• Pathophysiology
• Clues to anatomic location
• Neuroimaging
• Astrocytoma
• Oligodendroglioma
• Ganglioglioma
• DNETs
• Meningioma
• Metastatic
• Treatment
• Prophylaxis
• AED treatment
• Surgical planning and prep
• Postoperative complications
• Future trends
• References

Mechanisms of tumor-related epileptogenesis remain poorly understood. In tumor-associated epilepsy, nontumoral surrounding tissue may cause seizures.39 Abnormal growth kinetics of tumors can affect surrounding neurons morphologically and biochemically, altering neuronal structure and affecting the release of neurotransmitters and neuromodulators such as gamma-aminobutyric acid (GABA) and somatostatin. These changes may cause seizures through hyperexcitability or reduced inhibition. 40,41

The hippocampus may become involved—either directly, through tumor extension, or indirectly, through increased excitatory input caused by a tumor—and may contribute to seizure amplification and propagation.42

Tumors can disrupt normal electrical functional patterns, causing increased local coherence, or similarity of electrical activity seen electrographically within a cortical region, which is a similar pattern observed in epileptic foci.43 These changes, induced by a tumor in the surrounding tissue, contribute to the formation of the epileptogenic zone.

Cortical connections contribute to generation and maintenance of seizures. Aggressive white-matter neoplasms are less likely to cause seizures because they do not directly irritate cortex, and tumor growth may disrupt the spread of epileptic activity.17

Adapted from: Mangano FT, McBride AE, and Schneider SJ. Brain tumors and epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;175–194.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Seizures, often complex partial, may be the first symptom of a brain tumor. Although seizure type does not reliably distinguish seizures caused by a tumor from those with other etiologies,32,36,44,45 clinical ictal characteristics, such as focal clonic activity, may suggest that seizure onset is occurring in a focal region and an associated lesion must be excluded.

Clinical seizure semiology provides clues for the region of ictal onset and its potentially associated focal lesion. The International League against Epilepsy has described seizure syndromes according to anatomic location:46

For example, very brief seizures with abundant posturing activity at onset and quick termination suggest a frontal lobe origin. Psychical symptoms with automatisms suggest temporal lobe origin. Seizure localization is complicated, however, by the difficulty of distinguishing seizure onset from manifestations of seizure spread.

Reviews of detailed seizure classification and ictal semiology are available.46–48

Adapted from: Mangano FT, McBride AE, and Schneider SJ. Brain tumors and epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;175–194.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Computed tomography (CT) scans of the head are usually reserved for the acute evaluation of new-onset seizures, owing to their ready availability in settings such as the emergency room. They can detect etiologies such as acute hemorrhage or trauma50 but they are less sensitive than magnetic resonance imaging (MRI) in detecting structural lesions. Middle and posterior fossa lesions can be masked by bone artifact on CT. 49

MRI

MRI is the gold standard in evaluating epilepsy. It can identify lesions, such as a neoplasm, that may be missed on CT. New-onset nontraumatic seizures should be evaluated with gadolinium-enhanced T1-weighted, T2-weighted, and fluid-attenuated inversion recovery (FLAIR) images. To evaluate a chronic disorder, however, the use of contrast may be unnecessary unless there has been a recent change in seizure type, frequency, or intensity.51

MRI is free of radiation and is therefore very safe.52 It can be used to verify the placement of invasive electrodes in evaluations for epilepsy surgery, and to document the extent of cortical resection after surgery.

Some brain tumors have characteristic findings that can distinguish them from non-neoplastic lesions or even suggest a specific type of tumor. It may be difficult, however, to differentiate low-grade gliomas from other tumor types presenting with epilepsy:

• Astrocytomas characteristically show a T2-signal increase and a nonspecific T1 signal of solid components (see Figure1). Cystic components are isointense to cerebrospinal fluid.

Figure 1. Low-grade astrocytoma. (A) MRI fluid-attenuated inversion recovery (FLAIR) axial image without contrast enhancement. (B) T1-weighted axial image after gadolinium infusion. Images show an abnormal increased signal in the right anterior temporal lobe (arrow).

• Oligodendrogliomas look like astrocytomas but may have a honeycomb and stippled amorphous appearance with areas of superficially distributed calcifications.53
• Gangliogliomas have no specific MRI features distinguishing them from other gliomas (see Figure 2).

Figure 2. Ganglioglioma. (A) T1-weighted axial image of a left frontoparietal space-occupying lesion (arrow). (B) Note no appreciable contrast enhancement (arrow) after gadolinium infusion.

• DNETs (dysembryoplastic neuroepithelial tumors) usually affect the frontal and temporal lobes in children, also appearing similar to low-grade gliomas, except that edema is rarely appreciated (see Figure 3). Kuroiwa et al. described DNETs as hypointense on T1-weighted sequences and hyperintense and well demarcated on T2-weighted sequences with no contrast enhancement noted.54

Figure 3. Dysembryoplastic neuroepithelial tumor (DNET). T2-weighted axial MRI of a right medial temporal infiltrative lesion demonstrating abnormal signal intensity.

• Glioblastoma multiforme (GBM) displays a heterogenous signal on T1- and T2-weighted imaging and inhomogeneous postgadolinium ring enhancement with nonenhancing areas representing necrosis (see Figure 4).55

Figure 4. Glioblastoma multiforme. Gadolinium-enhanced axial T1-weighted MRI showing a left-sided multicystic necrotic lesion with a solid enhancing component in the temporoparietal region.

• Meningiomas are usually isodense on T1- and T2- weighted images and demonstrate intense postgadolinium enhancement in the T1 sequences (see Figure 5).56

Figure 5. Meningioma. Gadolinium-enhanced axial T1- weighted MRI showing a homogenously enhancing extra-axial lesion extending into the left-middle cranial fossa.

Focal calcifications are seen in 25% of tumors, but CT scans show hyperintensity in more than 70%.55 To identify focal lesions, T2-weighted sequences are more sensitive to low-grade tumors, arteriovenous malformations, focal gliosis, and hamartomas.57–59

Other techniques

Other neuroimaging techniques, while not currently primary neurodiagnostic modalities in the evaluation of tumors and epilepsy, are helpful adjuncts. They can increase the level of certainty that the region of seizure activity and eloquent cortex have been correctly identified, provide prognostic tumor data, and guide intracranial electrode placement.

Positron emission tomography (PET) scanning is a functional glucose metabolic imaging technique that assesses cerebral metabolism. Patients with low-grade epileptogenic tumors may demonstrate areas of hypometabolism interictally, and hypermetabolism may be seen during ictal events. These areas tend to be larger than the anatomic abnormality itself.60 PET with fluoro-2-deoxy-D-glucose (FDG) uptake can have prognostic value in low-grade gliomas.61 Those tumors that display areas of increased FDG uptake are likely to recur or progress to higher grades.

Derlon et al. compared metabolic patterns between astrocytomas and oligodendrogliomas using PET FDG (glucose) and 11C-L-methylmethionine (amino acid) uptake.62 Although both tumors showed glucose hypometabolism, amino acid uptake was increased only in oligodendrogliomas. This suggests that specialized PET protocols may aid in distinguishing tumor types. Continued research using this technology may help improve diagnosis, therapy, and assessment of possible tumor progression.

Single photon emission computerized tomography (SPECT) is a functional cerebral perfusion imaging technique used in the noninvasive physiologic evaluation of intractable seizures to help define focal areas of abnormality. SPECT is less expensive than PET and is available in more hospitals. Electrographically, widespread blood flow changes may be seen during a seizure, but well-timed SPECT injections close to ictal onset may identify the origin of seizure onset. SPECT aids in localization by demonstrating cerebral areas that have decreased regional cerebral blood flow (rCBF) interictally and increased areas of rCBF ictally. There are several difficulties in accomplishing ictal SPECT, however. Injecting the radioisotope on time can be a challenge (particularly with nocturnal seizures), given the unpredictability and short duration of some seizures, the need to obtain the isotope, the limit of its half-life, and the limited sensitivity and specificity of postictal data.63

More recently, co-registered subtraction SPECT imaging from MRI has been shown to improve reliability in localizing seizure foci postictally.64

Magnetic resonance spectroscopy (MRS) is a noninvasive technique that measures metabolic activity, allowing for the comparison of neural and tumoral elements containing protons. Relevant metabolites are creatine, N-acetylaspartate, lactate, and carbohydrate-containing phospholipids. Assessment of carbohydrate (CHO) peaks and lac tate levels helps to assess tumor aggressiveness and distinguish radiation damage from tumor recurrence.

In a recent study of 11 pediatric patients with low-grade gliomas, Lazareff et al. showed that MRS CHO values were a viable noninvasive prognostic tool to follow tumor progression, with higher ratios correlating with more rapid tumor growth.65

MRS has also been shown to be of prognostic value when treating recurrent malignant gliomas with radiosurgery.66

Functional MRI (fMRI) is another noninvasive imaging technique that maps changes in rCBF and concentrations of oxyhemoglobin or deoxyhemoglobin on task performance. It is a useful tool to identify regions of eloquent cortex that need to be spared in lesion resection.67,68

Adapted from: Mangano FT, McBride AE, and Schneider SJ. Brain tumors and epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;175–194.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

The astrocytoma is the most common intra-axial brain tumor. Astrocytomas are classified on a four-grade scale.122,123 Grades I and II are considered low-grade gliomas, grade III is anaplastic, and grade IV is glioblastoma multiforme. Grades III and IV are considered high-grade gliomas.

Histologically, the diagnosis of low-grade gliomas is based on minimal hypercellularity and pleomorphism, with no vascular proliferation or necrosis. (See Figure 6). These characteristics escalate to excessive pleomorphism, increased mitotic activity, necrosis, pseudopalisading, and endothelial proliferation in glioblastoma multiforme. Generally, most gliomas stain positively for glial fibrillary acidic protein (GFAP).

Figure 6. Low-grade astrocytoma. 200. Hematoxylineosin (H&E) stain of mildly atypical neoplastic glial cells with a fibrillar and myxoid background.

Cortical astrocytomas may arise from different cell lineages than white-matter astrocytomas. Piepmeier et al. showed that type I cortical astrocytomas had different expression of GFAP and gangliosides than type II fibrillary astrocytomas.125 This may affect the differing prognosis of astrocytoma subtypes.

Distribution and presentation

In adults, low-grade gliomas have been more frequently associated with seizure disorder than glioblastoma multiforme, but both can be epileptogenic. Most cases present between the ages of 21 and 40 years, but low-grade gliomas are also a significant cause of epilepsy in children. Seizures are the most common presentation of low-grade glioma, and the low-grade glioma is the most common neoplasm responsible for tumor-related intractable epilepsy.21

The anatomic distribution of low-grade gliomas in several reports20,40,45,113–115 (not including locations spanning two lobes, such as frontoparietal) was:

• Frontal—83
• Temporal—119 (see Figure 1)
• Parietal—31
• Occipital—14

In Fried’s study of 65 patients with limbic and neocortical gliomas, 63% of low-grade gliomas were temporal, 18% were occipital, and 11% were frontal.124 These tumors show indolent behavior, with an average 15-year history of seizures. After a 17-year follow-up, only one patient had died from the tumor. Gross total resection gains excellent seizure control, and subtotal resection is the most important factor in the failure to control seizures and tumor recurrence.26,114

Treatment and prognosis

Glioblastoma multiforme, which is less likely than low-grade astrocytomas to produce seizures, primarily affects white matter and deeper structures (see Figure 4). These tumors have greater rapidity of growth associated with destruction of neural elements. In one study, only two of 24 patients became seizure-free after resection.21 Gross total resection does not generally control seizures, and surgery alone may be inadequate treatment of the tumor without adjuvant radiation and chemotherapy.

High-grade gliomas tend to recur. Treatment of recurrences depends on the patient’s clinical status and the anatomic accessibility of the lesion. If the area is surgically accessible, the recurrence is usually addressed with a second resection and adjuvant whole-brain radiation, stereotactic radiosurgery (SRS), or chemotherapy. A second resection can increase survival by an average of 36 weeks, with 28% of patients showing an improvement in the Karnofsky Performance Scale.127 Adjuvant SRS can also improve survival.128 When compared to brachytherapy, median survival data are similar, but SRS offers the advantage of an outpatient procedure versus the need for a 1-week hospital stay for interstitial brachytherapy.129

In children, supratentorial glial tumors tend to be grade I or II. Hirsch and colleagues reported that epilepsy was the presenting symptom in 76% of children who had astrocytomas or oligodendrocytic tumors.113 After tumor resection alone, there was no tumor recurrence in 82% of patients, and 81% of patients were seizure-free. Berger and coworkers reported total seizure relief in 93% of children who underwent resection of the tumor and epileptic focus using electrocorticography (ECog).40

In a separate study comparing postoperative seizure outcome in children versus adults, all 13 pediatric patients became seizure-free and 11 of them were able to discontinue antiepileptic drugs (AEDs). In the adult group, 47% required AEDs to maintain seizure freedom.45 Low-grade glioma in a child has a 10-year survival of 87%.130 Gross total resection of low-grade gliomas is the treatment of choice for children, and adjuvant radiation and chemotherapy are reserved for recurrence. For children, adjuvant whole-brain radiation therapy is not efficacious in preventing recurrence, and it is generally not prescribed because of the risk of cognitive deterioration.130

Although histologically identical to tumors in adults, high-grade gliomas in children tend to have a better prognosis, and survival seems to be based on completeness of resection. In one study of 31 children, those who received a gross total resection had a progression-free survival of 7 years. Progression-free survival was 5 months in those who had only a biopsy, and 11.5 months in those who had a subtotal resection.126 Patients who presented with long-standing symptoms, seizures, and tumors in the cerebral hemispheres had longer survival and better prognosis.

Stereotactic radiosurgery, although not without complications, is a promising therapy that limits radiation exposure to a developing brain. It can be used to surgically treat incurable gliomas in children.78 In a study by Grabb and colleagues, 25 children who underwent surgical resection or biopsy subsequently had SRS for treatment of tumors. Of 13 children with benign gliomas, 11 showed tumor control after SRS, and all 13 were alive at a median follow-up of 21 months. Of 12 children with malignant tumors, 7 died after a median survival of 6 months, and only 3 showed tumor control after SRS.

Adapted from: Mangano FT, McBride AE, and Schneider SJ. Brain tumors and epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;175–194.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Oligodendrogliomas comprise 4–5% of central nervous system neoplasms. They arise in the cortical white matter and tend to grow slowly.131

Oligodendroglial tumors are closely related to fibrillary astrocytic tumors and are generally graded as oligodendroglioma, or anaplastic oligodendrogliomas if they have a high cell density, mitotic rate, and necrosis.132

Histologically, cells have the small rounded nuclei of oligodendrocytes with variable densities in cell population and pleomorphism. They display a characteristic “fried egg” appearance (see Figure 7) and may show necrosis infrequently.

Figure 7. Oligodendroglioma. 200 Microscopic section of uniform glial cells with characteristic "fried egg" appearance (arrow).

Presentation and prognosis

Oligodendrogliomas present with seizures in 70–90% of cases.24,25 Seizure patterns may be nonspecific: one-third of patients present with generalized seizures, one-third with partial seizures, and one-third with mixed seizure types.24 Younger patients often present with seizures and therefore are diagnosed earlier than adults, who may present with other neurologic symptoms.

In Olson’s study of 106 patients, the median age at presentation was 37 years. The overall median time to progression was 5 years, with a median survival of 17 years.

Presentation at a young age, seizures, and a Karnofsky Performance Status over 70 (able to live at home and care for self) are significant positive prognostic indicators for survival in low-grade tumors.24,133,134 Children who present with anaplastic oligodendroglioma have a survival time of only 17 months, compared to 72 months for children with low-grade neoplasms.135

Postoperative malignant progression of a low-grade oligodendroglioma can occur but generally requires long intervals.136

Treatment

Surgical resection is the gold standard of treatment. A seizure-free success rate between 50% and 70% was reported postoperatively by Whittle.24 Adjuvant radiation therapy does not appear to increase survival and increases morbidity in up to 33% of patients.25,137

Postoperative chemotherapy with procarbazine, lomustine, and vincristine (PCV) for low-grade oligodendrogliomas may afford positive results in up to 62% of patients.138 PCV is also effective against high-grade tumors.139

Adapted from: Mangano FT, McBride AE, and Schneider SJ. Brain tumors and epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;175–194.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

In 1930, Courville defined the term ganglioglioma as tumors consisting of astrocytic neuronal components with rare mitotic figures (see Figure 8).140 Approximately 50% show focal areas of calcification. Generally, they are benign growths that occur over a long clinical course and present with no specific radiologic characteristics.144

Figure 8. Ganglioglioma. 200x Photomicrograph of an admixture of mildly atypical neoplastic glial cells and neurons.

Gangliogliomas make up between 0.3% and 8.0% of primary brain tumors, with the higher rates in children. The mean age at presentation is 9.5 years.30,141,142

Distribution and presentation

Most are located supratentorially, often in the temporal lobes.143 In one study of 137 patients, 65% were located in the frontal, temporal, or frontotemporal regions, versus only 8% in the midline or deep structures.141(See Figure 2.)

In a study by Otsubo and colleagues, 59% of patients presented with seizures. Of these, 64% had complex partial seizures, 32% had secondarily generalized seizures, and 4% presented with generalized seizures.

Treatment and prognosis

Optimal treatment includes gross total resection. Adjuvant chemotherapy or radiation therapy is generally not indicated.38

Postoperative 5-year survival of hemispheric gangliogliomas has been reported as 93%, although seizure relief statistics were lower than expected.145 Morris and colleagues reported freedom from seizures in 79% (30 of 38) of patients at 6 months, and 72% at 1 year postoperatively.137 Favorable prognostic factors included younger patient age, benign histopathology, stable clinical status at admission, decreased duration of seizure disorder, and lack of generalized features of seizures.137,141

Another group reported that among patients who presented with neurologic deficits or symptoms of increased intracranial pressure, those who were given adjuvant radiation had a postoperative 5-year survival of 53% versus 11% for those who did not receive radiation.141

Rarely, these tumors (as well as dysembryoplastic neuroepithelial tumors [DNETs]) may be associated with a rare postoperative disorder, with schizophreniform features of paranoia, depression, and psychosis. This psychosis does not seem to accompany other tumor types resected for intractable epilepsy.151,152

Adapted from: Mangano FT, McBride AE, and Schneider SJ. Brain tumors and epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;175–194.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

In 1988, Daumas-Duport described a surgically curable tumor highly associated with intractable partial epilepsy and normal neurologic examination.29 The temporal cortex was the location of 62% of these tumors, with 31% in the frontal cortex(see Figure 3). Case reports have described DNETs to occur in multifocal areas, including the caudate nuclei, midbrain, and diencephalon.29,146,147

Histologically, DNETs are composed of neurons, astrocytes, and oligodendrocytes (see Figure 9). Immunohistochemistry for glial fibrillary acidic protein (GFAP), S-100 protein, and neuronal markers synaptophysin, neurofilament (RT97), and neuron-specific enolase establish the presence of astrocytic and neuronal components, while GFAP reactivity is negative for an oligodendrocytic component.148,149

Figure 9. Dysembryoplastic neuroepithelial tumor (DNET). 200x Intracortical nodule of variably sized oligodendroglial-like cells and disordered neurons demonstrating microcyst formation.

Although questions remain regarding the origin of this tumor, they may have a germinal origin.29,146,147

Treatment and prognosis

At the time of resection, patients’ ages ranged from 3 to 30 years, and patients presented with a longstanding history of symptoms, ranging from 2 to 18 years.29 Patients should be treated with gross total resection and considered cured after surgery.29,149,150 In the series by Daumas-Duport, 30 of 39 patients were seizure free postoperatively, 3 had rare seizures, and 4 had significant reductions in seizures.

Radiation and chemotherapy have not demonstrated a clear benefit, and withholding adjuvant therapy for this type of tumor prevents future deleterious side effects.29

Rarely, these tumors (as well as gangliogliomas) may be associated with a rare postoperative disorder, with schizophreniform features of paranoia, depression, and psychosis. This psychosis does not seem to accompany other tumor types resected for intractable epilepsy.151,152

Adapted from: Mangano FT, McBride AE, and Schneider SJ. Brain tumors and epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;175–194.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Meningiomas account for 14% to 19% of all primary intracranial neoplasms, with a peak incidence around 45 years of age and a female preponderance.28,154,155 Predisposing factors include:156

• previous radiation
• type II neurofibromatosis
• monosomy and/or deletions of chromosome 22

Meningiomas arise from the arachnoid cap cells and form an encapsulated mass that is usually slow growing, eventually creating mass effect on the brain (see Figure 5). Histologically, they classically manifest a whorled cellular pattern, psammoma bodies with differing degrees of fibrous connective tissue, blood vessels, and, if malignant, mitotic activity and invasion of cortex.

Generally, meningiomas are classified on a four-grade system:

• Grade I—benign
• Grade II—atypical
• Grade III—anaplastic
• Grade IV—sarcomatous

The great majority of meningiomas (94%) are benign.158

Location and presentation

Meningiomas most commonly arise on the brain convexity or in a parasagittal location (36%), with 50% located between the coronal and lambdoid sutures and 20% anterior to the coronal suture.157

Headaches are a common symptom, but one study found seizures in 64.7% of patients.28 In Penfield’s series,20, 68% of meningiomas were associated with seizures.

Treatment and outcome

Complete surgical resection should be the goal for accessible tumors. A 4.2-fold excess risk of death has been reported with partial resection compared to gross total resection.163 Adjuvant radiation treatment, although controversial, has been used with some success. In one study the time to recurrence after nonradiated subtotal resections was 66 months, versus 125 months for radiated subtotal resections.164

Stereotactic radiosurgery (SRS) is now used to treat meningiomas that are nonoperable, small, recurrent, or a result of a subtotal resection. The goal is to prevent further tumor growth and preserve normal neurologic function. This is a safe and effective primary or adjuvant therapeutic strategy.165–168 SRS is not indicated for large tumors (>3 cm) or those less than 5 mm from the optic nerve or chiasm.

Few studies focus on seizure outcomes after resections of meningiomas. Flyger and colleagues studied the neogenesis of seizure disorders postresection.161 They observed that 41.1% of patients with no preoperative seizure disorder developed epilepsy postoperatively. Similarly, Foy et al. reported a 22% risk of postoperative seizures after meningioma resection.162 Parietal tumors were the most epileptogenic, followed by frontal and occipital tumors.

Predicting recurrence is related to tumor grade and degree of resection. Benign tumors recur in 3% at 5 years, compared to 78% recurrence at 5 years for anaplastic tumors.159 Gross total resection has a reported recurrence rate of 7% at 5 years, compared to 37% if the resection is partial.160

Adapted from: Mangano FT, McBride AE, and Schneider SJ. Brain tumors and epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;175–194.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Metastases occur in approximately 40% of cancer patients, increase in frequency with prolonged survival from the primary disease, and represent a poor prognostic factor. Metastatic disease to the brain occurs in 15–28% of all cancer patients.169,170 Brain metastases usually occur in supratentorial watershed areas, but gastrointestinal and genitourinary carcinomas tend to metastasize to the posterior fossa.171 Lung and breast carcinomas are the most common primary tumors that spread to the brain (see Figure 10).171,172 Other primary tumors that progress to involve the central nervous system include gastrointestinal cancers, pelvic cancers, melanoma, and renal cell carcinomas.

Figure 10. Metastatic lung adenocarcinoma. 200x . Photomicrograph of sheets of highly pleomorphic malignant cells with epithelial characteristics. Note focal glandular formation (arrow).

Presentation

Brain metastasis may be discovered serendipitously in an asymptomatic patient, or it may present as signs and symptoms of anatomic mass effect, intracranial hemorrhage, or seizures.154 Headaches are the most common presenting symptom, but epilepsy is also a common presentation, observed in 15–25% of patients.27 In one study, 17% of patients with brain tumors and epilepsy had metastatic disease after further evaluation. Most lesions were located in the centroparietal cortex.173

Treatment and prognosis

A patient presenting with a brain metastasis has a 1-month expected survival with no treatment, about 2 months with corticosteroids, and 3 to 6 months with whole-brain radiation.174–177 Patchell and colleagues found that patients with single brain metastases who had surgical resection followed by radiotherapy had fewer recurrences of cancer in the brain than similar patients treated with surgery alone. The likelihood of death from neurologic causes also decreased, but there was no significant increase in the duration of functional independence.178

In another study, comparing a group with surgical resection and radiation therapy with a group that had only brain biopsy and radiation, the group with surgical resection had a better survival, 40 weeks versus 15 weeks.185

Long-term survival greater than 10 years has been reported in a small subset of patients with metastatic non–small-cell lung carcinoma who were treated with surgical resection and radiation.

Stereotactic radiosurgery is another treatment modality that has gained popularity in recent years. Patients who respond best to this treatment are those with controlled systemic disease and non-melanoma primary histology. Such patients have a median survival of 39 weeks.79

Multiple metastases occur in 66% of patients. Some benefit from radiation therapy, but most are treated medically with corticosteroids and antiepileptic drugs. The overall prognosis for this subset of patients is poor, with survival ranging from 2 to 6 months.

Patients with metastatic brain disease and epilepsy are a treatment challenge. Selection of treatment must take into account not only seizures and other neurologic dysfunction, but also the systemic disease and the potential morbidities and mortality associated with treatment.

Adapted from: Mangano FT, McBride AE, and Schneider SJ. Brain tumors and epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;175–194.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Tumors are often treated surgically. Regardless of surgical approach, surgery provides tissue for accurate diagnosis and evaluation for possible adjuvant therapy. Surgery also is indicated to decrease seizure activity and potentially decrease the need for AEDs and the risk of sudden unexpected death.98,99

The pathology of the lesion is the most important prognostic factor. When radiologic studies fail to determine the nature of the lesion, a biopsy may be necessary. Adjunctive therapies such as chemotherapy, radiation therapy, or both are often considered following surgery, especially for aggressive histologies.

Surgical risks are determined by lesion location, its proximity to eloquent cortex, and the involvement of vascular structures and nerves. The patient’s medical condition is yet another important factor to consider. Severe cardiopulmonary or organ-system disease may be a contraindication to general anesthesia.

In treating children, early surgical intervention may permit the developing brain of the young child to recover quickly and maximize plasticity.

Nonsurgical treatment

Some tumors are best treated by observation for progression. Other tumors, such as those in deep subcortical regions, may be surgically inaccessible. Nonsurgical treatment of brain tumors can include chemotherapy, radiation, or radiosurgery.

Chemotherapy

Chemotherapeutic options include local agents applied directly on the tumor bed, or systemic intravenous agents. To control local tumor recurrence or progression in a tumor bed, surgeons may implant agents such as iodine-125 seeds or bischloroethyl-nitrosourea biodegradable wafers.69–72 Theoretical advantages to such therapy include direct delivery of high concentrations of drug or radiation to the tumor bed and increasing penetration into surrounding tissue.

Systemic chemotherapy may increase both survival and quality of life. Temozolomide, for example, an oral cytotoxic alkylating agent that methylates guanine, has been beneficial in clinical trials to treat recurrent glioblastoma multiforme.73 In a study of 225 patients, temozolomide delayed disease progression for a median of 12 weeks and led to 6-month survival of 60%, compared to only 44% for patients given procarbazine.74 In treatment for recurrent anaplastic astrocytomas, it was well tolerated, with a progression-free survival of 5.4 months and an overall median survival of 13.6 months in a group of 109 patients.75

Radiation

Cranial irradiation may reduce seizures in patients with unresected, partially resected, or recurrent tumors.47,100,101 Acutely, however, cranial irradiation may worsen seizure control.

Radiosurgery

Stereotactic radiosurgery (SRS) allows a radiation beam to be maximally and precisely focused on the tumor, with sparing of surrounding normal brain tissue. Since its inception by Lars Leskell in 1951, radiosurgery has evolved significantly. Under specific circumstances, it can be used to treat benign, malignant, and metastatic tumors of the brain, as well as vascular malformations. Several studies have recently suggested a use of this therapy for treating lesional and nonlesional epilepsy.76–80 The role of radiosurgery and its use with other treatment modalities remains to be further clarified.

Adapted from: Mangano FT, McBride AE, and Schneider SJ. Brain tumors and epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;175–194.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

The need for seizure prophylaxis for patients with brain tumors who have not developed epilepsy is controversial. Overall, studies have found no significant difference in development of late seizures between patients receiving and not receiving antiepileptic drug (AED) prophylaxis, suggesting that AEDs do not prevent epileptogenesis.81–84 Potential AED side effects and the possibility that patients may remain seizure-free without treatment may weigh against prophylactic AED therapy. A recent practice parameter by the American Academy of Neurology recommends against AED prophylaxis in patients with newly diagnosed brain tumors, since it is not effective in preventing seizures.85

The evidence regarding perioperative AED prophylaxis is less conclusive. Postoperative seizures occur most often in the first week to first month postsurgery, for patients both with and without tumors.86,87 Although many patients with brain tumors receive AED prophylaxis in the perioperative period, no definite benefit has been demonstrated.82,85 Patients with brain tumors are often given prophylactic AEDs to avoid ictal complications in the perioperative period, but there is no controlled evidence that perioperative AED prophylaxis is effective.83,85,88 If patients are treated perioperatively, tapering and discontinuation of the AEDs after the first postoperative week is recommended.85

Adapted from: Mangano FT, McBride AE, and Schneider SJ. Brain tumors and epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;175–194.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Potential interactions exist between AEDs and medications used in tumor therapy. Enzyme-inducing AEDs, such as phenytoin, phenobarbital, and possibly carbamazepine, can induce steroid metabolism and thereby decrease the effectiveness of steroids.89,90 Phenytoin and phenobarbital also may decrease effective concentrations of antineoplastic drugs.92 One study suggests that phenytoin may have immunosuppressive potential.91

Conversely, chemotherapy may alter blood concentrations of AEDs. For example, increased phenobarbital and phenytoin levels and resultant clinical toxicity can occur during procarbazine therapy.48 Subtherapeutic AED levels and an increased risk of seizures can develop in patients treated with other chemotherapeutic agents.85,93,94 Decreased absorption of valproic acid and carbamazepine or increased metabolism of phenytoin during concurrent treatment with chemotherapeutic agents may account for these alterations.85,93,94 Besides these alterations due to drug interactions or changes in absorption or metabolism, toxicity may occur when AEDs are adjusted in compensation, and a rebound occurs as chemotherapy cycles are concluded.

Side effects

A variety of adverse side effects have been reported in patients taking AEDs while being treated for brain tumors:

• Patients treated with phenytoin or carbamazepine who also receive cranial radiation therapy have experienced more frequent cutaneous skin reactions, including erythema multiforme and Stevens-Johnson syndrome.95,96
• Patients with brain tumor taking phenobarbital may develop reflex sympathetic dystrophy, affecting the shoulder and hand particularly, usually contralateral to the tumor.97
• Carbamazepine rarely causes agranulocytosis and leukopenia, which could complicate use of concomitant chemotherapy agents.
• Valproic acid may cause hepatic toxicity, prolonged bleeding time, and thrombocytopenia.48

Such potential side effects have contributed to the argument against prophylactic AEDs for seizure-free tumor patients.

Other prescribing considerations

Other AED considerations concern the route of administration, the rapidity of reaching therapeutic levels, and known idiosyncratic and dose- related AED side effects. Medications that are available in intravenous form, such as phenytoin, phenobarbital, and valproic acid, offer an alternative route of administration and can be loaded quickly, allowing for rapid attainment of therapeutic levels, if clinically necessary.

Adapted from: Mangano FT, McBride AE, and Schneider SJ. Brain tumors and epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;175–194.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

The most common surgical intervention for intractable complex partial seizures associated with a temporal lobe mass is the temporal lobectomy, but techniques vary widely between institutions.11 Some centers advocate the removal of the tumor alone, whereas others stress the importance of resecting the ictal focus, if separate from tumor pathology.23,32,40,45,110–113 Epilepsy surgery, rather than tumor resection, may be more likely to be considered in patients with a longer duration of epilepsy.

Gross total resections are approached with standard craniotomy techniques or via computer-assisted stereotactic cranial procedures. When removal of only the tumor is advocated, gross total resection has been reported as providing greater seizure control than partial resection, with an overall range of 80–88% of patients with temporal or extratemporal lesions achieving complete postoperative relief from seizures.32,112–116

Conversely, authors have long suggested that to control seizures it may be necessary to remove epileptogenic cortex beyond the tumor, because it is the cortex adjacent to the tumor margins that is most likely responsible for epileptogenesis.36,45,110,111,117,118 Seizure relief after resection for the tumor and the epileptogenic zone has been reported as ranging from 80% to 95% for temporal and extratemporal lesions. Surgical strategies are varied and include resection of epileptogenic cortex and mesial temporal structures.

Presurgical evaluation: EEG

Initially, an MRI is most sensitive for identification of a structural lesion. A routine electroencephalogram (EEG) may demonstrate correlating cerebral dysfunction and a potential epileptogenic zone. Interictal EEG and ictal video-EEG may show mirror foci, false localization, secondary epileptogenesis, or even false lateralization with ictal onset in tumor patients, however.102–104

In most cases, seizures originate in the vicinity of the tumor. Focal background abnormalities with polymorphic slow wave frequencies may be seen in only 32–44% of patients.47 Noninvasive video-EEG monitoring may identify ictal onset, but long-term invasive video-EEG recording with extraoperative epidural, subdural, or depth electrodes may be needed to define an epileptogenic zone using ictal data at seizure onset.47,105 These data are usually the single most reliable way of defining an epileptogenic focus via EEG.106

Presurgical evaluation: Mapping brain function

Neuropsychological testing can assess functional abilities and potential regions of dysfunction that may coincide with the location of a tumor. The Wada test, with intracarotid amobarbital injection, can determine lateralization of language and memory.107 After amobarbital injection into either internal carotid artery, unilateral hemispheric function is tested, allowing comparison of the language and memory function of each hemisphere independently. This knowledge may be crucial in determining whether resection will be performed near language areas. Functional magnetic resonance imaging (fMRI) is being studied as a possible noninvasive substitute for the Wada test.

SPECT and PET scans can confirm a functional relationship between the radiologic lesion and the epileptogenic area.

Electrocorticography (ECog) may be performed to more precisely identify dysfunctional regions, as well as the epileptogenic zone. ECog involves recording of electrical activity through epidural, subdural, or depth electrodes on the cortex. Cortical mapping with electrical stimulation of the cortex and cortical somatosensory evoked potentials may be required to more precisely determine areas of eloquent cortex, such as motor and language regions, if the ictal focus lateralizes to this region, or to guide resection of tumors involving eloquent cortex.108,109

The use of ECog data in modifying the extent of surgical resection is controversial. ECog may demonstrate slow wave activity over the tumor, whereas epileptiform activity may be seen from normal-appearing cortex. There is no clear correlation between the presence of spikes on ECog over the tumor and seizure outcome postoperatively.119 New postresection discharges are considered to be activation phenomena, unless these discharges are sustained, independent, or clearly epileptiform,120,121 but residual spikes do not necessarily correlate with poor postoperative seizure control.

Only one prospective study of ECog during tumor surgery was published. Tumor resection was performed and not altered by ECog findings before or after resection. The frequency of spike discharges on ECog before and after resection was equal between patients who were seizure-free after surgery and those with persistent seizures.119 ECog may not be necessary during tumor resection in patients with well-controlled preoperative seizures.45 Further controlled prospective analyses of ECog in tumor surgery are needed.

Postoperative follow-up

Postoperative follow-up is usually scheduled for 1 and 6 months after surgery. It includes a neuropsychologic assessment, EEG, and MRI.

Adapted from: Mangano FT, McBride AE, and Schneider SJ. Brain tumors and epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;175–194.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Figures specifically covering morbidity and mortality of tumor-associated epilepsy surgery are not available, but studies of epilepsy surgery by type of procedure have reported that the anterior temporal lobectomy for epilepsy carries a 0.0–0.7% mortality.179–181 Extratemporal lobectomies have 0–9% mortality. Permanent hemiparesis has been reported in between 1% and 2% of cases.

In a series of 429 patients, wound infection was the most common surgical complication, occurring in 3.5% of cases. Neurologic morbidity was reported in 5.4%, with 3.03% occurring transiently and 2.33% occurring permanently.181 These risks must be weighed against the benefits of better quality of life with relief of seizures. About 60–80% become seizure-free and another 10% or more have a significant improvement (>90% relief) in seizure activity.

Adapted from: Mangano FT, McBride AE, and Schneider SJ. Brain tumors and epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;175–194.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

The future of epilepsy surgery for tumors depends largely on the development and practical applications of current research trends. In the operating room, the use of robotics and real-time MRI continues to decrease mortality and morbidity. Further research on invasive EEG monitoring and electrocorticography should improve the guidance of surgical resection and enhance postoperative seizure freedom. The inception of intraoperative image-guided neurosurgery has further optimized the ability to achieve the greatest area of resection and assess for potential complications.182,183 Such technology could be applied to functional magnetic resonance imaging (fMRI) so that eloquent cortex can be more precisely identified during surgery.

A cure for primary brain tumors and metastatic disease awaits developments outside the operating room. Current trends include the use of:184

• boronated compounds, which may spare normal cells
• radioactive compounds attached to “cancer-seeking” molecules
• gene therapy
• antiangiogenesis therapy
• immunotherapy

Although at this time such technology has not made a definitive impact on treatment, one must only consider what doctors of a century ago would have thought about the medical and surgical progress that has occurred since the early twentieth century.

Adapted from: Mangano FT, McBride AE, and Schneider SJ. Brain tumors and epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;175–194.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

1. Aretaeus; Adams F, trans-ed. The Extant Works of Arataeus the Cappodocian. London: Printed for the Sydenham Society, 1856.

2. Galen; Daremberg C, trans. Oeuvres Anatomiques, Physiologiques, et Madicales de Galien. Paris: J. B. Bailliere, 1854.

3. Kocher T. Chirurgische beitrage zur phisiologie des gehirns und ruckenmarks. Deutsche Zeitschr F Chir 1893;35:433–494, 36:1–93.

4. Adams F. The genuine works of Hippocrates. London: Printed for the Sydenham Society, 1849.

5. Jackson JH. Selected writings of John Hughlings Jackson. London: Hodder and Stoughton Ltd, 1931.

6. Horwitz H. Library: historical perspective. Neurosurgery 1999;44:906–910.

7. Jackson JH. Localized convulsions from tumor of the brain. Brain 1882;5:364–374.

8. Horsley V. Brain surgery. BMJ 1886;2:670–675.

9. Horwitz H. Library: historical perspective. Neurosurgery 1995;36:428–432.

10. Bennett A, Godlee SR. Excision of a tumor from the brain. Lancet 1884;2:1090–1091.

11. Adelson PD. The surgical management of epilepsy in children. Contemp Neurosurg 1995;17(23):1–8.

12. Yeh HS, Kashiwagi S, Tew J, Berger T. Surgical management of epilepsy associated with cerebral arteriovenous malformations. J Neurosurg 1990;72:216–223.

13. Hauser W, Annegers J, Kurland L. Prevalence of epilepsy in Rochester, Minnesota: 1940–1980. Epilepsia 1991;32:429–445.

14. Luhdorf K, Jensen LK, Plesner AM. Etiology of seizures in the elderly. Epilepsia 1986;27:458–463.

15. Paeschel SM, Louis S, McKnight P. Seizure disorders in Down’s syndrome. Arch Neurol 1991;48:318–320.

16. Brodie M, Shorvon SD, Canger R. Commission on European affairs: appropriate standards of epilepsy care across Europe. Epilepsia 1997;38:1245–1250.

17. Ketz E. Brain Tumours and Epilepsy. In P Vinken, G Bruyn (eds), Handbook of Clinical Neurology. Amsterdam: North Holland Publishing, 1974;254–269.

18. Black P. Brain tumors (First of two parts). N Engl J Med 1991;324:1471–1476.

19. Rasmussen T, Blundell J. Epilepsy and brain tumour. Clin Neurosurg 1959;7:138–158.

20. Penfield W, Erickson TC, Tarlov I. Relation of intracranial tumors and symptomatic epilepsy. Arch Neurol Psychiatry 1940;44:300–315.

21. Le Blanc FE, Rasmussen T. Cerebral Seizures and Brain Tumors. Amsterdam, Netherlands: North Holland Publishing, 1974.

22. Strobos R, Alexander E, Masland R. Brain tumor presenting as convulsive disorder. Diseases of the nervous system. 1958;19:518–522.

23. Cascino G. Epilepsy and brain tumors: implications for treatment. Epilepsia 1990;3:S37–S44.

24. Whittle I, Beaumaont A. Seizures in patients with supratentorial oligodendroglial tumors. Clinicopatho- logical features and management considerations. Acta Neurochir 1995;135:19–24.

25. Olson J, Reidel EM, DeAngelis LM. Long-term outcome of low-grade oligodendroglioma and mixed glioma. Neurology 2000;54:1442–1448.

26. Morris H, Estes ML, Gilmore R, et al. Chronic intractable epilepsy as the only symptom of primary brain tumor. Epilepsia 1993;34:1038–1043.

27. Vecht CJ. Clinical management of brain metastasis. J Neurol 1998;245:127–131.

28. Howng SL, Kwan AL. Intracranial meningioma. Gaoxiong Yi Xue Ke Xue Za Zhi 1992;8:312–319.

28A. Lieu AS, Howng SL. Intracranial meningiomas and epilepsy: incidence, prognosis and influencing factors. Epilepsy Res 2000;38:45-52.

29. Daumas-Duport C, Scheithauer B, Chodkiewicz J, et al. Dysembryoplastic neuroepithelial tumor: a surgically curable tumor of young patients with intractable partial seizures. Neurosurgery 1988;23:545–556.

30. Otsubo H, Hoffman H, Humphreys R, et al. Detection and management of gangliogliomas in children. Surg Neurol 1992;38:371–378.

31. Ventureyra E. Surgery for childhood epilepsy and epileptic syndromes. Contemp Neurosurg 1997;19:1–6.

32. Blume W, Girvin J, Kaufmann J. Childhood brain tumors presenting as chronic uncontrolled focal seizure disorders. Ann Neurol 1982;12:538–541.

33. Sjors K, Blennow G, Lantz G. Seizures as the presenting symptom of brain tumors in children. Acta Paediatr 1993;82:66–70.

34. Williams B, Abbott K, Manson J. Cerebral tumors in children presenting with epilepsy. J Child Neurol 1992;7:291–294.

35. Suarez J, Sfaello Z, Guerrero A, et al. Epilepsy and brain tumors in infants and adolescents. Childs Nerv Syst 1986;2:169–174.

36. Zentner J, Wolf HK, Ostertun B, et al. Surgical treatment of neoplasms associated with medically intractable epilepsy. Neurosurgery 1997;41:378–387.

37. Lee TK, Nakasu Y, Jeffree MA, et al. Indolent glioma: a cause of epilepsy. Arch Dis Child 1989;64:1666–1671.

38. Ventureyra E, Herder S, Mallya B. Temporal lobe gangliogliomas in children. Childs Nerv Syst 1986;2:63–66.

39. Haglund MM, Berger MS, Kunkel DD, et al. Changes in gamma-aminobutyric acid and somatostatin in epileptic cortex associated with low grade glioma. J Neurosurg 1992;77:209–216.

40. Berger MS, Geyer JR, Keles GE, Ojemann GA. Seizure outcome in children with hemispheric tumors and associated intractable epilepsy: the role of tumor removal combined with seizure foci resection. Pediatr Neurosurg 1991;17:185–191.

41. Petroff O, Rothman DL, Behar KL, Mattson RH. Low brain GABA levels associated with poor seizure control. Ann Neurol 1996;40:908–911.

42. Freid I, Kim JH, Spencer DD. Hippocampal pathology in patients with intractable seizures and temporal lobe masses. J Neurosurg 1992;76:735–740.

43. Towle VL, Carder RK, Khorasani L, Lindberg D. Electrocorticographic coherence patterns. J Clin Neurophysiol 1999;16:528–547.

44. Boon P, Williamson P, Fried I, et al. Intracranial, intraaxial, space-occupying lesions in patients with intractable partial seizures: an anatomoclinical, neuropsychological, and surgical correlation. Epilepsia 1991;32:467–476.

45. Berger MS, Ghatan S, Haglund MM, et al. Low grade gliomas associated with intractable epilepsy: seizure outcome utilizing electrocorticography during tumor resection. J Neurosurg 1993;79:62–69.

46. Proposal for revised classification of epilepsy and epileptic syndromes. Commission on Classification and Terminology of the International League against Epilepsy. Epilepsia 1989;30:389–399.

47. Morris H, Estes M. Brain Tumors in Chronic Epilepsy. In E Wyllie (ed), The Treatment of Epilepsy: Principles and Practice (2nd ed). Baltimore: Williams & Wilkins, 1996;637–639.

48. Weinstock A, Cohen BH. Seizures in Patients with Brain Tumors and Cancer. Philadelphia: Churchill Livingstone, 2000.

49. Jack CR. Magnetic resonance imaging in epilepsy. Mayo Clin Proc 1996;71:695–711.

50. Henry TR. Neuroimaging in epilepsy. Contemp Neurosurg 1996;18(2):1–8.

51. Bradley WG, Shey RB. MR imaging evaluation of seizures. Radiology 2000;214:651–656.

52. Sperling M. Neuroimaging in epilepsy: recent developments in MR imaging, positron emission tomography, and single-photon emission tomography. Neurol Clin 1993;11:883–903.

53. Lee C, Duncan VW, Young AB. Magnetic resonance features of the enigmatic oligodendroglioma. Invest Radiol 1998;33:222–231.

54. Kuroiwa T, Kishiawa T, Kato A, et al. Dysembryoplastic neuroepithelial tumors: MR findings. J Comput Assist Tomogr 1994;18:352–356.

55. Boyko O. Adult Brain Tumors. In DD Stark, WG Bradley Jr, (ed), Magnetic Resonance Imaging (3rd ed). St. Louis: Mosby, 1999.

56. Fujii K, Fujita N, Hirabuki N, et al. Neuromas and meningiomas: evaluation of early enhancement with dynamic MR imaging. AJNR Am J Neuroradiol 1992;13:1215–1220.

57. Kuzniecky R, de la Sayette V, Ethier R, et al. Magnetic resonance imaging in temporal lobe epilepsy: pathological correlations. Ann Neurol 1987;22:341–347.

58. Sperling MR, Wilson G, Engel J Jr, et al. Magnetic resonance imaging in intractable partial epilepsy: correlative studies. Ann Neurol 1986;20:57–62.

59. Theodore WH, Dorwart R, Holmes M, et al. Neuroim- aging in refractory partial seizures: comparison of PET, CT, MRI. Neurology 1986;36:750–759.

60. Henry TR, Sutherling WW, Engel J Jr, et al. Interictal cerebral metabolism in partial epilepsies of neocortical origin. Epilepsy Res 1991;10:174–182.

61. DeWitte O, Levivier M, Violon P, et al. Prognostic value of positron emission tomography with [18F] fluoro-2-deoxy-d-glucose in the low-grade glioma. Neurosurgery 1996;39:470–477.

62. Derlon JM, Petit-Taboue MC, Chapon F, et al. The in vivo metabolic pattern of low-grade brain glioma: a positron emission tomographic study using 18F-fluorodeoxyglucose and 11C-l-methylmethionine. Neurosurgery 1997;40:276–288.

63. Duncan R, Patterson J, Roberts R, et al. Ictal/post-ictal SPECT in the presurgical localization of complex partial seizures. J Neurol Neurosurg Psychiatry 1993;56:141–148.

64. O’Brien TJ, So EL, Mullan MB, et al. Subtraction SPECT co-registered to MRI improves postictal SPECT localization of seizure foci. Neurology 1999;52:137–146.

65. Lazareff JA, Bockhorst HJ, Curran J, et al. Pediatric low-grade gliomas: prognosis with proton magnetic resonance spectroscopic imaging. Neurosurgery 1998;43:809–818.

66. Graves EE, Nelson SJ, Vigneron DB, et al. A preliminary study of the prognostic value of proton magnetic resonance spectroscopic imaging in gamma knife radiosurgery of recurrent malignant gliomas. Neuro- surgery 2000;46:319–328.

67. Nimsky C, Ganslandt O, Kober H, et al. Integration of functional magnetic resonance imaging supported by magnetoencephalography in functional neuronavigation. Neurosurgery 1999;44:1249–1256.

68. Atlas SW, Howard RS, Maldjian J, et al. Functional magnetic resonance imaging of regional brain activity in patients with intracerebral gliomas: findings implications and clinical management. Neurosurgery 1996;38:329–338.

69. Patel S, Breneman JC, Warnick RE, et al. Permanent iodine-125 interstitial implants for the treatment of recurrent glioblastoma multiforme. Neurosurgery 2000;46:1123–1130.

70. Valtonen S, Timonen U, Toivanen P, et al. Interstitial chemotherapy with carmustine-loaded polymers for high-grade glioma: a randomized double-blind study. Neurosurgery 1997;41:44–49.

71. Wang CC, Li J, Lee T. The delivery of BCNU to brain tumors. J Control Release 1999;61:21–41.

72. Westphal M, Daumas-Duport C, Thoron L, et al. Gliadel (polifeprosan 20 with carmustine 3.85% implant): a multinational phase III randomized double-blind trial in newly diagnosed malignant glioma. Proc Ann Meet Am Soc Clin Oncol 1999;18:A594.

73. Osoba D, Brada M, Yung WK, Prados M. Health-related quality of life in patients treated with temozolomide versus procarbazine for recurrent glioblastoma multi- forme. J Clin Oncol 2000;18:1481–1491.

74. Yung WK, Albright RE, Olson J, et al. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 2000;83:588–593.

75. Prados M, Yung A, Chang S, et al. A phase II trial of Temodal (temozolamide) in patients with anaplastic astrocytoma at first relapse. Proc Ann Meet Am Soc Clin Oncol 1999;18:A533.

76. Niranjan A, Lunsford LD. Radiosurgery: where we were, are, and may be in the third millennium. Neurosurgery 2000;46:531–543.

77. Consensus statement on stereotactic radiosurgery quality improvement. Neurosurgery 1994;34:193–199.

78. Grabb PA, Lunsford LD, Albright AL, et al. Stereotactic radiosurgery for glial neoplasms of childhood. Neurosurgery 1996;38:696–702.

79. Chen JC, Petrovich Z, O’Day S, et al. Stereotactic radiosurgery in the treatment of metastatic disease of the brain. Neurosurgery 2000;47:268–281.

80. Rutigliano MJ, Lunsford LD, Kondziolka D, et al. The cost effectiveness of stereotactic radiosurgery versus surgical resection in the treatment of solitary metastatic brain tumors. Neurosurgery 1995;37:445–455.

81. Boarini D, Beck D, VanGilder J. Postoperative prophylactic anticonvulsant therapy in cerebral gliomas. Neurosurgery 1985;16:290–292.

82. Foy P, Chadwick D, Rajgopalan N, et al. Do prophylactic anticonvulsant drugs alter the pattern of seizures after craniotomy? J Neurol Neurosurg Psychiatry 1992;55:753–757.

83. Cohen N, Strauss G, Lew R, et al. Should prophylactic anticonvulsants be administered to patients with newly diagnosed cerebral metastases? A retrospective analysis. J Clin Oncol 1988;6:1621–1624.

84. Mahaley M, Dudka L. The role of anticonvulsant medications in the management of patients with anaplastic gliomas. Surg Neurol 1981;16:399–401.

85. Glantz MJ, Cole BF, Forsyth PA, et al. Practice parameter: Anticonvulsant prophylaxis in patient with newly diagnosed brain tumors. Neurology 2000;54:1886–1893.

86. North J. Anticonvulsant prophylaxis in neurosurgery. Br J Neurosurg 1989;3:425–428.

87. North J, Hanieh A, Challen R, et al. Postoperative epilepsy: a double-blind trial of phenytoin after craniotomy. Lancet 1980;1:384–386.

88. Posner J. Neurologic Complications of Cancer. Philadelphia: FA Davis Co, 1995.

89. Wong DD, Longenecker RG, Liepman MI, et al. Phenytoin-dexamethasone: a possible drug-drug interaction. JAMA 1985;254:2062–2063.

90. Chalk J, Ridgeway K, Brophy T, et al. Phenytoin impairs the bioavailability of dexamethasone in neurological and neurosurgical patients. J Neurol Neurosurg Psychiatry 1984;47:1087–1090.

91. Kikuchi K, McCormick C, Neuwelt E. Immunosuppression by phenytoin: implication for altered immune competence in brain-tumor patients. J Neurosurg 1984;61:1085–1090.

92. Muller PJ, Tator CH, Bloom M. The effect of phenobarbital on the toxicity and tumoricidal activity of CCNU in a murine brain model. J Neurosurg 1980;52:359–366.

93. Neef C, Voogd-van derStraaten I. An interaction between cytostatic and anticonvulsant drugs. Clin Pharmacol Ther 1988;43:372–375.

94. Grossman SA, Sheilder VR, Gilbert MR. Decreased phenytoin levels in patients receiving chemotherapy. Am J Med 1989;87:505–510.

95. Momon HJ, Wen PY, Burns AC, Loeffler JS. Allergic skin reactions to anticonvulsant medication in patients receiving cranial radiation therapy. Epilepsia 1999;40:341–344.

96. Hoang-Xuan K, Delattre JY, Poisson M. StevensJohnson syndrome in a patient receiving cranial irradiation and carbamazepine. Neurology 1990;40:1144–1145.

97. Taylor L, Posner J. Phenobarbital rheumatism in patients with brain tumor. Ann Neurol 1989;25:92–94.

98. Leestma J, Annegers JF, Brodie MJ. Sudden unexplained death in epilepsy: observations from a large clinical development programme. Epilepsia 1997;38:47–55.

99. Buttner A, Gall C, Mall C, Weis S. Unexpected death in patients with symptomatic epilepsy due to glial brain tumors—a report of two cases. Forensic Sci Int 1999;100:127–136.

100. Rogers LR, Morris HH, Lupica K. Effect of cranial irradiation on seizure frequency in adults with low-grade astrocytoma and medically intractable epilepsy. Neurology 1993;43:1599–1601.

101. Moriarty GL, Dunn ME, Frost MD, et al. Contribution of radiotherapy and chemotherapy to seizure outcome after brain tumor resection. Epilepsia 1999;40:209–210(abst).

102. Cibula JE, Gilmore RL. Secondary epileptogenesis in humans. J Clin Neurophysiol 1997;14:111–127.

103. Blume W, Pillay N. Electrographic and clinical correlates of secondary bilateral synchrony. Epilepsia 1985;26:636–641.

104. Sammaritano M, De Lotbiniere A, Andermann F, et al. False lateralization by surface EEG of seizure onset in patients with temporal lobe epilepsy and gross focal cerebral lesions. Ann Neurol 1987;21:361–369.

105. Rosenbaum TJ, Laxer KD, Vessely M, Brewster Smith W. Subdural electrodes for seizure focus localization. Neurosurgery 1986;19:73–81.

106. Jayakar P, Duchowny M, Resnick TJ, et al. Localization of seizure foci: pitfalls and caveats. J Clin Neurophysiol 1991;8:414–431.

107. Wada J. Intracarotid injection of sodium amytal for the lateralization of cerebral speech dominance: experimental and clinical observation. J Neurosurg 1960;17:266–282.

108. Khajavi K, Comair YG, Wyllie E, et al. Surgical management of pediatric tumor-associated epilepsy. J Child Neurol 1999;14:15–25.

109. Morris H, Luders H, Hahn J, et al. Neurophysiological techniques as an aid to surgical treatment of primary brain tumors. Ann Neurol 1986;19:559–567.

110. Spencer D, Spencer S, Mattson R, Williamson P. Intracerebral masses in patients with intractable partial epilepsy. Neurology 1984;34:432–436.

111. Drake J, Hoffman H, Kobayashi J. Surgical management of children with temporal lobe epilepsy and mass lesions. Neurosurgery 1987;21:792–797.

112. Awad I, Rosenfeld J, Ahl J. Intractable epilepsy and structural lesions of the brain: mapping, resection strategies and seizure outcome. Epilepsia 1991;32:179–186.

113. Hirsch J, Sainte Rose C, Pierre-Kahn A, et al. Benign astrocytic and oligodendrocytic tumors of the cerebral hemispheres in children. J Neurosurg 1989;70:568–572.

114. Soffietti R, Chio A, Giordana MT, et al. Prognostic factors in well-differentiated cerebral astrocytomas in the adult. Neurosurgery 1989;24:686–692.

115. Fried I, Kim JH, Spencer DD, et al. Limbic and neocortical gliomas associated with intractable seizures: A distinct clinicopathological group. Neurosurgery 1994;34:815–824.

116. Cascino GD, Kelly PJ, Hirschorn KA, et al. Stereo- tactic resection of intraaxial cerebral lesions in partial epilepsy. Mayo Clin Proc 1990;65:1053–1060.

117. Gonzalez D, Elvidge AR. On the occurrence of epilepsy caused by astrocytoma of the cerebral hemispheres. J Neurosurg 1962;19:470–482.

118. Otsubo H, Hoffmann HJ, Humphreys RP, et al. Evaluation, surgical approach and outcome of seizure patients w,8–212.

119. Tran TA, Spencer SS, Javidan M, et al. Significance of spikes recorded on intraoperative electrocorticography in patients with brain tumor and epilepsy. Epilepsia 1997;38:1132–1139.

120. Pilcher WH, Sybergeld DL, Berger MS, Ojemann GA. Intraoperative electrocorticography during tumor resection: impact on seizure outcome in patients with gangliogliomas. J Neurosurg 1993;78:891–902.

121. Penfield W. Epilepsy and the Functional Anatomy of the Human Brain. Boston: Little, Brown, 1954.

122. Kleihues P, Burger PC, Scheithauer BW. Histological Typing of Tumors of the Central Nervous System. Berlin: Springer, 1993.

123. Greenberg M. Handbook of Neurosurgery (4th ed). Lakeland, FL: Greenberg Graphics, 1997.

124. Freid I, Kim JH, Spencer DD, et al. Limbic and neo- cortical gliomas associated with intractable seizures: a distinct clinicopathological group. Neurosurgery 1994;34:815–824.

125. Peipmeier JM, Freid I, Makuch R. Low-grade astrocytomas may arise from different astrocyte lineages. Neurosurgery 1993;33:627–632.

126. Campbell JW, Polack IF, Martinez AJ, et al. High- grade astrocytoma in children: radiologically complete resection is associated with an excellent long-term prognosis. Neurosurgery 1996;38:258–264.

127. Barker FG, Chang SM, Gutin PH, et al. Survival and functional status after resection of recurrent glioblastoma multiforme. Neurosurgery 1998;42:709–723.

128. Kondziolka D, Flickinger JC, Bissonette JD, et al. Survival benefit of stereotactic radiosurgery for patients with malignant glial neoplasms. Neurosurgery 1997;41:776–785.

129. Shrieve DC, Alexander E III, Wen PY, et al. comparison of stereotactic radiosurgery and brachytherapy in the treatment of recurrent glioblastoma multiforme. Neurosurgery 1995;36:275–284.

130. Laws ER, Taylor WF, Clifton MB, et al. Neurosurgical management of low-grade astrocytomas of the cerebral hemispheres. J Neurosurg 1984;61:661–673.

131. Reis Filho JS, Netto MR, Sluminsky BG, et al. Oligodendroglioma—a pathological and clinical study of 15 cases. Arq Neuropsiquiatr 1999;57:249–254.

132. Burger PC, Rawlings C, Cox EB, et al. Clinicopatho- logic correlations in the oligodendroglioma. Cancer 1987;59:1345–1352.

133. Bauman G, Lote K, Larson D, et al. Pretreatment factors predict overall survival for patients with low grade glioma—a recursive partitioning analysis. Int J Radiat Oncol Biol Phys 1999;45:923–929.

134. Salu J. Oligodendrogliomas—current state V–clinical peculiarities of the oligodendrogliomas. Neurochirugie 1999;10:394–396.

135. Rizk T, Mottolose C, Bouffett E, et al. Cerebral oligodendrogliomas in children: an analysis of 15 cases. Childs Nerv Syst 1996;12:527–529.

136. Saito A, Nakazato Y. Evaluation of malignant features of oligodendroglial tumors. Clin Neuropathol 1999;18:61–73.

137. Morris H, Matkovic, Z, Estes ML, et al. Ganglioglioma and intractable epilepsy: clinical and neurophysiologic features and predictors of outcome after surgery. Epilepsia 1998;39:307–313.

138. Soffietti R, Ruda R, Bradac GB, Schiffer D. PCV chemotherapy of recurrent oligodendrogliomas and oligoastrocytomas. Neurosurgery 1998;43:1066–1073.

139. Craincross J, Ueki K, Zlatescu MC, et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 1998;90:1473–1479.

140. Courville CB. Ganglioglioma: tumor of the central nervous system: review of the literature and report of two cases. Arch Neurol Psychiatry 1930;24:438–491.

141. Celli P, Nofrone I, Palma L, et al. Cerebral oligodendroglioma: prognostic factors and life history. Neurosurgery 1994;35:1018–1035.

142. Mork S, Lindeggard KF, Halvorsen TB, et al. Oligodendroglioma: incidence and biological behavior in a defined population. J Neurosurg 1985;63:881–889.

143. Johnson JH Jr, Hariharan S, Berman J, et al. Clinical outcome of pediatric gangliogliomas: ninety-nine cases over 20 years. Pediatr Neurosurg 1997;27:203–207.

144. Zimmerman RA, Bilaniuk LT. Computed tomography of intracerebral gangliogliomas. J Comput Tomogr 1979;2:63–66.

145. Lang FF, Epstein FJ, Ransohoff J, et al. Central nervous system gangliogliomas, part two: clinical outcome. J Neurosurg 1993;79:867–873.

146. Cervera-Pierot P, Varlet P, Chodkiewicz JP, DaumasDuport C. Dysembryoplastic neuroepithelial tumors located in the caudate nucleus area: report of four cases. Neurosurgery 1997;40:1065–1070.

147. Whittle IR, Dow GR, Lammie GA, Wardlaw J. Dysembryoplastic neuroepithelial tumour with discrete bilateral multifocality: further evidence for a germinal origin. Br J Neurosurg 1999;13:508–511.

148. Taratuto A, Pomata H, Sevlever G, et al. Dysembryo- plastic neuroepithelial tumor: morphological, immunocytochemical, and deoxyribonucleic acid analysis in a pediatric series clinical study. Neurosurgery 1995;36:474–481.

149. Honavar M, Janota I, Polkey CE. Histological heterogeneity of dysembryoplastic neuroepithelial tumors: identification and differential diagnosis in a series of 74 patients. Histopathology 1999;34:342–356.

150. Kirkpatrick P, Honaver M, Janota I, Polkey C. Control of temporal lobe epilepsy following en bloc resection of low-grade tumors. J Neurosurg 1993;78:19–25.

151. Taylor DC, Falconer MD. Clinical, socioeconomic, and psychological changes after temporal lobectomy for epilepsy. Br J Psychiatry 1968;114:1247–1261.

152. Andermann LF, Savard G, Meencke HJ, et al. Psychosis after resection of ganglioglioma or DNET: evidence for an association. Epilepsia 1999;40:83–87.

153. Black PM. Meningiomas. Neurosurgery 1993;32:643–657.

154. Black PM. Brain tumors (second of two parts). N Engl J Med 1991;324:1555–1564.

155. Wara W, Sheline GE, Newman H, et al. Radiation therapy for meningiomas. AJR Am J Roentgenol 1975;123:435–438.

156. Collins VP, Mordenskjold M, Dumanski JP. The molecular genetics of meningiomas. Brain Pathol 1990;1:19–24.

157. Yamashita J, Handa H, Iwaki K, et al. Recurrence of intracranial meningiomas with special reference to radiotherapy. Surg Neurol 1980;14:33–40.

158. Jaaskelainen J. Seemingly complete removal of histologically benign intracranial meningioma: late recurrence rate and factors predicting recurrence in 657 patients. A multivariate analysis. Surg Neurol 1986;26:461–469.

159. Jaaskelainen J, Haltia M, Servo A. Atypical and ana- plastic meningiomas: radiology, surgery and radiotherapy outcome. Surg Neurol 1986;25:233–242.

160. Mirimanoff RO, Dosoretz DE, Linggood RN, et al. Meningioma: analysis of recurrence and progression following neurosurgical resection. J Neurosurg 1985;62:18–24.

161. Flyger G. Epilepsy following radical removal of parasagittal and convexity meningiomas. Acta Psychiatr Neurol Scand 1956;31:245–251.

162. Foy PM, Copeland GP, Shaw MD. The incidence of postoperative seizures. Acta Neurochir 1981;55:253–264.

163. Kallio M, Sankilo R, Hakulinen T, et al. Factors affecting operative and excess long-term mortality in 935 patients with intracranial meningioma. Neurosurgery 1992;31:2–12.

164. Barbaro NM, Gutin PH, Wilson CB, et al. Radiation therapy in the treatment of partially resected meningiomas. Neurosurgery 1987;20:525–528.

165. Hakim R, Alexander E III, Loeffler JS, et al. Results of linear accelerator-based radiosurgery for intracranial meningiomas. Neurosurgery 1998;42:446–454.

166. Subach BR, Lunsford LD, Kondziolka D, et al. Management of petroclival meningiomas by stereotactic radiosurgery. Neurosurgery 1998;42:437–445.

167. Chang SD, Adler J Jr. Treatment of cranial base meningiomas with linear accelerator radiosurgery. Neurosurgery 1997;41:1019–1027.

168. Kondziolka D, Flickinger JC, Perez B, et al. Judicious resection and/or radiosurgery for parasagittal meningiomas: outcomes from a multicenter review. Neurosurgery 1998;43:405–414.

169. Zimm S, Wampler G, Stablein D, et al. Intracerebral metastases in solid-tumor patients: natural history and results of treatment. Cancer 1981;48:384–394.

170. Sorensen JB, Heine HH, Hansen M, Dombernowsky P. Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis. J Clin Oncol 1988;6:1474–1480.

171. Delattre JY, Krol G, Thaler ST, Posner JB. Distribution of brain metastases. Acta Neurol 1988;45:741–744.

172. Tsukada Y, Fouad A, Pickren JW, Lane WW. Central nervous system metastasis from breast carcinoma. Cancer 1983;52:2349–2354.

173. Neundorfer B. Epileptic seizures in brain metastases. Adv Neurosurg 1984;12:19–24.

174. Markesbery WR, Brooks WH, Gupta GL, Young AB. Treatment for patients with cerebral metastases. Arch Neurol 1978;35:754–756.

175. Ruderman NB, Hall TC. Use of glucocorticoids in the palliative treatment of metastatic brain tumors. Cancer 1965;18:298–306.

176. Cairncross JG, Kim JH, Posner JB. Radiation therapy for brain metastasis. Ann Neurol 1980;7:529–541.

177. Borgelt B, Gelber R, Kramer S. The palliation of brain metastasis: final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1980;6:1–9.

178. Patchell RA, Tibbs PA, Regine WF, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 1998;280:1485–1489.

179. Pilcher W, Rusyniak WG. Complications of epilepsy surgery. Neurosurg Clin North Am 1993;4:311–325.

180. Hennessy M, Langan Y, Elwes RD, et al. A study of mortality after temporal lobe epilepsy surgery. Neurology 1999;53:1276–1283.

181. Behrens E, Schramm J, Zentner J, Konig R. Surgical and neurological complications in a series of 708 epilepsy surgery procedures clinical study. Neurosurgery 1997;41:1–10.

182. Black PM, Moriarty T, Eben A, et al. Development and implementation of intraoperative magnetic resonance imaging and its neurosurgical applications. Neurosurgery 1997;41:831–845.

183. Rubino GJ, Farahani K, McGill D, et al. Magnetic resonance imaging-guided neurosurgery in the magnetic fringe fields: the next step in neuronavigation. Neuro- surgery 2000;46:643–654.

184. Gutin P, Posner JB. Neurooncology: diagnosis and management of cerebral gliomas—past, present, and future. Neurosurgery 2000;47:1–8.

185. Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med. 1990;322(8):494-500.

Adapted from: Mangano FT, McBride AE, and Schneider SJ. Brain tumors and epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;175–194.
With permission from Elsevier (www.elsevier.com).

Reviewed March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.