Seizure 23 (2014) 266–273
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Long-term outcome and predictors of resective surgery prognosis in patients with refractory extratemporal epilepsy Petra Hana´kova´ a,*, Milan Bra´zdil b,c, Zdeneˇk Nova´k c,d, Jan Hemza d, Jan Chrastina c,d, Hana Osˇlejsˇkova´ a, Marke´ta Hermanova´ e, Marta Pazˇourkova´ f, Ivan Rektor b,c, Robert Kuba a,b,c a
Epilepsy Center Brno, Department of Child Neurology, Brno University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic Epilepsy Center Brno, First Department of Neurology, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic c Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic d Epilepsy Center Brno, Department of Neurosurgery, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic e Department of Pathology, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic f Department of Radiology, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 10 June 2013 Received in revised form 2 December 2013 Accepted 4 December 2013
Purpose: We analyzed the long-term postoperative outcome and possible predictive factors of the outcome in surgically treated patients with refractory extratemporal epilepsy. Methods: We retrospectively analyzed 73 patients who had undergone resective surgery at the Epilepsy Center Brno between 1995 and 2010 and who had reached at least 1 year outcome after the surgery. The average age at surgery was 28.3 11.4 years. Magnetic resonance imaging (MRI) did not reveal any lesion in 24 patients (32.9%). Surgical outcome was assessed annually using Engel’s modified classification until 5 years after surgery and at the latest follow-up visit. Results: Following the surgery, Engel Class I outcome was found in 52.1% of patients after 1 year, in 55.0% after 5 years, and in 50.7% at the last follow-up visit (average 6.15 3.84 years). Of the patients who reached the 5-year follow-up visit (average of the last follow-up 9.23 years), 37.5% were classified as Engel IA at each follow-up visit. Tumorous etiology and lesions seen in preoperative MRI were associated with significantly better outcome (p = 0.035; p < 0.01). Postoperatively, 9.6% patients had permanent neurological deficits. Conclusion: Surgical treatment of refractory extratemporal epilepsy is an effective procedure. The presence of a visible MRI-detected lesion and tumorous etiology is associated with significantly better outcome than the absence of MRI-detected lesion or other etiology. ß 2013 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Epilepsy surgery Extratemporal Long-term outcome Histopathology Engel’s classification
1. Introduction More than 30 percent of patients with epilepsy are refractory to antiepileptic drug treatment.1 Partly because of this relatively high number, epilepsy surgery is an intrinsic part of the algorithm of epilepsy treatment. The short- or long-term efficacy of various types of resections for epilepsy in different anatomical locations has been widely studied.2–5 However, there have been only two ‘‘Class I’’ studies evaluating the effect of surgical treatment of epilepsy. Both of them were conducted in patients with refractory temporal lobe epilepsy
* Corresponding author. Tel.: +420 532 234 912; fax: +420 532 234 996. E-mail addresses: [email protected], [email protected] (P. Hana´kova´).
(TLE). Wiebe et al.6 published a randomized controlled study of surgery in TLE and endorsed surgery as a superior to prolonged treatment with antiepileptic drugs (AED). At one year after surgery, a statistically significant difference was confirmed between patients who underwent surgery and medically treated patients. Engel et al.7 recently published the results of an Early Randomized Surgical Epilepsy Trial (ERSET) study of TLE patients after two failed AED treatments. Among patients with newly intractable disabling mesial TLE, resective surgery plus AED treatment resulted in a lower probability of seizures at the 2-year followup visit than continued AED treatment alone. There has not been a similar controlled study focused on extratemporal epilepsy (exTLE). Literature data report a wide range of seizure freedom in exTLE patients, varying from 25% to 80%,2,3,8–16 Some predictive factors are believed to play roles in postsurgical outcome.
1059-1311/$ – see front matter ß 2013 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.seizure.2013.12.003
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A significantly better outcome is achieved if a lesion is identified on MRI or confirmed histologically. Several studies reported worse postoperative seizure reduction if a lesion was not found preoperatively on MRI.2,9,16,17 We evaluated 77 patients with refractory exTLE who underwent surgery in Epilepsy Center Brno. Our purpose was to evaluate seizure outcome following epilepsy surgery and to assess the impact of preoperative MRI, histopathological findings, number of preoperatively used antiepileptic drugs (AEDs), and other predictive factors. 2. Methods We retrospectively analyzed all of the patients with refractory extratemporal epilepsy (exTLE) who had undergone resective surgery in St. Anne’s University Hospital in Brno (Czech Republic) between August 1995 and January 2010 and who had reached at least 1 year outcome after the surgery. We identified 77 patients. Of those 77, 4 were excluded from the analysis because of lost outcome due to the death of the patients. The causes of death were: sudden unexplained death in epilepsy (SUDEP), drowning, heart attack, and traffic accident (each in one patient). We thus studied 73 patients with exTLE who achieved outcome longer than 1 year. We analyzed 40 patients who reached at least the 5year follow-up visit in more detail. The patients’ demographic data were obtained from medical charts. All patients underwent a complete preoperative evaluation to assess the extent of resection. 2.1. Video-EEG evaluation Scalp video-EEG was recorded with the international 10–20 system with additional electrodes (anterotemporal T1, T2 and supraorbital SO1, SO2). The scalp recording was performed on the 64-channel Brain Quick system (Micromed) or the 64-channel Alien Deymed system. Of the 73 patients, 38 (52.1%) underwent invasive EEG. Intracranial recordings with inserted depth electrodes alone were performed in 25 patients; depth electrodes in combination with subdural electrodes (strip or grid) were used in 6 patients; 4 patients were examined with subdural electrodes only. The invasive EEG had to be repeated in 3 cases. Intracerebral 5-, 10-, and 15-contact platinum semiflexible Microdeep electrodes DIXI or ALCIS (with an electrode diameter of 0.8 mm, a contact length of 2 mm, and a 1.5 mm distance between contacts) and 6- or 8contact platinum subdural strips electrodes (Radionics) or 32contact platinum subdural grids (Radionics) were used. The invasive video-EEG recording was performed with the 64-channel Brain Quick system (Micromed), and the 128-channel Alien Deymed system was used for intracranial video-EEG recording. Monopolar recordings (a reference electrode on the processus mastoideus) and special bipolar montages were used to evaluate the EEG activity. EEG was amplified with a bandwidth of 0.4– 100 Hz at a sampling rate of 128 Hz. 2.2. Other preoperative evaluation MRI scans were obtained using the Siemens 1.5 Tesla MRI scanner. We performed the following sequences in all patients: T1-weighted axial and coronal sections with and without contrast, T2-weighted, FLAIR-weighted, and TIR axial and coronal sections of the whole brain. MRI did not reveal a lesion in 24 (32.9%) of patients. Fluorodeoxyglucose positron emission tomography (FDG-PET) was performed in the interictal state on a Siemens tomography scanner. A complete neuropsychological evaluation was conducted on all patients. As needed, 24 of the 73 patients
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(32.9%) underwent interictal and ictal single-photon emission computed tomography (SPECT) to obtain the subtraction of ictal SPECT coregistred on MRI (SISCOM). 2.3. Histopathological evaluation Evaluable formalin-fixed paraffin-embedded tissues of extratemporal lobe resection specimens were available from all patients. All the paraffin-embedded tissue specimens, slides, and histopathology reports were retrieved from the files of the First Department of Pathological Anatomy of St. Anne’s University Hospital and examined by a histopathologist. All examined resected tissues were identically treated, fixed in a 10% neutral buffered formalin, grossly inspected, measured, and cut so as to obtain representative tissue slices perpendicular to the cortical surface. Representative tissue slices were routinely processed and paraffin embedded. 5 mm thick tissue sections were stained by hematoxylin and eosin, evaluated under light microscope, and reported. 2.4. Surgery procedure All procedures were performed in the Epilepsy Center Brno. The type and extent of the surgery was chosen individually on the basis of the preoperative evaluation. The surgical procedures included lesionectomy with resection of adjacent epileptogenic cortex, isolated lesionectomy, and corticectomy on the basis of invasive EEG, which was also performed with neocortical stimulation when the epileptogenic zone was located near the eloquent cortex. One patient underwent lobectomy and one had an extended extratemporal lesionectomy with amygdalohippocampectomy. Three patients underwent re-operation. The outcome after the re-operation was included in the study in these patients. Preoperative electrocorticography was performed in 59 patients; 29 patients underwent fMRI; 2 patients had awake craniotomy when the lesion was located close to or involving the eloquent cortex. 2.5. Evaluation of surgical outcome Surgical outcome was annually assessed using Engel’s modified classification for 5 years after surgery and at the latest follow-up visit.18 All patients were seen regularly (at least once per year) in the outpatient clinic and had results from at least 2 medical followup visits (after 1 year and at the last follow-up visit). The seizure outcome was evaluated at a given point in time (at the follow-up visit) and the time-point actually reflects the situation of the preceding entire year as well. 2.6. Statistical analysis Statistical analysis was performed using SPSS Statistics 18. Continuous variables were summarized using standard descriptive statistics (mean and standard deviation). The statistically significant difference between epilepsy duration, the age at epilepsy onset, the age at the time of epilepsy surgery, and surgical efficacy was determined using the analysis of variance (ANOVA). A chisquare test was used to evaluate the association between histological etiology and outcomes. The chi-square test was also used to evaluate the association between preoperative MRIdetected lesions and postsurgical outcome. A p value was considered as statistically significant if p < 0.05. We present the seizure outcomes of the 40 patients who reached the 5-year follow-up visit using Kaplan–Meier survival analysis.
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3. Results 3.1. Patient demographics We analyzed 73 patients (46 men and 27 women) aged from 1 to 51 years with an average of 28.3 11.4 years (a median age of 27 years). The average epilepsy duration was 14.0 10.6 years (ranged from 0.5 to 45 years). The average age at the time of epilepsy surgery was 28.3 11.4 years (ranged from 1 to 51 years) and the average age at epilepsy onset was 14.2 10.9 years (ranged from 0 to 48 years). At the time of surgery, 7 of the 73 patients (9.6%) were younger than 16 years. 3.2. Seizure onset zone Based on a preoperative investigation, we assessed the probable seizure onset zone (SOZ) in all patients. The SOZ was localized on the right side in 44 patients and on the left side in 29. The most frequent SOZ location was the frontal lobe (in 29 of the 73 patients; 39.7%). Other SOZ locations are shown in Fig. 1. 3.3. Seizure outcome All 73 patients reached the 1-year follow-up visit, 69 reached 2 years, 59 reached 3 years, 47 reached 4 years, and 40 reached 5 years. The last follow-up visit in all patients ranged from 1 to 15 years with an average of 6.15 3.84 years. At the 1-year follow-up visit, 38 of the 73 patients (52.1%) were classified as Engel I, 7 (9.6%) as Engel II, 16 (21.9%) as Engel III, and 12 (16.4%) as Engel IV. At the 5-year follow-up visit, 22 out of 40 patients (55.0%) were classified as Engel I, 6 (15.0%) as Engel II, 5 (12.5%) as Engel III, and 7 (17.5%) as Engel IV. At the last follow-up visit, 37 of the 73 patients (50.7%) were classified as Engel I, 11 (15.1%) as Engel II, 10 (13.7%) as Engel III, and 15 (20.5%) as Engel IV. Forty patients reached at least the 5-year follow-up visit, and the last follow-up visit for these 40 patients ranged from the 5-year visit to the 15-year visit, with an average of 9.23 2.82 years. Engel IA outcome was reached in 21 out of the 40 patients (52.5%) by the 1, 2, and 3-year follow-up visits, in 20 (50%) by the 4-year follow-up visit, and in 19 (47.5%) by the 5-year follow-up visit. At the last followup visit (average 9.23 years after the surgery), 15 of these 40 patients
Fig. 1. Localization of the seizure onset zone in all patients (F – frontal lobe epilepsy; CRE – central region epilepsy; OINZ – operculo-insular epilepsy; O – occipital lobe epilepsy; TPO – seizures arising from temporal-parietal-occipital boundary; Other – multilobar seizure onset) (displayed in number of patients; percentages).
(37.5%) were classified in the same category every year. We present the seizure outcomes of the 40 patients who reached at least the 5year follow-up visit in a Kaplan–Meier survival curve (Fig. 2). 3.4. Histopathology Histopathological findings are shown in Fig. 3. The most frequent findings were low grade gliomas, and developmental glioneural tumors [dysembryoplastic neuroepithelial tumor (DNET) and ganglioglioma] and malformations of cortical development (MCD) (each in 21 patients – 28.8%). In 7 of the 73 (9.6%), the histopathology was negative or inconclusive (all with preoperatively normal MRI). Four patients were classified as focal cortical dysplasia type IIIb according to ILAE classification (i.e. combination of ganglioglioma and FCD). The most frequent findings within the ‘‘tumoral group’’ were group with diagnosed oligodendroglioma (grade II) (in 6 out of 21 patients) and ganglioglioma (grade I) (in 5 out of 21 patients) and DNET (in 4 out of 21 patients) (see Fig. 3).
Fig. 2. Seizure outcome of the 40 patients who reached at least the 5-year follow-up visit in a Kaplan–Meier survival curve (displayed in number of patients; percentages). X-axis in years.
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Fig. 3. Histopathological findings in the whole group of 73 patients (displayed in numbers of patients; percentages).
3.5. Surgical complications
3.7. Predictors of postsurgical outcome
We observed 2 complications associated with invasive EEG monitoring (out of 38 procedures – 5.2%). We observed an asymptomatic hematoma following the depth electrode insertion in 1 patient and an edema following the grid placement in 1 patient. Both complications resolved without consequence without the need for surgical intervention. Following the epilepsy surgery, we observed surgery-related complications in 3 of the 73 patients (4.1%): a hematoma in the post-resection cavity in 1 patient and extracerebral bleeding into the subdural and/or epidural space in 2 patients. All 3 patients had revision of the bleeding and we did not observe any long-term consequences of these complications. Another 7 of the 73 patients (9.6%) had permanent neurological deficits following the surgery: paresis of the upper limb in 3 patients and hemiparesis in 1 patient following resection in the peri-central or parietal regions (in all classified as mild); 3 other patients had visual field deficits (quadrantopsia) after resection in either the parietal or occipital lobes. All of these complications were to be expected due to the surgery localization.
No statistically significant difference between epilepsy duration, the age at epilepsy onset, the age at the time of epilepsy surgery, and surgical efficacy was established by ANOVA (p = 0.481, 0.45, and 0.512, respectively). Preoperatively, 49 (67.1%) patients had abnormal MRI findings. Of these 49 patients, 30 (61.2%) were classified as Engel I at the last follow-up visit, 7 (14.3%) as Engel II, 4 as Engel III (8.2%), and 8 (16.3%) as Engel IV. Preoperatively, 24 (32.9%) patients had normal MRI findings. Of these 24 patients, 7 (29.2%) were classified as Engel I at the last follow-up visit, 4 (16.7%) as Engel II, 6 (25.0%) as Engel III, and 7 (29.2%) as Engel IV. The difference in Engel I outcome at the last follow-up visit between these two groups was statistically significant [x2 (1) = 6.62; p < 0.01] (Fig. 5). Of those 24 patients with normal MRI, 13 had FCD diagnosed histopathologically (5 patients type IA, 4 IB, 4 IIB), 7 specimens were negative or inconclusive, in 3 patients gliosis was confirmed, and in 1 ganglioglioma of grade I. Of the 21 patients with low-grade gliomas and developmental glio-neural tumors, 16 (76.2%) had Engel class I outcome at the last follow-up visit (Fig. 6); in the 52 patients with other histopathological finding (Fig. 3) 21 (40.4%) were classified as Engel I at the last follow-up visit. This difference was statistically significant [x2(2) = 6.67; p = 0.035]. The patients with low-grade gliomas and developmental glioneural tumors had better outcomes (Engel class IA in 66.7%) than the patients diagnosed with cortical dysplasia (Engel class IA in 28.6%). This difference was statistically significant [x2(2) = 6.69; p < 0.01].
3.6. Antiepileptic drug treatment following the surgery The number of AEDs used in the past history of the patients at the time of the surgery varied from 2 to 14 with an average of 6.8 3.2. The policy in our center is to start to discontinue AEDs after successful surgery based on individual decisions for each patient. At the 5-year follow-up visit, 10 of the 40 patients (25.0%) were completely off AEDs (Fig. 4A). At the 5-year follow-up visit, among the 19 patients classified as Engel IA, AED treatment was completely withdrawn in 10 patients (52.6%) and partially withdrawn in 26.3% (Fig. 4B). At the last follow-up visit in all patients, 10 of the 73 patients (13.7%) were completely off AEDs, in 12 patients (16.4%) the AEDs had been partially withdrawn (at least one AED from the combination), and in 14 patients (19.2%) the AEDs remained unchanged. In the remaining 37 patients (50.7%), the AED treatment was changed after the surgery. At the last follow-up, among the 32 patients classified as Engel IA, AED treatment was completely withdrawn in 31.3% and partially withdrawn in 34.4%.
4. Discussion We revealed a relatively stable postoperative outcome. At the 1year follow-up visit in all patients, 52.1% of patients were classified as Engel I; 5 years after surgery, 55.0% were classified as Engel I; at the last follow-up visit (mean 6.15 years after surgery), 50.7% were classified as Engel I. Literature data report a wide range of seizure freedom, varying from 25% to 80% of patients with exTLE.2,3,8–16 Some studies analyzed the results of either resective surgery or other ‘‘palliative’’ procedures like corpus callosotomy and multiple subpial transsections.19,20 Other studies provided an analysis of ‘‘neocortical’’ epilepsies, combining the results of TLE and exTLE patients.21 Comparisons of studies in patients with exTLE are
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Fig. 4. (A) Antiepileptic medication at the 5-year follow-up visit for the group of 40 patients who reached this follow-up (displayed in number of patients; percentages). (B) Antiepileptic medication for patients classified as Engel IA at the 5-year follow-up visit (displayed in number of patients; percentages).
particularly unreliable. The heterogeneity of exTLE surgery was noticed in the data pooled by Te´llez-Zenteno et al.4 They reported long-term seizure freedom in 34% of patients in grouped extratemporal resections, of which 27% were with frontal lobe resections and 46% with both parietal and occipital lobe resections. McIntosh et al.11 studied 81 patients with exTLE; the study showed that the probability of complete seizure freedom at 5 years postoperative is 15%. This type of measure might be misleading because it is not usual to use it in these types of studies. On the other hand, this measurement reflects the proportion of patients whose outcome is really excellent from a long-term point of view.
In our study, 37.5% of the patients were completely seizure free at the 5-year follow-up visit (i.e. classified as Engel IA at each followup). This number is more than twice that of the McIntosh study. The better outcome in our study might be explained by the higher number of patients with benign tumors or DNET and the lower number of patients with focal cortical dysplasia (FCD) in comparison to the McIntosh study. Patients with FCD (both types I and II) were more than 50% of the patients in the McIntosh study, but less than 30% in our study. This difference emphasizes the large diversity of surgical series of exTLE patients published in the literature.
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Fig. 5. Postsurgical outcome at the last follow-up visit; difference between patients with ‘‘lesional’’ and ‘‘nonlesional’’ preoperative MRI (displayed in number of patients; percentages). *p < 0.01.
In our patients, postoperative outcome was stable over time (the differences in Engel I outcome gathered at 1-year, 5-year, and last follow-up visits were insignificant). Elsharkawy et al.22 reported similar results in 218 patients with exTLE patients. Jeha et al.2 observed decreased surgical efficacy over time in 70 patients with frontal lobe epilepsy. While 56% of those patients were seizure free at the 1-year follow-up visit, only 30% were seizure free after 5 years.
Postsurgical outcome is significantly affected by many factors, the most important of which are the finding of a lesion on preoperative MRI and ‘‘positive’’ histopathological findings. Te´llezZenteno et al.16 evaluated the predictive factors for better postsurgical outcome in more detail in a meta-analysis of 40 studies, of which 13 were performed on patients with exTLE. In these groups, the odds of being seizure free at least one year after surgery are two to three times higher in patients with a
Fig. 6. Postsurgical outcome at the last follow-up visit; difference between patients with benign neoplasm + developmental glio-neural tumors and malformation of cortical development (displayed in number of patients; percentages). *p < 0.01.
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preoperative MRI-detected lesion or confirmed histopathological findings than in those with no MRI-detected lesion and negative histopathological findings. The proportion of seizure-free patients was 35% in nonlesional epilepsy and 60% in lesional epilepsy. We confirmed a statistically significant association between a preoperative MRI-detected lesion and the postoperative outcome. Other studies have shown a worse postoperative seizure reduction if no lesion was found preoperatively on MRI.2,17,22–25 On the other hand, Ansari et al.8 found no significant association between MRIdetected lesion and good outcome. These results are poorly comparable to ours because of differing interpretations of ‘‘lesional’’ and ‘‘nonlesional’’ epilepsy. Ansari et al. classified tumors, vascular malformations, and tuberous sclerosis as ‘‘lesional’’ epilepsy and did not include these abnormal findings in their study. All other pathologies, such as malformations of cortical development including cortical dysplasia, polymicrogyria, ulegyria, gliosis, and chronic inflammation, were classified as a ‘‘nonlesional’’ epilepsy, although some (for example cortical dysplasia) can be visible as an MRI-detected lesion. The authors divided the patients classified with ‘‘nonlesional’’ epilepsy in two groups: those with a visible MRI-detected lesion and those with a normal MRI. We classified all of the patients with visible MRIdetected lesions as having ‘‘lesional’’ epilepsy (including cortical dysplasia with a positive finding on MRI). In the study by Ansari et al.,8 the most frequent abnormal finding seen was cortical dysplasia, which can be more extended and diffused than a visible MRI-detected lesion, particularly in younger patients3,26 and hence, could have worse postoperative outcome. One of the possible reasons for higher efficacy of surgery in lesional epilepsy could be the easier surgical performance and complete resection of the epileptogenic zone. This might result in a better outcome in patients with benign tumors, because pathological neoplastic tissue is more visible and easily distinguishable from the normal tissue during surgery.27 In our study, benign neoplasms, developmental glio-neural tumors and malformations of cortical development were histologically diagnosed as the most frequent pathological findings. Boesebeck et al.27 reported a similar distribution of tumors and malformations in a group of 81 patients as compared to our study. We found better outcomes at the last follow-up visit in patients with benign neoplasms + developmental glio-neural tumors than in patients with cortical dysplasia. In agreement with our study, tumorous etiology has shown a more favorable seizure outcome in extratemporal epilepsies.27,28 This association is also supported by the results of two studies that reported from 80% to 82% of patients to be seizure free after tumor resection reported worse surgical outcomes when cortical dysgenesis was confirmed in a tissue specimen.5,29,30 Other authors reported that a malformation of cortical development may be poor congruence with electrographic and with structural and functional radiological findings.17,31,32 In our study, 52.1% of patients underwent invasive EEG (depth or subdural electrodes alone or in combination at the same time). The frequency of use of invasive EEG is reported in a wide range. McIntosh et al.11 used intracranial electrodes in 26 out of 81 patients (32.1%). Subdural grids and epidural or depth electrodes were used more frequently (66 out of 81 patients, 81.5%) in a retrospectively study by Boesebeck et al.27 in which patients had MRI-detected lesions defined histologically as tumors, vascular lesions, and cortical gliosis. Jeha et al.2 published the results of 70 patients with frontal lobe epilepsy. Of those 70, 47 (67.1%) underwent invasive EEG. The different results mostly depend on the strategy of each center, on the availability of neuroimaging methods during the presurgical evaluation, and on the placement strategy of either depth or subdural electrodes. In 9.6% of patients, we noticed permanent neurological deficits (mild paresis following the resection in the peri-central
or parietal regions and visual field deficits after resection in the posterior quadrant). All of these complications are to be expected due to the location of the surgery and all of the patients accepted these deficits prior to the surgery. The complications are more frequent in extratemporal than in temporal localization because of the eloquent cortex in this area and the need for a large resection to achieve a better postsurgical outcome.33 The spectrum of complications in other studies is very similar to our findings. The number is generally low. Elsharkawy et al.22 observed outcomes and complications in 218 patients with extratemporal refractory epilepsy who had surgery between 1991 and 2005. Overall, 4.6% had permanent and 5.0% had transient neurological deficits. The most frequent were paresis, visual field defects, and facial palsy. Mulholland et al.12 reported a relatively high percentage of complications. They observed postoperative complications (namely meningitis, brain abscess, and wound infection) in 3 patients (17.6%). But the whole group contained only 17 patients. They recorded minor complications in 4 patients, including blurring of vision, trembling in the arm, and cephalohematoma. It is challenging to compare complications with other studies because of non-uniform classification systems. In our study, the number of AEDs used in the past history of the patients at the time of surgery varied from 2 to 14 with an average of 6.8. In a study by Mulholland et al.,12 a similar average of 6.5 AEDs per patient was used. At the last follow-up visit, among 32 patients classified as Engel IA, AED treatment had been withdrawn completely in 31.3%. The previously published results of similar studies are conflicting. Kerling et al.34 published a prospective pilot study of AED withdrawal in 34 out of 60 patients who underwent surgery. He compared this group with 26 patients without discontinuation of AEDs. All of the patients with extratemporal epilepsy (6 out of 34) were in the withdrawal group. The association with a higher risk of seizure recurrence was confirmed (38.5% in the group with unchanged medication as compared to 23.6% in the withdrawal group). In contrast, Schiller et al.,35 reported a higher risk of seizure recurrence after discontinuation of AEDs (7% of patients with unchanged medication versus 36% in withdrawal group). In our study, we did not confirm a statistically significant difference between epilepsy duration and surgical efficacy. We did not find a difference in epilepsy duration between patients with lesional (14.0 years) and nonlesional (14.3 years) epilepsy, either. However, epilepsy duration is still a discussed predictive factor.24 In our patients, the time from seizure onset to surgery was similar to that in the study by Elsharkawy et al.36 who reported 17.8 10.0 years. There are inconsistencies among the published results. Our conclusion is in line with studies by Jeha et al.,2 Ansari et al.,8 McIntosh et al.11 and Boesebeck et al.27 In contrast, Kral et al.24 found an association between epilepsy duration and postoperative outcome, but that study observed only patients with FCD. Teutonico et al.,37 confirmed a statistically significant association in 120 children under 16 years of age. Therefore in our results, we have to consider different histological etiology as well as the wide range of patient ages. Elsharkawy et al.22 described a significant association between epilepsy duration and outcome by univariate analysis, but this was not confirmed by multivariate analysis. The theory that epilepsy duration affects outcome through other factors is supported by these results. 5. Conclusions In conclusion, our results showed that surgery for patients with exTLE is an effective procedure with relatively stable efficacy over time. The number of patients included in the study did not allow us to analyze the efficacy of the surgery in patients with different SOZ
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localizations. Such a detailed analysis would lead to a relatively smaller number of patients. Because of the controversies and diversities within the literature data concerning this issue, a prospective controlled trial in the future will be necessary to confirm the results obtained from retrospective analyses. The presence of preoperative MRI-detected lesions and the histopathological finding of low-grade tumors (and including developmental glio-neural tumors) seem to be the two most important factors influencing the favorable prognosis for patients with extratemporal epilepsy. The relatively higher incidence of permanent neurological deficit postoperatively both in our study and in other studies is undoubtedly caused by the necessity of performing the surgery near the eloquent regions (sensory-motor region, visual cortex, etc.). Conflicts of interest None of the authors has any conflict of interest to disclose. 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 the project ‘‘CEITEC – Central European Institute of Technology’’ (CZ.1.05/1.1.00/02.0068) from the European Regional Development Fund. Supported by the project (Ministry of Health, Czech Republic) for conceptual development of research organization 65269705 (University Hospital Brno, Brno, Czech Republic). Thanks to Anne Johnson for grammatical assistance. References 1. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314–9. 2. Jeha LE, Najm I, Bingaman W, Dinner D, Widdess-Walsh P, Lu¨ders H. Surgical outcome and prognostic factors of frontal lobe epilepsy surgery. Brain 2007; 130:574–84. 3. Spencer SS, Berg AT, Vickrey BG, Sperling MR, Bazil CW, Shinnar S, et al. Initial outcomes in the Multicenter Study of Epilepsy Surgery. Neurology 2003;61: 1680–5. 4. Te´llez-Zenteno JF, Dhar S, Wiebe S. Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain 2005;128: 1188–98. 5. Zentner J, Hufnagel A, Ostertun B, Wolf HK, Behrens E, Campos MG, et al. Surgical treatment of extratemporal epilepsy: clinical, radiologic, and histopathologic findings in 60 patients. Epilepsia 1996;37:1072–80. 6. Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med 2001;345:311–8. 7. Engel Jr J, McDermott MP, Wiebe S, Langfitt JT, Stern JM, Dewar S, et al. Early randomized surgical epilepsy trial (ERSET) study group. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA 2012;307:922–30. 8. Ansari SF, Tubbs RS, Terry CL, Cohen-Gadol AA. Surgery for extratemporal nonlesional epilepsy in adults: an outcome meta-analysis. Acta Neurochir 2010;152:1299–305. 9. Elsharkawy AE, Behne F, Oppel F, Pannek H, Schulz. Hoppe M, et al. Long-term outcome of extratemporal epilepsy surgery among 154 adult patients. J Neurosurg 2008;108:676–86. 10. Jehi LE, O’Dwyer R, Najm I, Alexopoulos A, Bingaman W. A longitudinal study of surgical outcome and its determinants following posterior cortex epilepsy surgery. Epilepsia 2009;50:2040–52.
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11. McIntosh AM, Averill CA, Kalnins RM, Mitchell LA, Fabinyi GCA, Jackson GD, et al. Long-term seizure outcome and risk factors for recurrence after extratemporal epilepsy surgery. Epilepsia 2012;53:970–8. 12. Mulholland D, Ali Z, Delanty N, Shahwan A, O’Brien DF. An outcome of seventeen patients treated surgically for intractable extratemporal epilepsy. Ir Med J 2010;103:211–3. 13. Rossi GR, Colicchio G, Scerrati M. Resection surgery for partial epilepsy. Relation of surgical outcome with some aspects of the epileptogenic process and surgical approach. Acta Neurochir 1994;130:101–10. 14. Siegel AM. Presurgical evaluation and surgical treatment of medically refractory epilepsy. Neurosurg Rev 2004;27:1–18. 15. Te´llez-Zenteno JF, Wiebe S. Long-term seizure and psychosocial outcomes of epilepsy surgery. Curr Treat Options Neurol 2008;10:253–9. 16. Te´llez-Zenteno JF, Ronquillo LH, Moien-Afshari F, Wiebe S. Surgical outcomes in lesional and non-lesional epilepsy: a systematic review and meta-analysis. Epilepsy Res 2010;89:310–8. 17. Kutsy RL. Focal extratemporal epilepsy: clinical features, EEG patterns, and surgical approach. J Neurol Sci 1999;166:1–15. [18]. Engel Jr J, Van Ness PC, Rasmussen TB. Outcome with respect to epileptic seizures. In: Engel Jr J, editor. Surgical treatment of epilepsies. 2nd ed. New York: Raven Press; 1993. p. 609–21. 19. De Tisi J, Bell GS, Peacock JL, McEvoy AW, Harkness WF, Sander JW, et al. The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study. Lancet 2011;378:1388–95. 20. Matheson JM, Mackenzie RA, Henderson T. Seizure outcome for surgery of extratemporal epilepsy. J Clin Neurosci 1997;4:441–6. 21. Kim DW, Kim HK, Lee SK, Chu K, Chung CK. Extent of neocortical resection and surgical outcome of epilepsy: intracranial EEG analysis. Epilepsia 2010;51: 1010–7. 22. Elsharkawy AE, Pannek H, Schulz R, Hoppe M, Pahs G, Gyimesi C, et al. Outcome of extratemporal epilepsy surgery experience of a single center. Neurosurgery 2008;63:516–25. 23. Chapman K, Wyllie E, Najm I, Ruggieri P, Bingaman W, Lu¨ders H. Seizure outcome after epilepsy surgery in patients with normal preoperative MRI. J Neurol Neurosurg Psychiatry 2005;76:710–3. 24. Kral T, Clusmann H, Blu¨mcke I, Fimmers R, Ostertun B, Kurthen M, et al. Outcome of epilepsy surgery in focal cortical dysplasia. J Neurol Neurosurg and Psychiatry 2003;74:183–8. 25. Siegel AM, Jobst BC, Thadani VM, Rhodes CH, Lewis PJ, Roberts DW, et al. Medically intractable, localization-related epilepsy with normal MRI: presurgical evaluation and surgical outcome in 43 patients. Epilepsia 2001;42:883–8. 26. Cohen-Gadol AA, Ozduman K, Bronen RA, Kim JH, Spencer DD. Long-term outcome after epilepsy surgery for focal cortical dysplasia. J Neurosurg 2004; 101:55–65. 27. Boesebeck F, Janszky J, Kellinghaus C, May T, Ebner A. Presurgical seizure frequency and tumoral etiology predict the outcome after extratemporal epilepsy surgery. J Neurol 2007;254:996–9. 28. Aykut-Bingol C, Bronen RA, Kim JH, Spencer DD, Spencer SS. Surgical outcome in occipital lobe epilepsy: implications for pathophysiology. Ann Neurol 1998;44: 60–9. 29. Goldring S, Rich KM, Picker S. Experience with gliomas in patients presenting with a chronic seizure disorder. Clin Neurosurg 1986;33:15–42. 30. Hirabayashi S, Binnie CD, Janota I, Polkey CE. Surgical treatment of epilepsy due to cortical dysplasia: clinical and EEG findings. J Neurol Neurosurg Psychiatry 1993;56:765–70. 31. Palmini A, Andermann F, Aicardi J, Dulac O, Chaves F, Ponsot G, et al. Diffuse cortical dysplasia, or the ‘double cortex’ syndrome. The clinical and epileptic spectrum in 10 patients. Neurology 1991;41:1656–62. 32. Palmini A, Andermann F, Olivier A, Tampieri D, Robitaille Y, Andermann E, et al. Focal neuronal migration disorders and intractable partial epilepsy: a study of 30 patients. Ann Neurol 1991;30:741–9. 33. Cascino GD. Surgical treatment for extratemporal epilepsy. Curr Treat Options Neurol 2004;6:257–62. 34. Kerling F, Pauli E, Lorber B, Blu¨mcke I, Buchfelder M, Stefan H. Drug withdrawal after successful epilepsy surgery: how safe is it? Epilepsy Behav 2009;15:476–80. 35. Schiller Y, Cascino GD, So EL, Marsh WR. Discontinuation of antiepileptic drugs after successful epilepsy surgery. Neurology 2000;54:346–9. 36. Elsharkawy AE, Pietila¨ TA, Alabbasi AH, Pannek H, Ebner A. Long term outcome in patients not initially seizure free after resective epilepsy surgery. Seizure 2011;20:419–24. 37. Teutonico F, Mai R, Veggiotti P, Francione S, Tassi L, Borrelli P, et al. Epilepsy surgery in children: evaluation of seizure outcome and predictive elements. Epilepsia 2013;54:70–6.
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Long-term outcome and predictors of resective surgery prognosis in patients with refractory extratemporal epilepsy Petra Hana´kova´ a,*, Milan Bra´zdil b,c, Zdeneˇk Nova´k c,d, Jan Hemza d, Jan Chrastina c,d, Hana Osˇlejsˇkova´ a, Marke´ta Hermanova´ e, Marta Pazˇourkova´ f, Ivan Rektor b,c, Robert Kuba a,b,c a
Epilepsy Center Brno, Department of Child Neurology, Brno University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic Epilepsy Center Brno, First Department of Neurology, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic c Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic d Epilepsy Center Brno, Department of Neurosurgery, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic e Department of Pathology, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic f Department of Radiology, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 10 June 2013 Received in revised form 2 December 2013 Accepted 4 December 2013
Purpose: We analyzed the long-term postoperative outcome and possible predictive factors of the outcome in surgically treated patients with refractory extratemporal epilepsy. Methods: We retrospectively analyzed 73 patients who had undergone resective surgery at the Epilepsy Center Brno between 1995 and 2010 and who had reached at least 1 year outcome after the surgery. The average age at surgery was 28.3 11.4 years. Magnetic resonance imaging (MRI) did not reveal any lesion in 24 patients (32.9%). Surgical outcome was assessed annually using Engel’s modified classification until 5 years after surgery and at the latest follow-up visit. Results: Following the surgery, Engel Class I outcome was found in 52.1% of patients after 1 year, in 55.0% after 5 years, and in 50.7% at the last follow-up visit (average 6.15 3.84 years). Of the patients who reached the 5-year follow-up visit (average of the last follow-up 9.23 years), 37.5% were classified as Engel IA at each follow-up visit. Tumorous etiology and lesions seen in preoperative MRI were associated with significantly better outcome (p = 0.035; p < 0.01). Postoperatively, 9.6% patients had permanent neurological deficits. Conclusion: Surgical treatment of refractory extratemporal epilepsy is an effective procedure. The presence of a visible MRI-detected lesion and tumorous etiology is associated with significantly better outcome than the absence of MRI-detected lesion or other etiology. ß 2013 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Epilepsy surgery Extratemporal Long-term outcome Histopathology Engel’s classification
1. Introduction More than 30 percent of patients with epilepsy are refractory to antiepileptic drug treatment.1 Partly because of this relatively high number, epilepsy surgery is an intrinsic part of the algorithm of epilepsy treatment. The short- or long-term efficacy of various types of resections for epilepsy in different anatomical locations has been widely studied.2–5 However, there have been only two ‘‘Class I’’ studies evaluating the effect of surgical treatment of epilepsy. Both of them were conducted in patients with refractory temporal lobe epilepsy
* Corresponding author. Tel.: +420 532 234 912; fax: +420 532 234 996. E-mail addresses: [email protected], [email protected] (P. Hana´kova´).
(TLE). Wiebe et al.6 published a randomized controlled study of surgery in TLE and endorsed surgery as a superior to prolonged treatment with antiepileptic drugs (AED). At one year after surgery, a statistically significant difference was confirmed between patients who underwent surgery and medically treated patients. Engel et al.7 recently published the results of an Early Randomized Surgical Epilepsy Trial (ERSET) study of TLE patients after two failed AED treatments. Among patients with newly intractable disabling mesial TLE, resective surgery plus AED treatment resulted in a lower probability of seizures at the 2-year followup visit than continued AED treatment alone. There has not been a similar controlled study focused on extratemporal epilepsy (exTLE). Literature data report a wide range of seizure freedom in exTLE patients, varying from 25% to 80%,2,3,8–16 Some predictive factors are believed to play roles in postsurgical outcome.
1059-1311/$ – see front matter ß 2013 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.seizure.2013.12.003
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A significantly better outcome is achieved if a lesion is identified on MRI or confirmed histologically. Several studies reported worse postoperative seizure reduction if a lesion was not found preoperatively on MRI.2,9,16,17 We evaluated 77 patients with refractory exTLE who underwent surgery in Epilepsy Center Brno. Our purpose was to evaluate seizure outcome following epilepsy surgery and to assess the impact of preoperative MRI, histopathological findings, number of preoperatively used antiepileptic drugs (AEDs), and other predictive factors. 2. Methods We retrospectively analyzed all of the patients with refractory extratemporal epilepsy (exTLE) who had undergone resective surgery in St. Anne’s University Hospital in Brno (Czech Republic) between August 1995 and January 2010 and who had reached at least 1 year outcome after the surgery. We identified 77 patients. Of those 77, 4 were excluded from the analysis because of lost outcome due to the death of the patients. The causes of death were: sudden unexplained death in epilepsy (SUDEP), drowning, heart attack, and traffic accident (each in one patient). We thus studied 73 patients with exTLE who achieved outcome longer than 1 year. We analyzed 40 patients who reached at least the 5year follow-up visit in more detail. The patients’ demographic data were obtained from medical charts. All patients underwent a complete preoperative evaluation to assess the extent of resection. 2.1. Video-EEG evaluation Scalp video-EEG was recorded with the international 10–20 system with additional electrodes (anterotemporal T1, T2 and supraorbital SO1, SO2). The scalp recording was performed on the 64-channel Brain Quick system (Micromed) or the 64-channel Alien Deymed system. Of the 73 patients, 38 (52.1%) underwent invasive EEG. Intracranial recordings with inserted depth electrodes alone were performed in 25 patients; depth electrodes in combination with subdural electrodes (strip or grid) were used in 6 patients; 4 patients were examined with subdural electrodes only. The invasive EEG had to be repeated in 3 cases. Intracerebral 5-, 10-, and 15-contact platinum semiflexible Microdeep electrodes DIXI or ALCIS (with an electrode diameter of 0.8 mm, a contact length of 2 mm, and a 1.5 mm distance between contacts) and 6- or 8contact platinum subdural strips electrodes (Radionics) or 32contact platinum subdural grids (Radionics) were used. The invasive video-EEG recording was performed with the 64-channel Brain Quick system (Micromed), and the 128-channel Alien Deymed system was used for intracranial video-EEG recording. Monopolar recordings (a reference electrode on the processus mastoideus) and special bipolar montages were used to evaluate the EEG activity. EEG was amplified with a bandwidth of 0.4– 100 Hz at a sampling rate of 128 Hz. 2.2. Other preoperative evaluation MRI scans were obtained using the Siemens 1.5 Tesla MRI scanner. We performed the following sequences in all patients: T1-weighted axial and coronal sections with and without contrast, T2-weighted, FLAIR-weighted, and TIR axial and coronal sections of the whole brain. MRI did not reveal a lesion in 24 (32.9%) of patients. Fluorodeoxyglucose positron emission tomography (FDG-PET) was performed in the interictal state on a Siemens tomography scanner. A complete neuropsychological evaluation was conducted on all patients. As needed, 24 of the 73 patients
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(32.9%) underwent interictal and ictal single-photon emission computed tomography (SPECT) to obtain the subtraction of ictal SPECT coregistred on MRI (SISCOM). 2.3. Histopathological evaluation Evaluable formalin-fixed paraffin-embedded tissues of extratemporal lobe resection specimens were available from all patients. All the paraffin-embedded tissue specimens, slides, and histopathology reports were retrieved from the files of the First Department of Pathological Anatomy of St. Anne’s University Hospital and examined by a histopathologist. All examined resected tissues were identically treated, fixed in a 10% neutral buffered formalin, grossly inspected, measured, and cut so as to obtain representative tissue slices perpendicular to the cortical surface. Representative tissue slices were routinely processed and paraffin embedded. 5 mm thick tissue sections were stained by hematoxylin and eosin, evaluated under light microscope, and reported. 2.4. Surgery procedure All procedures were performed in the Epilepsy Center Brno. The type and extent of the surgery was chosen individually on the basis of the preoperative evaluation. The surgical procedures included lesionectomy with resection of adjacent epileptogenic cortex, isolated lesionectomy, and corticectomy on the basis of invasive EEG, which was also performed with neocortical stimulation when the epileptogenic zone was located near the eloquent cortex. One patient underwent lobectomy and one had an extended extratemporal lesionectomy with amygdalohippocampectomy. Three patients underwent re-operation. The outcome after the re-operation was included in the study in these patients. Preoperative electrocorticography was performed in 59 patients; 29 patients underwent fMRI; 2 patients had awake craniotomy when the lesion was located close to or involving the eloquent cortex. 2.5. Evaluation of surgical outcome Surgical outcome was annually assessed using Engel’s modified classification for 5 years after surgery and at the latest follow-up visit.18 All patients were seen regularly (at least once per year) in the outpatient clinic and had results from at least 2 medical followup visits (after 1 year and at the last follow-up visit). The seizure outcome was evaluated at a given point in time (at the follow-up visit) and the time-point actually reflects the situation of the preceding entire year as well. 2.6. Statistical analysis Statistical analysis was performed using SPSS Statistics 18. Continuous variables were summarized using standard descriptive statistics (mean and standard deviation). The statistically significant difference between epilepsy duration, the age at epilepsy onset, the age at the time of epilepsy surgery, and surgical efficacy was determined using the analysis of variance (ANOVA). A chisquare test was used to evaluate the association between histological etiology and outcomes. The chi-square test was also used to evaluate the association between preoperative MRIdetected lesions and postsurgical outcome. A p value was considered as statistically significant if p < 0.05. We present the seizure outcomes of the 40 patients who reached the 5-year follow-up visit using Kaplan–Meier survival analysis.
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3. Results 3.1. Patient demographics We analyzed 73 patients (46 men and 27 women) aged from 1 to 51 years with an average of 28.3 11.4 years (a median age of 27 years). The average epilepsy duration was 14.0 10.6 years (ranged from 0.5 to 45 years). The average age at the time of epilepsy surgery was 28.3 11.4 years (ranged from 1 to 51 years) and the average age at epilepsy onset was 14.2 10.9 years (ranged from 0 to 48 years). At the time of surgery, 7 of the 73 patients (9.6%) were younger than 16 years. 3.2. Seizure onset zone Based on a preoperative investigation, we assessed the probable seizure onset zone (SOZ) in all patients. The SOZ was localized on the right side in 44 patients and on the left side in 29. The most frequent SOZ location was the frontal lobe (in 29 of the 73 patients; 39.7%). Other SOZ locations are shown in Fig. 1. 3.3. Seizure outcome All 73 patients reached the 1-year follow-up visit, 69 reached 2 years, 59 reached 3 years, 47 reached 4 years, and 40 reached 5 years. The last follow-up visit in all patients ranged from 1 to 15 years with an average of 6.15 3.84 years. At the 1-year follow-up visit, 38 of the 73 patients (52.1%) were classified as Engel I, 7 (9.6%) as Engel II, 16 (21.9%) as Engel III, and 12 (16.4%) as Engel IV. At the 5-year follow-up visit, 22 out of 40 patients (55.0%) were classified as Engel I, 6 (15.0%) as Engel II, 5 (12.5%) as Engel III, and 7 (17.5%) as Engel IV. At the last follow-up visit, 37 of the 73 patients (50.7%) were classified as Engel I, 11 (15.1%) as Engel II, 10 (13.7%) as Engel III, and 15 (20.5%) as Engel IV. Forty patients reached at least the 5-year follow-up visit, and the last follow-up visit for these 40 patients ranged from the 5-year visit to the 15-year visit, with an average of 9.23 2.82 years. Engel IA outcome was reached in 21 out of the 40 patients (52.5%) by the 1, 2, and 3-year follow-up visits, in 20 (50%) by the 4-year follow-up visit, and in 19 (47.5%) by the 5-year follow-up visit. At the last followup visit (average 9.23 years after the surgery), 15 of these 40 patients
Fig. 1. Localization of the seizure onset zone in all patients (F – frontal lobe epilepsy; CRE – central region epilepsy; OINZ – operculo-insular epilepsy; O – occipital lobe epilepsy; TPO – seizures arising from temporal-parietal-occipital boundary; Other – multilobar seizure onset) (displayed in number of patients; percentages).
(37.5%) were classified in the same category every year. We present the seizure outcomes of the 40 patients who reached at least the 5year follow-up visit in a Kaplan–Meier survival curve (Fig. 2). 3.4. Histopathology Histopathological findings are shown in Fig. 3. The most frequent findings were low grade gliomas, and developmental glioneural tumors [dysembryoplastic neuroepithelial tumor (DNET) and ganglioglioma] and malformations of cortical development (MCD) (each in 21 patients – 28.8%). In 7 of the 73 (9.6%), the histopathology was negative or inconclusive (all with preoperatively normal MRI). Four patients were classified as focal cortical dysplasia type IIIb according to ILAE classification (i.e. combination of ganglioglioma and FCD). The most frequent findings within the ‘‘tumoral group’’ were group with diagnosed oligodendroglioma (grade II) (in 6 out of 21 patients) and ganglioglioma (grade I) (in 5 out of 21 patients) and DNET (in 4 out of 21 patients) (see Fig. 3).
Fig. 2. Seizure outcome of the 40 patients who reached at least the 5-year follow-up visit in a Kaplan–Meier survival curve (displayed in number of patients; percentages). X-axis in years.
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Fig. 3. Histopathological findings in the whole group of 73 patients (displayed in numbers of patients; percentages).
3.5. Surgical complications
3.7. Predictors of postsurgical outcome
We observed 2 complications associated with invasive EEG monitoring (out of 38 procedures – 5.2%). We observed an asymptomatic hematoma following the depth electrode insertion in 1 patient and an edema following the grid placement in 1 patient. Both complications resolved without consequence without the need for surgical intervention. Following the epilepsy surgery, we observed surgery-related complications in 3 of the 73 patients (4.1%): a hematoma in the post-resection cavity in 1 patient and extracerebral bleeding into the subdural and/or epidural space in 2 patients. All 3 patients had revision of the bleeding and we did not observe any long-term consequences of these complications. Another 7 of the 73 patients (9.6%) had permanent neurological deficits following the surgery: paresis of the upper limb in 3 patients and hemiparesis in 1 patient following resection in the peri-central or parietal regions (in all classified as mild); 3 other patients had visual field deficits (quadrantopsia) after resection in either the parietal or occipital lobes. All of these complications were to be expected due to the surgery localization.
No statistically significant difference between epilepsy duration, the age at epilepsy onset, the age at the time of epilepsy surgery, and surgical efficacy was established by ANOVA (p = 0.481, 0.45, and 0.512, respectively). Preoperatively, 49 (67.1%) patients had abnormal MRI findings. Of these 49 patients, 30 (61.2%) were classified as Engel I at the last follow-up visit, 7 (14.3%) as Engel II, 4 as Engel III (8.2%), and 8 (16.3%) as Engel IV. Preoperatively, 24 (32.9%) patients had normal MRI findings. Of these 24 patients, 7 (29.2%) were classified as Engel I at the last follow-up visit, 4 (16.7%) as Engel II, 6 (25.0%) as Engel III, and 7 (29.2%) as Engel IV. The difference in Engel I outcome at the last follow-up visit between these two groups was statistically significant [x2 (1) = 6.62; p < 0.01] (Fig. 5). Of those 24 patients with normal MRI, 13 had FCD diagnosed histopathologically (5 patients type IA, 4 IB, 4 IIB), 7 specimens were negative or inconclusive, in 3 patients gliosis was confirmed, and in 1 ganglioglioma of grade I. Of the 21 patients with low-grade gliomas and developmental glio-neural tumors, 16 (76.2%) had Engel class I outcome at the last follow-up visit (Fig. 6); in the 52 patients with other histopathological finding (Fig. 3) 21 (40.4%) were classified as Engel I at the last follow-up visit. This difference was statistically significant [x2(2) = 6.67; p = 0.035]. The patients with low-grade gliomas and developmental glioneural tumors had better outcomes (Engel class IA in 66.7%) than the patients diagnosed with cortical dysplasia (Engel class IA in 28.6%). This difference was statistically significant [x2(2) = 6.69; p < 0.01].
3.6. Antiepileptic drug treatment following the surgery The number of AEDs used in the past history of the patients at the time of the surgery varied from 2 to 14 with an average of 6.8 3.2. The policy in our center is to start to discontinue AEDs after successful surgery based on individual decisions for each patient. At the 5-year follow-up visit, 10 of the 40 patients (25.0%) were completely off AEDs (Fig. 4A). At the 5-year follow-up visit, among the 19 patients classified as Engel IA, AED treatment was completely withdrawn in 10 patients (52.6%) and partially withdrawn in 26.3% (Fig. 4B). At the last follow-up visit in all patients, 10 of the 73 patients (13.7%) were completely off AEDs, in 12 patients (16.4%) the AEDs had been partially withdrawn (at least one AED from the combination), and in 14 patients (19.2%) the AEDs remained unchanged. In the remaining 37 patients (50.7%), the AED treatment was changed after the surgery. At the last follow-up, among the 32 patients classified as Engel IA, AED treatment was completely withdrawn in 31.3% and partially withdrawn in 34.4%.
4. Discussion We revealed a relatively stable postoperative outcome. At the 1year follow-up visit in all patients, 52.1% of patients were classified as Engel I; 5 years after surgery, 55.0% were classified as Engel I; at the last follow-up visit (mean 6.15 years after surgery), 50.7% were classified as Engel I. Literature data report a wide range of seizure freedom, varying from 25% to 80% of patients with exTLE.2,3,8–16 Some studies analyzed the results of either resective surgery or other ‘‘palliative’’ procedures like corpus callosotomy and multiple subpial transsections.19,20 Other studies provided an analysis of ‘‘neocortical’’ epilepsies, combining the results of TLE and exTLE patients.21 Comparisons of studies in patients with exTLE are
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Fig. 4. (A) Antiepileptic medication at the 5-year follow-up visit for the group of 40 patients who reached this follow-up (displayed in number of patients; percentages). (B) Antiepileptic medication for patients classified as Engel IA at the 5-year follow-up visit (displayed in number of patients; percentages).
particularly unreliable. The heterogeneity of exTLE surgery was noticed in the data pooled by Te´llez-Zenteno et al.4 They reported long-term seizure freedom in 34% of patients in grouped extratemporal resections, of which 27% were with frontal lobe resections and 46% with both parietal and occipital lobe resections. McIntosh et al.11 studied 81 patients with exTLE; the study showed that the probability of complete seizure freedom at 5 years postoperative is 15%. This type of measure might be misleading because it is not usual to use it in these types of studies. On the other hand, this measurement reflects the proportion of patients whose outcome is really excellent from a long-term point of view.
In our study, 37.5% of the patients were completely seizure free at the 5-year follow-up visit (i.e. classified as Engel IA at each followup). This number is more than twice that of the McIntosh study. The better outcome in our study might be explained by the higher number of patients with benign tumors or DNET and the lower number of patients with focal cortical dysplasia (FCD) in comparison to the McIntosh study. Patients with FCD (both types I and II) were more than 50% of the patients in the McIntosh study, but less than 30% in our study. This difference emphasizes the large diversity of surgical series of exTLE patients published in the literature.
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Fig. 5. Postsurgical outcome at the last follow-up visit; difference between patients with ‘‘lesional’’ and ‘‘nonlesional’’ preoperative MRI (displayed in number of patients; percentages). *p < 0.01.
In our patients, postoperative outcome was stable over time (the differences in Engel I outcome gathered at 1-year, 5-year, and last follow-up visits were insignificant). Elsharkawy et al.22 reported similar results in 218 patients with exTLE patients. Jeha et al.2 observed decreased surgical efficacy over time in 70 patients with frontal lobe epilepsy. While 56% of those patients were seizure free at the 1-year follow-up visit, only 30% were seizure free after 5 years.
Postsurgical outcome is significantly affected by many factors, the most important of which are the finding of a lesion on preoperative MRI and ‘‘positive’’ histopathological findings. Te´llezZenteno et al.16 evaluated the predictive factors for better postsurgical outcome in more detail in a meta-analysis of 40 studies, of which 13 were performed on patients with exTLE. In these groups, the odds of being seizure free at least one year after surgery are two to three times higher in patients with a
Fig. 6. Postsurgical outcome at the last follow-up visit; difference between patients with benign neoplasm + developmental glio-neural tumors and malformation of cortical development (displayed in number of patients; percentages). *p < 0.01.
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preoperative MRI-detected lesion or confirmed histopathological findings than in those with no MRI-detected lesion and negative histopathological findings. The proportion of seizure-free patients was 35% in nonlesional epilepsy and 60% in lesional epilepsy. We confirmed a statistically significant association between a preoperative MRI-detected lesion and the postoperative outcome. Other studies have shown a worse postoperative seizure reduction if no lesion was found preoperatively on MRI.2,17,22–25 On the other hand, Ansari et al.8 found no significant association between MRIdetected lesion and good outcome. These results are poorly comparable to ours because of differing interpretations of ‘‘lesional’’ and ‘‘nonlesional’’ epilepsy. Ansari et al. classified tumors, vascular malformations, and tuberous sclerosis as ‘‘lesional’’ epilepsy and did not include these abnormal findings in their study. All other pathologies, such as malformations of cortical development including cortical dysplasia, polymicrogyria, ulegyria, gliosis, and chronic inflammation, were classified as a ‘‘nonlesional’’ epilepsy, although some (for example cortical dysplasia) can be visible as an MRI-detected lesion. The authors divided the patients classified with ‘‘nonlesional’’ epilepsy in two groups: those with a visible MRI-detected lesion and those with a normal MRI. We classified all of the patients with visible MRIdetected lesions as having ‘‘lesional’’ epilepsy (including cortical dysplasia with a positive finding on MRI). In the study by Ansari et al.,8 the most frequent abnormal finding seen was cortical dysplasia, which can be more extended and diffused than a visible MRI-detected lesion, particularly in younger patients3,26 and hence, could have worse postoperative outcome. One of the possible reasons for higher efficacy of surgery in lesional epilepsy could be the easier surgical performance and complete resection of the epileptogenic zone. This might result in a better outcome in patients with benign tumors, because pathological neoplastic tissue is more visible and easily distinguishable from the normal tissue during surgery.27 In our study, benign neoplasms, developmental glio-neural tumors and malformations of cortical development were histologically diagnosed as the most frequent pathological findings. Boesebeck et al.27 reported a similar distribution of tumors and malformations in a group of 81 patients as compared to our study. We found better outcomes at the last follow-up visit in patients with benign neoplasms + developmental glio-neural tumors than in patients with cortical dysplasia. In agreement with our study, tumorous etiology has shown a more favorable seizure outcome in extratemporal epilepsies.27,28 This association is also supported by the results of two studies that reported from 80% to 82% of patients to be seizure free after tumor resection reported worse surgical outcomes when cortical dysgenesis was confirmed in a tissue specimen.5,29,30 Other authors reported that a malformation of cortical development may be poor congruence with electrographic and with structural and functional radiological findings.17,31,32 In our study, 52.1% of patients underwent invasive EEG (depth or subdural electrodes alone or in combination at the same time). The frequency of use of invasive EEG is reported in a wide range. McIntosh et al.11 used intracranial electrodes in 26 out of 81 patients (32.1%). Subdural grids and epidural or depth electrodes were used more frequently (66 out of 81 patients, 81.5%) in a retrospectively study by Boesebeck et al.27 in which patients had MRI-detected lesions defined histologically as tumors, vascular lesions, and cortical gliosis. Jeha et al.2 published the results of 70 patients with frontal lobe epilepsy. Of those 70, 47 (67.1%) underwent invasive EEG. The different results mostly depend on the strategy of each center, on the availability of neuroimaging methods during the presurgical evaluation, and on the placement strategy of either depth or subdural electrodes. In 9.6% of patients, we noticed permanent neurological deficits (mild paresis following the resection in the peri-central
or parietal regions and visual field deficits after resection in the posterior quadrant). All of these complications are to be expected due to the location of the surgery and all of the patients accepted these deficits prior to the surgery. The complications are more frequent in extratemporal than in temporal localization because of the eloquent cortex in this area and the need for a large resection to achieve a better postsurgical outcome.33 The spectrum of complications in other studies is very similar to our findings. The number is generally low. Elsharkawy et al.22 observed outcomes and complications in 218 patients with extratemporal refractory epilepsy who had surgery between 1991 and 2005. Overall, 4.6% had permanent and 5.0% had transient neurological deficits. The most frequent were paresis, visual field defects, and facial palsy. Mulholland et al.12 reported a relatively high percentage of complications. They observed postoperative complications (namely meningitis, brain abscess, and wound infection) in 3 patients (17.6%). But the whole group contained only 17 patients. They recorded minor complications in 4 patients, including blurring of vision, trembling in the arm, and cephalohematoma. It is challenging to compare complications with other studies because of non-uniform classification systems. In our study, the number of AEDs used in the past history of the patients at the time of surgery varied from 2 to 14 with an average of 6.8. In a study by Mulholland et al.,12 a similar average of 6.5 AEDs per patient was used. At the last follow-up visit, among 32 patients classified as Engel IA, AED treatment had been withdrawn completely in 31.3%. The previously published results of similar studies are conflicting. Kerling et al.34 published a prospective pilot study of AED withdrawal in 34 out of 60 patients who underwent surgery. He compared this group with 26 patients without discontinuation of AEDs. All of the patients with extratemporal epilepsy (6 out of 34) were in the withdrawal group. The association with a higher risk of seizure recurrence was confirmed (38.5% in the group with unchanged medication as compared to 23.6% in the withdrawal group). In contrast, Schiller et al.,35 reported a higher risk of seizure recurrence after discontinuation of AEDs (7% of patients with unchanged medication versus 36% in withdrawal group). In our study, we did not confirm a statistically significant difference between epilepsy duration and surgical efficacy. We did not find a difference in epilepsy duration between patients with lesional (14.0 years) and nonlesional (14.3 years) epilepsy, either. However, epilepsy duration is still a discussed predictive factor.24 In our patients, the time from seizure onset to surgery was similar to that in the study by Elsharkawy et al.36 who reported 17.8 10.0 years. There are inconsistencies among the published results. Our conclusion is in line with studies by Jeha et al.,2 Ansari et al.,8 McIntosh et al.11 and Boesebeck et al.27 In contrast, Kral et al.24 found an association between epilepsy duration and postoperative outcome, but that study observed only patients with FCD. Teutonico et al.,37 confirmed a statistically significant association in 120 children under 16 years of age. Therefore in our results, we have to consider different histological etiology as well as the wide range of patient ages. Elsharkawy et al.22 described a significant association between epilepsy duration and outcome by univariate analysis, but this was not confirmed by multivariate analysis. The theory that epilepsy duration affects outcome through other factors is supported by these results. 5. Conclusions In conclusion, our results showed that surgery for patients with exTLE is an effective procedure with relatively stable efficacy over time. The number of patients included in the study did not allow us to analyze the efficacy of the surgery in patients with different SOZ
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localizations. Such a detailed analysis would lead to a relatively smaller number of patients. Because of the controversies and diversities within the literature data concerning this issue, a prospective controlled trial in the future will be necessary to confirm the results obtained from retrospective analyses. The presence of preoperative MRI-detected lesions and the histopathological finding of low-grade tumors (and including developmental glio-neural tumors) seem to be the two most important factors influencing the favorable prognosis for patients with extratemporal epilepsy. The relatively higher incidence of permanent neurological deficit postoperatively both in our study and in other studies is undoubtedly caused by the necessity of performing the surgery near the eloquent regions (sensory-motor region, visual cortex, etc.). Conflicts of interest None of the authors has any conflict of interest to disclose. 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 the project ‘‘CEITEC – Central European Institute of Technology’’ (CZ.1.05/1.1.00/02.0068) from the European Regional Development Fund. Supported by the project (Ministry of Health, Czech Republic) for conceptual development of research organization 65269705 (University Hospital Brno, Brno, Czech Republic). Thanks to Anne Johnson for grammatical assistance. References 1. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314–9. 2. Jeha LE, Najm I, Bingaman W, Dinner D, Widdess-Walsh P, Lu¨ders H. Surgical outcome and prognostic factors of frontal lobe epilepsy surgery. Brain 2007; 130:574–84. 3. Spencer SS, Berg AT, Vickrey BG, Sperling MR, Bazil CW, Shinnar S, et al. Initial outcomes in the Multicenter Study of Epilepsy Surgery. Neurology 2003;61: 1680–5. 4. Te´llez-Zenteno JF, Dhar S, Wiebe S. Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain 2005;128: 1188–98. 5. Zentner J, Hufnagel A, Ostertun B, Wolf HK, Behrens E, Campos MG, et al. Surgical treatment of extratemporal epilepsy: clinical, radiologic, and histopathologic findings in 60 patients. Epilepsia 1996;37:1072–80. 6. Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med 2001;345:311–8. 7. Engel Jr J, McDermott MP, Wiebe S, Langfitt JT, Stern JM, Dewar S, et al. Early randomized surgical epilepsy trial (ERSET) study group. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA 2012;307:922–30. 8. Ansari SF, Tubbs RS, Terry CL, Cohen-Gadol AA. Surgery for extratemporal nonlesional epilepsy in adults: an outcome meta-analysis. Acta Neurochir 2010;152:1299–305. 9. Elsharkawy AE, Behne F, Oppel F, Pannek H, Schulz. Hoppe M, et al. Long-term outcome of extratemporal epilepsy surgery among 154 adult patients. J Neurosurg 2008;108:676–86. 10. Jehi LE, O’Dwyer R, Najm I, Alexopoulos A, Bingaman W. A longitudinal study of surgical outcome and its determinants following posterior cortex epilepsy surgery. Epilepsia 2009;50:2040–52.
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