The presurgical evaluation of patients with medically refractory seizures is critical in the preparation of the patient for epilepsy surgery. The main objectives of this presurgical evaluation are to identify the origin of the seizure and to evaluate the feasibility of performing surgery safely with minimal risk of producing adverse neurologic or neuropsychological consequences.1 Presurgical evaluation involves extensive invasive and noninvasive investigations and is performed by a multidisciplinary team that typically includes a neurologist, a neurosurgeon, a psychologist, and a neuroradiologist.2 Anesthetic drugs are used to provide conscious sedation or general anesthesia in some of the diagnostic tests and for the surgical procedures. Recently, there has been an increasing interest in expanding the role of the anesthesiologist and the use of anesthetic drugs in providing anesthesia and/or sedation during more of the presurgical evaluation tests, and using anesthetic drugs to assist in the localization of the seizure focus and in functional mapping of the brain. The 2 major components of presurgical evaluation are localization of the seizure focus and identification of functional areas of brain near the seizure focus. Good surgical outcome depends on complete resection of seizure foci without any damage to eloquent brain.3 The purpose of this report is to review the presurgical evaluation techniques including neuroimaging, neuroelectrophysiology studies, functional assessment tests, and the anesthetic management of patients during these procedures. Anesthetic drugs used for localization and for pharmacoactivation of seizure foci and the functional cortex are also reviewed (Table 1).
PRINCIPLES OF LOCALIZATION OF THE SEIZURE
The cause of seizure activity may be from a single focus or multiple foci in different areas of the brain. An epileptogenic focus has been described to consist of several different zones based on the generation of the seizures and the electrophysiologic manifestations of epilepsy (Table 2). These zones determine the planned extent of the surgical resection4,5 (Fig. 1). The ultimate goal of the presurgical evaluation is the identification of the epileptogenic zone. When this area of brain tissue is removed, the seizures should be abolished. Various testing modalities, as shown in Table 1, are used to localize these zones. There is no specific test or investigation to identify epileptogenic zones and because of overlapping of the different zones, the identification of any one zone can assist in the estimation of the epileptogenic zone. The ictal onset zone is rarely identified and may actually be contained within the epileptogenic focus. The irritative zone is the most expansive area, which when identified may be helpful in directing one to the epileptogenic zone.
METHODS OF PRESURGICAL EVALUATION
Presurgical evaluation begins with a complete history of the patient’s epilepsy, physical and neurologic examination, routine scalp electroencephalography (EEG), and imaging of the brain to assess structural abnormalities. These investigations are then complemented by a variety of noninvasive and invasive investigations, with or without anesthesia. In addition to this, pharmacoactivation, which is the induction of an epileptogenic event by the IV administration of epileptogenic drugs, may be used. Pharmacoactivation has been used for intraoperative electrocorticography (ECoG) for more than 50 years.6 The basic principle of pharmacoactivation is to selectively increase the cortical excitability, particularly of the irritative zones, to produce an increase in interictal epileptiform activity.6 This triggered interictal epileptiform activity mostly represents the irritative zone and will help to localize the epileptogenic zone.
Computed tomography (CT) is not routinely included in the preoperative investigation for the localization of seizure foci. However, CT, with or without contrast, is frequently used to exclude gross structural lesions in patients when they initially present with seizures.7
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) is the best imaging study to detect structural lesions in patients with focal epilepsy. Common structural lesions include hippocampal sclerosis, focal cortical dysplasia, low-grade tumors, vascular malformations, and gliosis.8–10 Hippocampal sclerosis is the single most common pathology underlying refractory focal epilepsy in young adults. The sensitivity of MRI for detecting this is more than 95% and surgical removal can lead to freedom from seizures in up to 80% of patients.9 Focal cortical dysplasia is probably the most common cause of refractory extratemporal focal epilepsy, especially in children. Unfortunately, MRI is less sensitive in detecting this. Overall, MRI does not reveal any significant pathology in at least 20% of patients with chronic focal epilepsy.10 These patients will require other investigation modalities for localization of their seizure foci.
Single Photon Emission Computed Tomography
The only imaging modality that is able to reliably visualize the ictal onset zone and the brain regions involved in a seizure is single photon emission computed tomography (SPECT) scanning.11 This is performed by injecting radioactive tracers (99mTc-labeled compounds) IV during a seizure followed by the SPECT scan.12 During the seizure, increased cerebral blood flow will cause increased tracer uptake in that seizure focus. The tracers are lipophilic amines that rapidly cross the blood-brain barrier forming a hydrophilic compound that is trapped within the cells. The cerebral uptake is complete within 2 minutes and less than 5% is redistributed later. SPECT scans can be acquired up to 4 hours after injection.13
Positron Emission Tomography
Another nuclear tomographic technique is the positron emission tomography (PET) scan, which uses 18-fluorodeoxyglucose tracers to measure the neuronal uptake of glucose providing a visualization of cellular metabolism.11 Fluorodeoxyglucose is taken up and metabolized by brain tissue. An area of hypometabolism or reduction in tracer uptake may indicate the epileptogenic zone. PET scans are usually acquired during the interictal period and thus show the regions of the brain that function abnormally between seizures. PET scanning may overestimate the hypometabolic area and this limits its usefulness as a guide to the extent of surgical resection.13 PET serves mainly as a supplementary investigation in patients with negative MRI findings.
Magnetic Source Imaging
Magnetoencephalography (MEG) is a noninvasive magnetic source imaging technique used to measure the very weak magnetic signals that are generated by the natural electrical activity of the brain.13 MEG provides direct information about evoked and spontaneous neural activity and the location of their sources in the brain. Graphically, MEG mimics EEG signals, but is a different electrophysiologic process in the brain. Currents that flow in fissures and sulci, which comprise a majority of the human brain surface, generate recordable MEG signals, whereas EEG is more sensitive to recording activity from the gyral crests.14 Furthermore, MEG records intracellular electrical currents in contrast to EEG, which records extracellular currents. MEG is ideal for examining brain function in relationship to behavior and for identifying functional abnormalities such as epilepsy. MEG is mainly used either alone or along with EEG in patients with a normal MRI or those suspected of multifocal epileptic discharges. Combining MEG and MRI data produces an anatomical map that can provide a detailed picture of the relationships among behavior, brain structure, and brain function.15
Role of the Anesthesiologist
Anesthesia for Imaging Techniques
Most noninvasive investigations such as CT, MRI, PET, SPECT, and MEG do not usually require sedation or general anesthesia except in pediatric patients and in some adults who are not cooperative or do not tolerate these procedures awake. The administration of anesthesia for CT and MRI has been well described and would be similar for the PET and SPECT.16 Anesthesia or sedation for MEG is more complex as MEG recordings are very sensitive to anesthetic drugs because the intracellular currents and magnetic fields are extremely small. In early attempts to record MEG under anesthesia, the failure rate was reported to be approximately 25%.17–20 The proper choice of anesthetic drugs for MEG recording is important and has been shown to reduce the failure rate from 35.5% to 5.8%.17 The use of benzodiazepines as premedication prolongs the MEG scan duration and increases the failure rate up to 73%.17–20 Chloral hydrate provides an acceptable level of sedation and has been shown not to affect the interictal discharges. Sevoflurane is frequently used for gas induction in pediatric anesthesia, but its use in patients with epilepsy is controversial because nonspecific spike activation may occur. Propofol has been shown not to alter MEG recordings when compared with nonanesthetized patients,18 but it has also been shown to decrease MEG spike frequency from 79% to 36%.18 This spike frequency was significantly lower in patients with nonlesional (no MRI lesion) epilepsy (30%) compared with patients with lesional epilepsy (83%). Because the use of MEG is mainly indicated in patients with nonlesional epilepsy, propofol may not be the best drug for sedation during MEG.19 The effects of different doses of propofol on MEG recordings have been compared with dexmedetomidine.20 High-dose propofol (≥200 μg/kg/min) was associated with high-frequency artifact that interfered with the identification of epileptiform discharges. Low-dose propofol infusion (≤100 μg/kg/min) did not produce artifacts but required coadministration of fentanyl to prevent patient motion. In contrast, dexmedetomidine infusions were not associated with signal artifacts and provided satisfactory immobility.20 Currently, dexmedetomidine seems to be the best drug for MEG because of the absence of adverse effects on interictal activity.
Pharmacologic activation during PET and SPECT has been reported in the literature but is limited to case reports.21 The epileptic spike activation with clonidine premedication and methohexital anesthesia in patients with medically intractable focal epilepsy has also been reported. Clonidine increased focal epileptiform discharges and the addition of methohexital further enhanced the total number of spikes.22 Methohexital alone has shown to activate spikes and help in localization of the epileptogenic focus.23–25 Etomidate has been shown to increase spike frequency in MEG recordings.26 The brain area with etomidate-induced spike activation was consistent with spontaneous MEG findings and simultaneous EEG recordings.26 Although all these results were based on small case series, the use of anesthetic drugs for pharmacoactivation seems possible and warrants further studies to demonstrate the sensitivity, specificity, and safety of different drugs in MEG.
Scalp EEG is usually the first investigation to confirm the diagnosis of epilepsy. However, a single episode of scalp EEG recording is rarely sufficient for complete localization of the epileptogenic focus. The hallmark of epilepsy in EEG recordings is the transient, sharp “epileptiform” potentials, which stand out strikingly from the background activity. These potentials are also called interictal (between seizures) epileptiform activities. Video EEG is the most widely used noninvasive technique for localization.27 Patients are usually admitted to a specialized unit for a few days to 2 weeks to have continuous video EEG monitoring to record seizure activity. In some centers, patients are tapered off antiepileptic medications before EEG video monitoring is performed, so as to produce an ictal event. The EEG data along with their clinical presentation are analyzed to identify the seizure foci.
Intracranial EEG recordings, also called chronic intracranial ECoG, are an invasive preoperative evaluation technique. They are considered when other techniques (video EEG, MRI) fail to localize the seizure foci or other tests have disconcordant results (e.g., video EEG shows left-sided seizures and MRI has a lesion on the right side).28 The main advantage of this technique is to record the seizure event with less interference from skin, blood, and tissues on EEG, and this enables a more detailed analysis. The use of intracranial electrodes in temporal lobe epilepsy has been diminishing over recent years but they are still used in 40% to 70% of patients with extratemporal epilepsy and in those with bilateral seizure foci.28 Grid, strip, depth, and needle (foramen ovale) electrodes are often implanted to record the ECoG and can also be used for functional cortical mapping. Strip electrodes are linear arrays of 2 to 16 disk electrodes embedded in a strip of silastic. Grid electrodes are parallel rows of electrodes that can be configured in standard or custom designs according to the surgeon’s preferences and the manufacturer’s capabilities. Grid and strip electrodes are designed to be in direct contact with brain neocortex. All of these electrode types are made of biologically inert, radio-opaque, and MRI-compatible materials (e.g., silastic, stainless steel, platinum). Subdural grid electrode placement usually requires a full craniotomy. Strip electrodes are usually placed in the subdural space via bur holes except in patients who have had a prior craniotomy with heavy scarring that may indicate the need for epidural placement. Depth electrodes are multicontact, thin, tubular, and rigid or semirigid electrodes that penetrate the brain to allow recording from deep structures such as the hippocampus and amygdala. Depth electrodes are most often used in conjunction with other subdural strip or grid electrodes so that multiple brain areas are sampled simultaneously to avoid false localization based on insufficient data collection. Foramen ovale electrodes are epidural electrodes with 5 to 10 contact points and they are inserted percutaneously under fluoroscopic guidance. After electrode placement, patients are monitored with electrodes in place in a monitoring unit for 2 to 7 days to record their typical seizures. The aim of the recordings is to obtain 3 or more concordant ictal or interictal events, which is usually sufficient to delineate the site for surgical resection.28,29
Role of the Anesthesiologist
Anesthesia for Intracranial Electrodes Insertion
The anesthetic considerations for implantation of electrodes are similar to craniotomy procedures in patients with epilepsy. These procedures may require a large craniotomy or multiple bur holes and include the use of fluoroscopy and/or neuronavigation. These are often lengthy procedures and general anesthesia is most frequently used. The electrodes are bulky and brain shrinkage may be required. Hyperventilation should be used gently and briefly because hyperventilation may precipitate seizure activity and may be less effective in patients with complex partial seizures, who may have lower CO2 reactivity of cerebral blood flow.30 Mannitol is used if additional brain relaxation is required. However, the putative space created by a fluid shift could adversely contribute to hematoma formation after closure. The recording of ECoG and any stimulation testing is done postoperatively in an epilepsy-monitoring unit.
Once all monitoring is completed, intracranial electrodes need to be removed within 4 weeks of implantation because of the risk of infection.29 Intracranial subdural strip electrodes can be removed without an open surgical procedure by placing gentle traction on the electrodes with the patient under conscious sedation or general anesthesia. Removal of the grid requires opening of the craniotomy and anesthesia. However, if resective surgery is planned at the same time, the relationship of the grid to the underlying cortex must stay unchanged while the craniotomy is reopened. The dura is opened, with the grid-stabilizing sutures left intact and all relations between electrode contacts and unique underlying cortical topography (e.g., blood vessels) left undisturbed. Once these relations have been documented and the surgeon has extrapolated the mapped data to the underlying cortex, the grid is removed and resection can be started.29
Intraoperative ECoG and pharmacoactivation of epileptiform discharges using anesthetic drugs is a well-established technique during the definitive operation for determining the extent of the surgical resection. However, pharmacoactivation with anesthetic drugs is also used in the presurgical evaluation of patients who already have implanted intracranial electrodes but have not demonstrated adequate seizures during their observation period. Thus, pharmacologic activation studies can be performed in the operating room when the patient comes for the removal of their intracranial electrodes (Fig. 2). These pharmacoactivation studies can also help reduce the duration of the intracranial electrode implantation and thereby reduce the risk of infection. Successful pharmacoactivation has been reported in the literature.6 The major problem with pharmacologic activation is the specificity because some anesthetic drugs cause nonspecific activation. Short-acting barbiturates, especially methohexital, have been used extensively for successful activation.31 Activation with alfentanil (50–75 μg/kg IV) was shown to have high sensitivity (96.5%) in the hippocampal and parahippocampal regions, but 38% of patients also had seizures as seen on ECoG (electrographic seizures).32 Activation with etomidate (0.1 mg/kg) was shown to be safe, specific, and to reliably identify the epileptic region.33 Effects of propofol on intracranial electrodes have been studied by many groups of investigators with grid, strip, and depth electrodes.33–36 Most of these studies showed that the gradual administration of propofol is not associated with significant changes in spike frequency and hence a sedative dose of propofol does not have a role in seizure foci localization.
Neuropsychological testing, also known as neurocognitive or functional testing is regarded as the integral component of the presurgical assessment for the majority of patients. These test memory, language, motor skills, attention, concentration, visual spatial skills, executive abilities, and emotional function.37 Functional abnormalities that cannot be determined by other tests (imaging or EEG) can be identified and they will assist in assessing for the lateralizing of the dysfunctional hemisphere.38 They also provide important information on the lateralization of cognitive functions such as language and memory.
Functional MRI (fMRI) is mainly used for identifying areas of eloquent cortex, including motor, sensory, language, and memory areas. Brain activity during cognitive processes can be observed by the cerebral blood oxygenation level–dependent contrast, which assesses the change in blood flow related to the use of energy by brain cells.39 In practice, patients are required to perform different tasks during the imaging to map the corresponding functional cortex. For example, language tests on verbal fluency and semantic tasks are used to show the Broca area. Language tasks that stress comprehension or story listening can activate the Wernicke area.40
Wada Test (Intracarotid Amobarbital Procedure)
The Wada test, named after Canadian epileptologist Juhn Wada, has been used for more than half a century to assess lateralization of language and memory before epileptic surgery, particularly when temporary lobectomy and amygdalohippocampectomy are contemplated.41 The basic principle of the Wada test is to transiently anesthetize one hemisphere, thereby testing the residual function of the contralateral hemisphere. The test is conducted with the patient awake. A short-acting anesthetic drug (traditionally, sodium amobarbital) is introduced into the internal carotid artery via a transfemoral catheter. After confirmation of anesthesia of the injected hemisphere by clinical (presence of hemiplegia) and electrophysiologic (EEG) methods, the patient is engaged in a series of language and memory tests. Language lateralization is determined by conducting tasks to test various components of language, including expressive language, receptive language, naming, repetition, and complex syntactical comprehension. The memory is evaluated by showing a series of items or pictures to the patient and testing their memory after the effect of the medication is dissipated. The procedure is then repeated on the other hemisphere at least 30 minutes after the initial injection or on a different day.42 The protocol was originally standardized by the Montreal Neurological Institute, although different variations are used.43
The use of the Wada test has declined over the past years as other noninvasive tests were introduced.44 The fMRI has been shown to identify language dominance with up to 95% accuracy.45 Therefore, the use of Wada for the sole purpose of language lateralization is seldom justified.46 Currently, there is no alternative to the Wada test to identify memory lateralization and to assess the risk of postoperative memory loss. Hence, many centers still perform the Wada test on select groups of patients who are at risk of postoperative memory loss and also in patients with atypical or bilateral language representation or inconclusive fMRI language lateralization.47
Role of the Anesthesiologist
Anesthetic Drugs for Wada Test
Sodium amobarbital is the standard drug used in the Wada test because of its short duration of action and low toxicity, as well as clinicians’ extensive experience with its effects. Recently, the supply of sodium amobarbital was disrupted worldwide, which has led to exploration of other possible drugs.48 The ideal pharmacokinetic properties should be short duration of action (approximately 15 minutes) to allow adequate time for language and memory testing without second dosing, little residual disturbance in consciousness to allow multiple tests in a single session, and no epileptogenic potential. Pentobarbital, methohexital, secobarbital, etomidate, and propofol have all been investigated as substitutes.49–57 The results are summarized in Table 3. These drugs are similar to amobarbital in determination of language and memory lateralization. However, there are differences in the pharmacokinetic properties and the associated side effects of individual drugs.
Both the anesthesiologists and the use of anesthetic drugs have an important role in the presurgical evaluation of patients with epilepsy for the localization of seizure foci and in identifying the functional cortex. Understanding the principles of seizure localization and the effects of anesthetic drugs in various preoperative investigations is essential for the proper use of anesthetic drugs. We believe that the input of the anesthesiologist may improve the reliability and safety of the preoperative localization of seizure foci.
Name: Jason Chui, MBChB, FANZCA, FHKCA.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Jason Chui approved the final manuscript.
Name: Lashmi Venkatraghavan, MD, FRCA, FRCPC.
Contribution: This author helped write the manuscript.
Attestation: Lashmi Venkatraghavan approved the final manuscript.
Name: Pirjo Manninen, MD, FRCPC.
Contribution: This author helped write the manuscript.
Attestation: Pirjo Manninen approved the final manuscript.
This manuscript was handled by: Gregory J. Crosby, MD.
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