Seizure (2007) 16, 479—484

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Perioperative fluctuations of lamotrigine serumlevels in patients undergoing epilepsy surgery

Friedemann Paul a,d,*, Christian Veauthier a, Georg Fritz b,Thomas-Nicolas Lehmann c, Orhan Aktas d, Frauke Zipp d,Heinz-Joachim Meencke a

aDepartment of Epileptology, Evangelisches Krankenhaus Konigin Elisabeth Herzberge,Herzbergstrasse 79, D-10365 Berlin, GermanybDepartment of Anaesthesiology, Virchow-Klinikum, Charite, D-13344 Berlin, GermanycDepartment of Neurosurgery, Virchow-Klinikum, Charite, D-13344 Berlin, GermanydCecilie-Vogt-Clinic for Molecular Neurology and Max-Delbrueck-Center forMolecular Medicine, Chariteplatz 1, D-10098 Berlin, Germany

Received 5 November 2004; received in revised form 1 March 2007; accepted 12 March 2007

KEYWORDSAcetaminophen/paracetamol;Dexamethasone;Epilepsy surgery;Focal epilepsy;Lamotrigine;Postoperative seizures;Serum level

Summary

Summary: Some patients undergoing epilepsy surgery suffer from early postoperativeseizures which may have a negative impact on later outcome. Factors contributing tothese seizures have not to date been examined systematically. We hypothesized thatreduction of postoperative serum levels of antiepileptic drugs (AED) may be one riskfactor for early postoperative seizures.Methods: We retrospectively reviewedmedical records from 20 patients treated withlamotrigine (LTG) who underwent epilepsy surgery between January 1997 and Feb-ruary 2004. Demographic data, anaesthesiological and surgical procedures, co-med-ication, and pre- as well as one or more postoperative LTG serum levels wereevaluated.Results: We found a significant decrease in LTG serum levels, amounting to more than20% (mean 46%, range 21.9—69.1%), in 16 of 20 patients (80%). Six patients (30%)suffered from seizures in the first 2 weeks after surgery. In three patients, post-operative seizures occurred isochronically with the LTG serum level nadir. Themagnitude of the reduction in serum levels was not influenced by age, sex, durationof the operation, the type of anaesthetic drugs or the postoperative co-medication.Discussion: Reductions in LTG serum levels are a relevant contributing factor for earlypostoperative seizures. Postoperative alteration of the gastrointestinal motility and

* Corresponding author at: Cecilie-Vogt-Clinic for Molecular Neurology, Chariteplatz 1, D-10098 Berlin, Germany.Tel.: +49 30 450 539028; fax: +49 30 450 539906.

E-mail address: friedemann.paul@charite.de (F. Paul).

1059-1311/$ — see front matter # 2007 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.doi:10.1016/j.seizure.2007.03.006

480 F. Paul et al.

transient time leading to delayed absorption and reduced bioavailability of AEDmay bea major risk factor. Therefore, close monitoring of postoperative LTG serum levels isnecessary and should lead to a temporary dose augmentation and/or anticonvulsant co-medication with benzodiazepines in case of a pronounced reduction of serum levels.# 2007 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Introduction

Epilepsy surgery is an established therapeutic alter-native for a subgroup of patients with medicallyintractable focal epilepsies.1 Although as many as49% of patients may develop seizures in the earlypostoperative period and these seizures may pre-dict subsequent seizure recurrence,2—4 our knowl-edge of the precipitating conditions of seizures inthe first few postoperative days is sparse. One ofthese conditions might be fluctuations in the serumlevels of the antiepileptic drugs (AED) usually con-tinued after surgery for a duration of at least 2years. Few retrospective studies have previouslyassessed changes in postoperative serum levels ofcarbamazepine (CBZ), lamotrigine (LTG) or oxcar-bazepine (OXC).5—8 Our observation of early post-operative seizures associated with a pronounceddecrease in LTG serum levels a few days aftersurgery in two of our patients prompted us to per-form a systematic retrospective review of medicalrecords as well as surgery and anaesthesia protocolsfrom patients operated on in our clinic under med-ication with LTG.

Figure 1 Pre- and postoperative LTG serum levels. X-axis–—LTG serum levels at different timepoints: preopera-tive serum level, postoperative serum levels at POD 1/2,3/4, 5/6, 7/8, 9/10 and 11—13. Y-axis–—LTG serum level inmg/l. Red circles indicate patients with seizures isochro-nic to postoperative serum level nadir. (For interpretationof the references to colour in this figure legend, thereader is referred to the web version of the article.)

Patients and methods

Patients and procedures

Out of a total number of 272 surgically treatedepilepsy patients (anterior temporal lobectomy/amygdalohippocampectomy, implantation of sub-dural grid electrodes) between January 1997 andFebruary 2004, we identified 20 patients (12 female,8 male,mean age 34 years (range 13—56)), whowereon stable medication with LTG at least 1 month priorto surgery and from whom at least one serum levelfrom the last or second last day before surgery andfrom 1 postoperative day (POD) during the first 2weeks after surgery was available. The number ofavailable postoperative LTG serum levels and theduration of the follow-up period ranged from 1 to 6and from POD 1/2 to POD 13, respectively (Fig. 1). Allserum samples were drawn during drug fasting in themorning. Mean preoperative LTG dose was 551 mg/day (200—800, S.D. 136.7). Twelve patients had anLTGmonotherapy, 8 patients received co-medicationwith other AED (2 CBZ (1000 mg, 1800 mg), 3 levetir-

acetam (LEV) (2000 mg, 3000 mg, 3500 mg), 1 val-proic acid (VPA) (2000 mg), 1 OXC (2700 mg) and 1primidone (PRM) (625 mg)).

All patients received total intravenous anaesthe-sia (TIVA) with propofol and remifentanil; threepatients received additional inhalation anaesthesiawith isoflurane. In all patients rocuronium or cisa-tracurium was used for muscle relaxation, and40 mg dexamethasone, 2 g ceftriaxone or 3 g ampi-cillin/sulbactam and 1 or 2 g metamizole wereadministered at the end of the operation. Meanduration of the operations was 275 min (120—390,S.D. 67.4). As the intra- and postoperative blood losscould not be quantified precisely in the majority ofcases, we decided to exclude this variable. Post-operative drug regimes varied remarkably: 17 out of20 patients received oral dexamethasone startingwith 24 mg daily (3 � 8 mg) on POD 1 and a dailydose reduction of 4—6 mg; 3 patients did not receivesteroids. In 12 cases the H2-antihistamine ranitidinewas given for postoperative ulcer prophylaxis, 3patients had proton pump inhibitors (omeprazole,esomeprazole) and 5 patients had no ulcer prophy-laxis. Seven out of 20 patients received paracetamol(acetaminophen) for postoperative analgesia; 13patients received other oral analgetics (metami-zole, ibuprofen).

Perioperative fluctuations of lamotrigine serum levels 481

Besides testing for AED serum levels, routinepostoperative monitoring of the patients until dis-charge from the ward (usually 10—14 days aftersurgery) included the following procedures: drawingof blood samples (white blood cell count, haemo-globin, platelet count, Na, K, CRP, glucose, liverenzymes) at least every other day, daily measure-ment of body temperature, measurement of bloodpressure and pulse three times daily, urine analysisat least once during the first few postoperative days,and a neurological examination at least every otherday. If necessary, further diagnostic examinations(computed tomography of the brain, ECG, etc.)were performed.

Statistics

Established parameters of descriptive statistics(mean, range, standard deviation) were calculated.A Wilcoxon rank-sum test was used for pre- andpostoperative comparisons, and a Mann—Whitneytest for between group comparisons. A p-value<0.05 was considered significant. All procedureswere performed with SPSS version 12.0.

Results

In the entire group, mean decrease of LTG serumlevels from the preoperative baseline was 37% (meanpreoperative level 8.1 mg/l (3.4—16.2, S.D. 3.6),lowest mean postoperative level 5.1 mg/l (1.4—9.9, S.D. 2.6; p = 0.001). Sixteen out of 20 patients(80%) showed a decrease in LTG serum levels frombaseline of more than 20% (21.9—69.1%, mean 46%)(p < 0.001, Table 1, Fig. 1), 2 patients had increased

Table 1 Mean pre- and postoperative serum levels (range)from preoperative baseline

Several subgroups with different postoperative medications are listeantihistamines; PPI: proton pump inhibitors; S.D.: standard devp < 0.001.

serum levels (+41.1%, +35.9%) and 2 patients showedminor changes (�7.7%, +15.3%). Decrease of LTGserum levels did not differ significantly betweenmen and women, patients with or without paraceta-mol, with or without isoflurane anaesthesia, withdifferent medication for ulcer prophylaxis or withor without dexamethasone. Furthermore, the mag-nitude of the decrease was influenced neither by agenor by the preoperative serum level.

Six patients (four with LTG monotherapy, twowith LEV co-medication) suffered from one or moreseizures within the early postoperative period (POD1 to POD 13); two additional patients presumablyhad one seizure each, but documentation was insuf-ficient. Five out of the six patients showed a reduc-tion in LTG levels of between 22.2% and 66.3% (mean48.4%) from the preoperative baseline, one patienthad a non-significant increase of 15.3%. There was,however, no significant difference in decrease ofserum levels between the group of patients withdocumented postoperative seizures (n = 6) and thegroup of patients without postoperative seizures(n = 14). In four patients with postoperative sei-zures, serum levels from the day on which theseizures occurred were documented in the medicalrecords. In three of these patients seizures corre-lated with the nadir of the serum levels (pat. 9: POD5, decrease of 52.7%; pat. 11: POD 4, decrease of66.3%; pat. 14: POD 4, decrease of 22.2%; see Fig. 1,red circles). The fourth patient (pat. 12, LTG mono-therapy) had one seizure on POD 3; the serum levelon this day was 8.2 mg/l versus 9.9 mg/l preopera-tively. This patient’s LTG level further decreased to5.8 mg/l, which led to the administration of 30 mgclobazam. The remaining two patients with post-operative seizures had serum levels drawn 1 day

of LTG in 16 patients with a decrease of more than 20%

d. Abbreviations–—PCM: paracetamol (acetaminophen); H2: H2-iation. *Difference significant from preoperative baseline at

482 F. Paul et al.

prior to or not more than 1 day after the seizure.Patient 2 (LTG monotherapy) had blood samplesdrawn 2 days prior to and 1 day after the seizure;at both timepoints, serum levels were reduced (pre-operative: 7.4 mg/l, POD 1: 3.0 mg/l (�59.5%), POD4: 5.1 mg/l (�31.1%)). Patient 19 (co-medicationwith LEV) had a seizure on POD 1, the LTG serumlevel on POD 2was 6.8 mg/l compared to a preopera-tive value of 5.9 mg/l. In all six patients sufferingfrom postoperative seizures a dose augmentation ofLTG (between 50 mg and 200 mg daily, increase ofbetween 10% and 25% compared to the preoperativedose) was performed and/or additional clobazammedication was temporarily administered to preventfurther seizures. In none of these 6 patients were thepostoperative seizures related to fever, infections, orlaboratory abnormalities such as metabolic distur-bances or electrolyte imbalance.

In the subgroup of eight patients with anticonvul-sant co-medication, serum levels changed as follows:the PRM (1 pat.) and VPA (1 pat.) levels remainedunchanged (pre-/postoperative 6.0 mg/l versus5.2 mg/l and 102 mg/l versus 96 mg/l, respectively),the patient with OXC co-medication showed adecrease of 41.8%, 1 patient with CBZ co-medicationhad a fair increase (pre-/postoperative 7.3 mg/lversus 10.8 mg/l) and the second CBZ patient hada decrease of 51.6%. LEV serum levels (3 pats.) werenot routinely examined as there was no valid assayavailable at that time in our institution.

Discussion

Our study revealed a pronounced decrease ofbetween 22% and 69% of LTG serum levels in 16out of 20 patients (80%) compared to the preopera-tive steady state. Amongst these 16 patients, 5 hadpostoperative seizures between POD 1 and POD 13.In 3 of these, seizures were associated with the LTGserum level nadir. As the postoperative seizures inthese patients could not be explained by fever,infections or laboratory abnormalities, it is verylikely that the reduction of LTG serum levels aftersurgery played a crucial role. Reduction of AEDserum levels is a well-known seizure-provoking con-dition.9 The factors contributing to the postopera-tive decrease of serum levels are, however, elusive.Besides the surgical procedure itself, possible influ-encing factors include the anaesthetic drugs, theperioperative medication (muscle relaxation, anti-biotics) and the postoperative medication, whichincluded dexamethasone, H2-antihistamines (rani-tidine) or proton pump inhibitors (omeprazole,esomeprazole), and the analgetics paracetamol(acetaminophen), metamizole and ibuprofen. Little

is known about drug interactions of these co-med-ications with LTG or other AED.

Feil et al.8 examined perioperative serum levelsof LTG and OXC, and found relevant fluctuations inpatients who received isoflurane and barbituratesas anaesthetics. However, none of our patientsreceived barbiturates, and only three had isoflur-ane anaesthesia; these patients did not show amore pronounced reduction in LTG levels than thepatientswithout isoflurane. Therefore, isoflurane isunlikely to be the major cause of the decreasedserum levels.

Another influencing co-medication may be dexa-methasone, which was administered in 17 patients.Sabers et al. found a significant reduction of LTGlevels under oral contraceptives10,11 and speculatedthat this might be due to the elimination of LTGprimarily by glucuronidation, as oral contraceptivesinduce themetabolism of some other glucuronidateddrugs such as paracetamol and clofibric acid.12,13

Dexamethasone is a steroid as well, so similar effectson thepharmacokinetics of LTGmaybeassumed. Twoof 3 patients who did not receive dexamethasone hadonly minor fluctuations in their LTG levels (�7.7%,+15%), but the small number of patients does notallow firm conclusions to be drawn regarding possibleinteractions of LTG with dexamethasone.

Drug interactions of H2-antihistamines and pro-ton pump inhibitors with LTG have not been thor-oughly investigated. Although sample sizes werelimited, the lack of changes dependent on thesedrugs in our study is in line with Ebert et al., whofound negligible effects of the H2-antihistaminecimetidine on the pharmacokinetics of LTG inhealthy subjects after administration of a singleoral dose of 25 mg LTG.14

Paracetamol (acetaminophen), given in sevencases for postoperative analgesia, can reduce LTGserum levels.15 This may be a relevant co-factor insome patients but cannot explain sufficiently thedecrease of postoperative LTG serum levels in theentire cohort, as the magnitude of the decrease wassimilar in patients with and without paracetamol(Table 1).

The fact that our study could not show a firmassociation between the decrease of the serumlevels and certain co-medications may be due tothe lack of standardised treatment regimes in theearly postoperative period, leading to small samplesizes in the different subgroups. On the other hand,this observation may equally point to the anaes-thetics (TIVA, given to all patients in our cohort) as afactor influencing postoperative serum level reduc-tions. All types of anaesthesia may cause delayedgastric emptying and alteration of bowel motility,16

which has also been separately shown for TIVA

Perioperative fluctuations of lamotrigine serum levels 483

with propofol and remifentanil in humans.17 Thismay lead to a delayed absorption of orally adminis-tered medications and an alteration of theirbioavailability.16,17

The major limitation of our study is, thus, itsretrospective character and the relatively smallsample size, which hampers the assessment of theimpact of the perioperative procedures (surgery,anaesthesia, postoperative medication) on theserum levels of LTG. However, as our knowledgeof perioperative fluctuations in AED serum levelsis exiguous, this work alerts us to the relevance ofdecreased AED serum levels as a factor contributingto early postoperative seizures. Early postoperativeseizures of whatever cause may have a negativepsychological impact on patients, who signed con-sent for epilepsy surgery with high expectationsregarding seizure freedom, mostly after a long his-tory of medically intractable epilepsy. Furthermore,early postoperative seizures may have negativeprognostic implications for later outcome.2—4 Ascertain conditions related to surgery, such as anaes-thesia, are unavoidable, all susceptible factorswhich can contribute to postoperative seizures,such as decrease of serum levels of AED, shouldbe eliminated as far as possible. Presumably, a post-operative reduction of serum levels is not a phe-nomenon specific to LTG: the serum levels of otherAED might also be influenced by perioperative pro-cedures, anaesthetics and postoperative medica-tion, a possibility which needs further evaluation.The very small number of patients with anticonvul-sants given as co-medication in our study (CBZ, PRM,LEV, VPA, OXC) does not permit any conclusions to bemade regarding these AED. Interestingly, elevatedpostoperative serum levels of CBZ were reported ina previous retrospective study in about 50% ofpatients undergoing epilepsy surgery, and interac-tion with fentanyl was assumed.7 On the other hand,9% had a reduction of postoperative CBZ levels in thesame study.

As an increasing number of patients will probablybe eligible for epilepsy surgery owing to improvedselection procedures and optimised surgical techni-ques, prospective studies are urgently needed toassess the factors influencing perioperative fluctua-tions in AED serum levels and their impact on earlypostoperative seizures. It would be desirable toreach a consensus amongst experts in the field ona standardized perioperative management ofpatients undergoing epilepsy surgery regardinganaesthesia, postoperative co-medication presum-ably interacting with the AED, and dose titration ofthe AED.

The results of our study lead us to make thefollowing recommendations regarding the perio-

perative management of epilepsy patients withLTG: (i) a preoperative dose augmentation of 10—20% should be considered in order to avoid insuffi-cient postoperative serum levels and to eliminateone susceptible factor which contributes to post-operative seizures; (ii) a subsequent reduction indosage to the preoperative steady-state dose couldbe performed about 2 weeks later after discontinua-tion of other potentially interacting drugs such assteroids, drugs for ulcer prophylaxis and analgetics;(iii) postoperative serum levels of LTG should bemonitored closely (at least every other day) duringthe first 2 postoperative weeks; (iv) a serum levelreduction of more than 20% should initiate furthercautious dose augmentation and/or temporary add-on medication with benzodiazepines; (v) postopera-tive analgesia with paracetamol should be handledwith caution, as an interaction with LTG cannot beruled out. Therefore, metamizole or ibuprofen maybe preferable alternatives.

Appendix A. Supplementary data

Supplementary data associated with this articlecan be found, in the online version, at doi:10.1016/j.seizure.2007.03.006.

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