Psychiatric Adverse Effects of Levetiracetam in Malignant Glioma Populations; a Retrospective Cohort Study
DOI:
https://doi.org/10.31584/jhsmr.2021814Keywords:
Drug-Related Side Effects and Adverse Reactions, glioma, levetiracetam, mental disordersAbstract
Objective: Levetiracetam is commonly used in malignant glioma populations because of its efficacy, limited drug-drug interactions and adverse effects. Although, there has been growing evidence of adverse neuropsychiatric side effects from levetiracetam; however, such evidence in malignant brain tumor settings is limited. Hence, we hypothesized that malignant glioma patients exposed to levetiracetam would also experience more adverse neuropsychiatric effects compared to patients not receiving this medication.
Material and Methods: A retrospective cohort analysis was conducted in 150 high grade malignant glioma patients at our Cleveland Clinic Cancer Center; from 2013-2014, comparing the accumulative adverse neuropsychiatric outcomes between patients who received levetiracetam and patients who did not (n=108 and 42, respectively). A sub-analysis of each specific neuropsychiatric side effect between these two groups was performed.
Results: Patients with malignant glioma receiving levetiracetam had increased risk of developing neuropsychiatric adverse effects compared to the non-levetiracetam group (odds ratio=2.08, p-value=0.040, 95% confidence interval=1.00-4.36). After adjusting for confounding factors, past psychiatric history and the interaction between seizure and levetiracetam use was significantly associated with neuropsychiatric problems. Delirium, psychosis, and irritability were more common in the levetiracetam group, and likely led to more psychiatric referrals, starting of psychotropic medications, and vitamin B6 use.
Conclusion: Incidence of neuropsychiatric presentations in malignant glioma patients was higher in the levetiracetam exposed group than the non-exposed group. The changes, or emergence of new neuropsychiatric behaviors should prompt clinicians to search for possible causes; including levetiracetam adverse effects, so they can be managed accordingly.
References
Kerkhof M, Vecht CJ. Seizure characteristics and prognostic factors of gliomas. Epilepsia 2013;54(Suppl 9):12-7.
Oushy S, Sillau SH, Ney DE, Damek DM, Youssef AS, Lillehei KO, et al. New-onset seizure during and after brain tumor excision: a risk assessment analysis. J Neurosurg 2018;128: 1713-8.
Maschio M. Brain Tumor-related epilepsy. Curr Neuropharmacol 2012;10:124-33.
Moots P, Maciunas R, Eisert D, Parker R, Laporte K, Abou-Khalil B. The course of seizure disorders in patients with malignant gliomas. Arch Neurol 1995;52:717-24.
Toledo M, Sarria-Estrada S, Quintana M, Maldonado X, Martinez-Ricarte F, Rodon J, et al. Epileptic features and survival in glioblastomas presenting with seizures. Epilepsy Res 2017;130:1-6.
Oberndorfer S, Piribauer M, Marosi C, Lahrmann H, Hitzenberger P, Grisold W. P450 enzyme inducing and non-enzyme inducing antiepileptics in glioblastoma patients treated with standard chemotherapy. J Neurooncol 2005;72:255-60.
Kerkhof M, Dielemans J, Breemen M, Zwinkels H, Walchenbach R, Taphoorn M, et al. Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme. Neuro Oncol 2013;15:961-70.
Vecht C, Royer-Perron L, Houillier C, Huberfeld G. Seizures and anticonvulsants in brain tumours: frequency, mechanisms and anti-epileptic management. Curr Pharm Des 2017;23:6464-87.
Kerrigan S, Grant R. Antiepileptic drugs for treating seizures in adults with brain tumours. Cochrane Database Syst 2011; CD008586.
Shi C, Lamba N, Zheng LJ, Cote D, Regestein QR, Liu CM, et al. Depression and survival of glioma patients: a systematic review and meta-analysis. Clin Neurol Neurosurg 2018;172: 8-19.
Rooney AG, Carson A, Grant R. Depression in cerebral glioma patients: a systematic review of observational studies. J Natl Cancer Inst 2011;103:61-76.
Song L, Quan X, Su L, Wang K, Wang H, Wu L, et al. Inflammation and behavioral symptoms in preoperational glioma patients: is depression, anxiety, and cognitive impairment related to markers of systemic inflammation?. Brain Behav 2020;10. doi: 10.1002/brb3.1771.
White J, Walczak T, Leppik I, Rarick J, Tran T, Beniak T, et al. Discontinuation of levetiracetam because of behavioral side effects: a case-control study. Neurology 2003;61:1218-21.
Wade J, Dang C, Nelson L, Wasserberger J. Emergent complications of the newer anticonvulsants. J Emerg Med 2010;38:231-70.
Alsaadi T, El Hammasi K, Shahrour TM. Does pyridoxine control behavioral symptoms in adult patients treated with levetiracetam? Case series from UAE. Epilepsy Behav Rep 2015;4:94-5.
Doi M, Takahashi F, Kawasaki Y. Bayesian noninferiority test for 2 binomial probabilities as the extension of Fisher exact test. Stat Med 2017;36:4789-803.
Nick TG, Campbell KM. Logistic regression. Methods Mol Biol 2007;404:273-301.
Chen B, Detyniecki K, Choi H, Hirsch L, Katz A, Legge A, et al. Psychiatric and behavioral side effects of anti-epileptic drugs in adolescents and children with epilepsy. Eur J Paediatr Neurol 2017;21:441-9.
Halma E, De Louw A, Klinkenberg S, Aldenkamp A, DM I, Majoie M. Behavioral side-effects of levetiracetam in children with epilepsy: a systematic review. Seizure 2014;23:685-91.
Maschio M, Dinapoli L, Sperati F, Pace A, Fabi A, Vidiri A, et al. Levetiracetam monotherapy in patients with brain tumor-related epilepsy: seizure control, safety, and quality of life. J Neurooncol 2011;104:205-14.
Usery J, Michael L, Sills A, Finch C. A prospective evaluation and literature review of levetiracetam use in patients with brain tumors and seizures. J Neurooncol 2010;99:251-60.
Belcastro V, Pisani LR, Bellocchi S, Casiraghi P, Gorgone G, Mula M, et al. Brain tumor location influences the onset of acute psychiatric adverse events of levetiracetam therapy: an observational study. J Neurol 2017;264:921-7.
Bedetti C, Romoli M, Maschio M, Di Bonaventura C, Nardi Cesarini E, Eusebi P, et al. Neuropsychiatric adverse events of antiepileptic drugs in brain tumour-related epilepsy: an Italian multicentre prospective observational study. Eur J Neurol 2017;24:1283-9.
Piedad J, Rickards H, Besag F, Cavanna A. Beneficial and adverse psychotropic effects of antiepileptic drugs in patients with epilepsy: a summary of prevalence, underlying mechanisms and data limitations. CNS Drugs 2012;26:319-35.
Cramer J, De Rue K, Devinsky O, Edrich P, Trimble M. A systematic review of the behavioral effects of levetiracetam in adults with epilepsy, cognitive disorders, or an anxiety disorder during clinical trials. Epilepsy Behav 2003;4:124-32.
Foley K, Bugg K. Separate episodes of delirium associated with levetiracetam and amiodarone treatment in an elderly woman. Am J Geriatr Pharmacother 2010;8:170-4.
Habets J, Leentjens A, Schijns O. Serious and reversible levetiracetam-induced psychiatric symptoms after resection of frontal low-grade glioma: two case histories. Br J Neurosurg 2017;31:471-3.
Hwang E, Siemianowski L, Sen S, Patel R. Levetiracetam: an unusual cause of delirium. Am J Ther 2014;21:225-8.
Molokwu O, Ezeala B, Adikaibe B, Onwuekwe I. Levetiracetaminduced rage and suicidality: two case reports and review of literature. Epilepsy Behav Case Rep 2015;4:79-81.
Downloads
Published
How to Cite
Issue
Section
License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
