EEG in Brain Tumors

A brain tumor is one of the scariest diagnoses a patient can hear. Until the past 4 decades, with advent of advanced imaging (CT scanning, MRI), localization of brain tumors and other focal lesions was difficult. Old neuroimaging techniques consisted of skull radiography, which was usually negative, and pneumoencephalograms, which were invasive, painful, and often uninformative.

Electroencephalograms (EEGs) in humans started in the 1920s; in 1936, Walter, who introduced the term "delta waves," first identified the association between localized slow waves on EEG and tumors of the cerebral hemispheres. ^[1] Delta is the frequency of EEG that is less than 4 Hertz (Hz), whereas the normal alpha frequency is between 8 and 12 Hz. This established EEG as an important tool for localizing brain tumors. For the next 4 decades, electroencephalographers mounted an enormous effort to improve accuracy of localization and to seek clues to underlying pathological processes.

Experience has shown EEG to be somewhat reliable in localizing lesions involving superficial portions of the cerebral hemispheres, though it is of limited value in deep-seated lesions, especially posterior fossa tumors. The role of EEG in detecting focal cerebral disturbances has undergone a significant change since the development of CT scan and MRI.

Today, EEG is primarily used to complement these studies by evaluating functional changes in the patient's condition, especially in regards to seizures and epilepsy; it demonstrates aspects of brain physiology that are not reflected in structural neuroimaging. Functional neuroimaging techniques, such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), and functional MRI (fMRI), can exhibit physiologic changes but not with the temporal resolution of EEG. ^[2] Furthermore, EEG provides the only continuous measure of cerebral function over time and is the diagnostic test of choice regarding seizures and epilepsy, which is common with brain tumors.

This article reviews the major EEG changes that occur with different brain tumors. 

Classification

The following is the 2021 WHO Classification of CNS tumors (adapted): ^[3]

I. Gliomas, glioneuronal tumors, and neuronal tumors - High-grade gliomas, astrocytic gliomas, ependymal tumors

II. Choroid plexus tumors

III. Embryonal tumors - Medulloblastoma, neuroblastoma

IV. Pineal tumors - Pineocytoma, Pineoblastoma

V. Cranial and paraspinal nerve tumors - Schwannoma, neurofibroma, perineurioma, paraganglioma, nerve sheath tumor 

VI. Meningiomas

VII. Mesenchymal, non-meningothelial tumors - Hemangiomas, chordoma

VIII. Melanocytic tumors

IX. Hematolymphoid tumors - CNS lymphomas, Histiocytic tumors

X. Germ cell tumors - Teratoma, Germinoma

XII. Tumors of the sellar region - craniopharyngioma, pituitary adenoma

XIII. Metastases to the CNS

Brain tumors presenting with seizures

Seizures are encountered in up to 50% of patients with brain tumors. Twenty to forty percent of patients experience a seizure by the time their tumors are diagnosed, and an additional 20%–45% of patients who do not initially present with seizures eventually develop them. ^[4] Randomized clinical trials have not shown a benefit for anticonvulsant prophylaxis in patients with newly diagnosed brain tumors, including gliomas, meningiomas, and metastases. ^{[5, 6, 7]}

The mechanism of epileptogenesis in tumors is incompletely understood and is believed to be multifactorial. Seizures may present with tumors that are both intra-axial/infiltrative, such as astrocytomas, and extra-axial/distortive, such as meningiomas. ^[8] Low-grade, well-differentiated gliomas have the highest incidence of seizures. Tumors located in the limbic regions, especially the temporal lobe, and in primary or secondary motor/sensory cortices, are regarded as particularly epileptogenic, although systematic data are sparse. Thus, location and size of tumor, especially the degree of swelling and enhancement, may be markers of risk of seizures. ^[9]

The most common seizure semiology is simple partial, followed by complex partial, although specific seizure semiology is dependent on location. Approximately half of the patients also experience secondary generalized seizures. ^{[10, 11, 12]} Tumor-related seizures also occur more frequently in younger patients than in older patients. ^{[12, 13]}

The existence of preoperative seizures markedly increases the risk of postoperative seizures. Some studies have found no correlation with degree of subtotal resection, extent of surgery, age at diagnosis, pathological grade, or serum level of anticonvulsant drug ^[12] , but most have found superior seizure control in patients with total resection ^[10] . In one study, half of postoperative seizures occurred more than one month after the surgery, and half were recurrent ^[12] , including most of those that occurred late.

EEG abnormalities in brain tumors depend on the stage at which the patient presents for evaluation. EEG changes observed with tumors result mainly from disturbances in bordering brain parenchyma, since tumor tissue is electrically silent (with the possible exception of tumors containing neuronal elements, such as gangliogliomas). For this reason, EEG localization often is misleading, although lateralization is generally reliable.

Brain tumors may be associated with various EEG findings. The following may be seen at the time of diagnosis: ^[14]

• Focal slow activity

• Focal attenuation of background activity

• Asymmetric beta activity

• Disturbance of the alpha rhythm

• Interictal epileptiform discharges (spikes and sharp waves)

• Normal EEG

Activation procedures are usually of limited value in patients with tumors, although hyperventilation occasionally can accentuate focal slowing. Asymmetries of photic driving can be useful at times, although they also can be misleading.

A normal EEG occurs only in about 5% of hemispheric tumors but in 25% in deeper tumors.

Slow wave activity

Focal delta (EEG frequency < 4 Hz) activity is the classic electrographic sign of a local disturbance in cerebral function; however, if the lesion is small, it could be theta activity (4–8 Hz). A structural lesion is strongly suggested if the delta activity is continuously present; shows variability in waveform amplitude, duration, and morphology (polymorphic); and persists during changes in physiologic states, such as sleep or alerting procedures. When focal delta is found without a corresponding imaging abnormality, it is usually in the setting of acute seizures (especially postictally), nonhemorrhagic infarction, or trauma.

Clinical and experimental observations indicate that polymorphic delta activity (PDA) results primarily from lesions affecting cerebral white matter; involvement of superficial cortex is not essential, and lesions restricted to the cortical mantle generally do not produce significant delta activity. Functional deafferentation of cortex likely is critical. ^[15]

Delta activity that fails to persist into sleep or attenuates significantly with arousal or eye opening is less indicative of structural pathology, as is rhythmic or sinusoidal delta. The latter usually occurs intermittently and is termed intermittent rhythmic delta activity (IRDA). It is usually bilateral and of high amplitude and is typically maximal occipitally (OIRDA) in children and frontally (FIRDA) in adults. Unlike PDA, IRDA increases in drowsiness and attenuates with arousal. IRDA often is observed without structural pathology, as in metabolic encephalopathies, but it also can occur with diencephalic or other deep lesions; in this situation, an amplitude asymmetry can be present, with higher amplitude ipsilateral to the lesion.

As in other clinical settings, theta activity is indicative of less severe localized or diffuse dysfunction than delta activity and is observed more commonly with functional than structural disturbances. When unaccompanied by delta activity, theta is less likely to indicate a lesion that produces a focal neurological deficit or seizures.

Localized attenuation of background activity

Since tumor tissue probably does not generate electrical activity detectable with conventional recording techniques, electrical silence is the best localizing sign of a cerebral tumor. However, it is a rare finding, occurring only when the tumor involves significant cortical areas with minimal subcortical disruption. Incomplete loss of activity, especially faster normal rhythms, is observed more commonly and is diagnostically helpful.

Alpha rhythm

Alpha rhythm is the posterior dominant rhythm with eyes closed that is reactive; in normal adults, it is greater than 8.5Hz. By the time the patient presents with focal or diffuse neurological symptoms and signs, disturbance of the alpha rhythm may be observed. Slowing of the alpha rhythm ipsilateral to a tumor is more common and significant than asymmetry of amplitude. However, disturbance of alpha rhythm depends on the site of the tumor. The more posterior the location, the more the alpha tends to be slowed, nonpersistent, or disturbed by admixed theta waves. Rarely, the alpha rhythm may also fail to block the eye opening on the side of the neoplasm (Bancaud phenomenon).

Beta activity

Abnormalities of beta activity usually are limited to voltage asymmetries. To be considered unequivocally abnormal, a persistent amplitude difference of one third or greater (expressed as a fraction of the higher voltage) should be present. Diminished beta activity results either from cortical dysfunction, as in parenchymal tumors, or from an increase in resistance of the medium-separating cortex from scalp-recording electrodes, as in meningiomas or subdural collections. Focally increased beta activity usually is associated with a skull defect, called breach rhythm. Certain medications can cause increased presence or prominence of beta activity.

Interictal epileptiform discharges

Isolated discharges

Spikes, sharp waves, or spike-wave complexes occurring with consistent localization are observed sometimes early in the course of brain tumors. However, they are more common either as early findings of slowly growing neoplasms associated with seizures or later after focal slowing has developed.

Periodic lateralized epileptiform discharges

Patients with tumors may exhibit periodic lateralized epileptiform discharges (PLEDs) at times, particularly after a series of seizures. Most patients with this EEG finding have had or will have seizures, if they are observed sufficiently closely and persistently; the pattern likely represents a transitional state between ictal and interictal epileptiform discharges. Aggressiveness of treatment depends in part on whether the discharges are resolving (ie, becoming less sharp, more localized, and further apart) or the opposite.

Seizure patterns

When prolonged electrographic seizures (>10 min) are recorded during a routine EEG, status epilepticus should be suspected. Clinical accompaniments may be subtle, as in aphasic or other forms of nonconvulsive status, particularly when the patient's baseline condition has been compromised by the tumor, its treatment, or complications.

Since EEG reflects activity of cortical neurons, hemispheric tumors affect EEG most consistently and prominently. Slowing is Location is an important determinant of the likelihood and nature of EEG abnormalities.

Supratentorial tumors

Frontal lobe tumors characteristically cause focal PDA, which accurately localizes the lesion. Especially if the lesion is close to the midline, PDA may be bilateral, but of higher amplitude and lower frequency ipsilateral to the tumor. In some cases, slowing may be IRDA rather than PDA. This occurs most often when deep structures such as the corpus callosum are involved (eg, butterfly glioma). The alpha rhythm (the posterior dominant rhythm) is often preserved.

Temporal gliomas are generally the easiest to localize on EEG, since PDA occurs over the tumor site in more than 80% of patients. EEG from the contralateral hemisphere may be normal or may show much milder slowing. Since these tumors often are associated with seizures, they may demonstrate interictal epileptiform discharges. These discharges may be identical to those associated with nonneoplastic lesions such as mesial temporal sclerosis (which does not enhance, unlike most tumors), especially when the tumor is located medially, as is often the case with very slow-growing tumors, such as gangliogliomas and dysembryoplastic neuroepithelial tumors.

Parietal tumors less often produce localized slowing; PDA usually is lateralized but often not clearly localized. When phase reversals are present, they may be temporal or frontal rather than parietal. In centroparietal tumors, mu rhythms (sensory motor cortical rhythm) may be attenuated ipsilaterally, but occasionally may be more persistent and of higher amplitude.

Occipital gliomas often produce focal changes, especially PDA and alpha rhythm abnormalities. Occipital meningiomas, mainly of the tentorium, can cause more focal EEG changes.

Deep hemispheric tumors

Deep hemispheric tumors include those than impinge on the lateral and third ventricles and surrounding structures, including the diencephalon, basal ganglia, and corpus callosum. Neuroimaging has led to earlier diagnosis of smaller tumors that may be associated with normal EEGs.

The typical EEG finding is IRDA. This finding classically has been associated with hydrocephalus or increased intracranial pressure, but this belief may not be valid, since IRDA is uncommon in hydrocephalus of nonneoplastic origin and is not present in benign intracranial hypertension. PDA and epileptiform discharges typically do not occur with intraventricular and sellar tumors

In hypothalamic hamartomas, ictal and interictal EEG discharges may be seen over the frontal or temporal lobe, depending on whether anterior or posterior hypothalamus is involved.

In the sellar region, the EEG is usually normal, although bitemporal slowing may be seen, especially with large lesions.

Infratentorial tumors

In brainstem and cerebellar tumors, EEG is more often abnormal in children than in adults. If present, slowing is most often posterior and bilateral. IRDA may be observed, possibly more so if hydrocephalus is present. EEG is usually normal in cerebellopontine angle tumors. Slowing is often intermittent and usually but not always ipsilateral to the lesion; it may be bilateral or even predominantly contralateral. Cerebellar spikes and seizures can be seen.

EEG patterns are not specific for tumor pathology, but some general correlations exist.

• Slowly growing extra-axial tumors, such as meningiomas, produce the mildest EEG disturbances, whereas rapidly growing intra-axial tumors, such as glioblastomas, cause the most marked abnormalities.

• Benign intra-axial tumors, such as astrocytomas or oligodendrogliomas, are intermediate in their effects on the EEG.

• Interictal discharges most commonly are observed initially in slowly growing tumors and often are observed later in the course of higher-grade lesions.

Location is important in the EEG findings because the temporal lobe is one of the more epileptogenic zones.

Meningiomas

Being extra-axial, meningiomas compress the brain but cause little destruction of brain tissue. Therefore, meningiomas of the anterior or middle cranial fossa, unless large, infrequently alter EEGs. Convexity meningiomas are more likely to cause EEG changes. Focal slowing, FIRDA, or beta asymmetry may be seen. Epileptiform discharges are observed only in a minority of patients, despite their propensity to have seizures. ^{[16, 17]} Some patients may have multiple meningiomas.

Gliomas

Slowly growing gliomas such as oligodendrogliomas and fibrillary astrocytomas (excluding tumors of deep structures) often can be distinguished from the more rapidly growing anaplastic astrocytoma and glioblastoma multiforme.

With more benign tumors, which are comparatively circumscribed, the abnormalities tend to be localized and within the theta range. Indolent gliomas commonly cause seizures, and epileptiform activity may appear before significant slowing. Later, delta appears, often intermittently and at 2-3 Hz. Still later, focal PDA becomes persistent.

In rapidly growing tumors, relatively more overall abnormality is present, and the background (particularly the alpha rhythm) is more impaired and disorganized. Glioblastomas produce the most widespread, slowest (often 1 Hz or less), and largest (100-200 µV) delta waves. These tumors cause prominent PDA, with marked alteration of background rhythms. Also, the high incidence of necrosis makes "flat PDA" (low-amplitude slow delta with diminished fast activity) more likely.

Glioneuronal tumors

Glioneuronal tumors are highly epileptogenic. Electrographically, they can be associated with continuous spike discharges and spike-bursts. ^[18]

Metastases

Metastatic tumors to the brain occur commonly with carcinomas of lung, kidney, and breast and with melanomas and chorionic carcinomas. When metastases are present bilaterally, slowing often appears diffuse, although it is often asymmetric; slowing from multiple bilateral lesions is often difficult to distinguish from a toxic-metabolic disturbance. Meningeal carcinomatosis usually causes changes that correlate with the clinical situation; when deposits are widespread and cause an encephalopathy, slowing is usually diffuse.

Isolated metastases usually cause less prominent abnormalities than gliomas of similar size and location. Slow waves show higher frequency, lower amplitude, and less persistence than with high-grade gliomas, and normal background rhythms are more likely to be preserved.

Paraneoplastic syndromes

Cancer's remote effects are well known but are often hard to diagnose. Limbic encephalitis, often with Hu antibody and anti-NMDA receptor encephalitis syndrome, can have seizures as clinical symptoms, with the latter even presenting with status epilepticus. ^[19]  One of the unique findings on EEG in anti-NMDA patients is "extreme delta brush" (frontally dominant delta waves with overriding fast activity). ^[20]  Other findings include frontotemporal slowing and less commonly epileptogenic discharges. ^[21]  The advent of paraneoplastic antibodies (Hu, NMDA) allows these diagnoses to be made; however, the treatment is essentially the treatment of the tumor. The NMDA receptor antibody syndrome, which is now probably the best characterized paraneoplastic syndrome, requires tumor removal (ovarian teratoma in female) and is more treatable with immunosuppressive agents, such as high-dose steriods, IVIG, plasmapheresis, and other immunomodulating agents.

Radiation necrosis

An unfortunate late side effect of radiation therapy of brain tumors is radiation necrosis. Radiation necrosis can look like a growing mass and may be hard to distinguish from tumor growth or recurrence on neuroimaging on CT scanning or MRI and may require a PET scan to determine if it has a hypometabolic or hypermetabolic pattern. Because radiation necrosis is not growing cells, an inflammatory process affects normal tissue at the tumor interface, which can produce slowing and inflammatory eye disease.

Because of improvements in neuroimaging and neurosurgery and recognition of the benefits of early resection, serial EEG studies now are rarely performed prior to surgery. Older studies suggest that EEG evolution during tumor growth is characterized mainly by increased slowing—lower frequency, higher amplitude, more persistence, and wider distribution—with rate of change depending mainly on rate of tumor growth. In addition, epileptiform discharges are more likely to occur as the tumor grows.

Occasionally, successful treatment with steroids or chemotherapy can cause reduction in slowing and epileptiform activity.

Following resection, dramatic changes may occur in the EEG; these usually stabilize over periods of weeks to months. Since screening for tumor recurrence now depends on neuroimaging, serial EEGs usually are reserved for patients with clinical changes that are not explained by imaging, particularly when seizures are suspected.

EEG changes after neurosurgery

EEG changes after neurosurgery usually exhibit the following features:

• In the immediate postoperative period, the EEG frequently deteriorates, with prominent focal and sometimes generalized slowing. Localized PDA can occur if, for example, the temporal or frontal lobe was retracted to provide access to a deep tumor.

• After a week or so, EEG abnormalities improve, and slow waves diminish, although much individual variation exists.

• In most patients, the residual EEG abnormality becomes stable 3-4 months after craniotomy.

• Abnormalities seldom resolve completely; residual abnormality depends largely on completeness of tumor excision.

• Subsequent localized or generalized increase in slowing or loss of background activity strongly suggests tumor recurrence.

• With further progression, delta activity increases in voltage while frequency becomes slower and distribution wider.

• Emergence of epileptiform activity without changes in focal or generalized slowing may occur and does not necessarily imply tumor recurrence.

• Defects in the bone and scalp result in a "breach rhythm" consisting of a wide variety of EEG changes, including a high voltage 6-11 Hz mu-like rhythm in the centrotemporal areas as well as sharp waveforms with a negative polarity. ^[22]

  • Replacement of the skull defect with a bone or prosthetic flap often does not significantly affect these waveforms. Evaluation of postoperative epileptiform activity, therefore, is challenging because breach activity may mimic epileptiform discharges, and their distributions are expected to overlap.

  • In a majority of patients, it may be impossible to confidently determine the existence of epileptiform activity. The existence of a breach rhythm does not indicate an increased propensity for seizures. ^[23] Appearance of a postoperative breach rhythm is almost universal. Preoperative and postoperative recordings on a patient with an oligodendroglioma illustrate these changes (see the images below). At times, such rhythmic activity can suggest a seizure pattern, but it does not have the characteristic evolution of frequency, amplitude, and distribution of an ictal discharge. Because of these factors, a magnetoencephalogram, which is not as significantly affected by skull defects, may be preferable to the EEG in these patients.

    Preoperative EEG in a patient with a right temporal oligodendroglioma. Polymorphic delta activity is localized mainly over the right anterior-midtemporal region, with some centroparietal spread; alpha is preserved. (Longitudinal bipolar montage; right temporal chain is bottom 4 channels. Calibration: 1 second, 50 mV.)

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    Patient with a right temporal oligodendroglioma after tumor resection. The patient is drowsy, and bilateral alpha is not present, but right posterior alphalike activity with intermixed sharp theta constitutes a breach rhythm. Beta also is increased on that side, and polymorphic delta activity is less prominent. (Irregular eye movement artifact is observed bilaterally in anterior derivations.)

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Use of EEG to predict postoperative seizures

Because of the tendency of focally increased high-frequency activity after craniotomy to sharpen the contour of background waves, identification of interictal epileptiform discharges is difficult. A distribution other than the breach rhythm, asymmetric up-slope and down-slope, extremely sharp peak, and prominent after-coming slow wave suggest epileptogenicity. However, the degree of slowing (predominantly delta rather than theta) may be associated more closely with seizures than with amount of sharp activity. ^[24] Similar lack of predictive value of interictal discharges has been noted in other studies. ^[16]

Complications of brain tumors and their treatment

A perioperative stroke with sizable territory infarct typically exhibits increased slowing in the region of the stroke, with loss of fast activity if cortex is involved. Hemorrhagic stroke or hemorrhage into the tumor bed also is accompanied by increased slowing, which may be bilateral if deep structures are affected.

If chemotherapy or radiation is effective, slowing can diminish even without surgery. Conversely, late effects of radiation can result in increased slowing, as well as new epileptiform activity and clinical seizures in the case of radiation necrosis. EEG probably does not help in distinguishing recurrent tumor from radiation necrosis. In radiation-induced or chemotherapy-induced encephalopathies, including methotrexate leukoencephalopathy, slowing of the EEG usually parallels the clinical situation, though some studies suggest that chemotherapy is not the etiology of EEG slowing. ^[25]

The clinician and electroencephalographer also must remember that patients with brain tumors can develop additional diseases, particularly when immunosuppressed, such as progressive multifocal leukoencephalopathy or herpes simplex encephalitis. In these patients, EEG changes such as focal slowing or periodic discharges reflect the new condition.

Use of EEG in end-stage disease

A generalized tonic-clonic seizure frequently heralds the commencement of rapid cognitive deterioration in malignant gliomas. The resulting change in mental status may be due to the progression of disease coupled with radiotherapy/chemotherapy or to either frequent or ongoing seizures with postictal encephalopathy. Whether to escalate therapy with additional antiepileptic medication presents difficulty in management. Both conditions may result in slowing on routine EEGs. Although PLEDs and focal interictal epileptiform discharges may frequently be seen, they may not necessarily imply clinically significant changes in cognition if they were long-standing.

Baseline EEGs obtained previously may be helpful for comparison and may help to guide treatment decisions. Continuous EEG monitoring can identify subtle seizures and allow correlation of background organization and slowing to clinical improvement or deterioration.

The character and distribution of EEG changes produced by tumors depend primarily on lesion size, rate of growth, distance from the cortical surface, and specific structures involved.

In general, the following are true:

• PDA is the hallmark of tumor localization.

• Both metastatic tumors and gliomas commonly cause delta activity, often localized to the tumor site and neighboring zone, although bilateral slowing may occur. Changes are more marked with aggressive gliomas.

• Deep tumors are more likely to cause widespread hemispheric or bilateral slowing, often rhythmic (IRDA). Small deep tumors may cause no abnormalities, especially if the thalamus is not involved.

• When the tumor is growing rapidly and involves cortex, localized loss of background activity may occur.

• Spikes, sharp waves, or spike-wave discharges often are observed at the time of diagnosis in slowly growing tumors. With more malignant neoplasms, both seizures and epileptiform discharges occur later. Location of discharges does not always correlate with tumor location.

• Craniotomies and other interventions alter the EEG in usually predictable ways. Breach rhythm can complicate the interpretation of interictal epileptiform activity.

Despite advances in neuroimaging, EEG still offers a unique view of physiologic changes over time in patients with brain tumors, especially in regard to seizures.