Clinical Characteristics and Prognostic Significance of Subclinical Seizures in Focal Epilepsy: A Retrospective Study

We retrospectively reviewed the records of consecutive epileptic patients who underwent subsequent epilepsy surgery during scalp-VEEG evaluation with or without IEEG monitoring at the Epilepsy Center, Second Affiliated Hospital of Zhejiang University, from 2013 to 2020. This retrospective study was approved by the institutional review boards of the Second Affiliated Hospital of Zhejiang University (2013-032).

The inclusion criteria were as follows: (1) epileptic patients with VEEG monitoring, (2) undergoing subsequent surgery, (3) with at least 1-year follow-up. The exclusion criteria were as follows: (1) those who had experienced vagus nerve stimulation, (2) those who had secondary surgery (secondary surgery refers to a second operation when the results of the first surgery were deemed inadequate or the patient had intracranial surgery previously), (3) missing at follow-up, (4) incomplete clinical data.

VEEG was performed using digital VEEG systems (Nicolet, VIASYS, USA, and Biologic, NATUS, USA), with scalp electrodes placed according to the international 10-20 system, including anterior temporal electrodes and sphenoidal electrodes if necessary. All the patients were monitored for at least 24 h. The intracranial electrode location was designed based on the multidisciplinary discussions in our epilepsy center. IEEG was performed with a 256-channel NK system or a 128-channel XLTEK system. Antiepileptic drugs (AEDs) were administered at normal or reduced doses during the VEEG or IEEG recordings according to different demands. SCSs were defined as electrographic seizures with rhythmic ictal discharges that evolve in frequency and space and lack any objective or subjective alteration in behavior or consciousness [2, 3]. CSs were defined as clinically evident seizures, possibly captured on VEEG or IEEG monitoring [3]. Each SCS and CS was assessed by two professional electroencephalographers (Wenjie Ming and Zhongjin Wang) who were blind to the outcome. If there was any disagreement, then the EEG epochs were re-reviewed by the epileptologist (Shuang Wang). If SCSs were detected on scalp VEEG, they were defined as s-SCSs, and if SCSs were detected on IEEG, they were defined as i-SCSs. If CSs were detected on scalp VEEG, they were defined as s-CSs, and if CSs were detected on IEEG, they were defined as i-CSs.

Clinical, VEEG, IEEG, postoperative histopathology, and surgical outcome data were all collected. Epilepsy was classified into temporal lobe epilepsy (TLE) and extratemporal lobe epilepsy (ETLE), which included the frontal lobe, parietal lobe, occipital lobe, insular lobe, hypothalamus, and multilobe. The groups that were monitored by VEEG were classified into two subgroups: patients that had SCSs captured by VEEG (s-SCSs group) and patients that did not have SCSs captured by VEEG (non-s-SCSs group). The groups that were monitored by IEEG were classified into two subgroups: patients that had SCSs captured by IEEG (i-SCSs group) and patients that did not have SCSs captured by IEEG (non-i-SCSs group). Localization of SCSs and CSs was based on VEEG and IEEG finalized phase reports, which were done by board-certified adult or pediatric epileptologists and re-reviewed at patient management conferences. Concordance between SCSs and CSs was summarized into five categories [7]: SCS and CS localizations were consistent (SCSs = CSs); the localization of SCSs was contained within that of CSs (SCSs < CSs); the localization of CSs was included within that of SCSs (CSs < SCSs); SCSs and CSs had overlapping localizations (SCSs ∩ CSs); SCSs and CSs had different, nonoverlapping localizations (SCSs ≠ CSs). Patients were recommended for epilepsy surgery based on multidisciplinary discussions, and the surgical strategy was determined collectively by neurosurgeons and epileptologists. As for the definition of “incomplete resection,” there were several scenarios. When the lesion was magnetic resonance imaging (MRI)-positive, “incomplete resection” was defined as “the lesion was not totally removed, and the residual tissue can be identified on postoperative MRI.” When the routine MRI was negative, positron emission tomography (PET)/MRI co-registration and MRI postprocessing (morphometry analysis program) was performed to help localize the epileptogenic zone. When the imaging postprocessing findings were consistent with VEEG findings and semiology, then the “incomplete resection” was also defined as “the residual lesion can be identified on both postoperative MRI and preoperative imaging modalities.” When all presurgical imaging modalities failed to find the potential lesion, IEEG was performed. We determined the resection area based on the seizure onset of IEEG. If the seizure onset brain zone identified by the planted electrodes was removed, it was considered “complete resection”; if not, then “incomplete resection.” The pathological diagnoses were then categorized as follows: hippocampal sclerosis, focal cortical dysplasia, tumor, hemangioma/vascular malformation, arachnoid cyst, dermoid cyst, colloid cyst, and nonspecific. Seizure outcomes were evaluated according to the last visit or telephone interviews as specified in the Engel classification [15], and further classified as being in either the seizure-free group (Engel class Ia) or the non-seizure-free group (Engel class Ib–IV).

The data were presented as median (interquartile range) via SPSS version 23.0. Nonparametric Mann–Whitney U test was used to compare group differences on continuous variables. Categorical variables were analyzed by Pearson’s chi-square test or Fisher’s exact test. Univariate analysis results were then entered into a multivariable binary logistic regression/Cox regression model with statistical significance at P < 0.1. A logistic regression model was applied to determine the unique related factors of several variables on SCSs with statistical significance set at P < 0.05. To evaluate the predictors of seizure outcome, a Cox regression model was applied with statistical significance set at P < 0.05. Odds ratio (OR) and 95% confidence interval (CI) were also calculated for each of these parameters. The Kaplan–Meier survival analysis was used to calculate the seizure-free duration probability after surgery. To identify the threshold of continuous variables that could predict seizure outcomes, continuous variables were stratified, and the cutoff values were determined according to the Youden index in a receiver operating curve (ROC) analysis.

Of the 351 patients who initially met this study’s inclusion criteria, those with vagal nerve stimulation (n = 22), secondary surgery (n = 24), missing follow-up (n = 14), or incomplete clinical data (n = 5) were ultimately excluded. In total, 286 patients were enrolled for analysis (151 male, 135 female). There were 28 (9.79%) patients in the s-SCSs group and 253 (90.21%) in the non-s-SCSs group. The median duration of VEEG monitoring was 2 (interquartile range 1–4) days. The total number of patients with IEEG monitoring was 80, with 40 having had i-SCSs and 40 having had no i-SCSs captured (50%; Fig. 1). IEEG recordings identified 35 cases of SCSs that were not captured by VEEG, 18 of which (51.43%) were TLE patients. The median duration of IEEG monitoring was 8 (interquartile range 6.25–12) days. There were 166 patients (58.04%) who had pharmacoresistant epilepsy. The median age of seizure onset was 12 (interquartile range 6–22) years and the median epilepsy duration was 72 (interquartile range 18–168) months. There were 171 patients with TLE and 115 with ETLE (73 frontal, 16 parietal, 7 occipital, 2 insular, 3 hypothalamus, and 14 multilobe). The pathological types were classified as hippocampal sclerosis (n = 59), focal cortical dysplasia (n = 77), tumor (n = 86), hemangioma/vascular malformation (n = 31), arachnoid cyst (n = 3), dermoid cyst (n = 1), colloid cyst (n = 1), and nonspecific pathology (n = 25) (Table 1).

There were 24 patients (85.71%) who had SCSs recorded in the first 2 days among 28 patients with s-SCSs, and 32 (80%) patients who had SCSs recorded in the first 2 days among 40 patients with i-SCSs, proving that SCSs can generally be detected in the first 2 days through VEEG/IEEG recordings. We also compared the success rates in recording SCSs by the two different methods over the same time period (Table 2), and found that the detection rate of s-SCSs was always lower than that of i-SCSs. We further calculated the prevalence of SCSs at different monitoring times in all patients and found that the rate of patients with SCSs did not increase significantly with the extension of VEEG/IEEG recording time during the presurgical evaluation (Supplementary Fig. 1).

In the 28 patients with s-SCSs, five patients had no s-CSs. Among these five patients, s-SCSs helped to localize the epileptogenic foci to some extent. The localization of s-SCSs in the first two patients was consistent with imaging findings and symptomatology, and they became seizure-free after direct resection up through the last follow-up. The postoperative pathology of these two patients found a dysembryoplastic neuroepithelial tumor in the left parieto-occipital lobe and cavernous hemangioma in the left frontal lobe, respectively. In the third case, the localization of s-SCSs and interictal epileptic discharges suggested that the epileptogenic zone might be in the right frontal lobe, and MRI suggested focal cortical dysplasia in the right frontal lobe. This patient underwent direct resection but had seizure recurrence (Engel class II) in the first year after surgery when reducing the dose of antiepileptic drugs. The MRI imaging of the fourth patient suggested a tumor in the left parietal lobe, but the localization of s-SCSs was in the left temporal lobe. Considering that patient symptoms were consistent with MRI findings, this patient underwent direct resection and only had a few auras through 3-year follow-up. The remaining patient had deep electrodes implanted due to the negative MRI imaging, and the localization of s-SCSs was fully consistent with the resection. The postoperative pathology was focal cortical dysplasia type IIB in the right frontal lobe, and this patient was seizure-free through 2-year follow-up.

The remaining 23 patients had both s-SCSs and s-CSs. S-SCSs in three patients provided a localization value during the diagnosis process, while s-CSs did not. S-CSs in the other three patients showed localization value while s-SCSs did not. Finally, of the last 17 patients with both s-SCSs and s-CSs, 12 patients (70.59%) had identical localization between two ictal events (Table 3).

In the 40 patients with i-SCSs, one patient did not have i-CSs recorded. The seizure onset zone of i-SCSs in this patient suggested the left posterior central gyrus, consistent with imaging findings and patient symptoms. This patient was seizure-free within 2-year follow-up after resection with the pathology of focal cortical dysplasia type IIB. In the remaining 39 patients, the seizure onset zone of i-SCSs was totally consistent with the i-CSs in 21 patients (53.85%) (Table 3). These above cases suggest that the seizure onset zone of SCSs can provide useful localization information, especially when CSs are not captured.

Univariate analysis in patients who underwent VEEG monitoring found younger seizure onset (P = 0.001), children (P = 0.030), pharmacoresistant epilepsy (P = 0.056) and daily seizure (P = 0.032) were more common in patients with s-SCSs (Table 1). Logistic regression analysis found that seizure onset age (P = 0.004, OR 0.931, 95% CI 0.886–0.978) was significantly associated with the presence of s-SCSs (Table 4).

We further compared the clinical characteristics between the two groups based on IEEG monitoring. Univariate analysis revealed that reducing the dose of AEDs during IEEG recordings (P = 0.091), left lesion (P = 0.072), temporal lobe epilepsy (P = 0.012) and hippocampal sclerosis (P = 0.077) were associated with i-SCSs (Table 5). Logistic regression analysis showed that temporal lobe epilepsy (P = 0.015, OR 3.324, 95% CI 1.264–8.740) was significantly associated with the presence of i-SCSs (Table 6; Fig. 2). And among the 21 patients with temporal epilepsy in the i-SCS group, 17 (80.95%) had mesial temporal lobe epilepsy.

We further analyzed the relationship between lesion locations in MRI and SCSs in both the VEEG group (Supplementary Table 1) and the IEEG group (Supplementary Table 2), and found there was no difference in the VEEG group, while the IEEG group showed an MRI-positive lesion in the temporal lobe was associated with i-SCSs (P = 0.015), which was similar to the results from Table 5. In the VEEG group, there were some patients that had no PET data from their pre-surgical assessment, especially in patients with positive MRI. Therefore, we provided PET (positron emission tomography) data of the IEEG group and further analyzed the correlation between abnormalities from the PET scan and occurrence of SCSs in the IEEG group (Supplementary table 3), but no difference was found.

In the VEEG group, 208 of 286 (72.73%) patients remained seizure-free until the last follow-up. The median follow-up was 32 (interquartile range 18–52.25) months. The presence of s-SCSs did not affect seizure outcome. Univariate analysis found that longer duration (P = 0.040), history of focal to bilateral tonic–clonic seizure (P = 0.009), nonspecific pathology (P = 0.049), and incomplete resection (P = 0.012) through the last follow-up were associated with seizure recurrence (Table 7). Cox regression analysis also revealed that longer duration (P = 0.003, OR 1.003, 95% CI 1.001–1.005), history of focal to bilateral tonic–clonic seizure (P = 0.027, OR 1.665, 95% CI 1.060–2.613), nonspecific pathology (P = 0.018, OR 2.184, 95% CI 1.145–4.163), and incomplete resection (P = 0.004, OR 2.705, 95% CI 1.372–5.332) were statistically significant negative predictive factors for surgery outcomes through the last follow-up (Table 8).

In the IEEG group, 56 of 80 (70%) patients remained seizure-free through the last follow-up. The median follow-up was 23 (interquartile range 13–43.5) months. Univariate analysis found patients with i-SCSs (P = 0.015) and female patients (P = 0.062) had better seizure outcome through the last follow-up (Table 9). Cox regression analysis revealed i-SCSs was significantly associated with seizure outcome (P = 0.028, OR 0.371, 95% CI 0.153–0.898; Table 10).

Kaplan–Meier survival curves were used to illustrate postsurgical seizure freedom over time, across the study population (Fig. 3). Although patients in the IEEG group showed a lower rate of seizure freedom than the VEEG group, the difference was not statistically significant (Fig. 3a). By ROC analysis, we found that the epilepsy duration cutoff was 162 months; patients with longer seizure durations (especially > 162 months) were significantly more likely to have seizure recurrence (Fig. 3b). Regarding patients characterized as with/without a history of focal to bilateral tonic–clonic seizure (Fig. 3c), nonspecific pathology (Fig. 3d) and incomplete resection (Fig. 3e), the probability of seizure freedom showed distinct differences between groups. In the IEEG group, the non-i-SCSs group showed a sharp decrease in the probability of seizure freedom compared to the i-SCSs group (Fig. 3f).