Levetiracetam Induces a Rapid and Sustained Reduction of Generalized Spike-Wave and Clinical Absence

OBSERVATION Levetiracetam Induces a Rapid and Sustained Reduction of Generalized Spike-Wave and Clinical Absence

Jennifer Cavitt, MD; Michael Privitera, MD

Background: Levetiracetam (LEV) is a new antiepilep- Results: Spike-wave bursts increased from 4 to 56 per hour tic drug with efficacy in partial-onset seizures. We re- at baseline (4000 mg of LEV per day) to 406 to 914 per port a case in which generalized-onset absence seizures hour less than 48 hours after LEV discontinuation. Leve- responded clinically and electrographically to LEV. tiracetam treatment was restarted, and 3 hours after the first dose of 1000 mg, spike-wave bursts dropped to 135 Methods: We evaluated with continuous video/ per hour. Response was sustained during the next 2 days. electroencephalography an adult with generalized-onset seizures given 3 antiepileptic drugs, 1 of which was LEV. Le- Conclusions: This case showed a dramatic, rapid vetiracetam initiation 2 months before admission decreased effect of LEV discontinuation and reinstitution on gen- patient-reported seizures. Interictal electroencephalogra- eralized spike-wave burst frequency and clinical phy revealed generalized 3.5-Hz spike-wave and polyspike- absence. The effects were independent of reduction of wave discharges. Spike-wave bursts lasting 2 seconds or lamotrigine and without change in topiramate doses longer caused a pause in continuous reading aloud, con- and occurred in a time course consistent with LEV sistent with clinical absence seizures. Levetiracetam was pharmacokinetics. Levetiracetam may be effective in discontinued on admission, lamotrigine was gradually dis- generalized-onset epilepsy, and randomized, con- continued across 2 days, and topiramate was not changed. trolled trials are indicated. One encephalographer counted from video/electroencephalography recordings the number of spike-wave bursts in 1-hour time samples that included wake and sleep time. Arch Neurol. 2004;61:1604-1607

EVETIRACETAM (LEV) IS AN METHODS antiepileptic drug ap- proved in many countries for A 34-year-old woman with medication- use in patients with partial- resistant seizures since early childhood was ad- onset seizures. Although mitted to the Epilepsy Monitoring Unit at Uni- randomized,L double-blind, controlled versity of Cincinnati Hospital. She had a single, clinical trials have focused on patients with simple febrile seizure at age 18 months. Shortly partial-onset epilepsy,1-3 preliminary evi- after that, she began having frequent unpro- dence suggests LEV may also have an effect voked generalized tonic-clonic–type seizures, as on primary generalized seizure types as well as 2 other seizure types. Inpatient video/ 4-14 EEG monitoring at another epilepsy center in well. Animal studies in genetic models 1999 demonstrated generalized 4- to 5-Hz spike- of epilepsy and small open-label or single- wave discharges during clinical seizures, lead- blind trials in humans indicate LEV may ing to the diagnosis of atypical juvenile myo- reduce the frequency of generalized- clonic epilepsy. The patient described her typical onset seizures, but no randomized, con- seizures as being similar in character since early trolled trials have studied this. In addi- childhood. She reported that staring episodes tion, there is little published information lasting 3 to 7 seconds without postictal confu- regarding the effect of LEV on epilepti- sion were occurring 10 to 25 times per day, and form discharges on electroencephalogra- generalized tonic-clonic seizures were occur- phy (EEG).15-17 We evaluated with video/ ring 4 times per month. The patient reported that once or twice a month she experienced star- Author Affiliations: The EEG a patient with generalized absence– ing spells lasting 20 seconds to 2 minutes with Neuroscience Institute, type seizures who showed a dramatic moaning and some postictal confusion. Department of Neurology, response of generalized spike-wave burst Initiation of treatment with LEV and titra- University of Cincinnati, frequency and clinical absence to the dis- tion to 4000 mg per day 2 months prior to ad- Cincinnati, Ohio. continuation and then reinstitution of LEV. mission had resulted in a marked decrease in

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Prior to Drug Admission Day 1 Day 2 Day 3 Day 4 Day 5

LEV 4000 Discontinued upon admission 1000 (at 4 PM) 2000 3000 4000 (after 2000 mg morning dose at home) LTG 400 (level = 100 (at 9 AM, then discontinued) None None (level None None 3.9 µg/mL) Ͻ1.0 µg/mL) TPM 150 150 150 150 150 150 VPA NA NA NA NA 500 (at 6 PM) 500 (first dose at 8 AM)

Abbreviations: NA, not applicable; LEV, levetiracetam; LTG, lamotrigine; TPM, topiramate; VPA, valproic acid. *Data are presented as mg/d. Each hospital day represents a consecutive 24-hour period starting at 6 PM on January 2, 2002. Discharge on day 5, January 7, 2002, occurred at 11 AM.

ECG ECG F3-C3 F3-C3 C3-P3 C3-P3 P3-O1 P3-O1 FP2-F4 FP2-F4 F4-C4 F4-C4 C4-P4 C4-P4 P4-O2 P4-O2 FP1-F7 FP1-F7 F7-T3 F7-T3 T3-T5 T3-T5 T5-O1 T5-O1 FP2-F8 FP2-F8 F8-T4 F8-T4 T4-T6 T4-T6 T6-O2 T6-O2

Reading Pause Reading Pause Reading Reading Pause Reading

Figure 1. Spike-wave bursts correlate with pauses in continuous reading aloud.

patient-reported seizures. Treatment with lamotrigine (LTG) or longer (20 times in 4 minutes and 15 seconds) caused a de- for more than 8 months prior to admission had produced a mod- tectable pause (losing her place) in continuous reading aloud est reduction in patient-reported seizures. On admission, her (Figure 1), suggestive of absence seizures. One encephalog- LTG dose was 600 mg/d with a level of 3.9 µg/mL. Topiramate rapher counted from video/EEG recordings and hard copy EEG (TPM) therapy, 150 mg/d, was already in the process of being printouts the number of spike-wave bursts in 1-hour time slowly discontinued owing to intolerable adverse effects with samples that included both wake and sleep time. Of 1320 spike- doses of up to 400 mg/d. A previous trial of valproic acid years wave bursts analyzed, 75% lasted 2 seconds or longer. before had produced “the best” seizure control according to the patient, but it also caused intolerable nausea, vomiting, and di- arrhea. Renal and hepatic function were normal. Interictal EEG RESULTS showed generalized 3.5-Hz spike-wave and polyspike-wave discharges with bifrontal predominance; intermittent polymor- phic delta activity was also seen over the left temporal region. Spike-wave bursts occurred 4 to 56 times per hour dur- Magnetic resonance imaging showed slightly decreased vol- ing the first 36 hours. The frequency of spike-wave bursts ume and slightly increased signal in the right hippocampus com- increased to 406 to 914 per hour between 37 and 47 hours pared with the left, although several images were limited ow- after LEV discontinuation (Figure 2). During this pe- ing to motion artifact. Full scale IQ was in the borderline range. riod, approximately 50% of the EEG findings were spike- The patient was monitored with continuous video/EEG from wave bursts. The first dose of 1000 mg of LEV was given January 2, 2002, at 6 PM, to January 7, 2002, at 11 AM. Leveti- at 4 PM on January 4, 2002, and the EEG analysis at 7 PM racetam therapy was discontinued on admission (last dose, Janu- showed 135 spike-wave bursts per hour. A continued de- ary 2, 2002, before 12 PM), LTG therapy was gradually discontinued across 2 days, and TPM therapy was not changed (Table). crease to 30 to 126 per hour was seen during the next 2 No generalized tonic-clonic seizures and none with the longer days, as the daily dose of LEV (but not LTG) was in- staring spells and moaning were observed. Numerous absence- creased back to 100% of the baseline (maximum) dose. type seizures were the only seizures captured on video/EEG. Just prior to discharge, a retrial of valproic acid was Generalized spike-wave bursts consistently lasting 2 seconds initiated, despite the history of intolerable adverse ef-

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1000 100

900 Levetiracetam 90 Lamotrigine 800 Topiramate 80

700 70 % of Maximum Dose

600 60

500 50

400 40 No. of Spike-Wave Bursts per Hour No. of Spike-Wave

300 30

200 20

100 10

0 0

PM PM AM PM AM PM PM PM AM PM AM PM AM AM 7:45 9:40 11:30 2:11 9:19 2:30 4:00 7:00 9:00 6:00 6:15 4:00 12:30 5:00 January 2, 2002 January 3, 2002 January 4, 2002 January 5, 2002 January 6, 2002 January 7, 2002

Date and Time

Figure 2. Changes in spike-wave frequency and antiepileptic drug doses during hospitalization.

fects with this medication, based on the history of best tion predict that LEV should have been almost totally seizure control with valproic acid. At 1-month and cleared from the blood by 30 to 40 hours.18 The highest 8-month follow-up visits on valproic acid and LEV, no spike rate was at 37 to 47 hours after LEV discontinua- quantitative reduction in seizure frequency was seen in tion, which would correspond to the predicted trough patient seizure count reports. However, the patient and of LEV level. Levetiracetam peak effect is seen at 1 hour, her family did report an increased awareness of absence and we began seeing reduction of spike-wave bursts by seizures following evaluation in the epilepsy monitor- 3 hours. ing unit. Therefore, it is unclear whether this represents Our patient clearly has absence-type seizures, based a true increase in absence seizures or just an increase in on clinical and electrographic criteria. However, her age reporting. No intolerable adverse effects were reported at onset, clinical manifestation, and other seizure types following initiation of valproic acid therapy. do not correlate well with a known epilepsy syndrome. Based on the history and prolonged video/EEG results, COMMENT she most likely has an unspecified generalized epilepsy. This analysis of generalized spike-wave frequency as a This single case showed a dramatic, rapid effect of LEV function of time and maximum LEV dose provides evi- discontinuation and reinstitution on generalized spike- dence that in this patient LEV dramatically reduced ab- wave burst frequency and clinical absence. This effect oc- sence seizures in the acute setting. Accurate assessment curred independently of reduction of LTG and without of long-term absence seizure control was confounded by change in TPM doses, both of which are effective in gen- our inability to accurately count absence seizures as we eralized-onset seizures. Lamotrigine likely also affected could with simultaneous video/EEG monitoring. Given this patient’s baseline seizure control because the spike- wave burst frequency decreased to an intermediate level the problems with self-reporting of absence-type sei- (30-126/h) with restarting LEV and without restarting zures, quantifying seizure frequency with video/EEG in LTG. This represents more bursts than the baseline 4 to the epilepsy monitoring unit provides more reliable 56 per hour while on LEV, LTG, and TPM but fewer than documentation of clinical response in this patient, al- 19 the 406 to 914 per hour seen with discontinuing both beit during a very short period. Although the ability to LEV and LTG (TPM alone). The time course of these EEG generalize from single case studies is limited, this case changes appears to correlate with the expected pharma- suggests LEV may be effective in generalized-onset epi- cokinetics of LEV. The half-life of LEV is 6 to 8 hours. lepsy and, more specifically, in absence-type seizures. Levetiracetam levels were not obtained, but renal elimi- Thus, further study with randomized, controlled trials nation kinetics in a young patient with normal renal func- is indicated.

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Accepted for Publication: January 7, 2004. a novel antiepileptic drug, on convulsant activity in two genetic rat models of Correspondence: Michael Privitera, MD, The Neurosci- epilepsy. Epilepsy Res. 1995;22:207-213. 5. Grant R, Shorvon SD. Efficacy and tolerability of 1000-4000 mg per day of le- ence Institute, Department of Neurology, University of vetiracetam as add-on therapy in patients with refractory epilepsy. Epilepsy Res. Cincinnati, Medical Sciences Building ML 0525, 231 Al- 2000;42:89-95. bert Sabin Way, Cincinnati, OH 45267 (michael.privitera 6. Greenhill L, Betts T, Yarrow H. Effect of levetiracetam on resistant juvenile myo- @uc.edu). clonic epilepsy [abstract]. Seizure. 2002;11:531. Author Contributions: Study concept and design: Cavitt 7. Klitgaard H, Matagne A, Gobert J, Wulfert E. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. Eur J Pharmacol. 1998; and Privitera. Acquisition of data: Cavitt and Privitera. 353:191-206. Analysis and interpretation of data: Cavitt and Privitera. 8. Krakow K, Walker M, Otoul C, Sander JW. Long-term continuation of leveti- Drafting of the manuscript: Cavitt and Privitera. Critical racetam in patients with refractory epilepsy. Neurology. 2001;56:1772-1774. revision of the manuscript for important intellectual con- 9. Löscher W, Honack D. Profile of ucb L059, a novel anticonvulsant drug, in mod- tent: Cavitt and Privitera. Obtained funding: Cavitt and els of partial and generalized epilepsy in mice and rats. Eur J Pharmacol. 1993; 232:147-158. Privitera. Administrative, technical, and material support: 10. Wheless JW, Ng Y. Levetiracetam in refractory pediatric epilepsy. J Child Neurol. Cavitt and Privitera. Study supervision: Cavitt and Privi- 2002;17:413-415. tera. 11. Cohen J. Levetiracetam monotherapy for primary generalized epilepsy. Seizure. Funding/Support: This study was supported by an edu- 2003;12:150-153. cational grant from UCB Pharma Inc, Smyrna, Ga. 12. Abou-Khalil B, Hemdal P, Privitera MD. An open-label study of levetiracetam at individualized doses between 1000 and 3000 mg/day in adult patients with re- Acknowledgment: The authors would like to thank Nicole fractory epilepsy. Seizure. 2003;12:141-149. Bauer of The Neuroscience Institute, Cincinnati, Ohio, 13. Betts T, Yarrow H, Greenhill L, Barrett M. Clinical experience of marketed leve- for help in preparation of the figures. tiracetam in an epilepsy clinic: a one year follow up study. Seizure. 2003;12: 136-140. 14. Ben-Menachem E, Gilland E. Efficacy and tolerability of levetiracetam during 1-year REFERENCES follow-up in patients with refractory epilepsy. Seizure. 2003;12:131-135. 15. Betts T, Greenhill L. Effect of levetiracetam on photoparoxysmal responses (PPR) 1. Ben-Menachem E, Falter U; European Levetiracetam Study Group. Efficacy and in the EEG [abstract]. Seizure. 2002;11:531. tolerability of levetiracetam 3000 mg/d in patients with refractory partial sei- 16. Kasteleijn-Nolst Trenite DGA, Marescaux C, Stodieck S, Edelbroek PM, Oosting zures: a multicenter, double-blind, responder-selected study evaluating J. Photosensitive epilepsy: a model to study the effects of antiepileptic drugs: monotherapy. Epilepsia. 2000;41:1276-1283. evaluation of the piracetam analogue, levetiracetam. Epilepsy Res. 1996;25: 2. Cereghino JJ, Biton V, Abou-Khalil B, Dreifuss F, Gauer LJ, Leppik I; United States 225-230. Levetiracetam Study Group. Levetiracetam for partial seizures: results of a double- 17. Stodieck S, Steinhoff BJ, Kolmsee S, van Rijckevorsel K. Effect of levetiracetam blind, randomized clinical trial. Neurology. 2000;55:236-242. in patients with epilepsy and interictal epileptiform discharges. Seizure. 2001; 3. Shorvon SD, Lowenthal A, Janz D, Bielen E, Loiseau P; European Levetiracetam 10:583-587. Study Group. Multicenter double-blind, randomized, placebo-controlled trial of 18. UCB Pharma Inc. Keppra: Prescribing Information (Levetiracetam). Smyrna, Ga: levetiracetam as add-on therapy in patients with refractory partial seizures. Epilepsia. UCB Pharma Inc; 2002. 2000;41:1179-1186. 19. Browne TR, Dreifuss FE, Penry JK, Porter RJ, White BG. Clinical and EEG esti- 4. Gower AJ, Hirsch E, Boehrer A, Noyer M, Marescaux C. Effects of levetiracetam, mates of absence seizure frequency. Arch Neurol. 1983;40:469-472.

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