Accepted Article
Incidence of febrile seizure in patients with Down syndrome1 Shuichi Shimakawaa*, Takuya Tanabeb, MasaeOnoc, Michiko Nonakad, MitsuhikoNambue, TohruShinoharaf, Toshiya Nishikubog, Miho Fukuia, ShoheiNomuraa, Kohji Azumagawah, Hiroshi Tamaia a
Department of Pediatrics, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki-city, Osaka
569-8686, Japan
b
Department of Pediatric Neurology, Tanabe Children’s Clinic, 1-49-31 Higashiyama,
Hirakata, Osaka 573-1114, Japan c
Department of Pediatrics, Tokyo Teishin Hospital, 2-14-23 Fujimi, Chiyoda-ku, Tokyo
102-8798, Japan d
Hyogo PrefecturalChild Development Support Center, 2744 Shimizu Uozumi-cho, Akashi,
Hyogo 674-0074, Japan e
Department of Pediatrics, Tenri Hospital, 200 Mishima-cho, Tenri, Nara 632-8552, Japan
f
Department of Pediatrics, Kinki University Hospital, Faculty of Medicine, 377-2
Ohnohigashi, Sayama, Osaka 589-851, Japan g
Division of Neonatal Intensive Care, Perinatal Medical Center,Nara Medical University
Hospital, 840 Shijo-cho, Kashihara, Nara 634-8522,Japan h
Department of Pediatrics, Seikeikai Hospital, 4-2-10 Kouryounakamachi, Sakai-ku, Sakai,
Osaka 590-0024, Japan
*Corresponding author: Shuichi Shimakawa Department of Pediatrics, Osaka Medical College 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
Tel: +81-726-83-1221; Fax: +81-726-84-5798; E-mail: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/ped.12601
1 This article is protected by copyright. All rights reserved.
Accepted Article
Abstract
Aim:It is unclear whether the incidence of febrile seizure (FS) in children with Down syndrome (DS) is higher or lower than in the general population. In this study, we investigated the incidence of FS in patients with DS using mailed questionnaires. Methods: The questionnaires were distributed to parents or caregivers of patients with DS attending Osaka Medical College Hospital and six other facilities. The questionnaires were collected by mail from February 2012 to September 2013 from 323 families of patients with DS (176 were male, 147 were female; age range, 3 months to 47 years; median age, 5.0 years). To assess the incidence of FS in DS, we performed the following two analyses: (1) we calculated the incidence of FS among patients with DS between the ages of 4 and 20 years (n = 199; 113 were male, 86 were female), and (2) we extracted families with both DS and healthy siblings between the ages of 4 and 20 years (n = 150; 77 were male, 73 were female) and compared the incidence of FS in these sibling groups. Results:Five patients with DS had a past history of FS. The incidence of FS in DS was 2.5%. The incidence of FS was significantly lower in patients with DS compared with healthy siblings (P< 0.003, Odds ratio: 0.14). Conclusion: Our findings suggest that the incidence of FS is lower in patients with DS than in the general population.
Keywords: Down syndrome, febrile seizure, incidence of febrile seizure, sibling
2 This article is protected by copyright. All rights reserved.
Accepted Article
Introduction Febrile seizure (FS) is an acute symptomatic seizure that occurs during febrile illness,
and is common in infancy and childhood.1 In the pediatric population, FS is the most common neurological event, affecting between 2 and 14% of children worldwide.1, 2 It is unclear whether the incidence of FS in patients with Down syndrome (DS) is higher or lower than in the general population. Stafstrom et al. reported a lower incidence of FS (0.9%) in patients with DS compared with the overall prevalence of around 3% in the general population.3 However, Romano et al. reported that the incidence of FS in patients with DS is higher than in non-DS individuals.4 To the best of our knowledge, there is only one published old study on the occurrence of FS in DS in Japan, which reported an incidence of 0.5% in patients with DS (2 of 371 cases).5 In the present study, we investigate the incidence of FS in patients with DS. We also
examine whether the incidence is higher in patients with DS compared with their healthy siblings.
Subjects and Methods To investigate the incidence of FS in patients with DS,mail questionnaires were
distributed to parents or caregiver of patients with DS with all of full trisomy of chromosome 21 attending Osaka Medical College Hospital, Hyogo PrefecturalChild Development Support Center, Hyogo PrefecturalTsukaguchi Hospital,Kinki University Hospital, Nara Medical
University Hospital, Seikeikai Hospital, Tenri Hospital, or Tokyo Teishin Hospital at the time of the visits to their hospital for medical care, and collected by mail from February 2012 to September 2013. Attending physician who belonged to the hospitals checked the karyotypes in all patients with DS, before sending the questionnaires. Our questionnaire included the method used to diagnose DS, age, gender, with or without past history of FS, with or without 3 This article is protected by copyright. All rights reserved.
Accepted Article
complication of brain disorder caused by other conditions resulting from DS, with or without past history of afebrile seizure, and with or without complication of epilepsy. If the patient with DS had a past history of FS, the family was required to answer the following additional questions: age of onset, seizure duration, with or without diagnosis of FS performed by a medical doctor, seizure manifestation, cause of acute febrile illness, and with or without abnormalities in an electroencephalogram. Furthermore, we added the following questions on the healthy siblings of the patients with DS: number of healthy siblings, age, gender, with or without past history of FS, and with or without a disease diagnosed by a medical doctor. Finally, we included the definition of FS (see Appendix 1 for questionnaire). This investigation was approved by the ethics committee of Osaka Medical College. The questionnaire was collected from 323 families of patients with DS (176 were male,
147 were female; age range, 3 months to 47 years; median age, 5.0 years). All of the patients with DS were diagnosed by G-banding. To assess the incidence of FS in patients with DS, we performed the following two analyses: (1) we calculated the incidence of FS among patients with DS between the ages of 4 and 20 years (n = 199; 113 were male, 86 were female; age range, 4 to 20 years; median age, 8 years), and (2) we extracted families with both DS patients and healthy siblings between the ages of 4 and 20 years (n = 150; 77 were male, 73 were female; age range, 4 to 20 years; median age, 7 years) and compared the incidence of FS in these sibling groups. Differences in the incidence of FS between DS patients and healthy siblings were analyzed using the Fisher’s exact test. A P-value < 0.05 was considered
statistically significant.
Results
Five hundred and thirty questionnaires were distributed and 323 questionnaires were collected from families of patients with DS, a return rate 61%. 4 This article is protected by copyright. All rights reserved.
Accepted Article
A past history of FS was found in five patients with DS. The incidence of FS among
patients with DS was 2.5%. Although a complicating brain disorder was found in four patients with DS, they did not have a history of FS. A total of 14 patients with DS had experienced afebrile seizure. All of the 14 patients developing afebrile seizure did not experience febrile seizure. Among these 14 patients with DS with afebrile seizure, seven were diagnosed with epilepsy. In all of seven patients developing epilepsy, classification of seizure type and epilepsyand the antiepileptic drug wasnot identified, and in the other seven patients without diagnosis of epilepsy, the causes of afebrile seizures were not identifiedbecause of these data didnot include our questionnaires. The onset of epilepsy was infancy in 3 cases, childhood in one case, adolescence in 2 cases and unknown in one case.None of these 14 patients with DShad experienced FS. The clinical characteristic of patients with DS with FS are presented in Table 1. The age
of onset of FS was less than 6 months in patient 3, while it was more than 6 years in patient 5. The seizures were clustered over a single acute febrile episode in patient 4. The sibling of patients 1 had also experienced FS. Prolonged seizure did not develop in all subjects. Patient 3 and 4 developed FS with a focal component, whereas the remaining three subjects developed generalized seizure. Electroencephalography performed in patient 2 showed normal activity. As for the cause of febrile illness, influenza infection was diagnosed in patient 5, while it was undetermined in the remaining four patients with DS. We compared the incidence of FS in patients with DS and healthy siblings. All of them
were diagnosed with FS and epilepsy by a medical doctor.Among healthy siblings, 18 of 150 individuals had experienced FS and the patient of epilepsy was not found.In comparison, among patients with DS, 2 of 109 individuals had experienced FS and 4 of 109 individuals had diagnosed with epilepsy. The incidence of FS was significantly lower in patients with DS
5 This article is protected by copyright. All rights reserved.
Accepted Article
than in healthy siblings (P< 0.003, Odds ratio: 0.14) (Table 2). Complicating brain disorder
was not found in any of the healthy siblings.
Discussion
Based on data collected using mailed questionnaires, we obtained an incidence of FS in
patients with DS of 2.5%. Previous studies reported an incidence of FS in the general population of 7–9% in Japan.6, 7Furthermore, we found that the incidence of FS was significantly lower in patients withDS compared with healthy siblings. Therefore, the incidence of FS in patients with DS might be lower than in the general population. We also
examined whether an acquired factor, brain damage (e.g., resulting from asphyxia of the newborn or congenital heart disease), was a complication in patients withDS. No patients
with DS had acquired brain damage. Therefore, the incidence of FS was not impacted by acquired brain damage in patients with DS. Although the incidence of FS in patients with DS might be lower than in the general
population, a total of 14 patients with DS had experienced afebrile seizure.The patients with DS might develop seizure by lower grade fever than 38ºC. Because febrile seizure was usually defined as the seizure associated with a fever of 38ºC or higherfever,8 the seizure developed by lower grade fever than 38ºC might be not classified into febrile seizure, even if the patients with Down syndrome were easy to develop seizure by lower grade fever than 38ºC.There was another possibility that the patients with Down syndrome might have less chance with high fever than the healthy children because of their immunological features.AlthoughDS was the most common recognizable genetic syndrome with immune defects,9 to the best of our knowledge, we could not find the report that the body temperature elevated more in the patient with Down syndrome compared with the healthy children.
6 This article is protected by copyright. All rights reserved.
Accepted Article
Therefore, the incidence of FS, seizure developed by a fever of 38.0ºC or higher in patients
with DS might be lower than in the general population. The clinical characteristics of FS in DS were previously not adequately described.
Therefore, in the present study, we evaluated the clinical symptoms of complex FS, including the age of onset, seizure clustering during a single acute febrile episode, family history, and FS with a focal component. Electroencephalography performed in one of five subjects showed a normal record. Our present findings are consistent with a previous report in which electroencephalography findings were also normal in patients with DS with a past history of FS.5
Van Esch and colleagues examined the risk of developing FS in siblings of children with
FS. These authors found that the risk of FS in siblings (10%) was more than twice the average population risk (4%) in the Netherlands.10 In patients with DS with a healthy sibling with FS, the incidence of FS might be increased compared with patients withDS not having a healthy sibling with FS. In our study, patients withDS or healthy siblings who had experienced FS and also had a sibling with a past history of FS were found in three families. Both a patient with DS and his healthy sibling had experienced FS in one family, and both of two healthy siblings experienced FS in two families. However, we could not definitively determine whether the incidence of FS is higher or not in patients with DS having a healthy sibling with FS, because the number of healthy siblings with a past history of FS was only 18. The critical region for DS (DSCR) has been mapped to 21q22.11 A previous study found
cellular and cytoarchitectonic changes in DS, including a reduction in the number of granular cells (which play a role in GABAergic inhibition), lower neuronal density, retarded myelination, and dysgenesis of dendritic spines.11 These changes have been implicated in infantile spasms, which are particularly frequent in patients with DS.5,
11
In our present
investigation, epilepsy developed in only patients with DS, whereas epilepsy didnot develop 7
This article is protected by copyright. All rights reserved.
Accepted Article
in healthy sibling.However, because the incidence of FS in patients with DS was low in our present investigation, these cellular changes probably affect the development of epilepsy and do not substantially affect the development of FS. Moreover, it is interesting that five of six patients with deletion of the DSCR developed FS.12,
13
Therefore, the DSCR might be
implicated in the development of FS. Proinflammatory cytokines (particularly IL-1β)play a significant role in the pathogenesis
of FS.14 It is interesting that the levels of IL-1βwere significantly lower in the hippocampus of a DS mouse model (Ts65Dn) compared with control animals.15 However, to the best of our knowledge, the levels of proinflammatory cytokines have not been measured in patients with DS in the acute phase of febrile illness. Further investigation is needed to elucidate the pathophysiological mechanisms resulting in the lower incidenceof FS in DS.
Conclusion
The incidence of FS appears to be lower in individuals with DS compared with the
general population. Further investigation is needed to clarify why the incidence of FS in DS is low.
Acknowledgments The authors thank Dr. Hiroko Fujita (Department of Pediatrics, Hyogo Prefectural
Tsukaguchi Hospital) and Ms. Kiyoko Fukuoka (Coaching staff ofrehabilitation of babies with Down syndrome) for their suggestions for clinical practice and rehabilitation in Down syndrome.
8 This article is protected by copyright. All rights reserved.
Accepted Article
References
1 Reid AY, Galic MA, Teskey GC, Pittman QJ. Febrile seizures: current views and investigations. Can. J. Neurol. Sci. 2009;36:679-86. 2Hauser,WA. The prevalence and incidence of convulsive disorders in children.Epilepsia
1994;35:S1-6. 3Stafstrom CE, Patxot OF, Gilmore HE, Wisniewski KE. Seizures in children with Down
syndrome: etiology, characteristics and outcome. Dev. Med. Child.Neurol. 1991;33:191-200. 4Romano C, Tiné A, Fazio G, Rizzo R, Colognola RM, Sorge G, et al. Seizures in patients
with trisomy 21. Am. J. Med. Genet.Suppl. 1990;7:298-300. 5Tatsuno M, Hayashi M, Iwamoto H, Suzuki Y, Kuroki Y. Epilepsy in childhood Down
syndrome. Brain.Dev. 1984;6:37-44. 6 Kajitani T. Clinical feature, electroencephalographic manifestation, and prognosis of febrile seizure (in Japanese). Shonika.Rinsho.(Tokyo).2001;54:1923-30. 7 Oka E. Epidemiology of febrile seizure. Is the incidence rate of febrile seizure in Japanese people
higher
than
that
in
Caucasian
people
(in
Japanese).Shonika.Rinsho.
(Tokyo).1996;49:2353-7. 8Sugai K. Current management of febrile seizures in Japan: an overview.Brain.Dev. 2010;32:64-70. 9Ram G, Chinen J. Infections and immunodeficiency in Down syndrome.Clin. Exp.Immunol.2011;164:9-16. 10vanEsch A, Steyerberg EW, van Duijn CM, Offringa M, Derksen-Lubsen G, van Steensel-Moll HA. Prediction of febrile seizures in siblings: a practical approach. Eur. J.Pediatr.1998;157:340-4.
11Genton P, Bahi-Buisson N, Kaminska A, Elia M, and Gobbi G. Trisomy 21 (Down syndrome). In: Bureau M, Genton P, Dravet C, Delgado-Escueta AV, Tassinari CA, Thomas 9
This article is protected by copyright. All rights reserved.
Accepted Article
P, editors. Epileptic syndromes in infancy, childhood and adolescence, Paris: John Libbey, 2012; 554-5. 12Møller RS, Kübart S, Hoeltzenbein M, Heye B, Vogel I, Hansen CP, et al. Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly. Am. J. Hum.Genet.2008;82:1165-70. 13Yamamoto T, Shimojima K, Nishizawa T, Matsuo M, Ito M, Imai K. Clinical manifestations of the deletion of Down syndrome critical region including DYRK1A and KCNJ6. Am. J. Med. Genet.A 2011;155:113-9.
14Heida JG, Moshé SL, Pittman QJ. The role of interleukin-1beta in febrile seizures. Brain Dev 2009;31:388-93. 15Roberson R, Kuddo T, Horowitz K, Caballero M, Spong CY. Cytokine and chemokine alterations in Down syndrome.Am. J.Perinatol.2012;29:705-8.
10 This article is protected by copyright. All rights reserved.
Accepted Article
Table 1. Characteristics of patients with DS developing FS Total Number Age number of No. Sex of siblings Age at FS (years) siblings with FS
Clustering
Duration of FS
Seizure manifestation
EEG
1
10
Male
2
1
11 months
–
Incidence of febrile seizure in patients with Down syndrome1 Shuichi Shimakawaa*, Takuya Tanabeb, MasaeOnoc, Michiko Nonakad, MitsuhikoNambue, TohruShinoharaf, Toshiya Nishikubog, Miho Fukuia, ShoheiNomuraa, Kohji Azumagawah, Hiroshi Tamaia a
Department of Pediatrics, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki-city, Osaka
569-8686, Japan
b
Department of Pediatric Neurology, Tanabe Children’s Clinic, 1-49-31 Higashiyama,
Hirakata, Osaka 573-1114, Japan c
Department of Pediatrics, Tokyo Teishin Hospital, 2-14-23 Fujimi, Chiyoda-ku, Tokyo
102-8798, Japan d
Hyogo PrefecturalChild Development Support Center, 2744 Shimizu Uozumi-cho, Akashi,
Hyogo 674-0074, Japan e
Department of Pediatrics, Tenri Hospital, 200 Mishima-cho, Tenri, Nara 632-8552, Japan
f
Department of Pediatrics, Kinki University Hospital, Faculty of Medicine, 377-2
Ohnohigashi, Sayama, Osaka 589-851, Japan g
Division of Neonatal Intensive Care, Perinatal Medical Center,Nara Medical University
Hospital, 840 Shijo-cho, Kashihara, Nara 634-8522,Japan h
Department of Pediatrics, Seikeikai Hospital, 4-2-10 Kouryounakamachi, Sakai-ku, Sakai,
Osaka 590-0024, Japan
*Corresponding author: Shuichi Shimakawa Department of Pediatrics, Osaka Medical College 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
Tel: +81-726-83-1221; Fax: +81-726-84-5798; E-mail: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/ped.12601
1 This article is protected by copyright. All rights reserved.
Accepted Article
Abstract
Aim:It is unclear whether the incidence of febrile seizure (FS) in children with Down syndrome (DS) is higher or lower than in the general population. In this study, we investigated the incidence of FS in patients with DS using mailed questionnaires. Methods: The questionnaires were distributed to parents or caregivers of patients with DS attending Osaka Medical College Hospital and six other facilities. The questionnaires were collected by mail from February 2012 to September 2013 from 323 families of patients with DS (176 were male, 147 were female; age range, 3 months to 47 years; median age, 5.0 years). To assess the incidence of FS in DS, we performed the following two analyses: (1) we calculated the incidence of FS among patients with DS between the ages of 4 and 20 years (n = 199; 113 were male, 86 were female), and (2) we extracted families with both DS and healthy siblings between the ages of 4 and 20 years (n = 150; 77 were male, 73 were female) and compared the incidence of FS in these sibling groups. Results:Five patients with DS had a past history of FS. The incidence of FS in DS was 2.5%. The incidence of FS was significantly lower in patients with DS compared with healthy siblings (P< 0.003, Odds ratio: 0.14). Conclusion: Our findings suggest that the incidence of FS is lower in patients with DS than in the general population.
Keywords: Down syndrome, febrile seizure, incidence of febrile seizure, sibling
2 This article is protected by copyright. All rights reserved.
Accepted Article
Introduction Febrile seizure (FS) is an acute symptomatic seizure that occurs during febrile illness,
and is common in infancy and childhood.1 In the pediatric population, FS is the most common neurological event, affecting between 2 and 14% of children worldwide.1, 2 It is unclear whether the incidence of FS in patients with Down syndrome (DS) is higher or lower than in the general population. Stafstrom et al. reported a lower incidence of FS (0.9%) in patients with DS compared with the overall prevalence of around 3% in the general population.3 However, Romano et al. reported that the incidence of FS in patients with DS is higher than in non-DS individuals.4 To the best of our knowledge, there is only one published old study on the occurrence of FS in DS in Japan, which reported an incidence of 0.5% in patients with DS (2 of 371 cases).5 In the present study, we investigate the incidence of FS in patients with DS. We also
examine whether the incidence is higher in patients with DS compared with their healthy siblings.
Subjects and Methods To investigate the incidence of FS in patients with DS,mail questionnaires were
distributed to parents or caregiver of patients with DS with all of full trisomy of chromosome 21 attending Osaka Medical College Hospital, Hyogo PrefecturalChild Development Support Center, Hyogo PrefecturalTsukaguchi Hospital,Kinki University Hospital, Nara Medical
University Hospital, Seikeikai Hospital, Tenri Hospital, or Tokyo Teishin Hospital at the time of the visits to their hospital for medical care, and collected by mail from February 2012 to September 2013. Attending physician who belonged to the hospitals checked the karyotypes in all patients with DS, before sending the questionnaires. Our questionnaire included the method used to diagnose DS, age, gender, with or without past history of FS, with or without 3 This article is protected by copyright. All rights reserved.
Accepted Article
complication of brain disorder caused by other conditions resulting from DS, with or without past history of afebrile seizure, and with or without complication of epilepsy. If the patient with DS had a past history of FS, the family was required to answer the following additional questions: age of onset, seizure duration, with or without diagnosis of FS performed by a medical doctor, seizure manifestation, cause of acute febrile illness, and with or without abnormalities in an electroencephalogram. Furthermore, we added the following questions on the healthy siblings of the patients with DS: number of healthy siblings, age, gender, with or without past history of FS, and with or without a disease diagnosed by a medical doctor. Finally, we included the definition of FS (see Appendix 1 for questionnaire). This investigation was approved by the ethics committee of Osaka Medical College. The questionnaire was collected from 323 families of patients with DS (176 were male,
147 were female; age range, 3 months to 47 years; median age, 5.0 years). All of the patients with DS were diagnosed by G-banding. To assess the incidence of FS in patients with DS, we performed the following two analyses: (1) we calculated the incidence of FS among patients with DS between the ages of 4 and 20 years (n = 199; 113 were male, 86 were female; age range, 4 to 20 years; median age, 8 years), and (2) we extracted families with both DS patients and healthy siblings between the ages of 4 and 20 years (n = 150; 77 were male, 73 were female; age range, 4 to 20 years; median age, 7 years) and compared the incidence of FS in these sibling groups. Differences in the incidence of FS between DS patients and healthy siblings were analyzed using the Fisher’s exact test. A P-value < 0.05 was considered
statistically significant.
Results
Five hundred and thirty questionnaires were distributed and 323 questionnaires were collected from families of patients with DS, a return rate 61%. 4 This article is protected by copyright. All rights reserved.
Accepted Article
A past history of FS was found in five patients with DS. The incidence of FS among
patients with DS was 2.5%. Although a complicating brain disorder was found in four patients with DS, they did not have a history of FS. A total of 14 patients with DS had experienced afebrile seizure. All of the 14 patients developing afebrile seizure did not experience febrile seizure. Among these 14 patients with DS with afebrile seizure, seven were diagnosed with epilepsy. In all of seven patients developing epilepsy, classification of seizure type and epilepsyand the antiepileptic drug wasnot identified, and in the other seven patients without diagnosis of epilepsy, the causes of afebrile seizures were not identifiedbecause of these data didnot include our questionnaires. The onset of epilepsy was infancy in 3 cases, childhood in one case, adolescence in 2 cases and unknown in one case.None of these 14 patients with DShad experienced FS. The clinical characteristic of patients with DS with FS are presented in Table 1. The age
of onset of FS was less than 6 months in patient 3, while it was more than 6 years in patient 5. The seizures were clustered over a single acute febrile episode in patient 4. The sibling of patients 1 had also experienced FS. Prolonged seizure did not develop in all subjects. Patient 3 and 4 developed FS with a focal component, whereas the remaining three subjects developed generalized seizure. Electroencephalography performed in patient 2 showed normal activity. As for the cause of febrile illness, influenza infection was diagnosed in patient 5, while it was undetermined in the remaining four patients with DS. We compared the incidence of FS in patients with DS and healthy siblings. All of them
were diagnosed with FS and epilepsy by a medical doctor.Among healthy siblings, 18 of 150 individuals had experienced FS and the patient of epilepsy was not found.In comparison, among patients with DS, 2 of 109 individuals had experienced FS and 4 of 109 individuals had diagnosed with epilepsy. The incidence of FS was significantly lower in patients with DS
5 This article is protected by copyright. All rights reserved.
Accepted Article
than in healthy siblings (P< 0.003, Odds ratio: 0.14) (Table 2). Complicating brain disorder
was not found in any of the healthy siblings.
Discussion
Based on data collected using mailed questionnaires, we obtained an incidence of FS in
patients with DS of 2.5%. Previous studies reported an incidence of FS in the general population of 7–9% in Japan.6, 7Furthermore, we found that the incidence of FS was significantly lower in patients withDS compared with healthy siblings. Therefore, the incidence of FS in patients with DS might be lower than in the general population. We also
examined whether an acquired factor, brain damage (e.g., resulting from asphyxia of the newborn or congenital heart disease), was a complication in patients withDS. No patients
with DS had acquired brain damage. Therefore, the incidence of FS was not impacted by acquired brain damage in patients with DS. Although the incidence of FS in patients with DS might be lower than in the general
population, a total of 14 patients with DS had experienced afebrile seizure.The patients with DS might develop seizure by lower grade fever than 38ºC. Because febrile seizure was usually defined as the seizure associated with a fever of 38ºC or higherfever,8 the seizure developed by lower grade fever than 38ºC might be not classified into febrile seizure, even if the patients with Down syndrome were easy to develop seizure by lower grade fever than 38ºC.There was another possibility that the patients with Down syndrome might have less chance with high fever than the healthy children because of their immunological features.AlthoughDS was the most common recognizable genetic syndrome with immune defects,9 to the best of our knowledge, we could not find the report that the body temperature elevated more in the patient with Down syndrome compared with the healthy children.
6 This article is protected by copyright. All rights reserved.
Accepted Article
Therefore, the incidence of FS, seizure developed by a fever of 38.0ºC or higher in patients
with DS might be lower than in the general population. The clinical characteristics of FS in DS were previously not adequately described.
Therefore, in the present study, we evaluated the clinical symptoms of complex FS, including the age of onset, seizure clustering during a single acute febrile episode, family history, and FS with a focal component. Electroencephalography performed in one of five subjects showed a normal record. Our present findings are consistent with a previous report in which electroencephalography findings were also normal in patients with DS with a past history of FS.5
Van Esch and colleagues examined the risk of developing FS in siblings of children with
FS. These authors found that the risk of FS in siblings (10%) was more than twice the average population risk (4%) in the Netherlands.10 In patients with DS with a healthy sibling with FS, the incidence of FS might be increased compared with patients withDS not having a healthy sibling with FS. In our study, patients withDS or healthy siblings who had experienced FS and also had a sibling with a past history of FS were found in three families. Both a patient with DS and his healthy sibling had experienced FS in one family, and both of two healthy siblings experienced FS in two families. However, we could not definitively determine whether the incidence of FS is higher or not in patients with DS having a healthy sibling with FS, because the number of healthy siblings with a past history of FS was only 18. The critical region for DS (DSCR) has been mapped to 21q22.11 A previous study found
cellular and cytoarchitectonic changes in DS, including a reduction in the number of granular cells (which play a role in GABAergic inhibition), lower neuronal density, retarded myelination, and dysgenesis of dendritic spines.11 These changes have been implicated in infantile spasms, which are particularly frequent in patients with DS.5,
11
In our present
investigation, epilepsy developed in only patients with DS, whereas epilepsy didnot develop 7
This article is protected by copyright. All rights reserved.
Accepted Article
in healthy sibling.However, because the incidence of FS in patients with DS was low in our present investigation, these cellular changes probably affect the development of epilepsy and do not substantially affect the development of FS. Moreover, it is interesting that five of six patients with deletion of the DSCR developed FS.12,
13
Therefore, the DSCR might be
implicated in the development of FS. Proinflammatory cytokines (particularly IL-1β)play a significant role in the pathogenesis
of FS.14 It is interesting that the levels of IL-1βwere significantly lower in the hippocampus of a DS mouse model (Ts65Dn) compared with control animals.15 However, to the best of our knowledge, the levels of proinflammatory cytokines have not been measured in patients with DS in the acute phase of febrile illness. Further investigation is needed to elucidate the pathophysiological mechanisms resulting in the lower incidenceof FS in DS.
Conclusion
The incidence of FS appears to be lower in individuals with DS compared with the
general population. Further investigation is needed to clarify why the incidence of FS in DS is low.
Acknowledgments The authors thank Dr. Hiroko Fujita (Department of Pediatrics, Hyogo Prefectural
Tsukaguchi Hospital) and Ms. Kiyoko Fukuoka (Coaching staff ofrehabilitation of babies with Down syndrome) for their suggestions for clinical practice and rehabilitation in Down syndrome.
8 This article is protected by copyright. All rights reserved.
Accepted Article
References
1 Reid AY, Galic MA, Teskey GC, Pittman QJ. Febrile seizures: current views and investigations. Can. J. Neurol. Sci. 2009;36:679-86. 2Hauser,WA. The prevalence and incidence of convulsive disorders in children.Epilepsia
1994;35:S1-6. 3Stafstrom CE, Patxot OF, Gilmore HE, Wisniewski KE. Seizures in children with Down
syndrome: etiology, characteristics and outcome. Dev. Med. Child.Neurol. 1991;33:191-200. 4Romano C, Tiné A, Fazio G, Rizzo R, Colognola RM, Sorge G, et al. Seizures in patients
with trisomy 21. Am. J. Med. Genet.Suppl. 1990;7:298-300. 5Tatsuno M, Hayashi M, Iwamoto H, Suzuki Y, Kuroki Y. Epilepsy in childhood Down
syndrome. Brain.Dev. 1984;6:37-44. 6 Kajitani T. Clinical feature, electroencephalographic manifestation, and prognosis of febrile seizure (in Japanese). Shonika.Rinsho.(Tokyo).2001;54:1923-30. 7 Oka E. Epidemiology of febrile seizure. Is the incidence rate of febrile seizure in Japanese people
higher
than
that
in
Caucasian
people
(in
Japanese).Shonika.Rinsho.
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Table 1. Characteristics of patients with DS developing FS Total Number Age number of No. Sex of siblings Age at FS (years) siblings with FS
Clustering
Duration of FS
Seizure manifestation
EEG
1
10
Male
2
1
11 months
–
