Neoplastic Diseases

Lawrence D. Recht

Glantz Michael

Introduction

Seizures are frequently the first symptom in patients with brain tumors, and they represent an important cause of potentially preventable morbidity. They thus present a clinical problem requiring specific treatments that do not necessarily affect the course of the brain tumor but that generally improve quality of life.

Historical Perspectives

The first reports of a relationship between brain tumor and epilepsy were published before the 18th century, and a number of clinicians, including J. Russell Reynolds, drew attention to this problem in the early 19th century. Hughlings Jackson, however, was the first to point out a direct association between partial epilepsy and tumors.⁴⁰ Jackson also recognized the relationship between epileptogenicity and tumor involvement of the cortical gray matter.⁴⁰^,⁴¹

Since then, the evolution of neurosurgical techniques and the development of new imaging techniques have greatly facilitated the management of tumor-associated epilepsy. Nevertheless, controversy over optimal pharmacologic and surgical therapies persists, and seizures still represent one of the more commonly encountered problems in neuro- oncology.

Epidemiology

Although neoplasms of the brain account for only 1% of cases of epilepsy, seizures occur in approximately 50% of children with supratentorial tumors,⁴^,³⁹^,⁵⁰ and seizures develop in approximately 35% to 40% of adults with brain tumors.⁴⁸ The rate is much lower for tumors of the infratentorial or pituitary region, and consequently even higher for supratentorial lesions. Furthermore, because physicians who are not neurologists are apt to miss seizures with other than motor manifestations, these figures are probably underestimates.

In the majority of patients with supratentorial low-grade gliomas, seizure is the initial manifestation.⁴⁷^,⁶⁶ Seizures occur especially commonly in association with oligodendrogliomas. A recent retrospective study found seizures to be the first symptom in three quarters of patients with oligodendrogliomas.⁹¹ Seizures are also commonly encountered in patients with meningiomas. Although earlier workers reported that seizures were less frequently encountered in cases of more malignant glial neoplasms,²⁷ recent studies demonstrate that up to 60% of patients with malignant gliomas experience seizures at some time during their clinical course.⁵⁷ In contrast, the incidence of seizures in patients with cerebral metastasis is much lower; most reports suggest an incidence of 20% at time of presentation.¹⁸^,²⁸^,⁶³^,⁹⁶

Clinical Presentation

Clinical Correlates of Tumor-Associated Epilepsy

Despite the variable frequency of seizures as a function of histologic subtype, the most important factor associated with the development of seizure is probably tumor location.⁴⁴^,⁵² Seizures occur much more frequently in supratentorial (22%–68%) than infratentorial (6%) lesions.³¹^,⁶⁴^,⁷⁸ Moreover, the incidence of seizures increases as the site of tumor approaches the rolandic fissure.⁹⁰ As the distance from the central sensorimotor region increases, early-onset seizures are less likely to occur.⁶⁵ Similarly, superficial and cortical tumors are associated with a much higher incidence of epilepsy than are noncortical deep lesions (63% vs. 29%), and lesions entirely within the white matter infrequently produce seizures.

Other factors aside from location are also probably important determinants. Both the chronicity of tumor growth and patient age affect the incidence of epilepsy in intra-axial supratentorial neoplasms.²³^,²⁴^,²⁵^,³⁰^,³¹^,³⁴^,⁵⁴^,⁶⁴^,⁶⁹^,⁷⁰ Slowly growing tumors, such as gangliogliomas and dysembryoplastic neuroepithelial tumors, are overrepresented in patients with brain tumors who have seizures, whereas more rapidly growing tumors are less often epileptogenic. Thus, a seizure incidence of 70% is reported for astrocytoma, but only 37% for glioblastoma multiforme.⁴^,⁷⁰^,⁹⁰ Young age also is correlated with the presence of epilepsy.⁹¹

Seizure Types in Tumor-Associated Epilepsies

Since Jackson first noted, at the end of the last century, the relationship between uncinate seizures and tumors of the frontotemporo-orbital regions, many reports have documented the important relationship between the type of seizure and the presence of tumor. Despite occasional disagreement,⁴⁸^,⁸⁶ a correlation between a specific seizure type and either a particular neoplasm or specific tumor location has been commented on repeatedly. In an analysis of psychomotor attacks in 80 untreated patients with and without tumor, for example, olfactory and gustatory hallucinations were very suggestive of tumor.⁴³^,⁵² Muller (cited in Jackson⁴⁰) noted olfactory hallucinations, increasing frequency of attacks, and random variations in the type of attack (especially of motor seizures) to be particularly characteristic of tumor. For children, the probability of diagnosing an underlying tumor is higher in those with complex partial seizures (10%–46%) than in those with other seizure types.⁷^,⁸²^,⁹⁰

In a recent series of patients with oligodendroglial tumors, seizures were approximately equally divided between generalized, partial, and mixed types.⁹¹ In contrast, localization-related motor seizures, characterized by a clonic jerking of
the face or one extremity, are often characteristic of patients with intracranial metastases or malignant gliomas,⁴⁴^,⁴⁸ and these seizures are almost always seen in association with focal neurologic abnormalities.⁵⁷ Multifocal or bilateral neoplasms more often produce seizures than solitary neoplasms do,⁵⁷ and seizures tend to occur more frequently with lesions of the central nervous system (CNS) caused by metastatic melanoma, because these lesions involve gray matter and tend to be multiple.¹¹ Furthermore, partial seizures in patients with brain tumors are clinically significant, because they are rarely falsely localizing and thus provide a clue to tumor location.¹ Following partial or secondarily generalized seizures, many patients with underlying brain tumors exhibit a significant Todd’s paralysis; although usually transient, this may be permanent.⁵⁶

Diagnostic Evaluation

Because seizures are a presenting complaint in approximately 20% of patients with newly diagnosed brain metastases,⁶⁸ neuroimaging, preferably magnetic resonance imaging (MRI), is required in every patient with cancer in whom seizures develop. Since seizures also occur in up to 40% of neutropenic patients with infectious meningitis,⁵¹ are a common manifestation of leptomeningeal carcinomatosis, and have been reported as an early manifestation of limbic encephalitis, a spinal fluid analysis with careful assessment of the patient’s prior clinical course for possible epileptogenic drugs and metabolic aberrations is always indicated.

Before the advent of modern neuroimaging, the significance of a seizure as a first manifestation of brain tumor was insufficiently recognized, and the average delay between first seizure and tumor diagnosis was about 3 years.¹⁶^,⁴⁴^,⁸⁹ In recent years, however, scanning with computed tomography (CT) and MRI has made it possible to document that many low-grade gliomas have relatively benign pathologic features and, although they produce chronic epilepsy, tend to be associated with long survival.²⁶^,⁷¹ Furthermore, low-grade gliomas are serendipitously noted in up to 20% of resected surgical specimens from the brains of patients with chronic temporal lobe epilepsy.¹⁰^,⁵⁸^,⁷⁹^,⁸⁴ Therefore, it is the authors’ recommendation that all patients with a first seizure have a CNS imaging study, preferably an MRI scan, at the time of presentation.

Electroencephalography (EEG) is also useful in assessing these patients. Findings correlate with tumor location, and in approximately 40% of patients, the EEG abnormalities are lateralized to the side of the tumor.¹⁷ On the other hand, in the authors’ experience,³² EEG does not predict in which patients with supratentorial lesions late seizures will develop. Nevertheless, because EEG is relatively inexpensive and helps to localize the epileptogenic foci by a method different from neuroimaging, it remains a useful test for attempting to localize the physiologic seizure focus.

Differential Diagnosis

In patients with established cancer, the differential diagnosis of either isolated or multiple seizures includes more than just mass lesions, and the appropriate work-up must be designed accordingly. Although the differential diagnoses of a seizure in cancer patients are similar to those in patients without cancer, certain etiologies are specific to or more frequent in a patient with preexisting cancer. For example, hyponatremia, hypomagnesemia, and hypocalcemia all occur more frequently in patients with cancer owing to a number of factors, including dehydration and chemotherapy. These metabolic aberrations in turn predispose to seizures. Similarly, the immunosuppression associated with cancer and its treatment predisposes patients to meningitis, often with less common etiologic agents, such as Listeria and Cryptococcus. A partial list of potential causes of seizures in patients with cancer is given in Table 1.

Treatment and Outcome

Pharmacotherapeutic Aspects of Tumor-Associated Epilepsy

Seizures can be especially detrimental to patients with tumors because they can lead to breakdown of the blood—brain barrier⁶¹ and subsequent formation of brain edema. This process is probably related to seizure-induced arterial hypertension. Because the increase in blood flow and blood volume may worsen elevated intracranial pressure, leading to focal ischemia and sometimes infarction, the Todd’s paralysis that frequently follows these seizures tends to be more protracted (even permanent on occasion) than that occurring in patients with partial seizures and no tumor. This potential complication alone justifies instituting aggressive antiepileptic measures for these patients once a seizure has occurred.

As in the treatment of idiopathic seizures and secondary seizures not related to tumor, however, the efficacy of anticonvulsant therapy for tumor-associated epilepsy falls well short of complete control. Tumor-associated epilepsy tends to be relatively refractory to antiepileptic drugs (AEDs), and significant remission of seizures is rare.³⁴^,⁵⁷^,⁷⁸ Primary tumors tend to be more difficult to control than metastatic lesions (M. Glantz, unpublished observations), but seizures with onset late in a patient’s clinical course tend to be easier to control than those that are an initial manifestation of tumor.⁵⁷

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