Clinical Commentary

Encephalopathy induced by levetiracetamadded to valproate

Introduction

Levetiracetam (LEV), a new antiepileptic drug(AED), is available in Germany since 2000. Com-monly reported side effects are tiredness, sleepdisturbance or aggression. We recently observedthe manifestation of a LEV-induced encephalopa-thy in a patient treated with valproate (VPA).

Case report

A 28-year-old man suffering from idiopathic epi-lepsy with myoclonic-impulsive and generalizedtonic–clonic seizures was investigated in February2007. He reported about an increased frequency ofgeneralized tonic–clonic seizures and claimed oncognitive impairment.Onset of epilepsy was at the age of 17. We

investigated the patient in 1996 and registered anelectroencephalogram (EEG) with 9 per secondalpha rhythm and 3 per second generalized spike-and-wave discharges (not shown). Treatment withVPA was started and increased to 2000 mg ⁄day.Myoclonic seizures ceased, generalized tonic–clonic seizures manifested one to four times a year.In early 2006 an external neurologist added

LEV to VPA (2000 mg) and increased the dailydosage of LEV stepwise to 3000 mg. Quite

instantly, seizure frequency increased to twotonic–clonic seizures per month. LEV was reducedto 2000 mg, seizure frequency remained high.In February, 2007, the interictal EEG showed a

generalized slowing to 5 per second theta rhythmswith bilateral generalized high-amplitude dis-charges. Serum concentrations of AED were74.6 lg ⁄ml for VPA and 15 lg ⁄ml for LEV.Routine haematological and biochemical labora-tory screening was non-contributory. Neuropsy-chological testing showed impaired word fluency,psychomotor speed and working memory.LEV was tapered and lamotrigine (200 mg) was

added to VPA. The patient remained free fromseizures until the last visit in June 2007. At thatpoint of time the interictal EEG showed occipitalalpha activity and short paroxysms of bilateralgeneralized spike-and-wave discharges (Fig. 1B).The patient no longer complained of cognitiveimpairment.

Discussion

Encephalopathy induced by AED has beendescribed in patients treated with VPA, less oftenwith carbamazepine, phenytoin and vigabatrin andrecently in two patients treated with VPA andtopiramate (TPM) (1, 2). Typical findings are an

Acta Neurol Scand 2008: 117: 374–376 DOI: 10.1111/j.1600-0404.2007.00974.x Copyright � 2007 The AuthorJournal compilation � 2007 Blackwell Munksgaard

ACTA NEUROLOGICASCANDINAVICA

Bauer J. Encephalopathy induced by levetiracetam added to valproate.Acta Neurol Scand 2008: 117: 374–376.� 2007 The Author Journal compilation � 2007 Blackwell Munksgaard.

Background – We report on the manifestation of a levetiracetam(LEV)-induced encephalopathy. Findings – A 28-year-old mansuffering from idiopathic epilepsy with generalized seizures was treatedwith LEV (3000 mg) added to valproate (VPA) (2000 mg). Frequencyof generalized tonic-clonic seizures increased from one per 6 months totwo per month. Neuropsychological testing showed impaired wordfluency, psychomotor speed and working memory. The interictalelectroencephalogram (EEG) showed a generalized slowing to 5 persecond theta rhythms with bilateral generalized high-amplitudedischarges. Outcome – Following discontinuation of LEV, EEG andneuropsychological findings improved and seizure frequencydecreased.

J. BauerDepartment of Epileptology, Bonn University Hospital,Germany

Key words: epilepsy; valproate; levetiracetam;encephalopathy

J�rgen Bauer, Department of Epileptology, Bonn Uni-versity Hospital, Sigmund Freud Str. 25, D-53105 Bonn,GermanyTel.: 0049-228-287-16954Fax: 0049-228-287-14486e-mail: juergen.bauer@ukb.uni-bonn.de

Accepted for publication November 12, 2007

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increase in seizure frequency and a general slowingof EEG background activity (3–5). The patientreported here showed such clinical and EEG signs

which started simultaneously with the treatmentwhen LEV was added to VPA and ceased afterdiscontinuation of LEV.

Montage: Ear-Reference, 7µV/mm, 0.3 s, 70 Hz, Time line interval: 1.0 s

FP2-A2

FP1-A1

F4-A2

F3-A1

C4-A2

C3-A1

P4-A 2

P3-A 1

O2-A2

O1-A1

F8-A2

F7-A1

T2-A2

T1-A1

T4-A2

T3-A1

T6-A2

T5-A1

ECG

Date: 2007-02-02 Routine EEG

Date: 2007-06-12 Routine EEG

Montage: Ear-Reference, 7µV/mm, 0.3 s, 70 Hz, Time line interval: 1.0 s

FP2-A2

FP1-A1

F4-A2

F3-A1

C4-A2

C3-A1

P4-A 2

P3-A 1

O2-A2

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ECG

A

B

Figure 1. (A) Generalized slowing in the interictal electroencephalogram during encephalopathy. (B) Alpha rhythm with a gener-alized spike-wave discharge following discontinuation of levetiracetam.

Levetiracetam-induced encephalopathy

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It is debatable if LEV itself or the co-medicationwith VPA caused the encephalopathy. Hamer et al.(2) described two patients in whom TPM added toVPA induced encephalopathy. The authors con-cluded that TPM facilitated the toxic effect of VPAand contributed to a hyperammonemic encepha-lopathy because VPA was tolerated as add-ontreatment with other AED. One of their patientsrecovered following the decrease of VPA and theother one after discontinuation of TPM. In aprevious study VPA was added to other AED andcaused stupor which stopped after discontinuationof one of the other AED (6).We did not measure the serum ammonia con-

centrations. However, VPA-induced encephalopa-thy is not always related to an increase ofammonium (4, 5). There is no clinically relevantpharmacological interaction between VPA andLEV. LEV is a renally eliminated drug, whereasVPA inhibits cytochrome P450 liver enzymes.Studies on serum LEV concentrations showedincreased levels in patients treated with VPA (7).Coming back to this case report we are not able

to give a final explanation of the pathophysiolog-

ical mechanisms of the observed encephalopathy.The relatively high dosage of both AED is mostprobably not its cause. Possibly, LEV is able toprovoke encephalopathy when added to VPA.Interestingly, the add-on treatment with lamotri-gine was well tolerated.

References

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2. Hamer HM, Knake S, Schomburg U, Rosenow F. Valproate-induced hyperammonemic encephalopathy in the presenceof topiramate. Neurology 2000;54:230–2.

3. Bauer J, Elger CE. Valproate-associated encephalopathy(in German). Aktuel Neurol 1993;20:16–21.

4. Pakalnis A, Drake ME, Denio L. Valproate-associatedencephalopathy. J Epilepsy 1989;2:41–4.

5. Rangel RJ, Warner JJ, Wilder BJ. Valproic acid encepha-lopathy. J Epilepsy 1988;1:197–202.

6. Sackellares JC, Lee SI, Dreifuß FE. Stupor followingadministration of valproic acid to patients receiving otherantiepileptic drugs. Epilepsia 1979;20:679–703.

7. May TW, Rambeck B, Jurgens U. Serum concentrations oflevetiracetam in epileptic patients: the influence of dose andco-medication. Ther Drug Monit 2003;25:690–9.

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