Pediatr Transplantation 2014: 18: 412–413

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Pediatric Transplantation DOI: 10.1111/petr.12249

Letter to the Editor Busulfan triggers epileptic seizures under levetiracetam and valproic acid therapy In a variety of conditioning regimens, busulfan (Bu) is frequently used for hematopoietic stem cell transplantation (HSCT). Bu crosses the blood–brain barrier and at high doses can cause severe neurotoxicity, including seizures that are most commonly tonic–clonic in character (1). Bu-induced seizures develop in 7.5% of children and 10% of adults if anticonvulsant prophylaxis is not given simultaneously (2). Phenytoin, benzodiazepines, or newer anticonvulsants such as levetiracetam (LVT) are often used for seizure prophylaxis (2, 3). Some authors believe that routine use of anticonvulsant prophylaxis in patients receiving Bu chemotherapy is an outdated clinical practice (4). We herein present a patient who developed seizures under antiepileptic treatment with LVT and valproic acid (VPA) after Bu therapy. A 16yr-old female with acute myeloblastic leukemia underwent myeloablative allogeneic peripheral blood stem cell transplantation from her HLA full-matched brother in first hematological remission. She was scheduled for a myeloablative conditioning regimen consisting of intravenous Bu (3.2 mg/kg/day on days 8 to 5) and cyclophosfamide with sodium 2-mercaptoethane sulphonate (MESNA) (60 mg/kg/day on days 3 to 2). She was epileptic since six yr and was receiving LVT and VPA at doses 13 mg/kg/day, 26 mg/kg/day subsequently. The standard phenytoin prophylaxis was not started because she had already been taking antiepileptic drugs and was seizure free for four months. Before beginning the conditioning chemotherapy regimen, pediatric neurology consultation was performed. As her electroencephalogram (EEG) showed generalized epileptic abnormality, LVT dose was increased up to 25 mg/kg/day. On day 8, the patient was given the first i.v. Bu dose. On the second day, she developed generalized tonic–clonic seizures, loss of consciousness, and urinary incontinence. Her vital signs were stable. Her neurological examination was unremarkable. 412

The seizure was treated with intravenous midazolam. Laboratory tests were normal for all parameters, and all cultures were negative. The neurological examination was repeated every day without any problem. VPA level was 79 pg/mL, within normal limits. Within 48 h, she developed seizures two more times. LVT doses were increased up to 40 mg/kg/day. After the antiepileptic drug management, the seizures gradually ceased and did not recur. Daily pharmacokinetic profile of Bu levels was not carried out. Busulfan crosses the blood–brain barrier and at high doses can cause severe neurotoxicity (1). Morgia et al. reported a case with prolonged EEG abnormalities up to one month after Bu administration (5). It is now a common practice to give anticonvulsant prophylaxis along with high-dose Bu therapy, but this practice should be reexamined in light of newer antiepileptic drugs. Phenytoin has been the preferred drug to treat busulfan-induced seizures. Several limitations exist to using phenytoin as short-term antiseizure prophylaxis. It has a prolonged half-life and may require a loading dose to be effective for shortterm prophylactic use. More importantly, phenytoin is a potent inducer of cytochrome P450 hepatic enzymes that leads to higher clearance of Bu. Hence, concomitant use of phenytoin with targeted area under curve Bu may lead to less overall Bu exposure than expected, and this may affect outcomes of the HSCT (2, 3, 6). Benzodiazepines (clonazepam, lorazepam) are also commonly used for seizure prophylaxis with Bu administration. These drugs have undesirable effects such as sedation, incoordination, and risk of respiratory depression, especially in small children (6, 7). LVT has favorable pharmacokinetic properties that make it ideal for short-term use. A short half-life allows therapeutic steady-state concentrations to be attained rapidly within 48 h of repeat dosing, and it maintains a predictable, linear, and dose-proportional steady-state pharma-

Letter to the Editor

cokinetics. LVT does not affect cytochrome P450 hepatic enzymes, which may allow better dose assurance of targeted Bu levels (3). The mechanism of action of LVT is distinct from that of other antiepileptic drugs, its main functional binding site in the brain being synaptic vesicle glycoprotein 2A, which is ubiquitous in the brain (8). To our knowledge, this is the first report of such triggered epilepsy under combined multiantiepileptic drugs after Bu administration. Although dose adjustment of LVT was not enough to control seizures in this patient, LVT can be a drug of choice during the Bu administration in HSCT. Conflict of interest

The authors declare that they have no conflict of interest. Arzu Yazal Erdem1, Fatih Azık1, Bet€ ul Tavil1, 2 1 Serap Teber , Bahattin Tuncß and Duygu Ucßkan1 1 Department of Pediatric Hematology Oncology, Ankara Pediatric & Pediatric Hematology Oncology Training and Research Hospital, Ankara, Turkey, 2Department of Pediatric Neurology, Ankara Pediatric & Pediatric Hematology Oncology Training and Research Hospital, Ankara, Turkey E-mail: [email protected]

References 1. EBERLY AL, ANDERSON GD, BUBALO JS, MCCUNE JS. Optimal prevention of seizures induced by high-dose busulfan. Pharmacotherapy 2008: 28: 1502–1510. 2. CHAN KW, MULLEN CA, WORTH LL, et al. Lorazepam for seizure prophylaxis during high-dose busulfan administration. Bone Marrow Transplant 2002: 29: 963–965. 3. SONI S, SKEENS M, TERMUHLEN AM, BAJWA RP, GROSS TG, PAI V. Levetiracetam for busulfan-induced seizure prophylaxis in children undergoing hematopoietic stem cell transplantation. Pediatr Blood Cancer 2012: 59: 762–764. € 4. RUIZ-ARGUELLES GJ, GOMEZ-ALMAGUER D, STEENSMA DP. Outdated dogma? Busulfan, seizure prophylaxis, and stem cell allografting. Am J Hematol 2012: 87: 941. 5. La MORGIA C, MONDINI S, GUARINO M, BONIFAZI F, CIRIGNOTTA F. Busulfan neurotoxicity and EEG abnormalities: A case report. Neurol Sci 2004: 25: 95–97. € 6. INCECIK F, HERGUNER MO, ALTUNBASAK S. The efficacy and side effects of levetiracetam on refractory epilepsy in children. J Pediatr Neurosci 2012: 7: 19–22. 7. HAMIDIEH AA, HAMEDANI R, HADJIBABAIE M, AMINI M, SADRAI S, GHAVAMZADEH A. Oral lorazepam prevents seizure during high-dose busulfan in children undergoing hematopoietic stem cell transplantation: A prospective study. Pediatr Hematol Oncol 2010: 27: 529–533. 8. LYNCH BA, LAMBENG N, NOCKA K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA 2004: 101: 9861– 9866.

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Busulfan triggers epileptic seizures under levetiracetam and valproic acid therapy.

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