Comorbidity Headache and Epilepsy in Childhood

L. E. Yamane M. A. Montenegro Comorbidity Headache and M. M. Guerreiro Epilepsy in Childhood rgnlArticle Original

Abstract with idiopathic epilepsy. The headache usually starts in the same year or after the diagnosis of epilepsy. Rationale: Epilepsy and headache are both frequent in childhood. Because seizures are frequently a frightening event, other Key words medical conditions ± including headache ± are often neglected Epilepsy ´ headache ´ childhood not only by the patient, but also by the physician. The objective of this study was to verify the comorbidity between headache and epilepsy in childhood. Methods: This was a prospective study conducted at the pedi- Introduction atric epilepsy clinic of our university hospital. Fifty children with epilepsy and ability to describe their symptoms, between 5 and Headache is a frequent complaint in childhood and its diagnosis 18 years old, were interviewed according to a semi-structured and classification are based on clinical criteria according to the questionnaire. The headache was classified according to the In- International Headache Society [5]. Treatment options include ternational Headache Society. The frequency of headache was acute or episodic measures, prophylactic agents, and non-phar- compared with the findings of a control group composed by chil- macological or behavioral interventions [10]. dren without epilepsy, siblings of children with epilepsy. Results: Fifty children were evaluated, 29 boys, mean age 11 Epilepsy and headache are both frequent in childhood. Although years. Twenty-three (46%) patients presented with headache, as many antiepileptic drugs have proven efficacy in migraine pro- 99 opposed to only 1 (2.5%) in the control group (p < 0.01). Ten phylaxis [6,8,13,14], patients with epilepsy often present head- (43.5%) had migraine, 4 (17.4%) had tension type headache and ache, including migraine. However, because seizures are fre- in 9 (39.1%) the type of headache could not be established. In 9/ quently a dramatic and frightening event, other medical condi- 23 (39%) a temporal relationship between headache and epi- tions are often neglected not only by the patient, but also by the lepsy was present, 6 postictal and 3 preictal. There was no differ- physician. ence in gender, age, type of seizure and family history of headache in the groups of patients with or without headache. How- Most patients with chronic illness experience restrictions that ever, most patients with headache were older than 10 years may represent a major impact on their quality of life. As for (54.5%) and had idiopathic epilepsy (65.2%; p < 0.01). The head- adults, in childhood, recurrent headache episodes may be ex- ache usually started in the same year or after the diagnosis of ep- tremely disabling. The objective of this study was to evaluate ilepsy (95%; p < 0.01). the frequency and characteristics of headache in children with Conclusion: Headache and epilepsy are a common comorbidity epilepsy. in childhood, and occur mostly in children older than 10 years

Affiliation Department of Neurology, University of Campinas, Campinas, SP, Brazil Downloaded by: IP-Proxy CONSORTIUM:CAPES (UNICAMP Universidade Estadual de Campinas), Dot. Lib Information. Copyrighted material.

Correspondence Marilisa M. Guerreiro, M.D., PhD ´ Department of Neurology ´ University of Campinas ´ P.O. Box 6111 ´ 13083-970 Campinas, SP ´ Brazil ´ E-mail: [email protected]

Received: July 29, 2003 ´ Accepted after Revision: November 30, 2003

Bibliography Neuropediatrics 2004; 35: 99±102 Georg Thieme Verlag KG Stuttgart ´ New York ´ DOI 10.1055/s-2004-815831 ´ ISSN 0174-304X Patients and Methods Results

Patients Characteristics of the population This was a prospective study conducted at the pediatric epilepsy Fifty patients were evaluated, 29 boys, ages ranging from 5 to 18 clinic of our university hospital. We evaluated 50 consecutive pa- years (mean = 11). Twenty-eight (56%) patients had idiopathic, tients that met all the inclusion criteria. 13 (26%) cryptogenic, and 9 (18%) symptomatic epileptic syndromes. Thirty-five (70%) had partial and 15 (30%) had general- Inclusion criteria ized seizures (Table 1). ± age between 5 and 18 years; ± diagnosis of epilepsy according to the International League The type of antiepileptic drugs used were carbamazepine in 25 Against Epilepsy criteria [3]; patients, valproic acid in 16, clobazam in 5, phenytoin in 3, phe- ± patient should be able to describe his/her symptoms; nobarbital in 2 and topiramate in 1. ± informed consent signed by patient or guardian.

rgnlArticle Original Neuroimaging findings were normal in 42 (84%) patients. Four Exclusion criteria (8%) patients presented calcifications due to cysticercosis. Glio- ± unclear or unfaithful information given by patients or pa- sis, multiple calcifications due to toxoplasmosis, vascular lesion, rents; and focal cortical dysplasia were present in one patient each. ± mental retardation. EEG was normal in 28 (56%) patients, showed epileptiform ab- Data acquisition normalities in 16 (32%), non-epileptiform abnormalities in 5 Patients were interviewed according to a semi-structured ques- (10%) and for 1 this information was not available. tionnaire that included questions regarding type of headache, family history of headache, onset of headache in relation to the Twenty-three (46%) patients presented with headache, as op- diagnosis of epilepsy, timing of the headache according to the posed to only 1 in the control group (p < 0.01). Ten (43.5%) had seizure (preictal, ictal, or postictal), visual aura. Headache was migraine, 4 (17.5%) tension-type headache, and in 9 (39%) the classified according to the International Headache Society crite- type of headache could not be established. ria. Patients with visual aura were asked to draw a picture repre- senting the visual phenomena (Fig.1). There was no difference in the frequency of migraine among patients taking valproic acid (n = 4; 25%) or other types of antiepi- The frequency of headache was compared with that of a control leptic drug (n = 6; 24%; p = 0.941). For this analysis the patients group composed of patients without epilepsy, siblings of pa- taking topiramate (n = 1) or during withdrawal of the antiepilep- tients with epilepsy. We also assessed if patients taking valproic tic drug (n = 2) were excluded from the analysis. 100 acid ± which is considered effective for migraine prophylaxis ± presented a lower frequency of migraine. Patients with headache Among the patients with headache, there were 10 boys and 13 Statistical analysis was performed using the c2 test. girls. Fourteen had partial and 9 generalized seizures. There was Downloaded by: IP-Proxy CONSORTIUM:CAPES (UNICAMP Universidade Estadual de Campinas), Dot. Lib Information. Copyrighted material.

Fig.1aand baVisual aura associated with epilepsy (4 patients). b Visual aura associated with migraine (3 patients).

Yamane LE et al. Comorbidity Headache and ¼ Neuropediatrics 2004; 35: 99 ±102 Table 1 Characteristics of the patients Table 2 Characteristics of the patients with headache

Characteristics of the Patients Patients c2 Characteristics of the patients Patients with c2 patients with without headache headache headache (n = 23) (n = 23) (n = 27) Gender female 13 p = 0.376 Gender female 13 8 p =0.054 male 10 male 10 19 Age < 10 years 5 p = 0.0001 Age < 10 years 5 12 p = 0.091 ³ 10 years 18 ³ 10 years 18 15 Type of epileptic idiopathic 15 p = 0.0003 Type of idiopathic 15 13 p =0.466 syndrome cryptogenic 5

epileptic Article Original cryptogenic 5 8 symptomatic 3 syndrome symptomatic 3 6 Seizure type focal 14 p =0.140 Seizure type focal 14 21 p =0.193 generalized 9 generalized 9 6 Family history of positive 12 p =0.546 Family positive 12 9 p =0.135 headache negative 10 history of negative 10 18 n.a. 1 headache n.a. 1 0 Type of headache migraine 10 p =0.132 n.a. = not available tension type 4 not classified 9 Relationship be- before epilepsy 1 p =0.001 no difference between gender, seizure type, family history of tween onset of same year 14 headache and diag- headache, and type of headache (p > 0.05; Table 2). after epilepsy 8 nosis of epilepsy Temporal relation- yes 9 p =0.140 Most patients with headache were older than 10 years and had ship between head- no 14 idiopathic epilepsies (p < 0.01; Table 2). In 95% of the patients ache and epilepsy the headache started in the same year as or after the diagnosis Type of temporal re- preictal 3 p =0.157 of epilepsy (p < 0.01). In nine (39%) patients there was a temporal lationship between postictal 6 relationship between the headache and the epilepsy (seizure- headache and epilepsy associated headache), 3 preictal and 6 postictal. There was no ic- 101 tal headache. The type of preictal headache was migraine in 2 n.a. = not available and unclassified in 1. Two patients had postictal migraine and in 4 the type of postictal headache was unclassified. Migraine was the type of headache most often presented by our Visual auras patients. Clinical studies suggest that headache is commonly Eleven patients had visual auras, 1 epileptic, and 3 migraineous. associated with epilepsy, and there may be some similarities be- Because some had only blurred vision or blindness, only 7 pa- tween these two conditions [1,2,11,12,15]. This brings to mind tients were able to draw the visual phenomena. Four children whether both entities share a common pathophysiology. The with epileptic auras drew colorful pictures at the center of the neural mechanisms involved in migraine genesis are still un- visual field, while 3 children with migraineous auras drew dif- known. Although it is probably multifactorial, the interrelation- fuse and bright pictures (Fig.1). ship of vascular factors, genetic predisposition, trigeminal vascular reflex, spreading depression, and neurotransmitters such as serotonin and substances such as nitric oxide has not been clari- Discussion fied yet [18]. It is possible that some of these mechanisms also play a role in the genesis of seizures. Studies concerning the comorbidity headache/epilepsy are usually performed in adult populations, and are mostly about mi- There was a clear temporal relationship between the headache graine [1,2,11,12,15]. To our knowledge, this was the first study and the seizure in 39% (9/23) of the patients. Similarly to the that evaluated systematically the occurrence of headache ± not adult population, when there is a temporal relationship between Downloaded by: IP-Proxy CONSORTIUM:CAPES (UNICAMP Universidade Estadual de Campinas), Dot. Lib Information. Copyrighted material. only migraine ± in children with epilepsy. the two conditions, most seizure-associated headaches are postictal [4,9]. The type of seizure-associated headache was migraine We found that almost half of the patients with epilepsy also had (n = 4) or unclassified (n = 5). It is known that migraine is fre- headache. Although we could not identify risk factors associated quently associated with idiopathic epilepsy, especially benign with the comorbidity headache/epilepsy, most patients with occipital epilepsy of childhood [2]. However, the rate of unclassi- headache were older than 10 years and had idiopathic epilepsy. fied headache was also high, which is in keeping with the litera- Moreover, the onset of the headache was usually in the same ture [4]. This probably reflects the fact that the classification pro- year as or after the diagnosis of epilepsy. posed by the International Headache Society [5] does not include

Yamane LE et al. Comorbidity Headache and ¼ Neuropediatrics 2004; 35: 99 ±102 seizure-associated headache. Postictal headache may be related References to the region of the epileptic focus and the region of spread of the epileptic discharges [7]. 1 Andermann E, Andermann F. Migraine-epilepsy relationships: Epide- miological and genetic aspects. In: Andermann FA, Lugaresi E (eds). Migraine and Epilepsy. Boston: Butterworths, 1987: 281±291 Patients with migraine or occipital lobe epilepsy may have visual 2 Andermann F, Zifkin B. The benign occipital epilepsies of childhood: hallucinations, that is, the so-called ªauraº. Blindness, hemiano- an overview of the idiopathic syndromes and the relationship to mi- pia, and blurring of vision are features mainly associated with graine. Epilepsia 1998; 39: 9±23 3 migraine; however, they do occur in epilepsy. Occipital lobe sei- Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilep- zures are often characterized by elementary visual patterns such sies and epileptic syndrome. Epilepsia 1989; 30: 389 ±399 as small spots or colorful lights at the center of the visual field 4 Forderreuther S, Henkel A, Noachtar S, Straube A. Headache associat- [16,17]. The typical fortification spectra are nearly always indica- ed with epileptic seizures epidemiology and clinical characteristics. tive of migraine. Interesting to note is that the drawings of our Headache 2002; 42: 649±655 5 Headache Classification Committee of the International Headache So- patients are in keeping with the above observations: children ciety. Classification and diagnostic criteria for headache disorders,

rgnlArticle Original with epileptic auras drew central and colored pictures, while cranial neuralgias and facial pain. Cephalalgia 1988; 8: 1±96 children with migraineous auras drew diffuse and bright pic- 6 Hering R, Kuritzky A. Sodium valproate in the prophylactic treatment tures. of migraine: a double-blind study versus placebo. Cephalalgia 1992; 12:81±84 7 Ito M, Nakamura F, Honma H et al. Clinical factors associated with Although headache is a common comorbidity in children with post-ictal headache in patients with epilepsy. Acta Neurol Scand epilepsy, none of the patients was receiving specific treatment, 2000; 102: 129±131 8 either acute or prophylactic measures. All of them managed the Jensen R, Brinck T, Olesen J. Sodium valproate has a prophylactic effect in migraine without aura: a triple-blind, placebo-controlled crossover headache with over-the-counter medication, without medical study. Neurology 1994; 44: 647±651 advice. This clearly indicates that conditions other than epilepsy 9 Leniger T, Isbruch K, von der Driesch S, Diener HC, Hufnagel A. Sei- are often neglected by the physician. This is especially true in zure-associated headache in epilepsy. Epilepsia 2001; 42: 1176±1179 10 childhood; particularly because at this age the patients often do Lewis DW, Scott D, Rendin V. Treatment of paediatric headache. Ex- pert Opin Pharmacother 2002; 3: 1433±1442 not complain of new symptoms spontaneously. 11 Lipton RB, Ottman R, Ehrenberg BL, Hauser WA. Comorbidity of migraine: the connection between migraine and epilepsy. Neurology Surprisingly, although valproic acid is an antiepileptic drug con- 1994; 44: 28±32 12 sidered effective for migraine prophylaxis, we did not find a low- Marks DA, Ehrenberg BL. Migraine-related seizures in adults with epilepsy, with EEG correlation. Neurology 1993; 43: 2476±2483 er frequency of migraine in patients taking this drug. 13 Mathew NT, Rapoport A, Saper J, Magnus L, Klapper J, Ramadan N, Sta- cey B, Tepper S. Efficacy of gabapentin in migraine prophylaxis. Head- We conclude that the comorbidity between headache and epi- ache 2001; 41: 119±128 14 lepsy is common in childhood and frequently starts in the same Mathew NT, Kailasam J, Meadors L. Prophylaxis of migraine, trans- formed migraine, and cluster headache with topiramate. Headache 102 year as or after the diagnosis of epilepsy. Patients with the co- 2002; 42: 796±803 morbidity epilepsy and headache are usually older than 10 years 15 Ottman R, Lipton RB. Comorbidity of migraine and epilepsy. Neurol- and have idiopathic epilepsy. ogy 1994; 44: 2105±2110 16 Panayiotopoulos CP. Difficulties in differentiating migraine and epilepsy based on clinical and EEG findings. In: Andermann FA, Lugaresi E (eds). Migraine and Epilepsy. Boston: Butterworths, 1987: 31±46 Acknowledgements 17 Panayiotopoulos CP. Differentiating occipital epilepsies from migraine with aura, acephalgic migraine and basilar migraine. In: Pan- This study was supported by FAPESP (grant No. 02/06525±3). ayiotopoulos CP (ed). Benign Childhood Partial Seizures and Related Epileptic Syndromes. London: John Libbey & Co. Ltd., 1999: 281±302 18 Victor M, Ropper AH. Headache and other craniofacial pains. In: Victor M, Ropper AH (eds). Adams and Victors Principles of Neurology. New York: McGraw-Hill, 2001: 175±203 Downloaded by: IP-Proxy CONSORTIUM:CAPES (UNICAMP Universidade Estadual de Campinas), Dot. Lib Information. Copyrighted material.

Yamane LE et al. Comorbidity Headache and ¼ Neuropediatrics 2004; 35: 99 ±102