A comparison of comorbid headache between patients with temporal lobe epilepsy and juvenile myoclonic epilepsy

Headache is one of the most common symptoms of epilepsy comorbidities. However, the relationship between the epilepsy and headache still needs clarification. Previous studies mostly investigated the overall incidence and clinical features of the headache in patients with the epilepsy. Temporal lobe epilepsy (TLE) and juvenile myoclonic epilepsy (JME) are the common types of focal epilepsy and generalized epilepsy, respectively. Nevertheless, there was no study comparing the clinical features of headache between TLE and JME. This study aimed to analyze the headache features of these two types of epilepsy. Patients with either TLE or JME diagnosed with headache and referred to the West China Hospital of Sichuan University were consecutively recruited from June 2021 to June 2022. The duration of epilepsy was longer than 6 months in these patients. Data on headache and epilepsy were obtained through face-to-face questionnaires. The headache was classified according to the International Classification Headache Disorders-3rd edition (ICHD-III) criteria. χ2-test, t-test, rank-sum test, logistic regression modeling and Mann Whitney test were used to compare the clinical differences of the headache in TLE and JME. A total of 151 TLE patients and 30 JME patients were enrolled in this study. There was no significant difference in the family history of headache, epilepsy durations, headache types, proportion receiving analgesic therapy, the frequency of inter-ictal headache (inter-IH), and the quality of life in epilepsy -10 inventory (QOLIE-10) between the TLE and JME patients. Patients in the TLE group were significantly older (p = 0.004), and a lower percentage of them had a family history of epilepsy (p = 0.007) compared with the JME patients. The proportion of cases with refractory epilepsy was higher in the TLE group than that in the JME group (p < 0.001). The types of seizures in the TLE group varied from those in the JME group (p < 0.001). The composition of the antiseizure medications (ASM) applied in the TLE group differed from that in the JME group (p = 0.047), and the usage of oxcarbazepine was more frequently in the TLE group than in the JME group (p = 0.003). There was no difference in the headache types among patients with TLE or JME. Specifically, 67 (44.37%), 12 (7.95%), and 118 (7.95%) patients were found with inter-IH, pre-ictal headache (Pre-IH) and post-ictal headache (Post-IH) in the TLE group; while 8 (26.67%), 4 (13.33%) and 26 (86.67%) patients had inter-IH, Pre-IH and Post-IH in the JME group. Thirty-nine patients in the TLE group and 4 patients in the JME group were identified with more than one type of headaches, respectively. Tension-type headache (TTH) were found in 38 patients (25.17%) in the TLE group and 3 patients (10.00%) in the JME group, respectively; migraines were found in 10 patients (6.62%) in the TLE group and in 2 patients (6.67%) in the JME group. Patients in the TLE group had a higher headache-attributed lost time-90 days (HLT-90) score than those in the JME group (p = 0.019). The proportion of patients with inter-IH accompanied by nausea in the TLE group was higher than that in the JME group (p = 0.029), while the proportion of patients with frontal headache was lower than that in the JME group (p < 0.05). There was no significant difference in headache severity, quality, headache nature, unilateral/bilateral, and headache duration either in inter-IH or peri-ictal headache (Peri-IH) between the two groups. The logistic regression analysis suggested that except for HLT-90 (AUC = 0.622, p = 0.027), other factors were not found to be correlated with refractory epilepsy. The clinical features of headache differed between TLE and JME patients. TLE patients had a higher ratio of refractory epilepsy, more headache time loss compared with JME patients. HLT-90 was associated with the occurrence of refractory epilepsy in TLE patients. Taken together, we suggested that the comorbid headache may essentially be different between TLE and JME patients.


Study design and participants
This is a cross-sectional study enrolling both in-patients and out-patients at the Epilepsy Center of West China Hospital of Sichuan University from June 2021 to June 2022.The inclusion criteria include an age ≥ 18 years and the presence of headache symptoms in TLE and JME patients.The duration of epilepsy was longer than 6 months in these patients.Interrogation interviews were conducted to determine whether the patient had headaches during the course of epilepsy.Once the patient had confirmed the occurrence of headache, a face-toface questionnaire survey would be performed for characterizing the headache types, in other words, whether it was an inter-IH or peri-IH.Two neurologists were responsible for classifying the clinical characteristics of

Statistical analysis
Clinical variables in the TLE group and JME group were analyzed.We performed χ2 -test to compare the categorical variables.T-test and Mann Whitney U test were performed to evaluate the continuous variables with a symmetrical or asymmetrical distribution, respectively.A logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (CI) to assess the association between dependent and independent variables.Statistical significance was set at p value < 0.05.Statistical analyses in this study were performed with SPSS25.0.

Ethics approval and consent to participate
The Ethics Committee of West China Hospital of Sichuan University reviewed and approved the study.Informed consent was obtained for all participants.

Results
A total of 151 TLE cases and 30 JME cases were enrolled.The main clinical features of the patients are listed in Table 1, and the clinical features of epilepsy-related headaches are displayed in Table 2.There were 88 females in the TLE group and 18 females in the JME group.The mean age of the TLE patients and the IME patients at the interview was 30.65 ± 9.70 years and 24.57± 3.46 years, respectively.In this study, TLE patients were significantly older than JME patients (p = 0.004).The mean age at epilepsy onset in the TLE and JME patients was 18.15 ± 11.00 years and 14.62 ± 5.80 years, respectively.The patients' mean epilepsy duration in TLE group was 12.44 ± 9.61 years; the patients' mean epilepsy duration in JME group was 9.97 ± 5.71 years.Patients in the JME group more frequently had a family history of epilepsy than patients in the TLE group (p = 0.007), and the incidence of intractable epilepsy in the TLE group was higher than that in the JME group (p < 0.001).The types of seizures differed in the two groups (p < 0.001).Specifically, 21 patients (13.91%) developed complex partial seizure (CPS), 33 patients (21.85%) developed GTCS, and 97 patients (64.24%) developed both CPS and GTCS in the TLE group; while in the JME group, 20 patients (66.67%) developed GTCS, 1 patient (3.33%) developed absence, and 9 patients (30.00%) developed absence + GTCS.Twenty-two patients (14.57%) had seizures yearly or in a less frequency, 84 patients (55.63%) had monthly seizures, 29 patients (19.21%) had weekly seizures, and 16 patients (10.60%) had daily seizures in the TLE group.Twelve patients (40.00%) had seizures yearly or in a less frequency, 17 patients (56.67%) had monthly seizures, and 1 patient (3.33%) had monthly seizures in the JME group.In the TLE group, 37 patients (24.50%) were treated with antiseizure medications (ASM) monotherapy, 100 patients (66.23%) received polytherapy (≥ 2 ASM), and 14 patients (9.27%) had not received any treatment (Fig. 2); whereas in the JME group, 9 patients (30.00%) received ASM monotherapy, 20 patients (66.67%) received polytherapy, and only 1 patient (3.33%) had no therapy.In terms of ASM use, the proportion of the oxcarbazepine usage in the TLE group was higher than that in the JME group (p = 0.010), and the levetiracetam usage in the TLE group was lower than that in the JME group (p = 0.041).
We also compared the types of headaches observed in the two groups in our study.Overall, 67 patients (44.37%) had inter-IH, 12 patients (7.95%) had pre-IH, and 118 patients (78.15%) had post-IH in the TLE group; eight patients (26.67%) had inter-IH, 4 patients (13.33%) had pre-IH, and 26 patients (86.67%) had post-IH in the JME group.Of note, 39 and 4 patients were observed with more than one type of headaches in the TLE and JME groups, respectively (Fig. 3).There was no significant difference in terms of family history of headache, headache types, the proportion receiving analgesic therapy, frequency of inter-IH, and QOLIE-10 between TLE and JME patients (Table 1; Fig. 4).TTH were found in 38 (25.17%)TLE patients and 3 (10.00%)JME patients; migraines were found in 10 (6.62%) TLE patients and in 2 (6.67%)JME patients.TLE patients had a higher HLT-90 than JME patients in this study (p = 0.019).In the TLE group, the etiology was infection in 23 patients, and unknown in the remaining patients.The proportion of patients with inter-IH accompanied by nausea in the TLE group was higher than that in the JME group (p = 0.029), and the proportion of patients with headache located in the frontal was lower than that in the JME group (p < 0.05).The other headache features had no statistical ▲ We conducted ANOVA on the types of seizures, types of drugs taken and the frequency of GTCS episodes, the specific p-values were 0.662, 0.183, 0.312 respectively.※ Some of the patients had headaches located in more than one site.$ p < 0.05.⁜ Frequency was classified as: always, occurring after every seizure; often, occurring after more than two-thirds of seizures; sometimes, occurring after less than half of seizures; and rarely, occurring for only a few times.difference between the two groups (Table 2).To analyze the predictive value of the headache characteristics on the occurrence of refractory epilepsy, we performed logistic regression analysis.The results suggested that except for the HLT-90 (AUC = 0.622, p = 0.027), other factors were not found to be correlated with the occurrence of refractory epilepsy (Fig. 5).

Discussion
Headache is one of the most common comorbidities of epilepsy.However, limited studies have reported the incidence of headache in different types of seizures.As a result, we focused on the comparison of the clinical features of headache among TLE and JME patients in this study.TLE is reported to have a higher ratio of refractory epilepsy, and according to the previous literature, intractable epilepsy patients tend to develop more severe headache compared to patients with other types of epilepsies 22 .JME patients are usually therapeutically sensitive to appropriate ASM regimens, and JME and migraine both have genetic susceptibility.Given this, we compared comorbid headache in these two types of epilepsy and further explored the relationship between the clinical features of headache and epilepsy subtypes.Our results demonstrated that the clinical manifestations of headache differed between TLE and JME patients, suggesting that different mechanisms may underline the occurrence of comorbid depending on different types of epilepsy.
Our study showed no significant difference in family history of headache, duration of epilepsy, headache types, proportion receiving analgesic therapy, frequency of inter-IH, and quality of life in QOLIE-10 between TLE and JME patients.However, TLE patients presented an older age, a lower rate of family history of epilepsy, a higher proportion of refractory epilepsy than JME patients.Besides, they had different seizure types and ASM, all due  to differences in the epilepsy subtypes.It's well known that TLE is one of the common types of focal epilepsy and presented with a higher ratio of refractory epilepsy.TLE is usually characterized by recurrent complex partial seizures (with loss of consciousness), and some patients may also have secondary GTCS 23,24 .JME is a type of idiopathic generalized epilepsies characterized by paroxysmal activity of polyspike and slow wave, or spike and wave complexes in EEG and most JME patients respond well to the treatment of an appropriate ASM regimen [25][26][27] .Some JME patients have a genetic predisposition 28 .
Among all comorbid headaches, migraine has been well characterized.Studies have shown that epilepsy and migraine may share some common pathophysiological processes.Cortical spreading depression (CSD) is considered to be a possible shared pathophysiological mechanism for epilepsy and migraine.Epileptic discharges with or without additional cortical epileptic signs or symptoms might stimulate the onset of CSD, resulting in activation of the trigeminovascular system and headache 29 .In addition, some ASM such as sodium valproate and topiramate anticonvulsants are effective for migraine, suggesting that there is indeed a correlation between the two disorders.In addition to the two drugs mentioned above, ASM with analgesic properties, such as gabapentin may effects the characteristics of the headache.In our study, the proportion of the two groups of patients using  www.nature.com/scientificreports/ the above drugs no difference, so the difference of two groups of patients with headache characteristics could be due to the disease itself.It was worth noting that the proportion of migraine was lower in the TLE group, and this result was inconsistence with the report that the prevalence of migraine ranged from 9 to 30% [29][30][31][32][33] .It should be noted that the proportion of migraine in our study was obtained in the TLE patients who had headaches, so the real prevalence of migraine should be lower in unselected TLE patients.Of all the migraine patients, only three patients in the TLE group were found with aura.The possible reasons for this are follows: (1) the prevalence of migraine may be different in different epileptic subtypes, as Ito et al. reported that headache characteristics and migraine prevalence were different between TLE and occipital lobe epilepsy 34 .The reason behind the different prevalence of migraine between TLE and JME may involve differences in genetic background, as Schankin et al. inferred that JME patients have strong genetic background, JME appears to be an attractive homogenous subtype of epilepsy for genetic research on migraine.(2) The region of epileptic focus or spreading area of epileptic discharge may have a close relation to the induction of headache 35 .TLE discharges originate in the temporal lobe and may subsequently generalize to the whole brain, and JME is a type of idiopathic generalized epilepsies, the stimulation of the cerebral cortex of seizures may not as strong as in patients with JME, which may account for the lower prevalence of migraine in TLE.Meanwhile, the medial temporal lobe is associated with symptoms such as nausea and vomiting, which may also be the reason why TLE patients have more headaches with emesis symptoms.
The proportion of patients with inter-IH accompanied by nausea was higher and the proportion of patients with headache located in the frontal was lower in the TLE group than in the JME group.The reasons for the difference are not clear.Perhaps it is partly due to that different types of epilepsies had different epileptic foci and abnormal discharge.Our study also showed that patients in the TLE group had a higher HLT-90 than those in the JME group.Since no difference in the frequency of Inter-IH between TLE and JME patients was observed.
Post-IH is the most common comorbid headache of epilepsy.Some hypotheses hold that an increase in blood flow after a seizure or vascular changes triggered by neuronal discharges involving the hypothalamic and brain stem areas may have a role in the induction of Post-IH.A previous study indicated that GTCS and CPS may contribute to the incidence of Post-IH in TLE patients 34 .In our study, patients in the TLE group had more frequent CPS and/or GTCS, while the absence with GTCS episodes was more common in the JME group.Inconsistent with previous reports, the proportion of Post-IH and the characteristics of Post-IH between the two groups had no difference.
We also analyzed the predictive value of the headache characteristics on the occurrence of refractory epilepsy.The results suggested that except for the HLT-90, other factors were not found to be correlated with the occurrence of refractory epilepsy.Further prospective multi-center studies involving larger sample sizes should be conducted to powerfully answer this question.
No ictal headache was observed in our study.Due to the retrospective nature of this study and that most of the patients did not have EEG data at the time of getting headache attack, it was hard to confirm that the patients' headache was ictal headache, which is easy to classify this headache type as Inter-IH.So we may have missed such a difficult diagnosis in our study.
On the basis of our observation that the clinical features of headache differed between TLE and JME patients, we speculated that the nature of headache among epilepsy subtypes may probably not be simple but multifactorial.
Our study has some limitations.Firstly, the limited number of cases in the JME group and the retrospective nature of this study could lead to recall bias.In addition, the patients enrolled in this study were from one of the largest epilepsy centers in China, which had a high proportion of patients with refractory epilepsy, and this could have resulted in the selection bias of patients who received the interview.

Conclusion
The clinical characteristics of comorbid headache varied in TLE and JME patients.There was no difference in the composition of headache types between TLE and JME patients.TLE patients had a higher ratio of refractory epilepsy, more headache time loss compared with JME patients.HLT-90 was associated with the occurrence of refractory epilepsy in TLE patients.Taken together, we suggested that the comorbid headache may essentially be different between TLE and JME patients.

Figure 2 .
Figure 2. Details of the use of ASM in the TLE and JME groups.Chi-square test or Fisher exact test was used for statistical analysis.ASM antiseizure medications, TLE temporal lobe epilepsy, JME juvenile myoclonic epilepsy.

Figure 3 .
Figure 3. Venn diagram of headache types in the TLE and JME groups.TLE temporal lobe epilepsy, JME juvenile myoclonic epilepsy.

Figure 4 .
Figure 4. Details of inter-IH frequency in TLE and JME patients.Fisher exact test was used for statistical analysis.Inter-IH inter-ictal headache, TLE temporal lobe epilepsy, JME juvenile myoclonic epilepsy.

Figure 5 .
Figure 5. ROC curves of the predictive value of different clinical features of headache on intractable epilepsy in TLE group.For patients presented with more than one type of headache, the most severe type was recorded.AUC area under the curve, ROC receiver operating characteristic.

Table 1 .
Clinical features of TLE and JME patients.Figures are given as N (%), unless otherwise stated.The numbers in bold indicate statistical significance between two groups.TLE temporal lobe epilepsy, JME juvenile myoclonic epilepsy, SD standard deviation, CPS complex partial seizure, GTCS generalized tonic clonic seizure, ASM antiseizure medications, QOLIE-10 quality of life in epilepsy-10 inventory; Inter-IH, inter-ictal headache, Pre-IH pre-ictal headache, Post-IH post-ictal headache, TTH tensiontype headache, HLT-90 headacheattributed lost time-90 days.# T-test and Mann Whitney U test were performed to evaluate continuous variables with a symmetrical or asymmetrical distribution respectively.@ Fisher-Freeman-Halton extension of the Fisher exact test was used for count data.$ p < 0.05.*Only three patients with migraine in the TLE group had aura.

Table 2 .
Clinical We conducted a two-way analysis of variance (ANOVA) on the types of seizures, types of drugs taken and the frequency of GTCS episodes, the specific p-values were 0.542, 0.330, 0.464 respectively.***We conducted ANOVA on the types of seizures, types of drugs taken and the frequency of GTCS episodes, the specific p-values were 0.367, 0.269, 0.462 respectively.
features of epilepsy-related headaches.Figures are given as N (%), unless otherwise stated.The numbers in bold indicate statistical significance between two groups.Inter-IH inter-ictal headache, Pre-IH pre-ictal headache, Post-IH post-ictal headache, TLE temporal lobe epilepsy, JME juvenile myoclonic epilepsy.# T-test and Mann Whitney U test were performed to evaluate continuous variables with a symmetrical or asymmetrical distribution respectively.@ Fisher-Freeman-Halton extension of the Fisher exact test was used for count data.*Headache severity was measured by visual analog scale (VAS).&