Pediatric Neurology xxx (2015) 1e4
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
Diurnal and Seasonal Occurrence of Febrile Seizures Kirsi Mikkonen MD *, Matti Uhari MD, Tytti Pokka MSc, Heikki Rantala MD Department of Pediatrics, University of Oulu, Oulu, Finland
abstract BACKGROUND: Febrile seizures are the most common seizures in children, but their pathogenesis remains un-
known. Some studies have suggested an association between the light-dependent secretion of melatonin and the occurrence of febrile seizures. The diurnal and seasonal occurrence of febrile seizures could clarify the role daylight plays in febrile seizures. METHODS: In Finland, summer days are long and bright and winter days are short and dark. We evaluated the diurnal and seasonal occurrence of the first febrile seizures in 461 children and adjusted them according to the epidemiology of the febrile episodes in a population-based study of 1522 children. RESULTS: The first febrile seizure most often occurred in the evening, peaking between 6 and 10 PM (31%), and least often at night, in the early morning hours between 2 and 6 AM (8%) (P < 0.001). This diurnal pattern repeated itself in different seasons according to variance in daylight duration. Febrile seizures occurred irregularly throughout the year, most frequently in winter, concurrently with the febrile episodes, and least frequently in summer; this seasonal variation in the occurrence of febrile seizures disappeared however when adjusted for the number of febrile events. CONCLUSIONS: We found clear diurnal and seasonal variations in the occurrence of febrile seizures, even though they did not follow the amount of daylight. Our findings do not support the hypothesis that the diurnal and seasonal variation of daylight explains the occurrence of febrile seizures. Moreover, febrile events associated strongly with the occurrence of febrile seizures. Keywords: febrile seizure, seasonal variation, diurnal variation, daylight, melatonin, children
Pediatr Neurol 2015; -: 1-4 Ó 2015 Elsevier Inc. All rights reserved.
Introduction
Febrile seizures are the most common seizures in children, usually occurring between 6 months and 6 years of age and affecting about 2%-5% of all children.1,2 Their recurrence is common, with about 20%-30% of patients experiencing more than one febrile seizure.2 The pathogenesis of febrile seizures remains unknown. Changes in exposure to light synchronize the suprachiasmatic nucleus in the anterior hypothalamus of the brain, which coordinates many circadian rhythms, such as sleep, behavior, metabolism, and hormone secretion.3 Melatonin (N-acetyl-5-methoxytryptamine) is secreted mostly at night and in the dark, and exposure to light reduces its secretion.4 Melatonin seems to possess some Article History: Received October 25, 2014; Accepted in final form January 5, 2015 * Communications should be addressed to: Dr. Mikkonen; Children’s Castle, P.O. Box 280, FIN-00029 HUS, Finland. E-mail address: kirsi.h.mikkonen@hus.fi 0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.01.001
anticonvulsant effects5-8; some studies suggest an association between melatonin and the occurrence of febrile seizures9-11 also as an explanation to the epidemiology of febrile seizures.10,11 Many types of epileptic seizure occur according to a specific circadian rhythm.12 Because of its location in the far north (i.e., north of 60 N), Finland has very long, bright summer days and very long, dark winter nights. In the city of Oulu in northern Finland, the length of the day as measured from sunrise to sunset on the winter solstice in December is only about 3.5 hours; on the summer solstice in June it is more than 22 hours.13 Moreover, the duration of daylight in southern Finland differs from that in Oulu in northern Finland only by about 2-3 hours during the darkest or the brightest periods of the year.13 On the winter solstice in Oulu, the sun rises only 2 above the horizon, but on the summer solstice, it rises more than 48 above the horizon. We evaluated the diurnal and seasonal variations of the first febrile seizures and adjusted them to both the number of febrile episodes and the body temperature measured in connection with the febrile seizures.
2
K. Mikkonen et al. / Pediatric Neurology xxx (2015) 1e4
We hypothesized that if daylight or melatonin is a part of the pathogenesis of febrile seizures, the occurrence of febrile seizures should show diurnal and seasonal variations and associate with the duration of daylight, even when adjusted for the number of febrile episodes or body temperature. Patients and Methods We evaluated diurnal and seasonal variations in the occurrence of febrile seizures among 461 consecutive patients who had experienced their first febrile seizure. The patients were recruited between November 1986 and September 199014-16 and between January 1997 and December 2003,17 mostly from the Department of Pediatrics and Adolescence, Oulu University Hospital,14-17 but also from four other hospitals (Satakunta, Central Finland, Päijät-Häme, and South Karelian),17 each of which is the only children’s hospital in the region. The patients participated in our earlier risk factor and prevention trials of febrile seizures,14-17 which reported their detailed follow-up schedules.14-17 The study was carried out in accordance with the Declaration of Helsinki, the ethics committee of the University of Oulu Medical Faculty approved the protocols of the study, and the parents provided written, informed consent. We had a unique opportunity to compare the seasonal occurrence of febrile seizures with the seasonal variation of febrile episodes in children of the same age and from the same region. The population-based data on febrile episodes came from a study of 1522 children in 20 randomly selected day care centers in the region of Oulu, Finland, conducted between March 1991 and May 1992 (Table).18 In that study, the occurrence of infections and symptoms of the child were recorded in daily symptom diaries completed by the parents. The parents recorded their child’s body temperature in the diaries any time the child fell ill.18 Of the patients, 29% had experienced complex febrile seizure and 25% had parents or siblings who had experienced febrile seizure (Table). A febrile seizure was considered complex when it was either focal or prolonged (>15 minutes) or if more than one seizure had occurred within a 24-hour period. The hospital admission date was recorded for all 461 children included in the analysis of seasonal variation. For 223 of these patients, who were also included in the analysis of diurnal variation, hospital admission time was recorded, and the time the febrile seizure occurred was asked of the parents upon their arrival at the hospital. Patients’ body temperature was measured upon their arrival at the hospital. The control group of day care children (N ¼ 1522) experienced a total of 2478 febrile episodes (body temperature higher than 38 C) during the 15-month study period.
the brightest. Similarly, the year was classified into three 4-month periods according to the duration of daylight. The period from May to August was considered the brightest, and the period from November to February the darkest; March and April, together with September and October, formed one 4-month period during which the amount of daylight was between the length of the other two periods. We calculated the ratios of febrile episodes to febrile seizures to investigate whether the monthly occurrence of febrile seizures associated with the number of febrile episodes. The chi-squared goodness-of-fit test served to detect whether the observed diurnal proportions of febrile seizures depart from the even distribution. The Walter and Elwood test served to detect seasonal variation in the occurrence of febrile seizures.19 All data were analyzed with IBM SPSS Statistics for Windows, version 21.0, and Stata/IC for Windows, version 11.2.
Results
The occurrence of the first febrile seizure did not follow an even distribution (P < 0.001), and the number of febrile seizures increased during the day and in the evening, peaking between 6 and 10 PM (31%); the lowest number occurred at night in the early morning hours between 2 and 6 AM (8%) (P < 0.001) (Fig 1). The occurrence of febrile seizures followed the same pattern and peak hours during the 24-hour period, even when examined separately during the three 4-month periods based on the amount of daylight (Fig 2). The number of febrile seizures was the highest in winter, coinciding with a peak in febrile episodes, and the lowest during summer, coinciding with infrequent febrile episodes (Fig 3). When adjusted for the number of febrile episodes, we found no seasonal variation in the occurrence of febrile seizures (P ¼ 0.29). The maximum temperature of the fever in patients with febrile seizures (mean 39.7 C, range 37.6-42.0 C) was similar throughout the year. Discussion
In our study, children experienced their first febrile seizure most often in the evening and less frequently at
Statistics Day was classified into six 4-hour time periods according to the duration of daylight; the period from 10 AM to 2 PM was considered
TABLE. Demographic Characteristics of Patients With Their First FS and Controls With Febrile Episodes
Characteristic
Mean age, year (SD; range) Female (%) Simple/complex FS Family history of FS, yes/no* Family history of epilepsy, yes/noy
Patients
Controls
n ¼ 461
n ¼ 1522
1.7 (0.8; 0.3-5.6) 183 (40) 327/134 110/334 10/393
3.6 (1.8; 0.3-7.6) 758 (50) -
Abbreviations: FS ¼ Febrile seizure SD ¼ Standard deviation No data were available for *17 and y58 patients.
FIGURE 1. Diurnal variation in the occurrence of the first febrile seizure in children. Chi-squared test for even distribution P < 0.001.
K. Mikkonen et al. / Pediatric Neurology xxx (2015) 1e4
3
FIGURE 3. Seasonal variation in the occurrence of the first febrile seizures (histograms) and of the febrile episodes (curve) in children. No statistical differences in the occurrence of the first febrile seizure standardized for the number of febrile episodes per month among the child population in day care.
FIGURE 2. Diurnal variation in the occurrence of the first febrile seizures in children according to the amount of daylight throughout the year. The period from May to August was considered the brightest, and from November to February the darkest; March and April together with September and October fell between the others.
night. In an Italian study, the first febrile seizures peaked in the evening between 6 PM and 11:59 PM.10 In a Japanese study, febrile seizures occurred five times more often in the evening than in the morning, peaking in incidence at 4 PM and reaching its lowest incidence at 4 AM.20 Melatonin concentrations in healthy children, children with epilepsy, and children with febrile seizures are higher at night than during the day, with the highest concentration occurring at 4 AM,21 when the occurrence of febrile seizures in our study was the lowest. In our study, the occurrence of febrile seizure was the highest after plasma melatonin levels have normally already begun to rise (between 6 PM and 8 PM) from lower levels during the day.22 If melatonin plays a role in the pathogenesis of febrile seizures, febrile seizures should peak earlier. Melatonin concentrations are the highest in winter, the lowest in summer, and intermediate in spring and fall.23 The duration and amplitude of the melatonin peak correlate negatively with the amount of daylight,22 but this was not the case with the occurrence of febrile seizures and the amount of daylight in our study. The
peak time was not the brightest period of the day, and the diurnal febrile seizure pattern was similar across different seasons even though the duration of daylight varies considerably. The maximum body temperature during febrile seizure episodes throughout the year in our study remained constant. Studies have identified high body temperature during infections as the strongest explanatory variable for the occurrence of febrile seizures.14,24 Although researchers have also discussed the role of normal body temperature variation as a pathogenesis of febrile seizures,10,11,20 children at risk for febrile seizures (i.e., between 6 months and 6 years of age) have more stable body temperatures over a 24-hour period than do adults20,25; moreover, body temperature has shown no difference between the low- and highfrequency times of febrile seizures in a given day20 or during the year in our present study. These findings allow us to assume that body temperature variation and peak body temperature do not fully explain the epidemiology of febrile seizures. The children in our study experienced febrile seizures most often in the winter and less frequently during the summer. Febrile seizures often occur in winter, peaking from November to January10,11 and again in the summer, from June to August.11 These results have not been adjusted for the number of febrile or infection events in the general population in that area.10,11 In our study, after adjusting the frequency of febrile seizures to the number of febrile events in the child population of the same age and from the same area, the occurrence of febrile seizures associated strongly with febrile events. In conclusion, although the occurrence of febrile seizures showed clear diurnal and seasonal variation, it did not follow the distribution of the duration of daylight throughout the day or year. Our findings therefore do not support the diurnal and seasonal variation of daylight or melatonin secretion as an explanation for the occurrence of febrile seizures. Rather, our findings support the hypothesis
4
K. Mikkonen et al. / Pediatric Neurology xxx (2015) 1e4
that febrile and infection events strongly associate with febrile seizures. This study was supported by Special State Grants for Health Research in the Department of Pediatrics and Adolescence, Oulu University Hospital, Finland; the Arvo and Lea Ylppö Foundation and the Alma and K. A. Snellman Foundation, Oulu, Finland.
References 1. Commission on classification and terminology of the international league against epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia. 1989;30:389-399. 2. Nelson KB, Ellenberg JH. Prognosis in children with febrile seizures. Pediatrics. 1978;61:720-727. 3. Hastings M. The brain, circadian rhythms, and clock genes. BMJ. 1998;317:1704-1707. 4. Haldar C, Ahmad R. Photoimmunomodulation and melatonin. J Photochem Photobiol B. 2010;98:107-117. 5. Molina-Carballo A, Munoz-Hoyos A, Sanchez-Forte M, UberosFernandez J, Moreno-Madrid F, Acuna-Castroviejo D. Melatonin increases following convulsive seizures may be related to its anticonvulsant properties at physiological concentrations. Neuropediatrics. 2007;38:122-125. 6. Banach M, Gurdziel E, Jedrych M, Borowicz KK. Melatonin in experimental seizures and epilepsy. Pharmacol Rep. 2011;63:1-11. 7. Goldberg-Stern H, Oren H, Peled N, Garty BZ. Effect of melatonin on seizure frequency in intractable epilepsy: A pilot study. J Child Neurol. 2012;27:1524-1528. 8. Munoz-Hoyos A, Sanchez-Forte M, Molina-Carballo A, et al. Melatonin’s role as an anticonvulsant and neuronal protector: Experimental and clinical evidence. J Child Neurol. 1998;13:501-509. 9. Sanchez-Barcelo EJ, Mediavilla MD, Reiter RJ. Clinical uses of melatonin in pediatrics. Int J Pediatr. 2011;2011:892624. 10. Manfredini R, Vergine G, Boari B, Faggioli R, Borgna-Pignatti C. Circadian and seasonal variation of first febrile seizures. J Pediatr. 2004;145:838-839.
11. Tsuboi T, Okada S. Seasonal variation of febrile convulsion in japan. Acta Neurol Scand. 1984;69:285-292. 12. Loddenkemper T, Vendrame M, Zarowski M, et al. Circadian patterns of pediatric seizures. Neurology. 2011;76:145-153. 13. Finnish Meteorological Institute. http://en.ilmatieteenlaitos.fi/ weather/oulu. Updated 2014. 14. Rantala H, Uhari M, Hietala J. Factors triggering the first febrile seizure. Acta Paediatr. 1995;84:407-410. 15. Tarkka R, Rantala H, Uhari M, Pokka T. Risk of recurrence and outcome after the first febrile seizure. Pediatr Neurol. 1998;18: 218-220. 16. Uhari M, Rantala H, Vainionpaa L, Kurttila R. Effect of acetaminophen and of low intermittent doses of diazepam on prevention of recurrences of febrile seizures. J Pediatr. 1995;126:991-995. 17. Strengell T, Uhari M, Tarkka R, et al. Antipyretic agents for preventing recurrences of febrile seizures: Randomized controlled trial. Arch Pediatr Adolesc Med. 2009;163:799-804. 18. Uhari M, Mottonen M. An open randomized controlled trial of infection prevention in child day-care centers. Pediatr Infect Dis J. 1999;18:672-677. 19. Walter SD, Elwood JM. A test for seasonality of events with a variable population at risk. Br J Prev Soc Med. 1975;29:18-21. 20. Ogihara M, Shirakawa S, Miyajima T, Takekuma K, Hoshika A. Diurnal variation in febrile convulsions. Pediatr Neurol. 2010;42: 409-412. 21. Ardura J, Andres J, Garmendia JR, Ardura F. Melatonin in epilepsy and febrile seizures. J Child Neurol. 2010;25:888-891. 22. de Almeida EA, Di Mascio P, Harumi T, et al. Measurement of melatonin in body fluids: Standards, protocols and procedures. Childs Nerv Syst. 2011;27:879-891. 23. Davis S, Kaune WT, Mirick DK, Chen C, Stevens RG. Residential magnetic fields, light-at-night, and nocturnal urinary 6-sulfatoxymelatonin concentration in women. Am J Epidemiol. 2001;154: 591-600. 24. Berg AT, Shinnar S, Shapiro ED, Salomon ME, Crain EF, Hauser WA. Risk factors for a first febrile seizure: A matched case-control study. Epilepsia. 1995;36:334-341. 25. Garcia J, Rosen G, Mahowald M. Circadian rhythms and circadian rhythm disorders in children and adolescents. Semin Pediatr Neurol. 2001;8:229-240.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
Diurnal and Seasonal Occurrence of Febrile Seizures Kirsi Mikkonen MD *, Matti Uhari MD, Tytti Pokka MSc, Heikki Rantala MD Department of Pediatrics, University of Oulu, Oulu, Finland
abstract BACKGROUND: Febrile seizures are the most common seizures in children, but their pathogenesis remains un-
known. Some studies have suggested an association between the light-dependent secretion of melatonin and the occurrence of febrile seizures. The diurnal and seasonal occurrence of febrile seizures could clarify the role daylight plays in febrile seizures. METHODS: In Finland, summer days are long and bright and winter days are short and dark. We evaluated the diurnal and seasonal occurrence of the first febrile seizures in 461 children and adjusted them according to the epidemiology of the febrile episodes in a population-based study of 1522 children. RESULTS: The first febrile seizure most often occurred in the evening, peaking between 6 and 10 PM (31%), and least often at night, in the early morning hours between 2 and 6 AM (8%) (P < 0.001). This diurnal pattern repeated itself in different seasons according to variance in daylight duration. Febrile seizures occurred irregularly throughout the year, most frequently in winter, concurrently with the febrile episodes, and least frequently in summer; this seasonal variation in the occurrence of febrile seizures disappeared however when adjusted for the number of febrile events. CONCLUSIONS: We found clear diurnal and seasonal variations in the occurrence of febrile seizures, even though they did not follow the amount of daylight. Our findings do not support the hypothesis that the diurnal and seasonal variation of daylight explains the occurrence of febrile seizures. Moreover, febrile events associated strongly with the occurrence of febrile seizures. Keywords: febrile seizure, seasonal variation, diurnal variation, daylight, melatonin, children
Pediatr Neurol 2015; -: 1-4 Ó 2015 Elsevier Inc. All rights reserved.
Introduction
Febrile seizures are the most common seizures in children, usually occurring between 6 months and 6 years of age and affecting about 2%-5% of all children.1,2 Their recurrence is common, with about 20%-30% of patients experiencing more than one febrile seizure.2 The pathogenesis of febrile seizures remains unknown. Changes in exposure to light synchronize the suprachiasmatic nucleus in the anterior hypothalamus of the brain, which coordinates many circadian rhythms, such as sleep, behavior, metabolism, and hormone secretion.3 Melatonin (N-acetyl-5-methoxytryptamine) is secreted mostly at night and in the dark, and exposure to light reduces its secretion.4 Melatonin seems to possess some Article History: Received October 25, 2014; Accepted in final form January 5, 2015 * Communications should be addressed to: Dr. Mikkonen; Children’s Castle, P.O. Box 280, FIN-00029 HUS, Finland. E-mail address: kirsi.h.mikkonen@hus.fi 0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.01.001
anticonvulsant effects5-8; some studies suggest an association between melatonin and the occurrence of febrile seizures9-11 also as an explanation to the epidemiology of febrile seizures.10,11 Many types of epileptic seizure occur according to a specific circadian rhythm.12 Because of its location in the far north (i.e., north of 60 N), Finland has very long, bright summer days and very long, dark winter nights. In the city of Oulu in northern Finland, the length of the day as measured from sunrise to sunset on the winter solstice in December is only about 3.5 hours; on the summer solstice in June it is more than 22 hours.13 Moreover, the duration of daylight in southern Finland differs from that in Oulu in northern Finland only by about 2-3 hours during the darkest or the brightest periods of the year.13 On the winter solstice in Oulu, the sun rises only 2 above the horizon, but on the summer solstice, it rises more than 48 above the horizon. We evaluated the diurnal and seasonal variations of the first febrile seizures and adjusted them to both the number of febrile episodes and the body temperature measured in connection with the febrile seizures.
2
K. Mikkonen et al. / Pediatric Neurology xxx (2015) 1e4
We hypothesized that if daylight or melatonin is a part of the pathogenesis of febrile seizures, the occurrence of febrile seizures should show diurnal and seasonal variations and associate with the duration of daylight, even when adjusted for the number of febrile episodes or body temperature. Patients and Methods We evaluated diurnal and seasonal variations in the occurrence of febrile seizures among 461 consecutive patients who had experienced their first febrile seizure. The patients were recruited between November 1986 and September 199014-16 and between January 1997 and December 2003,17 mostly from the Department of Pediatrics and Adolescence, Oulu University Hospital,14-17 but also from four other hospitals (Satakunta, Central Finland, Päijät-Häme, and South Karelian),17 each of which is the only children’s hospital in the region. The patients participated in our earlier risk factor and prevention trials of febrile seizures,14-17 which reported their detailed follow-up schedules.14-17 The study was carried out in accordance with the Declaration of Helsinki, the ethics committee of the University of Oulu Medical Faculty approved the protocols of the study, and the parents provided written, informed consent. We had a unique opportunity to compare the seasonal occurrence of febrile seizures with the seasonal variation of febrile episodes in children of the same age and from the same region. The population-based data on febrile episodes came from a study of 1522 children in 20 randomly selected day care centers in the region of Oulu, Finland, conducted between March 1991 and May 1992 (Table).18 In that study, the occurrence of infections and symptoms of the child were recorded in daily symptom diaries completed by the parents. The parents recorded their child’s body temperature in the diaries any time the child fell ill.18 Of the patients, 29% had experienced complex febrile seizure and 25% had parents or siblings who had experienced febrile seizure (Table). A febrile seizure was considered complex when it was either focal or prolonged (>15 minutes) or if more than one seizure had occurred within a 24-hour period. The hospital admission date was recorded for all 461 children included in the analysis of seasonal variation. For 223 of these patients, who were also included in the analysis of diurnal variation, hospital admission time was recorded, and the time the febrile seizure occurred was asked of the parents upon their arrival at the hospital. Patients’ body temperature was measured upon their arrival at the hospital. The control group of day care children (N ¼ 1522) experienced a total of 2478 febrile episodes (body temperature higher than 38 C) during the 15-month study period.
the brightest. Similarly, the year was classified into three 4-month periods according to the duration of daylight. The period from May to August was considered the brightest, and the period from November to February the darkest; March and April, together with September and October, formed one 4-month period during which the amount of daylight was between the length of the other two periods. We calculated the ratios of febrile episodes to febrile seizures to investigate whether the monthly occurrence of febrile seizures associated with the number of febrile episodes. The chi-squared goodness-of-fit test served to detect whether the observed diurnal proportions of febrile seizures depart from the even distribution. The Walter and Elwood test served to detect seasonal variation in the occurrence of febrile seizures.19 All data were analyzed with IBM SPSS Statistics for Windows, version 21.0, and Stata/IC for Windows, version 11.2.
Results
The occurrence of the first febrile seizure did not follow an even distribution (P < 0.001), and the number of febrile seizures increased during the day and in the evening, peaking between 6 and 10 PM (31%); the lowest number occurred at night in the early morning hours between 2 and 6 AM (8%) (P < 0.001) (Fig 1). The occurrence of febrile seizures followed the same pattern and peak hours during the 24-hour period, even when examined separately during the three 4-month periods based on the amount of daylight (Fig 2). The number of febrile seizures was the highest in winter, coinciding with a peak in febrile episodes, and the lowest during summer, coinciding with infrequent febrile episodes (Fig 3). When adjusted for the number of febrile episodes, we found no seasonal variation in the occurrence of febrile seizures (P ¼ 0.29). The maximum temperature of the fever in patients with febrile seizures (mean 39.7 C, range 37.6-42.0 C) was similar throughout the year. Discussion
In our study, children experienced their first febrile seizure most often in the evening and less frequently at
Statistics Day was classified into six 4-hour time periods according to the duration of daylight; the period from 10 AM to 2 PM was considered
TABLE. Demographic Characteristics of Patients With Their First FS and Controls With Febrile Episodes
Characteristic
Mean age, year (SD; range) Female (%) Simple/complex FS Family history of FS, yes/no* Family history of epilepsy, yes/noy
Patients
Controls
n ¼ 461
n ¼ 1522
1.7 (0.8; 0.3-5.6) 183 (40) 327/134 110/334 10/393
3.6 (1.8; 0.3-7.6) 758 (50) -
Abbreviations: FS ¼ Febrile seizure SD ¼ Standard deviation No data were available for *17 and y58 patients.
FIGURE 1. Diurnal variation in the occurrence of the first febrile seizure in children. Chi-squared test for even distribution P < 0.001.
K. Mikkonen et al. / Pediatric Neurology xxx (2015) 1e4
3
FIGURE 3. Seasonal variation in the occurrence of the first febrile seizures (histograms) and of the febrile episodes (curve) in children. No statistical differences in the occurrence of the first febrile seizure standardized for the number of febrile episodes per month among the child population in day care.
FIGURE 2. Diurnal variation in the occurrence of the first febrile seizures in children according to the amount of daylight throughout the year. The period from May to August was considered the brightest, and from November to February the darkest; March and April together with September and October fell between the others.
night. In an Italian study, the first febrile seizures peaked in the evening between 6 PM and 11:59 PM.10 In a Japanese study, febrile seizures occurred five times more often in the evening than in the morning, peaking in incidence at 4 PM and reaching its lowest incidence at 4 AM.20 Melatonin concentrations in healthy children, children with epilepsy, and children with febrile seizures are higher at night than during the day, with the highest concentration occurring at 4 AM,21 when the occurrence of febrile seizures in our study was the lowest. In our study, the occurrence of febrile seizure was the highest after plasma melatonin levels have normally already begun to rise (between 6 PM and 8 PM) from lower levels during the day.22 If melatonin plays a role in the pathogenesis of febrile seizures, febrile seizures should peak earlier. Melatonin concentrations are the highest in winter, the lowest in summer, and intermediate in spring and fall.23 The duration and amplitude of the melatonin peak correlate negatively with the amount of daylight,22 but this was not the case with the occurrence of febrile seizures and the amount of daylight in our study. The
peak time was not the brightest period of the day, and the diurnal febrile seizure pattern was similar across different seasons even though the duration of daylight varies considerably. The maximum body temperature during febrile seizure episodes throughout the year in our study remained constant. Studies have identified high body temperature during infections as the strongest explanatory variable for the occurrence of febrile seizures.14,24 Although researchers have also discussed the role of normal body temperature variation as a pathogenesis of febrile seizures,10,11,20 children at risk for febrile seizures (i.e., between 6 months and 6 years of age) have more stable body temperatures over a 24-hour period than do adults20,25; moreover, body temperature has shown no difference between the low- and highfrequency times of febrile seizures in a given day20 or during the year in our present study. These findings allow us to assume that body temperature variation and peak body temperature do not fully explain the epidemiology of febrile seizures. The children in our study experienced febrile seizures most often in the winter and less frequently during the summer. Febrile seizures often occur in winter, peaking from November to January10,11 and again in the summer, from June to August.11 These results have not been adjusted for the number of febrile or infection events in the general population in that area.10,11 In our study, after adjusting the frequency of febrile seizures to the number of febrile events in the child population of the same age and from the same area, the occurrence of febrile seizures associated strongly with febrile events. In conclusion, although the occurrence of febrile seizures showed clear diurnal and seasonal variation, it did not follow the distribution of the duration of daylight throughout the day or year. Our findings therefore do not support the diurnal and seasonal variation of daylight or melatonin secretion as an explanation for the occurrence of febrile seizures. Rather, our findings support the hypothesis
4
K. Mikkonen et al. / Pediatric Neurology xxx (2015) 1e4
that febrile and infection events strongly associate with febrile seizures. This study was supported by Special State Grants for Health Research in the Department of Pediatrics and Adolescence, Oulu University Hospital, Finland; the Arvo and Lea Ylppö Foundation and the Alma and K. A. Snellman Foundation, Oulu, Finland.
References 1. Commission on classification and terminology of the international league against epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia. 1989;30:389-399. 2. Nelson KB, Ellenberg JH. Prognosis in children with febrile seizures. Pediatrics. 1978;61:720-727. 3. Hastings M. The brain, circadian rhythms, and clock genes. BMJ. 1998;317:1704-1707. 4. Haldar C, Ahmad R. Photoimmunomodulation and melatonin. J Photochem Photobiol B. 2010;98:107-117. 5. Molina-Carballo A, Munoz-Hoyos A, Sanchez-Forte M, UberosFernandez J, Moreno-Madrid F, Acuna-Castroviejo D. Melatonin increases following convulsive seizures may be related to its anticonvulsant properties at physiological concentrations. Neuropediatrics. 2007;38:122-125. 6. Banach M, Gurdziel E, Jedrych M, Borowicz KK. Melatonin in experimental seizures and epilepsy. Pharmacol Rep. 2011;63:1-11. 7. Goldberg-Stern H, Oren H, Peled N, Garty BZ. Effect of melatonin on seizure frequency in intractable epilepsy: A pilot study. J Child Neurol. 2012;27:1524-1528. 8. Munoz-Hoyos A, Sanchez-Forte M, Molina-Carballo A, et al. Melatonin’s role as an anticonvulsant and neuronal protector: Experimental and clinical evidence. J Child Neurol. 1998;13:501-509. 9. Sanchez-Barcelo EJ, Mediavilla MD, Reiter RJ. Clinical uses of melatonin in pediatrics. Int J Pediatr. 2011;2011:892624. 10. Manfredini R, Vergine G, Boari B, Faggioli R, Borgna-Pignatti C. Circadian and seasonal variation of first febrile seizures. J Pediatr. 2004;145:838-839.
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