Factors affecting interictal unilateral and bilateral discharges and ictal diffusion patterns of scalp electroencephalogram in temporal lobe epilepsy

The interictal discharges of temporal lobe epilepsy (TLE) can be unilateral or bilateral. In addition, the ictal electroencephalogram (EEG) showed the discharges also tend to spread to the contralateral brain in TLE. The factors influencing unilateral and bilateral interictal discharges in TLE as well as ictal diffusion patterns in scalp EEG during onset of seizure were evaluated in the present study. This was a retrospective analysis of 129 patients with TLE. Cases were classified into unilateral and bilateral discharge groups based on interictal discharge patterns in the EEG. Differences between the two groups in age, gender, disease duration, seizure frequency, magnetic resonance imaging (MRI) findings, origin of TLE, antiepileptic drug (AED) administration, and ictal diffusion patterns during seizures were statistically analyzed. In addition, the differences in ictal diffusion patterns between left and right TLE were statistically analyzed. Statistically significant differences were not observed in gender, disease duration, seizure frequency, MRI findings, administration of AEDs, and ictal diffusion patterns between interictal unilateral and bilateral discharge groups but with statistically significant differences in age and side of origin of the TLE. In addition, whether the EEG-recorded diffusion pattern was confined to the same hemisphere or spread to both hemispheres was investigated and shown statistically significant differences between the left and right temporal lobes. Age and side of origin of TLE affects the TLE interictal discharge patterns. Older patients are more prone to bilateral discharges. Bilateral discharges are more common in right TLE, and the onset of EEG more likely to bilateral diffusion in right TLE.


Introduction
Epilepsy is a common neurological disease, and temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy (DRE) [1], accounting for approximately 70% of epilepsy cases [2]. Electroencephalogram (EEG) is an important examination method for epilepsy diagnosis and treatment planning [3]. In epilepsy surgery, the determination and localization of epileptic foci are the core issues in the operative planning, and EEG examination is an important basis for planning surgical resection. The location and diffusion degree of interictal discharges, such as unilateral or bilateral interictal discharges, are important for the determination and localization of epileptic foci as well as the prognosis of surgery. In addition, the ictal EEG is used to locate the origin of the seizure. In our previous study [4], preoperative bilateral interictal discharges were shown to indicate poor prognosis of epilepsy surgery. Therefore, predicting the prognosis of the operation based on the diffusion degree of interictal EEG to reduce the risk and possible complications of the surgery is important. Surgery is an effective method to treat TLE [5], and EEG is important for preoperative assessment of this disorder. However, TLE is often associated with neuropsychological impairment [6], which may be associated with the affected diffusion degree of interictal EEG in TLE [7]. Unilateral or bilateral (synchronous or asynchronous) discharge patterns in interictal EEG in TLE are quite common in clinical practice. Furthermore, the diffusion degree of EEG in the ictal phase is often significantly larger than in the interictal phase. Therefore, evaluating the degree of neurological impairment and predicting the prognosis of surgery using interictal and ictal discharge patterns of TLE are important. However, the factors associated with the different discharge patterns of TLE have not been established. Questions such as whether the duration of the disease and frequency of seizures lead to an increase in the discharge degree of diffusion, whether the pattern of ictal diffusion during a seizure is associated with the pattern of interictal discharges, and whether ictal diffusion patterns are different between the left and right temporal lobes during seizures remain unanswered.
Therefore, in the present retrospective study, interictal and ictal EEG data of 129 patients with TLE were analyzed. The differences in age, gender, disease duration, seizure frequency, magnetic resonance imaging (MRI) findings, side of origin of TLE, antiepileptic drug (AED) administration, and ictal diffusion patterns between unilateral and bilateral discharge groups were statistically evaluated. In addition, the differences in ictal diffusion patterns between left and right TLE were analyzed.

Clinical case collection
A total of 129 cases of TLE were retrieved from Shengjing Hospital of China Medical University, Functional Neurosurgery Unit. A diagnosis of TLE was made based on EEG results, symptomology during the epileptic episode, and imaging examinations such as MRI and positron emission tomography (PET). The case selection criteria had to meet one of the following: (1) when MRI was negative, PET examination indicated hypometabolism mainly in the temporal area; simultaneously, interictal EEG was focused on the temporal area, and ictal symptoms indicated focal seizures; (2) when MRI was positive, the lesion was located in the temporal area, and the ictal symptoms were focal seizures. Data regarding age, gender, disease duration, seizure frequency, types of AEDs, interictal and ictal EEG, and MRI findings were collected. The study was approved by the Ethics Committee of China Medical University to which Shengjing Hospital is affiliated, and patients provided written, informed consent for the use of their data.

Classification of interictal discharge patterns
Scalp EEG (Nicolet, USA) with a 10-20 system including 22 record sites was used for monitoring, and the average reference electrode (AV) was used for recording. At least 24 h of recorded interictal EEG was required and had to include both waking and sleeping periods. The interictal discharge types were classified into the following four categories: (I) unilateral temporal discharges with or without frontal area discharges (Fig. 1a); (II) unilateral hemispheric discharges which involved at least three brain regions among the temporal, frontal, parietal, and occipital regions (Fig. 1b); (III) bilateral temporal discharges with or without frontal area discharges (Fig. 1c); and (IV) bilateral diffuse discharges. Bilateral synchronous (Fig. 1c) or asynchronous (Fig. 1d) discharge patterns were counted as bilateral discharges; types I and II were classified as unilateral discharge pattern and types III and IV as bilateral discharge pattern.

Classification of ictal diffusion patterns
At least two or more ictal EEGs were analyzed in the same case. The time window for the analysis of EEG was 2 min before the EEG change, during the onset, and 2 min after the seizure. Based on the side of origin, the direction of diffusion, and the extent of the involved brain areas, the ictal EEG patterns were classified into two categories: ictal pattern I, the origin and diffusion of EEG were localized to one hemisphere (Fig. 2a); ictal pattern II, regardless of bilateral or unilateral origin, bilateral hemispheres were involved in the ictal EEG. Furthermore, ictal pattern II included the following three types: II-1, originating in unilateral temporal area with or without frontal areas and spreading to both hemispheres (Fig. 2b); II-2, originating in unilateral temporal area with or without frontal areas, spreading to the ipsilateral hemisphere and eventually to both hemispheres (Fig. 2c); and II-3, originating in both hemispheres with or without unilateral hemispheric dominance in EEG manifestations (Fig. 2d).

Statistical analysis
The t-test was used to analyze statistical differences in age, gender, disease duration, and seizure frequency between the unilateral and bilateral discharge groups. The chi-square test for independence was used to compare differences in AED administration, MRI performance, side of origin of epilepsy, and ictal diffusion patterns between the two groups and left and right TLE. P < 0.05 was considered statistically significant.

Statistical results of factors affecting the interictal discharge patterns
The age in the unilateral discharge group ranged from 2 to 50 years with an average age of 29 years. The age in the bilateral discharge group ranged from 7 to 62 years with an average age of 35 years. The difference in age between the two groups was statistically significant (P = 0.02; Fig. 3a). The disease duration in the unilateral discharge group ranged from 0.1 to 35 years with an average duration of 11.6 years. The disease duration in the bilateral discharge group ranged from 0.1 to 40 years with an average course of 13.5 years. Statistically significant difference was not observed in the disease duration between the two groups (P = 0.25; Fig.  3b). In the unilateral discharge group, the seizure frequency ranged from 0.5 to 45 times/month with an average seizure frequency of 6.8 times/month. In the bilateral discharge group, the seizure frequency ranged from 1 to 30 Fig. 1 Several types of discharge patterns in interictal electroencephalogram (EEG; 10-20 system). a Observable interictal right temporal discharges with frontal area discharges. b Observable interictal discharges in the left hemisphere. c Noticeable interictal bilateral synchronous discharges (bilateral temporal with frontal area discharges). d Noticeable interictal bilateral asynchronous discharges. Each area separated by two gray vertical lines in the figure was 1 s, and the total duration for each EEG sample was 12 s. M electrode was a recording electrode located at the lower edge of the midpoint of the zygomatic arch: M1, left; M2, right times/month with an average seizure frequency of 6.5 times/month. Significant difference was not observed in the seizure frequency between the two groups (P = 0.84; Fig. 3c).
In the unilateral discharge group, 21 (28.4%) cases had no clear MRI abnormalities (negative), and 53 (71.6%) cases had clear abnormalities (positive). In the bilateral discharge group, 23 (41.8%) cases had no clear MRI abnormalities (negative), and 32 (58.2%) cases had clear abnormalities (positive). The difference in proportion of MRI with or without abnormalities between the two groups was not statistically significant (P = 0.11; Fig. 3d). The positive MRI findings included hippocampal sclerosis, unilateral hippocampal swelling, temporal lobe tumors, vascular malformation, encephalomalacia, and focal cortex dysplasia (FCD). In most cases of hippocampal sclerosis, unilateral hippocampal swelling, temporal lobe tumors, and vascular malformations, the interictal EEG discharges were mainly located in the ipsilateral temporal area of the lesion (  Fig. 2 Ictal diffusion patterns of electroencephalogram (EEG). a The EEG originates in the left F3 lead and spreads to other leads in the ipsilateral hemisphere. b The EEG originates in the right F8 and M2 leads and then spreads to bilateral hemispheres. c The EEG originates in the left T3 and T5 leads and spreads to ipsilateral M1 lead and then spreads to bilateral hemispheres. d The EEG originates in bilateral hemispheres with left M1 and T5 leads dominance. Each area separated by two gray vertical lines in the figure was 1 s, and the total duration for each EEG sample was about 36 s. M electrode was a recording electrode located at the lower edge of the midpoint of the zygomatic arch: M1, left; M2, right TLE in the bilateral discharge group ( Table 3). The difference in proportion of side of origin between the two groups was statistically significant (P = 0.02; Fig. 3e). There were 43 (58.1%) males and 31 (41.9%) females in the unilateral discharge group and 23 (41.8%) males and 32 (58.2%) females in the bilateral discharge group; however, the difference in gender ratio between the two groups was not statistically significant (P = 0.07; Fig. 3f).
In the unilateral discharge group, there were 10 (13.5%) cases with no AED administration, 39 (52.7%) cases with single AED administration, and 25 (33.8%) cases with administration of multi-AEDs (two or more drugs). In the bilateral discharge group, there were 6 (10.9%) cases with no AED administration, 22 (40.0%) cases with single AED administration, and 27 (49.1%) cases with multi-AED administration. The patients not administered AEDs were main subjects  Effects of age, disease duration, seizure frequency, magnetic resonance imaging (MRI) findings, side of epilepsy, and gender on interictal discharge patterns in temporal lobe epilepsy (TLE). a Statistically significant difference was observed in age between the unilateral and bilateral discharge groups; b statistically significant difference in the duration of disease was not observed between the two groups; c statistically significant difference in seizure frequency was observed between the two groups; d statistically significant difference in the proportion of MRI findings was not observed between the two groups; e statistically significant difference was observed between the two groups in the proportion of right and left TLE; f statistically significant difference was not observed in the gender ratio between the two groups. n.s., not significant; *, P < 0.05 who had seizures of short duration, low frequency, or undetectable ictal symptoms (such as loss of contact or automatism). With or without AED, the interictal discharge pattern in about 50% of cases was unilateral temporal discharges with or without frontal area discharges. When the number of AEDs increased, the proportion of interictal discharge patterns in bilateral temporal areas with or without frontal areas increased, indicating an obvious drug resistance in these TLE cases. The data showed that older patients with TLE were more likely to have bilateral discharges as evidenced on the interictal EEG. Furthermore, right TLE was more likely to be bilateral based on the interictal EEG.

Statistical results of ictal diffusion patterns
The side of seizure origin and diffusion direction on ictal EEG in the 129 cases were analyzed and classified into four diffusion patterns: ictal EEG localized to one hemisphere (10.24%); unilateral temporal discharges with or without frontal areas spreading to both hemispheres (54.33%); unilateral temporal discharges with or without frontal areas spreading from ipsilateral hemisphere to both hemispheres (8.66%); and discharges in both hemispheres with or without unilateral hemispheric dominance in EEG manifestations (26.77%). The cases with interictal unilateral or bilateral temporal discharges with or without frontal area discharges showed all four ictal diffusion patterns described above; however, the cases with interictal unilateral hemispheric discharges or bilateral diffuse discharges showed three and two patterns, respectively (Fig. 4a). In TLE, the side of origin could be located using scalp EEG most of the time, and the spread of ictal discharges in the EEG in the majority of cases had a wide diffusion pattern, with most having bilateral hemispheric involvement.
When analyzing the diffusion patterns of ictal EEG based on MRI findings, most cases of hippocampal sclerosis and unilateral hippocampal swelling mainly originated from unilateral temporal discharges with or without frontal areas and  spread to both hemispheres. In addition, the ictal EEG was localized to one hemisphere in 25% of tumor cases (Table 2). When analyzing the diffusion patterns based on the side of TLE, the ictal diffusion patterns in right or left TLE included all four ictal diffusion patterns mentioned above (Table 3). In statistical analysis, significant difference was not observed between the unilateral discharge group and the bilateral discharge group in the ratio of ictal EEG limited to the ipsilateral hemisphere to ictal EEG where the seizure had spread to both hemispheres (P = 0.12; Fig. 4b); however, statistically significant difference was observed in the ratio between right and left TLE (P = 0.02; Fig. 4c). The results indicated that right TLE was more likely to spread to both hemispheres during seizures.
Whether the administration of AEDs had an effect on the diffusion of ictal EEG was investigated. In all patients not administered AEDs, the ictal EEGs showed discharges spreading to both hemispheres. In approximately 10% of patients taking AEDs, the ictal EEGs that showed discharges were localized to one hemisphere. Therefore, the administration of AEDs may inhibit, to some extent, the widespread diffusion observed on ictal EEG.   Fig. 4 Patterns and differences in ictal diffusion in temporal lobe epilepsy (TLE). a The relationship between interictal and ictal electroencephalogram (EEG) patterns (I, unilateral temporal discharges with or without frontal area discharges; II, unilateral hemispheric discharges; III, bilateral temporal discharges with or without frontal area discharges; IV, bilateral diffuse discharges); b Statistically significant difference was not observed in the proportion of ictal EEG diffusion patterns confined to one hemisphere or diffused to both hemispheres between the unilateral and bilateral discharge groups; c statistically significant difference was observed in the proportion of ictal EEG diffusion patterns confined to one hemisphere or diffused to both hemispheres between the right and left TLE groups. n.s., not significant; *, P < 0.05

Discussion
The interictal discharge neural network of TLE may be relatively stable In the present study, the average age in the unilateral discharge group was older than in the bilateral discharge group; however, significant difference was not observed in the length of disease duration between the two groups; the average age of disease onset in the unilateral discharge group was older than in the bilateral discharge group. To the best of our knowledge, research on the relationship between age of onset and interictal discharge patterns of TLE has not been investigated to date. Our results showed that older patients were more prone to bilateral discharges, which may be due to the association between plasticity phenomena of the nervous system and age, causing the neural network more susceptible to generalization. In this retrospective study, the interictal discharge patterns of TLE were not affected by the patient's gender, disease duration, seizure frequency, MRI findings, and administration of AEDs. The results showed no correlation between duration of TLE and interictal unilateral or bilateral discharge patterns, indicating that interictal discharges are not a unilateral to bilateral process. In addition, a clear causal relationship was not observed between the degree of diffusion in the interictal brain area affected and seizure frequency, indicating the interictal discharge distribution in TLE may have its own stable neural network [8,9], and the seizure frequency may be associated with the degree of activation of the interictal discharge stable neural network. Clinically, most patients with TLE exhibit drug resistance or evolve into drug-resistant cases. Numerous theories and hypotheses regarding the causes of drug resistance in TLE have been proposed [10]. In addition, predicting whether TLE patients can become drug resistant due to the effects of initial drug treatment and seizure frequency has been investigated in previous studies [11,12]. Furthermore, the possible mechanism of drug resistance in TLE was investigated in several studies by detecting the levels of several target proteins, genes, and molecules [13][14][15]. In the present study, the average disease duration was 12.4 years, and the average seizure frequency was 6.6 times/month. These two indicators satisfied the diagnostic criteria for intractable TLE. According to our results, the use of AEDs had no significant effect on the interictal or ictal scalp EEG patterns of TLE. That is to say, the AED did not affect the stable neural network of TLE. Refractoriness to AEDs was evidence of drug resistance and indirectly proved the stable characteristics of the TLE neural network [16]. Therefore, we speculate that the interictal discharge patterns of TLE are determined by its interictal neural network [17]. Once formed, this neural network is relatively stable and not affected by the disease duration, seizure frequency, or drug factors.
The difference in the interictal discharge pattern and the ictal distribution between left and right TLE may be based on different neural networks Based on our findings, right TLE accounted for a higher proportion of bilateral discharges. The right TLE patients were more prone to bilateral discharges than the left TLE patients based on interictal EEG. In addition, discharges in right TLE patients tended to spread more to both hemispheres than in left TLE patients based on ictal diffusion patterns on EEG. However, the discharges in left TLE patients were more often limited to the same hemisphere during the seizure based on ictal diffusion patterns on EEG. In a previous study, the pathophysiology of epileptogenesis in left and right medial TLE (mTLE) was shown to possibly differ [18]. In terms of function, the neural function of the left temporal lobe is different from the right temporal lobe. For example, the left temporal lobe is generally closely associated with memory and speech, and the right temporal lobe is often closely associated with emotion, which also indicates the normal functional neural network is different in the two lobes. Therefore, the epileptic neural network may be different in left and right TLE patients, resulting in differences in the interictal discharge patterns, the ictal diffusion patterns, and degree of diffusion in the brain during the seizure. Using imaging studies, some researchers have proven differences in the neural network and functional anatomy between left and right TLE. A study by Sanjari Moghaddam H. et al. [19] showed that left and right mTLE had discrepant alternations in the white matter microstructure, including inferior longitudinal fasciculus, forceps minor, genu of corpus callosum, bilateral corticospinal tracts, and bilateral middle cerebellar peduncles, which indicated that left and right mTLE have different underlying pathologic mechanisms. Fang P. et al. [20] found anatomical connectivity differences between left and right mTLE and that left mTLE could be distinguished from right mTLE [21]. Based on their results, the EEG of right TLE showed the seizure spread more easily to both sides than the left side during both interictal and ictal periods. The medial temporal lobe structures are part of the limbic system. However, the limbic functional connectivity was more reduced in right TLE than left TLE [21]. This may be a possible factor why right TLE has a wider degree of diffusion than left TLE. In the present study, the proportion of bilateral hemispheres involved during the seizure was extremely high in both left and right TLE based on EEG recordings. In previous studies, numerous connections were shown between the two temporal lobes [22], and the occurrence of generalized seizures secondary to TLE correlated with the change of hippocampal-thalamic association [23]. Therefore, the wide diffusion degree of EEG findings during the seizure may be associated with the extensive neural connections between the temporal lobe and other regions of the brain [24].

Conclusion
In the present study, age and side of TLE affected the interictal discharge patterns in TLE patients. The elderly were more prone to bilateral discharges. In addition, bilateral discharges were more common in right TLE with ictal EEG predominantly showing bilateral diffusion. Author contributions All authors were involved in the study design, interpretation of the results, the reviewing and approval of the manuscript, and the decision to submit the article for publication. All authors also confirm accountability for the accuracy and integrity of the work.

Declarations
Ethical approval The study was approved by the Ethics Committee of China Medical University to which Shengjing Hospital is affiliated.
Consent for publication All authors consent to the publication of this manuscript.

Conflict of interest
The authors declare no competing interests.