Andermann and Andermann4 summarized a number of studies that examined the association between migraine and epilepsy. The prevalence of epilepsy in people with migraine ranged from 1% to 17%, with a median of 5.9%, substantially higher than epilepsy’s population prevalence of 0.5%. Migraine prevalence in patients with epilepsy ranged from 8% to 15%. Many of these studies were limited by the method of patient identification, the lack of appropriate control groups, and poorly specified definitions of migraine and epilepsy. Nonetheless, these studies powerfully argue that migraine and epilepsy are associated.
Ottman and Lipton43 examined the association between migraine and epilepsy using data from the Epilepsy Family Study of Columbia University. Subjects with epilepsy (probands) who were older than 18 years of age were identified and recruited from voluntary organizations for people with epilepsy. Among the probands with epilepsy, migraine prevalence was 24%. Migraine prevalence was 26% in the relatives with epilepsy. In the control group of relatives without epilepsy, only 15% had migraines. The gender-adjusted rate ratio (RR) for migraine in probands with epilepsy compared to relatives without epilepsy was 2.4 (95% confidence interval [CI]; 2.0–2.9). For relatives with epilepsy compared with relatives without epilepsy the RR was also 2.4 (95% CI; 1.6–3.8). These statistics indicate that the incidence of migraine is 2.4 times higher in people with epilepsy than in people without epilepsy.
Risk of migraine was not associated with the age of onset of epilepsy. The risk of migraine was elevated in both partial and generalized seizures, although the risk was higher for probands with partial-onset seizures than for those with generalized-onset seizures (RR = 1.3; 95% CI; 1.00–1.86). The risk of migraine was elevated in both idiopathic and symptomatic epilepsy. Probands with epilepsy caused by head trauma had a higher risk of migraine than probands with idiopathic or cryptogenic epilepsy (RR = 1.8, 95% CI; 1.32–2.43). Nonetheless, migraine risk was elevated in every subgroup of epilepsy defined by seizure type, age of onset, and etiology of epilepsy.44
The mechanisms of the association between migraine and epilepsy are complex and may be multifactorial.
One possibility is a simple unidirectional causal explanation. For example, migraine may cause epilepsy by inducing brain ischemia and injury. Under this hypothesis, we would expect the incidence of migraine to be elevated before, but not after, the onset of epilepsy. Alternatively, epilepsy may cause migraine by activating the trigeminovascular system. This hypothesis leads us to expect an excess risk of migraine after, but not before, the onset of epilepsy. The data show an excess risk of migraine both before and after seizure onset, leading to the rejection of both unidirectional causal models.
Marks and Ehrenberg6 explored the timing and features of headache in patients with epilepsy. They found that of 395 patients with epilepsy, 79 (20%) also had migraine according to International Headache Society (IHS) criteria. The attacks were completely independent in 66 (84%) of the 79 patients with both migraine and epilepsy. In the remaining 13 patients, a seizure immediately followed the migraine aura (migralepsy). Of these 13, 11 were women, 7 of whom had a catamenial pattern. Migralepsy was also seen in refractory patients with migraine and epilepsy in Andermann’s series,1 although this phenomenon does not account for the majority of the comorbidity.
Velioglu and Özmenoglu45 studied the relationship between migraine and epilepsy in 412 adults with epilepsy and reported that 14% had IHS migraine. Migraine-induced epilepsy (i.e., migralepsy) was found in 7 patients (1.7%); all had migraine with aura. These authors sometimes found it difficult clinically to distinguish the aura of migraine from the aura of epilepsy. Patients were at increased risk for both conditions if they had migraine with aura and catamenial epilepsy. Three of four patients with refractory seizures had improved control with the combination of antimigraine and antiepilepsy drugs.
Lenaerts46 evaluated the degree of comorbidity and tried to establish the pattern of temporal relationship between migraine and epilepsy in 201 patients from tertiary care clinics. He systematically reviewed charts, obtained additional information by telephone interviews where necessary, and applied IHS and International League Against Epilepsy diagnostic criteria. Two-tier grouping according to reason for referral (migraine or epilepsy) was done. Adequate information was obtained from 185 patients (113 women, 72 men). In the epilepsy-referred patient group (n = 103), 23% had migraine and a risk ratio of 1.9 (p = .01). In the migraine-referred group (n = 82), 11% had epilepsy and a risk ratio of 21 (p = .05). Of the 33 comorbid cases, 21 had their attacks in close temporal relation. The migraine attack preceded the seizure in 12 patients (57%; nine migraine with aura) and followed it in nine (43%; six migraine with aura). Migraine attacks equally precede or follow seizures, but migraine aura more often precedes the seizure (i.e., migralepsy).
Shared environmental risk factors may contribute to comorbidity. The risk of migraine is higher in subjects with epilepsy caused by head injury. Because head injury is also a risk factor for migraine,47 comorbidity may result, in part, from an effect of head injury on the risk of both disorders. Because risk is also significantly increased in people with idiopathic or cryptogenic epilepsy, however, known environmental risk factors cannot account for all of the comorbidity.
Ottman and Lipton7 tested the alternative hypothesis that shared genetic risk factors might account for comorbidity. They argued that the risk of migraine should be higher in families with genetic versus nongenetic forms of epilepsy, if genetic factors account for comorbidity. They further argued that the risk of epilepsy should be greater in the relatives of probands with migraine and epilepsy versus the relatives of probands with epilepsy alone. In a series of analyses, they adjusted for a number of potentially confounding factors, including age, gender, the familial aggregation of migraine, and the comorbidity of migraine and epilepsy. The analyses failed to confirm either of the authors’ hypotheses, leading them to reject the idea that genetic susceptibility accounts for comorbidity.43
Having rejected the unidirectional model, the environmental model, and the genetic hypothesis, they proposed that an altered brain state (increased excitability) might increase the risk of both migraine and epilepsy and account for comorbidity. Enhanced neuronal hyperexcitability and a reduced threshold to attacks figure prominently in the pathophysiologic models of migraine and epilepsy. Reduction in brain magnesium or perturbations in neurotransmitter systems may provide a basis for these alterations in brain excitability. In theory, genetic or environmental factors could produce these alterations. Regardless of mechanisms, these findings are important for clinical practice.
Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.
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