Postoperative seizure control in glioma patients with epilepsy
Editorial

Postoperative seizure control in glioma patients with epilepsy

Johan A. F. Koekkoek1,2, Charles J. Vecht3

1Department of Neurology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands; 2Department of Neurology, Medical Center Haaglanden, Hospital Antoniushove, Burgemeester Banninglaan 1, 2262 BA Leidschendam, The Netherlands; 3Service Neurologie Mazarin, UPMC, Centre Hospitalo-Universitaire Pitié-Salpêtrière, APHP, F-75013 Paris, France

Correspondence to: Johan A. F. Koekkoek. Department of Neurology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Email: j.a.f.koekkoek@lumc.nl.

Provenance: This is a Guest Editorial commissioned by Section Editor Dr. Xian-Xin Qiu [Shanghai Proton and Heavy Ion Center (SPHIC), a.k.a. the Proton and Heavy Ion Center of Fudan University Shanghai Cancer Center (FUSCC), Shanghai, China].

Comment on: Neal A, Morokoff A, O’Brien TJ, et al. Postoperative seizure control in patients with tumor-associated epilepsy. Epilepsia 2016;57:1779-88.


Submitted Mar 01, 2017. Accepted for publication Mar 15, 2017.

doi: 10.21037/tcr.2017.03.66


Gliomas account for approximately 80% of all primary malignant brain tumors with a rate of 2–8 cases per 100,000 person-years. Gliomas result in a disproportionate share of cancer morbidity, including focal neurological deficits, cognitive impairment and seizures. Seizures may occur in every type of glioma, although the epileptogenicity of gliomas tends to be inversely correlated to the growth rate of the tumor (1). Approximately 70–90% of all patients with low-grade glioma (LGG) develop epilepsy during the course of the disease, in comparison to 30–60% of patients with high-grade glioma (HGG) (2). Gliomas located in the frontal or temporal lobe, as well as cortical located tumors tend to be more epileptogenic (1). In the clinical management of gliomas it is of major importance to achieve seizure control, as seizures may negatively influence health-related quality of life and cause cognitive disturbances, particularly when uncontrolled (3). In spite of using multiple antiepileptic drugs (AEDs), about one third of low-grade glioma patients will not become seizure free (4). In addition, seizure control appears to be a dynamic phenomenon in patients with glioma, fluctuating during the course of the disease. Neal et al. aimed to characterize the patterns of postoperative seizure control in glioma patients and identify specific risk factor profiles (5).

In a retrospective single centre review of 186 patients with supratentorial grade II–IV glioma Neal et al. distinguished four patterns of postoperative seizure control: (I) completely seizure free; (II) seizures occurring only in the first 6 months postoperatively; (III) seizures alternating by periods of seizure control from 0–24 months postoperatively for at least 6 months, and from 24 months postoperatively for at least 12 months; (IV) never seizure free. In total, 119 patients (64%) were diagnosed with tumor-associated epilepsy, of whom 38 patients developed epilepsy after surgery. In patients with LGG and anaplastic glioma, fluctuating seizure control according to pattern C was most commonly found. Moreover, about two third of these patients showed at least one 12-month period of seizure freedom. The presence of preoperative seizures as well as an incomplete surgical resection were the most important clinical variables associated with seizure pattern D, i.e., patients who never became seizure free (5).

In line with the current literature on epilepsy in glioma patients, Neal et al. demonstrate that apart from AED treatment, a surgical resection may at least temporarily contribute to seizure control. Seizure freedom after surgery has previously been reported in 53–87% of LGG patients (6,7). In slow-growing glioneuronal tumors, such as gangliogliomas and dysembryoplastic neuroepithelial tumors (DNTs), long-term seizure freedom was observed in up to 94% of cases (8). In HGG patients with preoperative seizures, 77% of patients became seizure free 1 year after surgery (9). As a gross total resection is one of the strongest predictors of postoperative seizure-freedom, surgery is aimed at performing a maximally safe resection. However, gross total resection is only feasible in approximately half of cases and the epileptogenic zone may be located in extratumoral cortical areas as well (8). As a consequence, some patients will never become seizure free and refractory seizures may persist in 15–20% of patients after surgery (10,11). In addition, a less favorable outcome after surgery has been observed in case of preoperative seizures or focal seizures despite anti-epileptic drug therapy (6,12).

Although the evidence from the literature is limited, a decrease in seizure frequency has also been found after treatment with radiotherapy or chemotherapy. In the largest, mostly retrospective, patient series a more than 50% reduction in seizure frequency was observed in 44–77% of patients after irradiation or chemotherapy with temozolomide (13). LGG patients who received early radiotherapy more often showed seizure freedom after 12 months compared to patients who received late radiotherapy (75% vs. 59%) (14). Furthermore, patients with uncontrolled seizures may respond quickly to radio- or chemotherapy, even a few days or weeks after initiation of antitumor treatment (15). Other chemotherapeutic agents, including the combination of procarbazine, CCNU and vincristine (PCV), may contribute to a seizure reduction as well (16,17).

The occurrence of seizure control in patients with glioma not only depends on the resection, but is also influenced by factors related to tumor type, tumor status and its treatment and individual factors, which may be subject to change during the course of disease. Apart from symptomatic or localization-related epilepsy, the natural tendency of gliomas to recur as well as their infiltrative growth may cause an additional risk for seizure relapse (13,18). In comparison to GBM, patients with low-grade gliomas show a longer period before developing a pattern of fluctuating seizure control due to a longer survival (5). Nonetheless, it is still controversial whether seizure recurrence is directly related to tumor progression. In a retrospective study of 508 LGG patients undergoing resection, postoperative seizure relapse was not associated with tumor progression, whereas another series of 332 LGG patients reported a hazard ratio of 3.80 for tumor progression in case of seizure recurrence compared with ongoing seizure freedom (6,7).

Although the risk of seizure recurrence in glioma patients may vary during the course of disease, patients generally show a weaker response to AED treatment compared to the general epilepsy population (5). In addition, side effects are commonly observed, occurring in 20–40% of glioma patients, which might partly be attributable to enzyme-inducing AEDs such as phenytoin and carbamazepine, that may cause drug-drug interactions or interactions with chemotherapeutic agents or radiotherapy (19,20). As a consequence, there is currently a general consensus to avoid enzyme-inducing AEDs and to apply non-enzyme-inducing AEDs as levetiracetam, valproic acid and lately also lacosamide as first choice anticonvulsants (19,21,22). In glioma patients who achieve seizure freedom after tumor resection or other antitumor treatment, the question may arise whether AEDs can be withdrawn at some point, particularly when the patient experiences disturbing side effects. As there is little evidence available on its safety, AED withdrawal should be considered only in glioma patients with a favorable prognosis, who have achieved stable disease in combination with long-term seizure freedom (23).

Unfortunately, the study of Neal et al. suffers from a number of drawbacks. The most important one is that the authors have performed an analysis on the postoperative seizure course in gliomas without differentiating to the type of glioma. Low-grade gliomas (grade II), anaplastic astrocytomas (grade III) and high-grade gliomas or glioblastoma (GBM, grade IV) are treated as one group, while each has its own epilepsy characteristics with differences in presentation and frequency of seizures during follow-up. Besides, GBM is overrepresented with almost 60% of patients, while absolute numbers of grade II and III gliomas are small.

The course of postoperative seizures is divided up in grades A, B, C and D, of which the first three in fact represent all benign epilepsy courses. As course C receives the most attention, its definition is the more relevant as severity of the epilepsy is not accounted for, while most seizures in gliomas are partial ones not lasting longer than 30 seconds. Although the authors have performed multivariate analyses between tumor progression, defined as re-resection, and seizure course, they have not included tumor progression defined by receiving second line chemotherapy. Although alluded to in the discussion, one misses particularly an analysis on the relation between the time and potential of seizure recurrence and the timing of tumor recurrence. For those reasons the value of this paper relates mostly to the sub-analysis they performed on GBM, that is grade IV patients. On this group, the authors found that 48% of patients experienced postoperative seizure freedom with an even distribution in the remaining three epilepsy courses.

Overall, gliomas comprise a relatively heterogeneous group of brain tumors with a fluctuating seizure risk, depending on a wide range of factors including type of tumor, actual tumor status and its treatment. Neal et al. demonstrate the fluctuating course of seizures. Like many other clinical reports on epilepsy in gliomas, the results of this study should be interpreted with caution due to its retrospective design and the strong heterogeneity of the study population. Future prospective studies are highly needed to overcome these weaknesses. Therefore, accurate prospective monitoring of seizures, AED treatment, antitumor treatment and radiological follow-up is essential, using uniform outcome measures (24). In that case, it may become possible to predict more precisely when seizures may occur during the course of disease.


Acknowledgements

None.


Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.


References

  1. Smits A, Duffau H. Seizures and the natural history of World Health Organization Grade II gliomas: a review. Neurosurgery 2011;68:1326-33. [Crossref] [PubMed]
  2. Kerkhof M, Vecht CJ. Seizure characteristics and prognostic factors of gliomas. Epilepsia 2013;54:12-7. [Crossref] [PubMed]
  3. Klein M, Engelberts NH, van der Ploeg HM, et al. Epilepsy in low-grade gliomas: the impact on cognitive function and quality of life. Ann Neurol 2003;54:514-20. [Crossref] [PubMed]
  4. de Groot M, Reijneveld JC, Aronica E, et al. Epilepsy in patients with a brain tumour: focal epilepsy requires focused treatment. Brain 2012;135:1002-16. [Crossref] [PubMed]
  5. Neal A, Morokoff A, O'Brien TJ, et al. Postoperative seizure control in patients with tumor-associated epilepsy. Epilepsia 2016;57:1779-88. [Crossref] [PubMed]
  6. Chang EF, Potts MB, Keles GE, et al. Seizure characteristics and control following resection in 332 patients with low-grade gliomas. J Neurosurg 2008;108:227-35. [Crossref] [PubMed]
  7. You G, Sha ZY, Yan W, et al. Seizure characteristics and outcomes in 508 Chinese adult patients undergoing primary resection of low-grade gliomas: a clinicopathological study. Neuro Oncol 2012;14:230-41. [Crossref] [PubMed]
  8. Rudà R, Bello L, Duffau H, et al. Seizures in low-grade gliomas: natural history, pathogenesis, and outcome after treatments. Neuro Oncol 2012;14:iv55-64. [Crossref] [PubMed]
  9. Chaichana KL, Parker SL, Olivi A, et al. Long-term seizure outcomes in adult patients undergoing primary resection of malignant brain astrocytomas. Clinical article. J Neurosurg 2009;111:282-92. [Crossref] [PubMed]
  10. 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;44:822-30. [Crossref] [PubMed]
  11. Bauer R, Dobesberger J, Unterhofer C, et al. Outcome of adult patients with temporal lobe tumours and medically refractory focal epilepsy. Acta Neurochir (Wien) 2007;149:1211-6; discussion 1216-7. [Crossref] [PubMed]
  12. Kahlenberg CA, Fadul CE, Roberts DW, et al. Seizure prognosis of patients with low-grade tumors. Seizure 2012;21:540-5. [Crossref] [PubMed]
  13. 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;17:924-34. [Crossref] [PubMed]
  14. 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;366:985-90. [Crossref] [PubMed]
  15. Plathow C, Schulz-Ertner D, Thilman C, et al. Fractionated stereotactic radiotherapy in low-grade astrocytomas: long-term outcome and prognostic factors. Int J Radiat Oncol Biol Phys 2003;57:996-1003. [Crossref] [PubMed]
  16. Soffietti R, Rudà R, Bradac GB, et al. PCV chemotherapy for recurrent oligodendrogliomas and oligoastrocytomas. Neurosurgery 1998;43:1066-73. [Crossref] [PubMed]
  17. Frenay MP, Fontaine D, Vandenbos F, et al. First-line nitrosourea-based chemotherapy in symptomatic non-resectable supratentorial pure low-grade astrocytomas. Eur J Neurol 2005;12:685-90. [Crossref] [PubMed]
  18. Huberfeld G, Vecht CJ. Seizures and gliomas--towards a single therapeutic approach. Nat Rev Neurol 2016;12:204-16. [Crossref] [PubMed]
  19. 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;54:1886-93. [Crossref] [PubMed]
  20. Bénit CP, Vecht CJ. Seizures and cancer: drug interactions of anticonvulsants with chemotherapeutic agents, tyrosine kinase inhibitors and glucocorticoids. Neurooncol Pract 2016;3:245-60.
  21. Vecht CJ, Kerkhof M, Duran-Pena A. Seizure prognosis in brain tumors: new insights and evidence-based management. Oncologist 2014;19:751-9. [Crossref] [PubMed]
  22. Rudà R, Soffietti R. What is New in the Management of Epilepsy in Gliomas? Curr Treat Options Neurol 2015;17:351. [Crossref] [PubMed]
  23. Koekkoek JA, Dirven L, Taphoorn MJ. The withdrawal of antiepileptic drugs in patients with low-grade and anaplastic glioma. Expert Rev Neurother 2017;17:193-202. [Crossref] [PubMed]
  24. Avila EK, Chamberlain M, Schiff D, et al. Seizure control as a new metric in assessing efficacy of tumor treatment in low-grade glioma trials. Neuro Oncol 2017;19:12-21. [Crossref] [PubMed]
Cite this article as: Koekkoek JA, Vecht CJ. Postoperative seizure control in glioma patients with epilepsy. Transl Cancer Res 2017;6(Suppl 2):S313-S316. doi: 10.21037/tcr.2017.03.66