Characteristics of Headache in Children with Epilepsy

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Characteristics of headache in children with epilepsy

a, a a a a b

Hideaki Kanemura *, Fumikazu Sano , Sayaka Ishii , Tetsuo Ohyama , Kanji Sugita , Masao Aihara

Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Japan

Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Japan

A R T I C L E I N F O A B S T R A C T

Article history: Purpose: The association of headache with seizures is well known to neurologists but poorly understood.

Received 7 March 2013

The purpose of this prospective study was to evaluate the types and frequency of seizure-associated

Received in revised form 25 April 2013

headaches among pediatric patients with epilepsy, and to identify their risk factors with special

Accepted 26 April 2013

attention to the anatomic localization of the epileptogenic focus and seizure classiﬁcation.

Methods: Patients with focal and generalized active seizures and on treatment at the time of

Keywords:

questionnaire administration were included. Patients were prospectively interviewed by questionnaire

Children

as to whether or not they suffered from headaches associated with epileptic seizures.

Epilepsy

Results: Of 98 patients (age range: 5–18 years), 34 (34.7%) complained of seizure-associated headaches.

Frequent seizures

Headache In patients with seizure-associated headaches, headache was signiﬁcantly more frequent (31/74, 41.9%)

Partial seizure with partial seizures than with generalized seizures (3/24, 12.5%; p = 0.012). The frequency of seizure

attacks was 4.1 times per year in patients with seizure-associated headache and 1.3 times per year in

those with non-seizure-associated headache. Of the 34 patients, 20 (58.8%) complained of headache at

the frontal region.

Conclusions: The location of headache was not always in agreement with electroencephalographic focus.

Headache was more frequent in patients with partial epilepsy and frequent seizures.

1. Introduction Seizure-associated headaches, in particular post-ictal, can be of

4,5

the migraine, tension, or unclassiﬁed type of headache. An

Epilepsy and headache are paroxysmal disorders. Migraine, association with migraine has been reported in speciﬁc epileptic

which is one type of headache, and epilepsy are a heterogeneous syndromes, including benign occipital epilepsy of childhood and

6–8

family of chronic disorders with highly variable clinical features, benign rolandic epilepsy. Investigation of headaches with

natural histories, and patterns of treatment response. The characteristics of migraine would contribute to understanding

association of headaches with seizures is well known to the relationship between migraine and migraine-like, seizure-

neurologists but poorly understood. Patients with epilepsy often associated headache. However, seizure-associated headache has

have headaches during the postictal period. However, the not even been included in the headache classiﬁcation system of the

pathophysiology of such headaches remains unclear. International Headache Society (IHS), most likely due to underes-

Assessment of seizure-associated headaches is often neglected timation of its occurrence and to the different interests of the

when taking the history of epileptic seizures, because other doctors involved in patient care, especially of children. We are not

symptoms, such as disturbance of consciousness or motor aware of studies looking systematically for a correlation between

phenomena, predominate. Painful epileptic seizures are rare. pathologically veriﬁed partial epilepsy in children and the

Seizure-associated headache described by Gowers was studied in characteristics of associated headaches.

patients with different seizure patterns and syndromes. Seizure- Conﬁrming a previous study showing that almost 36% of the

associated headaches may be preictal, ictal, or postictal. A previous parents of children with headache were unaware of the

study with small patient numbers reported a frequency of 42–51% headache, Colombo et al. stressed that pediatric headache is

in patients with epilepsy for seizure-associated headaches. still under-diagnosed and is not adequately considered a health

problem in the medical community, as well as in social settings.

Although headache is commonly associated with seizures as an

inter-ictal, preictal, ictal, or postictal phenomenon, it is often

* Corresponding author at: Department of Pediatrics, Faculty of Medicine,

neglected because of the dramatic neurological manifestations of

University of Yamanashi, 1110 Chuo, Yamanashi 409-3898, Japan. 12

the seizure. Accordingly, in any study of the association between

Tel.: +81 55 273 9606; fax: +81 55 273 6745.

E-mail address: [email protected] (H. Kanemura). headache and epilepsy, a prospective study design is important

648 H. Kanemura et al. / Seizure 22 (2013) 647–650

Table 1

because it can be used to identify the true extent of the non-

Patients’ demographic and clinical features.

random epidemiological association between headache and

epilepsy. Seizure-associated Non-seizure-associated

headache (n = 34) headache (n = 64)

Thus, the purpose of this prospective study was to evaluate the

types and frequency of seizure-associated headaches in children Sex (male:female) 10:24 33:31

with epilepsy and to identify their risk factors with special Mean age (years) 12.4 (range: 8–17) 9.1 (range: 5–18)

Family history 3 9

attention to the anatomic localization of the epileptogenic focus,

Mean seizure frequency 4.1 (range: 1–7) 1.3 (range: 0–5)

seizure classiﬁcation (focal versus generalized), and antiepileptic (times/year) treatment.

2. Methods

conﬁdence interval 1.382–18.423; p = 0.012). Duration of headache

Patients with focal and generalized active seizures, with a was 1–12 h in 25 patients, and from 5 min to 60 min in another 9.

conﬁrmed diagnosis of epilepsy according to the International The headache occurred preictally in 10 (29.4%) of 34 patients

League Against Epilepsy (ILAE) and on treatment at the time of with seizure-associated headaches, postictally in 28 (82.4%) of 34

questionnaire administration, were included. Epilepsy type was patients, and both pre- and postictally in 4 (11.8%) of 34 patients.

determined according to the ILAE criteria on the basis of clinical None complained of peri-ictal headaches. In 34 patients with

symptoms, electroencephalography, and neuroimaging examina- seizure-associated headaches, 7 patients (20.6%) (2 males and 5

tions such as computed tomography or magnetic resonance females) had migraine-type headaches, such as throbbing uni/

imaging (MRI). Patients with progressive brain disease or recent bilateral pain, photophobia and/or phonophobia, nausea and

brain injury were excluded. Patients were prospectively inter- vomiting, and without aura, according to the diagnostic criteria

viewed by questionnaire as to whether they had headaches of the IHS. In this group with migraine, 1/7 (14.3%) had a family

associated with epileptic seizures, determining whether their history of migraine. The other (27/34, 79.4%) patients had tension-

epilepsy and headache occurred independently (inter-ictal head- type headache. In contrast, in the group without seizure-associated

ache), as well as in close temporal relation to the seizures, and headaches, 9/64 (14.1%) had a family history of migraine.

about their family history. In cases of a positive family history, the Twenty (58.8%) of the 34 patients with seizure-associated

diagnosis of migraine was conﬁrmed by a standardized interview headaches complained of headaches at the frontal region.

with the relatives. Centrotemporal and occipital localized headaches occurred in 10

The data obtained for each patient included seizure type, (29.4%) and 4 (11.8%), respectively. In 4 (40.0%) of the 10 patients

seizure frequency, and number of antiepileptic drugs taken. with centrotemporal localization and in 2 (50.0%) of the 4 patients

Seizure-associated headache was deﬁned as a headache beginning with occipital localization, the headaches were migraine-type.

within an hour before or after the seizure, and it was analyzed in Electroencephalogram (EEG) ﬁndings of the 34 patients with

three distinct groups. Pre-ictal headache was a headache that seizure-associated headache demonstrated frontal paroxysms in 8

began prior to a seizure and lasted until the onset of the seizure. (23.5%), central or centrotemporal paroxysms in 19 (55.9%),

Peri-ictal headache was a headache occurring simultaneously with occipital paroxysms in 4 (11.8%), and generalized paroxysms in

the other symptoms of a simple partial seizure. Post-ictal headache 3 (8.8%). With respect to the locations of EEG foci and headache

was a headache occurring immediately after cessation of any localization, in 6 (30.0%) of the 20 patients with frontal headache,

seizure. The headache classiﬁcation was based on the IHS EEG foci were in the frontal region. In 4 (40.0%) of the 10 patients

criteria. with centrotemporal headache, EEG foci were in the centrotem-

Demographic and clinical data were obtained through inter- poral regions. In 1 (25.0%) of the 4 patients with occipital headache,

views with patients and their relatives and by review of hospital EEG foci were in the occipital regions. Thus, the location of

charts. The decisive criteria for the location of the epileptic focus headache was not always in agreement with the location of EEG

were predominantly ipsilateral interictal epileptic abnormalities foci. In 4 (57.1%) of the 7 patients with migraine-type headache,

and unequivocal seizure onset. In all patients, MR images were EEG foci were in the centrotemporal regions.

acquired on a 1.5-T scanner with T1-fast ﬁeld echo, T2-weighted, Twenty-four (70.6%) of the 34 patients with seizure-associated

proton density, and ﬂuid attenuated inversion recovery images. headaches were treated with monotherapy by antiepileptic drugs.

Statistical evaluation was performed using the chi-square test and Ten (29.4%) of the 34 patients were treated by combinations of

Fisher’s exact test. antiepileptic drugs. Fourteen (29.8%) of 48 patients treated by

The study was carried out in accordance with the Declaration of valproate sodium (VPA) complained of headache, and 16 (32.7%) of

Helsinki. Informed consent was obtained from the patients and the 49 patients treated by carbamazepine (CBZ) complained of

parents of each patient. headache. There was no signiﬁcant correlation between the

existence of seizure-associated headache and antiepileptic treat-

3. Results ment by VPA (p = 0.327) and CBZ (p = 0.671). None of the patients

were treated by triptans or any other speciﬁc antimigraine

A total of 98 patients (43 males and 55 females; age range: 5–18 medication, except for VPA.

years) were interviewed. Of this group of 98 patients, 74 (75.5%)

had partial seizures, and 24 (24.5%) had generalized seizures. The 4. Discussion

demographic and clinical features of the patients are shown in

Table 1. Of the 98 patients, 34 (34.7%) patients (10 males and 24 The link between headache and seizures is controversial. In the

females; mean age 12.4 Æ 3.3 years) complained of seizure- present study of 98 children with epilepsy, 34 (34.7%) had seizure-

associated headaches. The frequency of seizure attacks was 4.1 times associated headache, which is similar to the frequency of 34%

per year in those with seizure-associated headache and 1.3 times per reported by Leniger et al. in 341 adult patients. Most previous

year in those with non-seizure-associated headache (Table 1). In studies discussed post-ictal headache and adult patients only, with

3,15

patients with seizure-associated headache, headache was present in an incidence ranging from 37% to 51%. It has been reported that

31/74 (41.9%) with partial seizures vs. 3/24 (12.5%) with generalized postictal migraine-type headache and tension-type headache were

seizures; the difference was signiﬁcant (odds ratio 5.047, 95% the most common, and that all patients with a history of migraine

H. Kanemura et al. / Seizure 22 (2013) 647–650 649

9 12,22–25,29

also had migraine-type postictal headache. The prevalence of overshadows the ictal and peri-ictal headache events.

migraine-type headache in epilepsy patients was 20.6% in the These ﬁndings may explain the present results.

seizure-associated group in the present study; this corresponds to A family history of migraine was found in 3 (8.8%) of 34 patients

5,16

earlier results. In an epidemiological study performed in Turkey with seizure-associated headaches. There was no signiﬁcant

in 1997, the prevalence of migraine headache was 10.9% in the association between headache and family history of migraine

male population and 21.8% in the female population. Of our and epilepsy. By contrast, Leniger et al. reported that a history of

patients with migraine-type headache, the prevalence was 7.0% in migraine was signiﬁcantly more frequent in the group of patients

males and 20.0% in females. with migraine-like, seizure-associated headache than in the other

16 4

In some earlier studies, headache was encountered more groups, which is incompatible with the present ﬁndings. It would

frequently in patients with epilepsy than in those without be difﬁcult to draw a conclusion from the present data. Moreover,

epilepsy. However, comparing the frequency of interictal as for the clinical features, it is difﬁcult to classify the brief attacks

primary headache among patients with epilepsy and the as migraine variants or as short-lasting headache syndromes.

prevalence of headache in the same age groups in the population Based on these results, the reason for the predominance of

study, the results seemed similar, suggesting that headache was migraine-like headache in patients with seizure-associated

not more frequent in patients with epilepsy than in the normal headache remains unclear. More studies will be needed to

population, a ﬁnding contrary to that of the earlier studies. understand this ﬁnding.

Spreading depression, an underlying common mechanism of In the present study, the prevalence of seizure-associated

migraine with aura and epilepsy, is often mentioned as headache was signiﬁcantly higher in the partial seizure group than

responsible for the close temporal relation between migraine in the generalized seizure group. However, the occurrence of

and epilepsy. In a recent report, migraine was far more seizure-associated headache, including migraine-like type,

frequent in subjects with epilepsy than in non-epileptic showed no relationship to the region of the epileptogenic focus,

controls, with a 16.5 times higher risk ratio in the subjects which is incompatible with earlier studies. EEG abnormalities in

with epilepsy than in controls. The present results demon- patients with migraine were not always associated with epilepsy.

strated that headache occurs more frequently in patients with In contrast, epileptiform activities on EEG were recorded in 2–7.3%

30,31

frequent seizures. These ﬁndings suggest that the presence of of children without epilepsy. In our preliminary study with

seizure-associated headache is related to the underlying migraine patients, the location of the EEG abnormality was

epileptogenic pathology. independent of the presence of epilepsy, and centrotemporal

Seizure-associated headache was present in patients with paroxysms were not always associated with epileptogenesis.

partial seizures, showing a signiﬁcant difference compared with Previous studies by Kramer and Nevo et al. showed that, despite

generalized seizures. This ﬁnding suggests that the regions of the high incidence of epileptic EEG abnormalities, the contribution

headache are localized. The majority of headache locations was in of EEG to diagnosis and treatment in children with chronic

32,33

the frontotemporal region, similar to that of the previous report by headache is minimal. It may be recommended that EEG should

Yankovsky et al. They reported that seizure foci tended to induce not be performed routinely in epilepsy patients with headache. The

consistently lateralized headache. Studying the exposed human present study did not address this topic because of its small sample

cerebral cortex during epileptic seizures, Penﬁeld and Jasper size.

observed widespread vasodilation and reactive hyperemia in the There appears to be a hierarchical organization based on

region of the discharging epileptic focus. The ipsilaterality of the ‘‘neuronal networks’’ that may be more or less prone to cortical

headache may be explained by activation of the trigemino- spreading depression (CSD) (migraine) and epileptic focal dis-

vascular system and neurogenic inﬂammation on the side of the charges (seizures). Parisi hypothesized the mechanism of

seizure focus in susceptible individuals. The present results were activation of headaches as follows: ‘‘Onset and propagation are

in agreement with those of Yankovsky. triggered when these neurophysiological events reach a certain

The present results showed that the headache location was not threshold (‘‘all-or-none events’’), which is lower for the onset of

always in agreement with the locations of EEG foci. Recent studies CSD than that of the seizure.’’ The triggering causes a ﬂow of ions

also reported that a wide range of patterns and localizations that mediate CSD above all through neuronal cytoplasmic bridges

(occipital, temporoparietal, and frontal) had been recorded during (intracellular gap junctions) rather than through interstitial spaces,

22–26 12 34

migraine-like complaints. As Parisi hypothesized, these as usually happens in the spread of epileptic seizures. The onset

ﬁndings suggest that an epileptic focus that activates the of the seizure facilitates the onset of CSD to a greater degree than

trigemino-vascular system might remain purely autonomic, the CSD facilitates the onset of the epileptic seizure. Thus,

without ictal neuronal activation of nonautonomic cortical areas. practicing physicians are more likely to observe epileptic patients

In patients with migraine in whom the aura triggers seizures, a with ‘‘comorbid’’ (peri-ictal and interictal) migraine than migraine

27 12

phenomenon referred to as migralepsy, the focus fails to reach subjects with ‘‘comorbid’’ epilepsy.

the symptomatogenic threshold required to induce sensory-motor VPA has been shown to be effective and is approved for the

manifestations, as has been described for other ictal autonomic prevention of migraines in adults. CBZ has also been used for the

28,29

manifestations in Panayiotopoulos syndrome. These ﬁndings prevention of headache. However, the present results showed no

may be responsible for the disagreement between the headache correlation between the existence of seizure-associated headache

and EEG foci locations. The present results may be explained by and antiepileptic treatment. In clinical practice, patients with

these ﬁndings and Parisi’s hypothesis. epilepsy complain of headache not infrequently. In contrast,

In addition, the present results showed that there were more painful epileptic seizures are rare. Cephalic pain is only one

signiﬁcant associations with headache in patients with partial subdivision along with abdominal pain that is associated with

epilepsy and more frequent seizures. As regards the higher abdominal auras and unilateral pain in somatosensory auras.

association between headache and focal epilepsy, Parisi et al. Therefore, clinicians often fail to explicitly ask patients about

speculated that possible explanations for this relationship were seizure-associated headache, although headache treatment might

that: (a) autonomic manifestations (such as ictal and peri-ictal be a therapeutic option. None of the present patients were treated

headaches) are more frequent in the pediatric age group than in with triptans or other antimigraine medications, but they used

adults; (b) in the pediatric age group, idiopathic partial epilepsy over-the-counter medications for any type of headache with

is more frequent; and (c) in generalized epilepsy, the picture variable effect. This is probably related to lack of awareness and

650 H. Kanemura et al. / Seizure 22 (2013) 647–650

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