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Abstract

Background

Headache is a known comorbid condition of epilepsy. However, the prevalence of headache comorbidity in patients with epilepsy and its influence on the psychology and daily life of patients with epilepsy remain undefined at present.

Methods

Clinical data were collected from consecutive patients with epilepsy prospectively through face-to-face questionnaires. According to the temporal relationship between headache and seizures, comorbid headache in patients with epilepsy was classified as preictal headache, ictal headache, postictal headache, and interictal headache. Patients with interictal headache were divided into the migraine group and the non-migraine group, and their clinical characteristics were compared with those of patients with epilepsy but without headache (no-headache group).

Results

A total of 460 patients with epilepsy were included in the study, and 211 (45.9%) had comorbid headache, among which five cases (1.1%) had preictal headache, 134 cases (29.1%) had postictal headache, 119 cases (25.9%) had interictal headache, and 47 cases (10.2%) had both postictal and interictal headache. Additionally, HAMA and HAMD scores in the migraine group were significantly higher than those in the non-migraine group and the no-headache group, and HIT-6 score in the migraine group was significantly higher than that in the non-migraine group.

Conclusion

Nearly half of patients with epilepsy have comorbid headache, mainly manifesting as postictal headache or interictal headache. Among patients with interictal headache, comorbid migraine has the most significant influence on their psychological state and daily life.

Graphical abstract

This is a visual representation of the abstract.

Keywords

epilepsy headache migraine comorbidity clinical characteristics

Introduction

Epilepsy is a disorder characterized by recurrent unpredictable seizures (1). Long standing epilepsy will present a variety of comorbidities, such as headache, anxiety, and depression (2). In clinical practice, numerous patients with epilepsy experience headaches after seizures, which is referred to as postictal headache. Some patients with epilepsy also experience headaches during the interictal period, meaning that seizures and headaches occur separately. This type of headache is called interictal headache (3). Furthermore, for another portion of patients with epilepsy, headache symptoms often appear as prodromal symptoms before the seizure, and this is known as preictal headache. The proportion of patients with epilepsy and comorbid headache varies in the literature, with some reports suggesting that the prevalence of migraine among patients with epilepsy is as high as 23.0%, or even higher (4,5).

Epilepsy and migraine are both common neurological disorders, and share the same inducing factors (such as stress, photic stimulation and alcohol intake) and genetic susceptibility (such as CACNA1A, ATP1A2 and SCN1A genes), indicating that their pathophysiological mechanisms might be similar (6 –8). Thus, clinical and basic research on the comorbid headache of epilepsy has been carried out in many countries over the years. Evidence from genetics and animal experiments indicates that both migraine and familial epilepsy present genetic variations and abnormal neuronal excitability. The common pathophysiological mechanisms include ion channel dysfunction, glutamate excitotoxicity, and mitochondrial dysfunction (5,6,9). At present, there are relatively few studies on the pathophysiological mechanism of tension-type headache and epilepsy, which may be related to nitric oxide synthesis and APOE4 gene expression (10 –13). Patients with epilepsy tend to have comorbid psychiatric disorders, among which depression and anxiety are the most prevalent (14). Moreover, compared to patients with epilepsy but without comorbid headache, comorbid headache in patients with epilepsy is likely to further aggravate the aforementioned psychiatric comorbidities, thereby resulting in adverse prognosis and severely affecting the quality of life of patients (2).

The prevalence of headache comorbidity in epilepsy has been reported differently in previous studies (15), and further epidemiological research is currently lacking. Additionally, there are relatively few reports on the analysis of the clinical characteristics of headache in patients with epilepsy and comorbid headache, as well as the influence of headache comorbidity on the psychological state and daily life of patients with epilepsy. Therefore, through collecting, organizing and following up the clinical characteristic data of headache comorbidity in patients with epilepsy in this study, we explore the prevalence, outline the clinical characteristics, and evaluate the impact of different types of headache comorbidity on patients with epilepsy.

Methods

Patients selection

This study prospectively and consecutively registered a total of 498 patients with epilepsy who were diagnosed and treated in the outpatient and inpatient departments of the Neurology Department of the First Affiliated Hospital of Zhengzhou University from 1 July 2020 to 31 December 2021. All patients were diagnosed with epilepsy by experienced neurologists in accordance with the epilepsy classification criteria issued by the International League Against Epilepsy (16). The clinical data of the patients were collected in the form of face-to-face questionnaires. This study was approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University.

Patients with epilepsy meeting the following criteria were included in this study: 1) age ≥ 3 years; 2) completed head magnetic resonance imaging (MRI) and long-term video electroencephalogram (EEG) examination; 3) could reliably describe their seizures and headache symptoms; 4) could cooperate in the assessment of anxiety and depression scales and headache impact test; 5) voluntarily signed the informed consent form. For non-adult patients, their guardians signed the informed consent form on their behalf.

The exclusion criteria were as follows: 1) age < 3 years; 2) the existence of acute symptomatic causes of epilepsy (such as metabolic disorders, toxic exposure, active central nervous system infections); 3) inability to accurately record seizures and headache symptoms due to language or intellectual problems; 4) concurrent organic diseases causing headache; 5) non-signature of the informed consent form.

Data collection

The clinical characteristics of patients with epilepsy were collected by epilepsy specialists through inquiries, including the epileptic course, etiology, seizure types, seizure frequency, medication status and efficacy of anti-seizure medications (ASMs), past medical history, as well as the results of head MRI, EEG and other auxiliary examinations. Meanwhile, a dedicated neurologist conducted evaluations of comorbid psychological disorders and the impact of headache on the daily life of enrolled patients using relevant scales, as follows:

1) Hamilton Anxiety Scale (HAMA): HAMA is a clinician-based questionnaire and has been verified to possess favorable reliability and validity. It is extensively applied in clinical settings and is frequently employed to evaluate the severity of anxiety in patients. HAMA encompasses 14 items, with each item adopting a 5-level scoring method ranging from 0 to 4 and classified as: no anxiety symptoms; mild; moderate; severe; extremely severe. The specific scoring standards of HAMA are as follows: no anxiety: total score < 7; possible anxiety: total score ≥ 7; definite anxiety: total score ≥ 14; definite significant anxiety: total score ≥ 21; possible severe anxiety: total score ≥ 29. The higher the score, the more severe the degree of anxiety. Generally, a HAMA total score of ≥14 indicates the existence of a clinically significant anxiety disorder in the evaluated individual (17). 2) Hamilton Depression Scale (HAMD): HAMD scale consists of three different versions: 17 items, 21 items, and 24 items. However, the HAMD-17 version is mostly used by clinical assessors. This scale can reflect the depressive symptoms of the evaluated subjects relatively accurately and is widely used in clinical practice. HAMD-17 adopts a 5-level scoring method ranging from 0 to 4, including: no depression symptoms; mild; moderate; severe; extremely severe. The specific scoring standards for HAMD-17 are as follows: no depression: total score 0–7; possible mild depression: total score 8–16; possible moderate depression: total score 17–23; possible severe depression: total score ≥ 24. The higher the score, the more severe the degree of depression. Generally, a HAMD total score of ≥17 indicates the existence of a clinically significant depressive disorder in the evaluated subject (18). 3) Headache Impact Test (HIT-6): HIT-6 is utilized to assess the influence of headaches on patients’ work, family and social activities. This scale consists of six questions to evaluate the impact of headaches on patients within four weeks. The HIT-6 score (ranging from 36 to 78 points) categorizes the above impact into four grades: no or mild (36–49 points), moderate (50–55 points), significant (56–59 points), and severe (60–78 points).

During the consultation process, if the patient voluntarily expressed the presence of headache symptoms, it was recorded as a chief complaint of headache. Furthermore, patients were classified into the headache group and the no-headache group based on whether they had comorbid headache throughout the course of epilepsy. According to the diagnostic criteria in the 3rd version of the International Classification of Headache Disorders (ICHD-3) issued by the Headache Classification Committee of the International Headache Society, comorbid headaches in patients with epilepsy were categorized into ictal and postictal headaches based on the relationship between headaches and seizures (19). Additionally, the classification of comorbid headaches, which also included preictal and interictal headaches, was often mentioned and utilized in previous studies, although their diagnostic criteria were not officially incorporated into ICHD-3 (20,21). Preictal headache was defined as a headache that emerged within 24 h before a seizure and persists until the seizure commenced. Ictal headache was defined as a headache that occurred during a focal seizure. Postictal headache was defined as a headache that occurred within 3 h after a seizure and ceased within 72 h. Interictal headache was defined as a headache that emerged at least 3 h after the seizure or a headache that did not persist after the onset of the seizure. Meanwhile, interictal headache was classified into migraine, tension-type headache, and unclassified headache, which were diagnosed in accordance with the diagnostic criteria outlined in ICHD-3. Detailed collection of headache characteristics of patients in the headache group was carried out, encompassing the onset of headache, inducing factors, location, nature, visual analogue scale (VAS) score, concomitant symptoms, duration, frequency, whether analgesic medications were taken and their efficacy, family history of headache, and previous history. When assessing whether migraine patients had aura or not, in addition to the routine inquiry, we also used visual aura pictures and the visual aura rating scale (VARS) (with a maximum score of 10 points; if the patient's score was ≥5 points, the sensitivity for diagnosing migraine with aura was 96% and the specificity was 98%) (22). Three months later, a follow-up was performed on patients in the headache groups regarding the control of epilepsy and headache, mainly including seizure frequency and HIT-6 score. Regarding headache severity, a VAS score of 1 to 3 was recorded as mild, 4 to 6 as moderate, and 7 to 10 as severe.

Statistical analysis

Qualitative data were presented as frequencies and percentages, and intergroup comparisons were conducted using the chi-square test or Fisher's exact test. Quantitative data that followed a normal distribution were expressed as the mean ± SD, and intergroup comparisons were performed using Student's t test. Quantitative data that did not follow a normal distribution were represented as the median (interquartile range) [M (P25, P75)], and intergroup comparisons were carried out using the Mann–Whitney U test. Statistical analyses of the data were conducted using SPSS 25.0 software. A p < 0.05 was considered statistically significant.

Results

A total of 498 consecutive patients with epilepsy were registered in this study. Eventually, 460 patients were included in the research, among whom 45.2% (208/460) were male and 54.8% (252/460) were female. The age range of all patients enrolled in this study was 7 to 67 years old, with a median age of 34 years and an average age of 35.2 ± 12.4 years.

Clinical characteristics of headache in patients with epilepsy

Among the 460 patients with epilepsy, 211 (45.9%) had comorbid headache, among which five cases (1.1%) had preictal headache, 134 cases (29.1%) had postictal headache, 119 cases (25.9%) had interictal headache, and 47 cases (10.2%) had both postictal and interictal headache. However, we did not find any patients with ictal headache. Patients with postictal headache were classified into mild headache group (36 cases, 26.9%), moderate headache group (93 cases, 69.4%), and severe headache group (five cases, 3.7%) according to the headache severity. Patients with interictal headache were classified into migraine group (38 cases, 8.3%), tension-type headache group (41 cases, 8.9%), and unclassified headache group (40 cases, 8.7%) in accordance with the diagnostic criteria of ICHD-3.

A total of five patients with epilepsy concurrently experienced preictal headache, none of which were accompanied by migraine auras. The headache could occur 30 min to 8 h before the seizure, with a median of 2 h, and persisted until the seizure. The median course of the headache was eight years (four years, 10 years). The median frequency of headache attacks was 0.5 times per month (0.25 times per month, 2 times per month). The headache severity was mild in two patients and moderate in three patients. The headache nature was distending pain in two patients, stabbing pain in one patient, and could not be described in two patients. The headache occurred before focal seizures in four patients and before focal to bilateral tonic-clonic seizure in one patient.

As indicated in Table 1, the headache severity in patients with postictal headache was mainly moderate (93 cases, 69.4%), and the location was mostly bilateral (98 cases, 73.1%). The nature of postictal headache was mostly distending pain. Additionally, the duration of headache was relatively longer for patients with moderate postictal headache, but the frequency of headache was relatively lower. As depicted in Table 2, the quantity distribution of patients with interictal headache in each group was relatively homogeneous. Compared with the tension-type headache group and the unclassified headache group, the headache of patients in the migraine group was mainly manifested as unilateral (29 cases, 76.3%), throbbing (25 cases, 65.8%), and moderate (31 cases, 81.6%) pain, and possessed a longer headache attack duration and a higher headache attack frequency. Furthermore, 68.1% (81/119) of the interictal headaches occurred after the onset of epilepsy, and 26.9% (32/119) occurred before the onset of epilepsy. In addition, we further explored the relationship between seizure types and comorbid headache types. As there were very few patients (only five cases) experiencing preictal headache and no patients experiencing ictal headache in this study, only patients with postictal headache or interictal headache were included in Table 3. The results showed that there was a significant correlation between seizure types and comorbid headache types (p < 0.0001). Patients with generalized seizures (85 cases, 63.4%) tended to experience postictal headaches and patients with focal to bilateral tonic-clonic seizures (62 cases, 52.1%) tended to experience interictal headaches.

Table 1.

Clinical characteristics of postictal headache in 134 patients.

Clinical characteristics		Mild headache (n = 36)	Moderate headache (n = 93)	Severe headache (n = 5)
Onset of headache (years)		8.1 ± 5.1	6.1 ± 5.5	7.4 ± 3.9
Headache location	unilateral	7 (19.4%)	29 (31.2%)	0 (0.0%)
Headache location	bilateral	29 (80.6%)	64 (68.8%)	5 (100.0%)
Headache nature (n, %)	throbbing	1 (2.8%)	6 (6.5%)	0 (0.0%)
	distending	20 (55.6%)	74 (79.6%)	2 (40.0%)
	tightening	7 (19.4%)	4 (4.3%)	0 (0.0%)
	others	8 (22.2%)	9 (9.7%)	3 (60.0%)
Duration (hours)		1.6 ± 0.8	8.9 ± 6.4	–
Frequency (times/month)		0.7 ± 0.5	0.3 ± 0.3	–

Table 2.

Clinical characteristics of interictal headache in 119 patients.

Clinical characteristics		Migraine (n = 38)	Tension-type headache (n = 41)	Unclassified headache (n = 40)
Onset of headache (years)		1.9 ± 1.0	1.5 ± 1.1	2.1 ± 1.5
Headache location	unilateral	29 (76.3%)	4 (9.8%)	10 (25.0%)
Headache location	bilateral	9 (23.7%)	37 (90.2%)	30 (75.0%)
Headache severity (n, %)	mild	4 (10.5%)	27 (65.9%)	31 (77.5%)
	moderate	31 (81.6%)	14 (34.1%)	9 (22.5%)
	severe	3 (7.9%)	0 (0.0%)	0 (0.0%)
Headache nature (n, %)	throbbing	25 (65.8%)	2 (4.9%)	3 (7.5%)
	distending	12 (31.6%)	5 (12.2%)	10 (25.0%)
	tightening	0 (0.0%)	29 (70.7%)	0 (0.0%)
	others	1 (2.6%)	5 (12.2%)	27 (67.5%)
Duration (hours)		7.4 ± 4.2	1.3 ± 1.0	0.4 ± 0.3
Frequency (times/month)		1.0 ± 0.6	0.4 ± 0.3	0.6 ± 0.4

Table 3.

Relationship between seizure types and comorbid headache types.

Seizure types	Postictal headache (n = 134)	Interictal headache (n = 119)	p value
Other focal seizures (n, %)	22 (16.4%)	11 (9.2%)	<0.0001
Focal to bilateral tonic-clonic seizure (n, %)	25 (18.7%)	62 (52.1%)
Generalized seizure (n, %)	85 (63.4%)	42 (35.3%)
Indefinite seizure (n, %)	2 (1.5%)	4 (3.4%)

Intergroup comparative analysis of patients with interictal headache

To further reveal the influence of interictal headache on patients with epilepsy, we classified patients with interictal headache into a migraine group and a non-migraine group, and their clinical characteristics were compared with those of patients with epilepsy but without headache (no-headache group). The results are presented in Tables 4 and 5 as follows: 1) In the comparative analysis of age, age at epileptic onset, seizure types and frequency, and the usage of valproate and topiramate among the migraine group, non-migraine group, and no-headache group, no significant differences were observed; 2) The proportion of female patients in the migraine group was higher than that in the no-headache group (^ap = 0.046); 3) The epileptic course in both the migraine group and the non-migraine group was shorter than that in the no-headache group (^ap = 0.004, ^bp = 0.003); 4) The ASMs types used by patients in the migraine group and the non-migraine group were more than those in the no-headache group (^ap = 0.041, ^bp = 0.002); 5) The seizure frequency in the migraine group and non-migraine group decreased significantly after the three-month visit; 6) The rate of headache complaint at the time of visit in the migraine group was significantly higher than that in the non-migraine group (^cp < 0.001); 7) There was a statistically significant difference in the use of analgesic medications between the migraine group and the non-migraine group (^cp < 0.001); 8) There were statistically significant differences in the family history of headache among the migraine group, the non-migraine group, and the no-headache group (^ap < 0.001, ^bp = 0.012, ^cp < 0.001); 9) In terms of HAMA score and HAMD score, both the migraine group and the non-migraine group were significantly higher than the no-headache group (^ap < 0.001, ^bp < 0.001), and the migraine group was significantly higher than the non-migraine group (^cp < 0.001); 10) The HIT-6 score of patients in the migraine group was significantly higher than that of the non-migraine group (^cp < 0.001). Although the HIT-6 score of patients in the migraine group decreased after the three-month visit, it was still significantly higher than that of the non-migraine group (^cp = 0.007).

Table 4.

Comparison of epileptic characteristics among groups.

Clinical characteristics	Migraine (n = 38)	Non-migraine (n = 81)	No-headache (n = 249)	p value
Gender (female) (n, %)	27 (71.1%)	52 (64.2%)	134 (53.8%)^a	0.046
Age (years)	31.8 ± 10.6	33.3 ± 11.5	35.1 ± 11.1	NS
Age at epilepsy onset (years)	28.4 ± 9.6	29.4 ± 10.7	28.9 ± 12.5	NS
Epileptic course (years)	2.0 (1.0, 3.0)	2.0 (0.0, 5.0)	5.0 (1.0, 9.0)^ab	<0.05
Seizure types
Other focal seizures (n, %)	3 (7.9%)	8 (9.9%)	20 (8.0%)	NS
Focal to bilateral tonic-clonic seizure (n, %)	20 (52.6%)	42 (51.9%)	130 (52.2%)
Generalized seizure (n, %)	13 (34.2%)	29 (35.8%)	89 (35.7%)
Indefinite seizure (n, %)	2 (5.3%)	2 (2.5%)	10 (4.0%)
Seizure frequency (times/month)	0.9 ± 0.5	0.7 ± 0.5	0.5 ± 0.4	NS
Seizure frequency after 3 months of visit (times/month)	0.2 ± 0.2	0.3 ± 0.2	-	NS*
ASMs types	1.6 ± 0.8	1.5 ± 0.6	1.3 ± 0.5^ab	<0.05
Valproate used (n, %)	10 (26.3%)	19 (23.5%)	69 (27.7%)	NS
Topiramate used (n, %)	5 (13.2%)	7 (8.6%)	20 (8.0%)	NS

p: migraine group vs no-headache group; ^bp: non-migraine group vs no-headache group; ^cp: migraine group vs non-migraine group; NS: ^ap/^bp/^cp > 0.05; NS*: ^cp > 0.05. ASMs: anti-seizure medications.

Table 5.

Comparison of headache and psychological state among groups.

Headache and psychological state	Migraine (n = 38)	Non-migraine (n = 81)	No-headache (n = 249)	p value
Headache complaint (n, %)	12 (31.6%)	4 (4.9%)^c		<0.001
Analgesic medications used (n, %)	6 (15.8%)	0 (0.0%)^c		<0.001
Family history of headache (n, %)	26 (68.4%)	11 (13.6%)^c	13 (5.2%)^ab	<0.05
HAMA score	12.9 ± 2.6	6.2 ± 3.0^c	4.7 ± 2.0^ab	<0.001
HAMD score	15.9 ± 2.5	12.6 ± 4.1^c	11.2 ± 2.3^ab	<0.001
HIT-6 score	49.7 ± 8.3	41.9 ± 4.3^c		<0.001
HIT-6 score after 3 months of visit	43.8 ± 5.4	41.3 ± 4.2^c		0.007

p: migraine group vs no-headache group; ^bp: non-migraine group vs no-headache group; ^cp: migraine group vs non-migraine group.

Discussion

Through the Global Burden of Diseases (GBD) studies, headache disorders, and in particular, migraine, have been shown to be among the most disabling disorders worldwide and impose a significant economic burden (23). In this study, 45.9% of patients with epilepsy had comorbid headache, among whom 54.8% were female, and the prevalence of interictal headache in patients with epilepsy was 25.9% (119/460), with the prevalence of migraine at 8.3% (38/460) and tension-type headache at 8.9% (41/460). A 2020 meta-analysis on the epidemiology of epilepsy comorbid with headache, encompassing 17 studies and a total of 5564 patients, revealed that the prevalence of headache among patients with epilepsy was 48.4%, and the prevalence of postictal headache (43.1%) and interictal headache (42.2%) was significantly higher than that of tension-type headache (26.2%), migraine with aura (26.0%), and migraine without aura (10.4%) (15). The same study indicated that the prevalence of comorbid headache in female patients with epilepsy was higher than that in male patients (63.0% vs 33.3%), and the high prevalence of headache in females is consistent with the results of this study. Furthermore, a study conducted among the general population in the mainland of China showed that the prevalence of primary headache was found to be 23.8%, with migraine accounting for 9.3% and tension-type headache accounting for 10.8%, which was similar to the prevalence of interictal headache (25.9%), interictal migraine (8.3%), and interictal tension-type headache (8.9%) but lower than the overall prevalence of comorbid headache (45.9%) in this study (24). Additionally, no patients experienced ictal headache in this study, which was consistent with the research of Chovatiya et al. (20). However, the prevalence of various types of interictal headaches in this study is relatively low, and no cases with migraine with aura were observed in patients with epilepsy and interictal headache. This may be related to the different prevalence rates in different regional populations, or it may be associated with the small sample size and recall bias of the patients in this study.

Regarding epilepsy-related headache, it is classified as migraine aura-triggered seizure and headache attributed to seizures that consist of ictal headache and postictal headache in ICHD-3, and comments have been also made on preictal headache in ICHD-3 (19). In this study, there were only five cases of preictal headache, with a stereotyped attack pattern, seizures occurred after the preictal headache in all cases, and there was no migraine aura. This is different from the three cases reported by Wang et al. (25), where seizures occurred after migraine aura. Thus, headache in the five cases was diagnosed as preictal headache rather than migraine aura-triggered seizure. Due to the low prevalence of preictal headache, more studies (such as functional MRI) are needed to explore its pathophysiological mechanism (26). Moreover, the diagnosis of preictal headache in our study was based on previous reports in the literature. However, there are still no published diagnostic criteria for preictal headache. It remains challenging to accurately distinguish between preictal headache and epileptic auras, especially when the preictal headache lasts for seconds to minutes rather than hours, and more studies are needed to establish the existence of preictal headache.

As outlined above, the prevalence of interictal headache in patients with epilepsy was almost identical to the prevalence of primary headache in the general population. Consequently, postictal headache, rather than interictal headache, might represent the critical factor contributing to the high prevalence of comorbid headaches in patients with epilepsy. In this study, the proportion of patients with postictal headache was found to be higher than that of patients with any other type of comorbid headache. Among patients with postictal headache, more than half of patients experienced moderate headache, which aligns with findings from a previous study (27). Furthermore, it has been reported that the location of postictal headache is mostly bilateral (28). We also identified that 73.1% (98/134) of postictal headaches were characterized by bilateral localization. Regarding the headache nature, 71.6% (96/134) of patients described their postictal headaches as distending pain. Distending pain is a type of dull pain that has been documented in published literature to characterize the nature of the headache (29). It is the feeling of pressure inside the head that radiates from the intracranial region to the extracranial region, accompanied by pain and characterized by a sensation of expansion, swelling, or fullness within the head during episodes of headache, as though the head were being inflated or filled with an internal force. In addition to distending pain, a small proportion of patients also described their postictal headaches as migraine-like throbbing pain or tension-type headache-like tightening pain. Moreover, the mean duration of postictal headache was reported to range from 5.9 h to 20 h (30). In this study, the moderate headache group had a mean postictal headache duration of 8.9 h, whereas the mild headache group had a mean duration of 1.6 h. Prior research has demonstrated that postictal headache occurs more frequently following generalized seizures compared to other seizure types (27,31). Interestingly, our findings also revealed that patients with generalized seizures (85 cases, 63.4%) tended to experience postictal headaches. In addition to postictal headache, drowsiness and fatigue are common postdromal symptoms after generalized seizures and may be mediated by ischemia and hypoxia attributed to generalized seizures (32,33). Meanwhile, according to the existing literature, the underlying mechanism of postictal headache might be that generalized seizures induce ischemia and hypoxia in the brain, which stimulate the production of inflammatory factors, resulting in aseptic inflammation and subsequently leading to postictal headache (34,35).

It has been reported in the literature that migraine is the predominant cause of years lost due to disability (36). In this study, the majority of patients with interictal headache had mild headache symptoms, and most patients in the migraine group did not require analgesic medications. However, the headache severity, anxiety score, depression score, and impact on daily life in migraine patients were higher than those in patients with other types of interictal headaches. Moreover, some of these patients had severe headaches that lasted for a long time. Two patients even needed hospitalization and intravenous infusion to relieve their headache each time. As shown in Table 4, the epileptic course was shorter in both the migraine group and the non-migraine group compared to the no-headache group, but the number of ASMs types used in the migraine group and the non-migraine group was greater than that in the no-headache group. This suggests that epilepsy might be more difficult to control in patients with interictal headache. In addition, no difference was identified in the seizure frequency between patients with interictal headache and those without, but the seizure frequency of patients with epilepsy in the migraine group and the non-migraine group was reduced after three months of antiepileptic treatment, and the HIT-6 score of these patients, which reflected the impact of headaches on daily life, was decreased as well. The decrease was more significant in the migraine group, suggesting that ASMs might be effective in treating migraine attacks. Some ASMs not only have the role in controlling seizures, but also can alleviate migraine attacks, thereby reducing the headache burden for patients. The potential mechanism by which some ASMs improve migraine might be that they have the function of ameliorating excessive activity in sensitized trigeminal sensory fibers, inhibiting the release of inflammatory mediators, or interfering with neuronal hyperexcitability (37). Besides headache, comorbid anxiety and depression also impose a heavy burden on patients with epilepsy and have a negative impact on their prognosis and quality of life (14). As a highly prevalent and disabling neurological disorder, migraine is also associated with a wide range of psychiatric disorders, such as anxiety and depression. And the relationship between migraine and psychiatric disorders is bidirectional, meaning that each disorder increases the risk of the other (38,39). Therefore, we should pay greater attention to the diagnosis and treatment of patients with epilepsy and comorbid migraine. To sum up, when neurologists treat patients with epilepsy, they should routinely ask whether the patients have comorbid headache, especially migraine. For patients with epilepsy and severe migraine, it is necessary to consider using migraine-relieving drugs or adjusting ASMs to valproate, topiramate, etc., which also have the effect of preventing migraine, so as to improve the quality of life for the patients and mitigate their anxiety and depression.

This study is a prospective, consecutively registered questionnaire survey of patients with epilepsy. All subjects were recruited from the same comprehensive epilepsy center (a tertiary epilepsy center). Besides exploring the prevalence of comorbid headache in patients with epilepsy, we also analyzed the impact of comorbid headache on the psychological state and daily life of patients with epilepsy. For interictal headache, we conducted an analysis of tension-type headache, in addition to the commonly studied migraine. However, this study still has certain limitations. For instance, it lacks data on the overall prevalence of headache in the general population visiting our hospital (excluding patients with epilepsy) as a control group for the patients with interictal headache. Additionally, the study lacks some detailed reports on certain aspects of epilepsy and headache, particularly regarding medication usage during acute migraine attacks (such as triptans), epilepsy types in patients, and the proportion of chronic migraine cases. Furthermore, the sample size of this study is relatively small, and the included patients with epilepsy received diverse treatment plans, making it difficult to analyze the effects of different treatment options on headache. In future studies, more patients should be included, more details about epilepsy and headache should be reported, and long-term follow-up should be conducted based on different antiepileptic treatment plans to compare their effects on headache.

Conclusion

Clinical implications

Nearly half of patients with epilepsy have comorbid headache, mainly manifesting as postictal headache or interictal headache.

Among patients with interictal headache, comorbid migraine has the most significant influence on their psychological state and daily life.

Footnotes

Acknowledgements

The authors thank the patients who participated in this study for their support of this study.

Author contributions

YC actively contributed to the study design, data acquisition, data analysis, and drafting of the manuscript. YL made significant contributions to the study design and critically revised the manuscript for important intellectual content. CW and HZ participated in the study design and data acquisition. CW was involved in the study design and performed statistical analysis. WC and YW were engaged in data analysis and played a role in revising the draft of the manuscript. All authors approve the final manuscript version to be published.

Data availability

Data will be made available upon reasonable request to the corresponding author.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics approval and informed consent

This study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University. Informed consent was obtained from all subjects involved in the study.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by funds from the National Natural Science Foundation of China, China (Grant No. 81771397).

ORCID iDs

Yuan Chen

Chengze Wang

Haifeng Zhang

Yake Zheng

Wenchao Cheng

Yuhan Wang

Yajun Lian

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The characteristics of headache in patients with epilepsy

Abstract

Background

Methods

Results

Conclusion

Keywords

Introduction

Methods

Patients selection

Data collection

Statistical analysis

Results

Clinical characteristics of headache in patients with epilepsy

Intergroup comparative analysis of patients with interictal headache

Discussion

Conclusion

Clinical implications

Footnotes

Acknowledgements

Author contributions

Data availability

Declaration of conflicting interests

Ethics approval and informed consent

Funding

ORCID iDs

References