Introduction

Headache is one of the common comorbid symptoms in patients with epilepsy. The prevalence of headache in unselected epilepsy patients was reported to be 52–66%1,2,3. The relationship between the comorbid headache and different types of epilepsies is still not fully understood4. Previous literature has shown that patients with headache comorbidity have lower quality of life than patients who didn’t. According to the temporal profile of epilepsy, the headache in epilepsy can be divided into inter-ictal headache (inter-IH) and peri-ictal headache (peri-IH). The headache occurred between seizures is known as inter-IH5. Peri-IH, known to be correlated with seizure, includes pre-ictal headache (pre-IH), ictal headache (IH) and post-ictal headache (post-IH). Studies have reported that generalized tonic–clonic seizures (GTCS) appeared to be more frequently accompanied by post-IH than the other types of seizure6,7,8. The diagnosis and treatment of comorbid headache are insufficient among epilepsy patients, especially the post-IH.

Literature has recorded that the inter-IH frequency in patients with epilepsy ranged from 19 to 34.3%, and the incidence of peri-IH ranged from 40 to 60%9,10. Different headache types in epilepsy patients may involve different pathophysiology. Of all types of headaches, migraine is considered most closely related to epilepsy, and there may be some common underlying pathophysiological mechanisms shared by migraine and epilepsy11. It’s noted that they have some common risk factors and triggering factors, and that the therapeutic drugs are similar, such as valproic acid and topiramate. Cortical spreading depression is a relatively well recognized mechanism for the occurrence of epilepsy comorbid migraine12, while post-IH may be related to post-attack cerebral vasodilatation13, and some special epilepsy may also involve genetic background, such as SCN1A, which has been linked to epilepsy and migraine14. The migraine frequency ranged from 8 to 24% in epilepsy patients according to previous studies15,16. Temporal lobe epilepsy (TLE) is one of the common types of focal epilepsy and is also among the most common types of refractory epilepsy. Juvenile myoclonic epilepsy (JME) is a type of idiopathic generalized epilepsies characterized by myoclonic jerks, GTCS, and absence seizures17. TLE and JME are totally different in terms of seizure types, selection of antiepileptic drugs, as well as prognosis. Overall, JME has a better response to antiepileptic drugs than TLE. There are few previous studies on the relationship between epilepsy subtypes and headache, and the relationship between classification of epilepsy and headache is unclear. Whether the comorbid headache in TLE varies from that in JME is still unknown. We here aimed to determine the clinical characteristics of the headache of TLE and JME patients. We also explored the correlation between the clinical factors of headache and the occurrence of refractory epilepsy among TLE patients, in order to discover the possible headache risk factors for refractory epilepsy.

Methods

The study was approved by the institutional review board of West China Hospital of Sichuan University (2022301). All participants provided detailed written information on the study and written informed consent was obtained in accordance with the Declaration of Helsinki.

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-to-face 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 headache according to the ICHD-III diagnostic criteria18, and epileptic seizures is classified according to the 2017 International League Against Epilepsy (ILAE) Commission report19. Patients with a duration of epilepsy less than 6 months, a single seizure, or a severe intellectual disability, and those who cannot cooperated with the questionnaire were excluded.

Data collection

Patient data were obtained by field investigation; demographic data were collected for all patients. The information collected on epilepsy includes the age at the onset of epilepsy, disease duration, seizure types, the frequency of seizures, the family history of epilepsy, whether there existed head traumas or febrile convulsions, the current antiepileptic medications, and the quality of life in epilepsy -10 inventory (QOLIE-10). The characteristics of headache include family history of headache, duration of headache, headache types, headache sites, quality of pain, headache severity according to the visual analog scale (VAS), headache quality, lateralization, frequency of inter-IH, usage of analgesic therapy. Headache severity was assessed based on the patient's memory of previous feeling of pain and indicated corresponding number on VAS (Fig. 1). Concomitant symptoms were also collected, such as nausea, emesis, photophobia, phonophobia, and whether symptoms worsening with physical activity. For those who were diagnosed with migraine, whether aura, like photophobia, flash, scotoma, blurred vision, visual field defects, sensory and language disorders, occurred before headache onset was collected.

Figure 1
figure 1

Visual analog scale (VAS). Mild pain: 1–3; Moderate pain: 4–6, severe pain: > 7.

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For peri-IH patients, the interview focused on questions on timing of onset (pre-ictal, ictal or post-ictal headaches) and frequency of headache. The frequency was classified into the following categories: 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 only for a few times. We also calculated the headache-attributed lost time-90 days (HLT-90). Finally, two neurologists respectively specialized in headache and epilepsy reviewed the clinical data of all the patients again to ensure the accurate classification.

Definitions and classifications

Intractable epilepsy is defined as persistent seizures despite a trial of at least 2 appropriately chosen ASM at optimal doses. Inter-IH manifested the headache during the interval period of epilepsy and it was considered not related to the epileptic seizure. Pre-IH develops within 24 h before the seizure10,20,21. Ictal headache develops during the seizure10. Post-IH usually develops within 3 h following a partial or generalized seizure and often resolves within 72 h after the seizure18. Inter-IH was divided into migraine (with or without aura), tension-type headache (TTH), and other primary headaches according to ICHD-III criteria18. All patients completed brain MRI, secondary headaches in structural epilepsies were not included in our study.

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).

Table 1 Clinical features of TLE and JME patients.
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Table 2 Clinical features of epilepsy-related headaches.
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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.

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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 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).

Figure 3
figure 3

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

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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.

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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.

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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 epilepsies22. 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 GTCS23,24. 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 regimen25,26,27. Some JME patients have a genetic predisposition28.

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 headache29. 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 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 epilepsy34. 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 headache35. 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 patients34. 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.