By Evan Noch, MD, PhD
Assistant Professor, Department of Neurology, Weill Cornell Medicine
Cancer cells form direct synapses with neurons, whose electrical activity stimulates brain tumor growth. Accumulating evidence suggests that epilepsy enhances the proliferation of malignant brain tumors and that improved management of epilepsy may reduce morbidity and mortality in these patients.
Mastall M, Wolpert F, Gramatzki D, et al. Survival of brain tumour patients with epilepsy. Brain 2021;144:3322-3327.
The field of cancer neuroscience has burgeoned in recent years as a result of the increasing awareness that cancer cells leverage neurons and glia to support their growth. It now is recognized that neurons form synapses with cancer cells and that neuronal electrical activity stimulates the growth of cancer within the brain. Likewise, there is increasing evidence that epilepsy may enhance brain tumor growth.
To better define the role of epilepsy in survival of patients with brain tumors, Mastall et al conducted a retrospective analysis of 2,500 consecutive brain tumor patients from institutional cohorts at the University Hospital in Zurich and from patient registries. Patients with meningioma were selected from an institutional cohort of consecutive patients with radiographic suspicion of meningioma; glioblastoma patients were selected from a population-based, prospective registry; and patients with brain metastases were selected from an institutional cohort.
The authors defined epilepsy and status epilepticus according to the International League Against Epilepsy and classified patients into three categories: those without epilepsy, those with status epilepticus, and those with epilepsy but without status epilepticus. In addition to demographic and histological factors, they recorded progression-free survival (PFS) and overall survival as well as the extent of resection and the radiographic contact of tumors to cortical margins.
Among all brain tumor patients in this study, seizures were the initial disease manifestation in 51% to 72% of patients. Demographic and cancer-specific factors between each seizure category within cohorts were well balanced. However, a greater percentage of patients with World Health Organization (WHO) grade II or III meningioma had seizures, as is expected for these tumors with greater malignant potential and frequent brain invasion. Interestingly, glioblastoma patients with seizures or status epilepticus had a higher Karnofsky performance score (KPS) and also more residual tumor after surgery. These findings could relate to better symptom control and follow-up in patients being treated for seizures or that less aggressive resections may have preserved neurological function in patients with residual disease. Expectedly, in patients with brain metastases, status epilepticus correlated with the number of brain metastases.
When examining the semiology of status epilepticus among these three cohorts, the authors found that 74% of patients exhibited nonconvulsive status epilepticus and that tumor progression often triggered epilepsy. No lobe of the brain was particularly associated with status epilepticus, but 91% of patients with status epilepticus demonstrated direct cortical contact of their brain tumors. Although mortality from status epilepticus was rare in this population, it most often occurred in those with brain metastases.
Since the survival of brain tumor patients may be affected by the onset and semiology of epilepsy, the authors investigated these factors in each cohort. In meningioma patients, they found that PFS was shorter in patients with status epilepticus, but there was no association between status epilepticus and PFS after adjustment for age, WHO grade, or extent of resection in a multivariate model. The only factor that predicted longer survival in this multivariate model was epilepsy without status epilepticus as the presenting feature of meningioma.
Conversely, in glioblastoma patients, status epilepticus, but not epilepsy alone, was an independent prognostic factor for poor survival after adjustment for age, methylguanine methyltransferase (MGMT) promoter methylation, KPS at diagnosis, and extent of resection, arguing for a pro-tumorigenic role of status epilepticus. Interestingly, the authors also found that median overall survival was prolonged in patients in whom epilepsy was the initial manifestation, suggesting that those who presented with seizures came to earlier clinical attention.
Similar to glioblastoma patients, status epilepticus in patients with brain metastases was associated with reduced overall survival after adjustment for age, primary tumor histology, surgical status, and graded prognostic assessment score. In these patients, epilepsy as a secondary disease manifestation, but not as the initial manifestation, was associated with unfavorable survival.
COMMENTARY
Neuronal activity stimulates the growth of brain tumors, and, therefore, epilepsy has been considered as a prognostic factor in brain tumor patients. In this study of patients with meningiomas, glioblastoma, and brain metastases, the authors found that status epilepticus was associated with poor survival in patients with glioblastoma and brain metastases but not in those with meningioma, a brain tumor with benign histology in 80% of cases. These findings lend support to the hypothesis that status epilepticus (and perhaps poorly controlled seizures in general) increase morbidity and mortality in these patients. Moreover, the authors found that epilepsy as the initial manifestation of brain tumors tends to lead to an earlier brain tumor diagnosis.
Although there was no association with epilepsy and survival in glioblastoma, seizures tended to herald tumor progression, arguing that new-onset or recurrent seizures should raise concern for tumor growth. Together, these results support the notion that status epilepticus is poorly prognostic for those with malignant brain tumors.
Future mechanistic studies should investigate how the type and degree of epilepsy regulates the growth of diverse brain tumors. Likewise, given the controversy over anticonvulsant choice and seizure control on brain tumor growth, more work is needed to guide clinical and oncological management in brain tumor patients with epilepsy.
