A, The concordant results of ≥2 presurgical evaluations. B, The presence of aura. C, Localizing patterns of fluorodeoxyglucose–positron emission tomography (FDG-PET). D, Ictal single-photon emission computed tomography (SPECT). E, Complete resection of areas of ictal onset with interictal spikes.
eTable. Results of univariate and multivariate analyses of predictors of seizure-free outcomes at the last follow-up
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Kim DW, Lee SK, Moon H, Jung K, Chu K, Chung C. Surgical Treatment of Nonlesional Neocortical Epilepsy: Long-term Longitudinal Study. JAMA Neurol. 2017;74(3):324–331. doi:10.1001/jamaneurol.2016.4439
What are the long-term surgical outcomes and the possible prognostic factors in patients with nonlesional neocortical epilepsy?
In a long-term study that included 109 patients, nearly 60% of patients with nonlesional neocortical epilepsy achieved long-term freedom from seizure. Several factors, including localizing patterns in functional neuroimaging, concordant results in presurgical diagnostic evaluations, and the presence of aura, were associated favorable surgical outcome.
Patients with nonlesional neocortical epilepsy can be good surgical candidates, and the presence of predictors of favorable surgical outcome would help select optimal candidates for surgical treatment.
The proportion of surgery for nonlesional neocortical epilepsy has recently increased, with a decrease in surgery for mesial temporal lobe epilepsy. However, there are only a few studies regarding the long-term surgical outcome and the potential prognostic factors for patients with nonlesional neocortical epilepsy.
To evaluate the long-term surgical outcome and to identify possible prognostic factors in patients with nonlesional neocortical epilepsy.
Design, Setting, and Participants
In a surgical cohort from September 1995 to December 2005 at the Seoul National University Hospital, we included 109 consecutive patients without lesions identifiable by magnetic resonance imaging who underwent focal surgical resection for drug-resistant neocortical epilepsy. Follow-up information for at least 10 years was available for all but 1 patient.
Main Outcomes and Measures
Univariate and standard multiple logistic regression analyses were performed to identify the predictors of surgical outcomes, and a generalized estimation equation model was used for the longitudinal multiple logistic regression analysis of up to 21 years of follow-up.
The patients consisted of 64 men and 45 women with ages at surgery ranging from 7 to 56 years (mean [SD], 27.1 [7.8] years). At 1 year after surgery, 59 of 109 patients (54.1%) achieved seizure freedom, and 64 of 108 patients (59.3%) achieved seizure freedom at the last follow-up. Only 11 of 108 patients (10.2%) experienced definite changes in postoperative seizure status. Localizing patterns in functional neuroimaging (strongest odds ratio [OR], 0.30 [95% CI, 0.14-0.66] for fluorodeoxyglucose–positron emission tomography; 0.37 [95% CI, 0.15-0.87] for ictal single-photon emission computed tomography), concordant results in presurgical diagnostic evaluations (OR, 3.15 [95% CI, 1.42-7.02]), the presence of aura (OR, 3.49 [95% CI, 1.54-7.92]), and complete resection of areas of ictal onset with frequent interictal spikes during the intracranial electroencephalographic study (OR, 0.37 [95% CI, 0.16-0.85]) were favorable surgical outcome predictors.
Conclusions and Relevance
Our study showed that nearly 60% of patients with nonlesional neocortical epilepsy achieved freedom from long-term seizure, and that changes in postoperative seizure status were rarely observed. Several predictors of favorable surgical outcomes were identified, which can help select optimal candidates for surgical treatment among patients with nonlesional neocortical epilepsy.
Epilepsy surgery is an effective therapeutic option for patients with focal seizures who do not respond to appropriate treatment with antiepileptic drugs (AEDs).1 Patients with mesial temporal lobe epilepsy (mTLE) with lesions identifiable by magnetic resonance imaging (MRI) are the most common surgical candidates,2-4 but the surgical outcomes in patients with nonlesional mTLE are also favorable when seizure semiology and the results of other presurgical evaluations indicate the mesial temporal lobe as the only epileptogenic area.5-7 In patients with neocortical epilepsy, seizure semiology and the results of presurgical evaluations other than MRI are less helpful in identifying the epileptogenic areas,3,8-13 so surgical treatment in neocortical epilepsy has been offered more frequently to patients with MRI-identifiable lesions14 with the less satisfactory surgical outcomes in patients with nonlesional neocortical epilepsy.1,15
In our previous study,16 we documented several predictors of favorable surgical outcome in patients with nonlesional neocortical epilepsy. Since that study, several other important predictors of surgical outcome in neocortical epilepsy, such as the complete resection of the epileptogenic lesion and the pathological grade of focal cortical dysplasia (FCD), have been identified.17-21 In addition, to our knowledge have been no studies of the longitudinal prognosis after resective surgery in nonlesional neocortical epilepsy, whereas it is well established that changes in postoperative status are not uncommon in patients with mTLE.2,22-24 We performed the present study to identify the longitudinal surgical outcome in patients with nonlesional neocortical epilepsy. We also investigated the prognostic implications of clinical factors and other possible predictors of surgical outcome.
We included 109 consecutive patients without MRI-identifiable lesions who underwent focal surgical resection for drug-resistant neocortical epilepsy at the Seoul National University Hospital from September 1995 to December 2005. The patients consisted of 64 men and 45 women with ages at surgery ranging from 7 to 56 years (mean [SD], 27.1 [7.8] years). Age at seizure onset ranged from 0 to 49 (13.6 [7.6]) years, and the duration of illness from 1 to 47 (13.4 [7.3]) years. All patients had drug-resistant epilepsy despite treatment with at least 2 appropriately chosen AEDs. We included only patients with focal resection and excluded patients with functional hemispherectomy, corpus callosotomy, hippocampal sclerosis on MRI, or a medial temporal ictal onset area during the intracranial electroencephalographic (EEG) studies.
A standard epilepsy brain MRI protocol was performed in all patients on either a 1.0- or 1.5-T unit (Signa Advantage; General Electric Medical Systems) with conventional, spin-echo T1-weighted sagittal and T2-weighted axial coronal sequences. T1-weighted 3-dimensional magnetization prepared rapid acquisition with gradient-echo sequences and 1.5-mm-thick sections of the whole brain, and T2-weighted and fluid-attenuated inversion recovery images with 3-mm-thick sections were also obtained in the oblique coronal plane of the temporal lobe.
Fluorodeoxyglucose–positron emission tomography (FDG-PET) was performed in 99 patients during the interictal period (no seizures lasting >24 hours). Axial raw data were obtained using a PET scanner (ECAT EXACT 47; Siemens-CIT) 60 minutes after the intravenous injection of fluorodeoxyglucose F 18 (FDG; 370 MBq). The FDG-PET images were assessed visually and by Statistical Parametric Mapping analysis, as described previously.25 Ictal single-photon emission computed tomography (SPECT) was performed in 71 patients during video-EEG monitoring. Technetium Tc 99m was mixed with hexamethylpropyleneamine oxime (925 MBq) and injected as soon as a seizure started. Interictal SPECT was performed to identify perfusion changes. Side-by-side visual analysis of interictal and ictal images and the subtraction method were performed using a method described previously.26 The results of FDG-PET and ictal SPECT were defined as localizing if the predominant hypometabolic area on the FDG-PET or the predominant hyperperfusion area on the ictal SPECT was confined to the resected lobe, and diffuse or multifocal abnormalities beyond the epileptogenic area were not considered as localizing even when they were located within the epileptogenic hemisphere including the epileptogenic area.
Interictal and ictal scalp EEG was performed in all patients using a video-EEG monitoring system, with electrodes placed according to the International 10-20 System and additional anterior temporal electrodes. A localized pattern of ictal-onset rhythm and interictal spike was defined as a localized ictal rhythm and interictal spike that was confined to the electrodes of an epileptogenic lobe or 2 adjacent electrodes. Intracranial EEG was also performed in all patients with a combination use of grids and strips. Grid and strip placements were determined by the seizure semiology and the results of presurgical evaluations. The distribution of seizure onset was categorized as focal (involving <5 adjacent electrodes), regional (≥5 adjacent electrodes), or widespread (>20 adjacent electrodes). The intracranial ictal onset area was defined as the area with the first sustained rhythmic change in EEG that was differentiated from the background and interictal waves. The onset frequency was characterized in rhythmic spikes or in traditional EEG bands: beta, alpha, theta, and delta. At least 3 habitual seizures were recorded during scalp and intracranial EEG studies. When necessary, preoperative and intraoperative functional mapping and intraoperative electrocorticography were also performed. The detailed methods used in presurgical evaluations were described previously.16,17
The resection margin was decided by an intracranial ictal onset area including the area with persistent pathological delta slow activity and the absence of an eloquent cortex. Complete resection was defined when the resection margin included (1) all of the ictal onset area spreading within 3 seconds after ictal onset and (2) the area of persistent delta slow activity when present near the ictal onset area during the intracranial EEG study. In patients with frequent interictal spikes outside the ictal onset area, the prognostic implication of the complete resection, including all the areas of ictal onset with frequent interictal spikes (more frequent than 0.2 Hz), was also studied. The criteria of resection margin of time limit of ictal onset (3 seconds) and frequency of interictal spikes (0.2 Hz) were adopted from our previous study of intracranial EEG in neocortical epilepsy.21 Complete tissue sections from cortical resections were immersion fixed in 10% buffered formalin, embedded in paraffin, and stained with hematoxylin-eosin, Bielschowsky stain, and cresyl violet. The pathologic finding of FCD was reevaluated and classified according to the recently revised classification scheme.25
Follow-up information for at least 10 years was available for all but 1 patient, who died in an accident after 3 years of follow-up. Surgical outcome was classified into 4 groups according to the Engel classification.27 Surgical outcome was also divided according to the presence (Engel class I) or absence (Engel classes II, III, and IV) of achievement of seizure freedom. Outcome was determined at each year up to 21 years after surgery. Patients whose outcomes changed during the follow-up period were also identified. In these patients, we attempted to isolate clinical characteristics related to specific patterns of change in outcome status during the follow-up. The surgical outcomes during the follow-up periods were estimated on a year-by-year basis, and the assessment of final surgical outcome was based on the seizure status during the past 2 years.
Surgical outcomes were assessed at each year during the postsurgical follow-up period. We studied the prognostic role of the clinical characteristics of the patients, such as age at surgery, age of onset, duration of epilepsy, seizure frequency per month, location of epileptogenic foci, the presence of aura, the possibility of localization or lateralization by seizure semiology, results of FDG-PET, ictal SPECT, interictal EEG, ictal EEG, and the features of the intracranial EEG study. We also studied the prognostic role of concordance in the localizing patterns in the epileptogenic areas of noninvasive presurgical evaluations (ie, FDG-PET, ictal SPECT, interictal EEG, and ictal EEG). Univariate analyses of the predictors of surgical outcomes were performed on these variables at 1 year, 10 years, and the last follow-up after surgery. Multiple logistic regression for multivariate analysis was also performed. In this analysis, we included independent variables with P < .05 in the univariate analysis. For multivariate analysis using repeated measures of outcome up to 21 years after surgery, we applied a generalized estimation equation (GEE) model.28 AutoRegressive order 1 structure was used to model the possible dependency among repeated measurements in a patient. The GEE method was applied because of the possible intrapatient correlations. All the analyses were performed using SAS statistical software (version 9.3; SAS Inc) and R language (version 3.2.0; R Foundation for Statistical Computing). The GEE analysis was performed using an SAS GENMOD procedure, and binary logistic regression was performed via an SAS LOGISTIC procedure.
Among the patients, 39 patients had frontal lobe epilepsy, 44 had neocortical temporal lobe epilepsy, 12 had parietal lobe epilepsy, 13 had occipital lobe epilepsy, and 1 had multifocal epilepsy. The most common pathological diagnosis was FCD (65 patients), followed by nonspecific gliosis (14 patients), mild malformation of cortical development (13 patients), polymicrogyria (4 patients), ischemic change (2 patients), and postinfectious change (1 patient). The pathological grade of FCD was further classified into FCD type I (48 patients) and FCD type II (16 patients), and 1 patient who had the pathological features of FCD and dysembryoplastic neuroepithelial tumor was classified as having FCD type III. At 1 year after surgery, 59 of 109 patients (54.1%) achieved seizure freedom (Engel class I), and an additional 37 patients (33.9%) experienced worthwhile improvement (Engel class II, III). Among the 59 patients with seizure freedom, 47 patients had a history of aura before surgery, and 17 of them had persistent aura despite the disappearance of clinical seizure. Two of 17 patients experienced early recurrence of clinical seizure, while 4 patients had gradual disappearance of aura during the long-term follow-up. The proportion of patients with seizure freedom and worthwhile improvement was not significantly changed at 10 years of follow-up after surgery because 64 of 108 patients (59.3%) achieved seizure freedom at 10 years after surgery and an additional 32 patients (29.6%) experienced worthwhile improvement (Table 1). When the last follow-up of each individual patient was considered, 64 of 108 patients (59.3%) achieved seizure freedom and an additional 33 patients (30.6%) experienced worthwhile improvement. All of the AEDs were withdrawn successfully without seizure recurrence in 23 out of 64 patients (35.9%) at the last follow-up. During the long-term follow-up, 6 patients experienced a gradual but definite improvement that could not be explained by a better compliance (running-down phenomenon), whereas 5 patients experienced aggravation of seizure during the follow-up or recurrence of seizure after the initial seizure-free period. However, the proportion of patients with changes in postoperative status was small compared with that of mTLE, and we could not find consistent patterns of a running-down phenomenon or delayed recurrence up to 21 years of follow-up (Table 1).
The univariate analysis revealed that localizing patterns in FDG-PET (odds ratio [OR], 0.30 [95% CI, 0.14-0.66]) and ictal SPECT (OR, 0.37 [95% CI, 0.15-0.87]), high concordance (≥2) in the noninvasive presurgical evaluations (OR, 3.15 [95% CI, 1.42-7.02]), and complete resection of areas of ictal onset with frequent interictal spikes during the intracranial EEG (OR, 0.39 [95% CI, 0.17-0.90]) were significant prognostic factors for postsurgical outcome at 1 year; however, none of these prognostic factors was an independent predictor of the seizure-free outcomes in the multivariate analysis. At 10 years of follow-up, the presence of aura (OR, 2.52 [95% CI, 1.12-5.68]), higher concordance (≥2) in the presurgical evaluations (OR, 2.41 [95% CI, 1.09-5.33]), and complete resection of areas of ictal onset with frequent interictal spikes (OR, 0.40 [95% CI, 0.18-0.92]) were significant prognostic factors, and the presence of aura (OR, 2.37 [95% CI, 1.01-5.56]) remained an independent prognostic factor in the multivariate analysis (Table 2). We also analyzed the surgical outcome at the last follow-up of the patients. The univariate analysis revealed that the presence of aura (OR, 3.49 [95% CI, 1.54-7.92]), higher concordance (≥2) in the presurgical evaluations (OR, 2.53 [95% CI, 1.15-5.57]), and complete resection of areas of ictal onset with frequent interictal spikes (OR, 0.37 [95% CI, 0.16-0.85]) were significant prognostic factors, and the presence of aura (OR, 3.48 [95% CI, 1.46-8.28]) and complete resection of areas of ictal onset with frequent interictal spikes (OR, 0.37 [95% CI, 0.15-0.91]) were independent prognostic factors in the multivariate analysis (eTable in the Supplement). By longitudinal analysis using GEE for repeated measures of outcome after surgery, localizing patterns of FDG-PET (OR, 0.33 [95% CI, 0.16-0.69]) and ictal SPECT (OR, 0.32 [95% CI, 0.14-0.74]) and higher concordance (≥2) in the presurgical evaluations (OR, 3.03 [95% CI, 1.45-6.33]) were significant predictors of seizure-free outcome; however, none of these parameters remained an independent prognostic factor in the multivariate analysis (Table 3). Surgical outcomes according to the results of important prognostic factors, including the concordant results of 2 or more presurgical evaluations, the presence of aura, localizing patterns of FDG-PET and ictal SPECT, and complete resection of areas of ictal onset with interictal spikes, are illustrated in the Figure.
Although patients with nonlesional neocortical epilepsy have not been considered as optimal candidates for surgical treatment, recent survey studies showed that there is a strong shift toward a greater proportion of surgery for nonlesional neocortical epilepsy, with a decrease in the number of surgical procedures for mTLE,29,30 while there are no significant changes in the total number of surgical procedures to treat epilepsy.31 However, there are only a few studies regarding the long-term surgical outcome and the potential prognostic factors for patients with nonlesional neocortical epilepsy. In the present study, we observed that nearly 60% of patients achieved long-term seizure freedom, and that all AEDs were withdrawn successfully in one-third of these patients. The chance of seizure freedom was lower than those of mTLE and lesional neocortical epilepsy2,19; however, it was notable that nearly 90% of patients benefited from resection surgery for nonlesional neocortical epilepsy.
Changes in postoperative seizure status during the long-term follow-up period are a rather common phenomenon in patients with mTLE.22 The achievement of delayed seizure freedom (ie, running-down phenomenon) occurs frequently in patients with rare postoperative seizure, and it has been speculated that the epileptogenic area in these patients was not completely resected but rather considerably reduced, and that the remaining smaller epileptogenic area gradually loses its power to generate seizures or can be controlled much better by AEDs than prior to surgery.23 Conversely, postoperative seizure recurrence in mTLE has been explained in 2 different ways: early postoperative seizure recurrence might be caused by an incomplete resection of the epileptogenic area, while late seizure recurrence might result from the development of a new epileptogenic area, possibly reflecting an underlying epileptogenic tendency.24 In our surgical cohort with mTLE, more than 30% of patients experienced changes in postoperative seizure status during the 5 years of follow-up after surgery,2 but only 11 of 108 patients (10.2%) experienced changes in postoperative seizure status in the present study of nonlesional neocortical epilepsy. The cause of this difference is not clear, but it may be related to the difference in pathology or epileptogenic neuronal networks between patients with mTLE and those with neocortical epilepsy.
Our univariate and multivariate analyses revealed that favorable surgical outcome predictors included the localizing patterns of functional neuroimaging (FDG-PET and ictal SPECT), concordant results of presurgical diagnostic evaluations, the presence of aura, and the complete resection of areas of ictal onset with frequent interictal spikes during the intracranial EEG study. Although the presence and the pathological grade of FCD were frequently associated with the outcomes of neocortical epilepsy surgery,17-19 our study failed to find a prognostic implication for the pathological diagnosis of FCD, including the presence and pathological grade of FCD, and the presence of developmental anomaly, including FCD. The role of functional neuroimaging in the prediction of the surgical outcome of neocortical epilepsy has been well documented,16,17 and the clinical importance of functional neuroimaging would be even higher in nonlesional neocortical epilepsy because localizing patterns in FDG-PET or ictal SPECT can be considered an important clue for the epileptogenic area, giving useful information in the placement of electrodes during intracranial EEG studies. Our study also showed that a favorable surgical outcome could be expected when the results of presurgical evaluations indicated concordant results regarding the epileptogenic area. It is easily conceivable that a high concordance in noninvasive presurgical evaluations can provide additional confidence to the localization of the epileptogenic area.19,32
It is a common assumption that auras reported by patients with partial seizures indicate the part of the brain in which seizures start, thus providing useful localizing information. Therefore, the presence of aura in concordance with an abnormality on neuroimaging is considered strong evidence of an epileptogenic area, and aura can act as a guiding parameter in the placement of intracranial EEG electrodes.33,34 Patients with mesial temporal and occipital lobe seizures have a higher chance of having auras, which could be explained by the fact that, compared with the widespread silent area of the frontal or parietal areas, the medial temporal and occipital lobes are closely related to the functionally eloquent areas.16,35 However, the localizing value of auras in epilepsy surgery has been questioned in some studies because many studies have failed to demonstrate any significant localizing value for isolated signs or symptoms,10,36,37 and MRI abnormalities had a more important prognostic value than did clinical semiology and EEG findings.12 In our previous study,38 certain types of aura conveyed important information regarding the differentiation of epilepsy syndromes, especially in patients with occipital and frontal lobe seizures. Although the present study showed that the presence of aura may have a prognostic implication in the surgical treatment of neocortical epilepsy, we failed to identify the prognostic role of the possibility of localization or lateralization by seizure semiology in our patients.
Intracranial EEG is one of the most important procedures for the planning of surgery and for achieving a favorable surgical outcome in respective epilepsy surgery. In nonlesional neocortical epilepsy, the identification of the resection margin by intracranial EEG is almost an essential part of the presurgical diagnosis; however, there are no consistent guidelines for resection based on intracranial EEG in neocortical epilepsy.21,39 Because electrodes implanted during intracranial EEG studies necessarily record from a limited area of cortex, the first EEG change does not always indicate a true ictal onset area, and some patterns may represent a propagated phenomenon.40 It has been documented that the localization patterns of ictal onset and complete resection of ictal onset area were associated with a favorable surgical outcome,17,18 and we found that the complete resection of areas of ictal onset with frequent interictal spikes was associated with a favorable surgical outcome in patients with nonlesional epilepsy.
This study had several limitations. First, the study included a small number of patients in a single epilepsy center. Therefore, we cannot generalize our results to all epilepsy surgery patients. Second, with the long duration of the inclusion period, it is possible that improved surgical skill or diagnostic sensitivity of functional neuroimaging affected the surgical outcomes. Finally, surgical treatment was offered more frequently to patients with localizing patterns in scalp EEG or functional neuroimaging, there is the possibility of selection bias.
Our study showed that nearly 60% of patients with nonlesional neocortical epilepsy achieved the long-term seizure freedom and that changes in postoperative seizure status were rarely observed. Several predictors of favorable surgical outcomes were identified, which can help select optimal candidates for surgical treatment among patients with nonlesional neocortical epilepsy.
Corresponding Author: Sang Kun Lee, MD, PhD, Department of Neurology, Seoul National University Hospital, 28, Yongkeun Dong, Chongno Ku, Seoul 110-744, Korea (firstname.lastname@example.org).
Accepted for Publication: September 12, 2016.
Published Online: January 3, 2017. doi:10.1001/jamaneurol.2016.4439
Author Contributions: Dr Kim had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Kim, Lee.
Acquisition, analysis, or interpretation of data: Kim, Moon, Jung, Chu, Chung.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: Lee.
Statistical analysis: Kim, Moon.
Study supervision: Lee.
Conflict of Interest Disclosures: None reported.
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