Electrocorticographic evidence and surgical implications of different physiopathologic subtypes of temporal epilepsy

Clinical Neurophysiology xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph

Electrocorticographic evidence and surgical implications of different physiopathologic subtypes of temporal epilepsy L. Vega-Zelaya a,1, C.V. Torres b,1, O. Garnes-Camarena a, G.J. Ortega b, E. García-Navarrete b, M. Navas b, R.G. Sola b, J. Pastor a,⇑ a b

Clinical Neurophysiology, University Hospital La Princesa, Madrid, Spain Neurosurgery, University Hospital La Princesa, UAM, Madrid, Spain

a r t i c l e

i n f o

Article history: Accepted 14 March 2014 Available online xxxx Keywords: Network theory Epileptic zone Anterior medial temporal resection Etomidate Lateral cortectomy

h i g h l i g h t s  Electrocorticography can distinguish between true focal and network-based physiopathology for

mesial temporal lobe epilepsy (MTLE).  Both types of physiopathology have different clinical implications: abolition of mesial spikes allows

the formation of respective mesial structures with very good outcome.  The epileptic zone would be located at the lateral cortex in some patients diagnosed with MTLE.

a b s t r a c t Objective: Mesial temporal lobe epilepsy (MTLE) might have a focal or a network physiopathology. Therefore, the objective of this study was to demonstrate that changes in the spiking activity during electrocorticography (ECoG) could reflect changes in the epileptic network, and the resection of the epileptogenic zone could eliminate the mesial spikes. Methods: Twenty-five MTLE patients were intraoperatively evaluated by ECoG and the mesial strip was maintained until the lateral cortectomy (LC) was completed. Total spiking activity (TSA, mean spikes/min for all the mesial channels) was computed off-line before and after LC. Either a tailored anterior medial temporal resection or LC was carried out based on the TSA changes. Results: The outcome at 19.1 ± 1.4 months was Engel’s class I, 84%; II, 8%; or III, 8%. During the LC, the TSA recorded from the mesial strip did not change in 14 patients, increased in three patients, and decreased in eight patients. In 20% of patients, the mesial activity completely disappeared, and the mesial structures were spared. All of these patients were Engel’s class IA. Conclusions: Our results strongly suggest the existence of physiopathologic differences in MTLE. The identification of these subtypes is fundamental for an individualized surgical approach. Significance: ECoG would be needed to offer a better surgical approach. Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Abbreviations: AMTR, anterior medial temporal resection; ECoG, electrocorticography; EL, epileptogenic lesion; EZ, epileptogenic zone; HS, hippocampal sclerosis; IOZ, ictal onset zone; IZ, irritative zone; LC, lateral cortectomy; LS, local synchronization; MTLE, mesial temporal lobe epilepsy; cTSA, caudal total spiking activity; TSA, total spiking activity; rTSA, rostral total spiking activity; v-EEG, videoelectroencephalography. ⇑ Corresponding author. Address: Clinical Neurophysiology, Hospital Universitario de La Princesa, C/Diego de León 62, Madrid 28006, Spain. Tel.: +34 91 5202213; fax: +34 91 4013582. E-mail address: [email protected] (J. Pastor). 1 Both authors have contributed equally.

1. Introduction Presurgical evaluation and surgical approaches to treat drugresistant partial epilepsy are carried out under the zone-oriented model (Carreño, 2001; Rosenow and Lüders, 2001) in many epilepsy centers around the world. Identification of significant areas such as the ictal onset zone (IOZ, cortical area where the seizure begins), the irritative zone (IZ, area showing interictal epileptiform discharges), and the epileptogenic lesion (EL, usually refers to a

http://dx.doi.org/10.1016/j.clinph.2014.03.027 1388-2457/Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Vega-Zelaya L et al. Electrocorticographic evidence and surgical implications of different physiopathologic subtypes of temporal epilepsy. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.03.027

2

L. Vega-Zelaya et al. / Clinical Neurophysiology xxx (2014) xxx–xxx

cerebral abnormality detected by in vivo neuroimaging) is essential to plan resective surgery. However, the anatomical location of these functional areas is not always clear. The manner in which the surgeon performs the surgery strongly depends on the relative location of these zones. Ideally, different zones significantly overlap in the same cortical region, which would be considered the target for resection. However, even in ideal cases, a significant minority of patients continue to experience seizures after the surgery. In the zone-oriented framework, it would be concluded that the epileptogenic zone (EZ, defined as the anatomic area necessary and sufficient for initiating seizures, and the removal or disconnection of which is necessary for abolition of seizures), which is an evolution of the classical concept of the epileptic focus, has not been removed. The approach described above has been challenged by an alternative network model for ictal state (Bartolomei et al., 2001) and also for a more general view of epilepsy (Spencer, 2002), in which attention is shifted from specific cortical areas (EZ, EL, IOZ, etc.) toward a characterization of the epileptic network itself (Sequeira et al., 2013). This concept has gained popularity over the recent years, mainly through neurophysiologic and imaging studies (Bonilha et al., 2010a,b, 2013; Ortega et al., 2008a,b; Palmigiano et al., 2012a,b; Pastor et al., 2006; Sequeira et al., 2013; Schevon et al., 2007; Spencer et al., 1992; Spencer, 2002). Under this perspective, a surgery strategy should consider that vulnerability to seizure activity in any part of the network is influenced by activity everywhere else in the network and that the network’s structure as a whole is responsible for the generation of seizures. In the particular case of mesial temporal lobe epilepsy (MTLE), seizures may entrain the limbic network from several different areas; the intrinsic electrical hyperexcitability associated with the network gives rise to seizure activity. Whether these areas match the IOZ is an open question. For instance, it is not unusual for the IOZ to display variability in location, even when producing clinically similar seizures. Moreover, seizure initiation is related to multiple neuronal assemblies located not only within the IOZ but also outside it (ipsilateral) and on the contralateral side (Bower et al., 2012). These considerations have been reinforced by interictal recordings using linear correlation and phase synchronization. The recordings show synchronous activity emerging from specific areas of the neocortex, which has persistent spatiotemporal features that are characteristic of each patient (Dauwels et al., 2009; Ortega et al., 2007, 2008a,b; Palmigiano et al., 2012a,b; Pastor et al., 2006; Schevon et al., 2007). Resection of the nodes with high local synchronization (LS), identified through off-line analysis of intraoperative electrocorticography (ECoG) recordings, correlates with good postoperative outcomes. By contrast, sparing these nodes is associated with an unfavorable outcome, despite complete resection of the mesial structures. Interestingly, the relationship of these areas with classical zones, for instance the IOZ (or IZ), is sharp (Dauwels et al., 2009), moderate (Schevon et al., 2007), or uncertain (Ortega et al., 2008a,b; Palmigiano et al., 2012a,b). In terms of the zone model, one is tempted to relate these LS areas with the EZ; its removal during surgery produces the abolition of seizures, which is the actual operational definition of the EZ. From the network point of view, however, these LS areas could be related to functional or structural properties of the epileptic network such as signal transmission and seizure appearance/propagation susceptibility. Changing the conceptual framework of MTLE necessarily involves changes in the preoperative evaluation and the surgical procedure. One can go a step further, however, and ask if it is possible to modify the network properties during the surgical procedure. More importantly, can it be known during the surgery that the EZ has been removed? The main points of this work are rooted in two related but independent hypotheses:

(i) Changes in interictal activity recorded in intraoperative ECoG might reflect, at least partially, the neurophysiological changes that occur in the epileptic network. Therefore, a change in the network’s structure during the surgical resection could be accompanied by a modification at the level of irritative activity. (ii) The EZ is related to the presence of spikes in the mesial area in patients with MTLE. Thus, resection of the EZ during surgery is tightly linked with abolition of mesial interictal spikes. To assess these hypotheses, we prospectively studied a series of 25 patients who underwent temporal lobe resections for refractory MTLE. The surgeries were performed in our National Reference Unit for Refractory Epilepsy between 2010 and 2012. To address the first hypothesis, we performed ECoG of the mesial region during resection of the lateral cortex. To assess the second hypothesis, we did not resect the mesial structures in patients where spikes completely disappeared after lateral cortex resection. We then evaluated the functional postsurgical outcome. Preliminary results were published in abstract form (Torres et al., 2013). 2. Methods 2.1. Patients and presurgical evaluation The study evaluated 25 patients (12 men and 13 women) who gave informed consent according to the Declaration of Helsinki. This research was approved by the Ethics Committee of the Hospital la Princesa. The mean age (±SEM) of the participants was 43.5 ± 3.0 years for the men and 38.5 ± 2.4 years for the women (n.s., two-tailed Student’s t-test). Male and female patients had a history of epilepsy of 22.8 ± 4.1 and 26.9 ± 2.7 years, respectively (n.s., two-tailed Wilcoxon–Mann–Whitney rank test). Clinical data from the patients are shown in Table 1. Presurgical evaluation followed the protocol of the Hospital La Princesa and was described in detail elsewhere (Sola et al., 2005; Pastor et al., 2005, 2008). Briefly, patients were evaluated by neurological, neuropsychological, and psychiatric assessments. Patients with a medical history of head trauma, nervous system infectious disease, or first relatives with a history of epilepsy were excluded. Ancillary tests included a 19-channel scalp electroencephalography (EEG) (CadwellÒ, Kennewick, WA, USA) following the international 10–20 system. Additionally, we employed interictal single photon emission computed tomography (SPECT) using 99mTc-HmPAO (General ElectricÒ, Fairfield, CT, USA). We also used 1.5-T magnetic resonance imaging (MRI) (General ElectricÒ, Fairfield, CT, USA) with a specific protocol for epilepsy. Finally, we used video-electroencephalography (v-EEG- XLTEKÒ, Oakville, ON, Canada) with 19 scalp electrodes according to the international 10–20 system, usually complemented with foramen ovale (FO) electrodes. Six-contact platinum FO electrodes with 1-cm center-to-center spacing (AD-TechÒ, Racine, USA) were inserted bilaterally under general anesthesia (Wieser, 1988; Pastor et al., 2008). In all cases, proper implantation was confirmed using fluoroscopic imaging in the operating room. During the v-EEG recording, antiepileptic drugs were progressively removed from the second to the fourth day (approximately 1/3 of a dose per day). v-EEG recording was utilized as long as necessary to record several of the patient’s habitual seizures. Interictal paroxysmal activity and seizure onset information were used to identify the IZ, symptomatogenic zone (SZ), and IOZ. Patients with a positive diagnosis of tumor or cortical dysplasia in the MRI were also excluded. However, when there was doubt about the radiologic diagnosis between hippocampal sclerosis (HS) and low-grade

Please cite this article in press as: Vega-Zelaya L et al. Electrocorticographic evidence and surgical implications of different physiopathologic subtypes of temporal epilepsy. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.03.027

Patients Age/ Epilepsy Semiology gender duration (years)

EEG

1

33/Fe

13

Epigastric aura

2

36/Fe

35

3

31/Fe

28

4

44/Ma

6

5

41/Fe

19

6

32/Ma

23

7

28/Ma

13

8

32/Fe

25

9

33/Fe

32

10

30/Ma

21

11

49/Ma

23

12

48/Ma

4

13

56/Fe

13

14

47/Ma

27

15

43/Fe

34

Disconnection, bilateral oroalimentary automatisms

16

41/Fe

22

17

45/Ma

5

Discomfort, anxiety, motor and sensorial dysphasia Epigastric sensation, disconnection left arm automatisms

18

43/Fe

37

Disconnection, cephalic and inferior limb automatisms, ictal speech.

19

51/Ma

33

Disconnection, mumbling, bimanual automatisms, postictal aphasia and confusion

Follow-up Surgery (months)

Outcome Pathology (Engel’s scale)

Left mesial T

24

Left AMTR

I

HS

Left mesial T

34

Left AMTR

I

HS

Left mesial T

24

Left AMTR

I

HS, Chaslin gliosis

Right mesial T

Right mesial T

28

Right AMTR

I

Type I cortical dysplasia

Yes

Left mesial and lateral T

Left mesial T

31

Left AMTR

II

Epileptogenic lesion

v-EEG

SPECT

MRI

FO Irritative area electrodes

IOZ/EZ

Left F

–

Left HS

Yes

Oral and right hand automatisms

Normal

Left T

Left HS

Yes

Disconnection and right arm automatisms. Occasional generalization Epigastric aura oroalimentary automatisms Disconnection, oroalimentary and left hand automatisms, right arm dystonic posture. Disconnection, oroalimentary and right hand, automatisms, distonic posture, left nose wiping Epigastric aura, disconnection, motionless, left hand and oroalimentary automatisms, Epigastric aura, intense fear, disconnection. Occasional generalization Disconnection. Postictal dysphasia

Right T

Right T

Yes

Right F–T

Bilateral T right> left Anteromesial Left T

Left HS vs. cortical dysplasia Normal

Left F–T. Left mesial T Left T > R mesial Left mesial T

Yes

Right HS

Left T

Normal

Bilateral F–P and left T–O

Right HS

Yes

Right mesial T

Right mesial T

22

Right AMTR

I

Reactive gliosis. Ectopic neurons in white matter. HS Gliosis. HS

Left T

Anteromesial left T

Left HS

Yes

Left T

Left mesial T

24

Left AMTR

I

Type I cortical dysplasia

Right T

Right T–P

No

Right lateral and mesial T

Right mesial T

14

Right AMTR

I

Ectopic neurons in molecular layer

Left T

Left F and T

Right HS vs. cortical dysplasia Left HS

Yes

Left mesial T

16

Left AMTR

I

HS

Left HS

Yes

Left mesial T

12

Left AMTR

III

HS, ectopic neurons in white matter

Right HS

Yes

Left mesial and lateral T Bilateral mesial T (L > R) Right mesial T

Right mesial T

18

Right AMTR

I

HS, ectopic neurons in white matter

Right mesial T

16

Right AMTR

I

HS, ectopic neurons in white matter

Left mesial T

16

Left AMTR

I

HS

Right mesial T

12

Right AMTR

I

HS

Right mesial T

12

Right AMTR

I

Type I cortical dysplasia I

Left T Epigastric aura, anxiety, disconnection, right arm automatisms. Stifling sensation, disconnection, right Normal hand and oroalimentary automatisms, left arm dystonic posture Fear and anxiety. bimanual Normal automatisms.

Left O and anteromesial left T Right anteromesial T Bilateral anteromesial T -

Right HS

Yes

Left HS

Yes

Normal

Right HS

Yes

Right T

-

Yes

Left T

Right HS vs. cortical dysplasia Normal

Anterobasal left T Anteromesial Normal right T and bilateral O F–P and left T Right HS

Bilateral F

No

Disconnection, motionless, right hand General automatisms slowing Disconnection, bimanual Right T automatisms, right hand nose wiping

Normal

Bilateral T

Left HS, F– T gliosis

Bilateral mesial T (R > L) Left mesial and lateral T Bilateral mesial and lateral T (R > L) Right lateral and mesial T

Yes

Left mesial T

Left mesial T

12

Left AMTR

I

Normal

Yes

Right mesial T

Right mesial T

8

Right AMTR

III

Subpial gliosis

Yes

Right mesial T Bilateral mesial T. Right predominance. Left mesial Left mesial T and lateral T

12

Right AMTR

I

HS, ectopic neurons

9

Left AMTR

I

Ectopic neurons in white matter. HS

L. Vega-Zelaya et al. / Clinical Neurophysiology xxx (2014) xxx–xxx

(continued on next page) 3

Please cite this article in press as: Vega-Zelaya L et al. Electrocorticographic evidence and surgical implications of different physiopathologic subtypes of temporal epilepsy. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.03.027

Table 1 Patients’ demographics, preoperatory tests, pathology results, and outcome according to Engel’s classification.

Yes Normal

34

23

35

34/Ma

36/Fe

60/Ma

23

24

25

F = frontal, T = temporal, P = parietal, O = occipital; Fe = female, Ma = male, HS = hippocampus sclerosis. AMTR, anterior medial temporal resection; LC = lateral cortectomy; IOZ = ictal onset zone, EZ = epileptic zone.

Ectopic neurons in white matter. Reactive gliosis I

Yes Right HS

Right mesial T

Right LC 26 Right mesial T

I

Yes

50 54/Ma 22

Bitemporal Anterior Disconnection, bimanual and bilateral T oroalimentary automatisms, postictal left hand scratching Normal Anteromesial Rising sensation from inferior limbs, left T disconnection, left arm hypertonia, right hand automatisms Disconnection, anxiety, oroalimentary Right T Anteromesial automatisms, word repetition right T

Right HS

Right mesial T

Right LC 12 Right mesial T

I Right LC 26

I Left LC 16

Left lateral and Left mesial T mesial T Right mesial T Right mesial T Normal –

Yes

I 27 Left HS 23 24/Fe 21

Epigastric aura, dizziness, Right T unintelligible mumbling Dizziness, ED unintelligible mumbling Left T

–

No

Left mesial T

Left mesial T

Left LC

II Left AMTR 20 Left T Left T No Right HS Bilateral anteromesial Left T Fear, disconnection, oroalimentary automatisms Postictal headache. 46 51/Fe 20

Follow-up Surgery (months) IOZ/EZ v-EEG

FO Irritative area electrodes MRI

Epileptogenic lesion

SPECT

EEG Patients Age/ Epilepsy Semiology gender duration (years)

Table 1 (continued)

Ectopic neurons in molecular layer and white matter Ectopic neurons in white matter Ectopic neurons in white matter Chaslin gliosis, ectopic neurons in the molecular layer and white matter Type I cortical dysplasia

L. Vega-Zelaya et al. / Clinical Neurophysiology xxx (2014) xxx–xxx

Outcome Pathology (Engel’s scale)

4

tumor or cortical dysplasia, the patients were included. Clinical data were carefully recorded and analyzed from the video recordings. MTLE was diagnosed according to classical criteria (Gil-Nagel and Risinger, 1997; Jette and Wiebe, 2013; Lüders, 2001; TéllezZenteno and Ladino, 2013). Moreover, patients were classified into different subtypes of temporal lobe epilepsy as mesial (M) or mesial–lateral (ML), according to the clinical semiology evaluated (Maillard et al., 2004). Bioelectrical activity recorded during ictal periods in both the scalp and FO electrodes was evaluated according to classical criteria (Pacia and Ebersole, 1997, 1999; Téllez-Zenteno and Ladino, 2013). Therefore, scalp patterns were categorized according to the classification of Pacia and Ebersole (Pacia and Ebersole, 1996) in different subtypes: (i) 1A, regular 5–9 Hz inferotemporal rhythm; (ii) 1B, a similar vertex/parasagittal positive rhythm; (iii) 1C, a combination of types 1A and 1B; (iv) 2A, irregular, polymorphic 2–5 Hz lateralized activity; (v) 2B, subtype 2A followed by patterns 1A; (vi) 2C, subtype 2A preceded by repetitive, sometimes periodic sharp waves; and finally (vii) type 3, without a clear lateralized EEG ictal pattern. Types 1A, 1B, and 1C are associated with MTLE, whereas patterns 2A, 2B, and 2C are more frequently associated with lateral temporal lobe epilepsy (LTLE). 2.2. Intraoperative evaluation Briefly, ECoG was performed with a grid of 4  5 electrodes (Pt/Ir) embedded in Silastic. Electrodes were 1.2 mm in diameter and had a 1-cm center-to-center interelectrode distance (AD-TechÒ, Racine, WI, USA). The grid was placed directly over the exposed lateral temporal cortex, and an eight-electrode mesial strip was introduced through the sylvian fissure. We pay special attention to ensure the placement of the strip as parallel as possible to the anterior–posterior axis of the temporal lobe, although some degree of inclination with respect to this axis is always observed. Relationships between the mesial strip and the regions removed can also be observed in Fig. 3. Recordings were performed with 32-channel Elite (CadwellÒ, Kennewick, WA, USA) and sampled at 1000 Hz with a bandwidth of 1.5–200 Hz for a minimum of 20 min. During recordings, the anesthesia level was stabilized by maintaining the bispectral index at values in the range of 55–60 under a low dose of sevoflurane (0.5%), remifentanil (0.1 mg/kg/min), and neuromuscular blockade. Fifteen minutes after the start of the ECoG, a bolus of 0.1 mg/kg i.v. etomidate was administered, and the increase in irritative activity was used to identify the area for resection. We defined three different functional areas according to the results of raw traces: (i) Irritative area: This area is defined by the presence of interictal epileptiform discharges identified as electrodes showing spikes (<80 ms) or sharp waves (80–200 ms) (AjmoneMarsan and O’Connor, 1973; Arion et al., 2006; Chatrian and Quesney, 1999) with an amplitude >3 standard deviations from the basal activity. (ii) Activity loss area: This area is defined by a decrease in the appearance of all frequencies, especially the faster alpha and beta bands. (iii) Normal activity area: In this region, neither irritative elements nor abnormal loss of bioelectrical activities were observed. The same neurosurgeon (RGS) intervened on all patients and the same clinical neurophysiologist (JP) performed the ECoG to introduce the least possible bias. Electrocorticographic findings were used to define the tailored resection area in the lateral and mesial regions. During resection of the lateral cortex, a continuous

Please cite this article in press as: Vega-Zelaya L et al. Electrocorticographic evidence and surgical implications of different physiopathologic subtypes of temporal epilepsy. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.03.027

L. Vega-Zelaya et al. / Clinical Neurophysiology xxx (2014) xxx–xxx

5

recording of the mesial area was performed, maintaining the mesial strip electrode in the same place. Once lateral resection was complete, we had two options: (i) Tailored anterior medial temporal resection (AMTR): If the irritative activity in the mesial strip persisted or increased, the area was resected according to the limit defined by the presence of spikes. (ii) Tailored lateral cortectomy (LC): If irritative activity disappeared in the mesial strip, we waited for 10 min and applied a second dose of etomidate to activate the bioelectrical activity. If irritative activity did not appear, then the mesial area was not removed. Total spiking activity (TSA) in the mesial strip was analyzed offline. The spikes for all eight channels (ni, i = 1, 2, . . ., 8) during the 3–5 min (Nt) before and after the end of the lateral resection were calculated according to the expression:

TSAðspikes=minÞ ¼

8 1X ni : Nt i¼1

Furthermore, this activity was divided into rostral total spiking activity (rTSA, S8–S5 electrodes) and caudal total spiking activity (cTSA, S4–S1 electrodes), with the above equation modified accordingly for the number of channels. To evaluate the relative distribution of irritative activity, we used a normalized coefficient (d, for distribution), namely,

d¼

rTSA  cTSA rTSA þ cTSA

If d = 1, then all the irritative activity was placed in the rostral half. If d = 1, then all the spiking activity was located in the caudal half. Obviously, when activity completely disappeared (e.g., rTSA + cTSA = 0), we could not apply this coefficient. Outcomes are determined by a modified version of Engel’s classification (Engel, 1987), where Engel’s III grade is defined as the disappearance of >75% of basal seizures at 12 months after surgery. The global functional result for a group of patients is evaluated according to a functional index (Pastor et al., 2005) which consists of assigning a value of 4 to Engel’s grade I, a value of 3 to Engel’s grade II, a value of 2 to Engel’s grade III, and a value of 1 to Engel’s grade IV. Therefore, a value of 4 implies that all patients in a group are of Engel’s grade I. On the contrary, a value of 1 implies that all patients are of grade IV.

Fig. 1. Characterization of patients during presurgical evaluation. Scalp and FO electrode recordings during the first periods of a seizure. (A) Left mesial temporal seizure. Patient 16; (B) Right mesial temporal seizure. Patient 25. lFO = left foramen ovale; rFO = right foramen ovale. Upper value of voltage in the calibration bar refers to scalp recordings; on the other hand, the lower one refers to FO electrodes.

2.3. Statistical analysis Comparisons between groups were performed using Student’s t-test for normal distributions or the Mann–Whitney rank sum test if normality failed. For groups before and after cortectomy, we used a paired Student’s t-test or signed-rank test if normality failed. If three groups were considered, we used the Kruskal–Wallis analysis of variance (ANOVA) on ranks. Normality was evaluated using the Kolmogorov–Smirnov test. Comparisons between proportions were assessed with a z-test with Yates correction. Pearson’s correlation coefficient was used to study the dependence between variables. A linear regression was calculated by the least-square sum. For the linear regression, the contrast hypothesis against the null hypothesis q = 0 used the formula

pffiffiffiffiffiffiffiffiffiffiffiffiffi r N2 t ¼ pffiffiffiffiffiffiffiffiffiffiffiffiffi ; 1  r2

which describes a Student distribution with N–2 degrees of freedom (Spiegel, 1991). SigmaStatÒ 3.5 software (Point Richmond, CA, USA) was used for statistical analyses.

Fig. 2. Graph showing the TSA before and after lateral cortical resection. Empty dots represent the no_change group, red dots represent the increase group, and blue dots correspond to the decrease group.

The significance level was set at p < 0.05. The results were shown as the mean ± SEM, unless otherwise indicated. 3. Results 3.1. Presurgical evaluation and surgical outcome All patients selected for this work were diagnosed with MTLE (Fig. 1) and classified as M or ML. None of the patients presented

Please cite this article in press as: Vega-Zelaya L et al. Electrocorticographic evidence and surgical implications of different physiopathologic subtypes of temporal epilepsy. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.03.027

6

L. Vega-Zelaya et al. / Clinical Neurophysiology xxx (2014) xxx–xxx

I, II, III, and IV, respectively, with a follow-up period of 19.1 ± 1.4 (range 8–34) months. Therefore, all patients were improved by the treatment, and there was a good result (Engel’s grade I + II) in 92.0% of subjects. The surgical complications observed included bleeding of the surgical bed, which spontaneously resolved (patient #5), seizures in the early postoperative period (patient #13), and cranial nerve paresis (patient #14). 3.2. ECoG findings

Fig. 3. Change in mesial temporal lobe activity after resection of the lateral cortex. Pictures and recordings correspond to the time indicated at left except for the third picture of A – showing the rostral electrodes of the mesial strip – that correspond to the second time indicated (42 min) after the mesial area was removed. In this case, the record was obtained at the first time (28 min), before the mesial resection. (A) Increase of irritative activity at the end of LC. Patient 16. (B) A complete disappearance of the irritative activity at the end of cortectomy. Patient 25. MR images show the AMTR and LC, respectively. Time of resection (in minutes) is shown at left of each recording. 0 min indicates the basal recording before the start of LC.

clinical or bioelectrical patterns suggestive of LTLE (Maillard et al., 2004, Table 2). Usually, symptoms were compatible with MTLE, but the patients rarely showed all the classical manifestations; a positive diagnosis usually required other electrodes than scalp electrodes during the v-EEG. Therefore, FO electrodes were used in 21/25 cases. Scalp bioelectrical patterns were typical in the majority of patients, showing type 1A in 17 patients, type 2A in 5 patients, and just one patient of types 1B and 3; on the other hand, in another patient no change in scalp was observed during seizures (Table 2). Ictal patterns recorded from FO electrodes showed typical recordings in all cases, with beta patterns in 10/23 cases, start–stop–start pattern in 8/23 cases, and sharp waves in 7/23 patients and cases. From a clinical point of view, seven patients were diagnosed as subtype M and 18 patients as ML. No patient showing ictal semiology compatible to lateral subtype (Maillard et al., 2004) or temporal ‘‘plus’’ epilepsy (Barba et al., 2007) was found. All patients were included in the M subtype but one showed ictal scalp pattern type 1 (6/7). However, patients included in the subtype ML showed 12/18 type 1 patterns, 5/18 type 2, and 1/18 type 3. The global functional outcome for the whole group was 21/25 (84.0%), 2/25 (8.0%), 2/25 (8.0%), and 0/25 (0.0%) for Engel’s grades

The irritative activity in the mesial strip during the basal recording (before the lateral cortical resection) was more frequently (20/25 patients, 80.0%; d < 0) located in the caudal region. In the other five patients (20.0%; d > 0), the majority of the spikes appeared rostrally. Considering the whole group, the cTSA was 18.5 ± 3.3 spikes/min and the rTSA was 8.9 ± 2.2 spikes/min. Although we did not differentiate between normal and loss-ofactivity areas, these data likely indicated that the rostral half of the strip predominantly lost activity. During the resection of lateral cortex, the TSA recorded from the mesial strip changed in 11/25 cases (44.0%), while in the remaining 14/25 patients (56.0%) the activity was not modified (Fig. 2). In the patients where activity changed, we observed a decrease in activity in eight patients, while in three patients the activity clearly increased. Therefore, we categorized the patients into one of three functional groups according to the observed activity in the mesial region after cortectomy: (i) the spiking activity did not change (no_change group), (ii) increased (increase group), or (iii) decreased (decrease group) with respect to the basal activity. It was remarkable that in 5/25 patients (20.0%), the activity in the mesial strip was completely abolished after the LC, while in three patients (12.0%) the mesial activity clearly increased after the cortectomy (Fig. 3). Usually, these changes were clear enough by visual inspection to choose the surgical approach. As shown in Fig. 3A, the irritative activity increased after LC. In this patient, AMTR was performed (see MRI inset). However, when the TSA disappeared after lateral resection, the surgery was stopped and the mesial structures were maintained in place (MRI inset in Fig. 3B). These data clearly showed that the presence of irritative activity in the mesial region was modulated by the lateral cortex. However, we wanted to know whether the gross structure of irritative activity in the mesial strip, that is, the balance of rostral/caudal predominance of spikes, was also changed after cortectomy. To address this point, we computed the coefficient d before (dbasal) and after cortectomy (dpost_resection) and plotted the result as a correlation graph (Fig. 4). The linear regression of d for the no_change group was dpost resection ¼ 1; 302  dbasal þ 0:368, r = 0.597 (p < 0.05, Student’s t-test); for the increase group, it was dpost resection ¼ 1:5376  dbasal þ 0:4859 r = 0.9942 (p < 0.05, Student’s t-test); and for the decrease group, it was dpost resection ¼ 1:5147  dbasal þ 0:0725 r = 0.9947 (p < 0.05, Student’s t-test). From these data, we concluded that there was a correlation between all groups, indicating that the gross structure was maintained after LC. We also observed that the slope was very similar for all three groups. 3.3. Prognostic factors A very important question was whether there were any differences in functional outcome between the groups. In Table 3, we have shown the functional outcomes, according to Engel’s scale, along with the functional index for every group. We did not find any statistically significant difference between the analyzed groups. However, it was remarkable (but not statistically significant) that all patients where the activity decreased after

Please cite this article in press as: Vega-Zelaya L et al. Electrocorticographic evidence and surgical implications of different physiopathologic subtypes of temporal epilepsy. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.03.027

L. Vega-Zelaya et al. / Clinical Neurophysiology xxx (2014) xxx–xxx Table 2 Ictal patterns observed in scalp and in FO electrodes and subtype of temporal lobe epilepsy. Patient

Scalp ictal pattern

FO electrodes ictal pattern

Clinical subtype

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

1A 1A No change 1A 1A 1A 2A 1A 3 1A 1A 2A 1A 1B 1A 1A 2A 2A 1A 1A 1A 1A 1A 1A 2A

Start–stop–start Beta anterior Sharp waves Start–stop–start Start–stop–start Beta anterior Beta intermedial – Beta intermedial Start–stop–start Beta anterior Beta anterior Start–stop–start Beta anterior Start–stop–start Sharp waves Sharp waves Sharp waves Sharp waves – Beta anterior Beta intermedial Start–stop–start Start–stop–start Beta intermedial

Medial Medial Medial Medial Medial–lateral Medial Medial–lateral Medial–lateral Medial–lateral Medial–lateral Medial–lateral Medial–lateral Medial–lateral Medial–lateral Medial–lateral Medial–lateral Medial–lateral Medial–lateral Medial Medial–lateral Medial Medial–lateral Medial–lateral Medial–lateral Medial–lateral

cortectomy were of Engel’s grade I, while only 11/14 patients (78.6%) of the no_change group were of grade I. The excellent result observed in the no_change group likely precluded a greater difference between the other two groups. Another important aspect to analyze was the association between the presence of an EL in the MRI and the different groups. The proportion of patients with an EL was 85.7%, 75.0%, and 66.7%, respectively, for the no_change, decrease, and increase groups (Table 1). There was no statistically significant difference between the groups, nor was any association observed between the presence of pathological findings and the different groups. These results suggested that the difference in spiking behavior after LC was not due to the proportion of patients with an EL in the imaging studies or pathology findings. However, the scarce number of patients precludes a sufficient power of the test to obtain conclusions. Patients included in the no_change group showed 78.6% cases of ictal scalp pattern type 1A or 1B, 14.3% cases of type 2A, and one more case (7.1%) of no significant change during the seizure. In the same way, the decrease group showed 75.0% cases with type 1A or 1B and one case in type 2A or 3 (12.5% each). Finally, 66.6% patients of the increase group were of type 2A, with 33.3% cases of type 1A, although FO recordings clearly showed a typical ictal pattern of MTLE. Except for the last group, where the scarce number of patients precludes a comparison, we have not observed differences between the no_change and decrease groups with respect to the ictal pattern.

7

In recent years, the classical view of focal epilepsy has been debated (Bartolomei et al., 2001, 2004; Bertram et al., 1998; Frei et al., 2010; Spencer, 2002). We consider two theoretical frameworks to explain the physiopathology of epilepsy: (i) the focal (or zone-oriented) and (ii) the network approaches. In both cases, the expected relationships between functional areas are different. In the first case, we expect the IOZ and EZ to be closely related. Most often, the IOZ is the preferred target in respective surgery, expected to validate the IOZ as the EZ postoperatively. In any case, for the focal theory, it is very difficult to explain a different anatomical placement for these functional areas. By contrast, it is easy to explain the presence of the EZ and IOZ in different anatomic areas in the network theory. Both predictions can help categorize the patients during the surgery. All patients included in this work were diagnosed with MTLE (Gil-Nagel and Risinger, 1997; Jette and Wiebe, 2013; Pacia and Ebersole, 1997, 1999; Téllez-Zenteno and Ladino, 2013) and categorized as M or ML subtypes (Maillard et al., 2004). In the majority of patients, a more discriminative technique, that is, FO electrode v-EEG, was required for a positive diagnosis. In this group of patients, 80.0% of patients had a positive MRI (HS vs. cortical dysplasia). In all cases, the observed symptomatology during the seizures was compatible with MTLE and patients showing clinical symptoms or signs suggest lateral or temporal ‘‘plus’’ epilepsies (Maillard et al., 2004; Barba et al., 2007). Although a significant percentage of patients can be included in the ML subtype, the ictal pattern detected by the FO electrodes showed that IOZ was placed at mesial structures. Therefore, from a clinical, pathological, and bioelectrical point of view, the patients can be considered as diagnosed with idiopathic/cryptogenic MTLE (ILAE 1981). Therefore, we expected similar behavior in the electrical activity of the mesial region after the lateral cortical resection. Surprisingly, in a significant percentage of patients (up to 44.0%), the activity clearly changed after removal of the lateral cortex. These changes ranged from a clear increase in mesial spiking activity to a decrease or even a complete abolition of the irritative activity in 20.0% of patients. To our knowledge, changes in spiking activity after LC are described for the first time in this work. The lateral cortex is implicated in the prognosis of MTLE (Ortega et al., 2008b), and the mesial area is related to the outcome (Palmigiano et al., 2012a,b). However, the relation between the outcome and the dynamic

4. Discussion In this work, we have shown that patients diagnosed with MTLE during presurgical evaluation expressed different spiking activities in mesial structures after LC. This change in bioelectrical activity was used to select the surgical technique for each patient, avoiding mesial resection in the patients where irritative activity completely disappeared. Importantly, in the patients where mesial structures were conserved, the postsurgical outcome was excellent.

Fig. 4. Changes of the spiking activity in the mesial region for different groups of patients. Linear regression of d for no_change (empty dots), increase (red dots), and decrease (blue dots) groups. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Please cite this article in press as: Vega-Zelaya L et al. Electrocorticographic evidence and surgical implications of different physiopathologic subtypes of temporal epilepsy. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.03.027

8

L. Vega-Zelaya et al. / Clinical Neurophysiology xxx (2014) xxx–xxx

Table 3 Contingency table showing the outcome for the three groups of patients. Outcome (Engel’s scale)

I II III Sum Functional index ( x  SEM)

Patient’s group

Sum

No_change

Decrease

Increase

11 2 1 14 3.71 ± 0.16

8 0 0 8 4.00 ± 0.00

2 0 1 3 3.33 ± 0.67

21 2 2 25 –

behavior of the mesial region during the lateral resection is not addressed. It has been shown that interictal epileptiform discharges may originate from a complex interaction between separate regions, resulting in propagation and recruitment of neuronal activity along specific neural pathways that usually involve mesial and lateral regions (Alarcon et al., 1997). It has been shown that different subsets of co-activated structures are involved in the generation of interictal activity and, more significantly, around 50% of patients with MTLE have independent interictal networks in the neocortex (Bourien et al., 2005). In fact, these co-activated structures could be anatomo-functional circuits of the temporal lobe. In addition, it is possible that the differential presence of mesial, mesial–lateral, or predominantly lateral structures could explain our results. Considering all of these facts and keeping in mind that all patients were diagnosed with MTLE, the role of the lateral cortex in controlling mesial activity can only be explained in the framework of a distributed or network theory (Bonilha et al., 2010a,b, 2013; Spencer et al., 1992; Spencer, 2002; Spencer et al., 2005). Therefore, we can reasonably speculate that there is some functional connectivity between lateral and mesial regions and, what is more relevant, the lateral cortex, in a significant percentage of patients, can modulate spiking activity in the mesial region. Importantly, this region can define the outcome in some MTLE patients, without the involvement of mesial areas. In approximately half of the patients, the TSA is not changed after LC. This fact does not exclude a distributed physiopathology but is congruent with a classical point of view of focal epilepsy. For this group of patients, the locations of the IOZ and EZ are in the same anatomical region, as the focal theory hypothesizes. Nonetheless, the abolition of spiking activity after LC is unexpected in the framework of the focal theory. These facts are relevant for the physiopathology of epilepsy (Stefan and Lopes da Silva, 2013). However, there is a more practical finding of this work, which is the clinical utility of monitoring mesial activity for the selection of surgical technique. Identification of the EZ is an operational definition (Carreño, 2001; Rosenow and Lüders, 2001). Thus, it is only by obtaining a good postsurgical outcome that we can be sure to have resected the EZ. Therefore, we can state that in the group of patients where irritative activity disappeared, the EZ is resected because Engel’s grade was IA for all patients. However, in four of the five patients, the IOZ is positively identified by means of FO electrodes in the mesial region of the temporal lobe (see Fig. 1B). Therefore, we show here that in some patients the IOZ and EZ are in different anatomical locations; in these patients, we obtain good results when we do not resect the IOZ. We cannot relate the different physiopathology to the presence of structural lesions in the imaging studies. We need a greater number of patients to assess this possibility. However, HS is found in approximately 40–65% of patients who undergo surgery for TLE. Whether HS is the cause or the consequence of repeated seizures is still a matter of debate (Jefferys, 1999). Although we are aware that the number of patients is low, we observe that the gross structure of the spiking activity after cortectomy does not change. Thus, it seems that the lateral cortex

modulates the spike frequency without affecting the rostro-caudal structure of the spiking activity. Our results strongly suggest the existence of pathophysiologic differences within the MTLE syndrome. The identification of these different subtypes is fundamental for an individualized surgical approach and for the consideration of new therapeutic strategies. ECoG might be a useful intraoperative tool to design individualized surgical approaches for the patients and to minimize the possibility of neurological sequelae. Further studies with a high number of patients are necessary to confirm these results. 5. Financial disclosure The authors have not had any financial support in conjunction with the generation of this submission. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Acknowledgments This work was supported by a Grant from the Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I+D+I), Instituto de Salud Carlos III, Subdirección General de Evaluación y Fomento de la Investigación PI12/02839, and PIP No. 11420100100261 CONICET. The authors report no conflict of interest concerning the material or methods used in this study or the findings specified in this paper. References Ajmone-Marsan C, O’Connor M. Electrocorticography. Amsterdam: Elsevier; 1973. Alarcon G, Garcia Seoane JJ, Binnie CD, Martin Miguel MC, Juler J, Polkey CE, et al. Origin and propagation of interictal discharges in the acute electrocorticogram. Brain 1997;120:2259–82. Arion D, Sabatini M, Unger T, et al. Correlation of transcriptome profile with electrical activity in temporal lobe epilepsy. Neurobiol Dis 2006;22:374–87. Barba C, Barbati G, Minotti L, Hoffmann D, Kahane P. Ictal clinical and scalp-EEG findings differentiating temporal lobe epilepsies from temporal ‘plus’ epilepsies. Brain 2007;130:1957–67. Bartolomei F, Wendling F, Bellanger JJ, Regis J, Chauvel P. Neural networks involving the medial temporal structures in temporal lobe epilepsy. Clin Neurophysiol 2001;112:1746–60. Bartolomei F, Wendling F, Regis J, Gavaret M, Guye M, Chauvel P. Pre-ictal synchronicity in limbic networks of mesial temporal lobe epilepsy. Epilepsy Res 2004;61:89–104. Bertram EH, Zhang DX, Mangan P, Fountain N, Rempe D. Functional anatomy of limbic epilepsy: a proposal for central synchronization of a diffusely hyperexcitable network. Epilepsy Res 1998;32:194–205. Bonilha L, Edwards JC, Kinsman SL, et al. Extrahippocampal gray matter loss and hippocampal deafferentation in patients with temporal lobe epilepsy. Epilepsia 2010a;51:519–28. Bonilha L, Elm JJ, Edwards JC, et al. How common is brain atrophy in patients with medial temporal lobe epilepsy? Epilepsia 2010b;51:1774–9. Bonilha L, Martz GU, Glazier SS, Edwards JC. Subtypes of medial temporal lobe epilepsy: influence on temporal lobectomy outcomes? Epilepsia 2013;53:1–6. Bourien J, Bartolomei F, Bellanger JJ, Gavaret M, Chauvel P, Wendling F. A method to identify reproducible subsets of co-activated structures during interictal spikes. Application to intracerebral EEG in temporal lobe epilepsy. Clin Neurophysiol 2005;116:443–55. Bower MR, Stead M, Meyer FB, Marsh WR, Worrell GA. Spatiotemporal neuronal correlates of seizure generation in focal epilepsy. Epilepsia 2012;53:807–16. Carreño MLH. General principles of presurgical evaluation. In: Lüders HOCY, editor. Epilepsy surgery. Philadelphia: Lippincot Williams & Wilkins; 2001. p. 185–99. Chatrian GE, Quesney LF. Intraoperative electrocorticography. In: Engel JJ, Pedley TA, editors. Epilepsy, the comprehensive text book. Philadelphia: Lippincot; 1999. Dauwels J, Eskandar E, Cash S. Localization of seizure onset area from intracranial non-seizure EEG by exploiting locally enhanced synchrony. Conf Proc IEEE Eng Med Biol Soc 2009:2180–3. Engel J. Outcome with respect to epileptic seizures. In: Engel Jr J, editor. Surgical treatment of epilepsies. New York: Raven Press; 1987. Frei MG, Zaveri HP, Arthurs S, et al. Controversies in epilepsy: debates held during the Fourth International Workshop on Seizure Prediction. Epilepsy Behav 2010;19:4–16.

Please cite this article in press as: Vega-Zelaya L et al. Electrocorticographic evidence and surgical implications of different physiopathologic subtypes of temporal epilepsy. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.03.027

L. Vega-Zelaya et al. / Clinical Neurophysiology xxx (2014) xxx–xxx Gil-Nagel A, Risinger MW. Ictal semiology in hippocampal versus extrahippocampal temporal lobe epilepsy. Brain 1997;120:183–92. Jefferys JG. Hippocampal sclerosis and temporal lobe epilepsy: cause or consequence? Brain 1999;122:1007–8. Jette N, Wiebe S. Update on the surgical treatment of epilepsy. Curr Opin Neurol 2013;26:201–7. Lüders H. Mesial temporal epilepsy. In: Lüders HOCY, editor. Epilepsy Surgery. Philadelphia: Lippincot Williams & Wilkins; 2001. p. 249–51. Maillard L, Vignal JP, Gabaret M, Guye M, Biraben A, McGonigal A, et al. Semiologic and electrophysiologic correlations in temporal lobe seizure subtypes. Epilepsia 2004;45:1590–9. Ortega GJ, Sola RG, Pastor J. Global interaction analysis in epileptic ECoG data. Am Inst Phys 2007;913:203–4. Ortega GJ, Sola RG, Pastor J. Complex network analysis of human ECoG data. Neurosci Lett 2008a;12(447):129–33. Ortega GJ, Menendez de la Prida L, Sola RG, Pastor J. Synchronization clusters of interictal activity in the lateral temporal cortex of epileptic patients: intraoperative electrocorticographic analysis. Epilepsia 2008b;49:269–80. Pacia SV, Ebersole JS. Localization of temporal lobe foci by ictal EEG patterns. Epilepsia 1996;37:386–99. Pacia SV, Ebersole JS. Intracranial EEG substrates of scalp ictal patterns from temporal lobe foci. Epilepsia 1997;38:642–54. Pacia SV, Ebersole JS. Intracranial EEG in temporal lobe epilepsy. J Clin Neurophysiol 1999;16:399–407. Palmigiano A, Pastor J, Sola RG, Ortega GJ. Significance of complex analysis of electrical activity in temporal lobe epilepsy: electrocorticography. Rev Neurol 2012a;55:207–16. Palmigiano A, Pastor J, Garcia de Sola R, Ortega GJ. Stability of synchronization clusters and seizurability in temporal lobe epilepsy. PLoS One 2012b;7:e41799. Pastor J, Hernando-Requejo V, Dominguez-Gadea L, et al. Impact of experience on improving the surgical outcome in temporal lobe epilepsy. Rev Neurol 2005;41:709–16.

9

Pastor J, Ortega GJ, Sola RG, Menéndez de la Prida L. Synchronization analysis of intraoperative electrocorticographic data: Inhomogeneous patterns of interictal activity in mesial temporal lobe epilepsy. Clin Neurophysiol 2006;117:S61. Pastor J, Sola RG, Hernando-Requejo V, Navarrete EG, Pulido P. Morbidity associated with the use of foramen ovale electrodes. Epilepsia 2008;49:464–9. Rosenow F, Lüders H. Presurgical evaluation of epilepsy. Brain 2001;124:1683–700. Schevon CA, Cappell J, Emerson R, et al. Cortical abnormalities in epilepsy revealed by local EEG synchrony. Neuroimage 2007;35:140–8. Sequeira KM, Tabesh A, Sainju RK, et al. Perfusion Network Shift during Seizures in Medial Temporal Lobe Epilepsy. PLoS ONE 2013;8(1):e53204. Sola RG, Hernando-Requejo V, Pastor J, et al. Pharmacoresistant temporal-lobe epilepsy. Exploration with foramen ovale electrodes and surgical outcomes, Rev Neurol 2005;41:4–16. Spencer SS. Neural networks in human epilepsy: evidence of and implications for treatment. Epilepsia 2002;43:219–27. Spencer SS, Guimaraes P, Katz A, Kim J, Spencer D. Morphological patterns of seizures recorded intracranially. Epilepsia 1992;33:537–45. Spencer SS, Berg AT, Vickrey BG, et al. Predicting long-term seizure outcome after resective epilepsy surgery: the multicenter study. Neurology 2005;65:912–8. Spiegel M. Teoría de la Correlación. In: Spiegel M, editor. Estadística. Madrid: McGraw Hill Interamericana; 1991. Stefan H, Lopes da Silva FH. Epileptic neuronal networks: methods of identification and clinical relevance. Front Neurol 2013;4:8. Téllez-Zenteno JF, Ladino LD. Temporal epilepsy: clinical, diagnostic and therapeutic aspects. Rev Neurol 2013;56:229–42. Torres CV, Pastor J, García-Navarrete E, Navas M, Gil-Simoes R, Sola RG. Electrocorticographic evidence of different physiopathologic types in mesial temporal epilepsy. Surgical Implications Stereotact Funct Neurosurg 2013;91(Suppl. 1):19. Wieser HG. Selective amygdalo-hippocampectomy for temporal lobe epilepsy. Epilepsia 1988;29:100–13.

Please cite this article in press as: Vega-Zelaya L et al. Electrocorticographic evidence and surgical implications of different physiopathologic subtypes of temporal epilepsy. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.03.027