Absence and Myoclonus Induced by AEDS

8/9/2019 Absence and Myoclonus Induced by AEDS

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doi:10.1093/brain/awl047 Brain (2006), 129, 12811292

Absence and myoclonic status epilepticusprecipitated by antiepileptic drugs in

idiopathic generalized epilepsyPierre Thomas,1 Luc Valton2 and Pierre Genton3

1Unite Fonctionnelle EEG-Epileptologie, Service de Neurologie, Hopital Pasteur, Nice, 2Unite dEpileptologie, Service deNeurologie, Hopital Rangueil, Toulouse and 3Centre Saint Paul-Hopital Henri Gastaut, Marseilles, France

Correspondence to: Pierre Thomas, MD, PHD, Unite Fonctionnelle EEG-Epileptologie, Service de Neurologie,Hopital Pasteur, 30 Voie Romaine, 06002 Nice, France

E-mail: [email protected]

Aggravation of idiopathic generalized epilepsy (IGE) syndromes by inappropriate antiepileptic drugs (AEDs)

is increasingly recognized as a serious and common problem. Precipitation of status epilepticus (SE) by inap-

propriate medication has rarely been reported. We retrospectively studied all adult patients with IGE takingat least one potentially aggravating AED, who developed video-EEG documented SE over 8 years, and whose

long-term outcome was favourable after adjustment of medication. We identified 14 patients (seven male

patients) aged 1546 years with a mean duration of epilepsy of 16.4 years. Video-EEG demonstrated typical

absence SE (ASE) in five, atypical ASE in five, atypical myoclonic SE (MSE) in three and typical MSE in one.

Epilepsy had been misclassified as cryptogenic partial in eight cases and cryptogenic generalized in four.

The correct diagnosis proved to be juvenile absence epilepsy (JAE) in six patients, juvenile myoclonic epilepsy

(JME) in four, epilepsy with grand mal on awakening (EGMA) in two and childhood absence epilepsy (CAE) in

two. All patients had been treated with carbamazepine (CBZ) and had experienced seizure aggravation or

new seizure types before referral. Seven patients had polytherapy with phenytoin (PHT), vigabatrin (VGB) or

gabapentin (GBP). Potential precipitating factors included dose increase of CBZ or of CBZ and PHT; initiation

of CBZ, VGB or GBP; and decrease of phenobarbital. Withdrawal of the aggravating agents and adjustment

of medication resulted in full seizure control. This series shows that severe pharmacodynamic aggravation of

seizures in IGE may result in ASE or MSE, often with atypical features.

Keywords: status epilepticus; adverse effects; antiepileptic drugs; epilepsy prognosis

Abbreviations: AEDs = antiepileptic drugs; ASE = absence status epilepticus; CAE = childhood absence epilepsy;CPE = cryptogenic partial epilepsy; EGMA = epilepsy with grand mal on awakening; GTCS = generalized tonic-clonic seizure;IGE = idiopathic generalized epilepsies; JAE = juvenile absence epilepsy; JME = juvenile myoclonic epilepsy;MSE = myoclonic status epilepticus; PSW = polyspike-and-wave; SE = status epilepticus; SW = spike-and-wave

Received October 31, 2005. Revised January 20, 2006. Accepted January 27, 2006. Advance Access publication March 2, 2006

Introduction

Treatment with antiepileptic drugs (AEDs) may provoke aparadoxical aggravation of epilepsy, both in adults (Lerman,1986; Bauer, 1996; Perucca et al., 1998) and in children(Guerrini et al., 1998; Usui et al., 2005). Various mechanisms

may be responsible, but the most puzzling is a truly inversepharmacodynamic effect, with increased seizure activity

sometimes associated with the appearance of new seizuretypes, which occurs without high drug level, drug toleranceor encephalopathy (Berkovic, 1998). Idiopathic generalized

epilepsies (IGE), a subgroup of epilepsies that are geneticallydetermined and have no structural or anatomic cause, areoften involved in this type of deterioration (Sazgar andBourgeois, 2003). In IGE, the use of ill-advised AEDs, espe-

cially carbamazepine (CBZ) and phenytoin (PHT) (Genton

et al., 2000; Osorio et al., 2000), either in monotherapy or in

combination, is a common problem, encountered in up to69% of patients in a recent series (Benbadis et al., 2003).Paradoxical aggravation in IGE usually results in subtle or

# The Author(2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected]


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Table

1

ClinicalcharacteristicsofpatientsatSE

Case

(sex,age)

Personalandfamily

history

Typeoffirst

seizure

age(years)

Syndromicclassification

atSE

AEDtreatmentatSE(mg/day)

Bloodlevels[mg/l]

Durationof

CBZtherapy

(years)

Treatmentafter

SE(mg/day)

EvolutionFollo

wup

(years)

Finalepileptic

syndrome

1(M,26)

FebrileSz

GTCS(14)

CPE(Rfrontal)

CBZ(1600)[9]

VGB(3000)[NA]

VPA(2000)[44]

3

LTG(200)VPA(1000)Noseizure(4.3)

EGMA

2(F,15)

Epilepsyinsister

Abs(11)

CPE(Lfrontal)

CBZ(800)[8]

PB100[18]

0.5

LTG(150)VPA(750)

RareAbs

(non-complianc

e)

(5.8)

JAE

3(F,39)

None

Abs(13)

CPE(Rfrontal)

CBZ(800)[7.6]

PB(50)[9]

PHT(350)[8.5]

4


JAE

4(M,28)

FebrileSz

MJ(16)

SGE

CBZ(1200)[7.3]

PB(150)[14]

VGB(2000)[NA]

4.5

PB(100)VPA(1000)

Noseizure(5)

JME

5(F,45)

Epilepsyinbrother

Abs(17)

CPE(Rtemporal)

CBZ(500)[5.2]

5

VPA(1000)

Noseizure(4)

JAE

6(F,25)

FebrileSz

Epilepsyinbrother

Abs(12)

CPE(temporal)

CBZ(1400)[8.7]

PB(150)[21.7]

4.5

VPA(1250)

Noseizure(4.75)

JAE

7(M,21)

Epilepsyinmother

Behaviouralproblems

CGTC(16)

CGE

CBZ(1200)[10]

GBP(800)[NA]

3


EGMA

8(M,46)

FebrileSz

Abs(5)

CPE(temporal)

CBZ(1200)[7.5]

PB(150)[22]

7

LTG(200)VPA(750)

Noseizure(7)

CAE

9(F,26)

Epilepsyinmaternal

grandmother

MJ(7)

SGE

CBZ(1600)[11]

PB(100)[18]

PHT(200)[5]

5.5

CLB(30)VPA(1500)

PB(75)

Noseizure(3.5)

JME

10(M,18)FebrileSz

MJ(16)

UndeterminedGE

CBZ(800)[6.3]

0.5

VPA(1000)

Noseizure(3.1)

JME

11(M,17)Behaviouralproblems

Abs(5)

CGE

CBZ(800)[6.5]

PHT(300)[8]

VPA(1000)[55]

0.25

VPA(1250)

Noseizure(7)

CAE

12(F,38)FebrileSz

Abs(17)

CPE(Lfrontal)

CBZ(800)[7.2]

0.5

VPA(500)TPR(100)

Noseizure(3)

JAE

13(F,25)Absincousin

MJ(16)

UndeterminedGE

CBZ(600)[7.4]

0.5

VPA(1000)

Noseizure(6)

JME

14(M,43)NeonatalSzin

paternaluncle

GTCS(20)

CPE(frontal)

CBZ(1000)[6.7]

CLB(30)[NA]

VGB(2000)[NA]

1

ESM(750)VPA(1000)Noseizure(7.5)

JAE

M:male;F:female;R:right:L:left;

SE:statusepilepticus;Abs:absences;GTC

S:generalizedtonic-clonicseizure;MJ:myoclonicjerks;CGE:cryptogenicgeneralizedepilepsy;CPE:

cryptogenicpartialepilepsy;SGE:symptomaticpartialepilepsy;NA:notavailab

le;CBZ:carbamazepine;CLB:clobazam;CNZ:clonazepam;ESM:ethosuximide;GBP:

gabapentin;LTG:

lamotrigine;PB:phenobarbital;PHT:phenytoin;TPR:topiramate;VPA:valproate;VGB:vigabatrin;JME:juvenilemyoclo

nicepilepsy;JAE:juvenileabsenceepilepsy;CAE:childhood

a b s e n c e e p i l e p s y ; E G M A : e p i l e p s y w i t h g r a n d m a l o n a w a k e n i n g

Status epilepticus and antiepileptic drugs Brain (2006), 129, 12811292 1283


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Table

2

Characteristicsofseizureaggravationandepisodesofstatu

sepilepticus

Case

(sex,age)

Seizurecharacteristics

duringaggravation(frequency)

Possiblecause

ofSE

Clinicalpresentation

ofSE(duration)

Icta

lEEGpattern

1(M,26)

Lossofcontactwithim

mediate

headandeyedeviation

totheL,

thenGTCS(1permonth)

Lossofcontactwith

delayedslightheadand

eye

deviationtotheL,followed

bysimplegesturalauto

matisms,

duration1020s(10p

ermonth)

Decr.VPA

Incr.CBZ

AtypicalASEwithmoderate

confusion,episodesofeye

rolling,versionofheadand

eyestotheL

ResolvedafterIVBZand

IVPHT(90min)

Sub

continuousdiffuse22.5HzSWandPSW

discharges

2(F,15)

GTCS(1permonth)

Lossofcontact,either

isolatedor

followedbyslighthead

andeyedeviation

totheR,duration

1020s(2030permonth)

Incr.CBZ

TypicalASEwithmildimpairment

ofconsciousnessandeyelid

myoclonias,inrelationtoserial

absencesinquicksuccession

ResolvedafterIVBZ(65min)

Rhy

thmic,generalized3HzPSWdischargeso

f510sduration

repeatedat510sintervals

3(F,39)

HeadandeyedeviationtotheL,

thenGTCS(1permonth)

Episodesofimpairedconsciousness

ofvaryingintensityatawakening,

lasting0.54h,(57permonth)

Incr.CBZ

Incr.PHT

AtypicalASEwithsevere

confusion,disinhibitionand

stereotypedrhythmicmovements

oftherightarm

Resolvedspontaneously(180min)

Generalized1HzPSWandSWdischargeswitha

Rp

redominance,alternatingwithrhythmicbu

rstsofslowwaves

4(M,28)

Clonic-tonic-clonicSz(3permonth)

AwakeningepisodesofMJofvarying

amplitude,moremarkedontheR,

increasedbyeyeclosure,

lasting3045min(6permonth)

OnsetofVGB

Severe,atypicalMSE.

Eyeclosureinducedrhythmic

burstsofeyelidmyoclonias

witheyelid-openingapraxia.

ResolvedafterIVBZ(45min)

Pseudo-rhythmic,continuousdiffuse46HzS

W

Majorincreaseofictalactivitywheneyeswer

eclosed

5(F,45)

GTCS(1peryear)Ser

ial,dailyepisodesof

mildintellectualimpairmentwithdiffuse

anxietylasting515s(30permonth)

Sleepdeprivation

AtypicalASEwithsubjective

cognitiveimpairment,and

unpleasantfeelingduring

discharges.ResolvedafterIVBZ

(210min)

Serialburstsofrapid,generalizedSp,followed

byslowPSW

lasting712s,repeatedat2040sintervals

6(F,25)

GTCS(2peryear)

Isolatedlossofcontact(10permonth)

Long-lastingepisodeofsubjective

cognitiveimpairmentw

ith

MJendinginaGTCSa

fter10h

(threeepisodes)

Incr.CBZ

TypicalASEwithsubjective

cognitiveimpairment,feeling

ofdrunkenness,rareMJ,and

unsteadygait.

Resolvedaftera

singleGTCS(140min)

Continuous,diffuse4HzirregularSW

1284 Brain (2006), 129, 12811292 P. Thomas et al.


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difficulties and behavioural problems had been interpretedas mild mental retardation in Patients 7 and 11, with doubt-

ful brainstem atrophy on MRI in the latter. Interictal EEGin these patients showed either slow SW or rhythmic slowwaves on a poorly organized, slow background activity.

Patient 10 had been classified as having undetermined

epilepsy following two GTCS prior to the introductionof CBZ, which produced severe aggravation with onset of

myoclonic jerks. The last patient (Case 13), despite an initialdiagnosis of generalized epilepsy and a good seizure controlwith valproate (VPA), was given CBZ because of weight gain

considered unacceptable.

Seizure aggravation

All patients had experienced seizure aggravation several

months before referral. Absence or myoclonic seizures weremarkedly increased in frequency, duration and/or severity infive patients (Cases 1, 2, 5, 9 and 12), while the others devel-

oped, in addition to their usual seizures, new seizure types:prolonged episodes of confusion and/or cognitive distur-

bances (Cases 3, 6, 7, 8, 13 and 14) later documented asepisodes of ASE; development of scotosensitivity with eyelidmyoclonia and myoclonic jerks associated with eye closure(Case 4); appearance of clusters of rhythmic 3 Hz myoclonic

jerks on awakening (Case 10); and episodes of unsteady gaitand clumsiness (Case 11). In contrast, except in Patients 4

and 11, GTCS frequency was less obviously increased thanother seizure types. In some patients (Cases 2, 7, 10, 11 and

13), clinical deterioration occurred soon after the introduc-tion of the drug later identified as responsible for theincreased seizure frequency. In the others (Cases 1, 3, 4, 5,

6, 8 and 9) aggravation had been more progressive and insi-dious, leading to the sequential addition of various AEDsby successive doctors over months.

Status epilepticus

Patients were either referred for assessment of intractable

epilepsy with elective video-EEG or were admitted to theemergency ward for an acute epileptic event and assessed

immediately. Five patients (Cases 2, 6, 8, 12 and 13) hadtypical ASE (Fig. 1A). Uncommon clinical features were

prominent in five others with atypical ASE (Cases 1, 3, 5,7 and 14): repeated versive movements; a peculiar compulsive

motor perseveration; an unpleasant, recurrent, stereotypedfeeling during discharges; repeated urination and a versive-

onset GTCS that did not interrupt the ASE. In these patients,ictal EEG showed continuous or intermittent discharges of

slow PSW, SW or slow waves at less than 2.5 Hz (Fig. 1B).Among the four patients with MSE (Cases 4, 9, 10 and 11),three had additional unusual features. In Case 4, paroxysmal

activity and eyelid myoclonia were considerably increasedat eyes-closure. In Patient 10, bursts of 3 Hz rhythmic mas-sive myoclonic jerks were time-locked to the PSW. Patient 11

had epileptic negative myoclonus organized in SE (Tassinari

et al., 1995) with interruption of tonic muscular activitytime-locked to the PSW discharges without an antecedent

positive myoclonic jerk (Fig. 2B).Intravenous (IV) benzodiazepines (BZD) alone (diazepam,

1020 mg, or clonazepam, 12 mg) successfully stopped SE

in eight patients. Two patients with ASE required combina-

tion therapy with either IV PHT (Case 1) or IV VPA (Case12). In three other patients (Cases 3, 13 and 14), SE ended

spontaneously and ASE ended with a GTCS in Patient 6.

Antiepileptic drug regimen

All patients received CBZ, with a mean exposure of 2.8 years

(range, 0.255.5 years), a mean dose of 1020 mg/day (range,5001600) and a mean blood level of 7.74 mg/l (range,

5.211). Four patients (Cases 5, 10, 12 and 13) receivedCBZ monotherapy, with a mean dose of 625 mg/day(range, 500800) and a mean blood level of 6.52 mg/l. Ten

patients took one or several other AEDs: phenobarbital (PB)in six (50150 mg/day); PHT in three (200350 mg/day);vigabatrin (VGB) in three (20003000 mg/day); VPA in

two (1000 and 2000 mg/day); gabapentin (GBP) in one(800 mg/day) and clobazam (30 mg/day) in one. In threepatients (Cases 2, 12 and 13), VPA had been replaced with

CBZ owing to side-effects (weight gain in two and fatigue inthe last). Among the 12 patients in whom SE was presumablyprecipitated by modification of the drug regimen, an increase

of CBZ dosage was implicated in 7.Blood test results were normal in all. Blood levels of CBZ,

PB, PHT and VPA were within the usual therapeutic ranges;levels of CBZ 10,11-epoxide, VGB, GBP and clobazam

were not assessed. None of the patients had acute AED with-drawal. Patient 8 had reduced PB by 50 mg/day two weeksbefore onset of SE, but was still receiving 150 mg/day (bloodlevel: 22 mg/l).

Final diagnosis, course and prognosis

Final syndrome diagnoses were as follows: juvenile absenceepilepsy (JAE) in six patients, juvenile myoclonic epilepsy

(JME) in four, epilepsy with grand mal on awakening(EGMA) in two and childhood absence epilepsy (CAE) in

two. All patients but one became seizure-free during follow-up (mean duration: 5.1 years, range 37.5 years), including

five on VPA monotherapy and eight with a combinationtherapy that included VPA. Patient 2 had persisting rare

absences due to poor compliance. In all patients, interictalEEGs after discontinuation of aggravating drugs and pre-

scription of adequate treatment showed either complete nor-malization or rare bursts of rapid SW or PSW on a normalbackground. A 24 h ambulatory EEG was recorded before

and after change of treatment in Patient 13 and demonstra-ted the occurrence of MSE at awakening on CBZ and thenear-complete disappearance of interictal changes on VPA

(Fig. 3).



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Discussion

Paradoxical seizure worsening by AED in IGE is not always

easy to diagnose. Although presenting with unusual ASEor MSE, all of our patients fulfilled criteria for this type ofaggravation (Genton and McMenamin, 1998). None hadtoxic AED levels, poor compliance, irregular lifestyles,

acute drug withdrawal or other metabolic encephalopathies.Before developing SE, all experienced a clear increase in

seizures and nine had new seizure types. Although we con-sidered the possibility of refractory frontal-lobe epilepsy

in cases with atypical ASE or unusual clinical seizurepatterns, the appearance of new seizure types was clearlyrestricted to the aggravating period.

This paradoxical aggravation of seizures should not be

confused with spontaneous fluctuations in seizure activity,because all patients had an immediate and satisfactory seizure

Fig. 1 Typical and atypical ASE in JAE. (A) This 15-year-old girl (Patient 2) with JAE was treated with PB, 100 mg/day, and VPA,1000 mg/day. Weight gain and an erroneous syndromic classification of CPE of frontal origin led to the replacement of VPA by CBZ,600 mg/day. When CBZ was raised to 800 mg/day, typical ASE developed, characterized by serial bursts of 3 Hz generalizedpolyspike-and-wave complexes, recurring every 510 s. Mild impairment of consciousness and eyelid myoclonia were prominentduring discharges. (B) This 39-year-old woman (Patient 3) with JAE had long-standing aggravation on CBZ, 800 mg/day, PHT,350 mg/day, and PB, 50 mg/day. Shortly after awakening, she very often had episodes of prolonged cognitive impairment of varyingintensity, one of which led to a car accident. During a 5-day video-EEG monitoring, a 180 min atypical ASE was recorded,with severe confusion, inappropriate familiarity, sexual disinhibition and a peculiar compulsive rhythmic stereotyped movement

of flexion-extension of the right arm. EEG shows continuous, diffuse, irregular, high-amplitude, 1 Hz polyspike-and-slow wave andspikeand-wave activity with slight right-sided predominance.



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Fig. 2 Positive and negative MSE as an effect of CBZ. ( A). This 18-year-old man (Patient 10) with JME received CBZ, 800 mg/day,from the onset and had since experienced numerous episodes of MSE lasting up to 30 min after awakening. EEG shows veryfrequent 1020 s bursts of generalized, rhythmic polyspike-and-slow wave complexes (PSW) at 3 Hz, synchronous with themyoclonia. Jerk-locked back-averaging of 30 traces shows that the last spike component precedes the onset of the myoclonic

jerk with a 48 ms delay. (B) This 17-year-old man (Patient 11) with CAE was poorly controlled on VPA, 1000 mg/day, and PHT,300 mg/day. Prolonged episodes of unsteady gait and clumsiness, related to negative MSE, occurred shortly after CBZ was added.EEG shows continuous 12 Hz PSW with a frontal predominance synchronous with the atonia. The EMG shows that interruptionof tonic muscular activity occurs without evidence of an antecedent positive myoclonic jerk. Silent period-locked back-averagingof 50 consecutive traces shows a 44 ms delay between the peak of the last spike and the onset of atonia. R Delt: right deltoid;L Delt: left deltoid; Av EEG: averaged EEG; AV rEMG: averaged rectified EMG; Lat: latency.



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control and EEG improvement or normalization when initialAED treatments were discontinued and replaced by an ade-quate medication. To confirm fully that narrow-spectrum

AEDs were the cause of aggravation, we would have hadto stop them first to observe spontaneous improvement

before reintroducing the potential aggravating drug. How-ever, all patients required immediate treatment following a

long-standing aggravation that terminated into SE. Further-more, this reintroduction procedure is obviously ethically

impossible just to acquire scientific evidence (Gelisse et al.,2004).

Our patients had various syndromes of IGE, a subgroup ofepilepsies that are more likely to be aggravated by narrow-

spectrum AEDs (Benbadis et al., 2003). This study shows thatthere are many clinical and EEG pitfalls in IGE diagnosisthat may result in erroneous classification and treatment

choices. Clinical manifestations may be asymmetric, withlateralized myoclonic jerks or versive onset of GTCS, parti-cularly in patients with JME (Montalenti et al ., 2001;

Usui et al., 2005). In this syndrome, EEG abnormalities

may be asymmetric or even focal (Lancman et al., 1994;Genton et al., 1995) and this EEG feature may even beexacerbated by inadequate treatment (Talwar et al., 1994).

In CAE and JAE, absences may be misdiagnosed as complexfocal seizures, particularly if ictal automatisms occur (Snead

and Hosey, 1985). Such confusing features were responsiblefor the choice of inappropriate treatment in most of our

patients. Abnormal neuroimaging may also cause misdiag-nosis in IGE, and such coincidental findings have been

demonstrated to have no impact on the clinical course ofJME (Gelisse et al., 2000).

In the present series, syndromic diagnosis was changedduring hospitalization, and the occurrence of SE was the

major reason. The phenomenology of SE helped somewhatin rectifying the syndromic diagnosis, as all patients with JAEpresented with ASE, and most patients with JME had MSE.

However, ASE was atypical in half the cases, and MSE wasatypical in three-quarters of them. Also, no patients pre-sented with generalized tonic-clonic SE, even those with a

final diagnosis of EGMA.

Fig. 3 This 25-year-old woman (Patient 13) with JME since age 16 had been on VPA, 1000 mg/day, which was changed at age 23 to CBZ,600 mg/day, by her general practitioner because of weight gain. She was referred at age 25 for severe generalized epilepsy with long-lastingepisodes of obtundation with asynchronous jerks of the limbs that occurred shortly after awakening and lasted up to 2 h. Top: 24 h

ambulatory EEG recording with quantification of the duration of paroxysmal activity (PA), performed on CBZ, 600 mg/day (blood level: 7.4mg/l), showing the presence of nearly continuous discharges of SW or PSW after awakening. Total duration of PA:45 min 30 s. Bottom: Same procedure 16 months later on VPA, 1000 mg/day (blood level: 88 mg/l). Total duration of PA: 15 s.



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MSE is a rare spontaneous complication of JME (Thomas

et al., 2005) and was found in three of our four JME pati-

ents. In two of these, the intensity of myoclonus, the durationof the episodes and their daily occurrence mimicked thesymptoms of a progressive myoclonus epilepsy. A major

increase in eyelid myoclonia and paroxysmal activity on

eye closure produced a clinical picture similar to apraxiaof eyelid opening (Defazio et al., 1998) in Patient 4. In Patient

10, rhythmic 3 Hz myoclonic jerks with abrupt on- and offset,but without impairment of consciousness resembled theEEG ictal pattern of epilepsy with myoclonic absences

(Bureau and Tassinari, 2005). Generalized MSE with onlynegative myoclonus was prominent in Patient 11, with a

final diagnosis of CAE. Although never documented inIGE in the form of SE, epileptic (Nanba and Maegaki,1999; Shirasaka and Mitsuyoshi, 1999) and non-epileptic

(Aguglia et al., 1987) negative myoclonus have been reportedas an adverse effect of CBZ in children with benign partialepilepsies.

Similarly, in absence epilepsies, the occurrence of typicalASE has been repeatedly reported as a rare spontaneous

complication (Kaplan, 2002), although prevalence may behigher in patients with persistence of typical absences inadult life (Michelucci et al., 1996), or in some recently iden-tified syndromes such as perioral myoclonias with absences

(Agathonikou et al., 1998) or phantom absences with GTCS(Panayiotopoulos et al. 1997b). In these idiopathic forms,

ASE is typically restricted to a prolonged variable confusi-onal state associated with symmetric and bilaterally synchro-

nous fast SW or PSW discharges (Shorvon, 1994). Clinicaland EEG features were clearly atypical in half of our ASEpatients, which could lead to a misdiagnosis of a cryptogenic

or symptomatic epilepsy syndrome (Kaplan, 2002). Osorioet al. (2000) recorded atypical ASE in eight patients receiv-ing both CBZ and PHT, four with CAE and four with JME.

Interestingly, ASE was much more resistant to IV BZD or IVVPA, compared with 10 ASE patients with IGE who eitherwere on no medication or were not being treated with thiscombination of AEDs. In our series, IV BZD or IV VPA

easily controlled SE in all patients, save for one who requiredIV PHT.

CBZ appears to be the major cause of seizure aggravationin our series: it was being taken by all patients when SE

developed, was the only drug in four cases and probablymasked or reduced the benefit of effective AEDs (PB and

VPA) in eight others. Although associated with other poten-tially aggravating agents (PHT, VGB, GBP) in seven patients,

SE was clearly triggered in two of them by starting CBZ andin three others by an increased CBZ dose. Other patients

had a longer exposure to CBZ, leading to an insidious wor-sening over months, which explained the successive additionof other drugs.

Exacerbation of seizures in patients treated with CBZ hassometimes been reported as a toxic effect with elevated CBZblood levels (Bauer, 1996), or with elevated 10,11 epoxy CBZ

levels, even without elevated CBZ levels (Dhuna et al., 1991;

So et al., 1994). However, in our patients, blood levels of CBZwere well below the toxic range, and none had clinical signs

of intoxication. Several seizure types can be aggravated bytherapeutic levels of CBZ, including typical and atypicalabsences (Lerman, 1986; Talwar et al., 1994; Parker et al.,

1998), tonic (Snead and Hosey, 1985), atonic (Shields and

Saslow, 1983) and myoclonic seizures (Parmeggiani et al.,1998; Genton et al., 2000). This paradoxical aggravation

has been most commonly reported in children with general-ized cryptogenic or symptomatic epilepsies (Guerrini et al.,1998) and is less well documented in adults (Liporace et al.,

1994). However, in a series of 59 children with various focalepileptic syndromes and CBZ-associated EEG changes

(Talwar et al., 1994), the appearance of generalized paroxysmal discharges after starting CBZ was highly correlatedwith seizure exacerbation.

In idiopathic epilepsies, CBZ can increase seizures inabsence epilepsies (Parker et al., 1998), benign epilepsywith centrotemporal spikes (Corda et al., 2001) and JME:

in a large retrospective series (Genton et al., 2000), 68% ofcases exposed to CBZ experienced seizure aggravation, mostly

in the form of increased myoclonus. De novo appearanceof absences (Yang et al ., 2003) and myoclonic jerks(Parmeggiani et al., 1998) has also been reported in patientswith GTCS only. Oxcarbazepine, a new drug chemically

related to CBZ can also exacerbate myoclonus and absenceseizures in JME and JAE (Gelisse et al., 2004)

Seizure exacerbation by PHT is often associated in IGEwith toxic drug levels (Bauer, 1996). PHT may increase

absences and tonic-clonic seizures in generalized epilepsies(Levy and Fenichel, 1968) and has also been reported toprecipitate ASE in JME and in CAE (Osorio et al., 2000).

PHT can also aggravate myoclonic jerks in patients withJME, but to a lesser extent than CBZ (Genton et al.,2000). Increased PHT dose was a co-factor in MSE in only

one of our patients.VGB has also been reported to aggravate absence, tonic

and myoclonic seizures, especially in children. However,except in absence epilepsies, clear aggravation of IGE is

relatively uncommon (Michelucci and Tassinari, 1989). Intwo patients with either CAE or JAE, adding VGB to a

previously inappropriate treatment dramatically increasedboth frequency and severity of ASE (Panayiotopoulos et al.,1997a). Similarly, in our series, starting VGB may have trig-

gered ASE in a JME patient (Case 4), and was a co-factor

in two other cases.Lamotrigine (LTG) has been shown to be useful for

absences, but may worsen myoclonic seizures in various clin-ical settings. Aggravation of IGE has been reported, including

six patients with JME that were clearly worsened (Birabenet al., 2000), three other patients who developed ASE withmild myoclonic components when switched from VPA

(Trinka et al., 2002) and five patients with exacerbation or

de novo appearance of myoclonic jerks (Crespel et al., 2005).However, five of our non-JME patients were finally control-

led on a combination of AEDs, including LTG.



11/12

There is some evidence for precipitating absences or myo-clonic jerks with GBP. However, if GBP-associated myoclo-

nus is relatively frequent, it may easily remain unnoticed(Asconape et al., 2000). One of our patients experiencedASE following the introduction of GBP, but CBZ dosage

had been increased at the same time.

Similarly, high-dose PB has been reported to increaseabsences (Bauer, 1996; Berkovic, 1998) but today most clin-

icians in developed countries use barbiturates sparingly inIGE. Six of our patients initially received PB, but its rolein the provocation of SE was unclear: although dosage had

been decreased in a single patient with ASE, it had remainedstable in five, and all were receiving other potentially aggra-

vating AEDs.This series also confirms the major efficacy of VPA in IGE

patients, a property that may have been masked by the co-

prescription of potentially aggravating AEDs in two cases.VPA may also be withdrawn owing to side-effects, and thecontrol of epilepsy typically worsens thereafter: this happ-

ened in three patients who were switched to CBZ for weightgain or asthenia. Syndromic worsening with VPA is very

unusual: eight children with absence seizures associatedwith generalized 3 Hz SW activity developed paradoxicalincrease in absences within days of starting VPA (Lerman-Sagie et al., 2001). These puzzling but well-documented cases

show that no AED can be excluded as a cause of paradoxicalaggravation of seizures.

Among cellular mechanisms by which AEDs may precipi-tate seizures, the gamma aminobutyric acid (GABA) system

is the most extensively studied. In a genetic absence ratmodel, a reverberating thalamocortical circuit generatesabnormal oscillatory rhythms, resulting in non-convulsive

seizures resembling human absences (Marescaux et al .,1992; McCormick, 2002). GABA-B-induced hyperpolariza-tion of thalamic relay neurons enhances oscillatory thala-

mocortical activity, leading to more prominent andsustained SW discharges (Liu et al., 1992). In this model,GABAergic drugs such as VGB, tiagabine and GBP, aswell as CBZ and PHT, increase SW discharges and clinical

seizures. In addition, if one superimposes a GABA-B receptoragonist, baclofen, on the gamma-hydroxybutyrate model

of absence seizures, ASE results (Snead, 1996). CBZ andPHT act mainly as voltage-dependent sodium channel

blockers, enhancing membrane stabilization, a propertythat may indirectly increase hypersynchronization of neuro-

nal discharges in a thalamocortical loop already showingintensified oscillatory activity (McLean and Macdonald,

1986).This series shows that severe pharmacodynamic AED-

induced seizure aggravation in IGE may express itself asASE or MSE, often with atypical clinical and EEG features.Careful syndrome diagnosis is needed to avoid such compli-

cations. Although the risk of aggravation has probablyincreased with the number of available narrow-spectrumanticonvulsants, CBZ appears to be the drug most

often implicated and should be contraindicated in absence

epilepsies and JME, and used with great care when a diagnosisof IGE is considered.

AcknowledgementsThe authors thank F. Andermann, F. Mauguiere and B. G.

Zifkin for their expert reviewing of the manuscript and help-ful comments.

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