Electroencephalogram abnormality and high-dose busulfan in conditioning regimens for stem cell transplantation

Abstract

Summary: Patients and methodsBetween June 1989 and November 1996, a total of 22 High-dose busulfan (BU) is widely used in combined chemotherapy before allogeneic or autologous bone patients with various hematological malignancies or immunodeficiencies received allogeneic BMT (14 cases) or marrow transplantation. Convulsions are reported as a side-effect of high-dose BU. We recorded electroenceautologous peripheral blood stem cell transplants (eight cases) after preparation with high-dose BU (Table 1). Thirphalograms (EEGs) before and on the third day of BU administration in 22 patients. Abnormal EEGs were teen patients had acute lymphoblastic leukemia (ALL): eight were in first complete remission (CR) and five were observed on the third day in 13 cases (59%). These patients were older (P Ͻ Ͻ Ͻ 0.05) and had had larger doses in second CR. Five patients had acute non-lymphoblastic leukemia (ANLL): three were in first CR and two were of BU (P Ͻ Ͻ Ͻ 0.025) than the nine patients with normal EEGs. Convulsions occurred in two of the 22 patients, in second CR. Five patients had other diseases: two nonHodgkin's lymphoma (NHL), one Wiskott Aldrich synone of whom was receiving prophylaxis with phenytoin. Gamma aminobutyric acid (GABA), a natural mediator drome (WAS), and one chronic myelogenous leukemia (CML). of defense against epileptic activity, concentrations in cerebrospinal fluid measured before and after adminis-The conditioning regimen used consisted of BU given orally over 4 consecutive days, followed by cyclophostration of BU showed no definite changes. Keywords: busulfan; convulsion; electroencephalogram; phamide (CY) and/or other drugs. The dose of BU was 16 mg/kg in older children and 500 mg/m 2 in younger chil-GABA dren. Every patient except when otherwise stated received anticonvulsant prophylaxis with phenytoin (4 mg/kg intravenously as a loading dose followed by 4 mg/kg/day High-dose busulfan (BU) is increasingly used in conditionorally). Phenytoin administration was begun 12 h before the ing regimens for bone marrow transplantation (BMT).first dose of BU and continued until at least 24 h after the Liver dysfunction is reported as a side-effect of high-dose last dose. BU. Since the introduction of high-dose BU in conditioning EEGs were recorded before, and on the third day of BU regimens for bone marrow transplantation, several cases of administration and were evaluated by pediatric neurolconvulsions have been reported, especially in adults. [1][2][3][4][5][6] In ogists. The administration of BU and phenytoin, and schedthe literature, convulsion occurs in adults after the second ule for EEG recording are illustrated in Figure 1. GABA day of therapy, more frequently after the last dose of BU.concentrations in cerebrospinal fluid samples were measPhenytoin is usually given to adult patients receiving highured in 12 of 22 patients, four with normal EEGs and eight dose BU, but convulsions still occur after prophylaxis. In with abnormal EEGs before and on the third day of BU children, the acute neurotoxicity o...

Busulfan in Hematopoietic Stem Cell Transplantation

“…In adults, seizures typically occur in the 3 rd or 4 th day of Bu administration, probably as a result of drug accumulation [36,40-44] . Even without overt seizure activity EEG abnormalities can occur in up to 60% of patients [42] . Various anticonvulsant medications have been used for seizure prophylaxis including phenobarbital sodium, benzodiazepines (clonazepam, lorazepam) and phenytoin [41,42,45-47] .…”

“…Even without overt seizure activity EEG abnormalities can occur in up to 60% of patients [42] . Various anticonvulsant medications have been used for seizure prophylaxis including phenobarbital sodium, benzodiazepines (clonazepam, lorazepam) and phenytoin [41,42,45-47] . Phenytoin has been widely used for seizure prophylaxis in patients receiving Bu as part of the conditioning regimen due to its non-sedating properties.…”

Neurological complications after stem cell transplantation in childhood

“…However, two patients (cases 2 and 11) developed generalized seizure despite phenytoin prophylaxis. We have previously reported that patients receiving BU can show electroencephalogram (EEG) abnormalities without having clinical symptoms, 24 especially older children. Therefore, it may be necessary to monitor the serum concentration of BU and administer antiepileptics during the conditioning.…”

“…Indications for transplantation were acute lymphoblastic leukemia in 31 patients (14 in first complete remission: 1CR), acute myelogenous leukemia in 14 (nine in 1CR), aplastic anemia in nine, non-Hodgkin's lymphoma in seven, myelodysplastic syndrome in four, rhabdomyosarcoma in three, Wiscott-Aldrich syndrome in three, chronic myelogenous leukemia in two, juvenile chronic myelogenous leukemia, neuroblastoma, fibrosarcoma, and yolk sac tumor in one each. Fifty-nine patients received intrathecal methotrexate (MTX) and cytarabine (AraC), and five received cranial irradiation (20)(21)(22)(23)(24) as central nervous system (CNS) prophylaxis before transplantation. We conducted careful neurological examinations according to the protocol of Hokkaido University School of Medicine Department of Pediatrics.…”

Optimal Prevention of Seizures Induced by High‐Dose Busulfan

“…Also, electroencephalogram abnormalities have been reported in patients receiving busulfan who did not experience seizures, confirming its neurotoxic effects. [11][12][13][14] Busulfan freely crosses the blood-brain barrier to achieve significant concentrations in the central nervous system. Busulfan concentrations in the central nervous system are similar to plasma concentrations, which most likely accounts for the neurotoxicity seen with high-dose busulfan.…”