Exacerbation of epileptic seizures by carbamazepine: Report of 10 cases

Seizure 1998; 7: 479-483

Exacerbation of epileptic report of 10 cases ANTONIA PARMEGGIANI,

seizures

by carbamazepine:

EMANUELA FRATICELLI & PAOLA GIOVANARDI

ROSSI

Department of Child Neurology and Psychiatry, Neurological Institute, University of Bologna, ltaly Correspondence to: Antonia Parmeggiani, M.D., Department Institute, via Ugo Foscolo 7, 40123 Bologna, Italy.

of Child Neurology

and Psychiatry,

Neurological

Carbamazepine (CBZ) is an effective anticonvulsant agent. Currentliteraturereportsdescribeseveralcasesof seizureexacerbation and/or EEG worsening due to CBZ with a high prevalence in children and adolescents: we report 10 new cases. Nine patients had epilepsy; one showed delayed psychomotor development and frequent EEG paroxysmal abnormahties. Four patients were on monotherapy, six on polytherapy. All but one had therapeutic CBZ plasma concentrations. Seizures increased in frequency in nine, and in eight patients new seizure types appeared, mostly absences. Cognitive functions/behaviour worsened in eight; EEG recordings showed sIowingbackgroundactivity and increased paroxysmalabnormalities,in six cases diffuse/generalized spike waves were seen and in two continuous spike wave discharges. The meantime of clinical EEG worsening was l-2 days after introduction of CBZ at therapeutic doses. After CBZ withdrawal clinical EEG improvement was evident in a few days. The underlying pathogenetic mechanism is not yet understood. However, the pathophysiol-

ogy of seizureexacerbationmight be relatedto the interactionbetweenage-relatedalterationsin the balanceof excitation and inhibition discharges. Key

words:

in the developing

thalamocortical

circuitry

and the essential activity of CBZ that tends to induce interictal

epilepsy;epileptic seizures;carbamazepine; antiepilepticdrugs;EEG paroxysmalabnormalities;drug-induced

seizures.

INTRODUCTION Carbamazepine (CBZ) is a well-known antiepileptic drug effective in partial and generalized tonicclonic seizures. CBZ presentsan anticonvulsant profile mainly becauseit interacts with sodium channels blocking the high-frequency, repetitive firing of action potentials, but also acting on synaptic transmission and neurotransmitter receptors including possibly NMDA receptors’. CBZ may sometimesexacerbate epileptic seizures and EEG paroxysmal abnormalities as an adverse effect*. We describe 10 new cases, with the aim of discussingthe causesof the CBZ seizure exacerbation.

MATERIALS

AND METHODS

We retrospectively considered 10 patients (five males, five females), with a mean age of 10 years 4 months, a mean follow-up time from the first to the last observation of 3 years 7 months, observed in the Department of Child Neurology and Psychiatry of the Neurological Institute of the University of Bologna 1059-131 l/98/060479

+ 05 $12.0010

from 1993 to 1996. Nine presented an epilepsy classified according to the International Classification (1989)3 and one showeddelayed psychomotor development and abundant EEG paroxysmal abnormalities. All manifesteda worsened clinical EEG picture during treatment with CBZ. All patients were monitored for CBZ plasma concentrations during stable treatment. For each case we considered: seizures, EEG tracings, cognitive functionslbehaviour before, during and after CBZ withdrawal and associatedantiepileptic drugs; before and after CBZ suspension(Table 1). Mean age at onset of CBZ therapy was 5 years 4 months, ranging from 6 monthsto 12 years 2 months. RESULTS Five patients had symptomatic partial (cases2, 3, 5, 6, lo), two cryptogenic partial (cases4, 7), and two severe myoclonic epilepsy (cases8, 9). One patient had never had epileptic seizuresbut showeda delayed psychomotor development associatedwith frequent EEG paroxysmal abnormalities during wakefulness and sleep; for this reason he had been treated with Q 1998 British Epilepsy Association

14 yr 4 mth

20 yr 4 mth

8 Yr

2 yr 7 mth

7 yr 2 mth

I7 yr 7 mth

3 yr 8 mth

7 Yr 8 mth

I3 yr

2F

3M

JF

SM

6M

7F

8F

9F

IOM

and EEG

partial

partial

partial

panial

drugs; activity:

symptomatic epilepsy

CF/B: CSW:

partial

severe myoclonic epilepsy

severe mywlonic epilepsy

cryplogenic epilepsy

symptomatic epilepsy

symptomalic epilepsy

cryptogenic epilepsy

symptomatic partial epilepsy

symptomatic pnrtinl epilepsy

Epilepsy psychomotor speech d&y, PA

AED: antiepileptic BA: background

Age 7 yr

1: CBZ and epileptic

Sex IM

cases

Table

cognitive conrinuous

reported

IQ

IQ

severe

““d

generalization: VPA: valproic

MR

IQ

MR

MR

mild-moderaw MR

normal

SG: secondary carbamazepine:

hypsarrhyrhma. focal. diffuse PA

focal. diffuse PA+tPS

unknown

normal

borderline

unknown

mulrifocal. diffuse PA

delayed psychomotor development

IlOIlWl

moderate

profound

CF/B before CBZ delayed speech psychomotor development

cases

slowing BA. focal PA

slowing BA. multifocal. diffuse PA

fu”crions/behnviour: spike waves; CBZ:

infantile spasms. generalized. absences

generalized, partial. absences

partial. generalized

panialfSG

partial

partiulfSG

pmial. absences

focal. diffuse

panial+SG PA

multifocal. diffuse PA

EEG before CBZ unknown

personal

panialfSG

seizures

exacerbation:

Seizures before CBZ no epileptic

seizure

increased genewlized, partial. absences increased absences with atonia

increased partial. generalized. myoclonic, absences

increased absences. tonic-clonic

increased panial. absences

increased panialrtSG. absences

increased “tonic, absences

increased absences

increased absences. p&al. myoclonus

Seizures during CBZ absenses

PA,

BA.

slowing BA. increased focal, diffuse PA +IPs slowing BA. increased focal. diffuse, generalized PA

slowing EA. increased mulrifocal. diffuse, generalized PA slowing BA, multifocal. diffuse, generalized PA +IPs

slowing BA. focal, diffuse. generalized PA

slowing BA. increased multifocal. generalized PA slowing BA, increased focal. diffuse, generalized PA

slowing focal. diffuse csw

slowing BA. focal slow waves. increased PA

EEG during CBZ slowing BA. csw -

MR

MR

severe MR. hypersalivation

mild-moderate

normal IQ. somnolence

normnl IQ. irritability. somnolence

MR

delayed psychomotor developmem, irritability. hyperkinesia. aggressiveness borderline IQ. aggressiveness. hypersalivatio”

mild

moderate

CF/B during CBZ swech psychomotor delay. . arremion deficit disorder, hyperkinesia profound MR. somnolence

IPS: intermittent photic stimulation: MR: mental retardation; acid: ESM: erhosuximide; PRM: primidone: CLB: clobazam;

CBZ PB

CBZ

CBZ

CBZ

CBZ CLB VPA

CBZ PB VPA

CBZ VPA ESM

CBZ VPA

CBZ PRM ESM

AED CBZ

mre

PA

PA

focal, diffuse reduction

focal, diffuse reduction

PA reduction

normal

PA

PA

mulrifocal. diffuse PA reduction

normal

IlOlllXll

focal. diffuse reduction

no more slow WBVES. muldfocal. diffuse PA reduction

EEG after CBZ focal. diffuse reduction

MR

IQ

MR

abnornwlities;

severe

IQ

MR

MR

mild-moderate

mild

normal

borderline

improvement

improvement

moderaw

profound

CF/B after CBZ soeech d&w

IQ: intellective quotient: PA: paroxysmal LTG: lamotrigine; PB: phenobarbital.

frequency reduction, absences

frequency reduction partialfSG, new seizures disappearance frequency reduction partialiSG. new scizurcs disappearance frequency reduction. new seizures disappearance frequency reduction partirl+SG. new seizures disappearance frequency reduction partial. new seizures disappearance frequency reduction partial. new seizures disappearance frequency reduction partial. generulized. new seizures disappearance frequency reduction

Seizures after CBZ no seizures

MR

VPA PB

VPA

VPA

VPA CLB

VPA ESM CLB

VPA PB

VPA ESM LTG

VPA

PRM ESM CLB

AED VPA

?

Carbamazepine

seizure

exacerbation

481 Wakefulness

-w-

5opvL. I set

Case 4

9

6 yr

9 mth

27 September

Fig. 1: Case 4, EEG recording during CBZ therapy in wakefulness paroxysmal abnormalities and generalized spike wave discharges

CBZ before our first observation (case 1). Mean age at onset of epileptic seizures was 2 years 5 months (range: 4 months-10 years).

Before CBZ treatment

(Table 1)

One case had only partial seizures, four cases had partial seizures with and without secondary generalization, and the other four had different types of associated seizures (infantile spasms, atypical absences, partial, generalized). Mental retardation was evident in four cases, a borderline IQ in one, delayed psychomotor development in two and three were normal. EEG findings in three patients were unknown, two presented slowing background activity, and seven had focal, multifocal and diffuse paroxysmal abnormalities (one hypsarrhythmia).

During CBZ treatment

(Table 1)

CBZ was utilized in monotherapy in four patients (40%) and in polytherapy in six (60%) (ethosuximide, primidone, phenobarbital, valproic acid, clobazam). The mean time of new appearance (case 1) or worsening of seizures was l-2 days after CBZ introduction with therapeutic doses. All but one patient (low dosage) had CBZ therapeutic plasma concentrations (normal range in our laboratory 5-10 pg/ml) during CBZ stable treatment. Seizures increased in frequency in nine cases (90%) and in eight (80%) new types appeared: atonic, tonic, myoclonic, partial and, most frequently, typ-

1994

N.1431

NPIB

showing slowing background activity, corresponding to a clinical absence.

frequent

multifocal

ical/atypical absences (eight cases). In case 1 only typical absences developed. Four patients (40%) manifested a worsening of behaviour: hyperkinesia, attention deficit disorders, aggressiveness, three patients exhibited somnolence, two hypersalivation, one became mildly mentally retarded, and two were unchanged. EEG recordings during wakefulness and sleep showed in all cases slowing background activity, increased paroxysmal abnormalities in six, diffuse/generalized spike waves at 2-3 Hz in six which were not present before in four cases, and continuous spike waves in two (Fig. 1). After CBZ withdrawal

(Table 1)

Time of CBZ withdrawal ranged from 15 to 45 days. Clinical EEG improvement was evident a few days after CBZ doses were lowered. Reduction of epileptic seizure frequency was evident in nine cases (90%), the disappearance of new seizure types was seen in seven, and case 1 became seizure-free. There was also a behaviour improvement in seven cases (70%), cognitive functions improved in three (30%), and one case became mildly mentally retarded (case 8) during evolution because she had severe myoclonic epilepsy. Recovery of EEG background activity occurred in all, reduction in frequency and diffusion/generalization of paroxysmal abnormalities in seven cases (70%), three cases (30%) had a surprising normal EEG (Fig. 2), and continuous spike waves disappeared. After CBZ withdrawal four patients (40%)

abnormalities.

were on monotherapy (valproic acid) and six (60%) were on polytherapy (valproic acid, phenobarbital, ethosuximide, primidone, clobazam, lamotrigine).

tic doses, even if it was not possible to document this event quantitatively in all our cases as the effect of CBZ-10, 11-epoxide*. At present, there is no consensus on the mechanism by which CBZ may precipitate epileptic seizures and

DISCUSSION

generalized EEG paroxysmal

CBZ is widely used in children and adults as an effective antiepileptic drug’. Several cases of increased seizure frequency, onset of new seizure types and/or worsening of EEG recordings have been reported mainly in children and adolescents*. Our data concerning seizure exacerbation and EEG findings during CBZ treatment are in line with literature reports*, but, in addition, we have described one patient without epilepsy who started to have seizures after CBZ treatment. Only a few authors reported in detail cognitive functionslbehaviour variations during CBZ therapyH: sleepiness, confusion, hypersalivation and mental deterioration. These characteristics are in line with what we observed in our cases and were reversible after CBZ suspension, probably due to general clinical EEG worsening caused by CBZ. In our cases, monotherapy or polytherapy, plasma level concentration did not seem to influence seizure exacerbation. There is probably a correlation between clinical worsening and starting therapy with therapeu-

are only some clinical EEG indications to avoid CBZ therapy: epilepsies characterized by mixed seizure types and generalized spike wave discharges, i.e. multifocal severe epilepsies are particularly at high risk, but patients with any type of idiopathic generalized epilepsy are also at risk*, lo. Several experiments in rats and cats demonstrated that CBZ can abolish the prolonged electrical activity which may develop into seizures, but not the interictal discharges”, ‘* and increased duration of spike wave discharges in rodent absence models 13. Certainly, young age and particularly the developing brain seem to be the factors of greatest susceptibility in epileptogenicity, and also in determining the clinical and electrical manifestations of epileptic seizures and EEG findings. It is important to take into account the high susceptibility to developing absences and generalized spike wave discharges in patients with CBZ seizure exacerbation, because this type of seizure generally occurs more frequently in children and adolescents14* 1’. The mechanism must in some way be linked to synap-

abnormalities2v9. There

Carbamaxepine

seizure exacerbation

tic connections, balancing of the inhibitory and excitatory systems, and development and changes in neurotransmitter synthesis with age’* l6 and particularly, for absences and generalized spike waves, in developing thalamocortical circuitry15. The occurrence of the other seizure types (atonic, myoclonic, tonicclonic) is more difficult to explain, especially if we consider Lennox-Gastaut syndrome and severe myoclonic epilepsy, where different types of seizure are combined and particularly susceptible to CBZ seizure exacerbation”, 18. There are no animal models that explain the coexistence of different seizure types15. However, it is interesting to note that CBZ seizure exacerbation in these syndromes may change during evolution. In fact, in a series of patients with the two syndromes and a long-term follow-up, we demonstrated that CBZ may be utilized after a time. More focal clinical EEG characteristics due to complete cerebral maturation may offer the possibility of successfully utilizing the drug19.

ACKNOWLEDGEMENTS

We are grateful to MS Silvia Muzzi, Mr Massimo Armaroli, and MS Elena Zoni for technical assistance. We thank MS Anne Collins for linguistic revision.

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