Recently, surgical resection of tumors and relevant epileptogenic foci has been proved as an effective treatment method for patients with LEATs, regardless of whether they are drug-resistant or not [4, 8, 9]. The long-term postoperative seizure outcomes and related prognostic factors were also widely discussed in the literature [8-11]. However, few data can be found to be concerned with cognitive functions of patients with LEATs and related risk factors are still unknown [6, 7, 12-15].
Cognitive functions and risk factors
Cognitive impairments commonly occur in patients with epilepsy, and approximately 20-70% of patients with seizures were reported in the literature presenting with various degrees of cognitive deficits [6, 7, 13, 15, 17, 19]. In present study, we specifically defined a cognitive deficit in patients with their neuropsychological scoring less than 80 scores, which was in line with the definition by Cormack et al. in their study [17]. We found 21.7% (30/138) of patients had an intellectual deficit, and 25.8% (32/124) of patients had a memory deficit before surgery, with their mean FSIQ and FSMQ being recorded at 88.6 ± 17.8 scores and 90.1 ± 25.4 scores, respectively.
Regarding to the risk factors, patient age at seizure onset and duration of epilepsy from seizure onset to surgery were commonly reported to be associated with cognitive deficits in patients with epilepsy [14, 17, 20-22], as well as in patients with LEATs or tumors belonging to LEATs [7, 12-15, 23], with a higher risk of cognitive deficits occurring in patients with earlier (or childhood) and prolonged seizure onsets. For example, Baxendale et al. [12] specifically evaluated 56 adults with DNT and medically intractable epilepsy and found the childhood-onset group had significantly lower scores on multiple domains of cognition, including IQ, reading, naming and verbal retention, et al., than those with an onset of seizures at the age of 12 or older; Faramand et al. [7] also reported higher preoperative FSIQ in children with epilepsy-associated GNTs of whom had an older age at seizure onset or shorter duration of epilepsy until surgery. And more specifically, Ramantani et al. [15] found children with GNTs and epilepsy duration to surgery over 4 years were at higher risk for overall cognitive impairment. Similarly, our study proved the adverse impact of older age at seizure onset on IQ in patients with LEATs; Also, we found the same relation between IQ deficits with longer epilepsy duration but just in univariate analysis, which may be attributed to the negative correlation between age of seizure onset and duration of epilepsy in our cohort (coefficient β = -3.159; F = 10.744; P = 0.001). In general, for younger patients or children with seizure onsets, the developing brain with its immature cognitive function is more likely to be disordered by longstanding EDs in brain, which, however, less occur in adults with epilepsy [21, 22, 24-26]. Thus, early seizure control by an effective treatment, such as surgical resection, is especially crucial to younger patients or children with LEATs [27, 28]. In particular, patient demographic features of age at surgery and gender were rarely reported to predict cognitive deficits in patients with epilepsy or with LEATs [7, 17, 21, 29].
For factor of number of AEDs or drug-resistance, many studies found that patients with more taken AEDs or with drug-resistant epilepsy had a higher risk of cognitive deficits [6, 13, 14, 22, 30]. For example, García-Fernández et al. [14] found children with developmental tumors in drug-resistant group when compared to those with no drug-resistant epilepsy obtained significantly poorer results in terms of general cognitive abilities (FSIQ, verbal IQ and performance IQ) as well as other cognitive domains (memory, verbal learning/reasoning/comprehension, et al.); Vogt et al. [6] found in patients with temporal LEATs that executive functions were worse in patients with a higher number of AEDs. Ko et al. [13] also found more AEDs taken before surgery was one of statistically significant factors associated with lower preoperative FSIQ scores in children with LEATs. In concordance with previous studies, we found the adverse impact of drug-resistance on IQ in our cohort by univariate analysis, but not for the number of AEDs. As it is known, AEDs are mostly neurosuppressive drugs that could suppress patient’s brain function when the drug burden is too heavy [22, 31]. Thus, if the postoperative seizure onsets are well controlled, the reduction or withdrawal of AEDs medication may partly improve the cognitive function of patients with LEATs, which has been reported by Skirrow et al. [19] who found the increase in IQ was associated with cessation of antiepileptic medication during postoperative follow-up in patients after temporal lobe surgery in childhood.
In addition, bilateral or generalized EDs on the brain may also have influence on cognitive function [13, 32, 33]. Ko et al. [13] found the presence of generalized EDs on video EEG was a significant factor associated with lower preoperative FSIQ scores in children with LEATs. Similarly, we found patients with lateral discordant EEG findings (or bilateral EDs) had lower FSIQ and FSMQ than other patients. Bilateral or generalized EDs may indicate that the brain of patients is widely affected by abnormal electrophysiological activities [33-35]. In particular, with further analysis, we found that patients with longer duration of epilepsy had a higher chance of discordant EEG findings (F = 4.04, P = 0.020). It has been speculated that patients with longer epilepsy duration are more likely to have distant or multifocal EDs [14, 21, 36]. Therefore, bilateral or generalized EDs might be as a result of the effects of prolonged seizures and directly disorder the cognitive functions of patients with epilepsy, and thus early seizure control might lower the risk of cognitive impairments in patients with LEATs.
The lateralization and localization of lesions (or epileptogenic focus) were also reported to have influence on cognitive function, and in particular, the left temporal lobe epilepsy (TLE) foci (especially the medial temporal lobe or hippocampus) are more likely to cause memory deficits than right temporal lobe [6, 12, 14, 15, 30]. However, Baxendale et al. [12] reported there were no significant localization effects (right vs. left; temporal vs. extratemporal) on any of the neuropsychological test scores in patients with epilepsy-associated DNT. Faramand et al. [7] also reported tumor location did not correlate with FSIQ outcomes in children with GNTs. In our cohort, we did not find any significant differences between tumor location and cognition deficits, except for the higher rates of memory deficits in patients with abnormal hippocampus (including HS or tumor involvement).
Previous studies have also reported that education level has an impact on overall cognitive performance of subjects [37-39], which was also found in our cohort of whom with higher academic achievement often obtained higher FSIQ and FSMQ. However, as Phuong et al. [30] said, it is difficult to determine how cognitive performances of patients with epilepsy and their education level impact each other, because repeated seizure onsets often stop children from schooling due to varieties of reasons that may partly include cognitive or psychiatric comorbidities related to epilepsy itself [39, 40]. Therefore, we finally didn’t take the education level into the multivariate analysis of predictors of cognitive outcomes, but we believe an active education to some extent is still important to reduce the cognitive decline of patients with epilepsy (especially for children) or patients requiring postoperative rehabilitation [41-44].
Other factors of seizure semiology (such as seizure type or frequency) and lesion characteristics (such as tumor types or tumor size) were rarely reported to impact patient’s preoperative cognitive functions [6, 13, 17, 20, 30]. However, we didn’t find any correlations of these clinical factors with cognitive deficits in our cohort of LEATs patients.
With respect to the postoperative cognitive outcomes, many studies have reported that epilepsy surgery would not increase cognitive impairments of patients, and in particular, postoperative cognitive outcomes were significantly depended on the preoperative cognitive status in patients with LEATs [7, 13, 15]. Ramantani et al. [15] found postsurgical overall cognitive functioning in children with epilepsy-associated GNTs were strongly correlated with presurgical cognitive functioning that in turn was markedly influenced by epilepsy duration. However, Faramand et al. [7] only found postoperative FSIQ was significantly influenced by preoperative FSIQ in children with GNTs, while duration of epilepsy and age at seizure onset did not significantly predict postoperative FSIQ. Other factors, including the site of surgical resection and the extent of resection, had been but less reported to be associated with cognitive impairments [7, 13, 19]. We also found postoperative FSIQ and FSMQ were closely influenced by preoperative FSIQ and FSMQ, respectively (FSIQ: R2=0.901, F=254.5, P<0.001; FSMQ: R2=0.677, F=50.3, P<0.001), but we did not further analyze the association of postoperative FSIQ or FSMQ deficits with other clinical factors due to the limited number of patients (30 cases) who underwent postoperative FSIQ/FSMQ evaluations.
In particular, some scholars believe that the improvement of cognition function in early period after operation is not obvious, and a significant improvement requires long-term clinical observation after surgery [13, 19]. For example, Ko et al. [13] found in children with LEATs that although the postoperative FSIQ was significantly influenced by preoperative FSIQ (coefficient β = 0.790, p < 0.001), the median change from preoperative to postoperative FSIQ was 0.0 (range: -5.8-14.0) when patients were evaluated at median of 21.0 (range: 13.2-31.0) months after the surgery. By contrast, Skirrow et al. [19] found a significant increase in IQ was found in patients with temporal lobe resection for HS or DNTs after an extended follow-up period of >5 years. In present study, despite the short-term postoperative observation period in our surgical cohort of a mean time of 24 months (range: 3-96 months), we have yet found a part of cognitive improvements of intelligence and memory function in 30% and 50% of patients, respectively.
Seizure outcomes and predictors
In recent years, many studies have proved that surgical resection of LEATs and relevant epileptogenic foci could help most of patients achieve satisfactory postoperative seizure control, and approximately 70-90% of patients could get seizure-free after epilepsy surgery [6, 7, 13]. In line with previous studies, we found 85.4% of patients in our cohort who were followed up at least 12 months got seizure-free and half of them (50.5%) had AEDs reduced or discontinued. However, there still were a part of patients (14.6%) with seizures uncontrolled; further analysis in our cohort found that patients with longer duration of epilepsy and discordant interictal EEG findings (or bilateral EDs) tended to had poor seizure outcomes after surgery.
Previous studies have also found that the duration of epilepsy is a risk factor for postoperative epilepsy prognosis in patients with LEATs, and early surgical resection was thus advised to achieve better seizure outcomes [7, 13]. Discordant EEG findings (or bilateral EDs) suggest that simple tumor resection couldn’t effectively control seizures [4, 13, 15]. It is worth noting that despite the discordant findings of the preoperative EEG with tumor locations in our cohort, 69% of these patients (20/29) still got seizure-free after surgery; and thus, surgical resection can also be recommended to obtain seizure freedom in nearly 2/3 of those patients. Other risk factors, such as age at surgery but at seizure onset, drug-resistant epilepsy, incomplete tumor resection, and early postoperative seizures or EDs, et al., have also been dispersedly reported in different surgical cohorts to be associated with postoperative seizure outcomes in LEAT patients [6, 7, 13-15, 20, 23], but none of associations were found in our study.
Limitations
The evidence from our study with LEATs cohort may compromise its retrospective nature and small sample size, especially the small number of patients with postoperative neuropsychological assessments. In addition, we just analyzed the general IQ and MQ without all specific domains of cognitive function. Even so, our results could also partly complement the undefined domains of the cognitive and seizure outcomes in patients with LEATs. In the future, a large, prospective and well-matched surgical cohort of LEATs from multiple epilepsy centers is still needed to get more comprehensive evidences concerning cognitive and seizure outcomes to guide the clinical treatment of patients with LEATs.