Epilepsy in glioma patients: mechanisms, management, and impact of anticonvulsant therapy

Neuro-Oncology Neuro-Oncology 18(6), 779– 789, 2016 doi:10.1093/neuonc/nov269 Advance Access date 2 November 2015 Epilepsy in glioma patients: mechanisms, management, and impact of anticonvulsant therapy Terri S. Armstrong, Robin Grant, Mark R. Gilbert, Jong Woo Lee, and Andrew D. Norden Corresponding Author: Terri S. Armstrong, PhD, ANP-BC, FAAN, FAANP, Room 577, 6901 Bertner Ave, Houston, TX 77030 (). Seizures are a well-recognized symptom of primary brain tumors, and anticonvulsant use is common. This paper provides an overview of epilepsy and the use of anticonvulsants in glioma patients. Overall incidence and mechanisms of epileptogenesis are reviewed. Factors to consider with the use of antiepileptic drugs (AEDs) including incidence during the disease trajectory and prophylaxis along with considerations in the selection of anticonvulsant use (ie, potential side effects, drug interactions, adverse effects, and impact on survival) are also reviewed. Finally, areas for future research and exploring the pathophysiology and use of AEDs in this population are also discussed. Keywords: anticonvulsant, epilepsy, glioma, seizure. Seizures are a well-recognized symptom of primary brain tumors, and they can occur at any point along the illness trajectory. Seizures often herald the diagnosis or progression but can also occur in patients when there is no evidence of tumor growth. Although the underlying pathophysiology is not well understood, seizures may be provoked by a variety of factors including the impact of the tumor cells on peritumoral cortex, brain edema, increased intracranial pressure, metabolic derangements related to treatment, comorbid conditions, intercurrent illness, or medication. The incidence of seizures is higher in patients with slowgrowing tumors compared with more rapidly growing tumors. Low-grade glioma patients who present with seizures in the absence of neurologic deficits have favorable survival outcomes,1 presumably because their tumors are slower growing and are more likely to have IDH1/2 mutations.2 Overall, the incidence of seizures in patients with low-grade tumors is estimated to be between 70% and 90%. Seizures are more common in oligodendrogliomas than astrocytomas3 and occur less frequently in older patients (aged ≥50 –60 y).4 In patients with glioblastoma (GBM), the incidence has been reported to be between 30% and 62%, with two-thirds of seizures occurring at presentation and one third during the course of the disease;5 – 7 however, a recent report noted a higher incidence during the follow-up period (48%).4 Seizures are most commonly associated with tumors of the frontal, temporal, and parietal lobes and are not typically observed with tumors of the deep structures, brainstem, or cerebellum. Brain tumor-related seizures may be focal seizures with or without altered awareness, generalized tonic-clonic seizures, or focal seizures with secondary generalization. Focal seizures occur in nearly 40% of patients with GBM, with 40% of these patients then experiencing secondary generalized seizures.5 Nearly a quarter of patients have both focal and generalized seizures, and status epilepticus has been reported in more than 10% of patients.5,8 In a recent series, 76% of GBM patients were seizure-free before surgery as compared with 77% –92% after surgery. Seizure control seems to be directly proportional to the extent of resection.5,9 In particular, gross total resection in patients with low-grade gliomas is associated with a higher rate of seizure control.10,11 Seizure recurrence or worsening seizure control may be associated with tumor progression following first-line treatment.8 Interestingly, both radiation therapy and use of temozolomide are associated with reduction of seizure frequency,12 especially in those with low-grade glioma.11,13 Prolonged seizure control is Received 1 August 2015; accepted 1 October 2015 # The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: . 779 Department of Family Health, University of Texas Health Science Center at Houston, Houston, Texas (T.S.A.); Edinburgh Centre for Neuro-Oncology, Edinburgh, UK (R.G.); Neuro-Oncology Branch, National Cancer Institute and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (M.R.G.); Division of EEG and Epilepsy, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts (J.W.L.); Center for Neuro-Oncology, Dana-Farber Cancer Institute; Division of Cancer Neurology, Department of Neurology, Brigham and Women’s Hospital; and Harvard Medical School, Boston, Massachusetts (A.D.N.) Armstrong et al.: Epilepsy in glioma patients associated with improved functional status, whereas drugresistant epilepsy has a negative impact on quality of life and neurocognitive function.14 In this review, we discuss the mechanisms by which seizures occur in brain tumor patients. We then consider the use of antiepileptic drugs (AEDs) including drug selection, management, associated short- and long-term side effects, and impact on patient function and quality of life. The mechanism of epileptogenesis in tumors is incompletely understood and is believed to be multifactorial. Seizures may occur in patients with tumors that are intra-axial/infiltrative or extra-axial/distortive.3 Seizures arise electrographically from the peritumoral cortex in most patients with brain tumors due to induced changes in these regions,15,16 rather than from the tumor proper, with the exception of glioneuronal tumors containing neuronal elements.17 The multiple mechanisms of epileptogenicity in brain tumors can be loosely classified as either being caused by direct effects of the tumor (tumorocentric) or due to changes in the extracellular milieu causing cortical hyperexcitability (epileptocentric).18,19 The mechanisms of preoperative seizures likely differ from those of postoperative seizures. In the latter, surgical complications (particularly after awake surgery and rarely effects of chemoradiotherapy) are thought to contribute. Although mechanisms of preoperative seizures are likely to be more informative about the basis of tumor-associated epileptogenicity, postoperative seizures carry far greater clinical relevance. Direct mass effects of the tumor alter the surrounding brain through edema,20 vascular insufficiency,21 and inflammation.22 The peritumoral cortex in patients with seizures reveals changes in synaptic vesicles and glial gap junctions.3 An increase in CX43 protein expression has been found in perilesional tissue of seizure associated with brain tumors, suggesting an increase in astrocytic gap junctions.23 There is persistence of neurons in white matter, which is sometimes related to tumor pathology, that may predispose these patients to seizures.24 Peritumoral pH is significantly elevated as compared with normal cortex. Th (...truncated)