Epilepsy surgery: Presurgical evaluation

INTRODUCTION — 

Epilepsy is one of the most common chronic neurologic disorders, and approximately 20 to 30 percent of patients with epilepsy will have medically and socially disabling seizure disorders. Such patients are at increased risk for serious morbidity and mortality, including cognitive disorders, depression, physical trauma, and sudden unexpected death in epilepsy.

Surgical therapy is an important and underutilized treatment in patients with drug-resistant focal epilepsy (DRE). The presurgical evaluation of potential candidates for epilepsy surgery is necessary to exclude seizure mimics, confirm the diagnosis of epilepsy, better define the epilepsy syndrome and classification, identify the epileptogenic zone, and determine the extent to which it can be resected while avoiding operative morbidity. All of these factors are important for directing treatment.

This topic will discuss the presurgical evaluation of adults with presumed DRE. Surgical treatment of epilepsy is reviewed separately. (See "Resective and ablative surgical treatment of epilepsy in adults".)

Other aspects of epilepsy management in adults and epilepsy surgery in children are discussed separately:

●(See "Overview of the management of epilepsy in adults".)

●(See "Evaluation and management of drug-resistant epilepsy".)

●(See "Seizures and epilepsy in children: Refractory seizures", section on 'Epilepsy surgery'.)

REFERRAL TO A COMPREHENSIVE EPILEPSY CENTER — 

Most individuals who will respond favorably to antiseizure medications are successfully managed within the first two years of treatment. Patients who do not respond favorably to two antiseizure medications used appropriately are likely to have drug-resistant epilepsy (DRE) and should be investigated for surgery and other alternative forms of treatment. (See "Evaluation and management of drug-resistant epilepsy", section on 'Definition'.)

In well-selected patients with DRE (eg, those with focal epilepsy), epilepsy surgery is superior to medical therapy [1,2].

A comprehensive evaluation is essential in patients with DRE. Patients should be referred to neurologists who have subspecialty expertise in epilepsy and are based at a comprehensive epilepsy center that has the necessary multidisciplinary resources and personnel.

●Candidates for surgical evaluation – Early referral for epilepsy surgery (as soon as drug resistance is ascertained) is supported by 2022 expert consensus recommendations from the International League Against Epilepsy (ILAE) [3]:

•We offer surgical evaluation to every patient with confirmed DRE up to 70 years of age as soon as drug resistance is ascertained.

•We discuss surgical evaluation with older patients (age >70 years) with DRE who have no surgical contraindication. Although age is not a contraindication for epilepsy surgery, experience is limited in the population of older adults. While randomized trial data are lacking, the available literature suggests that surgery is similarly effective in older and younger adults, although complication rates are higher in older adults (see "Resective and ablative surgical treatment of epilepsy in adults", section on 'Complications in older adults'). A 2024 systematic review and meta-analysis evaluated studies of epilepsy surgery performed after 1990 and included 11 case series and 14 cohort studies with 1111 older adults (age ≥50 years) and 4111 younger adults (age <50 years) as controls [4]. The pooled incidence of seizure freedom after epilepsy surgery for older adults was 70.1 percent; the incidence of seizure freedom in cohort studies was similar for older and younger adults (risk ratio [RR] 1.05; 95% CI 0.97-1.14).

•Surgery should only be considered in individuals with DRE without signs/symptoms of a progressive neurodegenerative condition.

•The ILAE recommends that surgical referral should not be offered to patients with active substance use disorder who are nonadherent with management.

Epilepsy surgery is particularly appropriate for patients with focal DRE when seizures are disabling or reduce the quality of life because of any of the following [5,6]:

•Impairment of consciousness

•Causing injury

•High seizure frequency

•Increased risk of mortality (eg, generalized tonic-clonic seizures, especially if three or more per year)

●Main factors associated with favorable surgical outcomes – The localization of seizure onset, underlying surgical pathology, and seizure type(s) are important determinants of surgical candidacy and outcomes. The most favorable candidates are those with magnetic resonance imaging (MRI)-identified lesions that represent both the pathologic process underlying the epileptogenic brain tissue and the location of seizure onset. Such MRI findings, together with concordant electroencephalography (EEG) data, are pivotal in selecting operative candidates and determining the strategy for the surgical procedure.

At most epilepsy centers, each patient's diagnostic evaluation is reviewed at a surgical epilepsy consensus conference before epilepsy surgery to discuss the surgical treatment plan and to consider potential alternative treatment options.

GOALS OF THE EVALUATION

Confirm the diagnosis — If not already done, patients with apparent or true drug-resistant epilepsy (DRE) require an evaluation to exclude seizure mimics, confirm the diagnosis of epilepsy, and better define the epilepsy syndrome and classification, which are all important for directing treatment.

Identify surgical candidates — Focal cortical ablation is most likely to benefit patients with drug-resistant focal epilepsy if the seizures emanate from a region (the epileptogenic zone) that can be removed with minimal risk of disabling neurologic or cognitive dysfunction. Thus, it is critical to identify the epileptogenic zone and determine the extent to which it can be resected while avoiding operative morbidity, especially injury to eloquent cortex (regions of the brain that subserve higher cortical function including language, motor, and sensory areas) [7].

In general, decisions about the potential effectiveness of focal cortical resection/ablation rely most heavily on the concordance of clinical seizure semiology (the key signs and symptoms that characterize a seizure), ictal and interictal scalp EEG findings, and structural MRI.

In adults, there are three major types of DRE that may be remedied with focal cortical resective/ablative surgery:

●Patients with mesial temporal lobe epilepsy with localization of the epileptogenic zone in the amygdala and hippocampus are the most common candidates for effective surgical therapy. (See "Resective and ablative surgical treatment of epilepsy in adults", section on 'Mesial temporal lobe epilepsy'.)

●Patients with lesional epilepsy with an unequivocal abnormality on brain MRI due to focal structural pathology, such as a low-grade glial tumor, cavernous malformation, or malformation of cortical development (MCD) with medically refractory seizures, may also be good surgical candidates. Surgical success varies with the specific pathologic finding. For example, operative outcomes are distinctly less favorable in individuals with focal cortical dysplasia and other MCDs. (See "Resective and ablative surgical treatment of epilepsy in adults", section on 'Lesional epilepsy'.)

●Patients with nonlesional focal epilepsy and a normal brain MRI are more challenging, but some of these patients are nonetheless good surgical candidates. Localization of the epileptic brain tissue in these patients often requires long-term intracranial EEG monitoring in addition to functional and metabolic brain imaging. (See "Resective and ablative surgical treatment of epilepsy in adults", section on 'Focal epilepsy with normal brain MRI'.)

Identify factors that may preclude surgery — Patients who are usually not surgical candidates for focal cortical resection/ablation include individuals with [8-11]:

●Bilateral or multifocal seizure onset

●Generalized-onset epilepsy

●Significant medical comorbidities

Likewise, patients in whom the site of seizure onset and initial seizure propagation is intimately associated with functional ("eloquent") cortex may not be appropriate candidates for resective/ablative surgery.

Intellectual disability has traditionally been a relative contraindication to temporal lobectomy because it implies bilateral and potentially diffuse rather than focal brain pathology. In some studies, low intelligence quotient (IQ) has been associated with lower postoperative seizure remission rates and increased risk of postoperative cognitive sequelae [12]. However, intellectual disability may not be an independent predictor of surgical outcome; some patients may still benefit from ablative surgery, depending on the type of epilepsy and the method of resective/ablative surgery [13].

Note that selected patients with DRE and multifocal- or generalized-onset epilepsy may be candidates for one of the neurostimulation techniques (vagus nerve stimulation, responsive cortical stimulation, deep brain stimulation), as reviewed separately. (See "Evaluation and management of drug-resistant epilepsy", section on 'Neurostimulation'.)

COMPONENTS OF THE EVALUATION — 

Standard components of the surgical evaluation are discussed below.

History and examination — The history and neurologic examination are critical to confirm the diagnosis and characterize seizure semiology and clinical localization. Emphasis should be placed on the presence of multiple or differing seizure semiologies, which may raise concern for multiple epileptogenic zones. The history should also explore epilepsy risk factors, including but not limited to a history of febrile seizures, central nervous system infection, head trauma, stroke, and family history of epilepsy [13]. The general and neurologic examination should identify any focal deficits and evaluate for evidence of syndromes associated with epilepsy (eg, tuberous sclerosis complex).

Comorbid psychiatric disease (eg, anxiety or depression) is common in patients with drug-resistant epilepsy (DRE) and has been associated with worse postsurgical seizure outcomes. While the presence of a psychiatric disorder does not preclude surgery, presurgical psychiatric evaluation and psychosocial assessment are advised to mitigate potential complications postoperatively [14]. (See "Resective and ablative surgical treatment of epilepsy in adults", section on 'Psychologic sequelae'.)

Neuropsychologic and psychiatric assessment — Neuropsychologic studies are performed to evaluate the presence of verbal or nonverbal learning and memory deficits at baseline; psychiatric evaluation should explore the personal and family history of psychiatric disorders, including anxiety, depression, suicidal behavior, and psychotic disorders [13,15,16]. The findings from this assessment are used to:

●Determine preoperative cognitive performance as a baseline that can be compared with a postoperative examination

●Identify and quantify ictal and postictal deficits as an aid to seizure characterization, lateralization, and localization

●Provide evidence-based predictions of cognitive risk associated with the proposed surgery

●Provide comprehensive preoperative counseling, including neuropsychologic education of the patient and family or guardian

●Identify and evaluate comorbid psychiatric disorders and patients at risk for postoperative psychiatric complications

Routine and video-EEG — Routine EEG recording with standard activating procedure and long-term scalp-recorded video-EEG monitoring are essential to confirm the diagnosis of epilepsy and to localize the site of seizure onset in individuals with focal epilepsy. Additional scalp-recorded EEG electrodes, including anterior or inferior temporal electrodes, are often placed to increase the diagnostic yield of the neurophysiologic studies. (See "Electroencephalography (EEG) in the diagnosis of seizures and epilepsy", section on 'Special electrode placement'.)

Interictal and ictal EEG patterns are utilized for surgical localization. Using computer-assisted video-EEG in an inpatient epilepsy monitoring unit, habitual seizures are recorded to determine the correlation between ictal semiology and EEG findings. The peri-ictal neurologic examination provides an additional functional assessment that can assist in lateralizing and localizing the epileptogenic zone.

Brain MRI — All patients undergoing surgical evaluation should have a high-resolution brain MRI with an epilepsy protocol that includes sequences optimized for visualization of the hippocampus and gray-white matter junction.

MRI epilepsy protocol — To optimize the yield, MRI should be performed using an epilepsy protocol. While epilepsy protocols vary depending on the institution and available technology, most recommendations agree that an epilepsy protocol for MRI should ideally include [17-20]:

●Standard T1-weighted images.

●Three-dimensional (3D) volumetric T1-weighted images (1 mm isotropic voxels) with high definition of the gray-white junction (eg, magnetization-prepared rapid acquisition gradient echo [MPRAGE] and 3D fast spoiled gradient recalled echo acquisition at steady state [3D fast spoiled GRASS or 3D-SPGR]) for evaluation of brain anatomy, detection of malformations of cortical development, and application of postprocessing techniques such as 3D reconstructions and volumetric analyses.

●Axial and coronal T2-weighted and T2-fluid-attenuated inversion recovery (FLAIR) imaging of the temporal lobes for assessment of hippocampal architecture, basal temporal encephaloceles, and cystic tissue components of other lesions.

●Axial and coronal T2-FLAIR imaging for assessing signal abnormalities and detection of hippocampal sclerosis, focal cortical dysplasia, tumors, inflammation, and scars.

●Axial T2*-weighted gradient echo (T*-GRE) or susceptibility-weighted imaging (SWI) for identification of vascular and calcified lesions such as cavernous malformations, arteriovenous malformations, small hemosiderin deposits, and prior traumatic brain injury.

A widely accepted imaging protocol for epilepsy-specific imaging based on the above sequences was shown to identify 99.4 percent of 2740 epileptogenic lesions, providing a reasonable balance between diagnostic accuracy and clinical feasibility [20].

Imaging sequences should consist of contiguous, thin (<1.5 mm) slices that cover the entire brain. All the above sequences should be obtained in two orthogonal planes, with coronal images obtained obliquely and oriented perpendicular to the hippocampus in such a way that allows direct comparison between the left and right hemispheres. The oblique coronal orientation minimizes partial volume effects that otherwise commonly obscure hippocampal sclerosis and small lesions in the temporal lobe.

●Use of contrast – The use of gadolinium-based contrast is not required for initial diagnostic MRI studies but can be used to better characterize pathologies seen on noncontrast study or to improve sensitivity in initially negative studies [17,21]. Postcontrast T1-weighted images are not useful in patients with mesial temporal sclerosis but are useful to detect tumors or vascular anomalies.

Advanced MRI techniques — Sensitivity also appears to be improved by more advanced MRI technologies.

●High field strength – Higher magnetic field strength (eg, 3-Tesla [3T] and 7-Tesla [7T]) MRI scanners and use of multichannel phased-array surface coils allow for a greater signal-to-noise ratio, improved image uniformity, and better spatial resolution [22]. These scanners aid in detecting focal cortical dysplasia and hippocampal sclerosis [13,23-27]. Though clinical availability is limited, 7T MRI has even greater ability than 3T MRI to detect structural lesions using gradient echo and FLAIR images and is especially promising for the detection of focal cortical dysplasias missed on conventional MRI [25-27].

●Susceptibility-weighted imaging – Susceptibility-weighted imaging (SWI), or susceptibility-weighted angiography (SWAN), is a three-dimensional MRI sequence with increased spatial resolution and improved detection of substances that cause magnetic susceptibility by distorting the local magnetic field, such as chronic blood products (ie, hemosiderin), deoxyhemoglobin in venous blood, iron (ie, ferritin), and calcifications. SWI is more sensitive in detecting cavernous malformations compared with both T2-weighted fast spin echo (FSE) and T2*-GRE sequences [28]. SWI also appears to be helpful in identifying epileptogenic, postinfectious, and calcified lesions (eg, cryptococcus, tuberculosis, cysticercosis) [29].

●Quantitative MRI – Quantitative MRI techniques have limited diagnostic value over and above visual inspection but may provide useful prognostic information. For cases of hippocampal sclerosis where qualitative radiologic findings are not seen, quantitative volumetric hippocampal analysis may help. Volumetry correlates well with histopathologically confirmed hippocampal cell loss [30]. Thus, reduced volume by quantitative analysis is an established surrogate marker for the presence and severity of hippocampal atrophy [31]. Automated software for generic quantitative morphometrics has substituted time-consuming manual techniques. Studies have shown that these automated techniques can detect hippocampal asymmetry and lateralize hippocampal atrophy accurately [32].

●Other MRI technologies – Diffusion tensor imaging (DTI) [33-35], magnetization transfer imaging [36], voxel-based analysis [37], and T2 mapping [38,39] are other technologies that show promise in the improved detection of both hippocampal sclerosis and malformations of cortical development. DTI provides information regarding the direction of the diffusion of water in each voxel and can be used to define major myelinated tracts (tractography) as part of a surgical evaluation; for example, it can demonstrate association tracts of the language areas and optic radiation and thereby predict deficits after surgery [40,41]. (See "Resective and ablative surgical treatment of epilepsy in adults".)

Specific pathologies — Structural causes of epilepsy that can be identified by MRI include [42-44]:

●Mesial temporal sclerosis – Mesial temporal sclerosis, also known as hippocampal sclerosis, is the most commonly diagnosed focal structural abnormality in patients with epilepsy. While most cases present in childhood, it is not uncommon for this disorder to first appear in young adults.

Primary imaging signs of mesial temporal sclerosis (image 1 and image 2) include:

•Reduced volume of the hippocampus

•T2- and T2-FLAIR-hyperintense signal

•Abnormal morphology (eg, loss of stratum lacunosum and moleculare on T2-weighted MRI)

Secondary signs include ipsilateral:

•Atrophy of the fornix, mammillary body, or both

•Enlargement of the temporal horn, choroidal fissure, or both

•Reduced volume of white matter in the parahippocampal gyrus

•Global reduction of temporal lobe white matter volume

Surgery or laser interstitial thermal treatment is often curative in patients who do not become seizure-free on medication. (See "Focal epilepsy: Causes and clinical features", section on 'Hippocampal sclerosis' and "Resective and ablative surgical treatment of epilepsy in adults", section on 'Mesial temporal lobe epilepsy'.)

●Malformations of cortical development – Malformations of cortical development (eg, focal cortical dysplasia) (table 1) are the second most common structural etiology for epilepsy [45,46]. When a patient with focal-onset epilepsy is found to have a normal MRI, an undetected focal cortical dysplasia is typically considered to be the most likely underlying lesion (image 3 and image 4).

With increasing use of higher-field MRI (ie, 3-Tesla [3T] and 7-Tesla [7T]), focal cortical dysplasia is being identified in a greater number of epilepsy patients. MRI is more sensitive for identifying focal cortical dysplasias with more severe pathologic grade than for milder lesions, and these are more amenable to surgical cure [47,48]. Subtle findings such as blurring of the gray-white junction or FLAIR-hyperintensity in subcortical white matter may be missed on initial interpretation of the MRI and identified when the study is re-reviewed (image 3) [46]. These lesions are congenital, and related epilepsy usually presents in childhood. However, it is not rare for epilepsy to first develop in young adults.

●Tumors, trauma, and vascular lesions – Low-grade glial or glioneuronal neoplasm is a cause of seizure in children and young adults (image 5). In older patients, cortical scarring (eg, encephalomalacia) after trauma or ischemic stroke, or higher-grade neoplasm may be a cause of seizure. (See "Seizures and epilepsy in older adults: Etiology, clinical presentation, and diagnosis".)

High-resolution structural MRI also has a high diagnostic yield in patients with tumors or vascular malformations (image 6). The latter are often best visualized on gradient-echo sequences, which are sensitive for blood products. Typical imaging features of tumors and vascular malformations are discussed elsewhere. (See "Overview of the clinical features and diagnosis of brain tumors in adults", section on 'Neuroimaging features' and "Brain arteriovenous malformations", section on 'Diagnosis' and "Vascular malformations of the central nervous system", section on 'Neuroimaging'.)

●Infections – Certain central nervous system infections, including neurocysticercosis, encephalitis, cerebral abscess, and granulomas, may cause epilepsy. Neurocysticercosis, caused by Taenia solium, is a common etiology of epilepsy in endemic populations. When neurocysticercosis is suspected, MRI with contrast is useful for identifying cysts and evaluating disease activity (image 7). However, computed tomography (CT) may add to the diagnostic evaluation as CT is more sensitive than MRI for detecting small areas of calcification. (See "Cysticercosis: Clinical manifestations and diagnosis" and "Cysticercosis: Epidemiology, transmission, and prevention".)

●Temporal encephaloceles – Temporal encephaloceles are parenchymal protrusions through a bony defect in the middle cranial fossa (image 8) [49-51]. They are a relatively rare cause of medically refractory epilepsy. Detection of encephaloceles is facilitated by thin-slice 3D MRI sequences and skull base CT. As with other lesions, a causal relationship between temporal encephaloceles and the epilepsy syndrome is not always clear, and the surgical approach to symptomatic lesions varies. (See "Resective and ablative surgical treatment of epilepsy in adults", section on 'Temporal encephaloceles'.)

Sensitivity — In 15 to 30 percent of patients with DRE, the brain MRI is negative; that is, no structural lesion can be identified [52-54].

While brain MRI is routinely used in the clinical evaluation of epilepsy, there remains a substantial gap between the sensitivity and specificity of MRI in different care settings [46,55]. In one study, 123 patients referred for epilepsy surgery evaluation previously had a "standard" MRI at an outside center (not attached to an epilepsy center) [55]. The original MRI interpretation was compared with a reinterpretation of the original MRI and with the results of a repeat MRI performed using a dedicated epilepsy protocol (see 'MRI epilepsy protocol' above). The sensitivity of MRI for focal lesions for each of these (the original MRI, the reinterpretation of the original, and the repeat MRI) was 39, 50, and 91 percent, respectively. This was a selected population with refractory epilepsy that excluded patients with acute focal brain conditions, including cerebral abscess and rapidly expanding brain tumors. In most cases, the missed diagnosis was hippocampal sclerosis.

Incidental and potentially incidental findings — Not all MRI abnormalities are associated with epileptic seizures. Punctate foci of T2-hyperintense signal in the white matter, many cystic lesions (arachnoid cysts, choroidal fissure cysts), lacunar strokes, ventricular asymmetry, diffuse atrophy, and isolated venous anomalies (eg, developmental venous anomalies that are not associated with cavernous malformation) are not known to be epileptogenic and should be considered incidental to a seizure diagnosis [21].

When a potentially epileptogenic structural abnormality is seen on brain MRI, it suggests an anatomic substrate for epilepsy, and provides support for a diagnosis of epilepsy. However, such findings should not be interpreted in isolation and must be correlated with the patient's seizure semiology and EEG findings. Several observations suggest that such findings might be incidental in a small proportion of patients:

●In patients with idiopathic generalized epilepsy, MRI abnormalities have been reported in up to 24 percent [56,57]. While most of these findings were not epileptogenic (eg, arachnoid cyst, diffuse cortical atrophy, etc), potentially epileptogenic lesions were seen in 3 to 4 percent. Similarly, one series reported abnormal MRI findings in 15 percent of 71 children with clinical and EEG features of benign childhood epilepsy with central midtemporal spikes [58]. Less than half of these findings were potentially epileptogenic. The benign course of these children's epilepsy syndromes suggests that these findings were truly incidental.

●In patients with psychogenic nonepileptic seizures, an abnormal brain MRI is reported in 10 to 38 percent [59-63]. Again, some but not all of these abnormalities were epileptogenic, such as posttraumatic gliosis and hippocampal sclerosis [62].

●In a study comparing brain MRIs in 51 healthy controls and 99 patients with temporal lobe epilepsy (TLE), increased signal was noted in one or both hippocampi in 29 percent of controls (compared with 47.5 percent of patients) [64]. Hippocampal atrophy was a more specific finding, noted in only one control participant versus 19 percent of patients; no control had both atrophy and increased signal in the same hippocampus. (See "Focal epilepsy: Causes and clinical features", section on 'Hippocampal sclerosis'.)

●In a study of 1000 healthy adult volunteers, intracranial abnormalities were observed in 4.2 percent of brain MRIs [65]. Pathologies included those that were potentially epileptogenic (eg, tumors, remote trauma) as well as those that were not (arachnoid cyst, empty sella, lacunar infarction). This study may have underestimated the prevalence of relevant abnormalities, especially mesial temporal sclerosis, since MRIs were not performed with a dedicated epilepsy protocol.

●Amygdala enlargement (AE) (image 9) is increasingly being reported on MRI in patients with TLE, with higher incidences reported in nonlesional TLE (12 to 63 percent) than in TLE with mesial temporal sclerosis (14 percent) [66-71]. This has led to the suggestion that it represents a distinct TLE subtype [72]. However, AE is observed at high rates in the amygdala contralateral to seizure onset [66], and epileptogenic activity appears to arise from the hippocampus, not the enlarged amygdala, at least in some cases [73]. Small sample sizes and variable methods for defining AE make it difficult to evaluate whether AE is specific to TLE [74]. Histopathologically, AE may be characterized by clustering hypertrophic neurons and vacuolation with slight gliosis or even no gliosis [73].

Another potential source of diagnostic confusion is that some patients may have acute MRI changes that are attributed to the effect of seizures rather than their cause. These are more common after prolonged seizures (eg, status epilepticus) or clusters of seizures and are characterized by focal cortical swelling, increased T2-FLAIR signal intensity, restricted diffusion, and focal parenchymal and/or leptomeningeal contrast enhancement that resolve on subsequent imaging studies. These are discussed separately. (See "Magnetic resonance imaging changes related to acute seizure activity".)

INDICATIONS FOR FURTHER EVALUATION — 

Additional studies may be needed for patients if any of the following apply [13]:

●Data from presurgical evaluation (EEG and MRI studies) are discordant or indeterminate regarding localization of the epileptogenic zone

●MRI does not define the lesion responsible for epilepsy (nonlesional)

●Patient is at high risk for developing a postoperative neurologic deficit

●The epileptogenic zone is in or adjacent to eloquent cortex

For patients with discordant data or nonlesional epilepsy, imaging with positron emission tomography (PET), single-photon emission computed tomography (SPECT) or invasive EEG monitoring can provide information that helps to localize the epileptogenic zone. The diagnostic yield of PET and SPECT in patients with neocortical epilepsy depends on multiple factors, including the underlying pathology, localization of the epileptogenic zone, and the specific neuroimaging technique. PET or SPECT studies may permit an anterior temporal lobe resection/ablation in patients with unilateral temporal lobe scalp-recorded seizures and negative brain MRI scans. Individuals with extratemporal seizures and normal brain MRIs (nonlesional epilepsy) almost invariably require intracranial EEG recordings or functional mapping for surgical localization, or both. (See 'Positron emission tomography (PET)' below and 'Single-photon emission computed tomography' below and 'Invasive EEG monitoring' below.)

Preoperatively, functional MRI and the intracarotid amobarbital procedure (also called the Wada test) are two methods used to assess language localization and predict postoperative language and memory outcomes. (See 'Speech and language localization' below.)

ADDITIONAL STUDIES — 

Positron emission tomography (PET), single-photon emission computed tomography (SPECT), and magnetoencephalography (MEG) typically play a confirmative role in cases of questionable structural lesions or in patients with multiple lesions or a normal MRI. Neuropsychologic testing and functional localization techniques are used to help localize the epileptogenic zone and determine the safety of the proposed procedure, for example by estimating cognitive reserve in the contralateral hemisphere.

Positron emission tomography (PET) — 18-F fluorodeoxyglucose PET (FDG-PET) demonstrates the topographic distribution of glucose uptake in the brain and provides a picture of cerebral metabolism (image 10). PET is obtained during interictal period since cerebral uptake occurs 30 to 40 minutes after injection and thus, unless a seizure is long-lasting, an area of uptake may not be detected during the ictus. The goal of interictal PET is to identify focal areas of decreased metabolism (ie, relative hypometabolism) that are presumed to reflect focal functional disturbances of cerebral activity associated with epileptogenic tissue, otherwise known as the functional deficit zone.

●For mesial temporal lobe epilepsy – Unilateral temporal lobe hypometabolism on PET correlates strongly with the temporal lobe of seizure origin and is predictive of seizure freedom following epilepsy surgery, independent of structural MRI findings [75,76]. In mesial temporal lobe epilepsy (MTLE), PET shows a widespread ipsilateral hypometabolism involving the mesial temporal structures, temporal pole, and lateral temporal cortex and often involving extratemporal areas including the insula, the frontal lobe, perisylvian regions, and the thalamus [77]. Given that the region of PET hypometabolism can extend beyond the epileptogenic lesion, PET should not be used to define margins for epilepsy surgery [78]. Furthermore, hypometabolism in the extratemporal regions and/or contralateral hemisphere in patients with MTLE is associated with a poorer response to epilepsy surgery [79].

Sensitivity for detecting relative temporal lobe hypometabolism with PET in MTLE ranges between 80 and 90 percent [80-87]. Visual assessment is less accurate than voxel-based morphometry, normalized to reference templates of healthy controls [88,89]. Much of the variability in sensitivity reflects the heterogeneity of the epilepsy more than it does the differences in quality or specifications of the PET camera [90]. Some reports suggest that the sensitivity of PET is increased when seizures are more frequent or when performed soon after a seizure has occurred [91].

Only a few patients in the above series included patients with MTLE without hippocampal sclerosis on MRI. However, these and other series have shown that PET can be helpful in lateralizing the epileptogenic temporal lobe in "MRI-negative" cases, with a yield that ranges from 45 to almost 90 percent [75,81-85,92-94].

Hypometabolic patterns on PET are predictive for surgical outcome in patients with MTLE [79,95]. Specifically, Engel class IA postsurgical outcome (ie, completely seizure-free after surgery) is associated with a focal anteromesial temporal hypometabolism, whereas suboptimal nonclass IA outcomes correlate with extratemporal metabolic changes [79].

●Extratemporal epilepsy – PET may be clinically useful in patients with extratemporal regions of seizure onset. This includes individuals with focal cortical dysplasia who may have an unremarkable MRI study. However, there is less information available regarding the usefulness of PET in extratemporal epilepsy, and it appears somewhat less sensitive in these cases [80,82,96-100]. An exception may be patients with cortical dysplasia, in whom the reported sensitivity of PET varies between 60 and 92 percent [101].

●Coregistration of PET and MRI – Coregistration of PET and MRI shows potential for improved sensitivity and specificity compared with either technology alone [102-104]. This is particularly useful in MRI-negative extratemporal lobe epilepsy for detecting focal cortical dysplasias and thus significantly improving the diagnosis and surgical outcome of these patients [103]. (See "Resective and ablative surgical treatment of epilepsy in adults", section on 'Malformations of cortical development'.)

●Limitations – A limitation of PET is that the area of hypometabolism typically extends beyond the epileptogenic zone, making it less useful for precise neuroanatomic localization [77,80,99,105].

●Other tracers – The use of other tracers (eg, [11C]flumazenil, [18F]FET, [18F]DPA-714, alpha methyl tryptophan, and serotonin agonists) remains largely experimental but holds promise for improving the sensitivity and specificity of PET for presurgical localization [82,87,91,99,106-115].

Single-photon emission computed tomography — Ictal SPECT studies are used to map increased cerebral blood flow (CBF) during seizures to assist in localizing the epileptogenic zone. While not technically feasible at all institutions due to logistic constraints of ictal tracer injection, SPECT is particularly useful in patients with a conflicting noninvasive epilepsy evaluation regarding localization of the epileptic brain tissue. SPECT findings can also influence the diagnostic strategy for placement of intracranial EEG electrodes. (See 'Invasive EEG monitoring' below.)

Neuronal activity is strongly correlated with regional CBF neurovascular coupling. As such, an assessment of regional CBF during a seizure (ictus) may enable localization of the seizure focus. In SPECT, regional CBF can be imaged using perfusion radiotracers 99mTc-hexamethylpropyleneamine-oxime (HMPAO) or 99mTc-ethyl cysteinate dimer (ECD), which have a rapid first-pass brain extraction that peaks within the first minutes of injection. SPECT obtained after 30 to 90 minutes for HMPAO and 30 to 60 minutes for ECD (range 10 minutes to six hours) provides a snapshot of CBF at the time of tracer administration.

●Techniques – Optimal evaluation of the epileptogenic focus with SPECT requires acquisition of two scans, one during the seizure (ictal) and one at baseline (interictal). The ictal scan requires the patient to be admitted to the hospital and monitored electrographically and clinically for seizure activity [116]; the radiotracer should ideally be administered within 20 seconds of electrographic seizure onset; injection after 45 seconds is more likely to be falsely localizing or nonlocalizing [91,117,118]. Increased regional CBF during the ictal phase (image 11) is followed by decreased CBF; the entire cerebral lobe and contralateral hemisphere may exhibit reduced perfusion after the seizure [119,120].

Subtraction ictal SPECT coregistered to MRI (SISCOM) is a modification of the ictal SPECT technique that superimposes ictal and interictal SPECT images and brain MRI (image 12). SISCOM has been used in patients with normal MRI studies, those with multifocal EEG or MRI abnormalities, and individuals with intractable epilepsy who are being considered for reoperation [121-126]. In a series of 51 patients undergoing surgical evaluation, SISCOM had a significantly higher rate of localization (88 versus 39 percent), better interobserver agreement, and better predictive value for surgical outcome compared with visual inspection of interictal and ictal images [123].

The sensitivity of SPECT is also improved by comparison of ictal and interictal SPECT studies with quantitative subtraction techniques or by statistical comparison with a control database (statistical parametric mapping). These methods permits better localization of the focal hyperperfusion abnormality concordant with the epileptogenic zone in patients with both temporal lobe and extratemporal epilepsy [105,121,127].

●Utility – SPECT can be useful in the identification of a possible epileptic focus, particularly when MRI is unremarkable, which can be further tested with intracranial EEG studies [128,129]. In some cases, re-evaluation of MRI prompted by abnormal SPECT has revealed a subtle structural lesion [130]. Ictal SPECT studies have a high yield in the evaluation of TLE that exceeds 90 percent, but the sensitivity for extratemporal seizure foci is lower [80,86,131-133]. In one study of 53 patients with secondary generalized seizures, ictal SPECT identified an unambiguous seizure focus in only 50 percent; however, when a single unambiguous region of CBF increase was seen, this was the correct localization in 80 percent [129].

●Limitations – SPECT studies have certain limitations in their utility to localize the seizure focus. Injection timing is critical; the tracer takes 30 seconds to reach the brain, and the switch from ictal hyperperfusion to postictal hypoperfusion can take place in less than one or two minutes [91,105,134]. Propagation of seizure activity from the original focus of seizure onset to other brain regions can be even quicker [135]. As a result, areas of ictal hyperperfusion on SPECT may represent a false localization demonstrating areas of seizure propagation rather than seizure onset [129,131]. This may make SPECT localization a less reliable predictor of surgical outcome compared with other imaging studies, at least in some case series [91,92]. One study suggested that an injection time of less than 20 seconds after seizure onset is an important predictor of accurate localization; technically, this can be difficult to execute [136].

Invasive EEG monitoring — In selected cases, invasive intracranial EEG monitoring combined with video monitoring is required to localize the epileptogenic zone or to map eloquent cortex before a resection/ablation can be performed [137]. These include the following clinical situations [13]:

●When noninvasive techniques fail to localize the area of seizure onset or have discordant results (the most frequent situation for intracranial EEG monitoring)

●Epileptogenic lesions with poorly defined borders (eg, focal cortical dysplasia)

●Dual pathology or multiple lesions

●A prior history of epilepsy surgery failure

●A need for functional mapping to determine precise location of areas of eloquent cortex in cases where the epileptogenic zone is nearby

Although use of intracranial electrodes in MTLE has diminished over time, invasive monitoring continues to be used commonly in patients with neocortical focal epilepsy, particularly those with a normal MRI or bilateral seizure foci. At tertiary epilepsy centers, intracranial EEG monitoring is needed for epilepsy surgery evaluation in 30 to 40 percent of cases [137]. (See "Resective and ablative surgical treatment of epilepsy in adults", section on 'Focal epilepsy with normal brain MRI'.)

Before invasive EEG recordings, patients usually undergo functional neuroimaging to include PET and/or ictal SPECT to better localize the epileptogenic zone and direct intracranial electrode placement. There are two main methods of intracranial EEG monitoring:

●Subdural electrodes – The strategy for intracranial EEG recordings often includes a combination of subdural strips or grids of electrodes and depth electrodes. Depth electrodes are implanted stereotactically by a neurosurgical team using brain imaging for localization. In two retrospective series of more than 400 patients, the major complication rate of invasive monitoring was 7 to 9 percent; the majority of these complications were either intracranial hemorrhage or infection [138,139]. Use of subdural electrodes may pose higher risk than use of depth electrodes [139-142].

●Stereoelectroencephalography (SEEG) – This is another invasive technique that is being increasingly used to evaluate patients with nonlesional drug-resistant focal epilepsy being considered for surgical treatment [143-148]. SEEG may be preferred in individuals with epileptogenic zones that are difficult to evaluate with subdural grid recordings, such as the insula, the depth of sulci, and mesial regions of cerebral cortex. In selected patients being considered for focal cortical resection/ablation, the effectiveness and safety of SEEG compares favorably with other methodologies for intracranial EEG recording [142-144,149], with a pooled complication rate of 1.3 percent across multiple studies [150].

Speech and language localization — In selected patients, eloquent cortex involved with speech and language function must be well defined to minimize operative morbidity before performing temporal lobe and frontal lobe resection/ablation. Speech, language, and, where indicated, motor and sensory mapping are most commonly done at the patient's bedside using implanted subdural or SEEG electrodes for long-term intracranial EEG monitoring. However, it can be carried out intraoperatively in awake patients.

Preoperatively, functional MRI (see 'Functional MRI' below) and the intracarotid amobarbital procedure, also called the Wada test (see 'Wada test' below), are two methods used to assess language localization and predict postoperative language and memory outcomes. Functional MRI is generally preferred over intracarotid amobarbital given its superior safety profile [151].

Functional MRI — Functional MRI (fMRI) can detect focal changes in blood flow and oxygenation levels that occur when an area of the brain is activated. A change in the level of neuronal activity is accompanied by a change in the ratio of concentration of oxy- to deoxyhemoglobin in the blood measured on MRI as the blood oxygen-level-dependent (BOLD) effect. fMRI can be used to noninvasively map eloquent cortex serving motor, sensory, and language functions (image 13) and is most commonly used as part of surgical planning to predict and limit postoperative neurologic deficits, particularly language function, though it may also be able to help predict memory outcomes [152-160].

In many epilepsy centers, fMRI has largely replaced intracarotid amobarbital procedures (Wada test) [161,162].

●Utility – A 2017 guideline and meta-analysis from the American Academy of Neurology (AAN) assessed the value of fMRI for patients with epilepsy in determining lateralization and predicting postsurgical language and memory outcomes [151]. The authors concluded that language lateralization based on fMRI was concordant with the Wada test in MTLE (concordance rate 87 percent) and in extratemporal lobe epilepsy (concordance rate 81 percent), but those data were insufficient for temporal tumors or lateral temporal cases. The guideline concluded that fMRI is possibly effective in predicting postsurgical language deficits in patients undergoing temporal lobectomy.

Early work suggested that fMRI may be able to visualize the functional anatomy of memory tasks and assist decision-making and planning of epilepsy surgery [156,163-170]. In another study, lateralization of memory using a picture recognition paradigm predicted postoperative verbal and visual memory outcome independent of the type of lesion, the side of the epileptic focus, or the type of preoperative memory profile [171]. However, a 2023 systematic review and meta-analysis found that task-based fMRI was more accurate at predicting postsurgical cognitive outcomes in patients with left-sided, rather than right-sided, TLE [172]. (See "Resective and ablative surgical treatment of epilepsy in adults".)

●EEG/fMRI – Simultaneous recording of EEG and fMRI can visualize the BOLD response during interictal or ictal epileptic activity. This emerging technique capitalizing on the spatial resolution of fMRI and the temporal resolution of EEG could assist in identifying targets for surgical treatment [173-180]. However, the utility of fMRI for this purpose is not yet established.

●Arterial spin labeling (ASL) – This MRI technique allows for the noninvasive measurement of CBF by tracing magnetically labeled endogenous water protons [181]. ASL can be performed during routine MRI without the need for intravenous (IV) contrast or exogenous tracers. Studies of ASL during interictal or postictal periods have shown variable concordance between area of CBF abnormality and presumed seizure onset zone in adult and pediatric patients [182-184]. In a relatively large study of patients undergoing ASL in the postictal period (within 90 minutes of EEG-confirmed seizure), 80 percent of patients had a partial or full concordance between areas of hypoperfusion and presumed seizure onset zone [185]. A 2021 meta-analysis of ASL for localization of seizure onset zone reported a diagnostic accuracy of 88 percent in cases where ASL abnormalities were seen [186]. Given that ASL is safe, noninvasive, easily accessible, and requires short acquisition time, it may become increasingly incorporated into the presurgical evaluation for patients with intractable epilepsy.

●Limitations – Interpretation of fMRI requires caution; it is an indirect measure of brain function. Discrepancies with the Wada test have been described [187-190]. Its sensitivity and specificity are imperfect (84 and 88 percent compared with the Wada test, in one meta-analysis), particularly in extratemporal epilepsy, and analyses have not been standardized [191]. Also, some patients cannot complete fMRI or have inconclusive fMRI results and still require preoperative Wada testing [190]. There are good data on its ability to lateralize language but not localize it adequately for surgical planning [192]. Thus, correct and clinically useful interpretation of fMRI for presurgical evaluation strongly depends on the expertise of the individual investigator and center.

Wada test — Intracarotid amobarbital administration is an invasive procedure that has been used for many years in surgical candidates to determine the language-dominant hemisphere as well as assess the risk of postoperative memory decline after temporal lobectomy [193-195]. Amobarbital or another anesthetic is injected into the internal carotid artery, temporarily suppressing function on that side while language and memory tests are performed.

Most centers use Wada tests only for patients with TLE at significant risk for cognitive decline (eg, left TLE with normal MRI, bilateral hippocampal atrophy, or bitemporal seizures). Neuropsychologic testing after intracarotid injection of amobarbital allows for assessment of language and memory function in each hemisphere independently. While complications are reported in up to 11 percent of patients, serious adverse events (stroke, carotid dissection, localized bleeding, and infection) occur in less than 1 percent [196,197].

Other anesthetic agents such as pentobarbital, etomidate, methohexital, and propofol have been investigated as alternatives to amobarbital, which has not been consistently available. In general, these agents appear to be well tolerated and produce results similar to amobarbital for presurgical testing [198-201]. Etomidate has been associated with adrenal insufficiency when used in critically ill patients [202]. In one study, propofol was associated with a higher risk of significant side effects, especially in older patients [203].

Lack of test standardization and selection bias limit our understanding of the reliability of the Wada test as a predictive tool.

Magnetoencephalography (MEG) and magnetic source imaging (MSI) — MEG is the recording of magnetic fields generated by intraneuronal electrical currents. MSI is the coregistration of MEG source localization with anatomic imaging, typically with MRI [204].

●Complementary to EEG – MEG is similar to EEG. However, while the electrical currents that are measured with EEG are attenuated in strength and spatially blurred by tissues between the brain and the scalp surface, the magnetic fields assessed by MEG are not significantly affected by intervening tissue layers [205]. As a result, MEG may allow for more clinically reliable localization of brain activity [206].

MEG and EEG can be viewed as complementary studies [207]. MEG is maximally sensitive to dipoles situated tangentially to the surface, whereas EEG is maximally sensitive to radial dipoles [208]. Single spikes with small amplitudes (eg, from mesial temporal sources) can be averaged to increase their signal-to-noise ratio. Averaged MEG spikes can thus be helpful in detecting discharges that are hidden in the background noise in simultaneous EEG recordings (waveform 1 and image 14). This phenomenon is reciprocal: In some cases, EEG spikes are more apparent on EEG than on MEG [207]. Some studies suggest that MEG has specific advantages for spike detection in extratemporal epilepsies, particularly those that lie superficially on the brain's surface [209-211].

●Utility – MEG/MSI have been approved for presurgical localization of epilepsy and may be particularly useful for localization of spike sources in patients with the following [105,210,212]:

•No lesion visible on MRI [210,213-218].

•Cystic lesions (posttraumatic encephalomalacia with prior surgical resection/ablation), to determine the relationship between the epileptogenic focus and the lesion; MEG/MSI also appears to be useful in identifying the extent of the epileptogenic lesion in patients with focal cortical dysplasia, cavernous angiomas, and tumors [219-223].

•MRI lesions of undetermined significance, including those with dual pathology or multifocal pathology such as tuberous sclerosis and others [224-226].

•Previous unsuccessful epilepsy surgery [219,227,228].

MEG is also approved for the localization of neuronal function (similar to evoked potentials and functional MRI [fMRI]) for language, sensorimotor, or visual cortex and has been used to localize other cortical functions as well. MEG language mapping has been shown to agree with results of the Wada test in 75 to 95 percent of patients [207,208,229-231].

A large study in 455 epilepsy patients demonstrated an average sensitivity for MEG of 70 percent for specific epileptic activity [232]. Among patients who underwent surgical therapy, MSI provided a localization in 89 percent, supplying additional information in 35 percent and information that was crucial to medical decision-making in 10 percent. Similar sensitivity has been reported in other studies [209,214,233-235].

Electrical source imaging (ESI) — ESI is a model-based imaging technique that integrates spatial and temporal components of EEG to identify the generators of abnormal electrical activity associated with seizures [236].

In electrical source localization, by reconstructing the electric potentials recorded with scalp EEG, the location of the underlying currents can be estimated and merged with structural images of individual patients. It is typically based on the analysis of interictal epileptiform discharges (IEDs) but can also be calculated from ictal EEG discharges [237,238].

ESI enhances noninvasive localization accuracy of the epileptogenic zone [236,239]. High density-based ESI using a high number (128 to 256) of recording EEG electrodes has further improved localization accuracy. In one study, the diagnostic performance of ESI compared favorably with that of MRI and PET [240]. Importantly, concordance of the ESI result and the epileptogenic lesion delineated by MRI was associated with a probability of being seizure-free (positive predictive value) of 92 percent. ESI may be particularly helpful in patients being considered for intracranial monitoring who have no cortical lesions on MRI or who have neocortical epilepsies, large cortical lesions, or EEG discharges with bilateral synchrony [241].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in adults".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Seizures (The Basics)" and "Patient education: Epilepsy in adults (The Basics)")

●Beyond the Basics topic (see "Patient education: Seizures in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Referral to comprehensive epilepsy center – We offer referral to a comprehensive epilepsy center for all patients with drug-resistant epilepsy (DRE) up to 70 years of age as soon as drug resistance is ascertained if patients are cooperative with management. We discuss surgical evaluation with patients age >70 years with DRE who have no surgical contraindication. Although age is not a contraindication for epilepsy surgery, experience is limited in the population of older adults. (See 'Referral to a comprehensive epilepsy center' above.)

●Goals of the evaluation – The goals of the evaluation are to exclude seizure mimics and confirm the diagnosis of epilepsy, identify surgical candidates, define the epileptogenic zone and eloquent cortex, and look for factors that may preclude surgery. The most favorable candidates are those with MRI-identified lesions that correlate with the electrophysiologic localization of seizure onset. (See 'Goals of the evaluation' above.)

●Components of the evaluation – Standard components of the evaluation include detailed neurologic history and examination, neuropsychologic and neuropsychiatric testing, routine EEG recordings with standard activating procedures, inpatient long-term video-EEG monitoring in an epilepsy monitoring unit, and high-resolution brain MRI. (See 'Components of the evaluation' above.)

●Structural causes of epilepsy – The most common structural causes of epilepsy in adults that can be identified by brain MRI include:

•Mesial temporal sclerosis (hippocampal sclerosis)

•Malformations of cortical development (eg, focal cortical dysplasia)

•Brain tumors, trauma, vascular lesions, and stroke

•Infections, including neurocysticercosis, encephalitis, cerebral abscess, granulomas

These are reviewed above. (See 'Specific pathologies' above.)

●Incidental imaging findings – Not all MRI findings are relevant; isolated findings of diffuse atrophy, punctate foci of T2 signal abnormalities in the white matter, and other nonspecific findings are not known to be epileptogenic. MRI findings should be correlated with the patient's seizure semiology and EEG findings; some potentially epileptogenic lesions may be incidental. (See 'Incidental and potentially incidental findings' above.)

●Additional investigations – Select patients (eg, those with discordant data regarding localization of the epileptogenic zone, nonlesional epilepsy, or at high risk for developing a postoperative neurologic deficit) may require functional and metabolic imaging using positron emission tomography (PET), single-photon emission computed tomography (SPECT), functional MRI, magnetoencephalography (MEG), magnetic source imaging (MSI), or electrical source imaging (ESI).

Positron emission tomography (PET), SPECT, and MSI are employed to better define the area of functional defect and epileptogenicity, to identify MRI-occult lesions, to identify the more active lesion in patients with dual or multiple pathologies, and to map neurologic functions as part of surgical planning.

Intracranial EEG monitoring, eloquent cortex mapping, preoperative formal speech and language testing, and visual field examinations are also performed in selected patients. (See 'Additional studies' above.)