Management of brain tumor-related epilepsy
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/neuroindia.NI_1076_16
Source of Support: None, Conflict of Interest: None
Seizures are common in both primary and metastatic brain tumors, although the rate of seizures differ significantly between the different types of neoplasms. Patients with brain tumor-associated seizures need treatment with antiepileptic drugs (AEDs) to prevent recurrence, whereas strong clinical data exists to discourage routine prophylaxis in patients who have not had seizures. The newer AEDs, such as levetiracetam, lamotrigine, lacosamide, topiramate, or pregabalin, are preferable for various reasons, primarily related to the side-effect profile and limited interactions with other drugs. If seizures persist despite initiation of an appropriate monotherapy (in up to 30–40% of cases), additional anticonvulsants may be necessary. Early surgical intervention improves seizure outcomes in individuals with medically refractory epilepsy, especially in patients with a single lesion that is epileptogenic. Data for this review article were compiled by searching for scholarly articles using the following keywords: brain tumor, epilepsy, seizure, tumor-related epilepsy, central nervous system, epidemiology, review, clinical trial, and surgery. Articles were screened for relevance by title and abstract, and selected for review and inclusion based on significant contribution to the topics discussed.
Keywords: Epilepsy, seizure, tumor
Seizures are a relatively common presentation in both primary and metastatic brain tumors [Table 1]. Approximately 30–50% of patients with brain tumors experience a seizure at presentation. An additional 10–30% will develop seizures at some point during the course of their disease.,,, It is important to note that the incidence of brain tumors as a cause of epilepsy is actually quite low, accounting for only approximately 4% of all patients with epilepsy.,
Difficulty in managing epilepsy in patients with brain tumors stems from an overall resistance to medical therapy, frequent interactions between antiepileptic drugs (AEDs) and chemotherapeutic agents, and potential adverse effects of both medical and surgical treatment. Moreover, seizures significantly impact the quality of life, and continued seizures are associated with a poorer outcome. This review will focus on discussing the literature that investigates tumor-related epilepsy in the context of understanding practice guidelines for AED use and management of refractory cases.
The pathogenesis of tumor-related epilepsy is not precisely known, though it certainly has a multifactorial pathogenesis [Figure 1]. The emergence of seizures may be caused by tumor histology and location, changes in neurotransmission, disruption of the blood–brain barrier, changes in gap junctions, molecular alterations, and alterations of the peritumoral environment, among other factors.
Tumor histology and location
The incidence of epilepsy varies among patients with different types of primary brain tumors [Table 1].,,,,,,, For example, patients with gliomas are more likely to experience seizures with a low-grade pathology compared with a high-grade one., A review of 1028 patients with primary brain tumors showed a difference of 49%, 69%, and 85% seizure prevalence in patients with World Health Organization (WHO) grade IV [glioblastoma multiforme (GBM)], WHO grade III (anaplastic glioma), and low-grade glioma, respectively. Dysembryoplastic neuroepithelial tumors (DNETs) and gangliogliomas are developmental brain tumors that have a very high seizure incidence (>80%)., The rate of tumor-related epilepsy differs on the basis of tumor location with the cortical location of the tumor commonly associated with the development of epileptic seizures. In contrast, infratentorial and sellar tumors rarely present with seizures. Further, occipital lobe lesions are less frequently associated with seizures than frontal, temporal, or parietal lobe lesions. In one study involving 112 patients with primary brain tumors, seizure rates with parietal, temporal, frontal, and occipital masses were reported to be 80%, 74%, 62%, and 0%, respectively. Lesions involving the mesial temporal lobe, insula, and other paralimbic structures are more likely to give rise to intractable epilepsy than those located in other brain regions., Interestingly, patients with metastatic brain lesions often experience seizures less frequently than those who have primary brain masses.,, Among different metastatic lesions, however, the seizure incidence also varies. Thus, seizures are quite common in metastatic melanoma with rates as high as 67%. This is thought to be related to the presence of multiple lesions, hemorrhage, and involvement of gray matter.,
Epileptogenesis is also affected by the type of primary tumor. In DNETs where the incidence of seizures approaches 100%, underlying developmental structural abnormalities such as cortical dysplasia also contribute to the generation of seizures [Figure 2]. The relatively high incidence of seizures in low-grade lesions may be due to slowly developing focal abnormalities by mechanical or vascular changes that partially isolate brain regions. Seizures seen in high-grade lesions may be due to the rapid tissue damage caused by necrosis or hemosiderin deposition [Figure 3]., 10, ,,,, In general, the seizure onset tends to be from the peritumoral tissue. It can be at a significant distance from the tumor margin and is usually eccentric to the tumor.
The exact mechanism by which tumors cause epileptogenesis in patients with brain tumors is unclear and is likely to be multifactorial and varied among different tumor types [Figure 1]. Animal studies of glioma have demonstrated increased glutamate (the principal excitatory neurotransmitter of the brain) release and neuronal hyperexcitability in the peritumoral region generating seizure activity. Surrounding peritumoral cortex may be spontaneously hyperexcitable because astrocytes in the peritumoral region lose their ability to regulate extracellular glutamate. A study of human tissues by Wolf et al., compared markers of glutamate and γ-aminobutyric acid (GABA; the principal inhibitory neurotransmitter of the brain) neurotransmission in resected tissues of patients affected by lesion-associated medically refractory epilepsy with similar lesions from patients who did not have chronic epilepsy. Specifically, they used immunohistochemistry to examine tissue slides for the presence of GABAA receptor, N-methyl-D-aspartate (NMDA) receptor subunit 1, and glutamate decarboxylase – the rate-limiting enzyme in the synthesis of GABA. The authors found that 73% of the specimens from patients with chronic epilepsy had distinct differences in these markers between the perilesional region and adjacent normal cortex. These results suggest that the balance between excitatory and inhibitory transmission is disrupted between lesional and adjacent normal cortex, which may contribute to focal seizure generation.
Another proposed mechanism by which brain tumors may induce seizures is through dysfunction of adenosine-mediated neurotransmission and dysregulation of adenosine kinase (ADK)., A study published in 2012 by de Groot et al., examined surgically-excised tumor tissue, peritumoral cortex, and normal cortical tissues obtained on autopsy to compare ADK expression levels in patients with and without epilepsy. Their results showed a stronger immunoreactivity for ADK in tumoral and peritumoral tissues compared to normal cortex or white matter, and expression of ADK was significantly higher in infiltrated peritumoral tissue from patients with epilepsy than those without. These results suggest that upregulation of ADK in peritumoral tissue may contribute to tumor-related epilepsy.
Blood–brain barrier disruption
Central nervous system (CNS) neurotransmission requires a tightly regulated microenvironment. The blood–brain barrier, at the level of the microvascular endothelium, is the major site for blood-CNS isolation or exchange of ions, neurotransmitters, macromolecules, neurotoxins, and nutrients. It has been suggested that disruption of the blood–brain barrier may contribute to the pathogenesis of tumor-related epilepsy. Animal models have shown epileptiform activity involving both glutamatergic and GABAergic transmission after disruption of the blood–brain barrier. Brain tumors can decrease the expression of junctional proteins such as claudin-1 and claudin-5. Increased release of vascular endothelial growth factor (VEGF) has also been reported,, which can exacerbate cerebral edema and contribute to seizure activity. Transforming growth factor beta (TGF-β) receptor stimulation may also contribute to epileptogenesis in these patients by causing accumulation of extracellular potassium and stimulation of NMDA-mediated hyperexcitability. Further, blocking TGF-β receptors has been shown to decrease the likelihood of epileptogenesis in vivo.
Gap junctions allow adjacent cells to communicate, and changes in tumoral and peritumoral gap junctions may play a role in tumor-related epilepsy. Glial cells, especially astrocytes, have a greater number of gap junctions than neurons, and the major protein involved in astrocytic gap junctions is connexion 43 (CX43). CX43 has been found to have increased expression in low-grade versus high-grade tumors and control brain tissue., This change was also seen in the peritumoral reactive astrocytes. If this differentially increased expression of CX43 seen in low-grade gliomas contributes significantly to the development of epileptogenesis, it may explain the difference in seizure incidence seen between low- and high-grade gliomas. Moreover, studies have shown that blocking communication at the level of gap junctions may have anticonvulsant effects.,
Molecular genetic changes
The genetic basis for some conditions that develop CNS tumors such as von Hippel–Lindau, tuberous sclerosis and neurofibromatosis are well understood. However, the contribution of genetic changes to the development of tumor-related epilepsy is not currently known. Genomic stability in tumors is decreased, which may lead to DNA strand breakage, rearrangements, mutations, and changes in gene expression. Some data exists to support the statement that downregulation of LGI1 (a tumor-suppressor gene) may lead to glioma progression,, and mutations in this gene can cause epilepsy.,, Other reports suggest that LGI1 may participate in cell-matrix interactions. Mutations in the phosphatase and tensin homolog (PTEN) tumor suppressor gene are found commonly in glioblastoma. Interestingly, animal models examining mutations in PTEN also result in seizures and neuronal changes similar to those seen in Lhermitte–Duclos disease. Several putative common pathways for the development of both glioma and tumor-related epilepsy have been reported, including changes in cytokines, neurotransmission, cell cycle control, DNA repair, apolipoprotein E, and neurotrophic factors.
Peritumoral environmental changes
The microenvironment within and surrounding the brain tumor differs substantially from normal brain tissue. Changes in tumoral and peritumoral neurotransmission have been already discussed. In addition, tumors often alter the permeability of new and existing vascular supply leading to breakdown of the blood–brain barrier. Growing intracranial lesions can lead to vasogenic edema, vascular insufficiency, inflammation, and altered metabolism. Studies using magnetic resonance spectroscopy have demonstrated decreased N-acetyl aspartate in the perilesional cortex, which correlated with the degree of edema. Tumoral hypoxia occurs from insufficient vascular supply and contributes to interstitial acidosis., This increases inward sodium currents ,, and NMDA receptor closure. Increased peritumoral sodium and calcium can also contribute to neuronal hyperexcitability.,,,
Not surprisingly, patients with tumor-related epilepsy can experience significant morbidity, cognitive deterioration, and decreased quality of life.,,, Seizures exhibited by patients with brain tumors are either partial or secondarily generalized tonic–clonic seizures. Patients who experience focal seizures will have a clinical presentation that is dependent upon the exact tumor location. For example, frontal lobe tumors may cause tonic–clonic movements involving one extremity whereas occipital lobe lesions are likely to cause visual disturbances. Other findings can include abrupt changes in behavior, neurologic status, or sensations such as abnormal smell or taste. While tumor-associated seizures may vary widely between individuals, they are typically stereotypic for each patient. Auras usually represent focal seizures, and the seizure may be followed by a variable postictal phase that may include fatigue, Todd's paralysis, agitation, or even frank psychosis, especially in case of a cluster of seizures. In addition, patients with both primary and metastatic brain tumors can suffer from status epilepticus. Status epilepticus is a medical emergency that carries high rates of mortality. A retrospective study by Cavaliere et al., examined 35 patients who experienced status epilepticus (SE) in the presence of a brain tumor. In the study, 57% patients were taking AEDs at the time of SE, although 55% of the patients were subsequently found to have low AED serum levels. SE occurred at the time of tumor diagnosis in 29% of the patients. While 16% of the patients with glioma or metastatic disease experienced radiologically stable SE, approximately 60% of SE in patients with meningioma had a stable disease. The thirty-day mortality in this series was reportedly 23%. When data from available, mostly retrospective, studies are examined, it appears that patients in SE with brain tumors have higher mortality rates than those who do not. In total, approximately 7% of all cases of SE are caused by brain tumors.
A 2009 observational study examined the medical records of 140 patients with brain tumors. The authors report that, in their cohort of 33 patients with a low-grade glioma, 75 patients with a high-grade glioma, and 32 patients with other tumors (meningiomas, brain metastases, ependymomas), 99 patients developed epilepsy throughout the course of their disease. Among patients with a low-grade glioma, 69.7% initially presented with an epileptic seizure. This differed from those who had a high-grade glioma (52%) or other brain tumors (25%). Low-grade tumors tended to experience secondary generalized seizures (40%), whereas high-grade gliomas most commonly experienced simple partial seizures (38%). Patients with other tumor types also most commonly had simple partial seizures (78.6%), and SE was noted in 5% of all patients in this study. Interestingly, seizure frequency or development of seizures was not associated with tumor progression. However, seizures at presentation may be a good prognostic sign for patients with GBM. Seizures later in the disease process, seizure recurrences, or SE during the course of the disease may be indicative of tumor progression.
Seizures represent an important source of morbidity in patients afflicted with brain tumors. Patients with brain tumors who have seizures are at increased risk of additional seizures,,, and thus require treatment with anticonvulsants. The definition of epilepsy was modified in 2014 and now includes at least two unprovoked (or reflex) seizures occurring >24 hours apart or one unprovoked (or reflex) seizure and a probability of further seizures of at least 60% occurring over the next 10 years. In most instances, having a brain tumor and a single seizure now will qualify for diagnosis of epilepsy. Hence, an unprovoked seizure in a patient with brain tumor should be treated with AEDs.
Choice of antiepileptic drugs
While limited number of randomized controlled trials have been performed to examine the superior efficacy of any one AED, it is generally recommended that clinicians begin treating patients with brain tumors experiencing seizures with newer AEDs such as levetiracetam, lamotrigine, lacosamide, topiramate, and pregabalin [Table 2].,,,,,,,,,,,,,,, These medications tend to have fewer interactions with cytotoxic drugs (CTD) [Table 3],,,, and lower side effect profiles.,,,, A retrospective study examined 282 patients with supratentorial brain tumors receiving either levetiracetam or valproic acid (VPA) treatment. In this study, the authors examined the rates of postoperative (<1 month) seizure rates as well as complications associated with AEDs. While the postoperative seizure rates were not significantly different between the two agents (7.8 and 6.5% respectively), complications were significantly higher in the VPA group compared to the levetiracetam group (26.8% versus 9.8%). Small trials examining drug efficacy have been reported in the literature, and are also reviewed elsewhere.,,,, A single-centre study of 140 patients with brain tumors reported that their most commonly used monotherapy agents were VPA (80%) and carbamazepine (12%). In this study, patients with a high-grade glioma required two AEDs in 63% of the patients versus 36% in patients with a low-grade glioma and in 29% of patients with other brain tumors. These data might suggest that seizures are more difficult to control medically in patients with a high-grade glioma. Seizure treatment with VPA or with the combination of VPA and levetiracetam had the best rates of seizure freedom (52% and 59%, respectively). In a small phase II randomized study, levetiracetam and pregabalin were shown to have efficacy as monotherapy for the treatment of tumor-related epilepsy, with rates of seizure freedom of 65% and 75%, respectively. Importantly, these drugs also have some of the lowest rates of drug interactions. The type of seizure a patient experiences will also affect the AED choice.
Common medical management problems in patients with brain tumors include seizures, venous thromboembolism, cognitive dysfunction, fatigue, and medication side effects. As these patients with additional comorbidities often require many additional medications, treating these patients presents a therapeutic challenge. Patients with brain tumors often also benefit from treatment with chemotherapy. Minimizing drug–drug interactions is paramount in choosing the proper AED. A review by Yap et al., examined drug interactions specifically between AEDs and chemotherapeutics. They identified carbamazepine, phenytoin, phenobarbital, and primidone as having substantial cytochrome P450 inducing effects, and VPA as having a major CYP450 inhibitory effect. These data serve to caution physicians in prescribing these AEDs for patients taking chemotherapeutics, increasing the need for careful monitoring of both AEDs and CTDs to ensure a therapeutic range without toxicity. As previously mentioned, some of the newer AEDs have fewer drug–drug interactions, and are thus more suitable to treat this patient population. Of course, AEDs themselves have side effects. In one series of patients with a malignant glioma who received long-term AED treatment with phenytoin, phenobarbital, carbamazepine, or valproate for seizures, 26% of the patients experienced rash whereas 14% experienced other adverse events.
One frequently cited cause for refractory epilepsy is overexpression of proteins leading to multidrug resistance. These proteins, such as P-glycoprotein, MRP1, and MRP5, act at the level of the blood–brain barrier to actively transport lipophilic drugs (like many AEDs) through the capillary endothelium.,,,, Interestingly, levetiracetam and VPA may not be substrates for these proteins, thus contributing to their better efficacy in these patients.,,
Monotherapy versus combination therapy
Treating seizures with monotherapy compared to multidrug regimens offers a safer therapeutic window, increased compliance, and is more cost effective. However, additional agents are sometimes necessary if patients experience breakthrough seizures unresponsive to dose escalation and monotherapy switching. Unfortunately, this appears to be a common event in patients experiencing seizures with brain tumors. In one series examining 99 patients, 54 patients did not respond to a single AED therapy. In these patients, the most effective combination therapy appeared to be VPA and levetiracetam. Despite optimal medical management, some studies report that as many as 60–70% of the patients will continue to have seizures., If seizures are not controlled with two AEDs, the addition of a third or fourth medication often has no benefit and these multiple drugs are utilized less frequently. When more than one AED is utilized, a concept of rational polytherapy should be followed and a good working knowledge of the AED is necessary to avoid drug-related side effects and drug–drug interactions.
While it is important to treat seizures in patients with primary or secondary brain tumors, prophylactic AED use is not recommended in the absence of a history of seizures., 11, ,,, A Cochrane review has systematically examined the use of AEDs for seizure prophylaxis in patients with brain tumors. In the study, the authors use first seizure occurrence as their primary outcome and adverse events as their secondary outcome. They included five randomized controlled trials totalling 404 participants. The review concluded that there was no difference in prevention of a first seizure between treatment (phenytoin, phenobarbital, or divalproex sodium) and control groups. As one might expect, the risk of adverse events was higher among those who received AEDs than those who did not (number needed to harm (NNH) 3, risk ratio (RR) 6.10, P = 0.046). These findings suggest that AEDs should not be used routinely for the prophylaxis of seizures in patients with brain tumors because they are not effective in preventing seizures and, in fact, cause harm through adverse events. However, some data exists to suggest that metastatic melanoma might be an exception to this rule. Risk factors for increased rates of seizures, and thus the impetus for prophylactic therapy, included hemorrhage, and multiple supratentorial lesions. The use of prophylactic treatment is discouraged not only because of their questionable efficacy in these patients, but because some AEDs are also known to interact with cytotoxic chemotherapeutics and steroids [Table 3]. In addition, AEDs themselves carry side effects that must be weighed against the potential benefit that the drug has to offer.
Some data exists to show that treatment of the brain tumor itself with radiotherapy and/or chemotherapy may improve seizure control.,,, Interestingly, this benefit does not necessarily correlate with changes in tumor burden on magnetic resonance imaging (MRI) or overall survival.,, A systematic review of 24 studies examined the benefits of antitumor treatment with either radiotherapy or chemotherapy on rates of tumor-related epilepsy. While not all studies reported reductions in tumor burden or benefits of treatment, all studies did report improvement in seizure outcomes after antitumor treatment.,
It is important that assessment of response to seizures from studies be well-defined and, ideally, uniform so that results may be compared between studies. Response to AED therapy in trials is usually defined as either a 50% reduction in seizure frequency from baseline or occasionally as seizure freedom. To this end, a seizure assessment tool has been proposed by Avila et al., that utilizes seizure classification, frequency, outcome, and severity to generate a composite score. Assessment tools such as this may be used clinically to aid in identifying disease progression before radiographic evidence is available  and in identifying effective therapy.,,
As surgery is the mainstay of brain tumor treatment, surgical interventions are employed more readily in tumor-related epilepsy than in any other type of epilepsy. The surgical therapy in a vast majority of the patients is directed to the tumor and not towards treating epilepsy per se. In patients who have failed monotherapy with two first line agents, surgery may be recommended if there is a correctable lesion.,, Patients with brain tumors usually fit in this category, and can benefit significantly from surgery. A properly thought out process ahead of tumor resection can provide a window of opportunity to address seizures during the same setting. This might not only cure or slow their tumor progression but might also decrease or eliminate seizures., A study of 207 patients with tumor-related epilepsy showed that 82% of the patients became seizure-free following surgery. A short duration of seizures before surgery and a single seizure focus improves outcomes for seizure freedom. A broader review of the literature consisting of 773 patients with tumor-related epilepsy reported within 20 series shows that approximately 71% of patients will achieve postoperative seizure freedom. This success was found to be proportionately higher among those who underwent gross total resection versus subtotal resection of the tumor. In a small series examining 36 patients with mesial temporal lobe tumors and seizures, most being resistant to AEDs, older patients, a large tumor size, and invasion beyond the mesial temporal lobe were associated with poor outcomes. Interestingly, they also found that a short duration of seizures was associated with a more aggressive disease, and those patients who had a mesial temporal lobe tumor were associated with chronic epilepsy. Epileptic patients who have DNETs or gangliogliomas are often good candidates for surgery because their epilepsy is exceptionally resistant to medical management.,
Studies using EEG mapping have shown that structural lesions can cause epileptic foci in the neighbouring or even remote areas of the brain., Maximum resection of the lesion offers the best chance for seizure freedom, though subtotal resections that include the lesion or epileptic focus will likely benefit the patient. Careful mapping is required to identify individuals in which the lesion may not be the primary epileptogenic focus. Approaching these patients with epilepsy surgery may be required to achieve maximal seizure freedom. Seizures occurring in patients with brain tumors can also be treated by addressing the mass regardless of whether or not the seizures are controlled with AEDs. In particular, improved seizure outcomes have been associated with finding a single lesion on imaging, a short duration of seizure disorder prior to surgery, finding a single focus on electroencephalography (EEG), and complete tumor resection. A systematic review reported that 87% of the patients who underwent gross total resection were seizure free versus 55% of those who had a subtotal resection. Of course, surgical planning must still weigh the potential benefits of surgery against the possible postsurgical morbidity. Surgery itself is not a benign treatment modality. Seizures may occur in the early postoperative period in approximately 15% of patients who undergo supratentorial tumor resection in addition to the other risks of surgery.
Tumors associated with long-term intractable epilepsy, for example, those in the mesial temporal lobe or insula, and childhood lesions such as glioneuronal tumors should be given additional consideration for an early surgical intervention not only for its reported superior treatment efficacy but also for achieving an increased quality of life and patient satisfaction., 114, ,,,,, Not surprisingly, the extent of surgical resection may correlate with the degree of seizure freedom postoperatively in these patients as well as those with many additional tumor types examined in other studies.,,,, Other factors that were found to predict postoperative seizure freedom are the time until surgery, localization of foci, concordant MRI and EEG findings, and lack of secondary generalization.
Surgical management of patients with tumor-related epilepsy begins with attempting to localize the seizure focus with routine scalp EEG. EEG measures the electrical field in the scalp that is generated by groups of neurons within the brain. Often, this provides insufficient data to allow an accurate localization for surgical planning. Mapping with invasive EEG (iEEG) monitoring leads to improved localization and outcomes, and includes those procedures which place electrodes (peg electrode, subdural grid, strip electrode, depth electrode) closer to the surface of the brain [Figure 4]. Electrocorticography (ECoG) uses subdural or depth electrodes to record activity directly from the brain. This technique may be used intraoperatively for short periods of time or extraoperatively for hours to days [Figure 4]. Stereoencephalography (SEEG) is a technique that uses multiple depth electrodes to record activity within the brain. The use of iEEG is recommended when scalp EEG is insufficient (e.g., shows bilateral ictal discharges, excessive artefacts); there is localization disagreement between imaging, scalp EEG, and neuropsychological testing; there is involvement of the eloquent cortex; lateralizing of the dominant epileptogenic temporal lobe is required., After electrodes are implanted, patients are kept on long-term video EEG monitoring until several seizures (3–5) are captured. This allows for the definition of the area of seizure onset as well as any surrounding tissue capable of generating or maintaining seizures. Surgery may then proceed to remove the tumor and the associated seizure foci. This may be accomplished through the use of ECoG or an awake craniotomy if the area involves the eloquent cortex.
In conclusion, current data supports the use of AEDs for the treatment of tumor-related epilepsy. Therapy should begin with the use of a newer AED as monotherapy [Table 2]. If this treatment fails, a second monotherapy may be tried. Subsequent attempts to control seizures might include combinations of first or second line agents. Surgical intervention may be necessary to obtain additional seizure relief if the medical management continues to fail. Factors associated with postoperative seizure freedom are the time until surgery, localization of foci, concordant MRI and EEG findings, and lack of secondary generalization. Patients with brain tumor-related epilepsy should be referred to an epilepsy center early in the course of the disease to maximize the likelihood of seizure freedom and improve the quality of life.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]