Journal http://jcn.sagepub.com/ of Child Neurology
Association Between Hypocapnia and Febrile Seizures Buket Kilicaslan, Ilknur Erol, Yasemin Ozkale, Semra Saygi and Cagla Sariturk J Child Neurol 2014 29: 599 originally published online 5 January 2014 DOI: 10.1177/0883073813513070 The online version of this article can be found at: http://jcn.sagepub.com/content/29/5/599
Published by: http://www.sagepublications.com
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Original Article
Association Between Hypocapnia and Febrile Seizures
Journal of Child Neurology 2014, Vol. 29(5) 599-602 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073813513070 jcn.sagepub.com
Buket Kilicaslan, MD1, Ilknur Erol, MD2, Yasemin Ozkale, MD3, Semra Saygi, MD2, and Cagla Sariturk, PhD4
Abstract The purpose of this study is to determine whether hyperthermia-induced hyperventilation with subsequent hypocapnia is relevant to febrile seizures in children. This is only the second study to measure pCO2 and pH values in children with febrile seizures. This prospective case-control study enrolled 18 children who presented with febrile seizures and 18 children who presented with a febrile illness without seizures. Venous blood gas analyses were measured both from the febrile seizure and control group. There was no significant difference in mean blood pH between the febrile seizure and control groups but blood pCO2 was significantly lower in the febrile seizure group. Patients with complex febrile seizures exhibited significantly lower pCO2 levels within 1 hour of seizure onset than patients with simplex febrile seizures. These data indicate that febrile seizures may be associated with hyperventilation and that the ensuing hypocapnia may contribute to the development of febrile seizures. Keywords febrile seizure, hypocapnia, complex febrile seizure Received May 7, 2013. Received revised September 19, 2013, and October 9, 2013. Accepted for publication October 22, 2013.
Febrile seizures are common during infancy and early childhood, particularly between 3 months and 5 years of age. By definition, febrile seizes are associated with fever but without evidence of intracranial infection or other defined causes.1 Febrile seizure is one of the most common benign neurological conditions of childhood; 2% to 5% of children under the age of 5 years experience febrile seizures.2 The prevalence of febrile seizures in Japan has been reported to range from 3.4% to 9.3%.3 In Turkey, the prevalence of febrile seizures has been reported as 2.6% to 8.9%.4,5 They are classified as ‘‘simple febrile seizures’’ if they are brief (15 minutes), have focal features, or recur within 24 hours.6 The rate of recurrence of febrile seizures has been reported to range from 29% to 55%.7 Genetic and environmental factors are thought to contribute to febrile epileptogenesis.8 Although a number of susceptibility genes associated with fever-induced convulsions have been identified, the precise epileptogenic mechanisms have not been determined.9 The pathogenic mechanisms and sequelae of febrile seizures have been extensively studied in rat pups exposed to elevated ambient temperature.10,11 While this model cannot reproduce all characteristics of human febrile seizures, sporadic seizures are difficult to study in humans. In animal models, hyperthermia causes hyperventilation with ensuing hypocapnia, leading to respiratory alkalosis, brain alkalosis, and seizures.12 Hyperventilation, which
by definition leads to a net loss of CO2 and to consequent respiratory alkalosis, is a standard method to induce absence seizures, complex partial seizures, and other epileptiform manifestations in human patients.13 It is not known whether hyperthermiainduced hyperventilation with subsequent hypocapnia and alkalosis is relevant to febrile seizures in human children. Despite evidence from both animal models and adult humans, this is only the second study to measure PCO2 and pH values in children with febrile seizures.14 This is the first study to compare children with febrile seizures and febrile children without seizures excluding the possibility of acidosis such as gastroenteritis.
1
Baskent University Faculty of Medicine, Adana Teaching and Medical Research Center, Department of Pediatrics, Adana, Turkey 2 Baskent University Faculty of Medicine, Adana Teaching and Medical Research Center, Department of Pediatric Neurology, Adana, Turkey 3 Baskent University Faculty of Medicine, Adana Teaching and Medical Research Center, Department of Pediatrics, Adana, Turkey 4 Baskent University, Adana Teaching and Medical Research Center, Division of Biostatistics, Adana, Turkey Corresponding Author: Ilknur Erol, MD, Baskent University Faculty of Medicine, Division of Pediatric Neurology, Adana Teaching and Medical Research Center, Baraj Yolu 1 Durak, Seyhan 01120, Adana, Turkey. Email: [email protected]
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Methods The authors enrolled 36 children admitted to the Department of Pediatrics and the Pediatric Emergency Department at Baskent University Hospital, Adana Teaching and Medical Research Center, Adana, Turkey, between October 2012 and January 2013. For the purposes of the study, the case definition of a febrile convulsion was a convulsive seizure in an infant or child in association with a fever of 38.0 C or higher without definitive evidence of neurological illness, metabolic abnormalities, central nervous system infections, or poisoning. Thus, both simple and complex febrile convulsions were included. The 18 children in the study group ranged from 6 to 60 months of age. The control group consisted of 18 children within the same age range randomly selected from children admitted for febrile illnesses without seizure. Children admitted for febrile illnesses such as gastroenteritis, lower respiratory tract infections, or central nervous system infections were excluded. The febrile illness, duration of seizures, medical history of patient and parents, and time of admission to the hospital after the febrile seizure were recorded. Venous blood gases were measured from the febrile seizure group within 1 hour of seizure and at 24 hours after a seizure attack. In the control group, venous blood gases were measured only once within 1 hour after a febrile period. In both groups, blood pH was measured. A pH of 7.35 to 7.45 and PCO2 of 35 to 45 mm Hg were considered physiologically normal. Data are presented as mean + standard error of the mean and as medians with ranges. Statistical analyses were performed using the SPSS 15.0 statistical package. For each continuous variable, distribution normality was checked by Kolmogorov-Smirnov and Shapiro-Wilk tests and by histograms. Categorical variables were compared by the w2 test. Means from seizure and control groups were compared by Student’s t tests if both data sets were normally distributed or by Mann-Whitney U tests if one or both data sets did not fit a normal distribution. Pre-post measures within groups were compared by paired-sample t tests if both data sets satisfied conditions of normality or by Wilcoxon tests if at least 1 distribution did not satisfy conditions of normality. Values of P < .05 were considered statistically significant.
Figure1. Comparison of pH values at 1 hour and at 24 hours in patient and in control group.
Results The authors examined the association between febrile seizures and hypocapnia by comparing blood pH and PCO2 of 18 children with febrile seizure (11 girls, 7 boys) to a control group of 18 children with febrile illness but no seizures (11 girls, 7 boys). Mean ages of children in the febrile seizure and control groups were 20.8 + 7.0 months and 30.4 + 19.8 months, respectively. No significant difference was observed in the gender ratio or age distribution between the febrile seizure group and the control group (P > .05). All of the children in the febrile seizure group were diagnosed with upper respiratory tract infections, including otitis media, tonsillitis, pharyngitis, and sinusitis. Six children in the control group were diagnosed with urinary tract infections. A history of recurrent febrile seizures was noted in 11 children of the febrile seizure group (61.1%), while only 1 child in the control group had a history of recurrent febrile seizures (5.6%). Ten children in the febrile seizure group (55.6%), but none of the control patients, had a family history of febrile seizures. In the febrile seizure group, 14 children were diagnosed
Figure 2. Comparison of pCO2 values at 1 hour and at 24 hours in patient and in control group.
with simple febrile seizures (77.8%) and 4 with complex febrile seizures (22.2%). The mean temperature in febrile seizure group was 38.6 C + 0.53 C (range, 38 C-40 C) and the mean temperature in control group was 38.5 C + 0.5 C (range, 38 C-39.5 C) at the time of admission. The difference was insignificant.
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Table 1. Comparison of Blood pH and PCO2 Values at 1 Hour and 24 Hours Postictal in Patients With Febrile Seizure and Control Group.
Patients with febrile seizure Control group
1 h (n ¼ 18) 24 h (n ¼ 18) 1 h (n ¼ 18)
pHa
P Value
PCO2a
7.40 + 0.06 7.39 + 0.05 7.37 + 0.05
.61
29.28 + 7.30 33.33 + 8.84 37.28 + 8.98
.16b .29c
P Value .12 .006b,d .19c
a
Values are mean + standard error of the mean. Comparison with febrile patient at 1 hour. c Comparison with febrile patient at 24 hours. d Significant (P < .05). b
Table 2. Comparison of Blood pH and PCO2 Values According to Seizure Types. pHa Recurrent febrile seizure (n ¼ 12) Nonrecurrent febrile seizure (n ¼ 24) Simple febrile seizure (n ¼ 14) Complex febrile seizure (n ¼ 4)
7.40 + 7.38 + 7.40 + 7.40 +
P Value 0.67 0.05 0.06 0.05
.13 .79
PCO2a 30.75 + 34.54 + 31.20 + 22.50 +
9.23 8.86 6.80 4.10
P Value .24 .03b
a
Values are mean + standard error of the mean. Significant (P < .05).
b
Both blood pH and PCO2 were measured within 1 hour after the febrile seizure and 1 hour of febrile period of control group. There was no significant difference in mean blood pH between the febrile seizure and control groups, but blood PCO2 was significantly lower in the febrile seizure group (Figures 1 and 2). At 24 hours after the febrile seizure event, PCO2 was not significantly different from that measured in the control fever patients (Table 1). The mean base excess in the febrile seizure group was –4.7 + 5.2 and the mean base excess in the control group was –3.0 + 5.5 at the time of admission. The difference was insignificant. Patients with complex febrile seizures exhibited significantly lower PCO2 levels within 1 hour of febrile seizure onset than did patients with simplex febrile seizures, whereas there was no significant difference in pH between these 2 groups at either 1 hour or 24 hours after the febrile seizure event. The significant difference in PCO2 observed between patients with simple and complex febrile seizures within 1 hour was no longer present at 24 hours after the febrile seizure. There was also no significant difference between the blood pH and PCO2 values of the group with recurrent febrile seizures and the group with nonrecurrent febrile seizures, although the mean values of blood pH were higher and PCO2 values were lower in the group with a history of recurrent febrile seizure (Table 2). There was only 1 patient with a recurrent febrile seizure in the control group; that patient’s blood pH was 7.31 and PCO2 value was 44 mm Hg. When the pH and PCO2 values of febrile seizure patients with a family history of febrile seizure were compared with values of those patients with no family history, no statistically significant differences were found.
Discussion Little is known of the mechanisms responsible for the initiation and maintenance of febrile seizures.12 Fever is an
elevation of body temperature induced by the thermoregulatory center of the hypothalamus, possibly to stimulate the immune system and preserve cell membrane integrity in response to pathogens.2 Fever is a direct cause of tachypnea in children with acute infections. O’Dempsey et al15 measured a 3.7 breath per minute increase for every 1 C increase in body temperature in a large cohort of children with fever and concluded that respiratory rate was partially dependent on body temperature in children with febrile illnesses.15 This elevated breathing rate during fever reflects the important role of ventilation in the regulation of mammalian body temperature. However, more rapid breathing can also alter blood gases and tissue pH; indeed, a decrease in blood PCO2 can develop during sustained hyperthermia.16 Moreover, hyperthermia leads to thermal tachypnea and age-dependent respiratory alkalosis that triggers and sustains convulsions in young rats.12 In 2011, Schuchmann et al14 examined the acid-base status of children with febrile seizures for the first time and concluded that a similar sequence of events leads to seizures in humans. The investigators observed a progressive decrease of the initially alkaline pH, which reached standard levels at 2 hours or later after febrile seizure onset in the hospital (0.5 hour or 1 hour vs 2 hours or 3 hours).14 That study compared febrile patients who had gastroenteritis and patients who had febrile seizures, whereas the current study compared patients who had febrile seizures and febrile patients who did not have gastroenteritis. Thus, in the current study, the possibility of acidosis was ruled out in both groups. Despite the higher mean blood pH values in the febrile seizure group, there was no significant difference in the current study. It is known that absence seizures can be reliably evoked by hypocapnia, although the critical PCO2 varies among children.17 Yang et al18 described a rare patient with nonlesional temporal epilepsy who developed complex partial seizures
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presenting as ictal fear while hyperventilating, a response attributed to the particular sensitivity of the anterior hippocampus (probably the amygdala) to hypocapnia. Similarly, hypocapnia in rats caused by fever-induced hyperpnea likely contributed to the generation of fever-induced seizures.19 Consistent with these experimental and clinical observations, the current study demonstrated a strong association between hypocapnia and febrile seizures. Morimoto et al19 also reported that seizure duration was longer at lower PCO2. In the current study, the PCO2 reduction following complex febrile seizures was statistically significant although smaller than that measured in patients with simple seizures. It is known that complex febrile seizures are one of the main risk factors for the development of epilepsy,20 suggesting frequent hypocapnia as a possible epileptogenic mechanism. Positive family history of febrile seizure is predictive of recurrent febrile seizures, but the number of febrile seizures does not predict the development of epilepsy.21 The current study found no significant difference in PCO2 reduction between patients with a positive family history of febrile seizures and those patients with no family history.
Conclusion The findings presented here suggest that febrile seizures may be associated with hyperventilation and that the ensuing hypocapnia may contribute to the development of febrile seizures. These data also indicate that the reduction in PCO2 during complex febrile seizures is significant. However, a larger patient sample and longer term follow-up are required to confirm these results. Author Contributions BK and IE wrote the manuscript. BK, IE, YO, and SS were involved in patient care, including administration of medication and routine clinical follow-up. IE was involved in editing the manuscript. CS conducted the biostatistical analysis of this study.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This study was supported by the Baskent University Research Fund.
Ethical Approval This study was approved by the Baskent University Institutional Review Board and Ethics Committee (project no. KA12/120). Informed consent was obtained from the parents of all children after through explanation of the study methods and goals.
References 1. Consensus Development Panel. Febrile seizures: long term management of children with fever-associated seizures. Pediatrics. 1980;66:1009-1012.
2. Siqueira LFM. Febrile seizures: update on diagnosis and management. Rev Assoc Med Bras. 2010;56:489-492. 3. Sugai K. Current management of febrile seizures in Japan: an overview. Brain Dev. 2010;32:64-70. ¨ ztu¨rk MK, O ¨ nal AE, Tu¨merdem Y. Prevalence of febrile con4. O vulsions in a group of children aged 0 to 9 years in a slum in _ _ Istanbul. Med Bull Istanbul. 2002;35:79-84. ¨ ¨ zmen M. Febril 5. Yu¨cel O, Tatlı B, Aydınlı N, C¸alıs¸ kan M, O _ Konvu¨lsiyonda Prospektif Izlem. C ¸ ocuk Dergisi. 2003;3(4): 262-267. 6. Berg AT, Shinnar S. Complex febrile seizures. Epilepsia. 1996; 37:126-133. 7. Berg AT, Shinnar S, Hauser WA, Leventhal JM. Predictors of recurrent febrile seizures: a metaanalytic review. J Pediatr. 1990;116:329-337. 8. Mewasingh LD. Febrile seizures. Clinical Evidence Handbook. June 2008, pp 91-93. 9. Baulac S, Gourfinkel-An I, Nabbout R, et al. Fever, genes and epilepsy. Lancet Neurol. 2004;3:421-430. 10. Holtzman D, Obana K, Olson J. Hyperthermia-induced seizures in the rat pup: a model for febrile convulsions in children. Science. 1981;213:1034-1036. 11. Baram TZ, Gerth A, Schultz L. Febrile seizures: an appropriate aged model suitable for long-term studies. Brain Res Dev Brain Res. 1997;98:265-270. 12. Schuchmann S, Schmitz D, Rivera C, et al. Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis. Nat Med. 2006;12:817-823. 13. Takahashi T. Activation methods. In: Niedermeyer E, Lopes da Silva F, eds. Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. 6th ed. Baltimore, MD: Williams & Wilkins; 2005:281-303. 14. Schuchmann S, Hauck S, Henning S, et al. Respiratory alkalosis in children with febrile seizures. Epilepsia. 2011;52: 1949-1955. 15. O’Dempsey TJD, Laurence BE, McArdle TF, et al. The effect of temperature reduction on respiratory rate in febrile illnesses. Arch Dis Child. 1993;68:492-495. 16. Mortola JP, Frappell PB. Ventilatory responses to changes in temperature in mammals and other vertebrates. Anny Rev Physiol. 2000;62:847-874. 17. Wirrell EC, Camfield PR, Gordon KE, et al. Will a critical level of hyperventilation-induced hypocapnia always induce an absence seizure? Epilepsia. 1996;37:459-462. 18. Yang CS, Chow JC, Tsai JJ, Huang CW. Hyperventilationinduced ictal fear in nonlesional temporal lobe epilepsy. Epilepsy Behav. 2011;21:100-102. 19. Morimoto T, Fukuda M, Aibara Y, et al. The influence of blood gas changes on hyperthermia-induced seizures in developing rats. Brain Res Dev Brain Res. 1996;92:77-80. 20. Nelson KB, Ellenberg JH. Prognosis in children with febrile seizures. Pediatrics. 1978;61:720-727. 21. Sfaihi L, Maaloul I, Kmiha S, et al. Febrile seizures: an epidemiological and outcome study of 482 cases. Childs Nerv Syst. 2012; 28:1779-1784.
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Association Between Hypocapnia and Febrile Seizures Buket Kilicaslan, Ilknur Erol, Yasemin Ozkale, Semra Saygi and Cagla Sariturk J Child Neurol 2014 29: 599 originally published online 5 January 2014 DOI: 10.1177/0883073813513070 The online version of this article can be found at: http://jcn.sagepub.com/content/29/5/599
Published by: http://www.sagepublications.com
Additional services and information for Journal of Child Neurology can be found at: Email Alerts: http://jcn.sagepub.com/cgi/alerts Subscriptions: http://jcn.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> Version of Record - Apr 29, 2014 OnlineFirst Version of Record - Jan 5, 2014 What is This?
Downloaded from jcn.sagepub.com at University of Alabama at Birmingham on September 30, 2014
Original Article
Association Between Hypocapnia and Febrile Seizures
Journal of Child Neurology 2014, Vol. 29(5) 599-602 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073813513070 jcn.sagepub.com
Buket Kilicaslan, MD1, Ilknur Erol, MD2, Yasemin Ozkale, MD3, Semra Saygi, MD2, and Cagla Sariturk, PhD4
Abstract The purpose of this study is to determine whether hyperthermia-induced hyperventilation with subsequent hypocapnia is relevant to febrile seizures in children. This is only the second study to measure pCO2 and pH values in children with febrile seizures. This prospective case-control study enrolled 18 children who presented with febrile seizures and 18 children who presented with a febrile illness without seizures. Venous blood gas analyses were measured both from the febrile seizure and control group. There was no significant difference in mean blood pH between the febrile seizure and control groups but blood pCO2 was significantly lower in the febrile seizure group. Patients with complex febrile seizures exhibited significantly lower pCO2 levels within 1 hour of seizure onset than patients with simplex febrile seizures. These data indicate that febrile seizures may be associated with hyperventilation and that the ensuing hypocapnia may contribute to the development of febrile seizures. Keywords febrile seizure, hypocapnia, complex febrile seizure Received May 7, 2013. Received revised September 19, 2013, and October 9, 2013. Accepted for publication October 22, 2013.
Febrile seizures are common during infancy and early childhood, particularly between 3 months and 5 years of age. By definition, febrile seizes are associated with fever but without evidence of intracranial infection or other defined causes.1 Febrile seizure is one of the most common benign neurological conditions of childhood; 2% to 5% of children under the age of 5 years experience febrile seizures.2 The prevalence of febrile seizures in Japan has been reported to range from 3.4% to 9.3%.3 In Turkey, the prevalence of febrile seizures has been reported as 2.6% to 8.9%.4,5 They are classified as ‘‘simple febrile seizures’’ if they are brief (15 minutes), have focal features, or recur within 24 hours.6 The rate of recurrence of febrile seizures has been reported to range from 29% to 55%.7 Genetic and environmental factors are thought to contribute to febrile epileptogenesis.8 Although a number of susceptibility genes associated with fever-induced convulsions have been identified, the precise epileptogenic mechanisms have not been determined.9 The pathogenic mechanisms and sequelae of febrile seizures have been extensively studied in rat pups exposed to elevated ambient temperature.10,11 While this model cannot reproduce all characteristics of human febrile seizures, sporadic seizures are difficult to study in humans. In animal models, hyperthermia causes hyperventilation with ensuing hypocapnia, leading to respiratory alkalosis, brain alkalosis, and seizures.12 Hyperventilation, which
by definition leads to a net loss of CO2 and to consequent respiratory alkalosis, is a standard method to induce absence seizures, complex partial seizures, and other epileptiform manifestations in human patients.13 It is not known whether hyperthermiainduced hyperventilation with subsequent hypocapnia and alkalosis is relevant to febrile seizures in human children. Despite evidence from both animal models and adult humans, this is only the second study to measure PCO2 and pH values in children with febrile seizures.14 This is the first study to compare children with febrile seizures and febrile children without seizures excluding the possibility of acidosis such as gastroenteritis.
1
Baskent University Faculty of Medicine, Adana Teaching and Medical Research Center, Department of Pediatrics, Adana, Turkey 2 Baskent University Faculty of Medicine, Adana Teaching and Medical Research Center, Department of Pediatric Neurology, Adana, Turkey 3 Baskent University Faculty of Medicine, Adana Teaching and Medical Research Center, Department of Pediatrics, Adana, Turkey 4 Baskent University, Adana Teaching and Medical Research Center, Division of Biostatistics, Adana, Turkey Corresponding Author: Ilknur Erol, MD, Baskent University Faculty of Medicine, Division of Pediatric Neurology, Adana Teaching and Medical Research Center, Baraj Yolu 1 Durak, Seyhan 01120, Adana, Turkey. Email: [email protected]
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Methods The authors enrolled 36 children admitted to the Department of Pediatrics and the Pediatric Emergency Department at Baskent University Hospital, Adana Teaching and Medical Research Center, Adana, Turkey, between October 2012 and January 2013. For the purposes of the study, the case definition of a febrile convulsion was a convulsive seizure in an infant or child in association with a fever of 38.0 C or higher without definitive evidence of neurological illness, metabolic abnormalities, central nervous system infections, or poisoning. Thus, both simple and complex febrile convulsions were included. The 18 children in the study group ranged from 6 to 60 months of age. The control group consisted of 18 children within the same age range randomly selected from children admitted for febrile illnesses without seizure. Children admitted for febrile illnesses such as gastroenteritis, lower respiratory tract infections, or central nervous system infections were excluded. The febrile illness, duration of seizures, medical history of patient and parents, and time of admission to the hospital after the febrile seizure were recorded. Venous blood gases were measured from the febrile seizure group within 1 hour of seizure and at 24 hours after a seizure attack. In the control group, venous blood gases were measured only once within 1 hour after a febrile period. In both groups, blood pH was measured. A pH of 7.35 to 7.45 and PCO2 of 35 to 45 mm Hg were considered physiologically normal. Data are presented as mean + standard error of the mean and as medians with ranges. Statistical analyses were performed using the SPSS 15.0 statistical package. For each continuous variable, distribution normality was checked by Kolmogorov-Smirnov and Shapiro-Wilk tests and by histograms. Categorical variables were compared by the w2 test. Means from seizure and control groups were compared by Student’s t tests if both data sets were normally distributed or by Mann-Whitney U tests if one or both data sets did not fit a normal distribution. Pre-post measures within groups were compared by paired-sample t tests if both data sets satisfied conditions of normality or by Wilcoxon tests if at least 1 distribution did not satisfy conditions of normality. Values of P < .05 were considered statistically significant.
Figure1. Comparison of pH values at 1 hour and at 24 hours in patient and in control group.
Results The authors examined the association between febrile seizures and hypocapnia by comparing blood pH and PCO2 of 18 children with febrile seizure (11 girls, 7 boys) to a control group of 18 children with febrile illness but no seizures (11 girls, 7 boys). Mean ages of children in the febrile seizure and control groups were 20.8 + 7.0 months and 30.4 + 19.8 months, respectively. No significant difference was observed in the gender ratio or age distribution between the febrile seizure group and the control group (P > .05). All of the children in the febrile seizure group were diagnosed with upper respiratory tract infections, including otitis media, tonsillitis, pharyngitis, and sinusitis. Six children in the control group were diagnosed with urinary tract infections. A history of recurrent febrile seizures was noted in 11 children of the febrile seizure group (61.1%), while only 1 child in the control group had a history of recurrent febrile seizures (5.6%). Ten children in the febrile seizure group (55.6%), but none of the control patients, had a family history of febrile seizures. In the febrile seizure group, 14 children were diagnosed
Figure 2. Comparison of pCO2 values at 1 hour and at 24 hours in patient and in control group.
with simple febrile seizures (77.8%) and 4 with complex febrile seizures (22.2%). The mean temperature in febrile seizure group was 38.6 C + 0.53 C (range, 38 C-40 C) and the mean temperature in control group was 38.5 C + 0.5 C (range, 38 C-39.5 C) at the time of admission. The difference was insignificant.
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Table 1. Comparison of Blood pH and PCO2 Values at 1 Hour and 24 Hours Postictal in Patients With Febrile Seizure and Control Group.
Patients with febrile seizure Control group
1 h (n ¼ 18) 24 h (n ¼ 18) 1 h (n ¼ 18)
pHa
P Value
PCO2a
7.40 + 0.06 7.39 + 0.05 7.37 + 0.05
.61
29.28 + 7.30 33.33 + 8.84 37.28 + 8.98
.16b .29c
P Value .12 .006b,d .19c
a
Values are mean + standard error of the mean. Comparison with febrile patient at 1 hour. c Comparison with febrile patient at 24 hours. d Significant (P < .05). b
Table 2. Comparison of Blood pH and PCO2 Values According to Seizure Types. pHa Recurrent febrile seizure (n ¼ 12) Nonrecurrent febrile seizure (n ¼ 24) Simple febrile seizure (n ¼ 14) Complex febrile seizure (n ¼ 4)
7.40 + 7.38 + 7.40 + 7.40 +
P Value 0.67 0.05 0.06 0.05
.13 .79
PCO2a 30.75 + 34.54 + 31.20 + 22.50 +
9.23 8.86 6.80 4.10
P Value .24 .03b
a
Values are mean + standard error of the mean. Significant (P < .05).
b
Both blood pH and PCO2 were measured within 1 hour after the febrile seizure and 1 hour of febrile period of control group. There was no significant difference in mean blood pH between the febrile seizure and control groups, but blood PCO2 was significantly lower in the febrile seizure group (Figures 1 and 2). At 24 hours after the febrile seizure event, PCO2 was not significantly different from that measured in the control fever patients (Table 1). The mean base excess in the febrile seizure group was –4.7 + 5.2 and the mean base excess in the control group was –3.0 + 5.5 at the time of admission. The difference was insignificant. Patients with complex febrile seizures exhibited significantly lower PCO2 levels within 1 hour of febrile seizure onset than did patients with simplex febrile seizures, whereas there was no significant difference in pH between these 2 groups at either 1 hour or 24 hours after the febrile seizure event. The significant difference in PCO2 observed between patients with simple and complex febrile seizures within 1 hour was no longer present at 24 hours after the febrile seizure. There was also no significant difference between the blood pH and PCO2 values of the group with recurrent febrile seizures and the group with nonrecurrent febrile seizures, although the mean values of blood pH were higher and PCO2 values were lower in the group with a history of recurrent febrile seizure (Table 2). There was only 1 patient with a recurrent febrile seizure in the control group; that patient’s blood pH was 7.31 and PCO2 value was 44 mm Hg. When the pH and PCO2 values of febrile seizure patients with a family history of febrile seizure were compared with values of those patients with no family history, no statistically significant differences were found.
Discussion Little is known of the mechanisms responsible for the initiation and maintenance of febrile seizures.12 Fever is an
elevation of body temperature induced by the thermoregulatory center of the hypothalamus, possibly to stimulate the immune system and preserve cell membrane integrity in response to pathogens.2 Fever is a direct cause of tachypnea in children with acute infections. O’Dempsey et al15 measured a 3.7 breath per minute increase for every 1 C increase in body temperature in a large cohort of children with fever and concluded that respiratory rate was partially dependent on body temperature in children with febrile illnesses.15 This elevated breathing rate during fever reflects the important role of ventilation in the regulation of mammalian body temperature. However, more rapid breathing can also alter blood gases and tissue pH; indeed, a decrease in blood PCO2 can develop during sustained hyperthermia.16 Moreover, hyperthermia leads to thermal tachypnea and age-dependent respiratory alkalosis that triggers and sustains convulsions in young rats.12 In 2011, Schuchmann et al14 examined the acid-base status of children with febrile seizures for the first time and concluded that a similar sequence of events leads to seizures in humans. The investigators observed a progressive decrease of the initially alkaline pH, which reached standard levels at 2 hours or later after febrile seizure onset in the hospital (0.5 hour or 1 hour vs 2 hours or 3 hours).14 That study compared febrile patients who had gastroenteritis and patients who had febrile seizures, whereas the current study compared patients who had febrile seizures and febrile patients who did not have gastroenteritis. Thus, in the current study, the possibility of acidosis was ruled out in both groups. Despite the higher mean blood pH values in the febrile seizure group, there was no significant difference in the current study. It is known that absence seizures can be reliably evoked by hypocapnia, although the critical PCO2 varies among children.17 Yang et al18 described a rare patient with nonlesional temporal epilepsy who developed complex partial seizures
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presenting as ictal fear while hyperventilating, a response attributed to the particular sensitivity of the anterior hippocampus (probably the amygdala) to hypocapnia. Similarly, hypocapnia in rats caused by fever-induced hyperpnea likely contributed to the generation of fever-induced seizures.19 Consistent with these experimental and clinical observations, the current study demonstrated a strong association between hypocapnia and febrile seizures. Morimoto et al19 also reported that seizure duration was longer at lower PCO2. In the current study, the PCO2 reduction following complex febrile seizures was statistically significant although smaller than that measured in patients with simple seizures. It is known that complex febrile seizures are one of the main risk factors for the development of epilepsy,20 suggesting frequent hypocapnia as a possible epileptogenic mechanism. Positive family history of febrile seizure is predictive of recurrent febrile seizures, but the number of febrile seizures does not predict the development of epilepsy.21 The current study found no significant difference in PCO2 reduction between patients with a positive family history of febrile seizures and those patients with no family history.
Conclusion The findings presented here suggest that febrile seizures may be associated with hyperventilation and that the ensuing hypocapnia may contribute to the development of febrile seizures. These data also indicate that the reduction in PCO2 during complex febrile seizures is significant. However, a larger patient sample and longer term follow-up are required to confirm these results. Author Contributions BK and IE wrote the manuscript. BK, IE, YO, and SS were involved in patient care, including administration of medication and routine clinical follow-up. IE was involved in editing the manuscript. CS conducted the biostatistical analysis of this study.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This study was supported by the Baskent University Research Fund.
Ethical Approval This study was approved by the Baskent University Institutional Review Board and Ethics Committee (project no. KA12/120). Informed consent was obtained from the parents of all children after through explanation of the study methods and goals.
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