Objectives: Liver transplant is currently the most effective option for patients with end-stage liver disease. Seizures are the most common neurologic complication after liver transplant. Posterior reversible encephalopathy syndrome is a neurologic syndrome characterized by lethargy, seizures, visual disturbances, and radiologic findings of edema in the posterior regions of the cerebral hemispheres. Levetiracetam is prescribed for a broad spectrum of seizure types but does not have a specific indication for epilepsy in children after solid-organ transplant. Our aim was to investigate the efficacy and tolerability of levetiracetam in pediatric transplant recipients with posterior reversible encephalopathy syndrome and epilepsy.
Materials and Methods: We reviewed records of patients treated for epilepsy due to posterior reversible encephalopathy syndrome after liver transplant seen at our pediatric neurology clinic between January 2010 and March 2019. Patients were assessed clinically and by neurologic examination, electroencephalography, and cerebral magnetic resonance imaging.
Results: Among 134 children who had undergone liver transplant between 2010 and 2019, 10 patients (6 males, 4 females; age range,7-19 y) who were diagnosed with posterior reversible encephalopathy syndrome and epilepsy were included in the study. All patients received levetiracetam at 20 mg/kg/day. After a mean follow-up of 28.9 months (range, 24-40 mo), 9 patients (90%) attained complete seizure freedom. One patient who had an underlying neurodegenerative disease (hemophagocytic syndrome) other than posterior reversible encephalopathy syndrome continued to have seizures under levetiracetam treatment. One patient had a mild adverse reaction (irritability) due to levetiracetam but did not require drug discontinuation.
Conclusions: In this study, 90% of patients with posterior reversible encephalopathy syndrome became seizure free with levetiracetam treatment. Our findings suggest that levetiracetam has a favorable efficacy for epilepsy due to posterior reversible encephalopathy syndrome in pediatric liver transplant recipients with tolerable adverse effects.
Key words : Antiepileptic drug, Neurologic complications, Seizure
Liver transplant (LT) has proven to be the most effective established procedure for children with irreversible liver failure. Although the perioperative management of LT has advanced during the past few decades, morbidity and mortality because of neurologic complications after transplant are still major issues.1 Seizures are the most common neurologic complication in children after LT. The causes of seizures after LT are usually multifactorial, including electrolyte and metabolic derangements, infections, and posterior reversible encephalopathy syndrome (PRES).2,3 Posterior leukoencephalopathy syndrome presents with clinical and radiologic features and includes symptoms such as encephalopathy, seizures, visual disturbances, and radiologic findings of bilateral gray and white matter edema in the posterior regions of the cerebral hemispheres.4,5
Because of the concomitant use of immunosuppressants, the choice of an antiepileptic drug for LT patients remains a considerable challenge. Levetiracetam is an effective and well-tolerated antiepileptic drug for adjunctive treatment of partial-onset seizure in children. Some studies have reported the safety and efficacy of levetiracetam in patients after LT.6,7 The purpose of this study was to investigate the efficacy of levetiracetam in children with PRES and epilepsy after LT.
Materials and Methods
In this retrospective single-center study, we reviewed the medical records of children who underwent LT at Baskent University (Ankara, Turkey) between January 2010 and March 2019. Patients treated with levetiracetam for epilepsy due to PRES after LT were included in the study. The diagnosis of PRES was made by the same pediatric neurologist according to radiologic findings (ie, hyperintensity in subcortical areas of the brain or in brainstem and cerebellum) and clinical presentation compatible with PRES, such as encephalopathy, seizures, and visual disturbances. Patients with cerebral infarction were excluded. Electroencephalographic (EEG) examinations were done for all patients, which were performed with electrodes placed according to the international 10-20 system. If seizure did not repeat and the results of the EEG were normal, levetiracetam was stopped in 12 to 30 months.
This retrospective study was approved by the ethics committee of our institutional review board, and the parents of all study participants provided written informed consent. Parameter frequencies, means, and medians were tabulated using descriptive statistics. Means between numerical parameters were compared using unpaired t test. Statistical analysis was done using SPSS software (SPSS: An IBM Company, version 21, IBM Corporation, Armonk, NY, USA).
Among 134 children who had LT between 2010 and 2019, 10 patients (13.4%) diagnosed with PRES and epilepsy were included in the study. The patients consisted of 6 boys and 4 girls (age range, 7 mo to 18 y; median age of 12.5 ± 0.46 y). Indications for LT were biliary atresia in 3 patients, progressive familial intrahepatic cholestasis in 2 patients, acute liver failure in 2 patients, unclassified in 2 patients, and Wilson disease in 1 patient. An EEG examination showed focal epileptic activity in 2 patients and generalized epileptic activity in 1 patient. All patients received levetiracetam at 20 mg/kg/day. After a mean follow-up of 28.9 months (range, 24-40 mo), 9 patients (90%) attained complete seizure freedom. One patient who had an underlying neurodegenerative disease (hemophagocytic syndrome) continued to have seizures under levetiracetam treatment. One patient had a mild adverse reaction (irritability) due to levetiracetam, but this did not require drug discontinuation. The demographic and clinical data of the 10 patients are summarized in Table 1.
Posterior reversible encephalopathy syndrome has been reported in 1% to 10% of pediatric LT recipients.3-5 In our study, the incidence of PRES associated with epilepsy was 13.4%. Immunosuppressive drugs such as tacrolimus and cyclosporine, hypertension, renal failure, and fluid retention have been reported to be causes of PRES. In our series, 7 patients were taking tacrolimus, 3 patients were taking cyclosporine, and 2 patients had hypertension at the time of their PRES episode. The 13.4% incidence of PRES in our study was higher than the previously reported incidence rates. This may be explained by the impact of the immunosuppressive agents and the underlying causes of liver disease.
The common symptoms noted during PRES episodes are seizures, altered mental status, visual symptomatology, and headache.2-5 Seizures are not only the most common neurologic symptom after LT but also the most common presenting symptom of PRES.7,8 The primary considerations to optimize antiepileptic treatment for LT patients include efficacy, safety and the tolerability profile, and pharmacologic interactions between antiepileptic drugs and immunosuppressive drugs. Generally, the older antiepileptic drugs such as phenytoin, phenobarbital, and carbamazepine have significant drug interactions with immunosuppressive agents.9 These drugs also have extensive hepatic metabolism, enzyme induction, and significant protein binding; because of the drug-drug interaction potential, these should be avoided in LT patients.10 For this reason, new antiepileptic drugs, including levetiracetam, gabapentin, pregabalin, and lacosamide, are drugs of choice for treatment of seizures in transplant recipients.
Levetiracetam is a new antiepileptic drug that was approved by the Food and Drug Administration for treatment of focal seizures in children. In this study, we described our experience with 10 children with diagnosis of PRES and epilepsy who were exposed to levetiracetam. To the best of our knowledge, this is the second study reporting results in a pediatric group of levetiracetam-treated LT patients beside the study by Kılıç and associates.7 In our study, we found a high response rate to levetiracetam treatment (90%). This high response rate is in line with results from studies in adults and children. In a study of 15 adult LT patients, Lin and colleagues reported that all patients remained seizure free during levetiracetam treatment.6 Kılıç and associates reported that 16 of 18 LT children who received levetiracetam for new-onset seizures remained seizure free. The authors also reported that, of 16 children who had remained seizure-free on levetiracetam, 3 had PRES.7
Levetiracetam has become one of the most frequently used antiepileptic drugs because of a favorable pharmacokinetic profile and a low incidence of adverse effects. The most commonly reported adverse effects at recommended dose include somnolence, dizziness, asthenia, nervousness, and irritability.11 In the present study, the only adverse event due to levetiracetam was irritability, which was observed in 1 patient.
This study does have limitations. One is the retrospective nature of the study. Second, this study was conducted at a single center and involved a relatively small group of patients.
Despite recent advances in immunosuppression and postoperative management, neurologic complications, including PRES and epilepsy, remain important problems after LT. However, our findings suggest that levetiracetam has a favorable efficacy for epilepsy due to PRES in children after LT with tolerable adverse effects.
Volume : 18
Issue : 1
Pages : 96 - 98
DOI : 10.6002/ect.TOND-TDTD2019.P34
From the 1Department of Pediatric Neurology, the 2Department of Pediatric
Gastroenterology, the 3Department of Transplantation, and the 4Department of
Anesthesiology, Başkent University, Ankara, Turkey
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Taner Sezer, Baskent University, Department of Pediatric Neurology, Yukarı Bahcelievler Mahallesi, Maraşel Fevzi Çakmak Caddesi, Ankara, Turkey
Phone: +90 312 2152114
Table 1. Demographic and Clinical Data of Study Patients