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Summary: Purpose: Prior studies have given conflicting data concerning the association of benign rolandic epilepsy of childhood (BREC) and migraine but were limited by lack of sensitive, diagnostic criteria for childhood migraine. By using revised International Headache Society (IHS-R) criteria, we compared the prevalence of migraine in children with BREC with that of those (a) with cryptogenic/symptomatic partial epilepsy and (b) without epilepsy.
Methods: Three cohorts of children, gender and age matched (within 1 year) were identified: (a) BREC, (b) cryptogenic/symptomatic partial epilepsy, and (c) no history of seizures. Parents were queried in a standardized interview about migraine and migraine equivalents in their child, and in either biologic parent. Migraine was defined by using the IHS-R (for children) and IHS criteria (for parents). Children with headache were divided into definite (meeting IHS-R criteria), probable (recurrent, throbbing headaches with nausea, vomiting, photophobia or phonophobia, not meeting IHS-R criteria), possible (recurrent headaches with throbbing character or associated nausea/vomiting), or nonmigraine groups. χ2 analysis was used to determine whether the cohort with BREC had a higher prevalence of definite, definite or probable, or definite, probable, or possible migraines or migraine equivalents than the other two cohorts.
Results: Each cohort consisted of 53 children (mean age, 9.8–9.9 years, M/F ratio, 35:18). Those with BREC had higher rates of definite and probable (p = 0.05), of definite, probable, and possible migraine (p = 0.05), and of migraine equivalents excluding motion sickness (p < 0.005) than did those without seizures; however, they did not differ significantly from the cryptogenic/symptomatic partial epilepsy cohort.
Conclusions: Partial epilepsy, regardless of etiology, is associated with higher rates of migraine in children. The pathophysiologic link between epilepsy and migraine is unknown.
Migraine is one of the most common causes of neurologic disability, affecting 4–10% of school-aged children (Sillanpaa, 1983; Mortimer et al., 1992; Abu-Arefeh and Russell, 1994; Raieli et al., 1995). Migraine increases with age, with a striking increase around puberty. Prevalence ranges from ∼3% between 3 and 8 years of age, to as high as 19% by early adolescence. Although the gender ratio is similar before puberty, significantly higher numbers of girls are affected after puberty. The inheritance of migraine both with and without aura is most likely multifactorial and controlled by more than one gene. Genetic and environmental factors play important roles in migraine pathogenesis, with genetic factors being more significant in migraine with aura than in migraine without aura. Congdon and Forsythe showed that 77% of children who had migraine with aura, and 67% who had migraine without aura had at least one first-degree relative with migraine (Congdon and Forsythe, 1979).
The impact of migraine on children and adolescents can be significant. Recurrent headaches may lead to school absenteeism, impaired school performance, and affected interpersonal development resulting from restricted sport, work, recreation, and family activities.
The diagnosis of migraine is based on clinical history and a physical examination that excludes signs of symptomatic causes of headache. The International Headache Society (IHS) has published criteria for this diagnosis (Headache Classification Committee of the IHS, 1988); however, the sensitivity of these “adult” criteria in children is low (Maytal et al., 1997). To address this low sensitivity, revised IHS (IHS-R) criteria were proposed and evaluated in a multicenter, prospective study by the Pediatric Headache Committee of the American Association for the Study of Headache in 1997 (Winner et al., 1997). Overall, the diagnosis of migraine with or without aura was established in 66% of cases by using IHS criteria, but improved to 93% by using IHS-R criteria. In children younger than 12 years, the results were even more striking, with diagnostic rates improving from 49 to 87%.
The incidence of migraine may be increased in children with BREC; however, studies have been limited by small numbers of patients and lack of clearly stated diagnostic criteria for childhood migraine (Kinast et al., 1982; Bladin, 1987; Giroud et al., 1989; Septien et al., 1991; Andermann and Andermann, 1992; Ong et al., 1999; Andermann, 2000). Hence, not all pediatric neurologists are supportive of this association (Santucci et al., 1985; Andermann and Zifkin, 1998).
Determination of whether migraine is more common in children with BREC may assist in our understanding of the pathophysiology of both BREC and migraine and would stimulate research in this area. Better understanding of pathophysiology may lead to more effective treatments. Second, if migraine is significantly more common in BREC, we would be able to offer anticipatory guidance to these children and their families, allowing earlier identification and treatment, to minimize the impact that recurrent migraine may have on school performance and social functioning.
In this study, we compared the prevalence of migraine in children and their biologic parents in three cohorts: BREC, cryptogenic or symptomatic partial epilepsy, and healthy controls, to determine whether migraine was more prevalent in the BREC group.
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Fifty-three children in each cohort were recruited. Gender ratio was 35M/18F, in each cohort, and mean ages (SD, range) were 9.8 years (2.6; 5.7–17.7) for the BREC cohort, 9.8 years (2.7; 5.2–17.0) for the cryptogenic/symptomatic partial epilepsy cohort, and 9.9 years (2.6; 5.8–18.2) for the nonseizure cohort (p = NS). Two of 55 cases of BREC approached for the study declined participation and were thus excluded from the study. Four of 57 controls with cryptogenic/symptomatic partial epilepsy did not consent to the interview. For these triads, another similar matched control with cryptogenic/symptomatic partial epilepsy was approached, and all agreed to participate. Seizure data for both the BREC and cryptogenic/symptomatic partial epilepsy are shown in Table 1. Compared with the cryptogenic/symptomatic partial epilepsy controls, cases with BREC were significantly more likely to have simple partial seizures (p < 0.01), to be taking fewer AEDs at present (p < 0.01) and ever (p < 0.03), and they tended to have fewer total seizures (p = 0.05). Of the cryptogenic/symptomatic partial epilepsy group, 15 (28%) had frontal foci, 12 (23%) had temporal foci, three (6%) had frontotemporal foci, three (6%) had occipital foci, one (2%) had parietal foci, eight (15%) had central foci, and 10 (19%) had foci in more than one region. Five (9.4%) of the cryptogenic/symptomatic partial epilepsy cohort had undergone prior epilepsy surgery.
Table 1. Characteristics of seizure cohorts
| ||BREC cohort||Cryptogenic/ symptomatic partial epilepsy cohort|
|Median age at seizure onset in yr (25, 75%ile)||7.3 (5.5, 8.5)||5.2 (3.0, 7.5)|
| -Simple partial only||23/53 (43%)||5/53 (9%)|
| -Complex partial ± simple partial||8/53 (15%)||20/53 (38%)|
| -2° generalized ± complex or simple partial||22/53 (42%)||28/53 (53%)|
|Median number of current AEDs (25, 75%ile)||1 (0, 1)||1 (1, 2)|
|Median number of AEDs ever used (25, 75%ile)||1 (0, 1)||2 (1, 3)|
|Median number of seizures in past (25, 75%ile)|| 5 (2, 16)|| 20 (7, 100)|
|Proportion seizure free in the past yr||17/53 (32%)||24/53 (45%)|
Prevalence of headache and migraine equivalents in cohorts
The number of cases in each cohort with definite, probable, possible, and nonmigraine headaches, and the number of cases in the two seizure cohorts with exclusively postictal headaches are shown in Table 2. No significant differences were found in prevalence of migraine between cases with BREC and cryptogenic/symptomatic partial epilepsy controls, although the latter group had a higher rate of headache confined to the postictal period (p < 0.02). Compared with nonseizure controls, cases with BREC tended to have higher rates of definite and probable migraine (p = 0.05) and of definite, probable, and possible migraine (p = 0.05). Eight children in the cryptogenic/symptomatic partial epilepsy cohort reported their headaches to occur solely postictally versus none in the BREC cohort. Of these eight, three had headaches resembling definite migraine, one had headaches resembling possible migraine, and four had headaches with no migrainous features.
Table 2. Prevalence of headache in cohorts
| ||BREC n = 53 (%)||Cryptogenic/ symptomatic partial epilepsy n = 53 (%)||p Valuea||Nonseizure n = 53 (%)||p Valueb|
|Definite migraine|| 3 (5.7%)|| 4 (7.5%)|| 0.70||1 (1.9%)||0.31|
|Definite or probable migraine|| 6 (11.3)|| 6 (11.3)||1.0||1 (1.9)||0.05|
|Definite, probable, or possible migraine||11 (20.8)|| 9 (17.0)|| 0.62||4 (7.5)||0.05|
|Nonmigraine||24 (45.3)||24 (45.3)||1.0||27 (50.9)||0.56|
|No headache||18 (34.0)||12 (22.6)|| 0.20||22 (41.5)||0.42|
|Postictal headache only||0||8c (15.1)||<0.02||N/A||—|
No significant differences were found between cohorts for migraine with aura, but numbers of children with this diagnosis were small (BREC, two of 53; cryptogenic/symptomatic partial epilepsy, one of 53; nonseizure, one of 53).
The prevalence of migraine equivalents for each cohort are shown in Table 3. Again, no significant differences were seen between the two epilepsy cohorts. However, compared with the nonseizure cohort, children with BREC had significantly higher rates of benign paroxysmal vertigo (p < 0.03) and of any migraine equivalent, excluding motion sickness (p < 0.005).
Table 3. Prevalence of migraine equivalents in cohorts
| ||BREC (%)||Cryptogenic/ symptomatic partial epilepsy (%)||p Valuea||Nonseizure (%)||p Valueb|
|Benign paroxysmal vertigo|| 5 (9.4%)|| 7 (13.2%)||0.54||0 (0%)||<0.03 |
|Cyclical vomiting|| 2 (3.8)||5 (9.4)||0.24||0 (0) ||0.15|
|Abdominal migraine|| 7 (13.2)||11 (20.8)||0.30||2 (3.8)||0.08|
|Alice in Wonderland|| 3 (5.7)||3 (5.7)||1.0 ||1 (1.9)||0.31|
|The Rushes|| 3 (5.7)|| 6 (11.3)||0.30||0 (0) ||0.08|
|Benign paroxysmal torticollis|| 1 (1.9)||2 (3.8)||0.56||0 (0) ||0.32|
|Aura only|| 5 (9.4)|| 8 (15.1)||0.37||1 (1.9)||0.09|
|Motion sickness||12 (22.6)|| 9 (17.0)||0.47||20 (37.7)||0.09|
|Any of the above equivalents||24 (45.3)||25 (47.2)||0.85||22 (41.5)||0.70|
|Any migraine equivalent excluding motion sickness||18 (34.0)||23 (43.4)||0.42||4 (7.5)|| <0.005 |
Prevalence of headache, aura only, and motion sickness in biologic parents of cohorts
We were able to speak directly to 91% of mothers (BREC cohort, 84%; cryptogenic/symptomatic partial epilepsy cohort, 92%; and nonseizure cohort, 93%) but only to 53% of fathers (BREC cohort, 58%; cryptogenic/symptomatic partial epilepsy cohort, 51%; and nonseizure cohort, 50%) who were reported to have headache. The prevalence of headache, aura without headache, and motion sickness in the biologic mothers and fathers of children in each of the three cohorts are shown in Table 4. No significant differences in either prevalence of migraine, aura only, or motion sickness were found between cohorts, with the exception that mothers of children with cryptogenic/symptomatic partial epilepsy had a significantly higher rate of aura only (p < 0.005).
Table 4. Prevalence of headache, aura only, and motion sickness in biologic parents
| ||BREC (%)||Cryptogenic/ symptomatic partial epilepsy (%)||p Valuea||Nonseizure (%)||p Valueb|
|Mother|| (n = 53)|| (n = 53)|| || (n = 53)|| |
| Definite migraine|| 12 (22.6%)|| 12 (22.6%)||1.0 || 13 (24.5%)||0.82|
| Definite or possible migraine||17 (32.1)||14 (26.4)||0.52||16 (30.2)||0.83|
| Nonmigraine||30 (56.6)||35 (66.0)||0.32||30 (56.6)||1.0 |
| Motion sickness||25 (47.2)||26 (49.1)||0.85||26 (49.1)||0.85|
| Aura only||3 (5.7)||14 (26.4)|| <0.005 || 9 (17.0)||0.07|
|Father|| (n = 50) || (n = 47) || || (n = 52) || |
| Definite migraine|| 5 (10.0)|| 8 (17.0)||0.31||5 (9.6)||0.95|
| Definite or possible migraine|| 7 (14.0)|| 9 (19.1)||0.50|| 7 (13.2)||0.94|
| Nonmigraine||19 (38.0)||26 (55.3)||0.09||29 (55.8)||0.07|
| Motion sickness||12 (24.0)||11 (23.4)||0.95||15 (28.8)||0.58|
| Aura only||2 (4.0)||5 (9.4)||0.21||2 (3.8)||0.97|
Epilepsy characteristics of children with BREC, stratified for presence of migraine
Of the 53 children with BREC, eight had a history of Todd paresis, two had at least one prior bout of status epilepticus, eight had developmental delay, and 12 had tried more than one AED. The presence of definite, probable, or possible migraine did not predict higher seizure number (p = 0.61), history of Todd paresis (p = 0.69), history of status epilepticus (p = 0.46), developmental delay (p = 0.21), or history of AED failure (p = 0.69).
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The literature to date has given conflicting data concerning the association of BREC and migraine (Kinast et al., 1982; Santucci et al., 1985; Bladin, 1987; Giroud et al., 1989; Septien et al., 1991; Andermann and Andermann, 1992; Andermann and Zifkin, 1998; Ong et al., 1999; Andermann, 2000), but all previously published studies were done before publication of the proposed IHS-R criteria. These criteria have improved diagnostic sensitivity, particularly in children aged 12 years and younger (Winner et al., 1997).
In 1989, Giroud et al. compared the incidence of migraine in four groups of children: (1) 28 children with absence epilepsy, (2) 42 children with BREC, (3) 38 children with partial epilepsy, and (4) 30 children with head trauma (Giroud et al., 1989). The incidence of migraine in BREC was 62%, compared with 34% in children with absence epilepsy, 8% in those with partial epilepsy, and 6% in those with a history of head trauma. In 1987, Bladin (Bladin, 1987) followed up 30 cases of BREC and noted that 20 (67%) patients had recurrent headaches during the evolution of seizures, and 24 (80%) developed typical migraine after remission of BREC. Two studies of the Cleveland Clinic suggested that children with migraine are more likely to show benign focal epileptiform discharges; however, none of these children studied had clinical seizures (Kinast et al., 1982; Ong et al., 1999). In contradistinction to these results, Santucci et al. (1985) found no significant difference in migraine prevalence between children with BREC and normal controls.
Although we did find that migraine tended to be more common in children with epilepsy compared with those without seizures, the prevalence did not differ between those with BREC and with cryptogenic/symptomatic partial epilepsy. Unlike the study by Bladin (1987), however, the majority of our children were surveyed during the “active” phase of their BREC, with 68% having had seizures within the preceding year. We therefore cannot comment on whether they will be more likely to develop migraine after remission of BREC. In addition, we found that migraine equivalents (excluding motion sickness) were also significantly more common in the cohorts with epilepsy.
The coexistence of migraine and epilepsy has been well documented in the adult literature. Ottman and Lipton (1994) found that adults with epilepsy had a twofold increased rate of migraine compared with their first-degree relatives. In children, only a single published study exists on this topic. Yamane et al. (2004) compared the prevalence of headache in 50 children with epilepsy with that of their nonepilepsy siblings and found that headache was significantly more common in the epilepsy group (46% vs. 2.5%; p < 0.01). Nearly half of children with headache had migraine, and more than one third described a temporal relation between their headaches and seizures. Some authors have also noted frequent postictal headache in children with occipital epilepsy (Andermann and Zifkin, 1998).
Several recent reports also found that migraine-like headaches occur in approximately one fourth of adults with partial epilepsy in the postictal period (Ito et al., 2004; Yankovsky et al., 2005). In our study, postictal headaches occurred much more commonly in those with cryptogenic/symptomatic partial epilepsy than in the BREC group (21 of 53 vs. four of 53; p < 0.001). However, migraine-like features were present in approximately half of postictal headaches in both cohorts; meaning that only two of 53 children with BREC but 10 of 53 children with cryptogenic/symptomatic partial epilepsy had postictal headaches with clear migrainous features. No child with BREC had exclusively postictal headaches, whereas this pattern was seen in eight of 53 cases of cryptogenic/symptomatic partial epilepsy.
The pathophysiologic link between epilepsy and migraine is unknown. Does an underlying susceptibility predisposes to both conditions, or do seizures predispose to migraine, or vice versa?
As previously noted, migraine has a strong genetic predisposition. However, in our study, we found no difference in the prevalence of migraine in the biologic parents of any of the cohorts, making it less likely that the seizure groups had a higher genetic predisposition to migraine. The rates of migraine found in parents in all three cohorts were consistent with those reported in epidemiologic studies (Sheffield, 1998). Similarly, Ottman and Lipton (Ottman and Lipton, 1996) also found no evidence of a shared genetic susceptibility for epilepsy and migraine.
Cerebral hyperexcitability has been implicated in both disorders. Although the underlying neurobiologic mechanisms for hyperexcitability are not well defined for migraine, dysfunction of mitochondria and low magnesium levels may play a role (Welch, 2005). Additionally, as ion channels directly control membrane excitability of neurons, they may play a pivotal role in both migraine and epilepsy. Also intriguing is the fact that many AEDs, which affect neuronal excitability, also have efficacy in the treatment of migraine (Welch, 2005). In migraine, however, evidence for abnormal channels exists only for one uncommon syndrome, familial hemiplegic migraine (FHM). FHM type 1 is due to a mutant calcium channel, which allows influx of calcium in response to small depolarizations insufficient to open wild-type channels (Bolay et al., 2002; Moskowitz et al., 2004), whereas type 2 results from an abnormal catalytic subunit of a sodium–potassium ATPase (De Fusco et al., 2003). Although various channelopathies have been demonstrated as causes for rare monogenic idiopathic epilepsy syndromes (Mulley et al., 2003), their etiologic role in the majority of epilepsies still must be defined.
Is it possible that recurrent seizures make the brain more susceptible to migraine or vice versa?Moskowitz and colleagues (2004) have shown that cortical spreading depression can activate the meningeal trigeminovascular afferents, resulting in changes in the meninges and brainstem in animals, consistent with activation of trigeminal nociceptive pathways and development of head pain (Bolay et al., 2002; Moskowitz et al., 2004). Although cortical spreading depression is more difficult to elicit in the human cortex, it may occur much more readily in injured human brain (Strong et al., 2002; Parsons et al., 2004). Recurrent seizures might also predispose to this phenomenon, and the particularly high prevalence of migraine-type headaches occurring periictally in both our study and those of others (Ito et al., 2004; Yankovsky et al., 2005) is of interest. Cortical spreading depression leads to significant changes in the composition of extracellular fluid in rats, including increases in glutamate and K+ ions (Somjen, 2001; 2002). These changes will, in turn, result in hyperexcitability and possibly lowering of the seizure threshold. Rare cases of “migralepsy” have been reported in which a classic migraine attack evolves into an epileptic seizure (Mulligan and Bromfield, 2005). Theoretically, repeated bouts of migraine in combination with genetic or environmental factors may lead to focal cortical injury and reorganization.
This study has number of strengths. Children were age and gender matched to control variations in migraine prevalence resulting from these factors. Our study also used well-defined, accepted IHS-R criteria to diagnose migraine in children. However, as most of our study population was younger than 12 years, an age at which diagnostic sensitivity can still be problematic, we included both probable and possible categories of migraine to capture children with probable migraine who did not clearly meet IHS-R criteria. We also specifically queried the timing of headaches in relation to seizures, allowing differentiation of headaches occurring solely during the periictal period, from those occurring at other times.
One possible weakness is that many of our patients in both epilepsy cohorts were taking AEDs, which may also be efficacious in the treatment of migraine (Welch, 2005). However, this potential confounder would lead to an underestimation of the true migraine prevalence in the epilepsy cohorts, meaning that children with partial epilepsy are even more likely to develop migraine than our study shows. Additionally, those with cryptogenic/symptomatic partial epilepsy were more likely to be taking AEDs at the time of study than were those with BREC, leading to greater potential to mask their migraine tendency. Therefore children with nonidiopathic partial epilepsy may be at highest risk of migraine.
A second weakness is that, although we attempted to speak to each parent with a history of headaches to increase the accuracy of our data, this was not possible for nearly half of fathers. As such, the prevalence data for migraine in fathers may be inaccurate.
This study confirms the increased prevalence of migraine in children with epilepsy; however, it does not support the concept that those with BREC have a substantially higher rate of migraine than do other epilepsy types. Further investigation of the underlying pathogenesis of this link may lead to improved understanding of the role of ion channels in focal epilepsies and migraine.