Headache

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Migralepsy: Is the Current Denition Too Narrow?

Ferdinando Maggioni, MD; Edoardo Mampreso, MD; Silvia Ruffatti, MD; Federica Viaro, MD; Viviana Lunardelli, MD; Giorgio Zanchin, MD

The relationship between epilepsy and migraine is complex and remains to be determined. We report 3 cases that address 2 questions on this topic. The rst and second cases showed an association between migraine without aura and the onset of epileptic seizures. The third case report describes a patient in whom migraine with aura occurred and was followed by the development of status epilepticus, which occurred 2 or 3 hours after the attack of migraine with aura. We discuss the present denition of migralepsy and reassess its denition by suggesting possible extensions to its current denition. Key words: migraine without aura, migraine with aura, epilepsy, status epilepticus, migralepsy

The clinically based hypothesis that migraine and epilepsy are related dates back to the 19th century.1,2 At present, these 2 disorders are considered 2 paroxysmal diseases that display epidemiological and clinical comorbidity.1 The prevalence of epilepsy in a population of migraine sufferers ranges between 1% and 17% with a median of 5.9%3 and this prevalence is conspicuously higher than the 0.5% prevalence of epilepsy that is found in the general population.4 The prevalence of migraine in patients with epilepsy is high and ranges between 8.4% and 20%.1 Headache develops very frequently after an epileptic seizure but it is rare that a migraine attack triggered an epileptic seizure (1.7-3%).5,6 This phenomenon, dened as migralepsy, is codied in International Classication of Headache Disorders II (ICHD-II), 1.5.5 (IHS, 2004).7 According to ICHD-II, the diagnosis of migralepsy should fulll 2 diagnostic criteria: 1. Migraine fullling criteria for 1.2 Migraine with aura (MA). 2. A seizure fullling diagnostic criteria for 1 type of epileptic attack occurs during or within one hour after a migraine aura. The other known associations between headache and epilepsy are also included in ICHD-II and are called Hemicrania epileptica 7.6.1 and Post-ictal headache 7.6.2.7
From the University of PaduaDepartment of Neurosciences, Padova, Italy (F. Maggioni, E. Mampreso, S. Ruffatti, F. Viaro, V. Lunardelli); University Headache Center, UCADH Department of Neurosciences, Padova, Italy (G. Zanchin). Address all correspondence to F. Maggioni, University of PaduaDepartment of Neurosciences, Via Giustiniani 5, 35128 Padova, Italy. Accepted for publication January 22, 2008.

In this communication, we report 3 cases. In 2 cases, the seizures were triggered by a migraine without aura (MO). In the third case, we describe a patient in which an MA attack resulted in the development of status epilepticus, and in which the seizures developed more than one hour after the attack of MA.

CASE REPORTS Case One.A 32-year-old woman shop assistant presented with a history of MO and epilepsy. The patient had been delivered by Cesarean section in the 8th month of her mothers pregnancy because of pre-eclampsia. Her mother suffered from MA and MO, but no other member of her family had a history of epilepsy. The patient was slightly mentally retarded, the cause of which had been investigated in her childhood. This investigation did not reveal any organic ndings. The patient had frequented a professional school. She underwent menarche when she was 11 years old and her menstrual cycles were regular. When the patient was 5 years old, she developed epileptic seizures that were typical of absence and tonic-clonic seizures. She was treated initially with phenobarbital and ethosuximide and then later with valproic acid (VPA). From the age of 8 years, the antiepileptic therapy was effective, and provided complete control of the attacks and electroencephalogram (EEG) normalization. The patient discontinued her therapy when she was 20 years old. From 2000 onward, the patient began experiencing MO attacks, which were characterized by a pulsating pain and were accompanied by phonophobia, photophobia, nausea, and often vomiting. She reported having between 2 and 3 attacks each month. One of the attacks was related to hermenses. The duration was between 8 and 12 hours.

Conict of Interest: None

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The patient treated herself with a nonsteroidal antiinammatory drug, and the treatment was efcacious. In 2003, the patient, after being free of seizures for 23 years, presented again with a tonic-clonic generalized epileptic attack and had a further 5 such attacks during the next 2 years. All the seizures occurred while she was experiencing an MO attack. On one occasion, status epilepticus developed. The results of physical and neurological examinations, and laboratory investigations, which included a complete blood count, coagulation studies, basic metabolic and thyroid function tests, electrocardiogram (ECG), X-ray of the chest, and brain magnetic resonance imaging (MRI) and angio-MRI using gadolinium, were negative. The results of the EEG revealed slightly abnormal activity. The patient recommenced antiepileptic therapy with VPA, and the treatment provided her with complete control of the seizure and migraine attacks. After 8 months, VPA was substituted with 100-mg lamotrigine b.i.d. because of an increase in the activity of her serum transaminases. Treatment with lamotrigine controlled the epileptic attacks, but not the MO attacks, which recurred at a frequency of 2 attacks each month.

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lepticus. She was married and was the mother of a 6-yearold daughter. At the time of the patients birth, her mother had had a dystocic labor that required a forceps delivery that resulted in hypoxic congenital encephalopathy, without neurological decit. When the patient was 3 years old, she had 3 generalized tonic-clonic seizures within a few months. She started treatment with phenobarbital, which was maintained until she was 10 years old. When she was 26, she experienced an attack that was characterized by visual disturbance. At the time, she reported: I see like a sparkling top, turning increasingly faster to the left side. This event, which lasted about 30 minutes, was followed by pulsating, severe, and diffuse pain that was aggravated by physical movement and was accompanied by nausea and vomiting. After about 3 hours, at home, she had a generalized tonicclonic epileptic seizure. During her transfer to the hospital and again in the ER, she had 3 tonic-clonic epileptic seizures with morsus and incontinence. The results of the laboratory investigations, an ECG, and radiological examination of the chest were negative. The results of brain MRI without enhancement by gadolinium showed numerous alterations in the region of the periventricular white matter.This nding was considered to be due to the hypoxic event that occurred at the time of her birth. The results of the EEG, which was performed in the ER, showed prolonged bursts of spikes in the right temporal region with hemispheric diffusions. The patient was treated with intravenously administered lorazepam, which resolved the attack. She was then transferred to the Neurologic Clinic for further assessment and subsequent treatment.Therapy with 400-mg carbamazepine b.i.d. was started. Over the next 3 years, the patient has had 5 attacks of MA that were followed 2 or 3 hours later by an epileptic seizure. These seizures were left motor focal seizures and showed secondary generalization with tonicclonic seizures and the development of status epilepticus. The results of an interictal EEG showed only rare bursts of bilateral temporal sharp activity. Her therapy was then modied, and at present the patient is being treated with 1800 mg/day VPA and 1000-mg levetiracetam b.i.d. She has remained asymptomatic for the last 2 years for both attacks of MA and epileptic seizures.

Case Two.A 19-year-old man student presented after 2 MO attacks, during which a generalized epileptic attack with tonic-clonic seizures occurred. His mother had suffered from MO but the patient reported that he had never suffered previously from migraine or had any seizures.At the time of presentation, he reported that he had had 2 migraine attacks, 2 months apart from one to the other. In each attack, he experienced pulsating pain in the left periorbital region, with nausea, phonophobia, and photophobia, all of which were aggravated by physical movement. During 1 attack, the patient vomited. Both attacks lasted about 5 hours and developed in the evening. During the attacks, the patient rested in bed and, in the drowsiness phase, he developed tonic-clonic seizures with tongue biting and incontinence. The physical, neurological, and laboratory examinations, which included a complete blood count, an ECG. X-ray of the chest, brain imaging (MRI and angio-MRI using gadolinium), and extracranial and transcranial Doppler sonography were normal. The results of the EEG performed some hours after the attacks showed only frontal minor sharp activity. After the second attack, therapy with 300-mg VPA b.i.d. was started. The results of follow-up examinations and of the EEG that were performed during the subsequent 18 months were negative and the patient reported that he was no longer experiencing MO attacks and seizures. Case Three.A 31-year-old woman bookshop clerk
was admitted to the emergency room (ER) with status epi-

DISCUSSION
The literature considered for the denition of migralepsy, in the references reported in ICHD-II, was derived by reviewing 2 published reports of 13 and 7 cases of MA, and a single case report in which the seizure was preceded by an MO attack and was due to a reversible lesion, as veried by a brain MRI scan.5,6,8 In the literature, we found

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descriptions of an additional 2 series of MA with seizures patients, namely, a report of 5 cases by Andermann3 and a report of 8 cases by Niedermeyer.9 The rst of these reports was published before the publication of IHS classication in 1988.10 In addition, there are 2 published case reports of MA.11,12 Therefore, to the best of our knowledge, there are 35 well-described cases of migralepsy in adults. Recently, Ludvigsson et al reported that MA could be considered a risk factor for unprovoked seizures in children.13 The relationship between MA and epilepsy is complex and the mechanism of the association is unknown. It is hypothesized that the occipital cortex of migraineurs has a low excitation threshold and a migraine attack may trigger the seizures.14 In this hypothesis, genetic factors may have a role in causing the primary seizure and the migraine attack because hereditary calcium channelopathies have been described.15 During MA cortical spreading depression occurs that could trigger subsequent seizures. In addition, there are changes in cerebral perfusion.16 This vascular mechanism could be also advocated to produce brain lesions that themselves could promote the occurrence of seizures.17 Headache develops very frequently in patients after an epileptic seizure but it is rare that a migraine attack triggers an epileptic seizure (1.7-3%).5,6 According to the denition given in ICHD-II, migralepsy is considered only to be associated with MA attacks.7 An MO attack is reported very rarely as being a trigger for an epileptic seizure. In this regard, we are aware of 3 case reports8,18,19 and 4 patients in a series of 59 patients with preictal headache in partial epilepsy.20 In this report, cases 1 and 2 provide evidence of the existence of a close relationship between MO and epilepsy. The mechanisms previously reported for MA could be hypothesized also to occur in MO, in which imaging studies point to the presence of silent cortical spreading depression.21-23 Moreover, the cortical blood ow changes closely resemble those observed in MA,22,23 without an evident clinical correlate.24 To explain the pathogenesis of the seizures in case 1, we hypothesize that the organic birth-related brain damage could favor seizures, even though the results of neuroimaging were negative, and normalization of EEG during childhood after the start of therapy occurred. Therefore, it is possible that the development of MO attacks could favor the recurrence of seizures. In case 2, which is a case of probable migraine because the patient had only 2 attacks, both seizures occurred between 4 and 5 hours after the beginning of an MO attack, when the patient was resting in bed and was falling asleep. Dozing and sleep are conditions that can lower the seizure threshold. According to the present denition of migralepsy in ICHD-II, these 2 cases are not con-

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sidered cases of migralepsy because they are associated with MO. In case 3, in which a correlation between MA and epileptic seizures exists, an organic predisposing condition that could favor the development of epileptic seizures was present. We highlight that this patient, after her childhood, presented always a close association between MA and the onset of seizures. According to the present denition of migralepsy in ICHD-II, this case also cannot be classied as one of migralepsy because the onset of seizures occurred more than one hour after MA. The fact that in the last 2 cases all migraine attacks and seizures occurred together could probably stress the role of migraine (MA, but also MO) on a pre-existing low epileptic threshold. In conclusion, we propose that further studies on this topic are required to clarify a possible extension to the denition of migralepsy that includes MO-triggered epileptic seizures. Furthermore, we suggest that these deliberations consider also that migralepsy include MA-associated epileptic seizures that occur during a migraine attack, and that the onset of seizures can be independent of the interval between aura and seizure. In addition, with reference to the rst of these 2 issues, we believe that migralepsy occurs more frequently than it is reported because the epileptic event overshadows the MO.

REFERENCES
1. Lipton RB, Ottman R, Ehrenberg BL, Hauser WA. Comorbidity of migraine: The connection between migraine and epilepsy. Neurology. 1994;44(10 Suppl. 7):S28-S32. 2. Bigal ME, Lipton RB, Cohen J, Silberstein SD. Epilepsy and migraine. Epilepsy Behav. 2003;4:S13-24. 3. Andermann F. Clinical features of migraine-epilepsy syndrome. In: Anderman F, Lugaresi E, eds, Migraine and Epilepsy. Boston, MA: Butterworth; 1987:20-89. 4. Hauser WA, Anneger JF, Kurlan LT. Prevalence of epilepsy in Rochester, Minnesota. Epilepsia. 1991;32:429-445. 5. Markas DA, Ehrenberg BL. Migraine-related seizures in adults with epilepsy, with EEG correlation. Neurology. 1993;43:2476-2483. 6. Velioglu SK, Ozmenoglu M. Migraine-related seizures in an epileptic population. Cephalalgia. 1999;19:797-801. 7. Headache Classication Subcommittee of the International Headache Society. The international classication of headache disorders: 2nd edition. Cephalalgia. 2004;24 (Suppl. 1):9-160. 8. Friedenberg S, Dodick DW. Migraine-associated seizure: A case of reversible MRI abnormalities and persistent non dominant hemisphere syndrome. Headache. 2000;40:487490. 9. Niedermeyer E. Migraine-triggered epilepsy. Clin EEG. 1993;24:37-43.

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10. Headache Classication Subcommittee of the International Headache Society. The international classication of headache disorders: 2nd edition. Cephalalgia. 1988;24 (Suppl. 1):9-160. 11. Friedenberg S, Dodick DW. Migraine-associated seizure: A case of reversible MRI abnormalities and persistent nondominant hemisphere syndrome. Headache. 2000;40:487490. 12. Milligan TA, Bromeld E. A case of migralepsy. Epilepsia. 2005;46:2-6. 13. Ludvigsson P, Hesdorffer D, Olafsson E, Kjattansson O, Hauser WA. Migraine with aura is a risk factor for unprovoked seizure. Ann Neurol. 2006;59:210-213. 14. Aurora SK, Cao Y, Bowyer SM, Welch KMA. The occipital cortex is hyperexcitable in migraine: Experimental evidence. Headache. 1999;39:469-476. 15. Welch KMA, Lewis D. Migraine and epilepsy. Neurol Clin. 1997;15:107-114. 16. Lauritzen M, Olesen J. Regional cerebral blood ow during migraine attacks by Xenon-133 inhalation and emission tomography. Brain. 1984;107:447-461. 17. Ottman R, Lipton RB. Is the comorbidity of epilepsy and migraine due to a shared genetic susceptibility? Neurology. 1996;47:918-924.

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18. Mateo I, Foncea N, Vicente I, Beldarrain MG, GarciaMonaco JC. Migraine-associated seizures with recurrent and reversible magnetic resonance imaging abnormalities. Headache. 2004;44:265-270. 19. Merlino G, Valente MR, DAnna S, Gigli GL. Seizures with prolonged EEG abnormalities during an attack of migraine without aura. Headache. 2007;47:919-922. 20. Yankovsky AE, Anderman F, Mercho S. Preictal headache in partial epilepsy. Neurology. 2005;65:1979-1981. 21. Cao Y, Welch KM, Aurora S, Vikingstad EM. Functional MRI-BOLD of visual triggered headache in patients with migraine. Arch Neurol. 1999;56:548-554. 22. Woods RP, Iacoboni M, Mazziotta JC. Bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med. 1994;331:1689-1692. 23. Geraud G, Denuelle M, Fabre N, Payoux P, Chollet F. Positron emission tomographic studies of migraine. Rev Neurol (Paris). 2005;161:666-670. 24. Sanchez-del-Rio M, Reuterb U, Moskowitz MA. New insights into migraine pathophysiology. Curr Opin Neurol. 2006;19:294-298.

Hemicrania ContinuaLike Headache With Leprosy: Casual or Causal Association?

Sanjay Prakash, MD; Saumil Y. Dholakia, MD

Hemicrania continua is a strictly unilateral, moderate to severe, continuous, indomethacin-responsive primary headache disorder with ipsilateral autonomic cranial symptoms at the time of exacerbations. We describe a 30-year-old woman with a 4-month history of indomethacin-responsive hemicrania continualike headache and one-month history of mononeuritis multiplex due to leprosy. Indomethacin was successfully weaned off after completion of antileprotic therapy. Key words: hemicrania continua, indomethacin-responsive headache, leprosy and cranial nerve palsy

Hemicrania continua (HC) is an unusual, though not rare, indomethacin-responsive primary headache. It is incorporated into group 4 of the International Headache Society (IHS) classication in the subheading of other
From the Department of Neurology, Medical College, Baroda, Gujarat, India (S. Prakash and S.Y. Dholakia). Address all correspondence to S. Prakash, O-19, Doctors Quarter, Jail Road, Baroda, Gujarat, 390001 India. Accepted for publication January 19, 2008.

primary headaches.1 HC is possibly a lifelong condition. Indomethacin provides only a remission, not a cure. Withdrawal of indomethacin generally allows the symptoms to appear after a variable latency period.2 Leprosy is one of the most important causes of peripheral neuropathy. Leprous neuropathy is characterized by the involvement of supercial nerve trunks in cooler regions of the body. Cranial nerve involvements, including the trigeminal nerve, are also commonly seen in patients of
Conict of Interest: None