Some patients with medically intractable epilepsy require surgery to control their seizures. The localization of the epileptogenic area is the cornerstone to guide treatment (Rosenow & Luders, 2001). The majority of refractory focal seizures originate from the temporal lobe, and its resection is a well-established procedure (Wiebe et al., 2001). It is estimated that approximately 50–62% of patients will remain seizure-free 5 years after surgery for temporal lobe epilepsy, depending on the pathogenic substrates associated with refractory seizures (Wieser et al., 2003; McIntosh et al., 2004; de Tisi et al., 2011).
However, the elapsed time for seizure recurrence after surgery is not uniform, and patients who continue to have seizures diverge into two different categories. First are the patients who derive no benefit from surgery, with either immediate postoperative seizures or only a brief period of seizure control. Others may have a longer period of seizure control after surgery but then subsequently recur (Schwartz et al., 2006). The differences between these two classes of patients perhaps reflect the appropriateness of resection, intrinsic tissue epileptogenicity, and long-term prognosis (Jehi et al., 2010). For example, patients with late recurrence of seizures usually have fewer attacks and a better quality of life when compared to individuals with early relapse (Lee et al., 2006; Buckingham et al., 2010). To date, each author has defined early or late seizure recurrence arbitrarily, creating obvious difficulties when interpreting data, and making it difficult for investigators to perform comparisons and understand the significance of findings. Mathematical or statistical tools have not, to our knowledge, been used previously for this purpose.
Early or late recurrence of seizures after surgery might be better seen as two distinct events. Although early recurrence might reflect an incomplete resection of the epileptogenic zone, late recurrence might reflect the development of a new epileptogenic process, possibly reflecting an underlying epileptogenic tendency. A better distinction and comprehension of these two different situations could lead to a more appropriate understanding of reasons for surgical failure. This is important because in the short run it would help to establish a more accurate long-term prognosis for patients earlier after surgery, and in the long run it might have an impact on planning better treatment protocols. Therefore, the main objective of this study was to establish a statistically oriented model for better discriminating patients with early or late seizure recurrence and to study the clinical, electrophysiologic, and neuroradiologic differences between these two groups of patients. It is our hope that this might help to better inform patients regarding their prognosis as well as to delineate research objectives for future treatments.
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Of the 247 patients who underwent surgery for temporal lobe epilepsy during the period under study, 219 satisfied our inclusion criteria. Of these, 107 (48.9%) had relapse of seizures. The median follow-up was 36 months (range 12–60). Based on the first event, 58 (54.2%) of these 107 patients experienced seizure recurrence before 6 months, 18 (16.8%) between 6 months and 1 year, 17 (15.9%) between 1 and 2 years, 5 (4.7%) between 2 and 3 years, 7 (6.5%) between 3 and 4 years, and 2 (1.9%) between 4 and 4 years (Fig. 1). Table 1 demonstrates the clinical characteristics of the included patients. Age at epilepsy onset ranged from 1 to 55 years of age (mean 16 years). Age at surgery ranged from 12 to 65 years (mean 34 years), and the time of epilepsy duration from 1 to 54 years of age (mean 20 years). Seventy-four patients (69.2%) had history of generalized seizures. A structural abnormality of any sort on MRI was identified in 87 (81.3%), with 57 (53.2%) having ipsilateral mesial temporal sclerosis.
Table 1. Characteristics of patients with recurrence of seizures
|History of febrile seizures||23 (21.5)|
|Seizure characteristics|| |
|Presence of aura||90 (84.1)|
|Generalized seizure||46 (43.0)|
|Second generalization||53 (49.5)|
|Any generalization||74 (69.2)|
|Postictal state||89 (83.2)|
|Interictal EEG|| |
|Interictal video-EEG|| |
|Unilateral concordant||47 (43.9)|
|Bilateral, multifocal, or generalized||46 (43.0)|
|Ictal video-EEG|| |
|Exclusively temporal concordant||79 (73.8)|
|Any alteration outside temporal concordant||27 (25.2)|
|MRI brain|| |
|Presence of lesion||87 (81.3)|
|Hemispheres with lesion|| |
|Only temporal concordant||37 (34.6)|
|Outside temporal concordant||37 (34.6)|
|Intracranial electrodes||44 (41.1)|
|Side of resection|| |
|Type of resection|| |
|Standard ATL||87 (81.3)|
|Tailored resection||4 (3.7)|
|ATL + tailored resection||4 (3.7)|
|Immediate postoperative seizure||20 (18.7)|
Figure 1. Percentage distribution of 107 patients with recurrence of seizures after surgery for temporal lobe epilepsy over time. Before 6 months (54.2%), from 6 months to 1 year (16.8%), from 1 to 2 years (15.9%), from 2 to 3 years (4.7%), and from 4 to 5 years (1.9%).
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Time of seizure recurrence
Using ROC curves, we found that a recurrence time of six postoperative months predicted long-term surgical outcome with the best sensitivity and specificity possible. The result was similar regardless of whether the Engel or ILAE classification was used. Using the Engel classification, patients could be divided into good long-term surgical outcome with an accuracy of 76.1% (95% CI = 0.665–0.867; p < 0.001). According to the ILAE criteria, accuracy was 72.9% (95% CI = 0.622–0.837, p < 0.001). This time frame was also useful for predicting the presence or absence of trigger events precipitating seizure recurrence, where the accuracy for predicting surgery outcome was 79.8% (95% CI = 0.707–0.890; p < 0.001; Fig. 2). Of interest, in all three curves, the highest sensitivity and specificity point to predict long-term seizure outcome was observed at 6 months after surgery (sensitivity 78.8%, specificity 72.1%). We therefore used this time to separate patients in two groups: the early recurrence group in which seizures returned within 6 months of surgery and the late recurrence group in which seizures returned after 6 months of surgery. We studied differences between these two groups in order to better understand factors associated with early or late seizure recurrence.
Figure 2. Receiver-operating characteristic (ROC) curves. (A) Association with outcome using Engel classification (I and II) and time of recurrence (AUC = 0.761; CI 95% 0.665–0.867; p < 0.001). (B) Association with outcome using ILAE classification (1, 2, and 3) and time of recurrence (AUC = 0.729; CI 95% 0.622–0.837, p < 0.001). (C) Association with trigger for seizures and time of recurrence (AUC 0.798; CI 95% 0.707–0.890; p < 0.001). The highest sensitivity and specificity scores combined in all curves were present at 6 months (sensitivity 78.8% and specificity 72.1%). This information was used to separate groups as early or late recurrence of seizures.
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Differences between early and late seizure recurrence
After dividing the patients into late and early recurrence based on the ROC curves, a univariate analysis was performed on preoperative and postoperative variables (Tables 2 and 3). Age of epilepsy onset was the only presurgical variable found to be significantly different between the two groups (Table 2). Patients with early seizure recurrence after surgery had an earlier age of epilepsy onset (13.4 years) than those with a late seizure recurrence (19.5 years; OR = 6.034; 95% CI = 1.056–11.013; p = 0.018). Neither the types of surgical procedures performed nor the pathologic diagnoses differed between those with late and early recurrence. Patients with early recurrence had a poorer long-term prognosis when compared to the late seizure recurrence group, as classified using the ILAE (OR = 4.545; 95% CI = 1.785–11.111; p = 0.001) or Engel (OR = 7.142; 95% CI = 2.564–20; p = 0.001) outcome scores. The Kaplan-Meier survival curves demonstrated a statistically significant difference when comparing time to recurrence between those with higher and lower Engel or ILAE scores when analyzing outcome at last follow-up (p < 0.001; Fig. 3). These showed that patients with a better Engel or ILAE score tended to recur later than those with a poorer score. Patients with late recurrence were 7.4 times more likely to experience a >50% reduction in seizures than patients with earlier recurrence (95% CI = 1.55–35.4; p = 0.005), considering the Engel classification, and 5.9 times more considering the ILAE outcome score (95% CI = 1.78–19.25; p = 0.002). In addition, the frequency of seizures was higher in the group of patients with early recurrence (p = 0.027). The mean number of attacks was 3.29 (standard deviation [SD] ± 5.83) per month for early recurrence and 1.13 (SD ± 2.23) for late recurrence. Seizures that recurred after 6 months were more often associated with discrete trigger events when compared with seizures that relapsed earlier (OR = 2.82; 95% CI = 1.81–4.39; p < 0.001). Patients with early recurrence required a higher number of AEDs after surgery (p = 0.013). After logistic regression, only age of epilepsy onset (p = 0.05), the presence of a trigger factor (p = 0.002), and severity of seizures (p = 0.032) remained significantly different between patients with early and late seizure recurrence (Table 4).
Table 2. Univariate analysis of the preoperative variables comparing early versus late recurrence of seizures
|Variable||Early (n = 58) n (%)||Late (n = 49) n (%)||p-Value|
|Male||24 (40.6)||21 (43.7)||0.749|
|Etiology (symptomatic)||48 (81.3)||39 (81.2)||0.989|
|Febrile seizure||12 (25)||11 (26.8)||0.844|
|Aura||48 (88.8)||42 (87.5)||0.828|
|Generalized seizure||26 (47.2)||20 (42.5)||0.633|
|Secondary generalization||33 (61.1)||20 (42.5)||0.062|
|Any generalization||42 (71.1)||32 (66.6)||0.615|
|Postictal||50 (94.3)||39 (86.6)||0.169|
|Interictal EEG abnormality||57 (98.2)||41 (93.7)||0.241|
|Interictal video-EEG (only temporal concordant)||22 (44)||25 (55.5)||0.349|
|Ictal video-EEG (only temporal concordant)||41 (69.4)||38 (79.1)||0.319|
|Presence of MRI lesion||49 (83)||38 (79.1)||0.608|
|Only unilateral lesion||39 (79.5)||33 (86.8)||0.375|
|Neuropsychology (only temporal concordant)||20 (37)||17 (35.4)||0.977|
|Investigation with intracranial electrodes||27 (45.7)||17 (35.4)||0.279|
|Side of resection (right)||26 (44.8)||20 (41.6)||0.744|
|Type of resection (standard ATL)||47 (81)||46 (93.7)||0.074|
|Pathology (single pathology)||47 (83.9)||40 (86.9)||0.817|
|Immediate postoperative seizure||12 (20.3)||8 (16.6)||0.628|
| ||Mean (SD)||Mean (SD)|| |
|Age of seizure onset||13.42 (10.45)||19.45 (15.42)||0.018|
|Age at surgery||33.46 (13.94)||36.54 (13.54)||0.250|
|Duration of epilepsy||19.26 (12.15)||21.41 (12.02)||0.406|
|Frequency (per month)||11.63 (9.54)||10.64 (8.6)||0.617|
|Current number of AED||2.16 (0.87)||1.95 (0.73)||0.213|
|Number of tried AED||2.57 (1.63)||2.27 (1.68)||0.486|
|Total number of AED||4 (2.01)||3.36 (1.85)||0.117|
Table 3. Univariate analysis of the postoperative variables comparing early versus late recurrence of seizures
|Variable||Early (58) n (%)||Late (49) n (%)||p-Value|
|Trigger of seizure||7 (13.7)||26 (60.4)||<0.0001|
|Different semiology||17 (32.6)||18 (43.9)||0.268|
|Significant improvement ILAE (1, 2, 3)||20 (43.4)||34 (77.2)||0.001|
|Significant improvement Engels (I, II)||20 (43.4)||37 (84)||0.001|
|Reoperation||10 (16.9)||1 (2)||0.021|
| ||Mean (SD)||Mean (SD)|| |
|Frequency (per month)||3.29 (5.83)||1.13 (2.23)||0.027|
|Current number of AED||2.07 (0.905)||1.59 (0.785)||0.013|
Table 4. Logistic regression of variables comparing early and late recurrence
|OR (95% CI)||p-Value||OR (95% CI)||p-Value|
|Age of seizure onset||6.034 (1.056–11.013)||0.018||1.043 (1–1.088)||0.050|
|Trigger of seizures||9.615 (3.521–26.315)||0.000||6.411 (1.956–21.013)||0.002|
|Significant improvement|| || || || |
|Engel (I, II)||6.849 (2.538–18.518)||0.001||3.558 (1.112–11.494)||0.032|
Figure 3. Kaplan-Meier curve of patients with recurrence of seizure after temporal lobe epilepsy analyzing time of first seizure after the procedure and outcome on the last follow-up. (A) Patients were separated as ILAE classification 1, 2 and 3 or ILAE 4, 5 and 6. (B) Patients were separated as Engel class I and II, or Engel class III and IV. In both cases, patients in the poorer outcome group (Engel III/IV or ILAE 4-6), recurred earlier than those with a better outcome.
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Running-down phenomenon was observed in six patients (5.6%). The time until seizure freedom was achieved varied from 7 to 15 months (mean 11.3 months). Two of these patients had recurrent seizures that had a different semiology when compared to the preoperative events.
In our cohort, patients with early recurrence were significantly more often submitted to an additional surgical procedure for seizure control. Fifteen patients with recurrent seizures (14%) were investigated with subdural electrodes, and 11 underwent additional resective surgery. Of those who had subdural recordings, ictal EEG alterations were lateralized to the side ipsilateral to the original surgery in 13 patients, contralateral in one patient, and in one patient showed a more diffuse epileptogenic area (Table 5). Of the 58 patients with early recurrence, 10 (16.9%) underwent an additional resection, whereas only one of the 49 patients (2%) with late recurrence underwent further surgery (OR = 9.59; 95% CI = 1.18–77.87; p = 0.021). The timing of the second surgery varied from 2 to 11 years after the original operation (mean 6 years). In one case, the repeat resection was abandoned following cortical stimulation, as the epileptogenic area overlapped with the language area. Of the remaining 10 patients, all reoperations were performed in the original hemisphere. The surgical plans accomplished were the removal of the temporal neocortex in four patients with previous selective amygdalohippocampectomies, the resection of the remaining mesial structures in three patients with previous tailored neocortical resections, and the additional resection of the temporal neocortex in three patients who had standard temporal lobectomies. At last follow-up, five of the reoperated patients were Engel class I, two were Engel II, two were Engel III, and one was Engel class IV. In all, 70% of the patients with reoperations had a significant (Engel class I or II) improvement, and 90% had more than a 50% reduction of seizures frequency following the second operation.
Table 5. Characteristics of reoperations
|Patient||Time of recurrence (months)||Time for reoperation (years)||Side of surgery||Outcome on last follow-up (ILAE/Engel)||Time of recurrence after 2nd surgery (months)|
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Several studies have investigated the risk for seizure recurrence after surgery by comparing patients who were seizure-free versus those who were not (Foldvary et al., 2000; McIntosh et al., 2004; Janszky et al., 2005; de Tisi et al., 2011). However, it is possible that not all surgical failures are equal and that patients who recur earlier are distinct from those who recur later, possibly reflecting a different mechanism for seizure recurrence as well as a different prognosis. In a few studies, seizure recurrence has been separated into early and late groupings; however, very little comparison of the possible differences between these two groups of patients has been undertaken. Furthermore, there is no agreement about the time cutoff for classifying seizure relapse as early or late. Although some authors advocate for 1 year (Schwartz et al., 2006) and others for 5 years (Sperling et al., 2008), others consider 2 years as the best cutoff (McIntosh et al., 2004; Kelemen et al., 2006). However, these classifications have been mostly arbitrary and do not reflect any possible statistical or neurobiologic mechanism for seizure recurrence. What is unique about the current study is that we had no preconceived notion as to what time cutoff would be used to separate early from late recurrence. Rather than arbitrarily choosing a cutoff, the data were examined and a statistically relevant cutoff was selected. A division at 6 months was best found to fit the data. Patients in whom seizures recurred within the first 6 months of surgery had an earlier age of onset, a worse surgical outcome, and a higher postoperative seizure frequency.
We found that early recidivists had a younger age of epilepsy onset than those with seizure recurrence after 6 months. This is an interesting finding that might reflect a more active epileptogenic process and it is in line with findings in the literature, suggesting lower chances for good seizure control in the early epilepsy onset group (Cendes, 2011). This is also in keeping with evidence that suggests that age of epilepsy onset or duration of epilepsy might be directly related with surgical prognosis (Aull-Watschinger et al., 2008).
Once a patient has the first seizure after surgery, it is useful to have some way to predict the long-term outcome. Our results suggest that patients who have a recurrence within 6 months after surgery have a worse prognosis, with higher seizure frequency and a more frequent need for subsequent intracranial recordings or additional resective surgery than those who have a recurrence after 6 months. This in line with the results of Radhakrishnan and Kelemen who showed that seizures that returned before 1 year after surgery have a worse prognosis (Radhakrishnan et al., 2003; Kelemen et al., 2006). Late relapse seems to be a more benign condition, with less frequent seizures, which is in keeping with Buckingham et al. (2010) who stated that seizures that return after a longer period have better long-term outcomes, with higher chances of remission.
In our study, seizures that returned later than 6 months after surgery were more commonly associated with discreet trigger events. Tapering or withdrawal of AEDs and psychological stress were the main factors associated with late recurrences. It is possible that certain patients without precipitating factors might remain seizure-free for longer periods and may experience a recurrence when faced with one of these trigger events (Schmidt et al., 2004). This may explain why these patients were less frequently considered for reoperation. It is also possible that these patients have a lower threshold for seizures. In the late recurrence group the reduced frequency of seizures, the minor severity of the symptoms, and the lower number of AEDs prescribed for seizure control is perhaps a reflection of a new epileptogenic process (Jehi et al., 2012).
The pathophysiologic difference between early recurrence with incomplete resection versus late recurrence with perhaps a brain with lower threshold for seizures or epileptogenicity is under discussion (Fong et al., 2011). We did not note any histopathologic or radiologic differences between early and late recurrences. It could be argued that 6 months is a precocious period for development of a new focus; however, it is very important to note that for a patient who used to have several seizures a week or a month, being free of attacks for this length of time very likely has some relationship to removal of some or all of an epileptogenic area. In addition, the time for a new area of cortex to become epileptogenic is unknown. It is obvious that the longer the time the greater the chances for relapse, but it is possible that 6 months is sufficient to clinically define this process.
We found that patients who were selected for a second surgery were more often those with an early seizure recurrence. From the 11 patients submitted to another surgical procedure for seizure control, 10 (90.9%) were included in the early seizure relapse group, and all of them had their prior surgical area extended. It is unclear why reoperations were not performed as frequently in the late recurrence group. Most of the postoperative patients with recurrent seizures are reevaluated at our center regardless of the time of recurrence, and time to recurrence is not specifically used as a deciding factor when considering additional surgery. As mentioned earlier, it is possible that due to the milder nature of the epilepsy in those with late recurrence that surgery was not felt to be necessary. It is also possible that the seizures were felt to be either multifocal, generalized, or of contralateral origin, supporting the hypothesis that these patients have either a lower seizure threshold or an underlying propensity to develop seizure foci; this is deserving of further study. Of those patients who underwent repeat surgery, five patients were rendered seizure-free, a finding that strongly implies that the reason for early recurrence in these patients was an incomplete resection of the epileptogenic zone, rather than a placebo effect or some unknown physiologic cause related to surgery in general. These findings are in keeping with Germano et al. (1994), who reported that the initial recurrence of seizures generally occurred during the first 6 months in a series of 40 patients needing reoperation for TLE seizures. However, the partial resection of the epileptogenic area may not be the main physiologic explanation for all early recurrences. Although 16.9% of early recurrences had repeat surgery and many did well, the majority (83.1%) did not have repeat surgery. It is possible that these patients had another epileptogenic zone that was not identified. It is interesting to observe that even when the seizures returned just after few months, the mean time for the second resection was 6 years after the original operation. Considering that the latest observed running-down phenomenon was 15 months postoperatively, and that 90% of the reoperated patients had some benefit from the second surgical procedure, it would be a reasonable strategy to consider investigation for another surgery by 2 years after the first surgical attempt.
The limitations of this study reside in its retrospective nature and the fact that some statistics are exploratory. It is also possible that there might be differences between the late and early recurrence groups that would be detected only with a group of patients larger than the 107 presented here.
Nonetheless, this study presents some important information regarding the timing of recurrence after surgery, and suggests that 6 months might be the most useful time cut-off for defining early versus late recurrence after surgery for TLE. Although preoperative characteristics are good predictors for remission or recurrence of seizures after surgery (McIntosh et al., 2001), once the primary goal is not achieved, the time of the first seizure might be an important predictor for long-term seizure outcome. In this venue our study might help regarding prognosis definition and planning future treatments. We propose that recurrence of seizures after surgery for temporal lobe epilepsy should be separated into early or late recurrences based on the time frame of 6 months following surgery. Patients with seizure recurrence within 6 months have worse outcomes, higher frequency of attacks, tend to use a higher number of AEDs, and carry a higher probability for reoperations when compared with those patients with late seizure recurrence.