Seizures in patients with primary and metastatic brain tumors
- Jan Drappatz, MD
Jan Drappatz, MD
- Associate Director
- Adult Neuro-Oncology Program
- Associate Professor
- Departments of Neurology and Medicine
- University of Pittsburgh
- Patrick Y Wen, MD
Patrick Y Wen, MD
- Section Editor — Neurooncology
- Professor of Neurology
- Harvard Medical School
- Edward K Avila, DO
Edward K Avila, DO
- Assistant Professor of Neurology
- Memorial Sloan-Kettering Cancer Center
Seizures are a common and potentially devastating complication of both primary and metastatic brain tumors . Such seizures are focal in origin and may either remain focal or secondarily generalize. The diagnosis of a seizure disorder is usually made clinically.
The epidemiology and treatment of seizures, prophylactic use of antiseizure drugs, and complications of therapy in patients with brain tumors will be reviewed here. The clinical manifestations of brain tumors and the general management of seizures are discussed elsewhere. (See "Clinical presentation and diagnosis of brain tumors", section on 'Clinical manifestations' and "Overview of the management of epilepsy in adults".)
Seizures are a relatively common problem in patients with brain tumors. Seizures may be the initial manifestation of a brain tumor or may occur during the course of disease. (See "Clinical presentation and diagnosis of brain tumors", section on 'Seizures'.)
Factors that influence the incidence of seizures include tumor-type and location:
●Among patients with primary brain tumors, seizures are less common with high-grade compared with low-grade gliomas . As an example, the prevalence rates of epilepsy in a series of 1028 patients with primary brain tumors were 49, 69, and 85 percent among patients with glioblastoma (GBM), anaplastic glioma, and low-grade glioma, respectively . However, in one carefully studied series of 75 high-grade gliomas, seizures were present at diagnosis in 35 (52 percent), but occurred at some time during the course of the disease in 60 (80 percent) . Dysregulation of adenosine kinase in the peritumoral region of astrocytic brain tumors has been postulated to play a role in tumor-related epileptogenesis .
- Avila EK, Graber J. Seizures and epilepsy in cancer patients. Curr Neurol Neurosci Rep 2010; 10:60.
- van Breemen MS, Wilms EB, Vecht CJ. Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management. Lancet Neurol 2007; 6:421.
- Lote K, Stenwig AE, Skullerud K, Hirschberg H. Prevalence and prognostic significance of epilepsy in patients with gliomas. Eur J Cancer 1998; 34:98.
- van Breemen MS, Rijsman RM, Taphoorn MJ, et al. Efficacy of anti-epileptic drugs in patients with gliomas and seizures. J Neurol 2009; 256:1519.
- de Groot M, Iyer A, Zurolo E, et al. Overexpression of ADK in human astrocytic tumors and peritumoral tissue is related to tumor-associated epilepsy. Epilepsia 2012; 53:58.
- Herman ST. Epilepsy after brain insult: targeting epileptogenesis. Neurology 2002; 59:S21.
- Villemure JG, de Tribolet N. Epilepsy in patients with central nervous system tumors. Curr Opin Neurol 1996; 9:424.
- Pace A, Bove L, Innocenti P, et al. Epilepsy and gliomas: incidence and treatment in 119 patients. J Exp Clin Cancer Res 1998; 17:479.
- Oberndorfer S, Schmal T, Lahrmann H, et al. [The frequency of seizures in patients with primary brain tumors or cerebral metastases. An evaluation from the Ludwig Boltzmann Institute of Neuro-Oncology and the Department of Neurology, Kaiser Franz Josef Hospital, Vienna]. Wien Klin Wochenschr 2002; 114:911.
- Cocito L, Audenino D, Primavera A. Altered mental state and nonconvulsive status epilepticus in patients with cancer. Arch Neurol 2001; 58:1310.
- Drislane FW. Nonconvulsive status epilepticus in patients with cancer. Clin Neurol Neurosurg 1994; 96:314.
- Hormigo A, Liberato B, Lis E, DeAngelis LM. Nonconvulsive status epilepticus in patients with cancer: imaging abnormalities. Arch Neurol 2004; 61:362.
- Morris PG, Gutin PH, Avila EK, et al. Seizures and radionecrosis from non-small-cell lung cancer presenting as increased fluorodeoxyglucose uptake on positron emission tomography. J Clin Oncol 2011; 29:e324.
- Rossetti AO, Stupp R. Epilepsy in brain tumor patients. Curr Opin Neurol 2010; 23:603.
- Rosati A, Buttolo L, Stefini R, et al. Efficacy and safety of levetiracetam in patients with glioma: a clinical prospective study. Arch Neurol 2010; 67:343.
- Usery JB, Michael LM 2nd, Sills AK, Finch CK. A prospective evaluation and literature review of levetiracetam use in patients with brain tumors and seizures. J Neurooncol 2010; 99:251.
- Maschio M, Dinapoli L, Gomellini S, et al. Antiepileptics in brain metastases: safety, efficacy and impact on life expectancy. J Neurooncol 2010; 98:109.
- Saria MG, Corle C, Hu J, et al. Retrospective analysis of the tolerability and activity of lacosamide in patients with brain tumors: clinical article. J Neurosurg 2013; 118:1183.
- Rossetti AO, Jeckelmann S, Novy J, et al. Levetiracetam and pregabalin for antiepileptic monotherapy in patients with primary brain tumors. A phase II randomized study. Neuro Oncol 2014; 16:584.
- de Groot M, Aronica E, Heimans JJ, Reijneveld JC. Synaptic vesicle protein 2A predicts response to levetiracetam in patients with glioma. Neurology 2011; 77:532.
- Weller M, Gorlia T, Cairncross JG, et al. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology 2011; 77:1156.
- Kerkhof M, Dielemans JC, van Breemen MS, et al. Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme. Neuro Oncol 2013; 15:961.
- Krauze AV, Myrehaug SD, Chang MG, et al. A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma. Int J Radiat Oncol Biol Phys 2015; 92:986.
- Happold C, Gorlia T, Chinot O, et al. Does Valproic Acid or Levetiracetam Improve Survival in Glioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma. J Clin Oncol 2016; 34:731.
- Kim YH, Kim T, Joo JD, et al. Survival benefit of levetiracetam in patients treated with concomitant chemoradiotherapy and adjuvant chemotherapy with temozolomide for glioblastoma multiforme. Cancer 2015; 121:2926.
- Rudà R, Trevisan E, Soffietti R. Epilepsy and brain tumors. Curr Opin Oncol 2010; 22:611.
- Englot DJ, Berger MS, Barbaro NM, Chang EF. Factors associated with seizure freedom in the surgical resection of glioneuronal tumors. Epilepsia 2012; 53:51.
- Phi JH, Kim SK, Cho BK, et al. Long-term surgical outcomes of temporal lobe epilepsy associated with low-grade brain tumors. Cancer 2009; 115:5771.
- Luyken C, Blümcke I, Fimmers R, et al. The spectrum of long-term epilepsy-associated tumors: long-term seizure and tumor outcome and neurosurgical aspects. Epilepsia 2003; 44:822.
- Chan CH, Bittar RG, Davis GA, et al. Long-term seizure outcome following surgery for dysembryoplastic neuroepithelial tumor. J Neurosurg 2006; 104:62.
- van den Bent MJ, Afra D, de Witte O, et al. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet 2005; 366:985.
- Rudà R, Magliola U, Bertero L, et al. Seizure control following radiotherapy in patients with diffuse gliomas: a retrospective study. Neuro Oncol 2013; 15:1739.
- Koekkoek JA, Kerkhof M, Dirven L, et al. Seizure outcome after radiotherapy and chemotherapy in low-grade glioma patients: a systematic review. Neuro Oncol 2015; 17:924.
- Pace A, Vidiri A, Galiè E, et al. Temozolomide chemotherapy for progressive low-grade glioma: clinical benefits and radiological response. Ann Oncol 2003; 14:1722.
- Frenay MP, Fontaine D, Vandenbos F, Lebrun C. First-line nitrosourea-based chemotherapy in symptomatic non-resectable supratentorial pure low-grade astrocytomas. Eur J Neurol 2005; 12:685.
- Sherman, JH, Moldovan, K, Yoeh, HK, et, al. Impact of temozolomide chemotherapy on seizure frequency in patients with low-grade gliomas. J Neurosurg 2011; 0:in press.
- Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010; 363:1801.
- Glantz MJ, Cole BF, Forsyth PA, et al. Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000; 54:1886.
- Sirven JI, Wingerchuk DM, Drazkowski JF, et al. Seizure prophylaxis in patients with brain tumors: a meta-analysis. Mayo Clin Proc 2004; 79:1489.
- Tremont-Lukats IW, Ratilal BO, Armstrong T, Gilbert MR. Antiepileptic drugs for preventing seizures in people with brain tumors. Cochrane Database Syst Rev 2008; :CD004424.
- Mikkelsen T, Paleologos NA, Robinson PD, et al. The role of prophylactic anticonvulsants in the management of brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2010; 96:97.
- Goldlust SA, Hsu M, Lassman AB, et al. Seizure prophylaxis and melanoma brain metastases. J Neurooncol 2012; 108:109.
- Szaflarski JP, Sangha KS, Lindsell CJ, Shutter LA. Prospective, randomized, single-blinded comparative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis. Neurocrit Care 2010; 12:165.
- Milligan TA, Hurwitz S, Bromfield EB. Efficacy and tolerability of levetiracetam versus phenytoin after supratentorial neurosurgery. Neurology 2008; 71:665.
- Rosengart AJ, Huo JD, Tolentino J, et al. Outcome in patients with subarachnoid hemorrhage treated with antiepileptic drugs. J Neurosurg 2007; 107:253.
- Shah D, Husain AM. Utility of levetiracetam in patients with subarachnoid hemorrhage. Seizure 2009; 18:676.
- Lwu S, Hamilton MG, Forsyth PA, et al. Use of peri-operative anti-epileptic drugs in patients with newly diagnosed high grade malignant glioma: a single center experience. J Neurooncol 2010; 96:403.
- Sughrue ME, Rutkowski MJ, Chang EF, et al. Postoperative seizures following the resection of convexity meningiomas: are prophylactic anticonvulsants indicated? Clinical article. J Neurosurg 2011; 114:705.
- Kuijlen JM, Teernstra OP, Kessels AG, et al. Effectiveness of antiepileptic prophylaxis used with supratentorial craniotomies: a meta-analysis. Seizure 1996; 5:291.
- Zachenhofer I, Donat M, Oberndorfer S, Roessler K. Perioperative levetiracetam for prevention of seizures in supratentorial brain tumor surgery. J Neurooncol 2011; 101:101.
- Komotar RJ, Raper DM, Starke RM, et al. Prophylactic antiepileptic drug therapy in patients undergoing supratentorial meningioma resection: a systematic analysis of efficacy. J Neurosurg 2011; 115:483.
- Wu AS, Trinh VT, Suki D, et al. A prospective randomized trial of perioperative seizure prophylaxis in patients with intraparenchymal brain tumors. J Neurosurg 2013; 118:873.
- Fuller KL, Wang YY, Cook MJ, et al. Tolerability, safety, and side effects of levetiracetam versus phenytoin in intravenous and total prophylactic regimen among craniotomy patients: a prospective randomized study. Epilepsia 2013; 54:45.
- Weston J, Greenhalgh J, Marson AG. Antiepileptic drugs as prophylaxis for post-craniotomy seizures. Cochrane Database Syst Rev 2015; :CD007286.
- Iuchi T, Kuwabara K, Matsumoto M, et al. Levetiracetam versus phenytoin for seizure prophylaxis during and early after craniotomy for brain tumours: a phase II prospective, randomised study. J Neurol Neurosurg Psychiatry 2015; 86:1158.
- Pourzitaki C, Tsaousi G, Apostolidou E, et al. Efficacy and safety of prophylactic levetiracetam in supratentorial brain tumour surgery: a systematic review and meta-analysis. Br J Clin Pharmacol 2016.
- Taylor LP, Posner JB. Phenobarbital rheumatism in patients with brain tumor. Ann Neurol 1989; 25:92.
- Mamon HJ, Wen PY, Burns AC, Loeffler JS. Allergic skin reactions to anticonvulsant medications in patients receiving cranial radiation therapy. Epilepsia 1999; 40:341.
- Delattre JY, Safai B, Posner JB. Erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and phenytoin. Neurology 1988; 38:194.
- Khafaga YM, Jamshed A, Allam AA, et al. Stevens-Johnson syndrome in patients on phenytoin and cranial radiotherapy. Acta Oncol 1999; 38:111.
- Hoang-Xuan K, Delattre JY, Poisson M. Stevens-Johnson syndrome in a patient receiving cranial irradiation and carbamazepine. Neurology 1990; 40:1144.
- Schlienger RG, Shapiro LE, Shear NH. Lamotrigine-induced severe cutaneous adverse reactions. Epilepsia 1998; 39 Suppl 7:S22.
- Hirsch LJ, Arif H, Nahm EA, et al. Cross-sensitivity of skin rashes with antiepileptic drug use. Neurology 2008; 71:1527.
- Franciotta D, Kwan P, Perucca E. Genetic basis for idiosyncratic reactions to antiepileptic drugs. Curr Opin Neurol 2009; 22:144.
- Bourg V, Lebrun C, Chichmanian RM, et al. Nitroso-urea-cisplatin-based chemotherapy associated with valproate: increase of haematologic toxicity. Ann Oncol 2001; 12:217.
- Krouwer HG, Pallagi JL, Graves NM. Management of seizures in brain tumor patients at the end of life. J Palliat Med 2000; 3:465.
- Oberndorfer S, Lindeck-Pozza E, Lahrmann H, et al. The end-of-life hospital setting in patients with glioblastoma. J Palliat Med 2008; 11:26.
- Pace A, Villani V, Di Lorenzo C, et al. Epilepsy in the end-of-life phase in patients with high-grade gliomas. J Neurooncol 2013; 111:83.
- Sizoo EM, Braam L, Postma TJ, et al. Symptoms and problems in the end-of-life phase of high-grade glioma patients. Neuro Oncol 2010; 12:1162.
- Pace A, Di Lorenzo C, Guariglia L, et al. End of life issues in brain tumor patients. J Neurooncol 2009; 91:39.
- Koekkoek JA, Dirven L, Sizoo EM, et al. Symptoms and medication management in the end of life phase of high-grade glioma patients. J Neurooncol 2014; 120:589.
- Davis MP, Walsh D, LeGrand SB, Naughton M. Symptom control in cancer patients: the clinical pharmacology and therapeutic role of suppositories and rectal suspensions. Support Care Cancer 2002; 10:117.
- Gustafson MC, Penovich PE, Frost MD. Levetiracetam absorption after rectal administration: 2 case reports (Abstr 2.358). Epilepsia 2005; 46 Suppl 8:2011.
- Bartz L, Klein C, Seifert A, et al. Subcutaneous administration of drugs in palliative care: results of a systematic observational study. J Pain Symptom Manage 2014; 48:540.
- Koekkoek JA, Postma TJ, Heimans JJ, et al. Antiepileptic drug treatment in the end-of-life phase of glioma patients: a feasibility study. Support Care Cancer 2016; 24:1633.
- CLINICAL MANIFESTATIONS
- Nonconvulsive status epilepticus
- DIAGNOSTIC EVALUATION
- Antiseizure drug therapy
- Tumor-directed therapies
- Patients without a history of a seizure
- Postoperative prophylaxis
- ADVERSE EFFECTS OF ANTISEIZURE DRUG THERAPY
- Side effects
- - Drug rash
- Drug-drug interactions
- SEIZURES AT THE END OF LIFE
- SUMMARY AND RECOMMENDATIONS