Usefulness of Intraoperative Electrocorticography for the Localization of Epileptogenic Zones

Abstract

Intraoperative electrocorticography (iECoG) is widely performed to identify irritative zones in the cortex during brain surgery; however, several limitations (e.g., short recording times and the effects of general anesthesia) reduce its effectiveness. The present study aimed to evaluate the utility of iECoG for localizing epileptogenic zones. We compared the results of iECoG and chronic electrocorticography (cECoG) in 25 patients with refractory epilepsy. Subdural electrodes were implanted with iECoG under general anesthesia (2% sevoflurane). cECoG recordings were performed for 3-14 days. The distribution of iECoG spikes was compared with cECoG spike, seizure onset zone, and resection areas. The concordance patterns of each distribution were classified into four patterns: Group 1: No spike in iECoG, Group 2: concordant (2a: iECoG smaller, 2b: iECoG larger, Group 3: discordant >50%). The concordance rate of interictal spikes, seizure onset zones, and resection areas were 88.0% (Group 2a: 72.0%, Group 2b: 16.0%), 70.0% (Group 2a: 25.0%, Group 2b: 45.0%), and 81.0% (Group 2a: 42.9%, Group 2b: 38.1%), respectively. The resection of iECoG spike areas significantly correlated with good surgical outcomes. The indication and limitations of iECoG need to be realized, and the complementary use of iECoG and cECoG may enhance clinical utility.

Introduction

The resection of the seizure focus is a curative procedure for refractory focal epilepsy,¹⁾ and effective epilepsy surgery requires the complete resection of epileptogenic zones.²⁾ Intraoperative electrocorticography (iECoG) and chronic electrocorticography (cECoG) are the main procedures performed to identify epileptogenic zones.^1,3) iECoG is intraoperatively recorded electrocorticography under general anesthesia and cECoG is extraoperatively recorded electrocorticography with implanted intracranial electrodes for a certain period. iECoG has several advantages over cECoG (e.g., unnecessity of cooperation, accessibility to deep structures through a removal cavity, and the postresection evaluation of remnants of the epileptogenic cortex). On the other hand, previous studies reported that general anesthesia affected epileptic discharges. Isoflurane at a concentration of 0.5%-1.5% or 0.5%-1.25% was shown to suppress spike activity.^4,5) However, Fiol et al. showed that 0.25%-1.25% isoflurane did not significantly affect spike activity.⁶⁾ Sevoflurane with 1.5 MAC (1.5-fold the minimum alveolar anesthetic concentration) elicited interictal spike activity at near burst-suppression doses.⁷⁾ Intravenous sedative-hypnotic drugs (droperidol, barbiturates, benzodiazepines, etomidate, and propofol) produced the dose-related depression of electroencephalogram (EEG) after initial activation.⁸⁾ The effects of anesthesia on spike activity are dose- and drug-dependent issues that remain controversial. In addition, the effects of anticonvulsants and short recording times need to be considered as limitations of iECoGs. The reliability of iECoGs is restricted by these limitations and, thus, is still unclear.

In the present study, we compared iECoG spike distribution with cECoG spike distribution, seizure onset areas, and resection areas to establish the utility of iECoGs.

Materials and Methods

Patients

Twenty-five patients (age 6-36 years old; 13 males, 12 females) with refractory focal epilepsy who underwent an invasive evaluation with intracranial electrodes between January 2019 and December 2021 were retrospectively included in the present study. Patient profiles are shown in Table 1. The patient's etiologies or pathologic diagnoses included focal cortical dysplasia in 10 patients, brain tumor in three patients, normal brain tissue in three patients, ulegyria in two patients, porencephaly in two patients, hippocampal sclerosis in two patients, herpes encephalitis in one patient, previous resection in one patient, old infarction in one patient, ectopic gray matter in one patient, and choroidal cyst in one patient. iECoG was recorded under general anesthesia for the implantation of intracranial electrodes in all patients. The resection areas were individually determined to include seizure onset zones, frequent cECoG spike distribution, and assumed epileptogenic lesions in the multidisciplinary presurgical conference. Fifteen patients became seizure-free after surgery (follow-up: 6-40 months, mean: 19.9 months). Surgical outcomes included 15 patients in International League Against Epilepsy (ILAE) class 1, two in class 2, two in class 3, one in class 4, five in class 5, and 0 in class 6. Information is provided to all included patients in the form of verbal informed consent and optout, and the study protocol was approved by the Institutional Review Board Committee of our institution (No. 292-101).

Table 1.

Patient Profiles

Pt	Age (yr)	Sex	Diagnosis	Etiology	Ictal onset	Resection area (palliative procedure)	Comparison of iECoG			Surgical outcome
							Spike	SOZ	Resection
1	8	Male	Rt. OLE	Ulegyria	Rt. Cun, PreCun, Rt. T-P	Rt. PreCun, Cun, SOG	2b	2b	2b	1
2	6	Female	Rt. OLE	FCD	Rt. O	Rt. P-O disconnection	2a	2b	2a	1
3	18	Male	Bil. hemispheric epilepsy	Herpes encephalitis	Lt. T-P, Rt. O	(Lt. T-P disconnection, Callosotomy)	2a	2a	NA	3
4	25	Male	Rt. PLE	Brain tumor	Rt. SMG	Rt. SMG	2a	NA	3	2
5	17	Female	Lt. TLE	FCD	Lt. mesial T	Lt. aTL	2a	NA	2a	1
6	16	Female	Bil. hemispheric epilepsy	Porencephaly, FCD	Bil. P-O	(Rt. P-O disconnection, Callosotomy, MST)	2a	2b	NA	5
7	36	Female	Lt. TLE	Brain tumor	Lt. mesial T	Lt. mesial T	2a	2b	2a	1
8	13	Female	Rt. TLE	Normal	Rt. T operculum	Rt. STG, SMG	2a	2b	2b	2
9	8	Female	Lt. FLE	FCD	Lt. F pole	Lt. F pole	2a	2a	2a	1
10	20	Female	Lt. TLE	Previous resection	Lt. basal T, T-O	Lt. lat T, (MHT, MST (SMG, AG) )	2a	2a	NA	5
11	18	Male	Rt. TLE	Normal	Rt. mesial T, lat T	Rt. aTL	2b	2b	2b	1
12	13	Female	Lt. F-TLE	Ulegyria	Lt. F-T-O	Lt. lat T-O, (MHT)	2a	3	NA	4
13	8	Female	Rt. T-PLE	Brain tumor	Rt. T-P	Rt. aTL, SMG	2a	2b	2a	1
14	9	Male	Lt. P-OLE	FCD	Lt. lat T, P	Lt. SMG, MTG, ITG	2a	2b	2b	1
15	9	Male	Rt. TLE	HS	Rt. T-O	Rt. aTL	2a	3	2b	5
16	11	Male	Rt. FLE	FCD	Rt. F	Rt. IFG	1	NA	2a	1
17	19	Male	Rt. FLE	Old infarction	Rt. F	Rt. F pole, MFG, pTr	1	NA	1	3
18	22	Male	Rt. T-OLE	Ectopic gray matter, FCD	Rt. basal T	Rt. aTL	2b	NA	2b	5
19	8	Male	Lt. FLE	FCD	Rt. F	Lt. MFG	2a	2a	2a	1
20	6	Female	Lt. FLE	FCD	Lt. F	Lt. MFG	2a	2a	2a	1
21	12	Male	Rt. TLE	Choroidal cyst	Rt. mesial T	Rt. aTL	2a	3	2a	1
22	14	Male	Rt. TLE	Normal	Rt. mesial T, P-O	Rt. aTL	1	1	1	1
23	8	Female	Rt. TLE	HS	Rt. mesial T, lat T	Rt. aTL, PostCG	2b	3	2b	5
24	12	Male	Lt. PLE	FCD	Lt. P	Lt. SPL	1	1	1	1
25	15	Female	Lt. FLE	Porencephaly	Lt. lat T, P	Lt. ITG, MTG, F operculum	2a	2b	2b	1

aTL: anterior temporal lobe (including mesial structure), Bil: bilateral, Cun: cuneus, F: frontal, FCD: focal cortical dysplasia, FLE: frontal lobe epilepsy, HS: hippocampal sclerosis, IFG: inferior frontal gyrus, ITG: inferior temporal gyrus, lat: lateral, Lt: left, MFG: middle frontal gyrus, MHT: multiple hippocampal transection, MST: multiple subpial transection, MTG: middle temporal gyrus, O: occipital, OLE: occipital lobe epilepsy, P: parietal, PLE: parietal lobe epilepsy, PostCG: postcentral gyrus, PreCun: precuneus, pTr: pars triangularis, Rt: right, SMG: supramarginal gyrus, SOG: superior occipital gyrus, SOZ: seizure onset zone, SPL: superior parietal lobule, T: temporal, TLE: temporal lobe epilepsy

Subdural electrode placement and iECoG

Strip or grid subdural electrodes were surgically implanted under general anesthesia. All antiepileptic drugs (AEDs) were discontinued from the morning of implantation. iECoG was recorded with the end-tidal sevoflurane concentration maintained at 2%, and the locations of the electrodes were adjusted based on iECoG findings. Five-minute iECoG was obtained under the following settings: a sampling rate of 1000-2000 Hz, a low filter setting of 0.5-2.0 Hz, and a high filter setting of 100-200 Hz using Neurofax EEG-1200 with the JE-120 amplifier (Nihon Kohden, Tokyo, Japan). Measurement conditions were adjusted accordingly depending on the influence of noise and intraoperative conditions. Grids consisted of 2 × 8 or 4 × 5 platinum electrodes and a center-to-center interelectrode distance of 10 mm with a recording diameter of 3 mm (Unique Medical Co., Ltd., Tokyo, Japan). The strip consisted of a single line of 6 electrodes in the same configuration as that used for the grids. Additional 4-line strip electrodes were placed on the skulls as neutral, reference, and system reference electrodes. The locations of the implanted electrodes were confirmed using presurgical 3-dimensionally reconstructed magnetic resonance imaging coordinated with postoperative high resolution volumetric computed tomography (1-mm-thick slices) to supply a visual correlation between the location of each electrode and the corresponding structures, as previously reported.^9-11)

cECoG recording

Extraoperative ECoG recordings were continuously recorded with a video for 3-14 days using NeurofaxEEG-1200 with a JE-120 amplifier (Nihon Koden, Tokyo, Japan). All AEDs were withdrawn until a sufficient number of habitual seizures were captured. Two board-certified epileptologists of Japan epilepsy society visually identified interictal epileptic discharges and also reviewed ECoG during seizures to reach a consensus on the seizure onset region. The distribution of cECoG spikes was defined as the areas in which interictal spikes were identified during the recording periods. cECoG recordings from intracranial electrodes were obtained under the following settings: a sampling rate of 2000 Hz, low filter setting of 0.016 Hz, and high filter setting of 600 Hz using Neurofax EEG-1200 with the JE-120 amplifier (Nihon Kohden, Tokyo, Japan). These recordings were analyzed with band-pass filtering between 5 and 600 Hz to localized interictal spike and seizure onset zones.

Comparison of iECoG findings with cECoG and resection areas

The distribution of iECoG spikes was compared with interictal spike and seizure onset zones recorded during cECoG and resection areas (excluding transection and palliative disconnective surgery) (Figs. 1a-d and 2a-d). The concordance patterns of each distribution were classified into four patterns: Group 1: No spike in iECoG, Group 2: concordant (2a: iECoG smaller, 2b: iECoG larger), Group 3: discordant (>50%) (Fig. 3a). Fisher's exact test was applied to evaluate the effects of iECoG spike area resection on surgical outcomes. A p-value < 0.05 was considered to be significant. Statistical analyses were performed using IBM SPSS Ver 25 (SPSS Inc., Chicago, IL).

Fig. 1.

(a) The waveform and intraoperative photograph of intraoperative electrocorticography (iECoG) in Pt. 25. Red squares indicate the waveforms and location of iECoG spikes.

(b) The waveforms and distribution of interictal spikes in chronic electrocorticography (cECoG) in Pt. 25. The dotted line indicates the boundary of interictal spike distribution.

(c) The waveform and location of seizure onset zones recorded during cECoG recordings in Pt. 25. The dotted line indicates the boundary of seizure onset zones.

(d) Intraoperative photograph and location of resection areas in Pt. 25. The dotted line indicates the boundary of resection areas.

Fig. 2.

(a) The waveform and intraoperative photograph of iECoG in Pt. 21 (right temporal lobe epilepsy). Red squares indicate the waveforms and location of iECoG spikes.

(b) The waveforms and distribution of interictal spikes in cECoG in Pt. 21. The dotted line indicates the boundary of interictal spike distribution.

(c) The waveform and location of seizure onset zones recorded during cECoG recordings in Pt. 21. The dotted line indicates the boundary of seizure onset zones.

(d) Intraoperative photograph and location of resection areas in Pt. 21. The dotted line indicates the boundary of resection areas.

Fig. 3.

(a) Schematic explanation of each concordance pattern: Group 1: No spike in iECoG, Group 2: concordant (2a: iECoG smaller, 2b: iECoG larger), Group 3: discordant (>50%).

(b) The percentage of each group in comparisons of iECoG spikes with cECoG spikes, seizure onset zones, and resection areas.

(c) The number of each group in International League Against Epilepsy (ILAE) surgical outcome classes 1-6.

Results

iECoGs were successfully recorded for a minimum of 5 min in all 25 patients. No spikes were detected in three patients. iECoG spikes were recorded at a frequency of 10 times or more per minute in 11 patients and at a frequency of 1-10 times per minute in the remaining 11 patients. cECoG was measured over a period of 3-14 days (mean 6.96 days). The interictal spikes of cECoG were identified throughout the recording periods in all patients. The interictal spike distributions of iECoG and cECoG were compared in all 25 patients. Three patients (12.0%) were classified as Group 1, 22 as Group 2 (88.0%; Group 2a: 18 cases, 72.0%; Group 2b: 4 cases, 16.0%), and 0 as Group 3 (Fig. 3b).

Regarding seizure onset zones, seizures were recorded during cECoG measurements in 21 patients, and seizure onset zones were identified in 20 patients. The seizure onset zone was not localizable in one patient due to the insufficient coverage of subdural electrodes.

Therefore, the distributions of iECoG spikes and cECoG seizure onset zones were compared in 20 patients. Two patients (10.0%) were classified as Group 1, 14 (70.0%) as Group 2 (Group 2a: 5 cases, 25.0%; Group 2b: 9 cases, 45.0%), and 4 (20.0%) as Group 3 (Fig. 3b).

Twenty-one out of 25 patients underwent resection or disconnection of the estimated seizure focus, while the remaining four underwent hippocampal transection, multiple subpial transection, or corpus callosotomy. These four patients were excluded from comparisons between iECoG spikes and resection areas. Consequently, iECoG spikes were compared with resection areas in 21 patients. Three patients (14.3%) were in Group 1, 17 in Group 2 (81.0%, Group 2a: 9 cases, 42.9%, Group 2b: 8 cases, 38.1%), and one in Group 3 (4.8%) (Fig. 3b).

In summary, the comparison of iECoG spikes with cECoG spikes, cECoG seizure onset zones, and resection areas revealed that concordance rates (Group 2) were 88.0% with cECoG spikes, 70.0% with seizure onset zones, and 81.0% with resection areas, and the most common pattern was Group 2a with cECoG spikes, resection areas, and Group 2b with seizure onset zones. Among 21 patients who underwent radical resective/disconnective surgeries, 15 achieved freedom from seizures (ILAE class I).

These seizure-free patients included nine in Group 2a (60%), two in Group 1 (13.3%), and four in Group 2b (26.7%). All patients in Group 2a were free of seizures after surgery, and statistical analyses revealed that Group 2a significantly correlated with freedom from seizures (p = 0.012) (Fig. 3c).

Discussion

Comparisons of iECoG spikes with cECoG spikes, cECoG seizure onset zones, and resection areas revealed that concordance rates were 88.0% with cECoG spikes, 70.0% with seizure onset zones, and 81.0% with resection areas. The most common pattern was Group 2a with cECoG spikes, resection areas, and Group 2b with seizure onset zones. Group 2a with resection areas significantly correlated with freedom from seizures.

In comparisons with cECoG spikes, iECoG spikes were distributed within the range of cECoG spikes (Group 2a) in 72.0% of patients, and three patients (12.0%) had no iECoG spikes (Group 1). Groups 1 and 2a both imply the higher spike detection of cECoG than iECoG. Two mechanisms need to be considered for this phenomenon. The first possibility is anesthetic effects. All patients in the present study were maintained at a concentration of 2% sevoflurane, equivalent to less than 1 MAC. A previous study reported that sevoflurane was associated with a volume-dependent decrease in spiking in patients with temporal lobe epilepsy.¹²⁾ However, another study showed that 1.5 MAC sevoflurane enhanced the frequency and distribution of interictal spikes more than 0.5 MAC sevoflurane.¹³⁾ The effects of sevoflurane on spikes remain controversial and were not clarified in the present study. As the second possibility, longer recording periods and the discontinuation of AEDs during cECoG recordings need to be considered. Regarding recording conditions, cECoG recording dominates iECoG (e.g., 3-14 days vs. 5-min recording periods and 3-14 days vs. 0-1 day with the discontinuation of AEDs). We speculate that the recording condition is the main reason that cECoG detected interictal spikes with higher sensitivity than iECoGs.

On the other hand, iECoG spikes were more broadly distributed than cECoG seizure onset zones (Group 2b) in 45.0% of patients, which corresponds to the biggest population in the comparison between iECoG spikes and cECoG seizure onset zones. The distribution of interictal spikes was previously reported to extend more than the seizure onset zone.¹⁴⁾ iECoG recordings evaluate the interictal phase of cortical excitation, but do not detect seizure generators. This point is also important in discussions of the discordant group between iECoG spikes and cECoG seizure onset zones (Group 3), which accounts for 20.0% of the patient population (4 patients). The present results showed that iECoG recordings of the interictal phase missed approximately 20% of seizure onset zones, which is a major limitation of this methodology.

In comparisons with resection areas, iECoG spikes were included within resection areas (Group 2a) in 42.9% of patients. All patients in Group 2a were free of seizures after surgery and Group 2a comprised 60% of postoperative seizure-free patients. Statistical analyses revealed that Group 2a significantly correlated with freedom from seizures, which suggests that iECoG spike areas need to be resected and showed a certain usefulness for iECoG recordings. However, we also noted that four patients with residual iECoG spike areas (Group 2b: 26.7% of seizure-free patients) and two patients with no iECoG spikes (Group 1: 13.3% of seizure-free patients) achieved freedom from seizures. This result indicates that iECoG did not identify epileptogenic zones or detect spikes in these patients, and, thus, is not satisfactory to establish “iECoG-guided” resection. The effectiveness of iECoG on surgical outcomes is affected by the limited recording time and the effects of anesthetic sedation, and largely depends on the underlying pathology.¹⁵⁾ The effectiveness of iECoG-guided resection in tumor-related epilepsy was previously reported;¹⁶⁾ whereas, in epilepsy of other etiologies, the role of a resection guide is more controversial. Therefore, our recommendation is the application of iECoG as an intraoperative guide of intracranial electrode placement; whereas, the efficacy of iECoG as a guide of resection remains questionable.

Several limitations of the present study need to be addressed. The research design was retrospective and the number of patients enrolled was small. Furthermore, inconsistencies in recording conditions, differences in electrode locations and numbers, and pathologies may have biased the results obtained. The accumulation of more cases and unified group analyses (e.g., same etiologies, specific sleep stage during cECoG recordings, unified brain regions, etc.) are needed to confirm the present results and establish the validity of iECoG recordings. Moreover, the effects of AEDs were not eliminated and may have affected iECoG recordings. In addition, spikes were detected by subjective visual inspections and interrater differences in detectability may have affected the results obtained. The autodetection algorithm for epileptic activities would solve this problem and is desired to be developed.

Despite these limitations, the present results reveal the concordance rates of iECoG spikes with cECoG spike and seizure onset zones. Furthermore, the resection of iECoG spike areas correlated with good surgical outcomes. However, iECoG may be limited in its ability to detect and delineate epileptogenic zones. The indication and limitations of iECoG need to be realized, and the complementary use of iECoG and cECoG may enhance clinical utility.

Conflicts of Interest Disclosure

The authors declare no conflicts of interest associated with this manuscript.