Epilepsy surgery is a well-established therapeutic intervention for patients with medically refractory seizures.1,2 The success of surgery is highly dependent on the accurate presurgical localization of the epileptogenic zone. A number of different techniques such as imaging, electrophysiological studies, and neuropsychological assessments are used to determine the location and the extent of the epileptogenic zone. Despite advances in noninvasive testing, the use of electrocorticography (ECoG) may still be needed in individuals in whom the noninvasive tests are inconclusive.3 ECoG is an invasive electrophysiological technique of direct recording of the cortical potentials from the surface of the brain. However, intraoperative ECoG is greatly affected by the anesthetic drugs, which alter the sensitivity and specificity of this technique. There is limited information available in the anesthesia literature on the techniques of intraoperative ECoG and the effects of anesthetic drugs on ECoG. The aim of this review is to provide an in-depth discussion on the principles of ECoG, the effect of anesthetic drugs on ECoG, and the use of intraoperative pharmacoactivation for seizure focus localization.
ECoG records cortical potentials directly from the cortex of the brain by means of surface or depth electrodes. Intraoperative ECoG has been used for many decades. Wilder Penfield and Herbert Jasper were the first to use ECoG during mapping of the cerebral cortex of humans during epilepsy surgery.3 Despite the other advances in presurgical localization modalities, ECoG is still used in approximately 60% to 70% of the epilepsy centers in North America to guide in the localization of the epileptogenic focus, for surgical resection, and to assess for the completeness of surgery.3
Intraoperative ECoG is performed by the placement of a special electrode array using strips, grid, and/or depth electrodes directly on the surface or within the substance of the brain. Historically, rigid electrodes with ball-shaped tips were used to achieve the contact between the electrode and brain tissue. These systems, known as Medussa or Montreal frame (Fig. 1), require individual placement of each of the 16 to 20 electrodes over the cortical region, while their other end is connected to a wooden frame at the craniotomy site. The Montreal frame has the advantage of allowing adjustment of the distance between the contacts, when the presumed area of interest proves to be smaller or larger than initially appreciated. It also allows access to the cortex for concomitant functional mapping. Recently, flexible disposable plastic grid or strip electrodes have become widely available and have largely replaced the use of the Montreal frame. Grids of disk electrodes are implanted within thin clear soft plastic sheets, which can be quickly and easily placed over a large region of exposed cortex with good contact. Different sizes and shapes of flexible grids and strips of electrodes are available. Depth electrodes, with recording contacts along the length of the electrode, may also be added to the montage to include recording from deeper structures such as the hippocampus and amygdala. All the ECoG recordings are digitalized and then displayed and recorded using computerized systems.
Background ECoG recording represents basal cortical activity. It is similar to scalp electroencephalography (EEG) but without the dispersion and attenuation of the potentials by the scalp and skull. Hence, ECoG typically has large amplitude ranging between 30 and 50 μV/mm. The frequency band-pass filter range is between 0.5 and 70 Hz, which ensures adequate capture of epileptiform discharges or activity. The background ECoG waveform pattern varies with different locations of electrodes, preexisting lesions, preoperative medications, and the presence of different anesthetic drugs. The area with a preexisting lesion (scar or sclerosis) generally shows a low amplitude and low-frequency activities. In contrast, anesthetic drugs usually cause an abundance of sharp contour, fast frequency activities that mimic epileptiform activities.3
ECoG for Intraoperative Localization of SeizureFocus
The hallmarks of epilepsy are the epileptiform potentials, which are sharp and transient and stand out strikingly from the background activity. In general, it is rare to capture a spontaneous seizure (ictal event) during ECoG recording but spontaneous interictal epileptiform activities (IEAs) are the most frequent type of recording found in the intraoperative ECoG (Fig. 2). IEAs are the EEG recordings obtained in the intervals between clinical seizures. These IEAs may present as spikes, polyspikes, sharp waves, spikes-and-waves, sharp-and-slow wave complexes, and/or any combination.4 Because of their spike patterns, they are also called interictal spikes. The presence of IEAs in a mentally and neurologically normal subject, in an appropriate clinical context, has a high positive predictive value for the diagnosis of epilepsy.5 However, its presence should be considered cautiously in subjects with mental retardation, antecedents of neurosurgical procedures, and chronic consumption of psychotropic drugs.3 IEAs or spikes usually represent the irritative zone, an area that surrounds the epileptogenic focus. Hence, intraoperative ECoG recordings of IEAs help to localize epileptogenic focus. The morphology of the interictal discharges can provide important information about the distance of the recording from an epileptogenic focus. The higher the amplitude of the IEAs, the closer the recording site to the epileptogenic focus and this information may be helpful to guide the extent of surgical resection. After resection ECoG may be used in some cases (nontemporal lobe resections) to assess the completeness of the surgical resections by looking for the presence of residual epileptiform activities.6
The major controversy of ECoG is the accuracy of localization. Since ECoG relies on a short intraoperative recording, the chances of capturing a spontaneous electroclinical seizure are relatively small. It relies heavily on the information obtained by analyzing the spontaneous IEAs and the induced ictal activities. Some authors believe that using IEAs to guide the resection can be misleading and may not coincide with the real foci.7–10 The use of induced electrographic seizures is not universally accepted as a safe replacement for the onset of spontaneous seizure activity.11 Others, however, dispute this view and believe that the ECoG can still provide reliable localization information with careful interpretation.12,13
ANESTHESIA AND INTRAOPERATIVE ECOG
An anesthetic technique for epileptogenic brain resection depends on the need for intraoperative ECoG and functional cortical mapping. The anesthetic considerations for resection of epileptic foci under general anesthesia without ECoG and brain mapping are similar to those of most open craniotomy procedures in a patient with epilepsy. In sharp contrast to this, use of intraoperative ECoG and functional cortical mapping require special considerations. Because ECoG recordings are highly affected by different anesthetics, awake craniotomy is the preferred technique to minimize the suppression and overactivation. However, complete cessation of all the anesthetic drugs may not be possible in all cases of awake craniotomy and general anesthesia will be needed in some patients. The choice of anesthetic drugs for sedation during awake craniotomy and for general anesthesia is important for successful ECoG recordings (Tables 1 and 2).
The first but difficult task in intraoperative ECoG is to obtain continuous background ECoG. The majority of anesthetic drugs affects neuronal transmission and has significant excitatory or inhibitory effects on cerebral cortical activities. The mechanism behind this conflicting effect is not completely understood. It may be that the ratio of affected inhibitory or excitatory neurons in both the cortical and subcortical brain structures changes with depth of sedation.14 In light anesthetic level, high-frequency low-amplitude waves are dominant. With increase of anesthetic depth, α-waves (8–12 Hz) become dominant and they are replaced by higher frequency β-activity (13–30 Hz). Finally, it progresses to high-amplitude low-frequency θ- (5–7 Hz) and δ-waves (1–4 Hz) as sedative or anesthetic depth increases.15 The presence of high-frequency β-waves can mimic and mask the epileptiform activities, whereas burst suppression pattern eliminates the interictal discharges. Therefore, maintaining a stable low anesthetic depth is important during intraoperative ECoG. Induction drugs, such as propofol and thiopental, can induce myoclonic movements not associated with EEG excitatory activity, whereas others, such as etomidate and methohexital, have been shown to generate both myoclonus and EEG-documented epileptiform activity in patients with epilepsy.16,17 Clear distinction between myoclonus and true clinical seizure is not easy even with an experienced neurologist, and the myoclonus-related ECoG activities are nonspecific and do not have a localization value in patients with epilepsy. Anesthetic drugs that cause myoclonus and/or proconvulsive should be used with caution. Seizures that occur before performing ECoG can be very problematic, because administration of any anticonvulsant such as propofol or thiopental may obscure the interictal and induced ictal discharges in the subsequent ECoG. The effects of anesthetic drugs on intraoperative ECoG recordings are summarized below.
Propofol is one of the most commonly used anesthetic drugs for awake craniotomy and intraoperative ECoG recording. Although there are many case reports in the literature related to propofol-induced tonic-clonic seizures, multiple studies have demonstrated that sedative doses of propofol have minimal effect on spontaneous IEAs and supported the use of propofol for sedation during awake craniotomy with intraoperative ECoG.18–23
Dexmedetomidine is a short-acting α-2 agonist with the properties of anxiolysis, analgesia, sedation, sympatholysis, and no respiratory-depressive effects. The combination of favorable pharmacokinetic and pharmacodynamic profiles has made dexmedetomidine useful in awake craniotomy for epileptic patients. Multiple studies have clearly demonstrated that dexmedetomidine does not affect the IEAs.24–27 The additional advantages of dexmedetomidine are absence of motor-stimulatory effect and no changes in background ECoG activities. Dexmedetomidine may be a better alternative to propofol in awake craniotomy for intraoperative ECoG.24–27
Synthetic opioids such as alfentanil, fentanyl, sufentanil, and remifentanil are commonly used in awake craniotomy. Opioids can be used safely in this patient population without a significant increase in the risk of perioperative seizures or changes in ECoG activities. However, high bolus doses of all the synthetic opioids can cause increase in interictal spike activities. Morphine and hydromorphone used at clinically relevant doses do not appear to have significant proconvulsant activity or any effect on ECoG discharges.16
When general anesthesia with inhaled drugs is used, these drugs may produce a shift in occipitally dominant α-waves to the frontal region.28 The resulting fast α-activity may resemble sleep spindles. Inhaled drugs have been shown to affect the background ECoG by suppressing the spontaneous interictal spikes even at 1 minimum alveolar concentration levels. Hence, lower concentrations of inhaled drugs may be required intraoperatively to minimize the suppressive effect to facilitate ECoG recordings. The patient should be well informed of the risk of awareness before the operation. Sevoflurane and enflurane have been shown to enhance nonspecific spike activities. The epileptogenic potential of isoflurane, desflurane, and halothane appears low, and use of a small concentration of isoflurane or desflurane for maintenance has been recommended.29
Nitrous oxide (N2O) alone can produce fast frontal dominant high-frequency (>30 Hz) activities. When combined with other volatile inhaled drugs, it appears to be “context sensitive” in its effect. Convulsions with spike and wave activity on EEG have been reported with combinations of isoflurane and N2O.30,31 It has been shown that N2O either alone or in combination with an inhaled drug (sevoflurane) depresses the interictal spike activity and hence it is recommended that N2O should be avoided during ECoG.32,33 However, Hosain et al.34 have shown that 50% to 70% N2O can be used during epilepsy surgery without any effect on interictal spikes and many centers routinely use N2O during ECoG.
Principles of Induced Epileptogenic Activity
Activation of intraoperative interictal epileptiform spikes may be required if there are no spontaneous interictal discharges during the intraoperative ECoG. This is more common in patients under general anesthesia. Iatrogenic activation may also provide more information even in those patients with spontaneous interictal spikes. Iatrogenic activation may switch spontaneous interictal epileptiform spikes into an electroclinical seizure, which improves the accuracy of the localization. In patients with multifocal epileptiform discharges, activation can cause organization and propagation of discharges, which may help to identify the specific epileptogenic foci.3 After iatrogenic activation 3 responses can occur: (1) run of interictal epileptiform discharges, (2) an electrographic seizures, and (3) electroclinical seizures.11 Location of electrically induced seizures (with or without prior interictal epileptiform discharges) has been shown to be a good indicator of the abnormally increased baseline excitability.11 The accuracy is even higher when an induced electroclinical seizure has the same characteristics as the patient’s typical spontaneous seizure in terms of pattern of onset and propagation. Several precautions should be taken before performing iatrogenic activation. Antiepileptic drugs and sterile ice-cold saline should be available on the surgical table.
The basic principle of pharmacoactivation is to selectively increase the cortical excitability, particularly of the irritative zones to produce an increase in IEAs. Although triggered IEAs only represent the irritative zone, resection of this area is usually sufficient to cover the epileptogenic zone (Fig. 3).
Successful activation is usually quoted as either an increase in the frequency of spiking or increase in the spike distribution and/or both.35 The effectiveness of a pharmacoactivating drug is quantified by the percentage increase in activation. How well the induced area matches with the epileptogenic zone determines the specificity of a pharmacoactivating drug. Nonspecific activation does not carry any localization values and may lead to localization confusion and failed surgery. Unfortunately, a majority of the previous studies did not measure this important variable. In reviewing the literature, there are 29 studies assessing the pharmacoactivation drugs during intraoperative ECoG under general anesthesia. The commonly used dosage, effectiveness, and specificity are listed in Table 3.
Potent μ-opioid receptor agonists can induce epileptiform activity and seizures in both epileptic and nonepileptic patients. Proposed mechanisms include opioid-induced disinhibition of GABAergic interneurons and inhibition of hyperpolarization-activated potassium currents. The high effectiveness and specificity of μ-agonists has led to their routine use in clinical pharmacoactivation. All the short-acting opioids have high effectiveness in activating epileptiform activities (ranged from 67.4% to 100%) but the specificity is not consistent among opioids.17 Alfentanil is the most well-studied drug, and it produces spike activation at wide clinical doses (20–100 μg/kg). It has been shown to be the most effective and specific when compared with remifentanil and fentanyl.36,49,51–53 In contrast, fentanyl was found to have contralateral activation in 50% of cases in 1 study.48 The specificity of remifentanil has not been evaluated.49,50,54 Therefore, alfentanil is a reasonable choice for pharmacoactivation with the current available evidence. However, it is important to note that the epileptogenic potential of opioids is highly attenuated by the prior administration of a benzodiazepine.6
SEDATIVE HYPNOTIC DRUGS
Methohexital was the most commonly used drug for pharmacoactivation until recently. A high percentage of spike activation (50%–85%) has been documented in the initial studies.37 However, later studies questioned the specificity and consistency in activation with different doses. Inappropriate activation by methohexital was reported up to 43% in 1 study.38 Other sedative hypnotic drugs have been described in the literature, but none has gained popularity. With respect to pharmacoactivation, propofol is generally considered to be depressant to ECoG recordings. Feasibility of spike activation with low-dose propofol (25 mg) during temporal lobectomy done under general anesthesia has been shown in 1 study39 but no other studies substantiate this finding. Etomidate (0.2 mg/kg) was shown to have a high activation rate (75%) in 1 study.55 Another study showed 95% successful spike activation with etomidate in patients with intracranial electrodes, but with a frequent incidence of myoclonus and pain.56 The use of etomidate in intraoperative ECoG has never been evaluated. Ketamine, a known neurostimulant, has been studied during the use of EEG, but with ECoG it does not have specificity as it activates globally rather than specifically.57
All inhaled drugs have been shown to have some degree of both activation and deterioration of spike activity. A majority of the inhaled drugs have been shown to activate interictal spikes and in some it is also dose dependent. Dose-dependent activation has a poor localizing value. With an increasing concentration of inhaled drug, interictal spike activation is seen in the nonepileptogenic cortex (poor specificity). Therefore, inhaled drugs are not used as pharmacoactivating drugs. Among the inhaled drugs, enflurane has been shown to activate interictal spikes and also ECoG seizures in a few case studies.40–42 There are no data on the specificity of enflurane activation and the spike activation appears to be dose dependent. The end-tidal concentration that triggers maximum epileptiform activity is reduced during hypocapnia. Sevoflurane, but not desflurane, has been reported to generate convulsions as well as electrical spike waves in both epileptic and nonepileptic patients.29,58,59 The frequency of spike wave activity with sevoflurane increases with dose escalation and hyperventilation.29,43,44 Widespread nonspecific neuroexcitatory activity was associated with sevoflurane, but it did not facilitate seizure focus localization in patients with temporal lobe epilepsy.44 Hyperventilation further exaggerates this nonspecific activation and decreases the prediction specificity of leads with ictal spikes.46
MANAGEMENT OF INTRAOPERATIVE SEIZURES
Intraoperative seizure is a known complication during ECoG and mapping in patients undergoing epilepsy surgery. They are mostly focal seizures related to cortical stimulation, and they usually resolve spontaneously after the cessation of stimulation. Placement of sterile ice-cold saline onto the cortex by the surgeon should be used as first-line treatment for electrographic or clinical seizures because it has a shorter suppression effect on the subsequent recordings. Generalized tonic-clonic seizures are less frequent and must be treated aggressively. Administration of small boluses of propofol (10–50 mg), benzodiazepines (midazolam 2–5 mg, diazepam 5–10 mg), or thiopental sodium (25–50 mg) may be needed in patients who fail to respond to ice-cold irrigation.60 However, the administration of these IV anesthetic drugs may suppress the IEAs and interfere with further ECoG recordings. In addition, other supportive measures such as securing the airway for airway protection especially with prolonged seizures may be needed. To prevent stimulation-triggered seizures, in patients with a significant amount of background IEAs, a loading dose of an antiepileptic drug may be given after the recording is completed.
Anesthesiologists have an important role in helping to determine the quality of intraoperative localization of epileptogenic foci. Understanding of the principles of seizure localization and the effects of anesthetic drugs on ECoG are essential for the proper use of anesthetic drugs whether the patient is under general anesthesia or is having an awake craniotomy for surgical resection of their epileptogenic focus. Anesthesiologists are also crucial to ensure the safe conduct of pharmacoactivation during intraoperative ECoG.
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: Pirjo Manninen, MD, FRCPC.
Contribution: This author helped write the manuscript.
Attestation: Pirjo Manninen approved the final manuscript.
Name: Taufik Valiante, MD, PhD, FRCS(C).
Contribution: This author helped write the manuscript.
Attestation: Taufik Valiante approved the final manuscript.
Name: Lashmi Venkatraghavan, MD, FRCA, FRCPC.
Contribution: This author helped write the manuscript.
Attestation: Lashmi Venkatraghavan approved the final manuscript.
This manuscript was handled by: Gregory J. Crosby, MD.
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