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Keywords:

  • Brain tumor;
  • Seizures;
  • Antiepileptic drugs;
  • Medical treatment

Summary

  1. Top of page
  2. Summary
  3. When Should Antiepileptic Drug Treatment Be Started?
  4. Which Factors Should Be Considered in AED Selection?
  5. Choice of Initial Treatment
  6. Managing Patients When Initial Monotherapy Failed
  7. Should AEDs Be Withdrawn in Seizure-Free Patients?
  8. Conclusive Remarks and Future Perspectives
  9. Disclosure
  10. References

Between 30% and 50% of patients with brain tumors first present with a seizure, and up to 30% more will develop seizures later. Therefore, optimal management of these patients requires a rational approach to the use of antiseizure medications. Based on current evidence, prophylactic prescription of long-term antiepileptic drugs (AEDs) in patients with brain tumors in patients who did not present with seizures is not justified. Because of the high risk of recurrence, however, AED treatment should be strongly considered after a single seizure considered to be due to a tumor. Because of the lack of well-controlled randomized trials, the decision on which AED provides the best risk–benefit ratio in the individual patient is based mostly on physician's judgment rather than sound scientific evidence. In patients who may require chemotherapy, a non–enzyme-inducing AED is preferred for initial treatment to minimize the risk of drug interactions that impact adversely on the outcome of anticancer chemotherapy. Several retrospective studies in seizure patients with glioblastoma treated with chemotherapy have provided evidence for a moderately improved survival with the use of valproic acid, possibly due to inhibition of histone deacetylase. However, valproic acid may also increase the hematologic toxicity of antineoplastic drugs, presumably by inhibiting their metabolism, and may independently impair hemostasis, which is of some concern for patients who require surgical intervention. Among newer generation AEDs, levetiracetam has a number of advantageous features, including availability of a parenteral formulation, but other agents such as gabapentin, lamotrigine, oxcarbazepine, topiramate, and zonisamide may also be considered. Potentially more effective treatments targeting specific mechanisms of epileptogenesis and ictogenesis are being investigated. Resection of the tumor, radiation therapy, or chemotherapy can bring refractory seizures under control or prolong the duration of seizure freedom, an effect that does not appear to be necessarily related to removal or shrinkage of the tumor mass. In patients with a successfully treated tumor and an overall good prognosis for long-term survival, gradual discontinuation of AEDs may be considered.

Between 30% and 50% of patients with brain tumors present with a seizure as their initial clinical manifestation, and up to 30% more will later develop seizures (Van Breemen et al., 2007). Management of seizures associated with tumors requires consideration of several aspects, including (1) a relatively high rate of recurrence after a first seizure, (2) increased sensitivity to the adverse effects of antiepileptic drugs (AEDs), (3) changes in clinical response in relation to the progression of the disease and, most importantly, (4) the possibility of adverse interactions between AEDs and anticancer agents. This article addresses several decision steps that physicians face when managing seizures in patients with brain tumors.

When Should Antiepileptic Drug Treatment Be Started?

  1. Top of page
  2. Summary
  3. When Should Antiepileptic Drug Treatment Be Started?
  4. Which Factors Should Be Considered in AED Selection?
  5. Choice of Initial Treatment
  6. Managing Patients When Initial Monotherapy Failed
  7. Should AEDs Be Withdrawn in Seizure-Free Patients?
  8. Conclusive Remarks and Future Perspectives
  9. Disclosure
  10. References

Because of the high risk of seizures in patients with brain tumors, particularly those with slow-growing tumors, some physicians elect to prescribe AEDs prophylactically in such patients even when there is no history of prior seizures. Likewise, AEDs are sometimes prescribed to prevent the development of postoperative epilepsy in seizure-free patients who have undergone resection of their tumor. In a retrospective survey of adults with newly diagnosed malignant gliomas undergoing surgery from 2003 to 2005 in southern Alberta, Canada, 44 (40%) of 110 patients without seizures were found to have been prescribed AED prophylaxis (Lwu et al., 2010). Of these, 30 continued prophylaxis for one or more weeks after surgery.

Prophylactic use of phenytoin for 1 week after severe brain trauma has been found to protect against the occurrence of acute symptomatic seizures (Chang & Lowenstein, 2003). However, long-term AED prescription before or after surgery in seizure-free brain tumor patients is not justified based on available evidence. A review published in 2000 by the Quality Standard Subcommittee of the American Academy of Neurology concluded that “in patients with newly diagnosed brain tumors, anticonvulsant medications are not effective in preventing first seizures” and “… prophylactic anticonvulsants should not be used routinely in patients with newly diagnosed brain tumors” (Glantz et al., 2000). The same guideline stated that “in patients with brain tumors who have not had a seizure, tapering and discontinuing anticonvulsants after the first postoperative week is appropriate, particularly in those patients medically stable and who are experiencing anticonvulsant-related side effects.” These recommendations remain valid and are further supported by two meta-analyses (Temkin et al., 2001; Sirven et al., 2004). The meta-analysis by Sirven et al. (2004), which covered all randomized trials conducted between 1966 and 2004, evaluated the seizure-protecting activity of AED prophylaxis versus no treatment or placebo in patients with brain tumors and no history of epilepsy. Five trials that investigated phenobarbital, phenytoin, or valproic acid in a total of 403 patients met eligibility criteria. No evidence of benefit from AED treatment was found at 1 week (odds ratio [OR] 0.91; 95% confidence interval [CI] 0.45–1.83) and at 6 months (OR 1.01; 95% CI 0.51–1.98) of follow-up. Likewise, no benefit was found for subgroups of patients with specific tumor pathology, including primary glial tumors (OR 3.46; 95% CI 0.32–37.47), cerebral metastases (OR 2.50; 95% CI 0.25–24.72), and meningiomas (OR 0.62; 95% CI 0.10–3.85).

If routine AED prophylaxis is not justified in seizure-free patients, the situation is different for patients with tumors who present with a single or multiple seizures (Van Breemen et al., 2007). The risk of recurrence after a single seizure is considerably higher in patients with structural brain pathology than in patients with no other risk factors for recurrence, and can be significantly reduced by prescription of long-term AED treatment (Kim et al., 2006). Therefore, initiation of treatment should be strongly considered in these patients, particularly in the presence of additional risk factors related to the type and location of the tumor and occurrence of interictal electroencephalography (EEG) epileptiform abnormalities (Soffietti et al., 2010). In patients with recurrent seizures, AED therapy is almost invariably indicated.

Which Factors Should Be Considered in AED Selection?

  1. Top of page
  2. Summary
  3. When Should Antiepileptic Drug Treatment Be Started?
  4. Which Factors Should Be Considered in AED Selection?
  5. Choice of Initial Treatment
  6. Managing Patients When Initial Monotherapy Failed
  7. Should AEDs Be Withdrawn in Seizure-Free Patients?
  8. Conclusive Remarks and Future Perspectives
  9. Disclosure
  10. References

Most of the available data on AED efficacy and safety in patients with epilepsy and brain tumors originate from uncontrolled studies, and no large-scale well-designed randomized trial has been performed in this population. Therefore, a fully evidence-based approach to AED selection in patients with epilepsy secondary to brain tumors is not possible at the present time. Factors to be considered in making treatment selection include relative efficacy in specific seizure type, tolerability profile, comorbidities, drug-interaction potential, and cost (Perucca & Tomson, 2011). Some of these factors are especially relevant for people with brain tumors, and will be discussed later in more detail.

Comparative efficacy

There is no evidence that the efficacy ranking of currently available AEDs differs for patients with brain tumors compared with patients with focal seizures from other etiologies. Seizure freedom rates in AED-treated patients with brain tumor vary across studies, presumably due to differences in methodology and characteristics of the population assessed. An early retrospective study from the United States found that 21 (72%) of the 29 patients with malignant gliomas who presented with seizures had subsequent (“recurrent”) seizures despite AED therapy (Moots et al., 1995). In a large population of patients with chronic epilepsy from France, however, seizure freedom rate in patients with brain tumors (46%) was similar to that reported for patients with normal magnetic resonance imaging (MRI) findings (42%), and epilepsy secondary to stroke (54%) or vascular malformations (50%), and greater than for patients with posttraumatic gliosis (30%), malformation of cortical development (24%), and hippocampal sclerosis (11%) (Semah et al., 1998). A United Kingdom study that followed mostly newly diagnosed epilepsy patients found that 52% of AED-treated patients with brain tumor were seizure-free, an outcome intermediate between that reported for posttraumatic epilepsy (35%) and that reported for epilepsies associated with cortical malformations (60%), cerebral atrophy (71%), and cerebrovascular disease (70%) (Mohanraj & Brodie, 2005). In a more recent cross-sectional study from Italy, dysembryoplastic neuroepithelial tumours (DNETs)/low-grade gliomas ranked third, after perinatal damage and mesial temporal sclerosis, in terms of probability of being associated with pharmacoresistant seizures (Fig. 1; Gilioli et al., 2012). Most of the estimates reported in the preceding studies were based on relatively small subgroups, and therefore should be regarded only as indicative. In general, secondary generalization seems to be preferentially affected by AED treatment, and can be completely suppressed, even when focal seizures persist (Hildebrand et al., 2005).

image

Figure 1. Relationship between proportion of patients with pharmacoresistant epilepsy and underlying etiology in a population of 1,115 adults with focal epilepsy who were enrolled consecutively at two epilepsy centers in Italy. Reproduced from Gilioli et al. (2012), with permission.

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Adverse effect profile

Limited evidence suggests that patients with brain tumors show increased susceptibility to the adverse effects of AEDs (Glantz et al., 2000; Van Breemen et al., 2007; De Groot et al., 2012; Maschio, 2012). This could be related to the underlying cerebral pathology, or to an interaction with anticancer therapy. In a study of patients with low-grade gliomas, the presence of epilepsy and exposure to AEDs were identified as independent risk factors for cognitive dysfunction, and AED use was associated with a sixfold increase in the prevalence of cognitive side effects compared with side effects of radiation therapy (Klein et al., 2002). The risk of AED-induced skin rashes, including Stevens-Johnson syndrome, is also increased in patients with brain tumors, an effect which, at least for phenytoin, carbamazepine, oxcarbazepine, and phenobarbital, seems to be related at least in part to exposure to cranial radiotherapy (Moots et al., 1995; Micali et al., 1999; Van Breemen et al., 2007; De Groot et al., 2012; Weller et al., 2012).

Interaction potential and outcome studies in patients receiving chemotherapy

The risk of interactions between AEDs and anticancer agents is a major concern. Enzyme-inducing AEDs such as carbamazepine, phenytoin, and barbiturates stimulate the activity of drug-metabolizing enzymes and enhance by this mechanism the metabolic clearance of many concomitantly administered drugs, including corticosteroids and several anticancer medications (Table 1). These interactions may decrease the effectiveness of anticancer therapy, although in the case of chemotherapeutic agents converted to active or toxic metabolites, the possibility of enhanced toxicity should also be considered. Although some anticancer drugs commonly used in primary brain tumors, such as temozolomide, do not seem to be susceptible to enzyme induction, for others, such as the salvage agents irinotecan, etoposide, and tyrosine kinase inhibitors (e.g., erlotinib and imatinib), the increase in clearance caused by enzyme inducers can be considerable, and may need to be compensated by a corresponding increase in the dose of the anticancer agent (Rossetti & Stupp, 2010). The clearance of many cytotoxic agents used to treat brain metastases from solid tumors is also enhanced considerably by enzyme-inducing AEDs (Table 1). Because enzyme induction is a reversible phenomenon, adjustments in the dosage of previously optimized anti-cancer drugs may be required if enzyme-inducing AEDs are discontinued.

Table 1. Anticancer agents
  1. The metabolism of anticancer agents may be stimulated by enzyme-inducing antiepileptic drugs such as carbamazepine, phenytoin, and barbiturates. Level of evidence varies for each of the interactions listed, interindividual variation can be considerable and not all enzyme-inducing agents share the same effect. For more information and a source of references, the reader is referred to recent reviews (Van Breemen et al., 2007; Weller et al., 2012)

Bortezomib

Carmustine

Cyclophosphamide

Docetaxel

Doxorubicin

Erlotinib

Etoposide

Everolimus

Gefitinib

Ifosfamide

Imatinib

Irinotecan

Lomustine

Methotrexate

Nitrosoureas (carmustine, lomustine, fotemustine, nimustine)

Paclitaxel

Pemetrexed

Sorafenib

Temsirolimus

Thiotepa

Topotecan

Vemurafenib

Vincristine

Vinorelbine

Because drug interactions vary depending on the type of antineoplastic regimen used, an adverse impact of enzyme induction on the outcome of cancer therapy has not been shown consistently in all populations. Specifically, although in some types of cancer, decreased survival after exposure to enzyme-inducing AEDs has been clearly shown (Relling et al., 2000), at least for patients with primary brain tumors, evidence is controversial. A retrospective study of 620 patients with glioblastoma enrolled in clinical trials of various (but ineffective) chemotherapeutic agents before the year 2000 found that overall survival and progression-free survival were paradoxically better in patients receiving enzyme-inducing AEDs (71% of the assessed cohort) than in those not exposed to enzyme inducers, the large majority of whom were not on AED therapy (Jaeckle et al., 2009). Although the authors were unable to identify possible bias, this study has been criticized on methodologic grounds (Rossetti & Stupp, 2010). Of interest, two other studies had reported improved outcomes in patients with brain tumor who were exposed to enzyme-inducing AEDs (Reardon et al., 2005; Groves et al., 2006). One possible explanation for these apparently paradoxical findings is that tumors associated with seizures may be diagnosed earlier, and therefore may have a better prognosis for that reason (French, 2006; Maschio, 2012). The difficulties in interpreting retrospective data are well exemplified by an earlier post hoc analysis of outcomes in 168 patients with glioblastoma who were exposed to standard treatments, including surgery, radiation therapy, and chemotherapy, mostly with chloroethylcyclohexylnitrosourea (CCNU) (Oberndorfer et al., 2005). The median survival of patients exposed to enzyme-inducing AEDs (10.8 months, n = 37) was moderately and nonsignificantly reduced compared with patients without seizures not receiving AEDs (11.6 months, n = 75), and was significantly shorter than that reported in patients taking non–enzyme-inducing AEDs, most of whom were on valproic acid (13.7 months, n = 33). Patients taking non–enzyme-inducing AEDs also showed a higher incidence of hematologic toxicity. Whether the lower survival of patients on enzyme inducers compared with patients mostly treated with valproic acid reflected an adverse effect of enzyme induction or a beneficial effect of valproic acid was unclear. In fact, findings from two subsequent studies suggested that valproic acid may indeed favorably influence prognosis in patients with glioblastoma.

Weller et al. (2011) analyzed the survival data of patients with glioblastoma who were enrolled in a randomized trial of radiotherapy alone versus radiotherapy plus temozolomide (Weller et al., 2011). Valproic acid had no apparent effect on survival for patients treated with radiotherapy alone. Conversely, for patients receiving temozolomide chemoradiotherapy, valproic acid appeared to confer greater survival benefits (hazard ratio [HR] 0.39; CI 0.24–0.63, n = 97) compared with treatment with enzyme-inducing AEDs only (HR 0.69, CI 0.53–0.90, n = 257) or no AED treatment (HR 0.67, CI 0.49–0.93, n = 175). Patients receiving valproic acid, however, were more likely to experience grade 3/4 thrombocytopenia and leukopenia than patients in the other groups. The apparent lack of effect of enzyme inducers on survival in this study is consistent with the report that the clearance of temozolomide, a drug cleared by hydrolysis and renal excretion, does not seem to be influenced by enzyme-inducing AEDs (Weller et al., 2012). Conversely, the improved prognosis in patients treated with valproic acid could be explained by valproic acid's ability to cause a minor reduction in temozolomide clearance (Weller et al., 2012) or, more likely, by some pharmacodynamics properties of valproic acid leading to potentiation of temozolomide activity at the site of action (see subsequent text). An apparently beneficial effect of valproic acid on survival in patients with glioblastoma who were treated with temozolomide chemoradiotherapy has been confirmed recently in a Dutch study (Kerkhof et al., 2013) in a population which included, however, some of the patients also evaluated by Weller et al. (2011). After adjusting for age, extent of resection, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, patients receiving valproic acid with temozolomide for at least 3 months (n = 108) were found to have a median survival of 69 weeks compared with 61 weeks for those receiving other AEDs (mostly levetiracetam, n = 57; HR 0.63; CI 0.43–0.92). Improved survival on valproic acid was also suggested by a study from Brazil that assessed treatment outcomes in children with a variety of malignant brain tumors (Felix et al., 2013). Because all of these studies were retrospective, the possibility of patient selection bias and other bias cannot be excluded, and confirmation in a prospective randomized trial is required.

In laboratory studies, valproic acid has been found to induce apoptosis, autophagy, growth arrest, and cell differentiation of tumor cells through inhibition of histone deacetylase and possibly other mechanisms (De Groot et al., 2012; Weller et al., 2012; You et al., 2012). Inhibition of tumor angiogenesis by valproic acid has also been reported (Osuka et al., 2012). These actions could contribute to inhibit tumor growth, and might explain the apparent prolongation of survival in brain tumor patients treated with valproic acid (Oberndorfer et al., 2005; Weller et al., 2011; Felix et al., 2013; Kerkhof et al., 2013). On the other hand, valproic acid also has intrinsic hematologic toxicity, particularly on platelet function, and inhibits a number of drug-metabolizing enzymes, causing an increase in the serum levels of some anticancer agents. Increased hematologic toxicity has indeed been reported when valproic acid was given in combination with temozolomide (Weller et al., 2011) and with other chemotherapeutic agents, including nitrosoureas, cisplatinum, and etoposide (Bourg et al., 2001; Oberndorfer et al., 2005).

Apart from the effect of AEDs on cancer treatments, a number of interactions have also been reported, whereby anticancer agents can increase or decrease the serum concentrations of AEDs (Van Breemen et al., 2007). To minimize the risk of changes in AED response, serum AED levels should be monitored, if possible, whenever changes are made to concomitant anticancer therapy.

Choice of Initial Treatment

  1. Top of page
  2. Summary
  3. When Should Antiepileptic Drug Treatment Be Started?
  4. Which Factors Should Be Considered in AED Selection?
  5. Choice of Initial Treatment
  6. Managing Patients When Initial Monotherapy Failed
  7. Should AEDs Be Withdrawn in Seizure-Free Patients?
  8. Conclusive Remarks and Future Perspectives
  9. Disclosure
  10. References

Most physicians prefer to initiate treatment with a non–enzyme-inducing AED, to minimize the risks of adverse interactions with anticancer agents (Rossetti & Stupp, 2010). AEDs that are frequently selected as first-line therapy include valproic acid and the second-generation non–enzyme-inducing AEDs lamotrigine, levetiracetam, oxcarbazepine, topiramate, and gabapentin (Rossetti & Stupp, 2010; Maschio, 2012), all of which are approved as initial monotherapy for focal seizures in Europe. Zonisamide is also approved in Europe for initial monotherapy of focal seizures and represents an alternative option, although experience with this agent in patients with brain tumors is more limited. Experience with other second-generation agents such as tiagabine, pregabalin, and lacosamide is mostly restricted to adjunctive therapy (Maschio, 2012).

Therapeutic studies in patients with brain tumor typically consist of retrospective or small prospective case series (Rossetti & Stupp, 2010; De Groot et al., 2012; Rudà et al., 2012), which are often heterogeneous in seizure frequency, tumor histology, disease phase, and exposure to chemotherapy (Rudà et al., 2012). Because of this, it has been difficult to assess treatment response in relation to specific clinical variables. Therefore, treatment choices are largely determined by physicians’ personal judgment and experience, and by individual patient characteristics, as for epilepsies with different etiologies (Perucca & Tomson, 2011).

As discussed in the previous section, valproic acid is considered the treatment of choice by some physicians, at least for glioblastoma patients, in whom there is suggestion of improved survival with this approach. Combined use of valproic acid and chemotherapy, however, may increase risk of hematologic toxicity, which requires careful monitoring. Valproic acid itself can cause thrombocytopenia, platelet dysfunction, and coagulation abnormalities, which represent a concern for patients in whom neurosurgery is envisaged (Gerstner et al., 2006). Although no clear evidence exists that valproic acid increases risk of adverse outcomes in patients undergoing neurosurgery (Ward et al., 1996; Anderson et al., 1997; Psaras et al., 2008), postoperative bleeding has been reported occasionally (Cannizzaro et al., 2007), and some neurosurgeons are accordingly reluctant to operate on patients treated with this drug. A commonly used alternative is levetiracetam, which has low interaction potential, usually good tolerability, and can be uptitrated relatively rapidly. In laboratory experiments, levetiracetam has been shown to enhance p53-mediated inhibition of MGMT, a DNA repair protein that has an important role in tumor cell resistance to alkylating agents, and to sensitize glioblastoma cells to temozolomide (Bobustuc et al., 2010); the clinical relevance of these findings is unknown. In a recent retrospective survey of glioblastoma patients treated at a Dutch center, valproic acid and levetiracetam were the most common initial monotherapies. Initial freedom from seizures was achieved in 41 (41%) of 100 patients taking valproic acid, in 16 (43.3%) of 37 patients taking levetiracetam, and in 89 (76.7%) of 116 patients taking subsequent combination therapy with the two drugs (Kerkhof et al., 2013). The high proportion of patients who went on to combination therapy in this study was explained by physicians’ preference for adding another AED instead of increasing dosage to the highest tolerated level, when seizure control was not achieved rapidly on monotherapy.

As discussed earlier, other second-generation AEDs are at times used in brain tumor patients, although there is limited evidence to support their early use (Rossetti & Stupp, 2010; Maschio, 2012). Although oxcarbazepine has a relatively low interaction potential, it does retain some enzyme-inducing and enzyme-inhibiting properties (Perucca, 2006) and may reduce the serum levels of certain anticancer drugs, such as imatinib (Pursche et al., 2008). At least for lamotrigine, topiramate, and zonisamide, the need for slow-dose titration and the lack of a parenteral formulation can be a disadvantage in this population.

Irrespective of the type of AED initially prescribed, treatment optimization in patients with brain tumor does not differ from that applicable to other forms of epilepsy. Individualized dose titration schemes should be implemented as appropriate, and dosage should be adjusted based on clinical response with the aid, whenever appropriate, of serum drug level monitoring.

Managing Patients When Initial Monotherapy Failed

  1. Top of page
  2. Summary
  3. When Should Antiepileptic Drug Treatment Be Started?
  4. Which Factors Should Be Considered in AED Selection?
  5. Choice of Initial Treatment
  6. Managing Patients When Initial Monotherapy Failed
  7. Should AEDs Be Withdrawn in Seizure-Free Patients?
  8. Conclusive Remarks and Future Perspectives
  9. Disclosure
  10. References

The management of brain tumor patients who do not achieve seizure freedom on the initial AED does not differ substantially from that applied to epilepsies from other etiologies (Perucca & Tomson, 2011). When treatment failure is caused by early tolerability problems such as a skin rash, an alternative monotherapy with an AED not likely to produce similar toxicity is generally warranted. In patients who have shown a partial but incomplete response to the initially prescribed drug at full doses, early introduction of combination AED therapy should also be considered, even though polytherapy can result in a greater burden of side effects. Patients with uncontrolled seizures despite apparently optimal treatment should be reviewed for potentially inadequate compliance. Finally, as in other forms of epilepsy, patients with pharmacoresistant seizures who have a good prognosis for survival should be evaluated for the possibility of epilepsy surgery.

Seizure control can be influenced by the evolution of the tumor and by its treatment. Recurrence of seizures in a patient with previously well-controlled seizures may be related to recurrence or progression of the tumor, to the side effects of cancer therapy (e.g., radionecrosis), or to other causes such as infectious or metabolic encephalopathy (Maschio, 2012). Conversely, resection of the tumor, radiation therapy, or chemotherapy can bring refractory seizures under control or prolong the duration of seizure freedom (Kahlenberg et al., 2012; Maschio et al., 2012; Rudà et al., 2012; Weller et al., 2012). In a recent nonrandomized study in patients with epilepsy and low-grade gliomas, the proportion achieving a >50% reduction in seizure frequency was greater among those treated with temozolomide in combination with AEDs (59%, n = 39) than in those treated with AEDs alone (13%, n = 30, p < 0.001; Sherman et al., 2011). It has been noted that improvement in seizure control after exposure to chemotherapy or radiation therapy often occurs without MRI evidence of tumor shrinkage (Sherman et al., 2011; Rudà et al., 2012). This suggests that, in addition to an effect on tumor mass, anticancer therapy may have direct effects on epileptic neurons or induce changes in the microenvironment in peritumoral tissue.

Should AEDs Be Withdrawn in Seizure-Free Patients?

  1. Top of page
  2. Summary
  3. When Should Antiepileptic Drug Treatment Be Started?
  4. Which Factors Should Be Considered in AED Selection?
  5. Choice of Initial Treatment
  6. Managing Patients When Initial Monotherapy Failed
  7. Should AEDs Be Withdrawn in Seizure-Free Patients?
  8. Conclusive Remarks and Future Perspectives
  9. Disclosure
  10. References

For brain tumor patients with epilepsy who achieve seizure freedom, the possibility of withdrawing AEDs should be considered. In general, AED withdrawal is more likely to be attempted in seizure-free patients with a successfully treated tumor and an overall good prognosis for long-term survival. Because no well-designed randomized AED withdrawal studies have been conducted in these patients, treatment decisions have to rely on extrapolation of results from other epilepsy populations, and limited evidence from uncontrolled studies. Factors that may impact on the risk–benefit ratio include seizure history, underlying pathology, outcome of surgical, radiation and medical treatment of the tumor, presence of AED side effects, and patient preference. In a retrospective study of 62 children with a variety of brain tumors in whom AEDs were withdrawn after a median of 5.6 years from the first seizure, and a median of 1.3 years without seizures, seizure recurrence rate was 27% over 5 years, with half the recurrences within the first 6 months (Khan and Onar, 2006). The strongest predictors of recurrence were more than one tumor resection, whole brain radiation therapy, and nonposterior fossa tumor, with a 47% recurrence rate over 2 years when all three predictors were present. A more recent retrospective study reviewed the seizure outcomes of patients with low-grade brain tumors and meningiomas over a median follow-up of 3.1 years (Das et al., 2012). Of 111 patients who were never started on AEDs or had AEDs withdrawn, only 11 (9%) developed seizures, whereas of 58 patients continuing on AEDs, 28 (48%) developed seizures. These findings were interpreted as evidence that physicians were able to identify those patients in whom discontinuation of AEDs would be least likely to cause recurrences of seizures.

Conclusive Remarks and Future Perspectives

  1. Top of page
  2. Summary
  3. When Should Antiepileptic Drug Treatment Be Started?
  4. Which Factors Should Be Considered in AED Selection?
  5. Choice of Initial Treatment
  6. Managing Patients When Initial Monotherapy Failed
  7. Should AEDs Be Withdrawn in Seizure-Free Patients?
  8. Conclusive Remarks and Future Perspectives
  9. Disclosure
  10. References

Current evidence does not support prescription of AEDs in patients with brain tumors who do not present with seizures. For seizure patients, the preferred treatment is currently a non–enzyme-inducing AED. Because of the lack of well-controlled trials, the decision on which AED provides the best risk–benefit ratio in the individual patient is based mostly on physician judgment rather than sound scientific evidence.

There is a great need for high-quality randomized studies to assess the comparative value of different treatments in brain tumor patients with seizures. A more rational treatment approach could be made possible by identification of predictors of response to specific AEDs. For example, a recent study provided preliminary evidence that the expression of synaptic vesicle 2A (SV2A) in tumor and peritumoral tissue may predict responsiveness to the antiseizure effect of levetiracetam in patients with glioma (De Groot et al., 2011). If these findings are confirmed, they could lead to a noninvasive test based on neuroimaging or other biomarkers, to identify individuals benefiting from this drug. Finally, renewed efforts in translational research are required to develop more effective agents to prevent and control seizures associated with brain tumors. Ideally, these treatments should target the epileptogenic processes operating in specific tumor types. Examples of potentially valuable compounds that are currently in preclinical or clinical investigation include sulfasalazine, a blocker of the cystine-glutamate antiporter (system Xc), to inhibit glutamate release, seizures, and tumor growth in glioma (Buckingham et al., 2011; Sontheimer & Bridges, 2012); bumetanide, an inhibitor of the sodium-potassium-chloride cotransporter isoform 1 (NKCC1), to inhibit tumor progression and inhibit seizure activity associated with glioma (Haas & Sontheimer, 2010; Conti et al., 2011; Algharabil et al., 2012); and everolimus to treat subependymal giant cell astrocytoma and reduce seizure frequency in patients with tuberous sclerosis complex (Krueger et al., 2010).

Disclosure

  1. Top of page
  2. Summary
  3. When Should Antiepileptic Drug Treatment Be Started?
  4. Which Factors Should Be Considered in AED Selection?
  5. Choice of Initial Treatment
  6. Managing Patients When Initial Monotherapy Failed
  7. Should AEDs Be Withdrawn in Seizure-Free Patients?
  8. Conclusive Remarks and Future Perspectives
  9. Disclosure
  10. References

The author has received speaker's or consultancy fees from Eisai, GSK, Lundbeck, Medichem, Sun Pharma, Supernus, UCB Pharma, Vertex, and Viropharma. The author confirms that he has read the Journal's position on issues involved in ethical publication and affirms that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. When Should Antiepileptic Drug Treatment Be Started?
  4. Which Factors Should Be Considered in AED Selection?
  5. Choice of Initial Treatment
  6. Managing Patients When Initial Monotherapy Failed
  7. Should AEDs Be Withdrawn in Seizure-Free Patients?
  8. Conclusive Remarks and Future Perspectives
  9. Disclosure
  10. References
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