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Table of Contents    
Year : 2013  |  Volume : 61  |  Issue : 2  |  Page : 105-106

Prophylactic antiepileptic drugs in brain tumors: What evidence is enough evidence?

R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India

Date of Submission10-Apr-2013
Date of Decision10-Apr-2013
Date of Acceptance11-Apr-2013
Date of Web Publication29-Apr-2013

Correspondence Address:
Kurupath Radhakrishnan
Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum - 695 011, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.111108

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How to cite this article:
Rathore C, Radhakrishnan K. Prophylactic antiepileptic drugs in brain tumors: What evidence is enough evidence?. Neurol India 2013;61:105-6

How to cite this URL:
Rathore C, Radhakrishnan K. Prophylactic antiepileptic drugs in brain tumors: What evidence is enough evidence?. Neurol India [serial online] 2013 [cited 2020 Nov 29];61:105-6. Available from:

Seizures occur in 30-100% of the patients with brain tumors, the incidence being largely determined by the tumor type. [1] Benign glioneural tumors such as ganglioglioma and dysembryoplastic neuroepithelial tumor have intrinsic epileptogenecity, and seizures occur in 90-100% of these patients mostly as the presenting manifestation. [1],[2] Seizures are less common in patients with gliomas, occurring in 30-70% of these patients. Out of these, seizures occur as the presenting manifestation in 30-50% of patients while 10-20% patients develop seizures later in the course of the illness. [1],[3]

There is no controversy regarding the use of antiepileptic drugs (AEDs) in patients with brain tumors who present with seizures. However, the prophylactic use of AEDs in brain tumor patients who do not have seizures continues to be debated and the practice varies widely across the centers. Majority of the neurosurgical centers in India and across the world use prophylactic AEDs in patients with brain tumors in spite of no evidence to support this practice. [4] This becomes more important as the use of AEDs is not entirely safe and can be associated with serious side-effects apart from increasing the cost of the treatment. There is evidence to suggest that the risk of potentially life threatening skin reactions with AEDs is higher in patients with brain tumors. [5] Similarly, AEDs are associated with the cognitive side-effects, which adversely affect the quality of life in patients with brain tumors. [6] Moreover, enzyme inducing AEDs have a potential of reducing the effectiveness of chemotherapeutic drugs and steroids. [7] In view of these potentially serious problems associated with AED use, it is essential that AEDs should be judiciously used and the practice of AED use should be guided by the sound evidence. Hence, it is imperative to critically evaluate the available evidence for and against the use of prophylactic AEDs in patients with the brain tumors. The questions, which need to be answered, are: (1) does the use of prophylactic AEDs prevent the occurrence of first seizure in patients with brain tumors? and (2) does the use of prophylactic AEDs increase seizure free and overall survival?.

This obviously is not a new debate and several randomized controlled trials (RCT) and meta-analyses have tried to answer this question. Based upon a meta-analysis of four RCTs and eight observational studies, a Quality Standards Subcommittee of the American Academy of Neurology (AAN) reported that prophylactic use of AEDs namely phenytoin, phenobarbital, and divalproex sodium is not effective in preventing the first seizure and improving the seizure free and overall survival in patients with brain tumors. [8] AAN guidelines based upon this report recommended that prophylactic anticonvulsants should not be used routinely in patients with newly diagnosed brain tumors. A subsequent meta-analysis and a Cochrane review of five RCTs also reported the similar findings. [9],[10] The Cochrane review also reported higher incidence of adverse reactions in patients taking AEDs. However, because of the heterogeneity involved in the studies, Cochrane review concluded that the evidence is neutral, neither for nor against prophylactic use of AEDs, in people with brain tumors. Similarly, none of the previous studies evaluated the effectiveness of seizure prophylaxis with newer AEDs, which have lower risk of side-effects and in patients with specific tumor types.

In this issue of Neurology India, Diego et al. reports the efficacy of prophylactic levetiracetam in preventing seizures at 3 and 6 months following surgery in patients with high grade gliomas. [11] They retrospectively analyzed the data of the patients operated at two centers wherein patients from Turin Neurosurgical Department were given prophylactic levetiracetam (n = 43) while patients from Alessandria (n = 48) did not receive any AED. At 6 months, seven patients (18.5%) in AED group and the nine patients (18.8%) in the non-AED group had seizures (P = 0.818, odds ratio = 0.869). A careful study design involving two centers, which might have avoided recruitment bias and the availability of levetiracetam serum levels are the highlights of this study. With a retrospective design and small sample size, this study provides class III evidence and further adds to the existing literature that prophylactic AEDs are not useful in preventing seizures following surgery in patients with high grade gliomas.

In spite of the majority evidence suggesting that the prophylactic AED use does not lower the risk of seizure occurrence in patients with brain tumors, this has not translated in general practice. This is partly due to the fact that the practice is largely guided by the personal preferences and the subjective sense of security provided by the AED use. This also raises the question of the quality of evidence available and close scrutiny does suggest that evidence is not as robust as it appears. Majority of the previous studies have been quite heterogeneous with regard to the tumor type, patient population, type of intervention, and outcome measures. The RCTs addressing this question have included, small number of patients, ranging from 63 to 100, with all types of primary and metastatic tumors, and a variable follow-up of 6-19 months. [8],[10] The other concern has been the lower overall rate of seizure occurrence in these patients ranging from 7% to 35%. With this lower rate of seizure occurrence, the minimum number of patients required to detect a significant change will be ~1,000 and most previous studies have been grossly underpowered in this regard. [12] However, it can be safely concluded that the protection offered by the prophylactic AED use in patients with brain tumors is small, if not negligible.

A well-conducted large multi-centric RCT with sufficient statistical power is the only way to obtain the evidence either for or against the prophylactic use of AEDs in neurosurgical practice in general and in patients with brain tumors in particular. This may be only way to change the presently prevalent subjective practice to a more evidence based practice. With a huge patient base to cater for, the neurosurgery fraternity of India is in a unique position to provide this evidence and will hopefully rise to the occasion.

  References Top

1.Van Breemen MS, Wilms EB, Vecht CJ. Epilepsy in patients with brain tumours: Epidemiology, mechanisms, and management. Lancet Neurol 2007;6:421-30.  Back to cited text no. 1
2.Luyken C, Blümcke I, Fimmers R, Urbach H, Elger CE, Wiestler OD, et al. The spectrum of long-term epilepsy-associated tumors: Long-term seizure and tumor outcome and neurosurgical aspects. Epilepsia 2003;44:822-30.  Back to cited text no. 2
3.Hildebrand J, Lecaille C, Perennes J, Delattre JY. Epileptic seizures during follow-up of patients treated for primary brain tumors. Neurology 2005;65:212-5.  Back to cited text no. 3
4.Siomin V, Angelov L, Li L, Vogelbaum MA. Results of a survey of neurosurgical practice patterns regarding the prophylactic use of anti-epilepsy drugs in patients with brain tumors. J Neurooncol 2005;74:211-5.  Back to cited text no. 4
5.Mamon HJ, Wen PY, Burns AC, Loeffler JS. Allergic skin reactions to anticonvulsant medications in patients receiving cranial radiation therapy. Epilepsia 1999;40:341-4.  Back to cited text no. 5
6.Klein M, Engelberts NH, van der Ploeg HM, Kasteleijn-Nolst Trenité DG, Aaronson NK, Taphoorn MJ, et al. Epilepsy in low-grade gliomas: The impact on cognitive function and quality of life. Ann Neurol 2003;54:514-20.  Back to cited text no. 6
7.Levin VA, Stearns J, Byrd A, Finn A, Weinkam RJ. The effect of phenobarbital pretreatment on the antitumor activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl-1-nitrosourea (PCNU), and on the plasma pharmacokinetics and biotransformation of BCNU. J Pharmacol Exp Ther 1979;208:1-6.  Back to cited text no. 7
8.Glantz MJ, Cole BF, Forsyth PA, Recht LD, Wen PY, Chamberlain MC, 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;54:1886-93.  Back to cited text no. 8
9.Sirven JI, Wingerchuk DM, Drazkowski JF, Lyons MK, Zimmerman RS. Seizure prophylaxis in patients with brain tumors: A meta-analysis. Mayo Clin Proc 2004;79:1489-94.  Back to cited text no. 9
10.Tremont-Lukats IW, Ratilal BO, Armstrong T, Gilbert MR. Antiepileptic drugs for preventing seizures in people with brain tumors. Cochrane Database Syst Rev 2008;16:CD004424.  Back to cited text no. 10
11.Diego G, Paolo PP, Romina A, Luigi R, Fulvio R, Marco A, et al. A retrospective two-centres study of antiepileptic prophylaxis in patients with surgically treated high-grade gliomas. Neurol India 2013. [In press]  Back to cited text no. 11
12.Forsyth PA, Weaver S, Fulton D, Brasher PM, Sutherland G, Stewart D, et al. Prophylactic anticonvulsants in patients with brain tumour. Can J Neurol Sci 2003;30:106-12.  Back to cited text no. 12


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