Temporallobe epilepsy (TLE) is one of the most common forms of epilepsy, first described by Hughlings-Jackson. In approximately 30% of patients, seizures are refractory to drug treatment.1Since the first randomized controlled trial by Wiebe et al. showed significantly improved outcomes with epilepsy surgery over drug treatment in refractory TLE, resective temporal lobe surgery (rTLS) has been a reasonable option for treatment in these patients.2In a meta-analysis including 32 studies with 2250 patients, Engel et al. reported that after rTLS, seizure freedom was achieved in 65% of patients with TLE.3In a recently published review, Englot and Chang reported that the existing data favoring surgery for appropriately selected candidates with refractory TLE are convincing and suggest that a cure is possible in some patients with this disorder.4Despite this fact and all achievements of modern presurgical evaluation in recent years, the presurgical prediction of seizure outcome remains difficult. The aim of this study was to evaluate seizure outcome in patients with drug-refractory TLE who underwent rTLS at our center and to determine features associated with unfavorable postsurgical seizure outcome.
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Population and Presurgical Evaluation
Patients with TLE who underwent rTLS between 2012 and 2017 were reviewed from the prospectively conducted epilepsy surgery database at our center. The formation of this database was approved by the local ethics committee. Given the retrospective nature of the study, written informed consent was not required.
During the studied period, rTLS was performed in a total of 184 patients. There were 23 cases lost to follow-up; the most common reason was treatment of patients from abroad who moved back to their countries after surgery. These patients did not complete the follow-up visits at our center. Because we included only patients with completed follow-up at 12 months after rTLS, complete data sets for 161 consecutive patients were available. All patients suffered from medically refractory TLE and had undergone adequate treatment with at least two first-line antiepileptic drugs. A retrospective analysis of clinical, radiological, histopathological, and perioperative findings was performed.
All patients were preoperatively assessed in the department of epileptology in a similar fashion and were considered to be suitable for surgery.5,6The evaluation included detailed history of seizures, medical history, high resolution 3-T MRI, neuropsychological assessment, and video-electroencephalography (EEG) monitoring using continuous recordings. In patients with absent or several lesions on MRI, PET and SPECT were performed to identify a seizure focus. In cases with inconclusive findings, invasive EEG monitoring was performed using stereotactically implanted depth electrodes.7
Surgical Procedures
All surgical procedures were performed while patients were under general anesthesia using intraoperative neuronavigation and intraoperative neurophysiological monitoring with motor evoked and somatosensory evoked potentials. The goal of surgery was to remove temporal and temporomesial structures, including the lesion depicted on MRI or anatomical area with presumed seizure focus.
Histopathological Examination
The resected tissue was obtained from all patients in this study. Standardized neuropathological analysis was performed in all preserved specimens by local neuropathologists. The histopathological findings were differentiated into three categories. First were hippocampal pathologies such as hippocampal sclerosis (HS) or hippocampal gliosis (HG) according to the International League Against Epilepsy (ILAE) classification.8Next were pathologies within the temporal lobe without the involvement of the hippocampus, such as gliosis, ganglioglioma, cavernoma, and focal cortical dysplasia (FCD). The diagnosis of HG was histologically confirmed as reactive astrogliosis without neuronal loss within the resected hippocampus. Neoplastic lesions were classified according to the WHO classification.9The FCD was classified according to the new ILAE classification.10The last category was no specific pathological changes.
Surgical Outcome Analysis
After rTLS, the outcome was assessed during follow-up visits at 6 and 12 months. Patients with a follow-up period less than 12 months were not included in this study. At the 12-month visit, all patients underwent a thorough clinical examination, evaluation of seizure outcome, video-EEG recording, 3-T MRI, and neuropsychological reassessment. The postoperative seizure outcome was assessed according to the ILAE classification.11The patients were divided into two groups according to seizure outcome: group I (ILAE class 1) and group II (ILAE class ≥ 2).
Surgically associated complications were assessed during the postoperative course of treatment. The clinically relevant events requiring surgical revision, such as bleeding complications and surgical site infections, were analyzed. Furthermore, relevant newly occurring neurological deficits such as motor deficits, aphasia, and cranial nerve palsy were assessed and analyzed.
All patients underwent MRI within 2–3 days postoperatively to detect the extent of resection of desired structures. Incomplete resection was determined in cases in which a substantial remnant of target tissue was not reached by resection as confirmed by postoperative MRI, whether it was from imprecise delimitation or surgical and functional limitation. The target structures were different according to the surgical procedure. In candidates who underwent selective amygdalohippocampectomy (sAHE) or anterior temporal lobectomy (ATL) with amygdalohippocampectomy (ATL with AHE), the resection was stated as incomplete if mesial temporal structures such as the hippocampus, amygdala, or superior part of the uncus were insufficiently removed. In patients who underwent temporal lesionectomy or ATL without AHE, the resection was incomplete if any parts of the epileptogenic lesion were not addressed by the surgery. After completion of the presurgical evaluation, the extent of resection and the desired structures that were intended to be removed were defined by the responsible epileptologist and reviewed by the interdisciplinary epilepsy surgery conference. In cases where needed, resection masks were generated and included in the intraoperative neuronavigation. Following surgery, the resection was matched with the presurgical resection mask to confirm the proper extent of resection. The postoperative MRI was performed in each patient within 2–3 days to confirm the extent of resection of addressed structures or lesions and rule out surgical complications such as bleeding, infarction, and damage to brain tissue along the surgical approach. The postsurgical MR images were analyzed by experienced neuroradiologists.
Neuropsychological Assessment
The neuropsychological evaluation focused on tests of verbal and nonverbal memory representing temporal lobe functions. In addition, attention and executive functions, visuospatial abilities, and language and motor functions were considered. Verbal memory was measured via the verbal learning and memory test (VLMT). For visual learning, the Diagnostikum für Zerebralschäden–Revised (DCS-R) was applied. Parallel versions of the VLMT and DCS-R were used to minimize practice effects at the follow-up. Attention was assessed by the EpiTrack screening tool and the d2 Aufmerksamkeitsbelastungstest. Language assessment comprised the BNT and the Token Test. Visuospatial abilities were evaluated via Leistungspruefsystem subtest 7 and Wechsler Adult Intelligence Scale block design. The tests and their references are described in previous articles.12Pre- and postoperative test results from each cognitive domain were summarized and classified into a 5-point scale, ranging from severely impaired to above average (severely impaired = 0, at least two test scores > 2 standard deviations below the mean of the normative sample; impaired = 1, at least two test scores > 1 standard deviation below the mean; borderline = 2, one test score below the mean; unimpaired = 3, no test score > 1 standard deviation below the mean; above average = 4, at least two test scores > 1 standard deviation above the mean). The distance between two subsequent categories approximately corresponds to one standard deviation from the mean standardized score across all test scores of the respective domain.
Ophthalmological Examination
Visual fields were examined in each patient pre- and postoperatively using kinetic Goldmann perimetry. A new postoperatively diagnosed visual field deficit (VFD) was classified as a superior quadrantanopia or homonymous hemianopia.
Statistical Analysis
Statistical data analysis was performed using the SPSS software package (IBM SPSS Statistics for Windows, version 25.0., IBM Corp.). Associations between parametric variables were analyzed using an unpaired, two-tailed Student t-test. For analysis of associations between nonparametric variables, the Mann-Whitney U-test was used. Associations of categorical variables were compared using the chi-square or Fisher exact test. Results with p values < 0.05 were considered statistically significant. For identification of independent risk factors for unfavorable postoperative seizure outcome (ILAE class ≥ 2), a multivariate logistic regression analysis was performed including the variables with significant p values in univariate analysis. The results of the analysis were presented by logistic regression as odds ratio (OR) with a 95% confidence interval (CI).
Results
Population and Presurgical Evaluation
In total, data from 161 patients who underwent rTLS for TLE were included in this analysis. There were 85 males (52.8%). The surgery was performed in 81 patients (50.3%) on the left side and in 80 (49.7%) on the right. The mean age at epilepsy onset was 17.32 ± 13.09 years, and the mean age at surgery was 36.1 ± 14.96 years. The mean duration of epilepsy was 19.1 ± 13.77 years. According to seizure outcome, 121 patients were assigned to group I (ILAE class 1) and 40 to group II (ILAE class ≥ 2). Regarding basic clinical characteristics such as age at seizure onset, age at surgery, duration of epilepsy, and side of surgery, there were no statistically significant differences (Table 1). During the presurgical evaluation, the invasive evaluation using depth electrodes was performed in significantly more patients in group II compared to group I (15 [37.5%] vs 21 [17.4%], p = 0.015). The analysis of preoperative MRI revealed the evidence of HS as the most common radiological pathology in both groups (79 [65.3%] in group I vs 20 [50.0%] in group II, nonsignificant difference). The distribution of other lesions is shown inTable 1. A negative MR image without any lesions was found significantly more often in group II compared with group I (8 [20%] vs 6 [5%], p = 0.007).
Patient demographics and characteristics according to ILAE seizure outcome class
| Characteristic | Overall | Group I (ILAE class 1) | Group II (ILAE class 2–6) | p Value |
|---|---|---|---|---|
| No. of patients | 161 | 121 | 40 | |
| Sex, n (%) | ||||
| Male | 85 (52.8) | 62 (51.2) | 23 (57.5) | NS |
| Female | 76 (47.2) | 59 (48.8) | 17 (42.5) | NS |
| Mean age at epilepsy onset ± SD, yrs | 17.32 ± 13.09 | 17.9 ± 13.59 | 15.56 ± 11.4 | NS |
| Mean duration of epilepsy ± SD, yrs | 19.1 ± 13.77 | 19.06 ± 13.8 | 19.4 ± 13.71 | NS |
| Mean age at surgery ± SD, yrs | 36.1 ± 14.96 | 36.66 ± 15.53 | 34.58 ± 13.12 | NS |
| Site of surgery, n (%) | NS | |||
| Lt | 81 (50.3) | 56 (46.3) | 25 (62.5) | NS |
| Rt | 80 (49.7) | 65 (53.7) | 15 (37.5) | NS |
| Invasive presurgical evaluation w/ depth electrodes, n (%) | 36 (22.4) | 21 (17.4) | 15 (37.5) | 0.015 |
| Preop MRI findings, n (%) | ||||
| Unilateral HS | 99 (61.5) | 79 (65.3) | 20 (50.0) | NS |
| Hippocampal lesions other than HS | 27 (16.8) | 20 (16.5) | 7 (17.5) | NS |
| Temporal lesion w/o hippocampal involvement | 21 (13.0) | 16 (13.2) | 5 (12.5) | NS |
| No lesion | 14 (8.7) | 6 (5.0) | 8 (20.0) | 0.007 |
| Histology of hippocampus, n (%) | ||||
| HS | 94 (58.4) | 77 (63.6) | 17 (42.5) | 0.026 |
| HG | 21 (13.0) | 10 (8.3) | 11 (27.5) | 0.005 |
| Histology of TL tissue w/o hippocampus, n (%) | ||||
| Temporal gliosis | 11 (6.8) | 6 (5.0) | 5 (12.5) | NS |
| Ganglioglioma | 9 (5.6) | 7 (5.8) | 2 (5.0) | NS |
| Cavernoma | 6 (3.7) | 5 (4.1) | 1 (2.5) | NS |
| FCD type I | 2 (1.2) | 2 (1.7) | 0 (0.0) | NS |
| Other | 6 (3.7) | 5 (4.1) | 1 (2.5) | NS |
| No specific histopathological changes | 12 (7.4) | 9 (7.4) | 3 (7.5) | NS |
NS = nonsignificant; TL = temporal lobe.
Surgical Procedures
Overall, the leading surgical procedure performed was transsylvian sAHE in 91 of 161 patients. The ATL with AHE was performed in 30 of 161 patients and without AHE in 15 of 161 patients. In 20 of 161 patients, a tailored lesionectomy without AHE was performed followed by lesionectomy with AHE in 5 of 161 patients. As shown inTable 2, the analysis revealed no differences related to surgical procedure between the two outcome groups.
Distribution of surgical modality and complications during the perioperative course of treatment according to seizure outcome
| Variable | Overall | Group I, n = 121 | Group II, n = 40 |
|---|---|---|---|
| Surgery modality | |||
| sAHE | 91 (56.5) | 67 (55.4) | 24 (60.0) |
| ATL w/ AHE | 30 (18.6) | 21 (17.3) | 9 (22.5) |
| ATL w/o AHE | 15 (9.3) | 11 (9.1) | 4 (10.0) |
| LE w/ AHE | 5 (3.1) | 4 (3.3) | 1 (2.5) |
| LE only | 20 (12.5) | 18 (14.9) | 2 (5.0) |
| Overall surgical complications | 19 (11.8) | 12 (9.9) | 7 (17.5) |
| Bleeding complication | 6 (3.7) | 4 (3.3) | 2 (5.0) |
| Surgical site infection | 9 (5.6) | 5 (4.1) | 4 (10.0) |
| Overall revision surgery | 13 (8.1) | 8 (6.6) | 5 (12.5) |
LE = lesionectomy.
Data are given as number (%). All statistical comparisons between the two groups for each variable were nonsignificant.
Histopathological Examination
The overview of the histopathological findings is shown inTable 1. There were significantly more patients with HS in the group with favorable seizure outcome (77 [63.6%] in group I vs 17 [42.5%] in group II, p = 0.026). Furthermore, the prevalence of HG was significantly higher in group II compared with group I (11 [27.5%] vs 10 [8.3%], p = 0.05). In regard to other histopathological findings, the groups did not differ significantly (Table 1).
Surgical Outcome Analysis
Of the 161 patients, at 6- and 12-month follow-up visits after rTLS a favorable seizure outcome with seizure freedom (ILAE class 1) was achieved in 121 patients (75.2%). The proportion of patients with ILAE class 2–6 was not significantly different for each ILAE class at the 6- and 12-month follow-ups, respectively (Table 3). The analysis of surgical complications revealed an overall complication rate of 11.8%. The overall rate of revision surgery was 8.1% (Table 2). Surgical site infections were the most frequent complication (in 9 [5.6%] of 161 patients), followed by bleeding complications (6 [3.7%] of 161 patients). The comparison of the two outcome groups revealed no significant differences, either for overall complication rate or rate of surgical revision, or for bleeding complications and infections in each group (Table 2). Transient motor neurological deficits such as paresis and hemiparesis occurred in 8 (4.9%) of 161 patients and were not significantly different between groups I and II (6 [4.9%] vs 2 [5%], nonsignificant). The postoperative MRI showed that desired extent of resection was significantly often not achieved in group II compared to group I (4 [10%] in group II vs 2 [1.7%] in group I, p = 0.034).
Seizure outcome according to ILAE classification at 6- and 12-month follow-up visits
| Follow-Up (mos) | ILAE Classification | ||||||
|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | Total | |
| 6 | 121 (75.2) | 9 (5.6) | 11 (6.8) | 10 (6.2) | 8 (5.0) | 2 (1.2) | 161 |
| 12 | 121 (75.2) | 10 (6.2) | 8 (5.0) | 10 (6.2) | 10 (6.2) | 2 (1.2) | 161 |
Data are given as number (%).
Neuropsychological Outcome
Before surgery, visual memory was impaired in 66% of patients, followed by verbal memory, language, and attention in approximately 50% each. Visuospatial functions were affected in 39% of cases. Preoperatively, there were no significant differences in performance between left and right TLE (p = 0.29–0.80;Fig. 1).
Comparative histogram demonstrates the results of the preoperative cognitive performance. The results from each cognitive domain are summarized and classified into a 5-point scale ranging from severely impaired to above average. The values represent cumulative percentage of performance categories in each tested cognitive domain according to the side of the TLE. Impaired = cumulative percentages of impaired and severely impaired performance categories; unimpaired = cumulative percentages of unimpaired and above-average performance categories; borderline = percentages of borderline performance categories. Visual memory was impaired in 66% of patients, followed by verbal memory, language, and attention in approximately 50% each, respectively. Visuospatial functions were affected in 39% of cases. Preoperatively there were no significant differences in performance between left and right TLE (p > 0.29–0.80).
组级别分析,通过重复测量s ANOVA, revealed an interaction effect of visual memory and surgical side (F [1,99] = 4.752, p = 0.032, η2= 0.046). Patient performance was worse after right-sided resections (Fig. 2, left). A significant main effect of surgery (F [1,101] = 10.831, p < 0.01, η2= 0.097) and a significant main effect of surgical side (F [1,101] = 4.379, p < 0.05, η2= 0.042) were found for verbal memory. There was a trend for an interaction of side and surgery (F [1,101] = 3.127, p = 0.08, η2= 0.03;Fig. 2, right). Attention significantly improved after surgery (F [1, 99] = 12.561, p < 0.01, η2= 0.113). Language and visuospatial abilities did not show significant changes.
Performance in visual and verbal memory before and after surgery according to the side of the resection. Group-level analysis revealed an interaction effect of visual memory and surgical side (F [1,99] = 4.752, p = 0.032, η2= 0.046). Patient performance was worse after right-sided resections than after left-sided resections (left). In addition, a significant main effect of surgery (F [1,101] = 10.831, p < 0.01, η2= 0.097) and a significant main effect of surgical side (F [1,101] = 4.379, p < 0.05, η2= 0.042) was found for verbal learning and memory. There was a trend for an interaction of side and surgery (F [1,101] = 3.127, p = 0.08, η2= 0.03) (right).
Consistent with the group-level analysis, individual-level analysis indicated that verbal memory decline was more frequent after left rTLS (63%) than after right rTLS (38%). Visual memory was worse for 48% of the patients after right-sided and for 25% after left-sided resections (χ2[6] = 11.373, p < 0.05). Deteriorations of visuospatial abilities and language were noted in 14%–19% of cases. Attention improved after surgery (39% vs 16%).Figure 3displays the number of patients with significant individual changes, corrected for floor effects.
Postoperative changes in performance categories according to side of resection. The histogram displays the number of patients with significant individual changes, corrected for floor effects. To account for floor effects, patients with the lowest possible baseline score without postoperative change were filtered. We identified 13 patients with floor effects in verbal memory, 15 patients in visual memory, 3 patients in attention, 2 patients in visuospatial abilities, and 1 in the language domain. This revealed a higher rate of postoperative decline in verbal memory after left-sided resections (χ2[2] = 9.160, p = 0.01). The other findings remained the same as in the whole sample. Considering ceiling effects, the results were not significantly different from the results obtained from the whole sample. The bars for verbal and visual memory exclude patients with floor effects. Theasterisksrepresent significant postoperative changes.
Postoperative Visual Field Impairment
总的来说,术后vfd和发生是很常见的ed in 82 (51%) of 161 patients. The most frequent VFD was superior quadrantanopia (40%). Homonymous hemianopia occurred in 11% of the patients. There was no statistically significant difference in the overall incidence rate of VFD in patients with selective versus nonselective procedures, either for superior quadrantanopia or for homonymous hemianopia (Table 4).
Occurrence of VFDs according to surgical procedures
| Surgical Procedures | |||
|---|---|---|---|
| Variable | Overall | Selective | Nonselective |
| No. of procedures | 161 | 91 | 70 |
| No VFD | 79 (49) | 39 (43) | 40 (57) |
| w /变频优越的象限盲 | 65 (40) | 43 (47) | 22 (32) |
| VFD w/ homonymous hemianopia | 17 (11) | 9 (10) | 8 (11) |
| Total | 161 (100) | 91 (100) | 70 (100) |
Data are given as number (%). All comparisons of VFDs between surgical groups were nonsignificant.
Multivariate Logistic Regression Analysis
We performed a stepwise multivariate logistic regression analysis using the variables “invasive preoperative evaluation,” “evidence of a lesion in preoperative MRI,” “histopathological evidence of HS,” “histopathological evidence of HG,” and “extent of resection on postoperative MRI” to find independent predictors for unfavorable seizure outcome (ILAE class ≥ 2). The analysis showed that the histopathological evidence of HG (OR 4.99, 95% CI 1.9–13.1, p = 0.001) and incomplete resection (OR 9.08, 95% CI 1.6–52.5, p = 0.014) were independent and significant predictors for unfavorable seizure outcome after rTLS in TLE (Table 5).
Multivariate logistic regression analysis of factors related to unfavorable seizure outcome (ILAE class 2–6)
| Seizure Outcome | Multivariate Analysis | ||||
|---|---|---|---|---|---|
| Factor Analyzed | Group I, n = 121 | Group II, n = 40 | OR | 95% CI | p Value |
| Invasive presurgical evaluation w/ depth electrodes | 21 (17.4%) | 15 (37.5%) | 2.01 | 0.8–5.1 | 0.144 |
| Preop MRI w/o lesion | 6 (5%) | 8 (20%) | 1.44 | 0.3–6.5 | 0.633 |
| Histopathological evidence of HS | 77 (63.6%) | 17 (42.5%) | 1.60 | 0.7–3.8 | 0.295 |
| Histopathological evidence of HG | 10 (8.3%) | 11 (27.5%) | 4.99 | 1.9–13.1 | 0.001 |
| Incomplete resection | 2 (1.7%) | 4 (10%) | 9.08 | 1.6–52.5 | 0.014 |
Discussion
Resective epilepsy surgery is an established treatment option in patients with focal refractory epilepsy, particularly those with TLE.2However, although it is effective, it has been demonstrated that seizure freedom rates decrease over time after surgery.13There are studies reporting that surgical treatment for TLE fails to provide a seizure-free outcome in 20%–30% of these patients.14,15The reasons behind failure of surgical treatment are multiple and comparison with existing data is difficult because of methodological issues. In this study, we tried to identify factors associated with unfavorable seizure outcome in patients with TLE who underwent rTLS. In the present study, a favorable seizure outcome (ILAE class 1) was achieved in 75% of patients 1 year after surgery, which is consistent with published data.16–20Schmeiseret al. reported on a series of 458 patients with TLE who were treated with different surgical approaches. They found no differences in short- and long-term seizure outcomes in regard to surgical approach.16Other studies addressing this aspect have shown comparable results regarding the seizure outcome between standard temporal lobectomy and sAHE.21,22The systematic review and meta-analysis by Josephson et al. shows that ATL is slightly more effective than sAHE regarding seizure outcome.18Some authors have reported that sAHE may carry the risk of seizure recurrence in patients with an unrecognized lateral temporal epileptogenic zone.23The analysis in this current series revealed that surgical modality did not have an impact on seizure outcome. The overall complication rate in our series was 11.8%, and a revision surgery was required in 8.1% of all patients. However, the reported complication rates are difficult to compare due to different surgical approaches, different underlying pathologies, and heterogeneous study populations. Surgical site infections were the most common complications (5.6%) in our series, followed by bleeding complications (3.7%). The reported rate of infections ranges between 1.5% and 8.5%.24,25The occurrence rate of new postoperative motor deficits (hemiparesis) as reported by Erba et al.25was 4.3%, and 1.2% in the series by Schmeiser et al.16In our series, hemiparesis occurred in 4.9% of patients and was completely resolved in all patients during the observation period. With respect to newly occurring neurological deficits, the comparison of patients with favorable and unfavorable outcomes in our series revealed no impact on seizure outcome. VFDs are a common side effect after TLS. Due to inconsistent and different definitions, the reported rate of VFDs has a very wide range (between 1.5% and 69%).24In their study, Schmeiser et al. reported on a large cohort of patients suffering from TLE (overall rate of 73%).26In patients who underwent ATL the overall rate was 83%, and in patients who underwent transsylvian sAHE the rate was 74%. In the current series, the overall rate of postoperative VFD is consistent with the reported literature. However, our results did not reveal any differences between selective and nonselective surgical procedures. Due to the fact that at our institution the sAHE was performed exclusively via a transsylvian approach, there are some limitations with regard to comparability of the data with other studies.
mesiotemporal和neocortical structures play an important role in memory function, postoperative memory impairment is a major sequela after rTLS. In the current series, left TLE patients were generally more impaired than right TLE patients, and verbal learning and memory deteriorated similarly in both groups. Language and visuospatial abilities did not show significant changes. Our findings are consistent with comparable previously published studies in which deterioration of verbal memory has been observed after left-sided resections and visual memory deterioration has been observed after right-sided resections.16,27Selective attention significantly improved after surgery, which could be due to the relatively high number of seizure-free patients in our study cohort.28
In a meta-analysis on a total of 3511 patients reported by Tonini et al., the authors found that intracranial monitoring was a predictor for unfavorable seizure outcome.29In accordance with these results, in the current series we found significantly more patients in the group with unfavorable seizure outcome who underwent invasive presurgical evaluation with depth electrodes. Interestingly, in multivariate logistic regression analysis in our series, this variable failed to be an independent predictor for an unfavorable seizure outcome. According to published data, about 20%–30% of patients with TLE have normal MRI without epileptogenic lesions.30,31The reported rates of seizure-free outcome following rTLS in these patients varied widely, between 20% and 80%.32,33In our studied population, the overall rate of patients with MRI-negative TLE was 8.7%. There were significantly more patients (20%) with negative MRI in the group with unfavorable seizure outcome compared to the 5% in the group with favorable seizure outcome. In contrast to the data published by Tonini et al., in the multivariate logistic regression analysis in the present series, negative MRI also failed to be an independent prognostic factor for unfavorable seizure outcome. These findings suggest that a normal MRI and the need for invasive presurgical evaluation are not always associated with worse postoperative seizure outcome. This suggestion can be supported by data reported by Sotero de Menezes et al.34and Roberts et al.35showing that seizure outcome in patients with normal MRI is comparable to that in patients with abnormal MRI. Ivanovic et al. showed similar results in their analysis.33
Regarding the histopathological findings, there are several studies suggesting that HS and its distinct pattern may predict surgical outcome in patients with TLE.36–38According to the ILAE Task Force, neuronal loss may affect all of the areas of the cornu ammonis (CA; HS ILAE type 1), predominantly CA1 (HS ILAE type 2), or predominantly CA4 (HS ILAE type 3).8Another pattern described in surgical specimens is astrogliosis without neuronal loss, and it is called “no hippocampal sclerosis, gliosis only.” It is unclear whether HG precedes neuronal loss leading to HS or whether it is a distinct disease entity. The data evaluating the impact of HG on seizure outcome in patients with TLE following resective surgery is scarce. The majority of the literature is focused on evaluation of the impact of HS on postsurgical seizure outcome. However, the identification of HG as an independent predictor for lack of seizure freedom in our series is an aspect that is underrepresented in the literature. Since ILAE developed a consensus classification of HS, several reports have been published to rule out the impact of subtypes of HS on postoperative seizure outcome. In their recently published series on 307 cases with TLE and HS, Gales et al. found no clear correlation between HS subtype and epilepsy surgery outcome.39Similar results were found by Deleo et al.40and Savitr Sastri et al.,41who showed no significant difference in short-term seizure outcome between patients with different HS subtypes. In their recently published series, Hattingen et al. found that patients with hippocampal “gliosis only” according to the ILAE classification have distinct histopathological and MRI patterns compared with HS.42In the current series, we did not distinguish between patient HS subtypes and seizure outcome. However, the analysis of histopathological features in our series revealed HS as the most frequent pathology. Furthermore, there were significantly more patients with HS in the group with favorable seizure outcome. In contrast, HG was found significantly more often in patients with unfavorable outcome. Yet, only HG was identified to be an independent predictor for unfavorable outcome in the multivariate logistic regression analysis. These findings may support the suggestion made by Hattingen et al., who identified HG as a distinct entity in patients with TLE. In our opinion, this finding is important given that several reports have recently been published describing features with the potential to distinguish between HG and HS on preoperative MRI using novel methods of neuroimaging.43傅rther progress in neuroimaging may allow us to detect the underlying pathology within the hippocampus more precisely on the preoperative scan. Thus, the fact that HG independently predicts seizure outcome is novel in relationship to prior publications.
The insufficient resection of epileptogenic structures is an obvious reason for continued seizures after epilepsy surgery.29,44The resection may prove difficult with structures involving eloquent brain area or those not easy to access surgically. There are several series reporting that further resection of residual epileptogenic structures can result in a seizure-free outcome.12,45This fact supports the suggestion that a subgroup of patients fail rTLS for TLE because of incomplete resection of mesial temporal structures. In accordance with these results, the analysis in our series shows significantly more patients with incomplete resection on postoperative MRI in the group with unfavorable seizure outcome. The data in the current study also revealed the evidence of HG and an incomplete resection of the epileptogenic lesion as independent predictors of unfavorable postoperative seizure outcome. Furthermore, the analysis shows that even though there were nonsignificant differences, there was a much higher proportion of gliosis in the specimen obtained from temporal lobe tissue among patients without effects on the hippocampus and with unfavorable seizure outcome compared to the seizure-free group. This could be caused by the fact that neocortical temporal lesions without clearly circumscribed pathology are less resectable. Thus, such lesions might possibly have worse results for reasons related to the lesion itself, not to the surgery.
Study Limitations
The present study has several limitations. One of the strengths of the present series is a relatively large study population, which was treated at a high-volume center in a standardized fashion. Our study suffers from the risk of bias inherent to retrospective cohort analysis. Even though data analysis was retrospective, data acquisition was prospective. However, the implementation of standardized neurosurgical approaches and strict variable definitions might mitigate some of the shortcomings of a retrospective study design.
Conclusions
Our analysis shows that rTLS is an effective treatment method in patients with refractory TLE. However, patients with a lack of lesions on MRI and placement of depth electrodes prior to rTLS are at higher risk for an unfavorable postsurgical seizure outcome. Therefore, these facts should be carefully taken into account, and each of these patients needs an individual approach during the selection process for surgery.
Disclosures
Dr. Helmstaedter reports receiving honoraria from UCB, Eisai, Precisis, and GW; receiving royalties from EpiTrack and NeuroCog FX; and being a consultant to Eisai, UCB, Precisis, and GW. Ms. Taube received support of non–study-related clinical or research effort from the University Hospital Bonn Department of Epileptology (European Reference Network EpiCARE Grant).
Author Contributions
Conception and design: Borger, Vatter. Acquisition of data: Borger, Hamed, Taube, Aydin, Ilic, Schneider, Becker. Analysis and interpretation of data: Borger, Taube, Helmstaedter, Vatter. Drafting the article: Borger. Critically revising the article: Schuss, Güresir, Becker, Helmstaedter, Elger, Vatter. Reviewed submitted version of manuscript: Hamed, Taube, Aydin, Ilic, Schneider, Schuss, Güresir, Becker, Helmstaedter, Elger, Vatter. Approved the final version of the manuscript on behalf of all authors: Borger. Statistical analysis: Borger, Taube. Administrative/technical/material support: Helmstaedter, Elger, Vatter.
Supplemental Information
Previous Presentations
Parts of this work were presented orally at the 69th Annual Meeting of the German Society of Neurosurgery in Münster, Germany, June 3–6, 2018, and at the 13th European Congress on Epileptology in Vienna, Austria, August 26–30, 2018.
References
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3 ↑
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4 ↑
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5 ↑
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6 ↑
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7 ↑
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8 ↑
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9 ↑
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11 ↑
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12 ↑
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13 ↑
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14 ↑
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15 ↑
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16 ↑
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HuWH,ZhangC,ZhangK,et al.Selective amygdalohippocampectomy versus anterior temporal lobectomy in the management of mesial temporal lobe epilepsy: a meta-analysis of comparative studies.J Neurosurg.2013;119(5):1089–1097.
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18 ↑
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WendlingAS,HirschE,WisniewskiI,et al.Selective amygdalohippocampectomy versus standard temporal lobectomy in patients with mesial temporal lobe epilepsy and unilateral hippocampal sclerosis.Epilepsy Res.2013;104(1-2):94–104.
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21 ↑
SchrammJ.Temporal lobe epilepsy surgery and the quest for optimal extent of resection: a review.Epilepsia.2008;49(8):1296–1307.
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22 ↑
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23 ↑
ParrentAG,BlumeWT.Stereotactic amygdalohippocampotomy for the treatment of medial temporal lobe epilepsy.Epilepsia.1999;40(10):1408–1416.
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24 ↑
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25 ↑
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26 ↑
SchmeiserB,DanielM,KogiasE,et al.Visual field defects following different resective procedures for mesiotemporal lobe epilepsy.Epilepsy Behav.2017;76:39–45.
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27 ↑
HelmstaedterC,RichterS,RöskeS,et al.Differential effects of temporal pole resection with amygdalohippocampectomy versus selective amygdalohippocampectomy on material-specific memory in patients with mesial temporal lobe epilepsy.Epilepsia.2008;49(1):88–97.
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28 ↑
HelmstaedterC,ElgerCE,WittJA.The effect of quantitative and qualitative antiepileptic drug changes on cognitive recovery after epilepsy surgery.Seizure.2016;36:63–69.
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29 ↑
ToniniC,BeghiE,BergAT,et al.Predictors of epilepsy surgery outcome: a meta-analysis.Epilepsy Res.2004;62(1):75–87.
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30 ↑
CarneRP,O’BrienTJ,KilpatrickCJ,et al.MRI-negative PET-positive temporal lobe epilepsy: a distinct surgically remediable syndrome.Brain.2004;127(Pt 10):2276–2285.
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31 ↑
Téllez-ZentenoJF,Hernández RonquilloL,Moien-AfshariF,WiebeS.Surgical outcomes in lesional and non-lesional epilepsy: a systematic review and meta-analysis.Epilepsy Res.2010;89(2-3):310–318.
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32 ↑
BienCG,SzinayM,WagnerJ,et al.Characteristics and surgical outcomes of patients with refractory magnetic resonance imaging-negative epilepsies.Arch Neurol.2009;66(12):1491–1499.
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33 ↑
IvanovicJ,LarssonPG,ØstbyY,et al.Seizure outcomes of temporal lobe epilepsy surgery in patients with normal MRI and without specific histopathology.Acta Neurochir (Wien).2017;159(5):757–766.
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34 ↑
Sotero de MenezesMA,ConnollyM,BolanosA,et al.Temporal lobectomy in early childhood: the need for long-term follow-up.J Child Neurol.2001;16(8):585–590.
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35 ↑
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36
de LanerolleNC,KimJH,WilliamsonA,et al.A retrospective analysis of hippocampal pathology in human temporal lobe epilepsy: evidence for distinctive patient subcategories.Epilepsia.2003;44(5):677–687.
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37
BlümckeI,PauliE,ClusmannH,et al.A new clinico-pathological classification system for mesial temporal sclerosis.Acta Neuropathol.2007;113(3):235–244.
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38
ThomM,LiagkourasI,ElliotKJ,et al.Reliability of patterns of hippocampal sclerosis as predictors of postsurgical outcome.Epilepsia.2010;51(9):1801–1808.
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39 ↑
GalesJM,JehiL,NowackiA,PraysonRA.The role of histopathologic subtype in the setting of hippocampal sclerosis-associated mesial temporal lobe epilepsy.Hum Pathol.2017;63:79–88.
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40 ↑
DeleoF,GarbelliR,MilesiG,et al.Short- and long-term surgical outcomes of temporal lobe epilepsy associated with hippocampal sclerosis: relationships with neuropathology.Epilepsia.2016;57(2):306–315.
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41 ↑
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42 ↑
HattingenE,EnkirchSJ,JurcoaneA,et al.Hippocampal “gliosis only” on MR imaging represents a distinct entity in epilepsy patients.Neuroradiology.2018;60(2):161–168.
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43 ↑
BernhardtBC,FadaieF,LiuM,et al.Temporal lobe epilepsy: hippocampal pathology modulates connectome topology and controllability.Neurology.2019;92(19):e2209–e2220.
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44 ↑
PaolicchiJM,JayakarP,DeanP,et al.Predictors of outcome in pediatric epilepsy surgery.Neurology.2000;54(3):642–647.
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45 ↑
HarroudA,BouthillierA,WeilAG,NguyenDK.Temporal lobe epilepsy surgery failures: a review.Epilepsy Res Treat.2012;2012:201651.
