Neuroimaging in identifying focal cortical dysplasia and prognostic factors in pediatric and adolescent epilepsy surgery

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1 FULL-LENGTH ORIGINAL RESEARCH Neuroimaging in identifying focal cortical dysplasia and prognostic factors in pediatric and adolescent epilepsy surgery *Yoon Hee Kim, *Hoon-Chul Kang, ydong-seok Kim, zse Hoon Kim, ykyu-won Shim, *Heung Dong Kim, and *Joon Soo Lee *Department of Pediatrics, Pediatric Epilepsy Clinics, Severance Children s Hospital, Epilepsy Research Center, Yonsei University College of Medicine, Seoul, Korea; ydepartment of Neurosurgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; and zdepartment of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea SUMMARY Purpose: The purpose of this study is to determine the sensibility of each imaging tool in identifying focal cortical dysplasia (FCD) in children and adolescents with epilepsy and to define the prognostic factors of pediatric and adolescent epilepsy surgery. Methods: We identified 48 children with FCD who underwent resective surgery and analyzed their preoperative data. The results of various anatomic and functional neuroimaging studies were compared for accuracy in locating the lesion. We also investigated clinical factors that affected the outcome of surgical treatment. Key Findings: Brain magnetic resonance imaging (MRI) was able to localize FCD in 30 patients and fluorodeoxyglucose positron emission tomography (FDG-PET) and/or subtraction ictal single photon emission computed tomography (SPECT) coregistered with MRI provided additional information that helped to define the lesion in 13 patients. When comparing the pathologic results between a mild malformation of cortical development (MCD) and FCD type I and II, we noted a strong tendency for patients with FCD to have MRI abnormalities (p = 0.005). In addition, severe pathologic features (Palmini s classification, FCD type II) (p = 0.025) showed significant correlation with a better surgical outcome. To define the primary epileptogenic area, various interictal epileptiform discharges and the results of multimodal neuroimaging studies were helpful, and younger age at the time of operation could aid in more favorable surgical outcomes (p = 0.048). Significance: Our study showed a significant relationship between pathologic grade and the detectability of FCD by brain MRI. In addition, early surgery can be justified by showing that advanced neuroimaging studies in children with FCD and even with extensive epileptiform discharges have a higher rate of success. KEY WORDS: Neuroimaging, Cortical dysplasia, Pediatric and adolescent epilepsy surgery. Cortical dysplasia (CD) is a derangement of cortical organization (Palmini, 2000; Bentivoglio et al., 2003; Foldvary- Schaefer et al., 2004) and the most predominant etiology in pediatric candidates for epilepsy surgery (Kloss et al., 2002). The histopathology of CD is classified into mild malformation of cortical development (MCD) with ectopically placed neurons, mild focal CD (FCD) type I (type IA, isolated architectural abnormalities, and type IB, additional immature or giant neurons) and severe type II (type IIA, Accepted November 17, 2010; Early View publication January 28, Address correspondence to Joon Soo Lee, MD, PhD and Heung Dong Kim, MD, PhD, Department of Pediatrics, Pediatric Epilepsy Clinics, Severance Children s Hospital, Brain Research Institute, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul, Korea. Joonsl96@yuhs.ac and hdkimmd@yuhs.ac Drs Yoon Hee Kim and Hoon-Chul Kang contributed equally to this work. Wiley Periodicals, Inc. ª 2011 International League Against Epilepsy presence of dysmorphic neurons, and type IIB, additional balloon cells) (Palmini et al., 2004). Recent advances in neuroimaging modalities have detected FCD that eventually evolves into secondary generalized epileptic encephalopathy in children with epilepsy (Lee et al., 1998; Widdess-Walsh et al., 2006). Brain magnetic resonance imaging (MRI) can detect FCD much better in severe pathologic subtypes than in mild subtypes (Kim et al., 2009a), and positron emission tomography (PET) has been suggested to be more helpful than magnetic resonance imaging (MRI) in detecting the mild pathologic subtype (Kim et al., 2000; Gupta et al., 2004; Salamon et al., 2008). Because surgical planning for a complete resection is more favorable in patients with FCD, which is well-demarcated in MRI, we assume that there is a strong tendency for patients with severe pathologic subtype-like balloon cells to have better surgical outcomes (Tassi et al., 2002; Lawson et al., 2005; Kim et al., 2009a). In pediatric and adolescent patients with more extensive epileptogenic areas, however, 722

2 723 Cortical Dysplasia in Epilepsy Surgery studies to verify the accuracy and effectiveness of these imaging modalities in localizing the epileptogenic foci are still lacking, and their relationships to the severity of the pathology have not been adequately evaluated. In addition, the prognostic factors of pediatric and adolescent epilepsy surgery in these patients are still controversial (Kloss et al., 2002; Tassi et al., 2002; Lawson et al., 2005). In this study, we directly compared MRI to other functional neuroimaging techniques to evaluate the roles of these studies in detecting CD, and also analyzed surgical outcomes according to pathologic subtypes of the dysplastic cortex and other clinical factors in children and adolescents with intractable epilepsy. Methods Patients Of 55 total patients who had undergone epilepsy surgery at Severance Children s Hospital from October 2003 to June 2009 with a pathologic diagnosis of CD, 48 cases were retrospectively evaluated. We excluded seven patients who had other potentially epileptogenic lesions such as hippocampal sclerosis in two patients, tuberous sclerosis in three patients, glioma in one patient, and periventricular heterotopia in one patient. The patients seizures were not controlled, despite the proper combination of anticonvulsant drugs. All patients were evaluated by video electroencephalography (EEG) monitoring, various neuroimaging studies including highresolution MRI, fluorodeoxyglucose (FDG) PET, and subtraction ictal single photon emission computed tomography (SPECT) co-registered to MRI (SISCOM). Semiology and electroencephalography All patients were examined using a video-eeg monitoring system with electrodes placed according to the international system to define the semiology of habitual seizures and to search for the epileptogenic foci. Epileptogenic areas were delineated primarily through the interpretation of EEG data, and other imaging modalities were used to reinforce the results. In patients who had conflicting results between evaluative modalities, direct cerebral monitoring results obtained through subdural electrodes were used to determine the surgical resective margins. At least five habitual seizures were recorded during scalp and intracranial EEG monitoring. Preoperative and intraoperative functional mapping and intraoperative electrocorticography were also performed as necessary (Kim et al., 2009b; Lee et al., 2010). Neuroimaging studies The standard MRI was performed with conventional spin echo T 1 -weighted sagittal, T 2 -weighted axial, flair axial, oblique coronal, and flair oblique coronal sequences, as well as with ultrafast gradient echo T 1 -weighted threedimensional (3D) coronal sequences. A Philips MRI Achieva 3.0 T Release (Philips Medical Systems, Best, The Netherlands) was used to acquire seizure-specialized sequences termed seizure phase 1 images, in accordance with the protocol described in our previously published study (Kim et al., 2009b; Lee et al., 2010). PET images were acquired using a GE ADAVANCE Scanner (GE, Milwaukee, WI, U.S.A.) in 3D mode. The transaxial resolution of the system was 5.2 mm full-width half-maximum (FWHM) at the center of the field of view (FOV). Approximately 5 mci of 18F-FDG was injected intravenously. The emission scan was started at 40 min after injection and lasted for 15 min, and an 8-min transmission scan was subsequently acquired for the purpose of attention correction. FDG-PET using a 10% cutoff threshold with an asymmetry index was processed by regional cortical FDG- PET abnormalities defined on partially volume-corrected PET images using an objective method based on a semiautomated definition of areas with abnormal asymmetry (Lee et al., 2001). Structural lesions were defined on the coregistered MRI. Grid placement was based on the hypometabolic lesions. For acquisition of SISCOM images, patients underwent ictal and interictal SPECT studies at intervals of <1 week. As a radiotracer, approximately MBq of technetium-99m ethyl cysteinate dimer was administered intravenously. Video-EEG monitoring was conducted continuously in the EEG monitoring unit while radiotracer was injected intravenously during the ictal period for acquisition of ictal SPECT. Seizure onset was defined as the time of earliest indication of auras or the beginning of rhythmic ictal discharges on EEG. Seizure termination was defined as the time when ictal movement ceased or the time of termination of the ictal discharge. Brain images were obtained using a brain-dedicated annular crystal gamma camera (Digital Scintigraphic Incorporated, Waltham, MA, U.S.A.) equipped with low-energy, high-resolution parallel-hole collimators. The FWHM of a high-resolution collimator is typically 7.5 mm at the center of rotation and 5.8 mm at the peripheral regions, 9 cm from the center of rotation. SPECT studies were taken for 20 min in a matrix with 38 angular increments. Transaxial images were obtained by the filtered back-projection method using a Butterworth filter (cutoff frequency of 1.1 cycles/cm, order no. 10). Attenuation correction was performed by Chang s method after correcting for scatter by the dual-energy window method, and coronal and sagittal images were generated. After acquisition of ictal and interictal SPECT images, 32 transaxial slices of both ictal and interictal scans were reconstructed and each paired image was generated with the same orientation and level for the construction of subtraction images. Paired ictal and interictal transaxial images were normalized to the total counts, and interictal images were subtracted from ictal images on a CeraSPET workstation (Digital Scintigraphic Incorporated). Subtraction images

3 724 Y. H. Kim et al. were generated without applying a threshold and were qualitatively evaluated. Seizure localization was determined when the pixels on ictal scans showed higher values than those on interictal scans of corresponding regions (Kim et al., 2009b; Lee et al., 2010). All images were categorized into two groups: localizing and nonlocalizing. Localizing was defined as allowing for localization of epileptogenic lesions, and nonlocalizing was defined as not clearly showing the locations of epiletogenic lesions. Surgery and pathology The surgical area was decided upon based on clinical, neuroimaging, and electrophysiologic results. In our center, the resection margin for epilepsy of the neocortical origin was defined by (1) the presence of either a discrete lesion on the MRI with a compatible ictal EEG or a massive and exclusive ictal-onset zone confirmed by intracranial EEG; (2) various interictal intracranial EEG findings including >3/s repetitive spikes, runs of repetitive spike and slow wave discharges, localized or spindle shaped fast activities, and electrodecremental fast activities; and (3) the absence of the eloquent cortex. Complete resection was defined by resection of all of the MRI-visible lesions as well as areas with seizure-onset zones on intracranial EEG (Kim et al., 2009b; Lee et al., 2010). The diagnosis and classification of pathologic CD were done according to the system devised by Palmini et al. (2004): ectopically placed neurons only (mild MCD), isolated architectural abnormalities (FCD type IA), additional immature or giant neurons (FCD type IB), presence of dysmorphic neurons (FCD type IIA), and additional balloon cells (FCD type IIB). In this study, we defined the severe pathologic subtypes as FCD IIA and FCD IIB, and the mild pathologic subtypes as the others for the prognostic factors. Statistical analysis The association between the pathologic subtypes and the diagnostic sensitivity of various neuroimaging studies were tested using a chi square test and Fisher s exact test. The correlation among each imaging modality was tested with McNemar s test. Univariate and multivariate analyses were used to predict the prognostic factor. We selected the proper variables for multivariate analysis through stepwise variable selection. SPSS version 17 (SPSS Datasolution Inc., Seoul, Korea) was used for this study and p-value <0.05 was considered statistically significant. Results Patients and surgical outcomes The ages of the 48 patients (boys 26, girls 22) at surgery ranged from 0.2 to 23 years old [mean standard deviation (SD); years]. The duration between seizure onset and epilepsy surgery ranged from 0.2 to 16 years (mean SD; years). The duration of the follow-up after surgery was between 0.7 and 5.5 years (mean SD; years). Patients were diagnosed with various epilepsy syndromes and also showed numerous seizure types. Seven patients (15%) were diagnosed with infantile spasms, 14 patients (30%) with Lennox-Gastaut syndrome, and two patients (2%) with early infantile epileptic encephalopathy. Among these 23 patients, only 7 patients had consistent focal ictal/interictal epileptiform discharges, and the other 16 patients had abundant generalized ictal/interictal discharges. Twenty-five patients (52%) had partial seizure with or without secondary generalization. Of these 25, three patients also had abundant generalized ictal/ interictal epileptiform discharges. Eighteen patients (38%) underwent multilobar resection. Thirty patients (63%) underwent single lobar resection: frontal in 25 patients, parietal in one patient, temporal in 2 patients, and occipital in 2 patients. Of 48 patients, Engel s class I outcome (free of disabling seizures) was achieved in 27 patients (56%); of these 27, 14 patients (29%) were able to discontinue anticonvulsants and the other 13 patients (27%) have gradually been decreasing their dosage and the number of medications. Engel s class II outcome (infrequent seizures) was achieved in 12 patients (25%); an additional 6 patients (13%) achieved class III (worthwhile improvement), whereas 3 patients (6%) had class IV (no significant reduction in seizure frequency). Diagnostic values of neuroimaging The diagnostic sensitivity of the MRI was 62% in a total of 48 patients and PET was 83% in 36 patients. The diagnostic sensitivity was the highest for SPECT, which was 89% in 27 patients (Fig. 1). The total number of patients who underwent MRI and PET were 36. There were 11 patients (31%) in whom the lesion was not detected in the MRI but in the PET, and 2 patients in reverse (6%). We used McNemar s test to clarify that the detection power of PET was better than that of MRI when the lesion was not detected in MRI. This clarification was statistically notable, with a p-value of In the MRI versus SPECT analysis, SPECT could detect the lesion better than MRI in MRI nonlocalizing (p = 0.020). In the PET versus SPECT analysis, however, there was no statistic difference in sensitivity (Table 1). When comparing pathologic results between MCDs and FCD types I and II, we noted a strong tendency for patients with FCD to have MRI abnormalities (p = 0.005) (Fig. 1A). However, between FCD type I and type II, there was not any difference in the detection rate by MRI (p = 1.000) (Fig. 1B). Prognostic factors Upon univariate analysis, younger age at operation (p = 0.048) and more severe pathologic features (FCD type

4 725 Cortical Dysplasia in Epilepsy Surgery A Figure 1. Diagnostic sensitivity according to pathologic subtypes, mild malformation of cortical dysplasia (MCD), and focal cortical dysplasia (FCD) (A) and according to pathologic subtypes, focal cortical dysplasia type I (FCD I), and focal cortical dysplasia type II (FCD II) (B). Epilepsia ILAE B Table 1. Correlation of neuroimaging studies in diagnosis of cortical dysplasia; McNemar s test Loc-Loc NLoc-Loc Loc-NLoc NLoc-NLoc p-value MRI-PET (n = 36) 4 11* MRI-SISCOM (n = 27) 2 8* PET-SISCOM (n = 24) 0 2* MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single photon emission computed tomography; Loc, Localizing; NLoc, nonlocalizing. *p < Table 2. Clinical prognostic factors of epilepsy surgery in children with intractable epilepsy; univariate analysis Seizure-free (n = 27, 56%) Not seizure-free (n = 21, 44%) p-value Age at operation 5.96 ± ± (years, mean ± SD) Duration of epilepsy 4.17 ± ± (years, mean ± SD) Male/female 12/15 14/ MRI, localization Ictal EEG, localized ictal onset zone Pathologic subtypes (severe:mild) 19:8 8: MRI, magnetic resonance imaging; EEG, electroencephalography. II by Palmini s classification) (p = 0.025) were significantly correlated with a better surgical outcome. Shorter duration of epilepsy before the operation tended to have more favorable surgical outcomes (p = 0.071), although without Table 3. Clinical prognostic factors of epilepsy surgery in children with intractable epilepsy; multivariate analysis p-value OR Age at operation (years, mean ± SD) Pathologic subtypes OR, odds ratio. statistical significance (Table 2). Upon multivariate analysis, these same variables were significantly associated with a better surgical outcome (Table 3). Interestingly, in 20 patients whose numbers included 10 of the 14 patients with Lennox Gastaut syndrome, 5 of 8 patients with infantile spasms, 2 of 2 patients with early infantile epileptic encephalopathy (EIEE), and 3 of 24 with partial seizures we could not completely resect areas with interictal/ictal epileptiform discharges and/or persistent polymorphic delta waves. Nevertheless, two patients with Lennox-Gastaut syndrome, four patients with infantile spasms, both patients with EIEE, and all three patients with partial seizures were able to obtain Engel s class I outcome.

5 726 Y. H. Kim et al. Discussion A high-resolution MRI could define most cases of FCD, and functional neuroimaging studies including PET and SISCOM provided additional information to delineate brain lesions in patients with mild MCDs. In terms of prognostic factors, more severe pathologic grade and younger age of operation were important factors in determining better surgical outcomes. Because pediatric CD has frequently been associated with early seizure onset, developmental delay, and poor outcome with antiepileptic medication, it is usually treated by epilepsy surgery instead of with medication only (Duchowny et al., 1998; Wyllie et al., 1998). The advanced MRI technique was able to detect more lesions in CD than before (Eriksson et al., 2004; Kim et al., 2009a), but the diagnostic sensitivity of mild MCD by MRI was 35%, which was lower than that of FCD by MRI (FCD type IA, 100%; FCD IB, 67%; FCD IIA, 73%; FCD IIB, 77%). Mild MCD was more detectable in PET and SPECT (Eriksson et al., 2004; Gupta et al., 2004; Salamon et al., 2008; Kim et al., 2009b). It was clarified that the percentage of cases with MRI discordance and PET localization was higher than that in reverse through the McNemar s test in p < The same result occurred in MRI versus SPECT, but in PET versus SEPCT, one of them did not detect the epileptogenic lesions any better than the other. In other words, PET and SPECT can detect epileptogenic lesions better than MRI, especially in the case of a nonlocalizing MRI. Focal hypometabolism of PET and the perfusion pattern of ictal/interictal SPECT were highly concordant to focal brain MRI lesions and could support ictal semiology and lateralized patterns of video-eeg monitoring to determine the area for intracortical recording (Obeid et al., 2009). On the other hand, those patients who do not display a lesion on brain MRI can benefit from functional imaging for focus localization (Kim et al., 2009b). We found pathologic grade to be correlated with surgical outcome, and those patients with FCD type II had a higher chance of being seizure-free after surgery. The correlation between detection from MRI in patients with severe pathology and a better surgical outcome has been described in earlier publications. Although Keene et al. (1998) and Kloss et al. (2002)) found no differences between histologic subtypes, most studies have agreed that FCD type IIB (with balloon cells) had the most favorable outcome (Chassoux et al., 2000; Tassi et al., 2002), although this subtype is believed to be associated with clinically and electrocorticographically increased epileptogenicity. Some studies have shown that patients with FCD type I and mild MCD had a better outcome compared with those who had more severe forms of CD (Palmini et al. 1994; Fauser et al., 2004). In this study, patients with FCD type II had a higher chance of seizure freedom. Previous studies have also shown that severe pathology can be more detectable by MRI, which can make surgical planning more accurate and thus lead to a successful surgical outcome (Tassi et al., 2002; Lawson et al., 2005; Kim et al., 2009a). However, we could not directly clarify this correlation between detection by MRI and surgical outcome. It can be assumed that severely dysplastic areas are more epileptogenic, regardless of the presence of an MRI abnormality, and that highly epileptogenic areas have a greater chance of accurate localization by other diagnostic modalities, such as scalp EEG and functional neuroimaging studies. Consistent with our observations, seizures of short duration or early epilepsy surgery has been associated with favorable surgical outcomes (Fauser et al., 2008). Several studies have documented the prognostic value of several clinical factors including the complete resection of areas showing frequent sharp waves and persistent slowing in adults (Kim et al., 2009a); we could not replicate the results of these reports. In pediatric epilepsy, there was also another aspect to determining surgical outcomes. Based on the scalp and intracranial EEG, complete resection in areas having ictal and interictal epileptiform discharges and persistent slowing was known to be an important predictor of good surgical outcomes in adults (Kim et al., 2009a). In this study, however, most patients who had secondary generalized epileptic encephalopathy, including Lennox-Gastaut syndrome, infantile spasms, early infantile epileptic encephalopathy, and some patients with partial seizures, had abundant ictal and interictal generalized epileptiform discharges, but could obtain favorable surgical outcomes without complete resection of the areas with abnormal EEG features. The Cleveland group recently reported excellent outcomes of resective epilepsy surgery in children and adolescents with a congenital or early acquired brain lesion and generalized EEG abnormalities (Wyllie et al., 2007). They also suggested that the most outstanding age-related variable was not the age at presurgical evaluation and surgery, but the age at the event of the brain lesions. Rather, in our data, the meaningful prognostic factor was the age of operation and epilepsy duration. The mechanisms responsible for generalized EEG abnormalities in children with congenital or early acquired brain lesions remain to be discovered. Recently, there have been several hypotheses including maladaptive neural-plasticity, abnormal network synchronization, and circuit alterations by kindling such as in the case of hypothalamic hamartoma (Cilio et al., 2003). The generalized and contralateral epileptiform discharges can be made by potentially secondary epileptogenesis resulting from an interaction between the early lesion and the developing brain (Lado et al., 2002). Older age and longer duration of epilepsy can enforce these processes and influence a poorer surgical outcome in pediatric epilepsy. In addition, early surgery can support functional plasticity in one s brain, since functional disability can be caused by surgical

6 727 Cortical Dysplasia in Epilepsy Surgery resection after the neural network is stabilized. Naturally, it would also be important to look at the long-term outcome in these cases. Finally, the MRI showed good accuracy in localizing epileptogenic areas, and the localizing power of FDG-PET and SISCOM in cases of mild MCD was helpful. Based on characteristic interictal EEG findings and by the help of multiple neuroimaging modalities, early surgery in intractable child epilepsy with CD can be justified. Disclosure We have no financial relationships relevant to the content of this article. 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. References Bentivoglio M, Tassi L, Pech E, Costa C, Fabene PF, Spreafico R. (2003) Cortical development and focal cortical dysplasia. Epileptic Disord 5(suppl 2):S27 S34. 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