seizure (8.7 pg/mL vs. 3.4 pg/mL, p < 0.05). In patients taking valproate (VPA, n = 9), thelevels of IL-1� were higher as compared to patients not treated with VPA. The results suggest arelationship between the cytokine system and characteristics of TLE such as side and pathology.

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© 2009 Elsevier B.V. All righ

∗ Corresponding author. Tel.: +49 6421 58 65200;ax: +49 6421 58 65208.

E-mail address: bauerse@med.uni-marburg.de (S. Bauer).

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920-1211/$ — see front matter © 2009 Elsevier B.V. All rights reserved.oi:10.1016/j.eplepsyres.2009.05.009

served.

ntroduction

ecent findings suggest involvement of inflammation in

he pathogenesis and the course of epilepsy (Vezzani andranata, 2005). In rodents, epileptic seizures induce rapidxpression of cytokine mRNA [interleukin (IL)-1�, IL-6 andumor necrosis factor (TNF) �] in glia cells. Intrahippocam-al injection of IL-1� enhances seizure duration (Vezzani et

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Cytokines in TLE

al., 2002). In addition, nuclear factor kappa B (NF�B), a tran-scription factor for different proinflammatory molecules,was upregulated in hippocampal astrocytes and neurons ofpatients with mesial temporal lobe epilepsy (TLE) due to hip-pocampal sclerosis (Crespel et al., 2002). Japanese patientswith TLE and hippocampal sclerosis (HS) were found to bemore likely homozygote for a certain IL-1� gene polymor-phism than TLE patients without HS or control subjects(Kanemoto et al., 2000). The authors hypothesized that ahigher production of IL-1� due to this polymorphism mayrender the carriers more susceptible to develop prolongedfebrile seizures and hippocampal sclerosis. Changes in sys-temic immune parameters were reported which includeincreased interictal IL-1 levels in pediatric epilepsy patients(Lorenz, 2001) and an increased IL-6 level in the cere-brospinal fluid (CSF) and serum several hours after partial orgeneralized tonic—clonic seizures (GTCS) in adult epilepsypatients (Lehtimaki et al., 2007; Peltola et al., 1998;Peltola et al., 2000). The systemic immune changes fol-lowing seizures may be mediated via neurotransmittersand the hypothalamic—pituitary—adrenal (HPA) axis (Wrona,2006).

The time course and extent of serum cytokine changesafter epileptic seizures as well as the factors that influencethese changes are not well-defined. Recently, increasedcytokine levels were reported after seizures (Lehtimakiet al., 2007; Sinha et al., 2008). However, these reportsincluded patients with different epilepsy syndromes (e.g.TLE and frontal lobe epilepsy, n = 12 (Lehtimaki et al.,2007)) or also patients with provoked seizures who wereobserved within several hours after seizures (Sinha et al.,2008). Low half-life of serum cytokines, on the other hand,might require immediate detection after a seizure which isonly possible during video-EEG monitoring. Therefore, weanalyzed prospectively the immediate postictal changes ofserum levels of the proinflammatory cytokines IL-1�, IL-6and TNF� in patients with well-defined TLE and aimed toidentify modifiers of these changes.

Patients and methods

Patients

Between 2004 and 2006, we studied consecutively patientswho were admitted to the video-EEG monitoring unit of ourtertiary epilepsy center for presurgical epilepsy evaluationand fulfilled the following criteria of eligibility.

Inclusion criteria:

1. diagnosis of medically intractable TLE based on seizuresemiology [epigastric or psychic auras, dialeptic or auto-motor seizure with or without secondary generalization(Luders et al., 1998)], interictal and ictal EEG recordings(interictal epileptic discharges and seizure onset zonemaximal in the anterior-temporal or sphenoidal elec-

trodes) and high resolution 1.5 Tesla MRI of the brain(with or without mesial temporal lobe pathology on imag-ing but without temporo-lateral pathology);

2. age between 18 and 65 years;3. written informed consent.

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Exclusion criteria:

. occurrence of seizures within the last 24 h before inclu-sion;

. concomitant neoplasm;

. concomitant infectious or inflammatory disease;

. acute severe neurological disease (i.e. ischemic stroke,intracerebral hemorrhage, etc.)

. surgery or significant trauma within the last two weeks;

. any immunomodulatory treatment within the last sixmonths;

. hepatic or renal insufficiency;

. severe psychiatric disease;

. pregnancy.

The study was approved by the local ethics committee.Video-EEG monitoring was performed using 21 scalp elec-

rodes which were attached according to the International0/20 system. In all patients, sphenoidal electrodes weredditionally inserted on day 2 of admission. The anticon-ulsant medication was discontinued in a stepwise fashionuring the monitoring at the discretion of the staff epilep-ologist. Ictal and interictal EEG was read by two boardertified epileptologists (FR, HMH). Seizures were classifiedccording to the semiological seizure classification (Luderst al., 1998).

aterial and methods

en mL serum blood samples were taken at 8 a.m., 12 p.m. andp.m. on admission day as baseline measurements. In all patients

erum was taken as soon as possible after the first seizure. Anothererum sample was taken 1 h after the seizure in 23 patients whoad no further seizures after the index seizure. The same proce-ure was repeated after 24 h in the 18 patients who experiencedo further seizures within the 24 h after the index seizure. Theerum samples were immediately centrifuged (3000 rpm, 4 ◦C) androzen at −80 ◦C until further processing. IL-1�, IL-6 and TNF� wereeasured by commercially available assays (PeliKine-compactTM,

anquin Reagents, Amsterdam, The Netherlands) according to theanufacturer’s instructions. Sensitivity was 0.4 pg/mL for IL-1�,

.2 pg/mL for IL-6 and 1 pg/mL for TNF�.

tatistics

esults are given as mean and standard errors of the meanSEM). To minimize the influence of a circadian rhythm inL-6 release (Vgontzas et al., 2005), we chose the ‘‘time-atched’’ baseline value at the admission day that wasrawn closest to time of occurrence of the index seizureor baseline comparisons.

The non-parametrical Wilcoxon matched pairs test wassed for comparisons of baseline with postictal valuesecause Gaussian distribution could not be presumed. Dif-erences between subgroups were established by usinghe non-parametrical Mann—Whitney U-test. For compu-ation, the software ‘‘BiAS für WindowsTM’’ (created by

anns Ackermann, University of Frankfurt, Germany) wassed.

As our analyses were exploratory and involved multipleests, all p-values were interpreted as descriptive measuresather than results of hypothesis testing. No adjustments

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Table 1 Patients’ characteristics.

Patient number Age (years) Epilepsy syndrome Seizure onset zone Seizure semiology (Luders et al., 1998) Etiology Medication at admission

1 38 TLE Left Automotor Ganglioglioma LEV, OXC2 42 TLE Left Automotor HS + temporobasal gliosis CBZ3 43 mTLE Right Automotor HS, history of meningitis CBZ, DZP, LTG4 43 mTLE Left Automotor HS LTG, VPA5 31 TLE Right Automotor → GTCS HS DZP, LTG, VPA6 56 TLE Left Automotor Unknown CBZ, LEV7 40 TLE Bitemporal Automotor Unknown LTG, OXC, VPA8 25 TLE Left Dialeptic Unknown LEV, TPM9 56 TLE Left Automotor HS CBZ, LTG, PRM

10 43 mTLE Right Automotor HS LEV, TPM11 41 TLE Left Automotor History of meningitis LTG12 29 mTLE Left Automotor HS LTG13 27 mTLE Right Autonomic HS CBZ, LTG14 38 mTLE Left Automotor HS, history of meningitis LEV, LTG, VPA, TPM15 32 mTLE Left Automotor → GTCS HS TPM, VPA16 42 mTLE Left Dialeptic Cavernoma CBZ, LEV17 45 TLE Left Automotor Unknown CBZ, LEV, VPA18 35 mTLE Left Automotor → GTCS HS, low-grade tumor CBZ, LEV, VPA19 24 mTLE Left Automotor HS GBP, LTG, TPM20 18 mTLE Left Automotor → GTCS HS, history of meningitis CBZ, LTG, TPM21 43 mTLE Right Automotor → GTCS Hamartoma TPM, VPA22 14 mTLE Left Dialeptic HS VPA23 25 mTLE Right Epigastric aura HS LTG24 45 mTLE Left Automotor HS LEV, OXC, TPM25 33 TLE Left Automotor Unknown CBZ

CBZ, carbamazepine; DZP, diazepam; GTCS, generalized tonic—clonic seizure; HS, hippocampal sclerosis; LEV, levetiracetam; LTG, lamotrigine; mTLE, mesial temporal lobe epilepsy; OXC,oxcarbazepine; PRM, primidone; TLE, temporal lobe epilepsy; TPM, topiramate; VPA, valpoate.

Cytokines in TLE 85

Table 2 Serum concentrations of IL-6, IL-1� and TNF� at baseline, immediately, 1 h and 24 h after the seizure.

Cytokine Baseline n = 25 Immediatelyafter theseizure n = 25

p-value (immediatelypostictal vs. baseline)

1 h after theseizure n = 23

24 h after theseizure n = 18

IL-6 (pg/mL) 2.42 (0.61) 3.65 (0.77) 0.007 3.77 (1.03) 4.54 (1.23).916 12.56 (3.65) 14.16 (4.70).738 7.01 (2.27) 6.59 (2.01)

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caspple(p = 0.016) (Fig. 3).

No significant correlation of VPA dosage with baselineconcentrations of IL-1� or TNF� was noted. The postictalchange of IL-1� serum concentration did not differ betweenpatients who took VPA and patients with other AED.

IL-1� (pg/mL) 12.67 (3.32) 13.83 (4.28) 0TNF� (pg/mL) 8.13 (2.89) 7.60 (2.32) 0

Data given as mean (SEM).

for multiple testings were performed. The significance levelwas set to p < 0.05.

Results

Twenty-five patients with temporal lobe epilepsy wereincluded (age: 37 ± 11 years, 13 female (52%); duration ofepilepsy: 21 ± 14 years; past seizure frequency: 30 ± 111per month, Table 1). Febrile seizures were reported bysix patients. The mean time interval between EEG seizureonset and postictal blood drawing was 10 ± 6 min (range2—23 min), the time interval between matched baseline andindex seizure was 101 ± 23 min (range 3—365 min). None ofthe seizures occurred during sleep.

We observed a significant increase of IL-6 in the imme-diate postictal state as compared to the baseline measures(p = 0.007, Table 2). The mean increase was 51% after 1 h(p = 0.001) and 87% after 24 h (p = 0.006). No significant pos-tictal changes were observed for IL-1� or TNF�.

We further stratified the patients according to seizuretype, gender, etiology, presence of febrile seizures andlateralization of seizure onset. The IL-6 levels wereslightly higher after secondary generalized tonic—clonicseizures (4.8 ± 2.22 pg/mL, n = 5) than after focal seizures(3.4 ± 0.85 pg/mL, n = 20). However, the difference was notsignificant. We found no influence of gender on baselinevalues or postictal changes of cytokine concentrations.

Baseline concentrations of IL-1�, IL-6 and TNF� didnot differ between patients with and without HS. How-ever, patients with HS (n = 16) showed significantly lesspostictal increase in IL-6 than patients with other eti-ologies (0.78 ± 0.61 pg/mL = 28% of baseline value vs.2.02 ± 0.92 pg/mL = 112% of baseline value, p = 0.03). Inaddition, the postictal values of IL-6 in patients with HS werenot significantly different from preictal baseline measure-ments (p = 0.27).

The IL-1� levels of patients with febrile seizures in theirmedical history (n = 6) showed a trend to decrease imme-diately after the seizure (−1.09 ± 0.44 pg/mL, p = 0.09) andwere significantly lower 1 h after the seizure as compared tobaseline levels (−1.40 ± 0.60 pg/mL; p = 0.03). In contrast,we found a non-significant increase of IL-1� in patients with-out febrile seizures (1.87 ± 1.58 pg/mL). The difference inthe postictal change of IL-1� between patients with andwithout a history of febrile seizures was statistically signifi-

cant (p = 0.03).

Patients with right-temporal seizure onset zone (n = 6)showed greater IL-6 serum levels than patients withleft-temporal seizure onset (n = 18) throughout all mea-surements. This difference reached the significance level

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igure 1 Levels of IL-6 in patients with right and left-emporal seizure onset (mean ± SEM). * p ≤ 0.05.

t 24 h after the index seizure (8.67 ± 3.52 pg/mL vs..36 ± 1.11 pg/mL, p = 0.034, Fig. 1). The IL-6 increase in themmediate postical state remained significant consideringatients with left or right-temporal seizure origin sepa-ately. There were no differences between both subgroupsn respect to serum levels of IL-1� or TNF�.

In patients taking valproate (VPA; n = 9), the serum con-entrations of IL-1�, but not the ones of IL-6 were highers compared to patients without VPA throughout all mea-urements (baseline: p = 0.049; immediate postical state:= 0.057; 1 h after seizure; p = 0.021; 24 h after seizure:= 0.009; Fig. 2). There was a trend toward higher serum

evels of TNF� in VPA-treated patients, but the differ-nce reached significance only at the 24 h measurements

igure 2 Serum concentrations of IL-1� in patients with andithout VPA (mean ± SEM). * p ≤ 0.05, ** p ≤ 0.01.

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igure 3 Serum concentrations of TNF� in patients with andithout VPA (mean ± SEM). * p ≤ 0.05.

We found no influence of intake of carbamazepine, lam-trigine, levetiracetam or topiramate on baseline values orostictal changes of cytokine concentrations. There was noorrelation between age, duration of epilepsy or past seizurerequency and baseline concentrations or postictal changesf IL-1�, IL-6 or TNF�, respectively.

iscussion

his prospective study showed a significant increase of IL-6n patients after complex partial and secondary generalizedonic—clonic seizures of temporal origin. This increase coulde detected minutes after the seizures and progressed over4 h. Right-sided seizure origin was associated with higherL-6 levels while hippocampal sclerosis was accompanied bylower postictal IL-6 increase. In patients with a history of

ebrile seizures a postictal decrease of IL-1� was found whilehere was a slight increase IL-1� in patients without febrileeizures. The intake of valproate was correlated with higherL-1� and TNF� blood levels.

Our findings confirm previous reports about postictallylevated IL-6 levels in serum and CSF. However, early studiesnvestigated seizures of different causes (including alco-ol withdrawal) with a latency of up to 72 h after seizuresPeltola et al., 1998; Peltola et al., 2000). A recent studyuring video-EEG monitoring included a small number ofatients (n = 12) without distinguishing between differentpilepsy syndromes and etiologies (Lehtimaki et al., 2007).n another recent study, cytokine levels were analyzed in00 patients presenting with first seizure or with differentpilepsy syndromes, respectively (Sinha et al., 2008). In theresent study, we provide first data on the influence of var-ous modifying factors on postictal cytokine changes in aarger, well characterized patient group.

IL-1�, IL-6 and TNF� share immuno-modulatory biolog-cal functions including the induction of fever, productionf acute phase proteins in hepatocytes and T-cell differen-iation (Curfs et al., 1997) and are produced by differenteukocyte subtypes, endothelium cells, muscle cells, neu-ons, glia and others. In addition, the pituitary gland is ableo secrete IL-6 (Lohrer et al., 2000; Spangelo and Gorospe,995). In vitro, membrane depolarization in murine neurons

ed to a nearly tenfold increase in IL-6 mRNA transcriptionnd electroshock in mice also caused an increase of neu-onal IL-6 expression (Sallmann et al., 2000). The observedime course with elevated IL-6 levels within a few minutesfter seizures and a further progress over the next 24 h in the

dirOr

S. Bauer et al.

resent study supports the view the electrical excitation ofeurons within the framework of an epileptic seizure led ton initial secretion of preformed IL-6 via neurotransmittersr the hypothalamic—pituitary—adrenal (HPA) axis (Wrona,006) and to subsequent increased in IL-6 expression. Neu-onal secretion of IL-6 has been described in vitro (Moller etl., 2006). However, it remains unclear from our results ifhe postictal increase of IL-6 was due to enhanced releaserom peripheral leukocytes or due to release from neuronsr glia cells.

We were able to show in a previous study that the dis-ribution of leukocyte subsets changes after partial andeneralized epileptic seizures (Bauer et al., 2008). Thisffect was probably mediated by an ictal epinephrinencrease. Epinephrine in turn leads to an enhanced produc-ion of IL-6 in muscle cells which is time-dependent andeaked 2 h after application in rodents (Frost et al., 2004).his time course makes this mechanism unlikely to explainhe present results because we observed an increase imme-iately after the seizures. IL-6 is also released by muscleells during exercise (Febbraio and Pedersen, 2002). Thus,he muscle activity during secondarily generalized seizuresay have caused the higher IL-6-levels in generalized as

ompared to focal seizures. The lack of statistical signifi-ance may be explained by the small number of patientsith generalized seizures (n = 6).

IL-6 seems to play a dichotomous role in the CNS.oth pro- and anti-inflammatory as well as neurotoxicnd neuroprotective effects are described (Bernardino etl., 2005). Transgenic mice chronically overexpressing IL-developed spontaneous seizures, reactive astrocytosis in

arious brain areas (Campbell et al., 1993) and hippocam-al paroxysmal EEG discharges (Steffensen et al., 1994).n contrast, IL-6 deficient knockout mice showed a highereizure susceptibility after treatment with chemical convul-ants (De Sarro et al., 2004). Application of IL-6 preventedMDA-induced toxicity in hippocampal neurons (Pizzi etl., 2004). In the present study, patients with HS lackedhe postictal IL-6 increase in contrast to patients with-ut HS. This may give rise to the hypothesis that IL-6xerts a neuroprotective effect in temporal lobe epilepsyhich helps preventing the development of HS assuming

he systemic IL-6 increase reflects similar changes in theesial temporal region. Further studies in this respect arearranted.

The role of IL-1� in the pathogenesis of febrile seizuress a matter of debate (Dube et al., 2005). A recenteta-analysis showed an association between an IL-1 geneolymorphism and temporal lobe epilepsy (Kauffman et al.,008). One study found increased IL-1� plasma levels withinmean time of 12 h after febrile convulsions compared withcontrol group of children who also suffered from fever

Tutuncuoglu et al., 2001). Other authors report a non-ignificant and time-dependent tendency toward decreasedL-1� plasma levels after febrile seizures (Haspolat et al.,002; Tomoum et al., 2007; Virta et al., 2002). The latteresults are consistent with our findings of postictal IL-1�

ecrease in patients with a history of febrile seizures. Anncreased ictal release of IL-1 decoy receptor or of otheregulatory cytokines might be responsible for this effect.ur results support the educated guess that IL-1� plays a

ole in the pathogenesis of febrile convulsions.

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Cerebral lateralization of immune functions has beenproposed (Meador et al., 2004). In general, left-hemisphericlesions are thought to reduced and right-hemispheric lesionswere reported to enhance functional parameters of theimmune system. Our finding of increased IL-6 levels inpatients with right-temporal lobe seizures lends further sup-port to this view of lateralized cerebral influence of immuneprocesses.

Patients taking VPA showed elevated IL-1�- and TNF�serum levels suggesting an immune modulating effect ofVPA. Various molecular modes of action of VPA have beendescribed (Blaheta and Cinatl, 2002): VPA increases the DNAbinding of activating protein-1 (AP-1) transcription factor.AP-1 in turn induces IL-1� expression (Kang et al., 2004;Koj, 1996). In contrast, the inhibition of protein kinase C andhistone deacetylase as well as the activation of peroxisomeproliferator-activated receptor (PPAR) by VPA (Blaheta andCinatl, 2002) may lead to a lower IL-1� and TNF� expression(Geng et al., 1993; Leoni et al., 2005). The results of pre-vious (Verrotti et al., 2001) and the present study indicatethat in vivo valproate enhances IL-1� and TNF�. The interac-tion of these oppositional mechanisms may explain why VPAinhibits the production of TNF� (Ichiyama et al., 2000) andother inhibitors of histone deacetylase prevent the releaseof IL-1� (Carta et al., 2006) in vitro while we in accordancewith earlier data (Verrotti et al., 2001) observed a contraryeffect in vivo. Further research should address the questionwhether the influence of VPA on cytokine production is ofrelevance for its anti-tumor effects.

In conclusion, epileptic seizures in patients with well-characterized TLE led to an immediate and long-lastingpostictal increase in systemic IL-6 levels. This rise of IL-6lacked in patients with HS. Further studies are necessary todetermine whether this is of pathophysiological relevance.In addition, our data provided further evidence for cerebrallateralization of immune functions and the immunomodu-lating effect of VPA.

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