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Purpose: Intracranial electroencephalography (EEG) monitoring is an important process in the presurgical evaluation for epilepsy surgery. The objective of this study was to identify the ideal resection margin in neocortical epilepsy guided by subdural electrodes. For this purpose, we investigated the relationship between the extent of resection guided by subdural electrodes and the outcome of epilepsy surgery.
Methods: Intracranial EEG studies were analyzed in 177 consecutive patients who had undergone resective epilepsy surgery. We reviewed various intracranial EEG findings and resection extent. We analyzed the relationships between the surgical outcomes and intracranial EEG factors: the frequency, morphology, and distribution of ictal-onset discharges, the propagation speed, and the time lag between clinical and intracranial ictal onset. We also investigated whether the extent of resection, including the area showing ictal rhythm and various interictal abnormalities—such as frequent interictal spikes, pathologic delta waves, and paroxysmal fast activity—influenced the surgical outcome.
Results: Seventy-five patients (42%) were seizure free. A seizure-free outcome was significantly associated with a resection that included the area showing ictal spreading rhythm during the first 3 s or included all the electrodes showing pathologic delta waves or frequent interictal spikes. However, subgroup analysis revealed that the extent of resection did not affect the surgical outcome in lateral temporal lobe epilepsy.
Conclusions: The extent of resection is closely associated with surgical outcome, especially in extratemporal lobe epilepsy. Resection that includes the area with total pathologic delta waves and frequent interictal spikes predicts a good surgical outcome.
Among patients with medically refractory epilepsy, perhaps half are candidates for focal resective surgery (Thadani & Taylor, 2007). Many studies of the prognostic factors for surgical outcomes have been published during the last decade. Major determinants of outcome are complete resection of magnetic resonance imaging (MRI)–visible lesions or the epileptogenic zone (Tassi et al., 2002; Cohen-Gadol et al., 2004; Fauser et al., 2004), underlying pathology (Berkovic et al., 1995; Tonini et al., 2004), the presence of a visible lesion on MRI (Hennessy et al., 2001; Tonini et al., 2004; Yun et al., 2006), and location of seizure focus (Téllez-Zenteno et al., 2005; Thadani & Taylor, 2007). Although temporal lobe resection for mesial temporal lobe epilepsy (mTLE) is the most frequently performed surgical procedure and usually predicts a favorable prognosis, surgical outcome in cases of neocortical epilepsy is generally less satisfactory than for patients with mTLE (Engel et al., 2003; Tonini et al., 2004; Téllez-Zenteno et al., 2005; Spencer & Huh, 2008). In terms of evaluation techniques, a concordance between diagnostic tests such as electroencephalography (EEG), MRI, ictal single-photon emission computed tomography (SPECT), or positron emission tomography (PET) is associated with a good surgical outcome (Thadani et al., 2004; Tonini et al., 2004; Yun et al., 2006).
Intracranial EEG is one of the most important procedures in planning surgery and achieving a good surgical outcome in resective epilepsy surgery. The objectives of intracranial EEG are to define interictal abnormalities and the ictal-onset zone, and to map the cortical function (Sperling, 2003). On the basis of these results, physicians can determine the extent of the surgical resection. The surgical outcome depends strongly on the identification and complete resection of a well-defined epileptogenic zone. Therefore, the extent of the resection may contribute to the surgical outcome (Widdess-Walsh et al., 2007). However, there are no consistent guidelines for resection based on intracranial EEG in neocortical epilepsy.
In mTLE, seizures are generated within a network of temporal lobe structures (e.g., limbic networks) or extratemporal structures (e.g., insular–frontal–opercular regions) (Henry et al., 1993; Bertram et al., 1998; Bartolomei et al., 2001; Bernasconi et al., 2004; Mueller et al., 2004; Lin et al., 2007). However, the nature of the epileptogenic zone network is unclear in neocortical epilepsy. An understanding of the neocortical epileptogenic network should allow the complete resection of the neocortical epileptogenic zone. Interpreting intracranial EEG is one of the processes that can extend our understanding of the neocortical epileptogenic network.
In this retrospective study, we attempted to identify, using surgical prognostic factors, the intracranial EEG findings that help to define the epileptogenic zone in focal neocortical epilepsy. We investigated the relationship between the extent of neocortical resection—based on the electrographic characteristics of intracranial EEG—and surgical outcomes.
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In this retrospective study, we found that the extent of resection was associated with the surgical outcome and that total resection, including all electrodes with ictal discharges during the first 3 sec, was a specific predictor of a good surgical outcome. Among the intracranial EEG findings, the total resection of electrodes displaying interictal pathologic delta waves or frequent interictal spikes was another strong predictor of a good surgical outcome (p = 0.001 and p = 0.02, respectively). Neither the distribution of ictal onset nor the propagation speed influenced the surgical outcome in patients with narrow neocortical resection. The presence of a visible lesion on MRI was significantly associated with a good surgical outcome (p < 0.001), which is consistent with the results of previous studies (Hennessy et al., 2001; Tassi et al., 2002; Cohen-Gadol et al., 2004; Tonini et al., 2004; Yun et al., 2006; Fauser et al., 2008).
A meta-analysis of the predictors of surgical outcome (Tonini et al., 2004) reported that various studies have confirmed a better surgical outcome after extensive resection than after limited resection. A recent study of subdural electrode analysis of cortical dysplasia (Widdess-Walsh et al., 2007) demonstrated that ictal onset at the edge of the subdural electrode coverage and incomplete resection of ictal epileptiform abnormalities predicted an increased risk of seizure recurrence. Another study also demonstrated that the complete resection of the ictal fields mapped with subdural electrode arrays gave a better prognosis than did partial resection (Jennum et al., 1993). We attempted to define more quantitatively the extent of resection that would achieve a good surgical outcome by dividing patients into three groups according to the extent of their resection. Our results should be helpful in deciding the extent of neocortical resection.
Subgroup analysis showed no relationship between the extent of resection and surgical outcome in neocortical TLE. In the meta-analysis discussed above, there was heterogeneity in the results assessing the extent of surgical resection and surgical outcome, and the authors suggested that the extent of resection may be affected by the underlying pathology and the site of surgery (Tonini et al., 2004). Although we tried to include only neocortical TLE patients in the present study, it is possible that some patients with “undetected” hippocampal epileptogenecity could be included in the present study, considering the most common pathology in our study was focal cortical dysplasia and the temporal cortical dysplasia is frequently associated with hippocampal sclerosis (Srikijvilaikul et al., 2003; Fauser et al., 2004), and it can in part explain the lack of relationship between the extent of resection and surgical outcome in the neocortical TLE subgroup.
It is important to note that the temporal lobe is a confined structure compared with the other lobes and, unlike mTLE, extra-TLE does not have a consistent epileptogenic network or spreading pathway. The epileptogenic network of extra-TLE is unknown, but based on our results, the initial ictal spreading area and the area with interictal abnormalities on intracranial EEG may be components of the epileptogenic network. There are a number of studies on the epileptogenic network in mTLE using various methods (Henry et al., 1993; Bertram et al., 1998; Bartolomei et al., 2001; Bernasconi et al., 2004; Mueller et al., 2004; Lin et al., 2007; Bartolomei et al., 2008). In these studies, epileptogenic zone giving rise to initial ictal discharge was more accurately defined as a network of neuronal structures rather than a focus of abnormal activity. The high epileptogenecity of hippocampus is generally accepted in patients with mTLE, so previous studies have focused on the epileptogenecity of parahippocampal areas and their connectivity with hippocampus. On the contrary, the analysis of epileptogenic zone in neocortical epilepsy is more complicated because of the heterogeneity of involved area and the underlying pathology. Moreover, the determination of epileptogenic network in neocortical epilepsy generally depends on proper electrode placement, but intracranial EEG monitoring was performed as a part of presurgical investigation, so the selection of patients and the implantation of electrodes were performed strictly according to the clinical needs of exact determination of the ictal-onset zone and eloquent area but not for a complete analysis of the neocortical epileptogenic network. It would be an important finding if we could map the epileptogenic network in neocortical epilepsy, but we think more elaborate design and analysis of intracranial electrical activity would be necessary to define the epileptogenic zone in neocortical epilepsy.
Our intracranial EEG findings indicated that two ictal-onset morphologies—sinusoidal waves and spikes or sharp waves—did not influence the surgical outcome. Furthermore, there was no significant difference in frequency between the three categories, although ictal onset in the beta or gamma range was more strongly associated with a good surgical outcome. The presence of focal high-frequency oscillations near the time of seizure onset may signify a proximity to the epileptogenic focus (Jirsch et al., 2006). In contrast, another study reported that patients with slow ictal-onset rhythms or repetitive sharp waves had a greater chance of being seizure-free than patients with low-voltage fast activity (Jung et al., 1999). Therefore, it remains unclear whether a specific ictal-onset morphology can predict a better surgical outcome.
As well as ictal intracranial EEG data, we investigated various interictal abnormalities. A resection that included frequent interictal spikes (> Hz) predicted a good surgical outcome. In these results, a concordance with the ictal discharges was important in deciding whether the electrodes with interictal spikes should be removed. Several authors have postulated that interictal epileptiform discharges are associated with good surgical outcomes in neocortical or medial TLE (Chee et al., 1993; Bautista et al., 1999; Lee et al., 2005; Stefan et al., 2008). The study of Bautista et al. demonstrated that the presence of interictal epileptiform discharges extending beyond the area of resection correlated with poor surgical outcomes in patients with extrahippocampal epilepsy. Therefore, they suggested that the spatial extent of the interictal epileptiform discharges may be a better estimate of the extent of the epileptogenic zone and should be used to determine the limits of surgical resection (Bautista et al., 1999). However, many are reluctant to rely on interictal spikes alone in planning surgery (Sperling, 2003). For example, multifocal spikes are common, and even though a structural epileptogenic lesion may be present focally, interictal spikes can be widespread in one or both hemispheres. Therefore, interictal spikes are most useful when considered in conjunction with ictal EEG findings (Sperling, 2003).
We also analyzed the relationship between interictal pathologic delta waves and surgical outcome, and the total removal of electrodes with pathologic delta waves resulted in a good surgical outcome. Therefore, pathologic delta waves can be one of the markers of local epileptogenicity in neocortical epilepsy. Furthermore, continuous focal delta activity strongly indicates the presence of underlying pathologic lesions. Not only the removal of the ictal-onset zone, but the removal of any pathologic lesion is important for a good prognosis in epilepsy surgery. In another study, interictal slow wave activities in the delta and theta bands were more frequent in the Engel I outcome group than in Engle II–IV group (Stefan et al., 2008). Focal spike activities and focal slowing represent functional disturbances, and they can provide additional information that can be used to define the extent of the resection.
Interictal or ictal paroxysmal fast activity has been proposed as a surrogate marker of epileptogenic networks (Rampp & Stefan, 2006; Widdess-Walsh et al., 2007; Jacobs et al., 2008). In our study, patients who underwent complete resection of fast activity had a better chance of a seizure-free outcome (57.1%, 8 of 14) than patients who underwent incomplete resection (33.3%, 2 of 6). However, this result was not statistically significant, also because the number of patients was small. In a previous study with focal cortical dysplasia (Widdess-Walsh et al., 2007), paroxysmal fast activity and slow runs of repetitive spikes were correlated closely with the ictal-onset zones. In our study, total removal of electrodes showing frequent interictal spikes was associated with a good surgical outcome, but we could not find any prognostic role of paroxysmal fast activity. We think this lack of association may be due to little overlap of interictal spikes and paroxysmal fast activity. Although there were overlap areas between these interictal patterns, repetitive interictal spikes were observed more frequently and the areas of interictal spikes were broader than those of paroxysmal fast activity in our study. To summarize, areas with both ictal onset and interictal abnormalities on intracranial EEG should be included in the limits of surgical resection if they are not located around the eloquent area.
Intracranial EEG monitoring was performed when other diagnostic modalities were nonconclusive or incongruent, and actually all patients with normal MRI who underwent surgical treatment underwent intracranial EEG monitoring. This particular indication of intracranial EEG monitoring in part explains the low diagnostic sensitivity of MRI in the present study and the apparent no outcome difference between the different pathologic subtypes. It is generally accepted that the surgical outcome of focal cortical dysplasia is no better than those of other pathologies, because the demarcation of the lesion is frequently poor and MRI frequently does not show any abnormalities in patients with pathologically proven focal cortical dysplasia (Widdess-Walsh et al., 2006). However, we believe that recruitment of a large number of patients may confirm the prognostic value of pathologic subtypes, even in patients who underwent intracranial EEG monitoring.
In conclusion, resection that includes more electrodes with ictal rhythm or interictal abnormalities predicts a good surgical outcome. However, it must be considered that the present study was retrospective design with a possibility of selection bias, and that more research is required to establish the surrogate intracranial EEG markers for the epileptogenic area to facilitate decisions regarding the extent of electrode resection.