Epilepsy occurs in 13% of all cancer patients and accounts for 5% of neurological manifestations. Half of all seizures in systemic cancer are associated with brain or leptomeningeal metastasis [1, 2]. Epilepsy may be the first sign of cancer either as manifestation of a primary brain tumor or from systemic cancer that presents with brain metastasis. Seizures are also an early sign of paraneoplastic encephalomyelitis, an intriguing albeit rare manifestation of cancer.

Seizures occur as the presenting symptom in 18% of patients with brain metastases; another 15% develop seizures later in the course of the disease [1, 4, 5]. The incidence varies from 16% with breast cancer, 21% with gastrointestinal metastases, 29% in lung cancer patients and up to 70% with melanoma, possibly due to its predisposition for intratumoral hemorrhage. In a retrospective study of 470 patients with brain metastases of any type, 24% of patients had one or more seizures at any point in their disease course [6]. The incidence can be higher for patients with metastases involving or adjacent to brain regions of high epileptogenicity, such as motor cortex, and in patients with multiple brain metastases.

About one-third of patients with meningioma present with epilepsy, of whom 70% have secondary generalized and 30% partial seizures. Seizures are more frequently seen with convexity-based lesions than with tumors in other regions, and are more common in the presence of manifest peritumoral edema [7–9]. Epileptic seizures occur in 30% of patients before surgery and in 26.6% patients after surgery. Of patients with preoperative epilepsy, 59.0% become seizure-free after surgery, and 20% of those without preoperative seizures will develop epilepsy after surgery. Risk factors for postoperative epilepsy are preoperative epilepsy, surgical complications including CNS infections, repeat craniotomy, intracranial hemorrhage, and tumor progression. Postoperative improvement or recovery from preoperative neurologic deficits is associated with improved seizure control [8, 9].

In addition to tumor type and grade, tumor location influences the incidence of epilepsy. Tumors located in superficial cortical areas are more likely to be associated with seizures as are as lesions centered in the temporal lobe, frontal lobe, or insula [5, 19–21]. Inherent epileptogenicity of structures in the mesial temporal lobe contributes to seizure generation in this region [22, 23]. Additionally, localization of tumor to eloquent or near-eloquent brain increases risk for seizures [24–26].

Low-grade brain tumors have a stronger predilection for epileptogenesis than more malignant brain cancers. In comparison to higher grade tumors such as glioblastoma, low-grade brain malignancies including gliomas more frequently present with seizures despite being larger in size at the time of discovery [21, 27]. This may be explained by the slow growth rate associated with low-grade lesions which favors development of seizure-prone changes like de-afferentation and disconnection of cortical areas leading to denervation hypersensitivity [28]. This slower rate of growth may also permit adaptive changes of the surrounding brain tissue to occur, thereby diminishing the development of focal neurological deficits.

Brain tumors can also affect the brain network distant to the original site, leading to disruptions in functional connectivity in remote areas [29]. Alterations in microenvironment including hypoxia and acidosis induce swelling and cell damage together with deregulation of sodium and calcium influx with generation of electrical impulses. Overexpression of voltage-gated sodium channels as well as changes in the SV2A synaptic vesicle protein associated with calcium accumulation may facilitate recurring generation of action potentials around tumor cells [30].

Molecular genotypes also contribute to seizures. Solitary 19q loss associated with anaplastic tumors and temporal lobe location [14] has been associated with secondary generalized seizures [31]. The presence of mutations in the mTOR pathway and BRAF V600E mutations as seen in 50% of gangliogliomas increases the risk for seizures [32]. Likewise mutations of codon 132 isocitrate-dehydrogenase 1 (IDH1), which are present in 71–88% of grade II astrocytomas and oligodendrogliomas are associated with seizures [33–36]. The IDH1 enzyme belongs to the Krebs citric acid cycle, catalyzing the conversion of isocitrate into alpha-ketoglutarate. Instead, the enzymatic product of the mutated gene produces 2-hydroxyglutarate. The latter structurally resembles glutamate, which may activate NMDA receptors with ensuing seizure activity. Altered expression of glutamate transporters, including the cysteine-glutamate transporter (xCT) system , increases the concentration of extracellular glutamate, which contributes to epileptic discharge, tumor proliferation, and peripheral excitotoxicity [37, 38]. Furthermore, dysregulation of intracellular chloride promotes glioma cell mitosis and migration, and γ-aminobutyric acid (GABA) signaling suppresses proliferation. In neurons, however, chloride accumulation leads to aberrant depolarization on GABA receptor activation, thereby promoting epileptic activity [26, 38]. Disturbances of chloride balance in gliomas are secondary to changes in chloride cotransporters by reduced KCC2 and increased NKCC1 expression with accompanying changes in GABA metabolism [39]. Glutamergic stimulation of NMDA- and AMPA-receptors activates intracellular mTOR, AKT, and MAPK signaling pathways leading both to cell growth and to epileptogenesis [40, 41].

In about half of cases, the first epileptic event presents as a generalized seizure, while partial seizures predominate thereafter [42]. In low-grade gliomas, seizures most frequently present as secondarily generalized seizures (70%), followed by simple partial seizures (24%), and complex partial (7%) [24]. In glioblastoma, the most frequent presenting seizure semiology is that of secondary generalization in 40% of cases, followed by partial seizures in 37% and both partial and generalized seizures in 14.4% [16, 43]. Status epilepticus is observed in 12% of cases [43].

In patients presenting with epilepsy, the number of seizures and their duration prior to surgery are predictive of postoperative seizure behavior [24, 44]. Furthermore, the underlying tumor histology can influence seizure control. DNETs show a postoperative seizure control of 83% compared to 78% in patients with gangliogliomas (Table 9.3) [13, 45].

Surgery plays an important role in seizure control . Rates of complete seizure freedom postoperatively range from 45 to 100%. In a systematic review on DNETs and gangliogliomas, 80% of patients with tumor-related epilepsy preoperatively became seizure free after surgery [13, 45–47]. The presence of preoperative partial seizures was associated with 87% seizure freedom after resection, as compared to 73% for generalized seizures. Duration of seizures shorter than one year and extensive tumor resection are both favorable prognostic factors for postoperative seizure control. This suggests that earlier intervention may lead to better control and that residual tumor increases the risk of postoperative seizures [45].

In low-grade gliomas , prognostic factors for good postoperative seizure control include generalized seizures, preoperative seizure control, extra-temporal location, and a gross tumor resection within <1 year after presentation [24, 48, 49]. Overall, seizure freedom is achieved in 74% of patients with generalized or mixed type epilepsy, in 63% with complex partial, and 53% with simple partial epilepsy (Table 9.3) [24]. In oligodendrogliomas, seizure control is linked to tumor control, independent of the presence of seizures as the first clinical sign [50]. AED-resistant seizures are not rare, occurring in 40% of patients.

In GBM, preoperative uncontrolled seizures and parietal lobe involvement are negative prognostic factors. Prolonged seizure control is associated with a better Karnofsky performance score [16].

Seizure as the presenting symptom of brain tumors is a favorable prognostic factor for survival, as are the number of seizures and duration of preoperative seizures [24, 44].

In low-grade gliomas, seizures without other neurological symptoms at presentation are associated with longer overall survival time (HR: 0.27) [50, 51]. Conversely, neurological deficits or a poor performance status at presentation are associated with worse longevity [49]. Overall, the presence of seizures, smaller tumor volume and extent of surgical resection are all associated with longer survival in low-grade gliomas [11].

In oligodendroglial tumors , uni- and multivariate analysis reveal that the presence of IDH1 mutation, co-deletion of 1p and 19q and frontal tumor location are positive prognostic factors regardless of presence of seizures [14, 52, 53]. Nonetheless, the relation between seizures and survival is remarkable. Patients with a single seizure prior to surgery (14% of all patients) do extraordinarily well, showing a 90% 10 year survival. In contrast, one-third of the small subgroup presenting with other neurological deficits (10% of all patients) die within 1 or 2 years. The remaining patients have either occasional or clearly relapsing seizures, and both groups show a steadily decreasing survival slope with a median survival of 10 years. However, patients with refractory seizures tend to do worse than those with controlled seizures [50].

Nevertheless, seizures as a good prognostic feature seem mainly a secondary phenomenon [38]. In low-grade gliomas, initial epilepsy as favorable prognostic factor could be explained by the association of the IDH1 mutation with formation of D-2HG, which may generate epileptic activity [36, 54]. In glioblastomas, new-onset epilepsy is associated with presentation at younger age, better overall health status and substantially smaller tumor size, which are all independent favorable factors for survival [55, 56].

Reappearance or worsening of seizures following a relatively long period of seizure control may signal progression or recurrence of glioma. In low-grade gliomas, relapse of seizures after a period of 6 months or more of seizure freedom is an indicator of tumor progression in about 50% of patients [24, 57]. Approximately 15% of glioblastoma patients have ongoing seizure activity despite multiple antitumor regimens [43]. Recurrence or worsening of seizures following a stable period in GBM heralds progression in approximately two-third of patients following first-line antitumor therapy [16, 24, 58]. This necessitates adjustment of seizure treatment and reevaluation of the tumor status of the patient. Thus, while early seizures in gliomas represent a favorable prognostic indicator with respect to survival, late recurring seizures are more likely to indicate progressive disease, often accompanied by adverse effects on cognition and quality of life.

Symptomatic management of seizures in cancer patient is in principle not different from other causes for focal epilepsy. Antiepileptic drugs can be initiated after the occurrence of a single seizure attributable to a brain tumor [71, 72]. In general, the choice of a specific AED is primarily based on the type of the epilepsy. Epilepsy in patients with brain tumors belongs to the type of partial epilepsy in adults, either with or without secondary generalized seizures, and is essentially based on focal lesion or brain damage. For this type of seizures, the International League against Epilepsy (ILAE) has updated the most appropriate AEDs based on a meta-analysis of large number of randomized controlled trials [73]. As such, levetiracetam (LEV) , carbamazepine , phenytoin , and zonisamide are considered class A anticonvulsants, based on trial quality for efficacy. Valproic acid (VPA) represents the only class B anticonvulsant. Gabapentin, lamotrigine, oxcarbazepine, phenobarbital, topiramate, and vigabatrin are class C agents [73]. Subsequently, the choice of the most fitting AED among the approved agents depends on individual patient factors, most importantly age, sex, weight, comorbidities, and concomitant therapy including drug interactions [74]. Regarding concurrent treatment, in neuro-oncology a consensus exists to avoid enzyme-inducing anti-epileptic drugs (EIAEDs) —phenobarbital, carbamazepine and phenytoin—as these accelerate the metabolism of many chemotherapeutic agents [71, 75]. For zonisamide , there is still limited experience with brain tumors [76]. Table 9.4 provides pharmacological details on anticonvulsant drugs.