Elsevier

The Lancet Oncology

Volume 13, Issue 9, September 2012, Pages e375-e382
The Lancet Oncology

Review
Epilepsy meets cancer: when, why, and what to do about it?

https://doi.org/10.1016/S1470-2045(12)70266-8Get rights and content

Summary

The lifetime risk of having epileptic seizures is profoundly increased in patients with cancer: about 20% of all patients with systemic cancer may develop brain metastases. These patients and those with primary brain tumours have a lifetime risk of epilepsy of 20–80%. Moreover, exposure to chemotherapy or radiotherapy to the brain, cancer-related metabolic disturbances, stroke, and infection can provoke seizures. The management of epilepsy in patients with cancer includes diagnosis and treatment of the underlying cerebral pathological changes, secondary prophylaxis with antiepileptic drugs, and limiting of the effect of epilepsy and its treatment on the efficacy and tolerability of anticancer treatments, cognitive function, and quality of life. Because of the concern of drug–drug interactions, the pharmacological approach to epilepsy requires a multidisciplinary approach, specifically in a setting of rapidly increasing choices of agents both to treat cancer and cancer-associated epilepsy.

Introduction

Epileptic seizures are a potentially life-threatening symptom of structural or metabolic brain dysfunction. They are among the most common presenting features of patients with primary brain tumours. They are also a frequent complication in patients with disseminated cancer, mostly because of solid brain metastasis or leptomeningeal disease, but they can also be caused by exposure to chemotherapy or radiotherapy to the brain, stroke, infection, or general disturbances (eg, of salt or liver metabolism associated with systemic cancer progression). This Review focuses on the relevance of epilepsy for clinical oncology, with specific consideration of the practical management of epilepsy in patients with cancer and the increasingly complex interactions between the pharmacological approaches to cancer versus cancer-associated epilepsy. Contemporary review articles on epilepsy in patients with primary brain tumours,1, 2 drug–drug interactions,3, 4 and drug-resistant epilepsy5 address specific aspects related to epilepsy and cancer.

Section snippets

Seizures and epilepsy: their nature and classification

An epileptic seizure is most often a transient event caused by abnormal excessive or synchronous neuronal activity in the brain and can often, but not always, be recognised clinically by symptoms and signs of neurological dysfunction, most commonly altered consciousness and uncontrolled motor activity. As such, seizures can occur in the presence of a transitory precipitating factor—eg, metabolic disturbance or exposure to a proconvulsive agent, including anticancer drugs—and are then a symptom

Interfaces of epilepsy and cancer

Patients with cancer have a major risk of developing epileptic seizures in the course of their disease, whereas those with epilepsy probably do not show an increased risk of cancer. Yet, whether antiepileptic drug treatment can affect the risk of development of cancer is unknown. Older antiepileptic drugs such as phenobarbital or phenytoin have been identified as tumour-promoting agents in animal studies, whereas theoretical considerations led to the hypothesis that valproic acid could have

Management of epilepsy in patients with tumours: general principles

The goals of epilepsy management include understanding of its origin, treatment of its cause when possible, prevention of further seizures, and limiting of their sequelae. The initial work-up of a suspected seizure requires an assessment of the circumstances of that episode and a thorough consideration of alternative diagnoses, mostly syncope, migraine, and cerebral ischaemia. History taking is commonly complemented by electroencephalography and cardiological assessments, dependent on the

Are patients with cancer at increased risk of epilepsy in the absence of CNS involvement?

The most common cause of seizures in patients with cancer is probably the development of solid brain metastases,9 but leptomeningeal involvement needs consideration. Accordingly, the initial work-up of a first seizure in any patient with cancer must include neuroimaging, preferably MRI to rule out brain metastases. Neuroimaging, however, might also show stroke or infectious complications, which may be more common in patients with systemic cancer than in the general population. The work-up may

Epilepsy in patients with systemic cancer and CNS involvement

Solid brain metastases seem to cause seizures less frequently than do primary brain tumours, which may be explained by their less infiltrative growth and their inability to biochemically modulate neuronal excitability. New-onset seizures in patients with known brain metastases may indicate haemorrhage into a metastatic lesion, notably in patients with metastatic melanoma, or tumour progression with associated oedema. Patients undergoing resection of single or multiple brain metastases do not

Epilepsy in patients with primary brain tumours

The lifetime risk of epileptic seizures in patients with primary brain tumours varies by diagnosis, age, and publication source. The incidence is lower in some of the most malignant brain tumours such as glioblastoma and primary CNS lymphoma, but higher in some more benign, but still infiltrative lesions such as WHO grade II diffuse gliomas. The reasons for these differences are multifold, but remain somewhat speculative. Typical features attributed to a high seizure risk include location in

Do antiepileptic drugs show intrinsic antitumour properties?

Intrinsic antitumour activity of some antiepileptic drugs and synergy with chemotherapy or radiotherapy have been suggested in some, but not all, studies. For example, phenytoin has been associated with antimitotic and anti-invasive properties, and valproic acid has been suggested to induce cell differentiation, growth arrest, apoptosis, and autophagy, and these effects were proposed to be mediated by histone deacetylase inhibitory properties.36, 37, 38, 39, 40 These issues were most often

Tolerability

Pharmacokinetic rather than pharmacodynamic interactions of antiepileptic and various anticancer drugs are the most important area to consider for the general oncologist at the interface between cancer care and epilepsy.3, 4 Although many antiepileptic drugs are metabolised in the liver, only some agents, such as phenytoin, carbamazepine and derivatives, and phenobarbital, induce CYP450-dependent hepatic enzymes and thus increase their own metabolism and, more importantly, the metabolism and

Frequently asked questions about epilepsy and cancer

The interface between cancer and epilepsy provides an area of many interesting observations, active clinical and laboratory research, and opportunities to improve quality of life and outcome in patients with cancer. Yet, there are many questions that arise in daily clinical practice, and for many of which there are no answers that could be based on several or even one adequate clinical trial.

The appendix summarises some of these classic questions (and answers). Improved cancer therapy and early

Conclusions

Recognition and secondary prophylaxis of seizures and epilepsy in patients with cancer are a major challenge that commonly needs a multidisciplinary approach. The major goals—freedom from seizures, seizure control with an acceptable safety and tolerability of antiepileptic drugs, and seizure control without interfering with the efficacy of cancer treatment—can often be achieved. However, careful monitoring and thoughtful clinical decision making are needed.

Search strategy and selection criteria

We identified data for this Review by searching PubMed between 2000 and 2012 with the search terms “epilepsy, brain tumor, review” (which identified 881 citations); “epilepsy, brain tumor, chemotherapy” (753 citations); “epilepsy, drug interactions, tumor” (114 citations); “partial epilepsy, randomized controlled trial” (614 citations); and “prognostic factors, epilepsy, glioma” (30 citations). We also identified articles through searches of our own files. Only papers in English were

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