INVITED REVIEW

Electrocorticography for Seizure Foci Mapping in Epilepsy Surgery Iván Sánchez Fernández*† and Tobias Loddenkemper*

Summary: Patients with refractory focal epilepsy are thoroughly evaluated to identify an area of cortex that, if removed or disconnected, will lead to seizure freedom. Clinical semiology, neuroimaging, and scalp electroencephalogram provide an approximation of this area, whereas intracranial recording may permit a more precise localization and investigation of a selected cortical area. Intraoperative electrocorticography delineates the irritative zone, and subdural electrode implantation also permits cortical stimulation of eloquent areas. Intraoperative electrocorticography rarely captures spontaneous seizures and may be influenced by the effect of anesthetic drugs, and the correlation between complete resection of the irritative zone and postsurgical seizure outcome is unclear. Extraoperative monitoring is often superior to intraoperative electrocorticography but may also be associated with more risk of adverse events. Further development of ultrahigh-density electrode arrays is providing novel insights into the role of microseizures and high-frequency oscillations on ictogenesis and epileptogenesis. Key Words: Children, Electrodes, Electroencephalogram, Epilepsy surgery, Microelectrodes, Seizure foci mapping. (J Clin Neurophysiol 2013;30: 554–570)

T

he main objective of presurgical evaluation in patients with refractory focal epilepsy is the identification of the area of cortex that is indispensable for the generation of clinical seizures: the epileptogenic zone (Carreño and Lüders, 2001; Rosenow and Lüders, 2001). If this zone is removed or disconnected, the patient will become seizure free (Carreño and Lüders, 2001; Lüders et al., 2009). The epileptogenic zone is a theoretical construct that cannot be precisely delineated using any present investigational technique before surgery.

From the *Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A.; and †Department of Child Neurology, Hospital Sant Joan de Déu, Universidad de Barcelona, Barcelona, Spain. I. Sánchez Fernández is funded by a grant for the study of Epileptic Encephalopathies from “Fundación Alfonso Martín Escudero.” T. Loddenkemper serves on the Laboratory Accreditation Board for Long Term (Epilepsy and ICU) Monitoring (ABRET), serves as a member of the American Clinical Neurophysiology Council (ACNS), serves on the American Board of Clinical Neurophysiology, serves as an Associate Editor of Seizure, performs Video EEG long-term monitoring, EEGs, and other electrophysiological studies at Children’s Hospital Boston and bills for these procedures, receives support from NIH/NINDS 1R21NS076859-01 (2011-2013), is supported by a Career Development Fellowship Award from Harvard Medical School and Children’s Hospital Boston, by the Program for Quality and Safety at Children’s Hospital Boston, by the Payer Provider Quality Initiative, receives funding from the Epilepsy Foundation of America (EF-213583 and EF-213882), from the Center for Integration of Medicine & Innovative Technology (CIMIT), the Epilepsy Therapy Project, the Pediatric Epilepsy Research Foundation, Cure, and received investigator-initiated research support from Eisai Inc and Lundbeck. Address correspondence and reprint requests to Tobias Loddenkemper, MD, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Fegan 9, 300 Longwood Avenue, Boston, MA 02115, U.S.A.; e-mail: tobias.loddenkemper@ childrens.harvard.edu. Copyright Ó 2013 by the American Clinical Neurophysiology Society

ISSN: 0736-0258/13/3006-0554

554

As the epileptogenic zone cannot be determined presurgically, other related areas are used to approximate the location and extent of the epileptogenic zone. These areas include the symptomatogenic zone, irritative zone, seizure onset zone, epileptogenic lesion, and functionaldeficit zone (Table 1 and Fig. 1) (Carreño and Lüders, 2001; Rosenow and Lüders, 2001). Different studies are performed to localize and delineate these zones: evaluation of seizure semiology; physical examination; neuropsychological testing; and neuroimaging techniques such as magnetic resonance imaging (MRI), functional MRI, single photon emission computed tomography, positron emission tomography, and scalp and intracranial electroencephalogram (EEG). All these studies are limited by their intrinsic sensitivity and specificity to localize the different zones. In addition, each of these zones provides only an estimation of the epileptogenic zone, and their importance to delineate the epileptogenic zone should be carefully weighed on an individual basis (Carreño and Lüders, 2001; Rosenow and Lüders, 2001). The overlap between the epileptogenic zone and its surrogate zones is far from perfect as illustrated by the fact that complete resection of these surrogate zones is not always necessary to achieve seizure freedom. Conversely, complete resection of any of these surrogate zones does not necessarily lead to seizure freedom. A large series of 149 patients with histologically confirmed malformations of cortical development showed that the factor most associated with positive surgical outcome was completeness of surgical resection, defined as complete removal of the structural MRI lesion (if present) and the cortical region exhibiting prominent ictal and interictal abnormalities on intracranial EEG (Krsek et al., 2009). In this series, seizure freedom occurred in 70% patients who had complete resections but in only 22% patients with incomplete lesionectomy (Krsek et al., 2009). In a series of 83 pediatric patients with incomplete resection of the seizure onset zone (as determined by EEG) or the epileptogenic lesion (as determined by MRI), the rate of seizure freedom was 41% in patients with incomplete resection by either MRI or EEG, 57% in patients with incomplete resection by MRI alone, 52% in patients with incomplete resection by EEG alone, and 24% in patients with incomplete resection by MRI and EEG (Perry et al., 2010). In contrast, the rate of seizure freedom was 77% in a control group of 48 patients with complete resection (Perry et al., 2010). Even if the results of this study demonstrate that complete resection of the epileptogenic lesion, and the seizure-onset zone is the most important predictor of seizure freedom, it also shows that a high proportion of patients with incomplete resection of the seizure-onset zone and/or the epileptogenic lesion can also achieve seizure freedom. Therefore, the final decision for surgical candidacy and the extent of the resection depends on the careful analysis of potential risks and benefits in light of data on localization and extent of the different zones including eloquent areas.

SCALP EEG AS A LOCALIZATION TECHNIQUE Scalp EEG provides an overview of the general distribution of the epileptiform activity. As a noninvasive technique, it is

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TABLE 1. Surgery

Definitions of the Brain Areas Relevant for Epilepsy

Symptomatogenic zone Irritative zone Seizure-onset zone Epileptogenic lesion Functional deficit zone Eloquent cortex

Area of cortex that, when activated by epileptiform discharges, produces symptoms during a seizure Area of cortex that generates interictal epileptiform discharges Area of the cortex that is involved during the EEG seizure onset Structural brain abnormality that is etiologically related to the epilepsy Area of cortex that is functionally abnormal in the interictal period Area of cortex that is indispensable for a specific cortical function

The epileptogenic zone is defined as the area of cortex that is indispensable for the generation of seizures. This is a theoretical construct that cannot be delineated with any present study. The surrogate brain areas defined provide an estimation of the epileptogenic zone (Rosenow and Lüders, 2001).

technically relatively easy to perform and has no major complications. Scalp EEG is, however, limited because the activity from deep or mesial brain areas is not recorded. In addition, the discharges recorded in the scalp are attenuated and distorted by the different layers between the scalp surface and the brain cortex, including scalp, bone, and meninges (Carreño and Lüders, 2001). It has been estimated that, at standard working gains, 6 cm2 of brain cortex need to discharge synchronously to generate a detectable potential in the scalp (Cooper et al., 1965). Epileptiform activity generated by a smaller cortical surface, with substandard amplitudes, or arising from deep or midline structures is usually not reflected on scalp EEG (Carreño and Lüders, 2001). As a result, it is difficult to precisely localize and determine the extent of the cortical area that is giving rise to an epileptiform discharge based on the distribution of epileptiform activity in the scalp EEG (Carreño and Lüders, 2001). Therefore, scalp EEG provides very good initial screening data for a tentative localization of seizures or interictal epileptiform discharges,

Electrocorticography

but intracranial recordings are needed for more precise localization of interictal and ictal epileptiform activity.

INTRACRANIAL EEG AS A LOCALIZATION TECHNIQUE Intracranial electrodes are used when there is reasonable evidence that the patient has a resectable epileptogenic focus but the noninvasively obtained information is insufficient to delineate the resectable area and related eloquent areas (Hamer and Morris, 2001). Intracranial electrodes register the cerebral electrical activity immediately under or around the electrode in the brain surface, and, therefore, epidural, subdural, or depth electrodes detect more subtle electrical discharges from smaller cortical areas than scalp electrodes (Carreño and Lüders, 2001). As a consequence, intracranial electrodes allow for a much more precise delineation of the relevant brain areas (Rosenow and Lüders, 2001). However, intracranial recordings also have drawbacks. As an invasive technique, it is associated with complications such as infection, hemorrhage, and potential for the development of increased intracranial pressure. In addition, the cortical area covered by the intracranial electrodes is limited, and therefore information from other brain areas may be missed (Carreño and Lüders, 2001), similar to the view of a histologic slice through a microscope or a magnification glass, whereas specific features can be identified better by means of zooming in, parts that lie outside the magnified area are difficult to assess at the same time. Differences between the 2 main techniques of intracranial recording, chronic intracranial recording, and intraoperative electrocorticography (ECoG) are presented in Table 2. Chronic intracranial recordings provide a detailed and prolonged sample of the ictal and interictal discharges, but recordings are also associated with a higher risk of complications. Electrocorticography provides information on interictal discharges within a more circumscribed and smaller cortical area and provides some flexibility to move the electrodes within the surgical field, but intraoperative ECoG also rarely records an ictal EEG sample. Electrocorticography can be repeated at different time points before, during, and after the resection and is usually associated with a lower risk of complications (Carreño and Lüders, 2001).

CHRONIC INTRACRANIAL RECORDING The main advantage of chronic intracranial recording is the collection of information for a period that is long enough to capture spontaneous seizures, and, therefore, it is the best technique to delineate the seizure-onset zone. The period of intracranial recordings varies depending on the seizure frequency of the individual patient and may also be limited by side effects, but recordings are, in general, performed over a 3- to 14-day period. Longer recordings, especially if lasting longer than 10 to 14 days, have a higher risk of complications (Hamer et al., 2002).

Clinical Application of Chronic Intracranial Recording FIG. 1. Scheme of the brain areas relevant for epilepsy surgery. Note that the location and extent of the epileptogenic zone cannot be directly evaluated. The illustrated zones provide an approximation of the epileptogenic zone (Table 1). Modified with permission from Wyllie’s Treatment of Epilepsy (Datta and Loddenkemper, 2011). Copyright Ó 2013 by the American Clinical Neurophysiology Society

The indications for chronic intracranial recording can be divided into 3 groups (Table 3 and Fig. 2): 1. Extent and distribution of the irritative and seizure-onset zones. Noninvasive techniques usually provide a rough localization of the epileptogenic area. Chronic intracranial recording provides more detail on the ictal and interictal discharges 555

I. Sánchez Fernández and T. Loddenkemper

TABLE 2.

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Main Differences Between Electrocorticography and Chronic Invasive Monitoring (Hamer and Morris, 2001)

Timeline Wakefulness/sleep Placement of electrodes Further recordings after surgical resection of the brain tissue Type of epileptiform activity recorded Localization of the recording electrodes Interpretive difficulties Safety Risk of complications

Electrocorticography

Chronic Invasive Monitoring

Minutes to hours Sedation Exact placement under direct visualization Frequent

Days to weeks Prolonged periods of spontaneous wakefulness and sleep No direct visualization during recording but CT/MRI control is possible Occasional

Interictal with very rare ictal recordings Limited and localized area Effects of anesthesia One surgical intervention Low

Ictal and interictal recordings Large number of electrodes covering a broader area Questionable effects of sudden drug withdrawal Two surgical interventions (placement and removal) Moderate to high

that help with the delineation of the area to be potentially resected (Hamer and Morris, 2001). 2. Irritative and seizure-onset zones in relationship to structural lesion. Structural brain lesions provide an initial rough localization of the area to be potentially resected. However, the area surrounding the lesion, especially if the lesion is dysplastic, may include occult pathology and/or be epileptogenic, and precise mapping of the discharging areas is required (Palmini et al., 1995). In addition, not all potentially epileptogenic lesions need to be resected. Patients with multiple structural lesions (such as patients with tuberous sclerosis complex or patients with dual pathology) may also benefit from a thorough identification of the individual lesion or group of lesions that are most epileptogenic and that may benefit from surgical resection (Romanelli et al., 2004). 3. Irritative zone and seizure-onset zone in relationship to eloquent cortex. The precise delineation of eloquent cortex (i.e., language, cognitive, motor, or sensory areas among others) may prevent functional deficits after epilepsy surgery (Hamer and Morris, 2001).

Prognostic Value of the Seizure Onset Zone Chronic intracranial recording is in many cases the best technique to delineate the seizure-onset zone, which provides one of TABLE 3.

the best approximations to the epileptogenic zone (Carreño and Lüders, 2001; Rosenow and Lüders, 2001). However, seizure-onset zone and epileptogenic zone do not necessarily overlap: some patients become seizure-free even if the ictal onset zone is not entirely removed during epilepsy surgery (Gilmore et al., 1994; Perry et al., 2010), and other patients continue to have seizures despite complete removal of the ictal onset zone (Carreño and Lüders, 2001).

INTRAOPERATIVE ELECTROCORTICOGRAPHY Electrocorticography recordings attempt to capture epileptiform activity directly from the brain surface during epilepsy surgery.

APPLICATION OF ELECTROCORTICOGRAPHY IN CLINICAL PRACTICE Indications for Electrocorticography Electrocorticography has been used to: (1) delineate the tissue that gives rise to epileptiform activity, (2) map out cortical function, and (3) predict the chances of success after surgery based on persistent or de novo spikes (Keene et al., 2000) (Table 3 and Fig. 2). Despite its common application, few studies have actually evaluated its effectiveness for these purposes, and there are no universally

Potential Indications for Intracranial Recording Extraoperative Recording (Chronic Intracranial Recording)

Generally indicated

Intraoperative Monitoring (Electrocorticography)

Precise delineation of nonlesional ictal onset zones Noninvasive localization methods are discordant Localization of the ictal onset zone in a large epileptic lesion that is not amenable to complete resection (i.e., focal cortical dysplasia) Several closely located potential ictal onset zones (anatomically normal or abnormal) Precise tailoring of surgical resection near eloquent areas Unclear lesion margins Generally not indicated Unilateral mesial temporal sclerosis with concordant PET results Well-defined ictal onset zone in noneloquent areas Hemispherectomy

Cortical stimulation Precise delineation of eloquent areas Delineation of irritative zone in large epileptic lesion that is not amenable to complete resection (i.e., focal cortical dysplasias) Precise tailoring of surgical resection near eloquent areas Unclear lesion margins Large irritative areas not amenable to be covered by ECoG Unilateral mesial temporal sclerosis with concordant PET results Well-defined ictal onset zone in noneloquent areas Hemispherectomy Brain zones and eloquent areas already well-defined with chronic monitoring

PET, positron emission tomography.

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Copyright Ó 2013 by the American Clinical Neurophysiology Society

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Electrocorticography

complications, but this needs to be weighed against potentially increased postoperative seizure freedom and potentially lifelong cortical deficits, if a functional cortical area is not considered. Furthermore, the prognostic significance of ECoG findings is frequently not well described. In patients who underwent successful chronic intracranial recordings, ECoG may not be necessary and may provide redundant information on the localization and extent of the irritative zone (Nair and Najm, 2008).

PROGNOSTIC VALUE OF THE IRRITATIVE ZONE

FIG. 2. Proposed treatment algorithm for medically refractory epilepsy. Chronic monitoring and ECoG are mainly used for precise delineation of the seizure-onset zone and irritative zone, especially, when near to eloquent areas. PET, positron emission tomography; SPECT, single photonemission computed tomography; VNS, vagal nerve stimulator. accepted indications for ECoG (Binnie et al., 2001; Keene et al., 2000). Electrocorticography helps to determine the extent of the irritative zone (preoperative ECoG) and to identify residual epileptiform discharge generating areas remaining after an initial surgical procedure (postoperative ECoG) (Binnie et al., 2001). Therefore, the utility of ECoG largely depends on the surgical approach. Electrocorticography is generally not useful in hemispherectomy, because the irritative zone does not need to be precisely delineated before surgery as the whole hemisphere will be resected or functionally disconnected. In contrast, tailored resections and lesionectomies often require ECoG to permit exact delineation of the area to be resected and to prevent resection of eloquent cortex (Binnie et al., 2001). Based on the same principle, ECoG has an important role in determining the extent of the primary excision and, possibly, its subsequent extension in extratemporal epilepsies. In contrast, temporal epilepsy surgeries are more anatomically standardized and can potentially benefit less from ECoG (Binnie et al., 2001). Incorrect delineation of the area to be resected, even by a few millimeters, may lead to injury of eloquent areas and, therefore, to loss of cortical function (Blume and Holloway, 2011). In these cases, ECoG may help determine gyral and sulcal portions that are appropriate or not for resection (Blume and Holloway, 2011). Electrocorticography is also used in patients who cannot tolerate chronic intracranial recordings. In those cases, ECoG with evoked potentials and cortical stimulation techniques may be able to successfully delineate the area to be resected (Simon et al., 2012).

Disadvantages and Limitations Electrocorticography adds substantially to cost, personnel, and equipment, and it requires training of a specialized neurophysiologic team and excellent communication with the neurosurgical team. Electrocorticography may also increase the length of the epilepsy surgery procedure, and therefore, increases the risk for Copyright Ó 2013 by the American Clinical Neurophysiology Society

Electrocorticography is performed during short periods of time. These assessments usually allow for a relatively straightforward delineation of the irritative zone but are generally insufficient to record seizures and delineate the seizure-onset zone (Kuruvilla and Flink, 2003; Rosenow and Lüders, 2001). Studies that try to correlate the extent of resection of the irritative zone with seizure outcome yield conflicting results (Asano et al., 2009; Bautista et al., 1999; Benifla et al., 2006; Cendes et al., 1993; Jooma et al., 1995; Krendl et al., 2008; Palmini et al., 1995; Rassi-Neto et al., 1999; San-juan et al., 2011; Schwartz et al., 1997; Sugano et al., 2007; Tripathi et al., 2010; Wennberg et al., 1998; Wray et al., 2012; Wyllie et al., 1987).

Irritative Zone and Seizure Outcome In a series of 61 patients with refractory seizures, good outcome (defined as seizure freedom, persistence of only auras, or reduction of more than 90% of seizure frequency) was achieved in 86% patients with complete resection of the ictal onset and irritative zones (resection of the ictal and interictal discharges as detected in chronic intracranial recording), whereas only 51% patients with incomplete resection achieved good outcome (Wyllie et al., 1987). Therefore, the complete resection of the irritative zone was established as a major predictor of seizure outcome. Subsequent studies showed conflicting results with some series demonstrating a strong prognostic value of interictal spiking (Bautista et al., 1999; Jooma et al., 1995; Palmini et al., 1995), whereas others could not find a good correlation between complete resection of the irritative zone and seizure outcome (Cendes et al., 1993; San-juan et al., 2011; Schwartz et al., 1997; Wray et al., 2012). The main findings of representative series are outlined in Table 4 (Asano et al., 2009; Bautista et al., 1999; Benifla et al., 2006; Cendes et al., 1993; Jooma et al., 1995; Krendl et al., 2008; Palmini et al., 1995; Rassi-Neto et al., 1999; San-juan et al., 2011; Schwartz et al., 1997; Sugano et al., 2007; Tripathi et al., 2010; Wennberg et al., 1998; Wray et al., 2012). Differences in the type of epilepsy (temporal vs. extratemporal, lesional vs. nonlesional, among others), in recording techniques, and in surgical protocols and determination of how intracranial spikes are defined may account for part of the diverging results. Extratemporal resections are anatomically less standardized than temporal resections and generally require a more precise tailoring of the area to be resected. Therefore, the role and impact of ECoG may be greater in selected extratemporal versus temporal epilepsies (Binnie et al., 2001). Surprisingly, different studies on the prognostic value of the irritative zone as assessed by ECoG provide conflicting results both in temporal (Cendes et al., 1993; Jooma et al., 1995; San-juan et al., 2011; Schwartz et al., 1997) and extratemporal epilepsies (Asano et al., 2009; Bautista et al., 1999; Palmini et al., 1995; Wray et al., 2012). A possible explanation for these results may be the surgical procedure itself. Many centers that have reported the use of ECoG during surgical resections did not actually tailor the resection solely based on ECoG findings (Ojemann, 1992). 557

Selected Results of Series Investigating the Prognostic Value of the Irritative Zone

Age Range (Years)

Rassi-Neto et al. (1999)

21

9–56

Lesional

Bautista et al. (1999)

13

17–56

Nonlesional: 9, lesional: 4

Sugano et al. (2007)

35

21.7 6 12.6†

Lesional

Temporal

Krendl et al. (2008)

55

34.7 6 8.1†

Nonlesional

Temporal

Tripathi et al. (2010)

157

Not provided

Nonlesional: 40, lesional 117

Jooma et al. (1995)

30

1–56

Cendes et al. (1993)

16

15–51

References

Copyright Ó 2013 by the American Clinical Neurophysiology Society

Lesional

Nonlesional: 14, lesional: 2

Temporal/ Extratemporal Both

Both but all extrahippocampal

Both

Temporal

Temporal

Main Findings Seizure freedom rate: 60% in 10 patients who underwent lesionectomy and 91% in 11 patients who underwent lesionectomy plus resection of the irritative zone Good seizure outcome (Engel classes I and II) in 7 patients with complete resection of the irritative zone and poor seizure outcome (Engel classes III and IV) in 6 patients with incomplete resection of the irritative zone Seizure freedom rate: 77% in 13 patients who underwent lesionectomy and 91% in 22 patients who underwent lesionectomy plus resection of the irritative zone Seizure freedom rate: 29% in 14 patients with $60 spikes/hour and 81% in 41 patients with ,60 spikes/hour Improvement from presurgical to postsurgical ECoG correlated significantly with good seizure outcome (Engel classes I and II): sensitivity: 100% (95% CI; 96– 100%); specificity: 68.3% (95% CI; 51.8–81.4%); positive predictive value: 89.9% (95% CI, 83.1–94.3%); negative predictive value: 100% (95% CI, 85–100%) Seizure freedom rate: 19% in 16 patients with lesionectomy and 93% in 14 patients with lesionectomy and resection of the perilesional irritative zone Similar interictal epileptiform activity after resection, regardless of epilepsy outcome

Prognostic Value of Interictal Spikes on Outcome According to This Study Correlated

Correlated

Correlated

Correlated

Correlated

Correlated

Not correlated

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No.Patients

Lesional/ Nonlesional*

I. Sánchez Fernández and T. Loddenkemper

558

TABLE 4.

(Continued )

No.Patients

Age Range (Years)

Lesional/ Nonlesional*

San-juan et al. (2011)

20

23–47

Nonlesional

Temporal

Benifla et al. (2006)

94

Not provided for the group of 94 patients with ECoG

Temporal

Wray et al. (2012)

52

Children (not provided for the group of 94 patients with ECoG) 0.25–17.4

Asano et al. (2009)

61

Wennberg et al. (1998)

References

Temporal/ Extratemporal

Nonlesional: 19, lesional: 33

Both

0.4–23

Lesional and nonlesional (numbers not specified)

Both

60

2–44

Nonlesional: 16, lesional: 44

Extratemporal (frontal)

Palmini et al. (1995)

18

0.4–16

Lesional

Both

Schwartz et al. (1997)

29

8–52

Nonlesional

Temporal

Main Findings

Prognostic Value of Interictal Spikes on Outcome According to This Study

Similar seizure outcome in 3 patients with and 17 patients without epileptiform activity detected by postsurgical ECoG The results of postoperative ECoG did not predict seizure outcome

Not correlated

Seizure freedom rate: 73% in 37 patients with postsurgical discharges and in 60% in 15 patients without postsurgical discharges Interictal spike frequency was correlated with seizure outcome in univariate analysis but did not correlate with seizure outcome after multivariate analysis A good seizure outcome (Engel class I) was highly correlated with the absence of epileptiform activity or its limitation to the resection border in postsurgical ECoG Excellent surgical outcome in 9/12 patients with complete resection of the irritative zone and in 0/6 patients with postsurgical persistence of the irritative zone Neither the presence nor the frequency of interictal spikes preor postsurgically correlated with seizure outcome

Not correlated

Not correlated

Not correlated

Correlated

Correlated

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Copyright Ó 2013 by the American Clinical Neurophysiology Society

TABLE 4.

Not correlated

*Lesions included tumors, malformations, vascular lesions, and infectious/inflammatory masses. Atrophy or mesial temporal sclerosis was not considered as lesional in this study. †Mean 6 standard deviation. Age range not available.

Electrocorticography

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Qualitative aspects of the epileptiform discharges such as amplitude, accompanying EEG features, morphology, or frequency may also influence outcome, but they have rarely been studied (Palmini et al., 1995; Stefan et al., 2008; Wu et al., 2010).

Postsurgical Interictal Spikes and Seizure Outcome There is no general agreement in the value of postoperative ECoG findings to predict seizure outcome (Nair and Najm, 2008). In a series of 80 patients with refractory temporal epilepsy, the presence of spikes in postresection ECoG was more frequent in patients with postoperative seizures (72%) than in seizure-free patients (47%) (Fiol et al., 1991). In contrast, in a study of 87 patients with temporal lobe epilepsy, postresection spikes and the change from preresection to postresection spikes did not correlate with seizure outcome (Kanazawa et al., 1996). In a series of 47 patients with medial temporal lobe epilepsy, there was no correlation between the presence or absence of postresection spikes and seizure outcome (Tran et al., 1995). In a study of 36 patients with brain tumor and seizures who underwent resection limited to the tumor margins, a correlation between preresection or postresection spikes, and seizure outcome could not be found (Tran et al., 1997). In a series of 94 patients with refractory temporal epilepsy, the presence of spikes in the postsurgical ECoG did not predict seizure outcome (Benifla et al., 2006). In another small study of 15 patients with refractory temporal lobe epilepsy, there was actually a nonsignificant tendency to better seizure outcome in patients with spikes than in patients without spikes in the postresection ECoG: seizure freedom was achieved by 8 of 10 (80%) patients with residual spikes and by 3 of 5 (60%) patients with no postsurgical spikes (Chen et al., 2006). These conflicting results may also be related to heterogeneous underlying mechanisms of spike generation seen on postresection ECoG. Postresection spikes are generally assumed to arise from unresected epileptogenic tissue with the potential to cause seizures. However, new spikes that were not present in the preoperative recording can be secondary to cortical isolation, to surgical trauma of the cortex, or to activation secondary to partial excision. Surgical isolation of normal cortex can cause a burst-suppression or spike burst-suppression pattern (Henry and Scoville, 1952; Hosain et al., 1995), and surgical injury to the cortex can cause postoperative spikes (MacDonald and Pillay, 2000; Schwartz et al., 2000). Both types of spikes are considered benign, that is, not able to produce seizures by themselves (Hosain et al., 1995; MacDonald and Pillay, 2000; Schwartz et al., 2000). Activation by partial excision may occur when a minor secondary focus that remained suppressed by its proximity to a dominant focus emerges after the resection of the primary focus. In most cases, this secondary focus is not able to trigger seizures by itself (Schwartz et al., 2000). In summary, not all types of spikes have the same prognostic significance: some are not related to the development of seizures after surgery and were classically termed “green spikes,” but others are related to the development of subsequent seizures and were classically termed “red spikes” (Rasmussen, 1983). Last but not least, the definition of a spike on ECoG remains controversial in different studies and may also account for some of the differences seen in outcome studies. We usually consider ECoG discharges epileptiform when a disruption of the background is present, when discharges are sufficient in amplitude to reflect a change greater than three times of the baseline amplitude variation, and when they are seen repeatedly in the same cortical area presenting with similar morphologic characteristics. Postresection ECoG might become of much greater value if 560

a means were found to distinguish new-onset benign spikes from pathologic spikes coming from residual epileptogenic tissue (Binnie et al., 2001). The localization of the postsurgical spikes may also play a role. A study of 140 patients with refractory mesial temporal lobe epilepsy showed that patients with hippocampal (but not cortical or parahippocampal) spikes in postresection ECoG had a significantly worse seizure outcome: an Engel class I seizure outcome was achieved in 29% patients with hippocampal spikes, in 73% patients who had no spikes in the hippocampus, and in 76% patients with no spikes at all (McKhann et al., 2000). In summary, there is evidence supporting the correlation between complete resection of the irritative zone and seizure outcome, but findings in the literature are not congruent. Occasionally, the finding of interictal spikes after epilepsy surgery justifies removal of additional tissue. The postresection ECoG may be of prognostic significance, especially when spikes are residual, not newly appearing spikes (Binnie et al., 2001).

Studies That Compare the Outcome of Epilepsy Surgery With and Without Electrocorticography The understanding of the role of ECoG in clinical practice has been limited by the fact that few studies have compared the outcome of patients who underwent ECoG-tailored resection with that of patients who underwent non–ECoG-tailored resection. In a series of 24 patients who underwent temporal resections, with 21 of them being ECoG tailored, it was concluded that limited resections of temporal structures were not associated with a poorer outcome as long as this decision was based on the distribution of epileptiform activity in presurgical ECoG, but it is not clear how the distribution of the epileptiform activity influenced the extent of surgical resection (Kanner et al., 1995). In a series of 42 patients with ECoGtailored temporal lobe resection, 27 (64.3%) had a Engel class I outcome after a median follow-up of 60 months (range, 44–121), but a comparison with patients who underwent non–ECoG-tailored temporal lobe resection was not available (Roberti et al., 2007). Another study comparing the postsurgical outcome of 20 patients who underwent temporal lobe resection tailored by ECoG and 19 patients who underwent temporal lobe resection without ECoG guidance found no significant differences in prognosis between the 2 groups: 75% patients with ECoG-guided resection and 79% patients with non–ECoG-guided resection became seizure free (Engel class I) (San-juan et al., 2011). The use of ECoG in this study was not randomized but was based on the availability of human and technical resources to perform the procedure, with the potential for selection bias (San-juan et al., 2011). The criteria for applying ECoG during surgery have been regarded as self-evident but have not been clearly defined or validated (Binnie et al., 2001). Randomized-controlled studies comparing the outcome of ECoG-tailored resections with non– ECoG-tailored resections in different epilepsy settings are not available and may be difficult to perform, as each case is unique. Although ECoG use may be evident in some cases, others may not require invasive monitoring. We suggest general indications during which ECoG may be helpful (Table 3 and Fig. 2).

SURGICAL CONSIDERATIONS Intracranial Recording The basic principle of intracranial recording has remained essentially the same since its introduction (Nair and Najm, 2008; Zumsteg and Wieser, 2000). The main types of electrodes used in Copyright Ó 2013 by the American Clinical Neurophysiology Society

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intracranial recordings are subdural electrodes in grid and strip arrays and depth electrodes. Foramen ovale electrodes and epidural electrodes are rarely used because of their limitations (Benbadis, 2000; Zumsteg and Wieser, 2000). Epidural electrodes do not allow cortical stimulation, unless a dural patch is cut to avoid stimulation of meningeal pain fibers, placement may be less accurate because sulcal anatomic landmarks are not apparent and is limited to the convexity of the brain and, therefore, cannot explore certain areas such as orbitofrontal or interhemispheric areas (Benbadis, 2000; Zumsteg and Wieser, 2000). Foramen ovale electrodes provide space-limited information and cannot detect seizure spread. In addition, there is the potential for false localization of an apparent seizure origin in the mesiobasal temporal lobe and missing the true origin outside this structure. Rare cases of subarachnoid hemorrhages or perforation of the brain stem have occurred (Zumsteg and Wieser, 2000). For all these reasons, epidural electrodes and foramen ovale electrodes have been largely supplanted by subdural and depth electrodes (Benbadis, 2000; Zumsteg and Wieser, 2000).

Metallurgy and Biological Safety of Subdural Electrodes Subdural electrodes are circular disks with a ball-shaped tip that facilitates brain contact (Blume and Holloway, 2011; Nair and Najm, 2008). Recording electrodes are usually made of platinum– iridium or stainless steel and some made of carbon or silver. On a theoretical basis, platinum should be slightly more stable than stainless steel when current is passed. However, the possibly greater instability of stainless steel, with possible diffusion of metal ions across the electrode–pial interface, should only be significant over

Electrocorticography

longer periods of stimulation than seen in clinical practice (Lesser and Gordon, 2000). Therefore, especially for intraoperative ECoG, the practical differences between metals in terms of safety should be relatively minor. Slightly different electrodes are usually used for intraoperative stimulation. Carbon-ball electrodes, silver probes, or silver balls can be used. Because these are used only acutely, the biological safety issues raised in the previous paragraph do not apply (Lesser and Gordon, 2000).

Subdural Grid Arrays Intracranial recording is classically performed using 2- to 5mm-diameter disk electrodes embedded in silicon elastometer (Nair and Najm, 2008; Ritaccio et al., 2011; Schevon et al., 2008). Electrodes are arrayed in linear dispositions and typically separated 10 mm from center to center (Ritaccio et al., 2011). The electrodes are placed between the dura and the arachnoid or placed on the exposed surface of the brain with the connecting wires exiting through a scalp incision (Ritaccio et al., 2011). Electrodes are distributed in a linear disposition in flexible strips or grids. Montages using angulated electrode placement should be avoided, because this can lead to false localization (Keene et al., 2000). For appropriate localization, the electrodes are placed in an equal distance apart (both in horizontal and vertical planes) and usually consist of a minimum of four electrodes in a straight chain (Keene et al., 2000). Electrode arrays can be placed in a highly variable distribution and shape to adapt to the areas of interest of the individual patient (Figs. 3 and 4). Depending on the area of interest and the clinical needs, strips consisting of 4 to

FIG. 3. Variability in the distribution of the electrode arrays based on individual epilepsy presentation. A, Extensive cortical coverage of the right pericentral area. B, Coverage of the left temporal lobe. C, Coverage of the right frontal area. Copyright Ó 2013 by the American Clinical Neurophysiology Society

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Biophysical Properties Independent of the electrode array, the reference electrode for recordings may be located over the contralateral scalp or a distant relatively normal or quiet cortical area. Use of a referential montage permits the identification of complex electrical spike fields including those created by dipoles that are often seen in ECoG (Blume and Holloway, 2011). Referential recording also avoids partial or complete “bipolar cancellation” of potentials that may be widespread in the ECoG recording field (Blume and Holloway, 2011). Because voltage of ECoG potentials are approximately 5 to 6 times higher than those of scalp recordings, usually around 300 to 500 mV, sensitivities are often set around 30 to 70 mV/mm (Blume and Holloway, 2011). Cerebrospinal fluid “bathes” the electrode environment during chronic recording, and fluid is irrigated during intraoperative recording. Therefore, it should be expected that a certain amount of current would be shunted during stimulation, with the exact amount varying in different settings (Lesser and Gordon, 2000). FIG. 4. Different macroelectrode strips for chronic and intraoperative intracranial recording.

8 electrodes or larger rectangular arrays of 64 electrodes or more may be used. For example, some centers place strips of 1/4 to 1/8 electrodes under the temporal lobe approaching mesial temporal regions to record from mesial temporal and basal temporal areas. Larger rectangular arrays ranging from 2/4 to 2/8 to 8/8 electrodes can be used, again depending on the clinical need, and these arrays can be tailored to fit the configuration of the suspected epileptogenic cortex (Lesser and Gordon, 2000) (Figs. 3 and 4). The array of subdural electrodes need to be placed on the leptomeninges, move with the pulsations of the brain, and should be flexible enough to minimize the risk of episodes of vessel thrombosis and increased intracranial pressure (Keene et al., 2000; Wong et al., 2009). By the same token, they should not move on closure of the operating field. Accurate placement can be difficult, in particular in mesial interhemispheric areas, because of subdural bridging veins, and may also pose a challenge in patients with previous brain surgeries because of adhesions and scarring. Rupture of bridging veins may lead to difficult to stop bleeding and even patient’s death. Therefore, electrode placement is dependent on the anatomic situation and on the experience of the surgeon (Zumsteg and Wieser, 2000). Subdural electrodes are best for recording the electrical activity of the neocortex.

Depth Electrodes and Areas That Are Difficult to Access To record from more difficult to access structures (such as the mesial temporal/frontal regions), either a flexible silastic grid can be inserted under the temporal/frontal region to reach the deeper structures or contact depth electrodes can be inserted through the brain (Keene et al., 2000). Depth electrodes are penetrating linear probes with multiple cylindrical contacts of 1.1 mm diameter and variable length and spacing, typically 4 to 12 contacts spaced 5 to 10 mm apart (Ritaccio et al., 2011; Zumsteg and Wieser, 2000). Depth electrodes are more invasive than subdural electrodes and, therefore, they are restricted to the detection of epileptiform activity in gray matter locations that cannot be accessed by other types of electrodes (Zumsteg and Wieser, 2000). Multiple depth electrode recordings can be instrumental when recording stereo-EEG tracings (Cossu et al., 2005). 562

Electrocorticography Duration The total recording time for an ECoG session is usually approximately 30 minutes, although longer times are occasionally necessary (Keene et al., 2000). In adults, the ECoG recording and, in particular, stimulation is usually done with the patient in the awake state; however, this may be often more difficult in children (Keene et al., 2000).

Complications Associated With Intracranial EEG Recording Implantation of intracranial electrodes during ECoG may be associated with undesirable morbidity and mortality. Unfortunately, there are no data on the specific complications of ECoG. Some information on complications may be inferred from studies on chronic invasive monitoring (Table 5). The most common complications during chronic recordings are cerebrospinal fluid leaks, meningitis, wound infection, hemorrhages/hematomas, transient or permanent neurologic deficits, and cerebral edema. Death as a complication of intracranial monitoring is a very rare event (Table 5) (Adelson et al., 1995; Burneo et al., 2006; Hamer et al., 2002; Johnston et al., 2006; Musleh et al., 2006; Önal et al., 2003; Wong et al., 2009). Some studies found a direct correlation between frequency of complications and number of electrodes, size of the grids, and/or duration of the intracranial recordings (Hamer et al., 2002; Önal et al., 2003; Wong et al., 2009). In contrast, other series did not reproduce this correlation (Burneo et al., 2006; Johnston et al., 2006; Musleh et al., 2006). These conflicting results may be partially attributed to: (1) a rate of complications that is too low to study correlations in some smaller series (Burneo et al., 2006; Johnston et al., 2006; Musleh et al., 2006), (2) different surgical techniques and varying criteria used in the definition of complications that hamper direct comparisons between the different studies (Burneo et al., 2006; Hamer et al., 2002; Johnston et al., 2006; Musleh et al., 2006; Önal et al., 2003; Wong et al., 2009), and (3) improvements in grid technology, surgical technique, and postoperative care, in addition to the individual institutional learning curve as suggested by the decreasing rate of complications in a large series with data from 17 consecutive years over time at 1 center (Hamer et al., 2002). When compared with chronic intracranial recordings, ECoG requires a lower number of electrodes, smaller electrode arrays, and, especially, much shorter duration of intracranial recordings. Therefore, the rate of complications in ECoG is expected to be inferior than in Copyright Ó 2013 by the American Clinical Neurophysiology Society

Complications Related to Chronic Implantation of Intracranial Subdural and Depth Electrodes

Study Johnston et al. (2006)

Median Age (Range) in Years

No. Patients (No. Implantation Procedures)

Mean (Range) of Monitoring Period in Days

10.9 (0.83–21.7)

112 (122)

7.1 (2–21)

22 (18)

Global Rate of Complications (%)

Burneo et al. (2006)

32 (9–65)

116 (116)

12.3 (3–29)

6 (5.2)

Hamer et al. (2002)*

24 (1–50)

187 (198)

11.6 (1–34)

52 (26.3)

Önal et al. (2003)

35 (35)

5 (3–10)

Not specified†

Adelson et al. (1995)

11 (1–18)

31 (31)

11 (3–23)

5 (16.1)

Wong et al. (2009)*

24 (10–51)

71 (71)

7 (NS)

18 (25.4)

Musleh et al. (2006)

11 (4–20)

29 (33)

7.2 (3–14)

2 (6.1)

563

*Did not include mild cerebrospinal fluid leak as a separate complication in the analysis. †Very high rate of transient neurologic complications. NS, not specified.

N (%) 7 (5.7) 4 (3.3) 3 (2.5) 3 (2.5) 2 (1.6) 1 (0.8) 1 (0.8) 1 (0.8) 0 (0) 3 (2.6) 1 (0.9) 1 (0.9) 1 (0.9) 1 (0.9) 0 (0) 24 (12.1) 22 (11.1) 5 (2.5) 5 (2.5) 3 (1.5) 1 (0.5) 7 (20) 5 (14.3) 5 (14.3) 4 (11.4) 3 (8.6) 1 (2.9) 0 (0) 27† 4 (12.9) 1 (3.2) 0 (0) 0 (0) 1 (1.4) 5 (7) 1 (1.4) 4 (5.6) 3 (4.2) 1 (1.4) 1 (1.4) 1 (1.4) 2 (2.8) 1 (1.4) 2 (2.8) 2 (6.1) 0 (0) 0 (0) 0 (0)

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11.7 (2–19)

Complications Need for repeated surgery for additional electrode placement Transient neurological deficits Aseptic meningitis Wound infection Cerebrospinal fluid leak Subdural hematoma Strip electrode fracture Symptomatic pneumocephalus Death Intracranial hemorrhage Meningitis Aseptic meningitis Transient neurologic deficits Status epilepticus Death Infection Transient neurologic deficit Epidural hematoma Increased intracranial pressure Infarction Death Cerebrospinal fluid leaks Cerebral edema Subdural hematoma Intracerebral hematoma Wound infection Meningitis Death Permanent neurologic complication Cerebrospinal fluid leaks Subdural hematoma Infection Death Significant cerebrospinal fluid leak Subdural hematoma Cerebral infarction Transient neurologic deficit Motor weakness Hemianopia Drowsiness Cerebral edema Osteomyelitis Status epileticus Death Wound infections Cerebrospinal fluid leaks Cerebral edema Death

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TABLE 5.

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chronic intracranial recordings. In summary, ECoG is considered to be a safe technique, and possible complications may be related to craniotomy and epilepsy surgery but can rarely be attributed to the ECoG procedure itself.

FACTORS THAT MODIFY THE EPILEPTIFORM ACTIVITY Conditions that may activate the epileptiform activity during ECoG include electrical stimulation of the cortex, antiepileptic drug reduction/withdrawal, several different anesthetic agents, and surgical trauma to the brain. These factors may increase spike frequency, the size of the irritative area, or the number of independent spike-generating foci.

Electrical Stimulation of the Cortex Electrocorticography is not limited to a passive recording of spontaneous brain electrical activity. While ECoG is performed, an electrical stimulus can be delivered between 2 electrodes (Keene et al., 2000). Examples for electrical stimulation paradigms include a diphasic pulse of 0.3 to 2 miliseconds applied at 50 to 60 Hz during 1 to 5 seconds with an intensity of 0.5 to 2 mA and a voltage of 1 to 15 V (Blume and Holloway, 2011; Keene et al., 2000). The stimulus can be progressively increased in steps of 1 to 2 mA up to 15 to 18 mA (Blume and Holloway, 2011; Schulz, 2008). Electrical stimulation of the cortex can elicit after discharges, subclinical EEG seizure patterns, habitual or nonhabitual auras, and habitual or nonhabitual clinical seizures (Schulz, 2008). Available data on cortical stimulation mainly derive from chronic intracranial recordings. Electrically induced auras and seizures frequently correlate with their spontaneous counterparts. In a series of 16 patients in whom electrical stimulation elicited habitual auras, the zone of auras correlated with the spontaneous seizure-onset zone in 12 patients (75%) (Schulz et al., 1997). In a study of 126 patients, the concordance between the site of the electrically induced auras or seizures with the spontaneous seizure-onset zone was 88% to 100% in patients with a single unilateral focus. Patients with more than 1 focus showed a decreased rate of concordance (Bernier et al., 1990). In contrast, after-discharge thresholds were not reliable predictors of the spontaneous seizure-onset zone (Bernier et al., 1990). In a study of 29 patients, neither after discharges, after discharges evolving to clinical seizures, or after discharges exceeding 10 seconds correlated topologically with the seizure-onset zone (Blume et al., 2004). Therefore, the localizing value of auras and clinical seizures seems superior to the localizing value of after discharges. In clinical practice, the contribution of intraoperative electrical stimulation to the localization of the epileptogenic zone is limited because: (1) after the occurrence of after discharges, stimulation should be stopped to avoid the risk of inducing seizures and (2) the duration of stimulation is usually kept at a minimum duration, reducing the chances of induced auras (Schulz, 2008). Consequently, scarce literature is available, and the value of electrical stimulation for informing postsurgical seizure outcome is not clear (Schulz, 2008). Mapping eloquent cortex, therefore, remains the main and usually sole purpose of electrical stimulation during ECoG (Blume and Holloway, 2011). Although extensive intrasurgical stimulation of the cortex for cortical mapping of eloquent areas was a standard procedure in earlier days of epilepsy surgery, improved extraoperative imaging techniques might have taken part of its room. In addition, stimulation results from chronic subdurally implanted grid recordings are often more reliable because of lack of confounders 564

such as anesthesia and lack of major time constraints during surgery. It continues to be helpful for the intraoperative delineation of language areas or the primary motor cortex (Schulz, 2008), if chronic subdural electrodes are not used.

The Influence of Antiepileptic Drug Reduction or Withdrawal on Epileptiform Activity To increase the chance of seizure occurrence during intracranial recordings, antiepileptic drugs are reduced or withdrawn during chronic subdural recordings. In a series of 35 patients, absent or subtherapeutic antiepileptic drug levels led to an increase in seizure frequency (Marks et al., 1991). In a study of 40 patients with refractory complex partial seizures, rapid antiepileptic drug reduction/ withdrawal caused a rebound effect: the frequency of focal seizures increased from baseline in 16 of 23 patients, and focal seizures appeared in 12 of 17 patients without focal seizures at baseline. The frequency of generalized seizures increased from baseline in 5 of 6 patients and generalized seizures appeared in 21 of 34 patients without generalized seizures at baseline (Marciani et al., 1985). In short, seizures occur more frequently when antiepileptic drugs are reduced or completely withdrawn. A potential concern with this provocation technique is that seizures after drug reduction or withdrawal could potentially be different from habitual seizures seen during medication treatment. In a series of eight patients, seizures increased in frequency, and secondary generalization was more often seen after drug reduction or withdrawal. In contrast, the localization and the morphology of the discharges at onset, the time to contralateral spread, and the coherence of EEG discharges did not change (So and Gotman, 1990). In a study of 33 patients, seizure frequency and duration increased after drug reduction/withdrawal, but the EEG seizure onset and the initial ictal signs showed no obvious changes (Zhou et al., 2002). In a series of 25 patients, most EEG and clinical features did not change after drug reduction/withdrawal. In this series, patients with multifocal seizures had these also before medication withdrawal, or multifocality was discovered after epilepsy surgery (Spencer et al., 1981). Together, these results suggest that seizures that occur during drug reduction/ withdrawal are usually an accurate sample of the baseline seizures. However, during seizure clusters after medication withdrawal, some areas of the brain can start to seize that usually do not spontaneously generate seizures. The appearance of a new area of seizure generation exclusively during drug reduction/withdrawal should be interpreted with caution and should not exclude the possibility of epilepsy surgery. Atypical seizures may represent a temporarily increased irritability focus secondary to the primary focus, a direct irritation from the intracranial electrodes, or may signal the presence of a latent epileptogenic focus that may be controlled with antiepileptic drug therapy (Engel and Crandall, 1983; Skidmore and Sperling, 2008). In summary, drug reduction/withdrawal increases seizure frequency and the overwhelming majority of resulting seizures display typical baseline EEG and clinical features. Atypical localizations that occur exclusively during intracranial recordings should be interpreted with caution.

The Influence of Anesthetic Agents in Epileptiform Activity Anesthetics and other medications used during ECoG may affect the EEG findings during the procedure. A study of 21 children compared epileptiform activity during both intraoperative ECoG under isofluorane anesthesia with during extraoperative ECoG Copyright Ó 2013 by the American Clinical Neurophysiology Society

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monitoring. Spike frequency was significantly decreased during intraoperative than during extraoperative ECoG (Asano et al., 2004). The pattern of discharges during intraoperative ECoG correlated well with the pattern seen during extraoperative ECoG only when discharges were frequent (more than 1 per minute) (Asano et al., 2004). With most anesthetic agents, beta activity initially increases, and then a mixture of theta and delta appears diffusely (Blume and Holloway, 2011). Drugs that have been reported to enhance epileptiform activity include methohexital (Wilder et al., 1971), fentanyl (Manninen et al., 1999), alfentanyl (Keene et al., 1997; Manninen et al., 1999), propofol (Hewitt et al., 1999; Smith et al., 1996), and thiopental (Hewitt et al., 1999). Isoflurane and sevoflurane decreases (Endo et al., 2002; Ito et al., 1988) or increases (Watts et al., 1999) epileptiform activity, and this pattern of both enhancing and reducing epileptiform discharges in different situations has been reported for many anesthetics (Kofke et al., 1997). Factors such as concomitant medications, the susceptibility of the individual patient, and, especially, the different doses of the drug (Fiol et al., 1993) can explain these different responses. In summary, EEG findings during anesthesia should be interpreted with caution and the influence of an individual drug varies in different situations and in different patients.

Surgical Trauma to Brain Surface The irritation produced by intracranial electrodes might cause epileptiform activity by itself. In a series of seven patients with brain tumor, two patients who did not have spikes or seizures before surgery developed spikes (but not seizures) after surgery. Therefore, surgical irritation of the neocortex might be sufficient to produce reactive epileptiform discharges even in the absence of preoperative seizures and spikes (Schwartz et al., 2000). During electrical stimulation of the brain, there is the theoretical potential for kindling, that is, the decrease in the susceptibility of the brain to epileptogenesis because of recurrent electrical stimulation or ongoing seizure. The stimulation intervals used for functional localization tend to be less epileptogenic, and the primate cortex and likely also the human cortex may be less likely to be kindled than other brain areas in many other species. To date, there is no clear evidence of a decreased seizure threshold in the brain areas that are subject to functional localization by means of stimulation (Lesser and Gordon, 2000). Electrode placement can potentially cause histologic damage in the cortex. In a histologic study of the brain tissue under subdural electrodes in three patients with anterior temporal lobe resection, mild diffuse gliosis of cortical layers I and II and an increase in mononuclear inflammatory cells in the subarachnoid space were present (Gordon et al., 1990). There was also an increase in periodic acid-Schiffe–positive granules in cortical layers I and II. These findings were interpreted as a foreign body reaction to the silastic sheet. In addition, there were focal microhemorrhages in the deep cortical layers with adjacent eosinophilic neurons that were interpreted as acute surgical artifact. However, there were no differences in histologic features, which could be correlated with the presence of electrodes per se (Gordon et al., 1990). Based on the available information, current electrical stimulation paradigms of the cortex during human clinical procedures do not seem to cause histological damage (Girvin, 1988; Gordon et al., 1990).

TECHNICAL ASPECTS FOR THE RECORDING EQUIPMENT

Electrocorticography

sampling, a process of measuring the amplitude of the continuous signal at regular intervals and converting each sample into a digital value. Sampling at points that are too close can generate excessive, correlated, and redundant data. Sampling at points that are too distant leads to aliasing: averaging of different values in a relatively long period of time. In general, sampling rate should ideally be three to four times higher than the fastest relevant component of the original data (Burgess, 2000b). The classic sampling rate was around 200 Hz, because frequencies above 70 Hz were considered to bear not clinically useful information. However, the increasingly recognized relevance of high-frequency oscillations (HFOs) (see below) is shifting sampling rates in ECoG toward 1000 to 2000 Hz (Zijlmans et al., 2012) or even higher (Usui et al., 2010) to prevent aliasing when analyzing higher frequencies.

Amplification EEG currents are extremely weak. The signals collected by scalp electrodes are attenuated by the meninges, cerebrospinal fluid, bone, and scalp. Although the intracranial electrodes in ECoG record directly from the brain surface (or through the pial layer of the meninges), the signal still requires amplification. For an amplifier to faithfully represent an event, the amplifier must have: (1) amplitude linearity: the relationship between input and output signals must be linear, (2) adequate bandwidth: the amplifier should amplify signals centered in the range of frequencies that are relevant to what is wanted to measure, (3) phase linearity: the shifts in time should be equal for all the frequencies, and (4) low noise: signals generated within the instrumentation should be minimized and should not interfere with the recorded signal. Deviations from these parameters can significantly disrupt the quality of the ECoG recording (Burgess, 2000b).

Filtering Intracranial EEG recordings are subject to fewer artifacts than scalp EEG, but filtering is still necessary. High-quality electrode contact is the foremost prerequisite for high-quality recording and this aspect is particularly relevant in intracranial recording where irregular brain surface can significantly disrupt the signal. No amount of artifact rejection or filtering can make up for poor-quality electrode contact. The objective of filtering is to make the waveform of interest standout from the background. To achieve this objective, the filter selectively amplifies the signal of the frequency bands of interest while markedly attenuating others. Although current digital filters represent an improvement compared with predigital technology, the ideal filter (that allows the pass of the wanted signals while attenuating the unwanted completely) is not realizable based on available technology. Therefore, the processed EEG tracing will always have some attenuation of the signal of interest and some amount of unwanted signal may persist (Burgess, 2000b).

Archiving EEG signal digitalization and increasing computer-storing capacity have allowed the increase in number of recording electrodes and sampling frequency.

Sampling

Electrical Safety

At present, most EEG signals are processed digitally. Analogto-digital conversion of the raw, amplified signal is done by

The recording and stimulating electrodes are purposefully low resistance to transmit the small voltage changes generated in the

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brain cortex or the small stimulating current. These low-resistant pathways can transmit unwanted electrical currents through the brain. Other potential sources of electrical currents are medical devices such as electrocardiogram monitors or catheters, metal objects such as bed frames, or personal devices such as radios or computers (Burgess, 2000a). The transmission of unwanted current can lead to the generation of EEG artifacts or even to electrical brain shock. These risks can be reduced by: (1) using power receptacles and adaptors with a ground prong, (2) connecting all the patientassociated equipment to 1 cluster of power receptacles, ideally with separation between lines and with removal of other sources of power from the patient environment, and (3) avoiding contact between the patient and low-resistant pathways such as metal beds, plumbing, metal architectural elements, or liquids (Burgess, 2000a).

MICROELECTRODES, ICTAL DIRECT CURRENT SHIFTS, MICROSEIZURES, AND HIGH-FREQUENCY OSCILLATIONS Microelectrodes and High-Density Arrays The electrodes used for intracranial recordings are classically around 3 to 5 mm in diameter with a distance of 1 cm between electrodes. They reflect the sum of the electrical potentials generated in their underlying cortex and cannot differentiate electrical activity in a submillimeter scale (Schevon et al., 2008). The search for a more precise localization and delineation of the cortical areas of interest has led to the use of closely spaced electrodes. Conventional intracranial macroelectrodes can be placed at a closer distance of 5 mm instead of the classical 1-cm separation from center to center (Neelon et al., 2006). Smaller electrodes are being developed to diminish electrode area of recording and interelectrode spacing. Two different studies on motor cortex mapping used epipial microelectrodes separated by 1 or 2 mm (Kellis et al., 2009; Leuthardt et al., 2009). A study of 14 patients with epilepsy and 2 patients with intractable facial pain performed intracranial recording with a total of 780 macroelectrodes of 1 to 10 mm2 area and interelectrode spacing of 10 mm and 756 microelectrodes of 1023 mm2 area and interelectrode spacing of 0.5 to 1 mm (Stead et al., 2010). In a study of 5 patients who underwent presurgical monitoring, interelectrode spacing was as low as 400 mm (Schevon et al., 2008). New technical approaches in electrode array development are oriented to: (1) the use of ultrahighdensity arrays with minimum electrode size and minimum interelectrode space to get maximal spatial resolution (Hollenberg et al., 2006; Rubehn et al., 2009; Thongpang et al., 2011), (2) the limitation of the number of wires, despite the increasing number of electrodes (Ritaccio et al., 2011), (3) the use of ultraflexible film electrodes to achieve maximal stability of the contact between electrode and cortex without applying significant pressure to the brain (Hollenberg et al., 2006; Rubehn et al., 2009; Thongpang et al., 2011), (4) the placement of electrodes in the epidural space keeping the dura intact to limit risk of infection and trauma to the underlying brain (Ritaccio et al., 2011), and (5) the transmission of data in a wireless manner to reduce the risk of infection further (Aceros et al., 2011; Borton et al., 2011).

Ictal Direct Current Shifts Ictal direct current shifts represent sustained paroxysmal depolarization shifts occurring in epileptic neurons and, thus, reflect the epileptogenic nature of neurons and adjacent glial cells in the epileptogenic area. On the EEG tracing, direct current shifts are 566

mainly seen as electrodecremental pattern or rhythmic fast activity and often occur during the initial phases of a seizure. Direct current shifts are better visualized with subdural electrodes rather than with scalp electrodes. They have been shown to specifically localize the ictal onset zone and, therefore, deserve further study (Ikeda, 2008).

Microseizures The use of ever smaller microelectrode arrays (Fig. 5) is providing relevant insights into seizure and epilepsy generation. Microseizures and microperiodic epileptiform discharges are highly focal low-frequency epileptiform-appearing events recorded from the neocortex (Schevon et al., 2008; Schevon et al., 2009). Microseizures and microperiodic epileptiform discharges seem to be frequent in the cortex and occur even in nonepileptic patients (Schevon et al., 2008; Stead et al., 2010). Microperiodic epileptiform discharges seem to originate at a highly focal source location, likely within a single cortical macrocolumn (Schevon et al., 2008, 2010). It has been hypothesized that seizures occur only when these discharges interact with similar discharges in other areas and spread (Schevon et al., 2008; Stead et al., 2010).

High-Frequency Oscillations In the past, EEG frequencies above 80 Hz were considered as not conveying clinically relevant information. In recent years, the widespread use of digital intracranial EEG recordings has allowed a more detailed analysis of HFOs and a better understanding of their role as biomarkers of the epileptogenic tissue. The definition of HFO is still in progress including the following suggestions: (1) waves with at least 4 consecutive oscillations different from baseline in the 80- to 500-Hz range (Jacobs et al., 2008) or (2) waves with a duration of at least 6 milliseconds and more than 6 peaks (positive plus negative) greater than 3 standard deviations above mean baseline in the 100- to 500-Hz range (Staba et al., 2002). High-frequency

FIG. 5. Different microelectrode arrays for electrocorticography (ECoG). Flexible thin-film micro-ECoG devices can be manufactured in a variety of sizes and configurations to acommodate various sizes, brain regions, and insertion methods. Reproduced with permission from Ritaccio et al., (2011). Copyright Ó 2013 by the American Clinical Neurophysiology Society

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oscillations are subclassified into ripples (80–250 Hz) and fast ripples (.250 Hz) (Zijlmans et al., 2012).

High-Frequency Oscillations as Biomarkers of the Epileptogenic Process High-frequency oscillations seem to reflect the intrinsic epileptogenicity of brain tissue. In an animal model of kainateinduced status epilepticus, all 19 animals with HFO after kainateinduced status epilepticus developed recurrent spontaneous seizures, whereas none of the 7 animals without HFOs after kainate-induced status epilepticus developed spontaneous seizures (Bragin et al., 2004). In the same study, the sooner the HFO appeared, the sooner clinical seizures developed and the higher the frequency of these seizures (Bragin et al., 2004). These observations are consistent with the hypothesis that HFO reflect the development of epileptogenic neuronal networks (Bragin et al., 2004). In addition, HFO seem to dynamically reflect the changes in epileptogenicity at different time points as suggested by a series of 12 patients in whom the reduction in antiepileptic drugs resulted in an increase of rates and mean duration of HFO (Zijlmans et al., 2009).

High-Frequency Oscillations as Localizers of the Epileptogenic Area The capacity of HFO to localize epileptogenic tissue is being intensively studied with encouraging results. In a series of 10 patients, the seizure-onset zone was better predicted by the HFO than by the interictal spikes (Jacobs et al., 2008). In a study of 20 patients, the area of HFO-generating tissue removed during surgery was larger in the 8 patients with a good outcome (Engel classes I and II) than in the 12 patients with a poor outcome (Engel classes III and IV) (Jacobs et al., 2010a). In addition, the HFO-generating area was a more useful predictor of good surgical outcome than the spikegenerating area or the seizure-onset zone (Jacobs et al., 2010a). In a series of 24 children studied with intraoperative ECoG, because of refractory epilepsy, all 19 patients with complete resection of the fast ripple–generating tissue became seizure free, whereas 5 of 5 children with incomplete resection of the fast ripple–generating tissue had remaining seizures after surgery (Wu et al., 2010). The potential impact of fast ripples on epilepsy surgery decision making is illustrated by the fact that 6 of 24 (25%) children in the study by Wu et al. (2010) may have undergone a resection different from the one that was actually performed if interictal fast ripples had been known at the time of surgery. There is an ongoing discussion whether HFO may be a nonspecific abnormal brain tissue signal unrelated to the epileptogenic zone, but several studies point in the direction of HFO as a specific marker of epileptogenicity. In a series of 12 patients with refractory epilepsy and different underlying lesions, the rates of HFO were more related to the areas involved in seizure generation than to the lesional areas (Jacobs et al., 2009). Another study of seven patients with refractory epilepsy suggested that the rate of occurrence of ripples within the seizure-onset zone was higher than outside the seizure-onset zone in four of seven patients and the rate of fast ripples was much higher within the seizure-onset zone than outside the seizure-onset zone in the four of five patients with fast ripples (Urrestarazu et al., 2007). In an animal model, fast ripples were shown to localize the epileptogenic area even when no underlying lesion and no neuronal loss were present (Jiruska et al., 2010b). In a series of 17 patients with nonlesional refractory focal seizures, interictal spikes identified the seizure-onset zone with a specificity of 30%, whereas the specificity of interictal ripples was 42% and of interictal fast ripples of 80% (Andrade-Valença et al., 2012). In Copyright Ó 2013 by the American Clinical Neurophysiology Society

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a study of 25 patients with intracranial EEG monitoring, interictal spikes varied in location between the interictal and the ictal periods, but the HFO remained located in the same area (Zijlmans et al., 2011). If these data are widely reproduced in different epilepsy centers, the area generating HFO may contribute to decision making in the presurgical evaluation of refractory epilepsy.

Clinical Application of High-Frequency Oscillations in Presurgical Evaluation The role of HFO in the presurgical evaluation of patients remains to be established, but initial results seem promising. In two patients with refractory focal seizures, resection of the areas with prominent HFO led to seizure freedom (Akiyama et al., 2005, 2006). In addition to spontaneous HFO, electrical microstimulation can induce HFO, as demonstrated in animal models (Rolston et al., 2010). These electrically induced HFO seems to reliably reflect the areas of spontaneous HFO: in a series of 20 patients, areas with spontaneous HFO correlated well with the areas of low threshold for electrically induced HFO, even in areas outside the seizure-onset zone (Jacobs et al., 2010b). If electrical stimulation is found to reliably reproduce HFO in the human brain and these HFO are demonstrated to be good biomarkers of the epileptogenic area, timing of the presurgical evaluation could be significantly reduced and associated complications may be minimized.

High-Frequency Oscillations and the Development of Seizures High-frequency oscillations may also provide additional insights into how epileptogenic tissue is able to generate seizures. The relationship of HFO and seizures is not completely understood, but it has been proposed that seizures occur when clusters of neurons generating fast ripples increase in size and coalesce with other clusters of neurons generating fast ripples (Bragin et al., 2000, 2002a). In several experimental models of epilepsy, an increase in the HFO is detected in the transition from the interictal to the preictal period (Jiruska et al., 2010a; Khosravani et al., 2005). In a series of 25 patients, HFO built up before seizure onset (Zijlmans et al., 2011). This increase in HFO during the preictal period is shown in both seizures of mesial temporal origin (Khosravani et al., 2009; Kobayashi et al., 2010) and seizures of neocortical origin (Worrell et al., 2004). Therefore, the possibility that HFO reflect a common underlying mechanism of seizure genesis merits further investigation.

Technical Requirements for Recording High-Frequency Oscillations Both microelectrodes and intracranial macroelectrodes can record HFO. A substantial difference is that, although microelectrodes can record ripples and fast ripples, macroelectrodes tend to record HFO in the ripple band and rarely record fast ripples (Worrell et al., 2008). The EEG needs to be sampled at around four times (or at least twice) the upper frequency of interest, because it takes several samples to form the wave shape: therefore, to properly analyze HFO, a sampling frequency of at least 2000 Hz should be considered (Zijlmans et al., 2012). High-frequency oscillations are sometimes recognizable in the unfiltered EEG (Jiruska et al., 2010b; Urrestarazu et al., 2007), but to make HFO detection easier, a high-pass filter is applied and the EEG amplitude is increased. The process of filtering the EEG signal can create “false” HFO that can be difficult to differentiate from “true” HFO (Bénar et al., 2010). Detection of HFOs by the human reviewer includes subjective components and extremely time consuming (Zelmann et al., 2009), but several 567

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automatic or semiautomatic algorithms for the detection of HFO have been proposed with encouraging results (Firpi et al., 2007; Gardner et al., 2007; Staba et al., 2002). Automated methods to accurately detect HFO may change the landscape of presurgical evaluation of epilepsy and may shorten the assessment time. It is tempting to hypothesize that microseizures and HFO represents two different manifestations of the same underlying process. The limited spatial extent of both microseizures and microdischarges is consistent with the restricted distribution previously demonstrated for HFO (Bragin et al., 2002b; Worrell et al., 2008). At present, however, any relationship between epileptiform micro-EEG features and HFO remains to be demonstrated (Schevon et al., 2008).

OUTLOOK The development of ultrahigh-density electrode arrays with an optimized contact to the cortical surface will provide a much more detailed representation of the cortical electrical activity in the near future (Bink et al., 2011; Kim et al., 2010a; Ritaccio et al., 2011; Viventi et al., 2011). This technical development may shed additional light on the role of microseizures and HFO in seizure generation at a microscopic level (Schevon et al., 2008; Stead et al., 2010; Zijlmans et al., 2012). The better understanding of the process of ictogenesis will open new therapeutic windows for seizure warning and preventive stimulation devices (Stead et al., 2010). In parallel, the analysis of high discharging frequencies is providing exciting results. In a small series of 5 patients with refractory neocortical epilepsy secondary to malformation of cortical development, very high frequency oscillations (1000–2500 Hz) were detected interictally and at seizure onset. The interictal very high frequency oscillations were interrupted by spikes, whereas the preictal very high frequency oscillations were sustained and uninterrupted during seizure onset. The area of very high frequency oscillation was always located within the seizure-onset zone, the irritative zone, and the area of HFO. Therefore, very high frequency oscillations deserve further study and may provide insights into epileptogenesis and ictogenesis (Usui et al., 2010). It has been shown that short-term recordings (around 10 minutes) during intraoperative ECoG can detect spontaneously occurring HFO that markedly correlate with seizure outcome (Wu et al., 2010). Once automated methods permit real-time HFO detection in the operating room, ECoG may potentially provide a straightforward and accurate way of determining the cortical area to be resected (Wu et al., 2010) if available data are confirmed. Novel ECoG source localization techniques may provide threedimensional and stereo-EEG information and help to define the resection area when it is in a deep sulcus or beyond recording planes (Kim et al., 2010b). Electrical stimulation of the cortex has been useful for delineating both the epileptogenic area and eloquent areas. In the future, electrically evoked HFO may substitute electrically evoked spikes for the localization of the epileptogenic area, as suggested by a study in which single pulse-evoked fast ripples had a specificity of 79% for the localization of the seizure-onset zone, whereas single pulse-evoked spikes had a specificity of 17%. In addition, 5 of 7 patients with ,50% fast ripples removed by resection had a poor outcome (van’t Klooster et al., 2011). Functional mapping of eloquent cortex may decrease the need for cortical electrical stimulation further, as suggested by a study in which performance of a task during passive recording of cortical activity correlated well with the eloquent areas (Brunner et al., 2009). 568

Technological advances may continue to increase indications of ECoG in epilepsy (Table 3). In addition, the growing field of brain–computer interfaces promises to develop even further applications for intracranial recordings and stimulation (Guger et al., 2009; Wolpaw et al., 2002).

CONCLUSIONS Electrocorticography represents the last step in the presurgical evaluation of patients with refractory epilepsy. It is performed during epilepsy surgery, is associated with relatively low risk, and provides sufficient flexibility to study the cortical area pre- and postsurgery. The main limitation of ECoG is that it rarely captures spontaneous seizures. A correlation between interictal discharges with postsurgical outcome has been suggested by several studies, but conflicting data remain. Technical advances in ECoG are providing relevant insights into the basic mechanisms of epilepsy and these are, in turn, fueling further technical advances to understand the process of ictogenesis and epileptogenesis better. REFERENCES Aceros J, Yin M, Borton DA, et al. A 32-channel fully implantable wireless neurosensor for simultaneous recording from two cortical regions. Conf Proc IEEE Eng Med Biol Soc 2011;2011:2300–2306. Adelson PD, Black PM, Madsen JR, et al. Use of subdural grids and strip electrodes to identify a seizure focus in children. Pediatr Neurosurg 1995;22:174–180. Akiyama T, Otsubo H, Ochi A, et al. Focal cortical high-frequency oscillations trigger epileptic spasms: confirmation by digital video subdural EEG. Clin Neurophysiol 2005;116:2819–2825. Akiyama T, Otsubo H, Ochi A, et al. Topographic movie of ictal high-frequency oscillations on the brain surface using subdural EEG in neocortical epilepsy. Epilepsia 2006;47:1953–1957. Andrade-Valença L, Mari F, Jacobs J, et al. Interictal high frequency oscillations (HFOs) in patients with focal epilepsy and normal MRI. Clin Neurophysiol 2012;123:100–105. Asano E, Benedek K, Shah A, et al. Is intraoperative electrocorticography reliable in children with intractable neocortical epilepsy? Epilepsia 2004;45:1091–1099. Asano E, Juhasz C, Shah A, et al. Role of subdural electrocorticography in prediction of long-term seizure outcome in epilepsy surgery. Brain 2009;132:1038–1047. Bautista RE, Cobbs MA, Spencer DD, Spencer SS. Prediction of surgical outcome by interictal epileptiform abnormalities during intracranial EEG monitoring in patients with extrahippocampal seizures. Epilepsia 1999;40:880–890. Bénar CG, Chauviere L, Bartolomei F, Wendling F. Pitfalls of high-pass filtering for detecting epileptic oscillations: a technical note on “false” ripples. Clin Neurophysiol 2010;121:301–310. Benbadis SR. Invasive electroencephalography in humans. In: Lüders H, Noachtar S, eds. Epileptic seizures. Pathophysiology and clinical semiology. Philadelphia: Churchill Livingstone, 2000:49–53. Benifla M, Otsubo H, Ochi A, et al. Temporal lobe surgery for intractable epilepsy in children: an analysis of outcomes in 126 children. Neurosurgery 2006;59:1203–1213; discussion 1213–1214. Bernier GP, Richer F, Giard N, et al. Electrical stimulation of the human brain in epilepsy. Epilepsia 1990;31:513–520. Bink H, Lai Y, Saudari SR, et al. Flexible organic electronics for use in neural sensing. Conf Proc IEEE Eng Med Biol Soc 2011;2011:5400–5403. Binnie CD, Polkey CE, Alarcón G. Electrocorticography. In: Lüders H, Comair Y, eds. Epilepsy surgery. Philadelphia: Lippincott Williams & Wilkins, 2001: 637–641. Blume WT, Holloway GM. Electrocorticography. In: Koubeissi MZ, Maciunas RJ, eds. Extratemporal lobe epilepsy surgery. Surrey: John Libbey, 2011:345–351. Blume WT, Jones DC, Pathak P. Properties of after-discharges from cortical electrical stimulation in focal epilepsies. Clin Neurophysiol 2004;115:982–989. Borton D, Yin M, Aceros J, et al. Developing implantable neuroprosthetics: a new model in pig. Conf Proc IEEE Eng Med Biol Soc 2011;2011:3024–3030. Bragin A, Mody I, Wilson CL, Engel J Jr. Local generation of fast ripples in epileptic brain. J Neurosci 2002a;22:2012–2021. Bragin A, Wilson CL, Almajano J, et al. High-frequency oscillations after status epilepticus: epileptogenesis and seizure genesis. Epilepsia 2004;45:1017–1023. Bragin A, Wilson CL, Engel J Jr. Chronic epileptogenesis requires development of a network of pathologically interconnected neuron clusters: a hypothesis. Epilepsia 2000;41(suppl 6):S144–S152. Bragin A, Wilson CL, Staba RJ, et al. Interictal high-frequency oscillations (80500 Hz) in the human epileptic brain: entorhinal cortex. Ann Neurol 2002b;52:407–415.

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Electrocorticography for seizure foci mapping in epilepsy surgery.

Patients with refractory focal epilepsy are thoroughly evaluated to identify an area of cortex that, if removed or disconnected, will lead to seizure ...
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