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Outcome of temporal lobe epilepsy surgery evaluated with bitemporal intracranial electrode recordings
Accepted Manuscript Title: Outcome of Temporal Lobe Epilepsy Surgery Evaluated with Bitemporal Intracranial Electrode Recordings Authors: Andreu Massot-Tarr´us MD, PhD David A. Steven MD, MPH Richard S. McLachlan MD Seyed M. Mirsattari MD, PhD David Diosy MD Andrew G. Parrent MD Warren T. Blume MD John P. Girvin MD Jorge G. Burneo MD, MSPH PII: DOI: Reference:
S0920-1211(16)30128-0 http://dx.doi.org/doi:10.1016/j.eplepsyres.2016.08.008 EPIRES 5562
To appear in:
Epilepsy Research
Received date: Revised date: Accepted date:
1-11-2015 2-8-2016 10-8-2016
Please cite this article as: Massot-Tarr´us, Andreu, Steven, David A., McLachlan, Richard S., Mirsattari, Seyed M., Diosy, David, Parrent, Andrew G., Blume, Warren T., Girvin, John P., Burneo, Jorge G., Outcome of Temporal Lobe Epilepsy Surgery Evaluated with Bitemporal Intracranial Electrode Recordings.Epilepsy Research http://dx.doi.org/10.1016/j.eplepsyres.2016.08.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Outcome of Temporal Lobe Epilepsy Surgery Evaluated with Bitemporal Intracranial Electrode Recordings Andreu Massot-Tarrús, MD, PhD; David A. Steven, MD, MPH; Richard S. McLachlan, MD; Seyed M. Mirsattari, MD, PhD; David Diosy, MD; Andrew G. Parrent, MD; Warren T. Blume, MD; John P. Girvin, MD; Jorge G. Burneo, MD, MSPH.
Epilepsy Program, Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada
Correspondence to: Jorge G. Burneo London Health Sciences Centre University Hospital B10-106, 339 Windermere Road London, ON N6G 2V4 Tel. +01519 663-3464 Fax +01519 663-3498 [email protected]
COVER TITLE: Temporal lobe epilepsy surgery Key words: Temporal lobe epilepsy, intracranial electrodes; outcome; surgery; seizures; bitemporal epilepsy. Number of text pages: 13. Number of words: 3383. Number of references: 41. Number of figures: 2. Number of tables: 3.
Abbreviations: TLE: Temporal lobe epilepsy; IIE: intracranial implantation of electrodes; ATL: anterior temporal lobectomy; ATL: anterior temporal lobectomy; BiTLE: Bilateral temporal lobe epilepsy; AEDs: antiepiepileptic drugs; MTS: mesial temporal sclerosis; NTLE: Neocortical temporal lobe epilepsy síndrome.
Authors contributions to the manuscript: Massot A.: Collected the data, conducted the statistical analysis and wrote the paper; J.G. Burneo: Collected the data, designed and supervised the project, and corrected the paper. D.A. Steven, R.S. McLachlan, S.M. Mirsattari, D. Diosy, A.G. Parrent, W.T. Blume and J.P. Girvin collected the clinical data and corrected the paper. Study Funding: None
Disclosure: Dr. Burneo has received honoraria for speaking engagements from UCB Canada and Eisai. He is part of the Advisory Board for Eisai and Sunovion. He has received financial support for research from UCB Canada and for educational activities from Eisai. He also has funding from the Ontario Brain Institute. McLachlan has received has received honoraria for speaking engagements from UCB Canada. The remaining authors have no conflicts of interest.
Highlights:
53% of TLEs requiring IIE previous to anterior temporal lobectomy are seizure free.
BiTLE diagnosed by IIE is associated with a higher risk of seizure recurrence.
Lesional MRI prognostic value is greater in unilateral TLE diagnosed with IIE.
The 42.9% of BiTLE diagnosed with IIE became seizure free after unilateral ATL.
IIE provides valuable presurgical prognostic information.
Abstract Background: Temporal lobe epilepsy (TLE) with unclear lateralization may require intracranial implantation of electrodes (IIE). We retrospectively assessed the association between the use of IIE and long-term outcomes in patients undergoing anterior temporal lobectomy (ATL). Participants and methods: We retrospectively reviewed the records of 1,032 patients undergoing epilepsy surgery at our center from 1977 to 2006. Patients who underwent ATL were included. Seizure outcome was assessed through final follow-up. Those who underwent scalp and IIE (mostly evaluated with temporal subdural strip electrodes) were compared. Results: From 497 patients who underwent ATL, 139 did so after IIE placement in the temporal lobes. Mean age at surgery was 32.3±12.3 years and median duration of follow-up 24 months (range: 6-36). Fifty-three percent of those evaluated with IIE were seizure-free at their last available visit (vs. 68% evaluated with only scalp EEG, p=0.002). Patients with lesional TLE generally had a better outcome (65.5% seizure free) than those without lesions (56.3%, p=0.093), especially for unilateral TLE diagnosed with IIE. In a multivariate Cox regression analyses adjusted for gender, neuropsychological concordance, pathological findings, and post-operative seizures, bilateral TLE predicted seizure recurrence in IIE patients (HR=2.08, 95% CI: 1.08-4.0, p=0.029). Conclusions: More than a half of those who undergo IIE in suspected TLE are seizure free after ATL. IIE allows for the identification of surgical candidates.
1. Introduction: Temporal lobe epilepsy (TLE) is the most common form of medically-intractable epilepsy (Spencer, 2002) and consequently, comprises as much as 60-80% of epilepsy surgeries (Tellez-Zenteno and Ladino, 2013). The majority of TLE patients are able to proceed directly to surgery when non-invasive investigations are concordant (Holmes et al., 2007). However, despite continued advances in non-invasive localization of seizure foci, some patients with discordant noninvasive data need to proceed to the intracranial implantation of electrodes (IIE) (Pacia and Ebersole, 1999, Dubeau and McLachlan, 2000). Reliable outcome data are necessary to decide on surgical candidacy, as well as patient counseling and post-operative management. Even though the outcomes of TLE patients undergoing surgery have been reported extensively (McIntosh et al., 2004), most of these investigations included patients with both scalp and IIE, making them difficult to interpret (Miller et al., 1994; Wiebe et al., 2001; Clusmann et al., 2002; Tanriverdi et al., 2008, Bell et al., 2009). Therefore, debate still exists about the utility of IIE as a means to guide surgical resections in TLE, particularly among nonlesional TLE patients (Immonen et al., 2010). The aim of this study was to assess the utility of IIE in the pre-surgical work-up and as a predictor of long-term outcome in TLE patients undergoing anterior temporal lobectomy (ATL), with special emphasis on MRI-negative cases.
2. Subjects and methods 2.1. Patient selection
The target group for this retrospective study consisted of consecutive patients who had undergone surgery for TLE and had been evaluated pre-operatively with scalp electrodes or IIE, only covering the temporal lobes. The Epilepsy Surgery Database at the London Health Sciences Centre was reviewed thoroughly to identify all epilepsy surgeries, identifying 1,032 patients who had undergone epilepsy surgery between 1977 and 2006. Patients with extra-temporal epilepsy or concomitant generalized epileptiform activity considered for ATL were excluded, as were any who had received non-resective treatments or non-temporal resections (n=506) and those with no available information about the type of presurgical evaluation (n=29) or outcome (n=18) (Figure 1).
2.2. Pre-operative patient evaluations All patients underwent continuous video-EEG telemetry in the Epilepsy Monitoring Unit, using the extended 10-20 International System of scalp electrode placement, plus two mandibular notch electrodes (Jasper 1958 et al., 1988) and/or IIE. All EEG were recorded in accordance with Canadian Society of Clinical Neurophysiology guidelines (Task Force of The Canadian Society of Clinical Neurophysiologists, 2002; Canadian Society Clinical Neurophysiologists, 2008). Intracranial EEG evaluations were individually pre-planned and assessed by a multidisciplinary team on the basis of seizure semiology and previous, findings upon scalp video-EEG monitoring, neuroimaging studies, and neuropsychological evaluation. During the period covered by this study we most frequently used subdural strip electrodes (ranging from four to eight contact electrodes), placed through posterior temporal burr holes under general anesthesia (Steven et al., 2007). For bi-temporal lobe cases, three lines of electrodes were inserted through a posterior temporal burr hole,
giving full coverage of the mesial, inferior and convexity surfaces of both temporal lobes (Figure 2). Recording time ranged from one to eight weeks. Bilateral temporal lobe epilepsy (BiTLE) was defined as patients with confirmed electroencefalografic seizures from both temporal lobes by scalp or IIE. Neuropsychological assessments were performed by one of our trained neuropsychologists prior to surgery, as per the standard protocol used at our center. We classified patients as normal, having a concordant temporal alteration, or having any other abnormality outside the epileptic temporal lobe (Keary et al., 2007).
2.3. MRI evaluation: All patients underwent magnetic resonance imaging (MRI) of the brain using a 1.5T MRI scanner, in accordance with our institution’s epilepsy protocol, and interpreted by a neuroradiologist with expertise in epilepsy. A non-lesional MRI was defined as either completely normal or showing only non-specific white matter abnormalities and/or diffuse cerebral atrophy.
2.4. Resective surgery: The surgical treatment was decided by our multidisciplinary epilepsy surgery team. Even in cases of BiTLE, sometimes a decision was made to proceed directly to ATL in patients who had strong unilateral predominance (So et al., 1989) and severe seizures. The limits for resection during standard lobectomies were 6–6.5 cm from the tip of the temporal lobe in the non-dominant hemisphere (Wiebe et al., 2001). The posterior limit in the dominant hemisphere was most often determined by cortical stimulation and intra-operative mapping of temporal speech areas, although a 4–5 cm limit was habitually observed. Mesial resection included the amygdala and, at a minimum, the
anterior 1.0 to 3.0 cm of the hippocampus (most commonly, 4.0 cm) (Wiebe et al., 2001). Resected areas were submitted for pathologic examination.
2.5. Follow-up: Seizure outcome was obtained from surgical discharge notes and follow-up visits in our epilepsy clinic. This included visits at one, six and twelve months after surgery, and at least annually beyond the first year. Outcome was stratified as seizure-free or seizurerecurrence at each follow-up visit and at the last available visit (defined as the last assessment performed after the surgery) (Wiebe et al., 2001). A patient was considered seizure-free if they had no seizures with loss of awareness (i.e., dyscognitive or generalized seizures) (Wieser et al., 2001). Postoperative seizures were defined as those occurring within the first four weeks after surgery. Patients were kept on antiepileptic medication at least during the first year after surgery. Subsequent slow tapering and eventual discontinuation of antiepiepileptic drugs (AEDs), if done, was tailored to the individual. Patients that underwent IIE were compared with those studied with scalp EEG. The study was approved by our institutional ethics committee.
2.6. Statistical analysis: Analyses were performed using the statistical package SPSS (Chicago, Ill., USA, version 17.0). Statistical significance for intergroup differences was assessed by the Pearson χ2 or Fisher’s exact test for categorical variables. For continuous variables that were non-normally distributed, values were expressed as medians [inter-quartile ranges (IR)], and statistical significance for intergroup differences assessed using MannWhitney tests. For variables that were normally distributed, values were expressed as
means ± SD, and significant intergroup differences identified using Student’s t tests. A value of p < 0.05 was considered statistically significant. The relationship between BiTLE, abnormal MRI and postoperative seizures, and the occurrence of seizures at the last available visit was evaluated by means of a KaplanMeier curve and the log-rank test. Finally, a Cox proportional hazards multivariate analysis was used to identify predictors of seizure recurrence, in which gender, handedness, neuropsychological evaluation concordance, histopathological and MRI findings, BiTLE, and post-operative seizures were included. Results were expressed as adjusted hazard ratios (HR) with corresponding 95% confidence intervals (CI).
3. Results: The study sample consisted of 497 patients (46.5% males) exclusively with TLE who underwent ATL after scalp EEG or IIE evaluation. Their median age at seizure onset was 12 years (IR 6-21 years) and their median duration of epilepsy before referral 16 years (7.5-25 years). Almost half of these patients (49.1%) had left-sided TLE, 43.1% right-sided TLE and 7.8% bi-temporal lobe epilepsy (BiTLE). The median time of the last follow-up visit was 24 (6-36) months. 80% had a lesion observable on MRI. Baseline characteristics of the study population are summarized in Table 1.
3.1. Post-surgical outcomes: Seizure outcome data were available for 477 of 497 patients (96%) over the first four weeks (post-operative seizures), for 419 patients at six months (84.3%), 356 (71.6%) at one year, and 199 (40%) at three years of follow-up. Of the original 497, 45 (9.4%) had had post-operative seizures. Seizure-free rates were 282 of 419 (67.3%) at the 6-month visit; 231 of 356 (64.9%) at one year; and 125 of 199 (62.8%) at three years. Overall,
306 of 479 (63.9%) patients were seizure-free the last time they were visited. The median time to recurrence was 6 months (IC 1-8), with 49.4% of recurrences occurring within the first five months and 84.9% within the first year. In the univariate analysis, BiTLE and post-operative seizures, were significantly associated with recurrent seizures at the last follow-up visit (45.9 vs. 54.1%, p=0.014 and 35.6 vs 64.4 %, p<0.001, respectively). On the other hand, histopathological evidence of mesial temporal sclerosis (MTS) (71.8 vs. 28.2%, p=0.010) was associated with seizure freedom, and younger age of epilepsy onset [12 (5-21) vs 13 (8-23) years, p=0.093] and a lesion visible on MRI (65.5 vs. 34.5%, p=0.093) showed a nonsignificance trend towards seizure freedom (Table 2).
3.2. Patients evaluated with intracranial electrodes: A total of 139 (28%) patients underwent IIE placement one or both temporal lobes prior to ATL. Relative to those who only had scalp EEG performed (n = 358), a smaller percentage of the IIE patients had an abnormal MRI study (69.4 vs. 83.6%, p=0.001) and right TLE (48.6 vs 28.8%, p<0.001), while a greater percentage had BiTLE (20.9 vs. 2.8%, p<0.001). IIE patients also required Wada testing more often (42.4 vs. 33%, p=0.02) and had a more prolonged period of follow-up (36 vs. 24 months, p<0.001). On the histopathology, they were more likely to have no abnormal findings (8.3 vs. 3.1%, p=0.014), and less likely to have either a tumor or multiple findings (6.1 vs. 20.4%, p<0.001; and 2.3 vs. 8.5%, p=0.015, respectively; Table 1). Regarding post-surgical outcomes, a significantly higher percentage of patients who had undergone IIE had postoperative seizures (13.8 vs.7.8%, p=0.045). Seizure freedom was reported by 60 of 112 (53.6%) at 6-months of follow-up, versus 72.6% of those evaluated with a scalp EEG (p<0.001). Corresponding percentages were 57% and 68%
at one year; 49.4% and 66.8% at two years (p=0.007); and 52.9% and 67.9% at three years (p=0.038). Overall, 70 of 132 (53%) of IIE patients were seizure free at the time of their last available visit versus 236 of 347 (68%) of those who had undergone scalp EEG (p=0.002). However, it may be taken into account that the median duration of follow-up is 2 years for scalp patients and 3 years for IIE patients. That can affect the proportion of seizure-free at last follow-up (expected to be lower in IIE patients because they were followed longer).
3.3. Bitemporal epilepsy: Patients with a final diagnosis of BiTLE (by scalp or IIE) had a higher risk of postoperative seizure recurrence when compared to those with unilateral TLE (p=0.018), at the last available visit . Furthermore, in a multivariate proportional hazards regression analysis (Cox regression), including the independent variables gender, handedness, neuropsychology testing discordance, post-operative seizures, and MRI and histopathological findings, BiTLE and post-operative seizures were the only predictors of seizure recurrence (HR 1.74; 95% CI 1.05 to 2.9; p = 0.032 and HR 1.83; 95% CI 1.15 to 2.91; p=0.011, respectively). When the scalp EEG and IIE subgroups were analyzed separately, presence of BiTLE was an independent risk factor among IIE patients (HR=2.08, 95% CI: 1.08-4, p=0.029) (Table 3). Seven of 18 (38.9%) BiTLE patients diagnosed by IIE were seizure free one year after surgery, and 12 of 28 (42.9%) at the time of the last available visit. Unilateral temporal lobe epilepsy cases also exhibited lower rates of seizure freedom among IIE patients: 56.7% seizure freedom at 6 months (vs. 72.2% of those diagnosed using scalp EEG, p=0.005) and 55.8% at last available visit (vs. 68.3%, p=0.018).
3.4. Patients with negative versus lesional MRI: A trend towards better seizure outcome was identified among those with a lesion on MRI (65.5% seizure-free vs. 56.3% among non-lesion cases, p=0.093). This difference expanded after BiTLE patients were excluded (67.3 vs.56.3%, p=0.054). This tendency seemed more pronounced in the IIE subgroup: excluding BiTLE cases, 60% of patients with a lesion on MRI were seizure free versus 41.9% among those with no lesion (p=0.09). Conversely, among those studied with scalp EEG, there was very little difference between those with versus without an MRI lesion (68.7 vs. 64.9%, p=0.58). Once again, the percentage of non-lesion patients who were seizure free was significantly lower among those patients studied via IIE (43.6 vs.64.9%, p=0.039), even after excluding patients with BiTLE (41.9 vs.64.3%, p=0.044).
3.5. Pathology: 82.9% of patients had an available post-surgical histopathological diagnosis. The worst outcomes were observed in those with multiple pathological findings (53.3% seizure free), no abnormal findings (57.1% seizure free), or some other finding besides MTS, dysplasia or a tumor (58.1%). In contrast, MTS and dysplasia patients had the best outcomes, with 71.8% and 68.8% seizure-free, respectively (Table 2).
4. Discussion: The main findings of the present study are that more than a half of patients who required IIE previous to ALT are seizure free; and that BiTLE diagnosed by IIE is associated with lower chances of seizure-freedom, independently of other risk factors. Moreover, the prognostic value of a lesion detected on MRI appeared to be greater in
patients diagnosed with unilateral temporal epilepsy using IIE. These findings support the utility of IIE in the pre-surgical work-up of TLE patients. This is the largest single-center series of ATL evaluated with IIE to our knowledge (Burgerman et al., 1995; Radhakrishnan et al., 1998; Wiebe et al., 2001; Paglioli et al., 2004; Bate et al., 2007; Tanriverdi et al., 2008; Bell et al., 2009; Immonen et al., 2010; Engel et al., 2012). Only 28% of our ATL patients required IIE. This rate concurs with most current studies (Berkovic et al., 1995; Clusmann et al., 2002; Tellez-Zenteno and Ladino, 2013) and is far from the 57% who required IIE before extra-temporal resections (Dubeau and McLachlan, 2000). Reasons to undergo IEE included: bitemporal lobe epilepsy, with the hypothesis that seizures originate in one temporal lobe and propagate fast to the contralateral one, to determine the proportion of seizures emanating from each temporal lobe in cases of true bitemporal lobe epilepsy, and when the question is mesial versus neocrtical temporal lobe epilepsy. All this particularly, when imaging fails to identify a lesion. The majority of patients were evaluated with temporal subdural strip electrodes, although intracerebral depth electrodes could also be used to acomplish these diagnostic goals. The comparation of both techniques was not an objective of the present study. 64.9% of all our patients were seizure free one year after surgery and 62.8% after three years. Similarly, in a systematic review that incorporated 1,769 patients, 65% of patients with ATL were free of disabling seizures at one year (Engel et al., 2003) and 58-66% after two to five years (Engel et al., 2003; Bate et al., 2007). These rates may decrease to 50 and 45% at seven and ten years, respectively (McIntosh et al., 2001). Seizure relief was achieved less frequently in series published before 1985 (approximately 55%) (Clusmann et al., 2002), probably related to the increasingly sophisticated pre-operative investigations that have since been developed.
Consequently, better outcomes could be expected among the more recent cases in our series. Our results also reaffirm the belief that patients who fail epilepsy surgery generally do so within the first few months (Bell et al., 2009). A less favorable prognosis was associated with BiTLE, lack of lesions on MRI and acute post-surgical seizures, all well-described negative prognostic factors (Pacia and Ebersole, 1999; McIntosh et al., 2001; Aghakhani et al., 2014). On the other hand, the duration of epilepsy was not associated with a poorer outcome, suggesting that this does not appear to be a risk factor for all TLE patients (Hufnagel et al., 1994; McIntosh et al., 2001; Vale et al., 2012; Ramey et al., 2013). On multivariate analysis, BiTLE and acute post-operative seizures were the only two independent risk factors that remained in the final model, both associated with almost double the hazard of seizure recurrence. The low number of patients with BiTLE diagnosed by scalp EEG is likely the reason for why BiTLE was not found to be an independent prognostic value in this group, but it was the opposite for those who underwent IIE. However, scalp EEG findings of ambiguous lateralization compared with the more precise picture provided by IIE recording may also contribute to this difference (Dubeau and McLachlan, 2000, Javidan, 2012). Additionally, ictal activity that cannot be appreciated on the scalp at all, such as that seen with simple partial seizures (Dubeau and McLachlan, 2000) or rapid secondary generalization from a focus, is readily recorded by IIE. On the other hand, the 42.9% of BiTLE IIE-diagnosed patients who became seizure free after unilateral ATL is not negligible. This percentage is similar to that observed in a previous series (Aghakhani et al. 2014), and certainly higher than the 8% achieved with AEDs (Wiebe et al. 2001). This being said, determining surgical candidacy and which side to perform resection among such patients remains challenging (Aghakhani et al., 2014; Wang et al., 2016).
In our cohort, the presence of abnormalities on MRI was a favorable prognostic indicator, with 65.5% becoming seizure free post-operatively versus 56.3% among MRI-negative cases. These seizure freedom rates have been fairly homogeneous across several recent studies (Clusmann et al., 2002; Bell et al., 2009; Immonen et al., 2010; Tellez-Zenteno et al., 2010) and are higher than those reported for extra-temporal epilepsy (Tellez-Zenteno et al., 2005). However, significantly disparate rates of surgical success can be found among non-lesional TLE patients in published research, ranging from 18% to 80%, though some studies were conducted prior to the widespread use of epilepsy neuroimaging protocols that are more sensitive at detecting MTS, and some used pathologic findings to categorize patients, information that is not available preoperatively (Cohen-Gadol et al., 2006; Bell et al., 2009; Bien et al., 2009). The presence of an abnormality on MRI appears to have higher prognostic value in unilateral TLE patients diagnosed with IIE, suggesting that the significance of a temporal lesion on MRI may be greater when BiTLE have been thoroughly excluded. Furthermore, the surgical approach to non-lesional TLE poses a significant challenge due to the uncertain involvement of mesial and/or lateral (neocortical) temporal regions in the generation of seizures. Invasive electrodes are a useful means of epileptic focus localization in these patients. In our series, 43.6% of the patients with no documented lesion who were evaluated by IIE experienced seizure freedom, a rate that is either similar to (Immonen et al., 2010) or lower (Ramey et al., 2013) than that reported for prior TLE studies. Several conditions could explain surgical failure in such cases: for example, dual pathology, remote areas of epileptogenicity, or diffuse epileptogenicity in the residual temporal lobe (Vale et al., 2012). The last of these is commonly related to seizures originating from the lateral temporal neocortex, with rapid and diffuse ictal spread. These neocortical regions are not resected through standard temporal lobectomy,
which spares a significant amount of the posterior and superior lateral temporal lobe, especially when eloquent areas in the dominant temporal lobe are involved (Immonen et al., 2010). Neocortical temporal lobe epilepsy syndrome (NTLE) may account for up to 67% of TLE patients, and frequently presents with a normal MRI (Pacia and Ebersole, 1999). The higher prevalence of MRI and pathology-negative patients among those evaluated by IIE, and of left temporal lobe involvement, may suggest NTLE as the primary reason for our IIE patients’ worse outcome, even after exclusion of BiTLE cases. The current study has definite limitations. First, the relatively large number of subjects lost to follow-up may have biased our outcomes, since whether individuals lost or maintained contact with our team might have been influenced by their outcome status. Unfortunately, this is a problem that has been reported for many large series (McIntosh et al., 2001). Second, only those who had respective surgery were included in the study, which results in significant selection bias. However, this study design allows us to examine the outcome of those patients in whom IIE confirmed the temporal origin of their epileptic foci. Third, complications from IIE or respective surgery were not evaluated. In any case, the surgical complication rates for subdural strips or depth electrodes implantation and resective procedures are below 5% in our Epilepsy Unit (Burneo et al., 2006; MacDougall et al., 2009). Finally, ours was a retrospective study, so that inferences about causation or risk cannot be made. Nonetheless, our results suggest that IIE provides valuable prognostic information about bi-temporal epileptic activity on TLE and reinforce the concept of MRI-lesion causality in patients with unilateral TLE. Despite technological advances and the mounting accumulation of evidence, many epileptologists remain uncertain about the efficacy and safety of costly surgical procedures like IIE, especially for MRI-negative patients. Our
results should not be used to foster skepticism towards surgery in non-lesional TLE patients who are otherwise good surgical candidates, since 56.3% of them achieved seizure freedom.
Figure 1. Description of the study population
Figure 2. Depiction of temporal coverage with implantation using subdural strips.
Table 1. Differences between ATL patients assessed with intracranial electrodes and those assessed with scalp EEG (n=497).
Table 2: Differences between seizure freedom and seizure recurrence at last clinic assessment among patients with ATL (n=479)
Table 3: Hazard ratios for seizure recurrence at the last clinic assessment among patients who underwent ATL (n=479)
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Paglioli, E., Palmini, A., Paglioli, E., da Costa, J.C., Portuguez, M., Martinez, J.V., et al., 2004. Survival analysis of the surgical outcome of temporal lobe epilepsy due to hippocampal sclerosis. Epilepsia 45 (11), 1383-1391. Pondal-Sordo, M., Diosy, D., Tellez-Zenteno, J.F., Sahjpaul, R., Wiebe, S., 2007. Usefulness of intracranial EEG in the decision process for epilepsy surgery. Epilepsy Res 74 (2-3), 176-182. Radhakrishnan, K., So, E.L., Silbert, P.L., Jack, C.R., Jr., Cascino, G.D., Sharbrough, F.W., et al. 1998. Predictors of outcome of anterior temporal lobectomy for intractable epilepsy: a multivariate study. Neurology 51 (2), 465-471. Ramey, W.L., Martirosyan, N.L., Lieu, C.M., Hasham, H.A., Lemole, G.M. Jr, Weinand, M.E., 2013. Current management and surgical outcomes of medically intractable epilepsy. Clinical Neurology and Neurosurgery 115 (12), 2411-2418. So, N., Olivier, A., Andermann, F., Gloor, P., Quesney, L.F., 1989. Results of surgical treatment in patients with bitemporal epileptiform abnormalities. Ann Neurol 25 (5), 432-439. Spencer, S.S., 2002. When should temporal-lobe epilepsy be treated surgically? Lancet Neurol 1 (6), 375-382. Steven, D.A., Andrade-Souza, Y.M., Burneo, J.G., McLachlan, R.S., Parrent, A.G., 2007. Insertion of subdural strip electrodes for the investigation of temporal lobe epilepsy. Technical note. J Neurosurg 106 (6), 1102-1106. Tanriverdi, T., Olivier, A., Poulin, N., Andermann, F., Dubeau, F., 2008. Long-term seizure outcome after mesial temporal lobe epilepsy surgery: corticalamygdalohippocampectomy versus selective amygdalohippocampectomy. J Neurosurg 108 (3), 517-524.
Task Force of The Canadian Society of Clinical Neurophysiologists, 2002. Minimal standards for electroencephalography in Canada. Can J Neurol Sci 29 (3): 216-220. Tellez-Zenteno, J.F., Dhar, R., Wiebe S., 2005. Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain 128 (Pt 5): 1188-1198. Tellez-Zenteno, J.F., Hernandez Ronquillo, L., Moien-Afshari F., Wiebe, S., 2010. Surgical outcomes in lesional and non-lesional epilepsy: a systematic review and metaanalysis. Epilepsy Res 89 (2-3): 310-318. Tellez-Zenteno, J.F., Ladino, L.D., 2013. Temporal epilepsy: clinical, diagnostic and therapeutic aspects. Rev Neurol 56 (4), 229-242. Vale, F.L., Pollock G., Benbadis, S.R., 2012. Failed epilepsy surgery for mesial temporal lobe sclerosis: a review of the pathophysiology. Neurosurg Focus 32 (3), E9. Wang, X., Zhang, C., Wang, Y., Hu, W., Shao, X., Zhang, J.G., et al. 2016. Prognostic factors for seizure outcome in patients with MRI-negative temporal lobe epilepsy: A meta-analysis and systematic review. Seizure. May;38:54-62. Wiebe, S., Blume, W.T., Girvin, J.P., Eliasziw, M. Effectiveness and Efficiency of Surgery for Temporal Lobe Epilepsy Study Group, 2001. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med 345 (5): 311-318. Wieser, H.G., Blume, W.T., Fish, D., Goldensohn, E., Hufnagel, A., King, D., et al., Commission on Neurosurgery of the International League Against Epilepsy, 2001. ILAE Commission Report. Proposal for a new classification of outcome with respect to epileptic seizures following epilepsy surgery. Epilepsia 42 (2), 282-286.
1,032 consecutive patients that underwent epilepsy surgery Non-temporal resection 354
Extra TLE 89
Type of surgery not available 51
Generalized epileptiform activity 10
Disconnection/MST 2 526 ATL Type of pre-surgical evaluation not available 29 497
358 evaluate with scalp EEG 139 evaluate with IIE
18 without available follow up 479
347 evaluated with scalp EEG
132 evaluated with IIE
MST=Multiple Subpial Transections; ATL=Anterior Temporal Lobectomy; IIE = Intracranial Implantation of Electrodes
Figure 2. Depiction of temporal coverage with implantation using subdural strips.
Table 1. Differences between ATL patients assessed with intracranial electrodes and those assessed with scalp EEG (n=497). ATL with scalp EEG
ATL with IEE
(n=358)
(n=139)
167 (46.6%)
64 (46%)
0.90
Variable
P-value
Gender (male) Handedness:
Right
288 (82.5%)
110 (82.7%)
0.96
Left
52 (14.9%)
18 (13.5%)
0.70
Ambidextrous
9 (2.6%)
5 (3.8%)
0.54
Age of seizure onset (years)
12 (5-23)
13 (6.5-19)
0.69
Age of referral (years)
32.65±12.35
31.4±12.16
0.30
Period from onset to referral (years)
15.5 (7-25)
16 (8-24)
0.88
Video EEG localization:
Left temporal
174 (48.6%)
70 (50.4%)
0.72
Right temporal
174 (48.6%)
40 (28.8%)
<0.001
Bitemporal
10 (2.8%)
29 (20.9%)
<0.001
MRI lesion
291 (83.6%)
93 (69.4%)
0.001
Amytal test
118 (33%)
59 (42.4%)
0.020
Follow-up (months)
24 (6-36)
36 (12-48)
0.001
NP-where dysfunction:
Temporal-concordant
108 (32%)
40 (33.9%)
0.7
Temporal-discordant
104 (30.8%)
35 (29.7%)
0.82
Extratemporal concordant
4 (1.2%)
-
-
Extratemporal discordant
1 (0.3%)
-
-
Unclear
39 (11.5%)
14 (11.9%)
0.82
Normal
25 (7.4%)
6 (5.1%)
0.44
Multiple
58 (17.2%)
24 (20.3%)
0.44
Histopathology: 11 (3.1%)
11 (8.3%)
0.014
Normal
MTS
115 (32.6%)
46 (34.8%)
0.64
Dysplasia
10 (2.8%)
8 (6.1%)
0.11
Tumor
72 (20.4%)
8 (6.1%)
<0.001
Other
111 (31.4%)
54 (40.9%)
0.05
Unknown
4 (1.1%)
2 (1.5%)
0.67
Multiple
30 (8.5%)
3 (2.3%)
Outcome (seizure freedom):
(n=347)
(n=132)
Post-operatively (1 month)
319 (92.2%)
112 (86.2%)
0.04
6-month outcome
223 (72.6%)
60 (53.6%)
<0.001
1-year outcome
174 (68%)
57 (57%)
0.05
2-year outcome
127 (66.8%)
40 (49.4%)
0.007
3-year outcome
89 (67.9%)
36 (52.9%)
0.04
Last available outcome
236 (68%)
70 (53%)
0.002
0.01
Results are expressed as n (percentage), means ± standard deviation, or medians (inter-quartile range), as appropriate. ATL=Anterior Temporal Lobectomy; TLE=Temporal Lobe Epilepsy; FT=Frontotemporal; VNS=Vagal Nerve Stimulator; MST=Multiple Subpial Transections; NP=Neuropsychology; MTS=Mesial Temporal Sclerosis
Table 2: Differences between seizure freedom and seizure recurrence at last clinic assessment among patients with ATL (n=479) Seizure freedom
Recurrence
OR (95% CI)
(n=306)
(n=173)
Gender (male)
138 (63%)
81 (37%)
1.07 (0.74-1.56)
0.72
Handedness (left or ambidextrous):
53 (66.3%)
27 (33.8%)
0.88 (0.53-1.46)
0.62
Age of seizure onset (years)
12 (5-21)
13 (8-23)
0.09
Age of referral (years)
32.4±12.9
32.1±11.1
0.78
Period from onset to referral (years)
16 (8-25)
14 (6-23.5)
0.21
Variable
P-value
Video EEG localization:
Left temporal
150 (64.9%)
81 (35.1%)
0.92 (0.63-1.33)
0.64
Right temporal
139 (65.9%)
72 (34.1%)
0.86 (0.59-1.25)
0.42
Bitemporal
17 (45.9%)
20 (54.1%)
2.22 (1.13-4.37)
0.018
MRI lesion
243 (65.5%)
128 (34.5%)
0.68 (0.43-1.07)
0.093
Postoperative seizures (yes)
16 (35.6%)
29 (64.4%)
3.70 (1.95-7.04)
<0.001
NP-where dysfunction:
Temporal concordant (yes)
85 (59.4%)
58 (40.6%)
1.29 (0.85-1.94)
0.23
Temporal discordant (yes)
89 (65.9%)
46 (34.1%)
0.85 (0.56-1.31)
0.47
Extratemporal concordant
2 (50%)
2 (50%)
1.78 (0.25-12.81)
0.62
Extratemporal discordant
1 (100%)
0 (0%)
n/a
1
Unclear
34 (65.4%)
18 (34.6%)
0.93 (0.5-1.72)
0.81
Normal
22 (73.3%)
8 (26.7%)
0.62 (0.27-1.44)
0.26
Histopathology:
Normal
12 (57.1%)
9 (42.9%)
1.33 (0.55-3.23)
0.52
MTS
112 (71.8%)
44 (28.2%)
0.58 (0.38-0.88)
0.01
Dysplasia
11 (68.8%)
5 (31.3%)
0.79 (0.27-2.31)
0.67
Tumor
50 (63.3%)
29 (36.7%)
1.02 (0.62-1.68)
0.94
Other
93 (58.1%)
67 (41.9%)
1.43 (0.97-2.12)
0.08
Unknown
4 (66.7%)
2 (33.3%)
0.87 (0.16-4.83)
1
Multiple
16 (53.3%)
14 (46.7%)
1.12 (0.68-1.84)
0.22
Table 3: Hazard ratios for seizure recurrence at the last clinic assessment among patients who underwent ATL (n=479) Variable
Gender (male)
ATL (n=479)
Scalp EEG (347)
HR (95% CI)
P-value
HR (95% CI)
P-value
HR (95% CI)
P-value
1.37 (0.97-
0.07
1.76 (1.14-2.7)
0.01
0.98 (0.54-
0.96
1.94) Handedness (left or
0.8 (0.55-1.15)
1.78) 0.22
0.15 (0.41-
0.69
1.14)
ambidextrous): Bitemporal video EEG
1.74 (1.05-
localization:
2.90)
MRI lesion
0.84 (0.56-
0.03
0.96 (0.65-
1.4 (0.49-3.97)
1.22 (0.59-
dysplasia, tumor or other)
2.56)
Post-operative seizures
1.83 (1.152.91)
0.56
1.46) 0.52
0.40
0.91 (0.54-
0.72
1.53)
2.08 (1.08-
0.03
0.82
0.99 (0.62-1.6)
0.68 (0.34-
0.28
1.36) 0.97
1.40) Histopatholgy: lesion (MTS,
0.85 (0.49-
4.00)
1.26) NP-temporal discordant
IIE (n=132)
0.88 (0.46-
0.7
1.68) 0.59
0.81 (0.29-
0.69
2.28) 0.01
2.72 (1.435.18)
1.40 (0.48-
0.54
4.10) 0.002
1.42 (0.712.86)
0.32
S0920-1211(16)30128-0 http://dx.doi.org/doi:10.1016/j.eplepsyres.2016.08.008 EPIRES 5562
To appear in:
Epilepsy Research
Received date: Revised date: Accepted date:
1-11-2015 2-8-2016 10-8-2016
Please cite this article as: Massot-Tarr´us, Andreu, Steven, David A., McLachlan, Richard S., Mirsattari, Seyed M., Diosy, David, Parrent, Andrew G., Blume, Warren T., Girvin, John P., Burneo, Jorge G., Outcome of Temporal Lobe Epilepsy Surgery Evaluated with Bitemporal Intracranial Electrode Recordings.Epilepsy Research http://dx.doi.org/10.1016/j.eplepsyres.2016.08.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Outcome of Temporal Lobe Epilepsy Surgery Evaluated with Bitemporal Intracranial Electrode Recordings Andreu Massot-Tarrús, MD, PhD; David A. Steven, MD, MPH; Richard S. McLachlan, MD; Seyed M. Mirsattari, MD, PhD; David Diosy, MD; Andrew G. Parrent, MD; Warren T. Blume, MD; John P. Girvin, MD; Jorge G. Burneo, MD, MSPH.
Epilepsy Program, Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada
Correspondence to: Jorge G. Burneo London Health Sciences Centre University Hospital B10-106, 339 Windermere Road London, ON N6G 2V4 Tel. +01519 663-3464 Fax +01519 663-3498 [email protected]
COVER TITLE: Temporal lobe epilepsy surgery Key words: Temporal lobe epilepsy, intracranial electrodes; outcome; surgery; seizures; bitemporal epilepsy. Number of text pages: 13. Number of words: 3383. Number of references: 41. Number of figures: 2. Number of tables: 3.
Abbreviations: TLE: Temporal lobe epilepsy; IIE: intracranial implantation of electrodes; ATL: anterior temporal lobectomy; ATL: anterior temporal lobectomy; BiTLE: Bilateral temporal lobe epilepsy; AEDs: antiepiepileptic drugs; MTS: mesial temporal sclerosis; NTLE: Neocortical temporal lobe epilepsy síndrome.
Authors contributions to the manuscript: Massot A.: Collected the data, conducted the statistical analysis and wrote the paper; J.G. Burneo: Collected the data, designed and supervised the project, and corrected the paper. D.A. Steven, R.S. McLachlan, S.M. Mirsattari, D. Diosy, A.G. Parrent, W.T. Blume and J.P. Girvin collected the clinical data and corrected the paper. Study Funding: None
Disclosure: Dr. Burneo has received honoraria for speaking engagements from UCB Canada and Eisai. He is part of the Advisory Board for Eisai and Sunovion. He has received financial support for research from UCB Canada and for educational activities from Eisai. He also has funding from the Ontario Brain Institute. McLachlan has received has received honoraria for speaking engagements from UCB Canada. The remaining authors have no conflicts of interest.
Highlights:
53% of TLEs requiring IIE previous to anterior temporal lobectomy are seizure free.
BiTLE diagnosed by IIE is associated with a higher risk of seizure recurrence.
Lesional MRI prognostic value is greater in unilateral TLE diagnosed with IIE.
The 42.9% of BiTLE diagnosed with IIE became seizure free after unilateral ATL.
IIE provides valuable presurgical prognostic information.
Abstract Background: Temporal lobe epilepsy (TLE) with unclear lateralization may require intracranial implantation of electrodes (IIE). We retrospectively assessed the association between the use of IIE and long-term outcomes in patients undergoing anterior temporal lobectomy (ATL). Participants and methods: We retrospectively reviewed the records of 1,032 patients undergoing epilepsy surgery at our center from 1977 to 2006. Patients who underwent ATL were included. Seizure outcome was assessed through final follow-up. Those who underwent scalp and IIE (mostly evaluated with temporal subdural strip electrodes) were compared. Results: From 497 patients who underwent ATL, 139 did so after IIE placement in the temporal lobes. Mean age at surgery was 32.3±12.3 years and median duration of follow-up 24 months (range: 6-36). Fifty-three percent of those evaluated with IIE were seizure-free at their last available visit (vs. 68% evaluated with only scalp EEG, p=0.002). Patients with lesional TLE generally had a better outcome (65.5% seizure free) than those without lesions (56.3%, p=0.093), especially for unilateral TLE diagnosed with IIE. In a multivariate Cox regression analyses adjusted for gender, neuropsychological concordance, pathological findings, and post-operative seizures, bilateral TLE predicted seizure recurrence in IIE patients (HR=2.08, 95% CI: 1.08-4.0, p=0.029). Conclusions: More than a half of those who undergo IIE in suspected TLE are seizure free after ATL. IIE allows for the identification of surgical candidates.
1. Introduction: Temporal lobe epilepsy (TLE) is the most common form of medically-intractable epilepsy (Spencer, 2002) and consequently, comprises as much as 60-80% of epilepsy surgeries (Tellez-Zenteno and Ladino, 2013). The majority of TLE patients are able to proceed directly to surgery when non-invasive investigations are concordant (Holmes et al., 2007). However, despite continued advances in non-invasive localization of seizure foci, some patients with discordant noninvasive data need to proceed to the intracranial implantation of electrodes (IIE) (Pacia and Ebersole, 1999, Dubeau and McLachlan, 2000). Reliable outcome data are necessary to decide on surgical candidacy, as well as patient counseling and post-operative management. Even though the outcomes of TLE patients undergoing surgery have been reported extensively (McIntosh et al., 2004), most of these investigations included patients with both scalp and IIE, making them difficult to interpret (Miller et al., 1994; Wiebe et al., 2001; Clusmann et al., 2002; Tanriverdi et al., 2008, Bell et al., 2009). Therefore, debate still exists about the utility of IIE as a means to guide surgical resections in TLE, particularly among nonlesional TLE patients (Immonen et al., 2010). The aim of this study was to assess the utility of IIE in the pre-surgical work-up and as a predictor of long-term outcome in TLE patients undergoing anterior temporal lobectomy (ATL), with special emphasis on MRI-negative cases.
2. Subjects and methods 2.1. Patient selection
The target group for this retrospective study consisted of consecutive patients who had undergone surgery for TLE and had been evaluated pre-operatively with scalp electrodes or IIE, only covering the temporal lobes. The Epilepsy Surgery Database at the London Health Sciences Centre was reviewed thoroughly to identify all epilepsy surgeries, identifying 1,032 patients who had undergone epilepsy surgery between 1977 and 2006. Patients with extra-temporal epilepsy or concomitant generalized epileptiform activity considered for ATL were excluded, as were any who had received non-resective treatments or non-temporal resections (n=506) and those with no available information about the type of presurgical evaluation (n=29) or outcome (n=18) (Figure 1).
2.2. Pre-operative patient evaluations All patients underwent continuous video-EEG telemetry in the Epilepsy Monitoring Unit, using the extended 10-20 International System of scalp electrode placement, plus two mandibular notch electrodes (Jasper 1958 et al., 1988) and/or IIE. All EEG were recorded in accordance with Canadian Society of Clinical Neurophysiology guidelines (Task Force of The Canadian Society of Clinical Neurophysiologists, 2002; Canadian Society Clinical Neurophysiologists, 2008). Intracranial EEG evaluations were individually pre-planned and assessed by a multidisciplinary team on the basis of seizure semiology and previous, findings upon scalp video-EEG monitoring, neuroimaging studies, and neuropsychological evaluation. During the period covered by this study we most frequently used subdural strip electrodes (ranging from four to eight contact electrodes), placed through posterior temporal burr holes under general anesthesia (Steven et al., 2007). For bi-temporal lobe cases, three lines of electrodes were inserted through a posterior temporal burr hole,
giving full coverage of the mesial, inferior and convexity surfaces of both temporal lobes (Figure 2). Recording time ranged from one to eight weeks. Bilateral temporal lobe epilepsy (BiTLE) was defined as patients with confirmed electroencefalografic seizures from both temporal lobes by scalp or IIE. Neuropsychological assessments were performed by one of our trained neuropsychologists prior to surgery, as per the standard protocol used at our center. We classified patients as normal, having a concordant temporal alteration, or having any other abnormality outside the epileptic temporal lobe (Keary et al., 2007).
2.3. MRI evaluation: All patients underwent magnetic resonance imaging (MRI) of the brain using a 1.5T MRI scanner, in accordance with our institution’s epilepsy protocol, and interpreted by a neuroradiologist with expertise in epilepsy. A non-lesional MRI was defined as either completely normal or showing only non-specific white matter abnormalities and/or diffuse cerebral atrophy.
2.4. Resective surgery: The surgical treatment was decided by our multidisciplinary epilepsy surgery team. Even in cases of BiTLE, sometimes a decision was made to proceed directly to ATL in patients who had strong unilateral predominance (So et al., 1989) and severe seizures. The limits for resection during standard lobectomies were 6–6.5 cm from the tip of the temporal lobe in the non-dominant hemisphere (Wiebe et al., 2001). The posterior limit in the dominant hemisphere was most often determined by cortical stimulation and intra-operative mapping of temporal speech areas, although a 4–5 cm limit was habitually observed. Mesial resection included the amygdala and, at a minimum, the
anterior 1.0 to 3.0 cm of the hippocampus (most commonly, 4.0 cm) (Wiebe et al., 2001). Resected areas were submitted for pathologic examination.
2.5. Follow-up: Seizure outcome was obtained from surgical discharge notes and follow-up visits in our epilepsy clinic. This included visits at one, six and twelve months after surgery, and at least annually beyond the first year. Outcome was stratified as seizure-free or seizurerecurrence at each follow-up visit and at the last available visit (defined as the last assessment performed after the surgery) (Wiebe et al., 2001). A patient was considered seizure-free if they had no seizures with loss of awareness (i.e., dyscognitive or generalized seizures) (Wieser et al., 2001). Postoperative seizures were defined as those occurring within the first four weeks after surgery. Patients were kept on antiepileptic medication at least during the first year after surgery. Subsequent slow tapering and eventual discontinuation of antiepiepileptic drugs (AEDs), if done, was tailored to the individual. Patients that underwent IIE were compared with those studied with scalp EEG. The study was approved by our institutional ethics committee.
2.6. Statistical analysis: Analyses were performed using the statistical package SPSS (Chicago, Ill., USA, version 17.0). Statistical significance for intergroup differences was assessed by the Pearson χ2 or Fisher’s exact test for categorical variables. For continuous variables that were non-normally distributed, values were expressed as medians [inter-quartile ranges (IR)], and statistical significance for intergroup differences assessed using MannWhitney tests. For variables that were normally distributed, values were expressed as
means ± SD, and significant intergroup differences identified using Student’s t tests. A value of p < 0.05 was considered statistically significant. The relationship between BiTLE, abnormal MRI and postoperative seizures, and the occurrence of seizures at the last available visit was evaluated by means of a KaplanMeier curve and the log-rank test. Finally, a Cox proportional hazards multivariate analysis was used to identify predictors of seizure recurrence, in which gender, handedness, neuropsychological evaluation concordance, histopathological and MRI findings, BiTLE, and post-operative seizures were included. Results were expressed as adjusted hazard ratios (HR) with corresponding 95% confidence intervals (CI).
3. Results: The study sample consisted of 497 patients (46.5% males) exclusively with TLE who underwent ATL after scalp EEG or IIE evaluation. Their median age at seizure onset was 12 years (IR 6-21 years) and their median duration of epilepsy before referral 16 years (7.5-25 years). Almost half of these patients (49.1%) had left-sided TLE, 43.1% right-sided TLE and 7.8% bi-temporal lobe epilepsy (BiTLE). The median time of the last follow-up visit was 24 (6-36) months. 80% had a lesion observable on MRI. Baseline characteristics of the study population are summarized in Table 1.
3.1. Post-surgical outcomes: Seizure outcome data were available for 477 of 497 patients (96%) over the first four weeks (post-operative seizures), for 419 patients at six months (84.3%), 356 (71.6%) at one year, and 199 (40%) at three years of follow-up. Of the original 497, 45 (9.4%) had had post-operative seizures. Seizure-free rates were 282 of 419 (67.3%) at the 6-month visit; 231 of 356 (64.9%) at one year; and 125 of 199 (62.8%) at three years. Overall,
306 of 479 (63.9%) patients were seizure-free the last time they were visited. The median time to recurrence was 6 months (IC 1-8), with 49.4% of recurrences occurring within the first five months and 84.9% within the first year. In the univariate analysis, BiTLE and post-operative seizures, were significantly associated with recurrent seizures at the last follow-up visit (45.9 vs. 54.1%, p=0.014 and 35.6 vs 64.4 %, p<0.001, respectively). On the other hand, histopathological evidence of mesial temporal sclerosis (MTS) (71.8 vs. 28.2%, p=0.010) was associated with seizure freedom, and younger age of epilepsy onset [12 (5-21) vs 13 (8-23) years, p=0.093] and a lesion visible on MRI (65.5 vs. 34.5%, p=0.093) showed a nonsignificance trend towards seizure freedom (Table 2).
3.2. Patients evaluated with intracranial electrodes: A total of 139 (28%) patients underwent IIE placement one or both temporal lobes prior to ATL. Relative to those who only had scalp EEG performed (n = 358), a smaller percentage of the IIE patients had an abnormal MRI study (69.4 vs. 83.6%, p=0.001) and right TLE (48.6 vs 28.8%, p<0.001), while a greater percentage had BiTLE (20.9 vs. 2.8%, p<0.001). IIE patients also required Wada testing more often (42.4 vs. 33%, p=0.02) and had a more prolonged period of follow-up (36 vs. 24 months, p<0.001). On the histopathology, they were more likely to have no abnormal findings (8.3 vs. 3.1%, p=0.014), and less likely to have either a tumor or multiple findings (6.1 vs. 20.4%, p<0.001; and 2.3 vs. 8.5%, p=0.015, respectively; Table 1). Regarding post-surgical outcomes, a significantly higher percentage of patients who had undergone IIE had postoperative seizures (13.8 vs.7.8%, p=0.045). Seizure freedom was reported by 60 of 112 (53.6%) at 6-months of follow-up, versus 72.6% of those evaluated with a scalp EEG (p<0.001). Corresponding percentages were 57% and 68%
at one year; 49.4% and 66.8% at two years (p=0.007); and 52.9% and 67.9% at three years (p=0.038). Overall, 70 of 132 (53%) of IIE patients were seizure free at the time of their last available visit versus 236 of 347 (68%) of those who had undergone scalp EEG (p=0.002). However, it may be taken into account that the median duration of follow-up is 2 years for scalp patients and 3 years for IIE patients. That can affect the proportion of seizure-free at last follow-up (expected to be lower in IIE patients because they were followed longer).
3.3. Bitemporal epilepsy: Patients with a final diagnosis of BiTLE (by scalp or IIE) had a higher risk of postoperative seizure recurrence when compared to those with unilateral TLE (p=0.018), at the last available visit . Furthermore, in a multivariate proportional hazards regression analysis (Cox regression), including the independent variables gender, handedness, neuropsychology testing discordance, post-operative seizures, and MRI and histopathological findings, BiTLE and post-operative seizures were the only predictors of seizure recurrence (HR 1.74; 95% CI 1.05 to 2.9; p = 0.032 and HR 1.83; 95% CI 1.15 to 2.91; p=0.011, respectively). When the scalp EEG and IIE subgroups were analyzed separately, presence of BiTLE was an independent risk factor among IIE patients (HR=2.08, 95% CI: 1.08-4, p=0.029) (Table 3). Seven of 18 (38.9%) BiTLE patients diagnosed by IIE were seizure free one year after surgery, and 12 of 28 (42.9%) at the time of the last available visit. Unilateral temporal lobe epilepsy cases also exhibited lower rates of seizure freedom among IIE patients: 56.7% seizure freedom at 6 months (vs. 72.2% of those diagnosed using scalp EEG, p=0.005) and 55.8% at last available visit (vs. 68.3%, p=0.018).
3.4. Patients with negative versus lesional MRI: A trend towards better seizure outcome was identified among those with a lesion on MRI (65.5% seizure-free vs. 56.3% among non-lesion cases, p=0.093). This difference expanded after BiTLE patients were excluded (67.3 vs.56.3%, p=0.054). This tendency seemed more pronounced in the IIE subgroup: excluding BiTLE cases, 60% of patients with a lesion on MRI were seizure free versus 41.9% among those with no lesion (p=0.09). Conversely, among those studied with scalp EEG, there was very little difference between those with versus without an MRI lesion (68.7 vs. 64.9%, p=0.58). Once again, the percentage of non-lesion patients who were seizure free was significantly lower among those patients studied via IIE (43.6 vs.64.9%, p=0.039), even after excluding patients with BiTLE (41.9 vs.64.3%, p=0.044).
3.5. Pathology: 82.9% of patients had an available post-surgical histopathological diagnosis. The worst outcomes were observed in those with multiple pathological findings (53.3% seizure free), no abnormal findings (57.1% seizure free), or some other finding besides MTS, dysplasia or a tumor (58.1%). In contrast, MTS and dysplasia patients had the best outcomes, with 71.8% and 68.8% seizure-free, respectively (Table 2).
4. Discussion: The main findings of the present study are that more than a half of patients who required IIE previous to ALT are seizure free; and that BiTLE diagnosed by IIE is associated with lower chances of seizure-freedom, independently of other risk factors. Moreover, the prognostic value of a lesion detected on MRI appeared to be greater in
patients diagnosed with unilateral temporal epilepsy using IIE. These findings support the utility of IIE in the pre-surgical work-up of TLE patients. This is the largest single-center series of ATL evaluated with IIE to our knowledge (Burgerman et al., 1995; Radhakrishnan et al., 1998; Wiebe et al., 2001; Paglioli et al., 2004; Bate et al., 2007; Tanriverdi et al., 2008; Bell et al., 2009; Immonen et al., 2010; Engel et al., 2012). Only 28% of our ATL patients required IIE. This rate concurs with most current studies (Berkovic et al., 1995; Clusmann et al., 2002; Tellez-Zenteno and Ladino, 2013) and is far from the 57% who required IIE before extra-temporal resections (Dubeau and McLachlan, 2000). Reasons to undergo IEE included: bitemporal lobe epilepsy, with the hypothesis that seizures originate in one temporal lobe and propagate fast to the contralateral one, to determine the proportion of seizures emanating from each temporal lobe in cases of true bitemporal lobe epilepsy, and when the question is mesial versus neocrtical temporal lobe epilepsy. All this particularly, when imaging fails to identify a lesion. The majority of patients were evaluated with temporal subdural strip electrodes, although intracerebral depth electrodes could also be used to acomplish these diagnostic goals. The comparation of both techniques was not an objective of the present study. 64.9% of all our patients were seizure free one year after surgery and 62.8% after three years. Similarly, in a systematic review that incorporated 1,769 patients, 65% of patients with ATL were free of disabling seizures at one year (Engel et al., 2003) and 58-66% after two to five years (Engel et al., 2003; Bate et al., 2007). These rates may decrease to 50 and 45% at seven and ten years, respectively (McIntosh et al., 2001). Seizure relief was achieved less frequently in series published before 1985 (approximately 55%) (Clusmann et al., 2002), probably related to the increasingly sophisticated pre-operative investigations that have since been developed.
Consequently, better outcomes could be expected among the more recent cases in our series. Our results also reaffirm the belief that patients who fail epilepsy surgery generally do so within the first few months (Bell et al., 2009). A less favorable prognosis was associated with BiTLE, lack of lesions on MRI and acute post-surgical seizures, all well-described negative prognostic factors (Pacia and Ebersole, 1999; McIntosh et al., 2001; Aghakhani et al., 2014). On the other hand, the duration of epilepsy was not associated with a poorer outcome, suggesting that this does not appear to be a risk factor for all TLE patients (Hufnagel et al., 1994; McIntosh et al., 2001; Vale et al., 2012; Ramey et al., 2013). On multivariate analysis, BiTLE and acute post-operative seizures were the only two independent risk factors that remained in the final model, both associated with almost double the hazard of seizure recurrence. The low number of patients with BiTLE diagnosed by scalp EEG is likely the reason for why BiTLE was not found to be an independent prognostic value in this group, but it was the opposite for those who underwent IIE. However, scalp EEG findings of ambiguous lateralization compared with the more precise picture provided by IIE recording may also contribute to this difference (Dubeau and McLachlan, 2000, Javidan, 2012). Additionally, ictal activity that cannot be appreciated on the scalp at all, such as that seen with simple partial seizures (Dubeau and McLachlan, 2000) or rapid secondary generalization from a focus, is readily recorded by IIE. On the other hand, the 42.9% of BiTLE IIE-diagnosed patients who became seizure free after unilateral ATL is not negligible. This percentage is similar to that observed in a previous series (Aghakhani et al. 2014), and certainly higher than the 8% achieved with AEDs (Wiebe et al. 2001). This being said, determining surgical candidacy and which side to perform resection among such patients remains challenging (Aghakhani et al., 2014; Wang et al., 2016).
In our cohort, the presence of abnormalities on MRI was a favorable prognostic indicator, with 65.5% becoming seizure free post-operatively versus 56.3% among MRI-negative cases. These seizure freedom rates have been fairly homogeneous across several recent studies (Clusmann et al., 2002; Bell et al., 2009; Immonen et al., 2010; Tellez-Zenteno et al., 2010) and are higher than those reported for extra-temporal epilepsy (Tellez-Zenteno et al., 2005). However, significantly disparate rates of surgical success can be found among non-lesional TLE patients in published research, ranging from 18% to 80%, though some studies were conducted prior to the widespread use of epilepsy neuroimaging protocols that are more sensitive at detecting MTS, and some used pathologic findings to categorize patients, information that is not available preoperatively (Cohen-Gadol et al., 2006; Bell et al., 2009; Bien et al., 2009). The presence of an abnormality on MRI appears to have higher prognostic value in unilateral TLE patients diagnosed with IIE, suggesting that the significance of a temporal lesion on MRI may be greater when BiTLE have been thoroughly excluded. Furthermore, the surgical approach to non-lesional TLE poses a significant challenge due to the uncertain involvement of mesial and/or lateral (neocortical) temporal regions in the generation of seizures. Invasive electrodes are a useful means of epileptic focus localization in these patients. In our series, 43.6% of the patients with no documented lesion who were evaluated by IIE experienced seizure freedom, a rate that is either similar to (Immonen et al., 2010) or lower (Ramey et al., 2013) than that reported for prior TLE studies. Several conditions could explain surgical failure in such cases: for example, dual pathology, remote areas of epileptogenicity, or diffuse epileptogenicity in the residual temporal lobe (Vale et al., 2012). The last of these is commonly related to seizures originating from the lateral temporal neocortex, with rapid and diffuse ictal spread. These neocortical regions are not resected through standard temporal lobectomy,
which spares a significant amount of the posterior and superior lateral temporal lobe, especially when eloquent areas in the dominant temporal lobe are involved (Immonen et al., 2010). Neocortical temporal lobe epilepsy syndrome (NTLE) may account for up to 67% of TLE patients, and frequently presents with a normal MRI (Pacia and Ebersole, 1999). The higher prevalence of MRI and pathology-negative patients among those evaluated by IIE, and of left temporal lobe involvement, may suggest NTLE as the primary reason for our IIE patients’ worse outcome, even after exclusion of BiTLE cases. The current study has definite limitations. First, the relatively large number of subjects lost to follow-up may have biased our outcomes, since whether individuals lost or maintained contact with our team might have been influenced by their outcome status. Unfortunately, this is a problem that has been reported for many large series (McIntosh et al., 2001). Second, only those who had respective surgery were included in the study, which results in significant selection bias. However, this study design allows us to examine the outcome of those patients in whom IIE confirmed the temporal origin of their epileptic foci. Third, complications from IIE or respective surgery were not evaluated. In any case, the surgical complication rates for subdural strips or depth electrodes implantation and resective procedures are below 5% in our Epilepsy Unit (Burneo et al., 2006; MacDougall et al., 2009). Finally, ours was a retrospective study, so that inferences about causation or risk cannot be made. Nonetheless, our results suggest that IIE provides valuable prognostic information about bi-temporal epileptic activity on TLE and reinforce the concept of MRI-lesion causality in patients with unilateral TLE. Despite technological advances and the mounting accumulation of evidence, many epileptologists remain uncertain about the efficacy and safety of costly surgical procedures like IIE, especially for MRI-negative patients. Our
results should not be used to foster skepticism towards surgery in non-lesional TLE patients who are otherwise good surgical candidates, since 56.3% of them achieved seizure freedom.
Figure 1. Description of the study population
Figure 2. Depiction of temporal coverage with implantation using subdural strips.
Table 1. Differences between ATL patients assessed with intracranial electrodes and those assessed with scalp EEG (n=497).
Table 2: Differences between seizure freedom and seizure recurrence at last clinic assessment among patients with ATL (n=479)
Table 3: Hazard ratios for seizure recurrence at the last clinic assessment among patients who underwent ATL (n=479)
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1,032 consecutive patients that underwent epilepsy surgery Non-temporal resection 354
Extra TLE 89
Type of surgery not available 51
Generalized epileptiform activity 10
Disconnection/MST 2 526 ATL Type of pre-surgical evaluation not available 29 497
358 evaluate with scalp EEG 139 evaluate with IIE
18 without available follow up 479
347 evaluated with scalp EEG
132 evaluated with IIE
MST=Multiple Subpial Transections; ATL=Anterior Temporal Lobectomy; IIE = Intracranial Implantation of Electrodes
Figure 2. Depiction of temporal coverage with implantation using subdural strips.
Table 1. Differences between ATL patients assessed with intracranial electrodes and those assessed with scalp EEG (n=497). ATL with scalp EEG
ATL with IEE
(n=358)
(n=139)
167 (46.6%)
64 (46%)
0.90
Variable
P-value
Gender (male) Handedness:
Right
288 (82.5%)
110 (82.7%)
0.96
Left
52 (14.9%)
18 (13.5%)
0.70
Ambidextrous
9 (2.6%)
5 (3.8%)
0.54
Age of seizure onset (years)
12 (5-23)
13 (6.5-19)
0.69
Age of referral (years)
32.65±12.35
31.4±12.16
0.30
Period from onset to referral (years)
15.5 (7-25)
16 (8-24)
0.88
Video EEG localization:
Left temporal
174 (48.6%)
70 (50.4%)
0.72
Right temporal
174 (48.6%)
40 (28.8%)
<0.001
Bitemporal
10 (2.8%)
29 (20.9%)
<0.001
MRI lesion
291 (83.6%)
93 (69.4%)
0.001
Amytal test
118 (33%)
59 (42.4%)
0.020
Follow-up (months)
24 (6-36)
36 (12-48)
0.001
NP-where dysfunction:
Temporal-concordant
108 (32%)
40 (33.9%)
0.7
Temporal-discordant
104 (30.8%)
35 (29.7%)
0.82
Extratemporal concordant
4 (1.2%)
-
-
Extratemporal discordant
1 (0.3%)
-
-
Unclear
39 (11.5%)
14 (11.9%)
0.82
Normal
25 (7.4%)
6 (5.1%)
0.44
Multiple
58 (17.2%)
24 (20.3%)
0.44
Histopathology: 11 (3.1%)
11 (8.3%)
0.014
Normal
MTS
115 (32.6%)
46 (34.8%)
0.64
Dysplasia
10 (2.8%)
8 (6.1%)
0.11
Tumor
72 (20.4%)
8 (6.1%)
<0.001
Other
111 (31.4%)
54 (40.9%)
0.05
Unknown
4 (1.1%)
2 (1.5%)
0.67
Multiple
30 (8.5%)
3 (2.3%)
Outcome (seizure freedom):
(n=347)
(n=132)
Post-operatively (1 month)
319 (92.2%)
112 (86.2%)
0.04
6-month outcome
223 (72.6%)
60 (53.6%)
<0.001
1-year outcome
174 (68%)
57 (57%)
0.05
2-year outcome
127 (66.8%)
40 (49.4%)
0.007
3-year outcome
89 (67.9%)
36 (52.9%)
0.04
Last available outcome
236 (68%)
70 (53%)
0.002
0.01
Results are expressed as n (percentage), means ± standard deviation, or medians (inter-quartile range), as appropriate. ATL=Anterior Temporal Lobectomy; TLE=Temporal Lobe Epilepsy; FT=Frontotemporal; VNS=Vagal Nerve Stimulator; MST=Multiple Subpial Transections; NP=Neuropsychology; MTS=Mesial Temporal Sclerosis
Table 2: Differences between seizure freedom and seizure recurrence at last clinic assessment among patients with ATL (n=479) Seizure freedom
Recurrence
OR (95% CI)
(n=306)
(n=173)
Gender (male)
138 (63%)
81 (37%)
1.07 (0.74-1.56)
0.72
Handedness (left or ambidextrous):
53 (66.3%)
27 (33.8%)
0.88 (0.53-1.46)
0.62
Age of seizure onset (years)
12 (5-21)
13 (8-23)
0.09
Age of referral (years)
32.4±12.9
32.1±11.1
0.78
Period from onset to referral (years)
16 (8-25)
14 (6-23.5)
0.21
Variable
P-value
Video EEG localization:
Left temporal
150 (64.9%)
81 (35.1%)
0.92 (0.63-1.33)
0.64
Right temporal
139 (65.9%)
72 (34.1%)
0.86 (0.59-1.25)
0.42
Bitemporal
17 (45.9%)
20 (54.1%)
2.22 (1.13-4.37)
0.018
MRI lesion
243 (65.5%)
128 (34.5%)
0.68 (0.43-1.07)
0.093
Postoperative seizures (yes)
16 (35.6%)
29 (64.4%)
3.70 (1.95-7.04)
<0.001
NP-where dysfunction:
Temporal concordant (yes)
85 (59.4%)
58 (40.6%)
1.29 (0.85-1.94)
0.23
Temporal discordant (yes)
89 (65.9%)
46 (34.1%)
0.85 (0.56-1.31)
0.47
Extratemporal concordant
2 (50%)
2 (50%)
1.78 (0.25-12.81)
0.62
Extratemporal discordant
1 (100%)
0 (0%)
n/a
1
Unclear
34 (65.4%)
18 (34.6%)
0.93 (0.5-1.72)
0.81
Normal
22 (73.3%)
8 (26.7%)
0.62 (0.27-1.44)
0.26
Histopathology:
Normal
12 (57.1%)
9 (42.9%)
1.33 (0.55-3.23)
0.52
MTS
112 (71.8%)
44 (28.2%)
0.58 (0.38-0.88)
0.01
Dysplasia
11 (68.8%)
5 (31.3%)
0.79 (0.27-2.31)
0.67
Tumor
50 (63.3%)
29 (36.7%)
1.02 (0.62-1.68)
0.94
Other
93 (58.1%)
67 (41.9%)
1.43 (0.97-2.12)
0.08
Unknown
4 (66.7%)
2 (33.3%)
0.87 (0.16-4.83)
1
Multiple
16 (53.3%)
14 (46.7%)
1.12 (0.68-1.84)
0.22
Table 3: Hazard ratios for seizure recurrence at the last clinic assessment among patients who underwent ATL (n=479) Variable
Gender (male)
ATL (n=479)
Scalp EEG (347)
HR (95% CI)
P-value
HR (95% CI)
P-value
HR (95% CI)
P-value
1.37 (0.97-
0.07
1.76 (1.14-2.7)
0.01
0.98 (0.54-
0.96
1.94) Handedness (left or
0.8 (0.55-1.15)
1.78) 0.22
0.15 (0.41-
0.69
1.14)
ambidextrous): Bitemporal video EEG
1.74 (1.05-
localization:
2.90)
MRI lesion
0.84 (0.56-
0.03
0.96 (0.65-
1.4 (0.49-3.97)
1.22 (0.59-
dysplasia, tumor or other)
2.56)
Post-operative seizures
1.83 (1.152.91)
0.56
1.46) 0.52
0.40
0.91 (0.54-
0.72
1.53)
2.08 (1.08-
0.03
0.82
0.99 (0.62-1.6)
0.68 (0.34-
0.28
1.36) 0.97
1.40) Histopatholgy: lesion (MTS,
0.85 (0.49-
4.00)
1.26) NP-temporal discordant
IIE (n=132)
0.88 (0.46-
0.7
1.68) 0.59
0.81 (0.29-
0.69
2.28) 0.01
2.72 (1.435.18)
1.40 (0.48-
0.54
4.10) 0.002
1.42 (0.712.86)
0.32