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

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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 sei- zures 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/electroencepha- lography 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- Lrandomized, 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 (REPRINTED) ARCH NEUROL / VOL 61, OCT 2004 WWW.ARCHNEUROL.COM 1604 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Table. Preadmission and Postadmission Antiepileptic Drug Dosing by Hospital Day* 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 dis- charges 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 discon- tinued 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- (REPRINTED) ARCH NEUROL / VOL 61, OCT 2004 WWW.ARCHNEUROL.COM 1605 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 1100 110 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.
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