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Comparison of Serum Zinc Levels Measured by Inductively Coupled Plasma Mass Spectrometry in Preschool Children with Febrile and Afebrile Seizures

Comparison of Serum Zinc Levels Measured by Inductively Coupled Plasma Mass Spectrometry in... Original Article Clinical Chemistry Ann Lab Med 2012;32:190-193 http://dx.doi.org/10.3343/alm.2012.32.3.190 I IS SS SN N 2 22 23 34 4- -3 38 80 06 6 • • e eI IS SS SN N 2 22 23 34 4- -3 38 81 14 4 Comparison of Serum Zinc Levels Measured by Inductively Coupled Plasma Mass Spectrometry in Preschool Children with Febrile and Afebrile Seizures 1 2 Jun-Hwa Lee, M.D. and Jeong Hyun Kim, M.D. 1 2 Departments of Pediatrics and Laboratory Medicine , Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea Received: August 26, 2011 Background: Changes in levels of trace elements have been proposed to underlie febrile Revision received: January 16, 2012 seizures. Particularly, low zinc levels have been proposed as related factor of febrile sei- Accepted: February 8, 2012 zure. In this study, we investigated whether mean serum zinc levels differed between chil- Corresponding author: Jeong Hyun Kim dren with febrile seizure and afebrile seizure. Department of Laboratory Medicine, Methods: Using inductively coupled plasma mass spectrometry, serum zinc levels were Samsung Changwon Hospital, Sungkyunkwan University School of measured in 288 children who had been diagnosed with febrile seizures (N = 248) and Medicine, 50 Hapsung-dong, Masan afebrile seizures (N = 40). Mean serum zinc levels were compared between the 2 groups. Hoewon-gu, Changwon 630-522, Korea Tel: +82-55-290-6095 Results: Mean serum zinc level was 60.5 ± 12.7 μg/dL in the febrile seizure group and 68.9 Fax: +82-55-290-6498 ± 14.5 μg/dL in the afebrile seizure group. A signifi cant difference in serum zinc levels was E-mail: [email protected] observed between the febrile and afebrile seizure groups (P < 0.001). © The Korean Society for Laboratory Medicine. Conclusions: Zinc levels in children with febrile seizure were signifi cantly lower than those This is an Open Access article distributed under the terms of the Creative Commons Attribution in children with afebrile seizure. Non-Commercial License (http://creativecom- mons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the Key Words: Zinc, Febrile seizure, Mass spectrometry original work is properly cited. electrolyte disturbances, reduction in serum and cerebrospinal INTRODUCTION fl uid (CSF) zinc levels, and low gamma-aminobutyric acid (GABA) Febrile seizure is one of the most common neurological problems levels are thought to play a role in the pathogenesis of febrile during childhood [1]. Approximately 2-5% of children are esti- seizure [6-10]. Among these factors, low zinc levels in both the mated to experience at least 1 epileptic seizure during a febrile CSF and serum have attracted interest, and studies on the cor- illness before they are 5 yr old. The incidence of febrile seizures relation between low serum zinc levels and febrile seizures are varies between 2% and 4% in Western countries, whereas the being currently conducted. incidence is 7% in Japan and higher in developing countries [2-4]. We compared serum zinc levels in preschool children with fe- Febrile seizures occur during infancy or childhood, typically brile seizures and those with afebrile seizures using inductively between 3 months to 5 yr of age. Seizures occurring with fever coupled plasma mass spectrometry (ICP-MS). in children who have suffered a previous non-febrile seizure are excluded from the defi nition of febrile seizures. Febrile seizures METHODS should also be distinguished from epilepsy, which is character- ized by recurrent non-febrile seizures [5]. We enrolled 288 children who were admitted to the Department The etiology and pathogenesis of febrile seizure remain un- of Pediatrics at the Samsung Changwon Hospital between Janu- known. However, several factors such as vitamin B6 defi ciency, ary 1, 2009 and February 28, 2011. Medical records were retro- 190 www.annlabmed.org http://dx.doi.org/10.3343/alm.2012.32.3.190 Lee J-H, et al. Serum zinc in children with febrile seizure spectively reviewed following approval for the study by the hos- 4), generalized tonic-clonic (N = 261), or myoclonic (N = 2). pital Institutional Review Board. To avoid probable confounding Mean serum zinc levels in the febrile seizure and afebrile sei- ± μ ± μ factors, only the specimen of the fi rst episode was considered zure groups were 60.5 12.7 g/dL and 68.9 14.5 g/dL, re- for a case of multiple seizure attacks in a child, and children spectively. An independent t-test showed that the mean serum older than 60 months were excluded. zinc levels in the febrile seizure group were signifi cantly different Febrile seizures were defi ned as seizures accompanied with (P < 0.001) from those in the non-febrile seizure group. The dif- fever ( ≥ 38 C) without central nervous system (CNS) infection, ference was significant even after correcting for age using an while afebrile seizures were defi ned as seizures due to non-fe- ANCOVA test (P < 0.001; Fig. 1). brile illness. Serum specimens were acquired from the febrile Mean serum CRP levels in the febrile seizure and afebrile sei- ± ± seizure and afebrile seizure group within the first 2 hr after a zure groups were 11.8 19.6 mg/L and 2.1 3.2 mg/L, respec- seizure attack. The specimens were stored at -20 C until analy- tively; the intergroup difference in mean serum CRP levels was sis. Serum zinc levels were analyzed using an Agilent 7500ce signifi cant (P < 0.001; Table 1). After correcting for serum CRP ICP-MS (Agilent Technologies, Inc., Tokyo, Japan). In addition, levels, the intergroup difference in the mean serum zinc levels the serum C-reactive protein (CRP) level in each patient was was statstically signifi cant (P = 0.003). measured for comparing serum zinc levels after correcting for The most common cause of fever in the febrile seizure group acute infl ammatory protein. was respiratory infections (62.5%) such as acute pharyngoton- Statistical analyses were performed using the Statistical Pack- sillitis, bronchitis, pneumonia, and infl uenza (Table 2). age for the Social Sciences (SPSS) 12.0 software (SPSS, Inc., Chicago, IL, USA) for Windows and Medcalc v11.2 (Mariakerke, DISCUSSION Belgium). Statistical signifi cance was estimated using indepen- dent t-tests and an analysis of covariance (ANCOVA) test. P val- Zinc is one of the most abundant trace elements in the body ues less than 0.05 were considered signifi cant. and is found at a high level in the CNS where it infl uences cell division and differentiation, which are required for normal CNS development [11, 12]. Most of the zinc in the brain is bound to RESULTS zinc-binding proteins that have functional and structural roles. A Characteristics of the patients included in this study are shown small portion of the zinc is present in the ion form; ionic zinc in Table 1. Mean temperatures of children in the febrile seizure ± ° ± ° and afebrile seizure groups were 38.3 0.9 C and 36.5 0.3 C, P < 0.001 respectively. Seizure was classifi ed as atonic (N = 21), focal (N = 120 Table 1. Clinical and laboratory characteristics of 288 children with febrile seizure and afebrile seizure Febrile seizure Afebrile seizure P value* Number 248 40 Age in months 26.8 ± 12.7 22.2 ± 15.4 < 0.001 Female sex (%) 115 (46.4) 21 (52.5) 0.499 Seizure type Atonic 13 8 Focal 3 1 GTC 231 30 Febrile seizures (N = 248) Afebrile seizures (N = 40) Myoclonic 1 1 Temperature (˚C) 38.3 ± 0.9 36.5 ± 0.3 < 0.001 Fig. 1. Comparison of serum zinc levels in children with febrile sei- zures and afebrile seizures. Mean serum zinc levels in the febrile Serum zinc (μg/dL) 60.5 ± 12.7 68.9 ± 14.5 < 0.001 seizure and afebrile seizure groups were 60.5 ± 12.7 μg/dL and Serum CRP (mg/L) 11. 8 ± 19.6 2.1 ± 3.2 < 0.001 68.9 ± 14.5 μg/dL, respectively. Mean serum zinc levels were signif- icantly different between these groups, according to an independent *The P value was calculated using independent t-tests. Abbreviations: GTC, generalized tonic seizure; CRP, C reactive protein. t-test (P < 0.001). http://dx.doi.org/10.3343/alm.2012.32.3.190 www.annlabmed.org 191 Serum zinc level (μg/dL) Lee J-H, et al. Serum zinc in children with febrile seizure Table 2. Causes of fever in the febrile seizure group children with febrile convulsions showed signifi cantly lower se- Cause of fever Male Female Total (%) rum zinc levels [6, 25]. In contrast to these previous studies, we analyzed data from a Acute pharyngotonsillitis 45 32 77 (31.0) large number of children with febrile seizures and considered Fever without localized signs 29 33 62 (25.0) confounding factors such as age and CRP levels. Although the Bronchitis 28 19 47 (19.0) correlation between zinc levels and aging or acute phase status Pneumonia 8 11 19 (7.7) is still debatable, zinc levels are known to increase with age until Inu fl enza 5 7 12 (4.8) adulthood, and the acute phase response has been associated Urinary tract infection 7 4 11 (4.4) with depressed serum zinc level in some studies [26, 27]. How- Acute gastroenteritis 5 3 8 (3.2) ever, in our study, zinc levels were signifi cantly different between Other 6 6 12 (4.8) the febrile and afebrile seizure groups after correcting for age or Total 133 115 248 serum CRP levels. We used ICP-MS, which is an effective technique for deter- has been suggested to be involved in specifi c physiologic mech- mining trace element levels [28-31]. Unlike inductively coupled anisms including synaptic neurotransmission. The mechanism plasma atomic emission spectrometry, ICP-MS can be used for underlying the role of zinc levels in seizures has been examined direct analysis of solution samples, can be used to measure in studies on mouse models and in vitro studies. A series of re- most elements, and provides much lower detection limits and ports have suggested that zinc modulates specifi c GABA recep- reliable isotopic analysis [32]. tors, and this mechanism is known to contribute to seizure inhi- One limitation of our study is the lack of a simple febrile or bition [13-15]. However, studies on humans have shown that healthy control group. Furthermore, ICP-MS has been recently the febrile seizure group has lower zinc level than the control developed, and reference ranges for zinc levels have not yet group with simple fever, although there is some disagreement been established. However, various analysis methods used in [16, 17]. previous studies have shown that serum zinc levels in healthy In febrile seizure, hypozincemia has been suggested as a children are higher than those in children with febrile seizure. possible change during the rising phase of body temperature in Ganesh et al. reported that the mean serum zinc level as mea- patients. Fever is thought to be mediated by an endogenous py- sured using atomic absorption spectrometry in samples from rogen. The infection state exhibits a non-specifi c host responses, healthy children between 3 months and 5 yr of age was 87.6 g/ including immune responses such as changes in the concen- dL, and the corresponding value in children with simple febrile trations of some plasma proteins. Many studies have shown that seizures was 32.17 g/dL [16]. Another study using plasma injecting infectious materials or cytokines such as tumor necro- emission spectrometry reported that serum zinc levels in pa- sis factor, interleukin-1, interleukin-6, and interferon causes hy- tients with simple febrile seizure and acute febrile illness were μ μ pozincemia accompanied by fever [18-23]. These results sug- 112.5 g/dL and 154.1 g/dL, respectively. A recent study of gest that infection leads to hypozincemia through endogenous mean serum zinc levels in healthy adults using ICP-MS reported pyrogenic substances. a similar result (80.45 g/dL) [33]. Although the difference in the In our study, the febrile seizure group had signifi cantly lower zinc levels in febrile seizure and afebrile seizure groups obtained serum zinc levels than the afebrile group. We analyzed differ- in our study is smaller than that reported in previous studies, it ences in serum zinc levels between the 2 groups after correct- is difficult to compare the serum zinc levels measured in the ing for age and CRP levels and observed that the difference re- present study with those of the previous studies because the mained signifi cant. Several reports have suggested that low se- analysis methods used were different. However, on the basis of rum levels of zinc may result in febrile seizures, but this is still previous studies, serum zinc levels in healthy and simple fever debated. Gündüz et al. [24] compared serum and CSF zinc lev- groups were presumed to be higher than those in the febrile els in patients with febrile and afebrile convulsions and healthy seizure group. controls; they concluded that compared to patients with afebrile In this study, the serum zinc level in patients with febrile sei- convulsions and healthy controls, patients with febrile convul- zure and afebrile seizure groups showed large overlap. Serum sions had lower serum zinc levels. According to previous stud- zinc levels are infl uenced by the time of day, the specifi c dis- ies, compared to a control group with fever but no convulsions, ease, or the presence of other trace elements [34]. Therefore, a 192 www.annlabmed.org http://dx.doi.org/10.3343/alm.2012.32.3.190 Lee J-H, et al. Serum zinc in children with febrile seizure 16. Ganesh R and Janakiraman L. Serum zinc levels in children with simple study design considering these effects is needed to further ex- febrile seizure. Clin Pediatr 2008;47:164-6. plain hypozincemia in febrile seizure children. 17. Garty BZ, Olomucki R, Lerman-Sagie T, Nitzan M. Cerebrospinal fl uid In conclusion, we showed that children with febrile seizures zinc concentrations in febrile convulsions. Arch Dis Child 1995;73:338-41. 18. Yamashiro O, Morimoto A, Sakata Y, Watanabe T, Murakami N. Febrile had signifi cantly lower serum zinc levels than those with afebrile and metabolic tolerance to endotoxin and human recombinant interleu- seizures. However, the mechanism of this altered serum zinc kin-1 beta in rabbits. Am J Physiol 1993;264:R1180-5. level in the febrile seizure group is poorly understood. Further 19. van Miert AS, van Duin CT, Wensing T. Fever and acute phase response induced in dwarf goats by endotoxin and bovine and human recombi- studies are needed to identify the cause of this observation. nant tumour necrosis factor alpha. J Vet Pharmacol Ther 1992;15:332- Authors’ Disclosures of Potential Conifl cts of 20. Sakata Y, Morimoto A, Long NC, Murakami N. Fever and acute-phase response induced in rabbits by intravenous and intracerebroventricular Interest injection of interleukin-6. Cytokine 1991;3:199-203. 21. Van Miert AS, Van Duin CT, Wensing T. Fever and changes in plasma No potential conflict of interest relevant to this article was re- zinc and iron concentrations in the goat. The effects of interferon induc- ers and recombinant IFN-alpha 2a. J Comp Pathol 1990;103:289-300. ported. 22. Morimoto A, Murakami N, Nakamori T, Sakata Y, Watanabe T. Brain re- gions involved in the development of acute phase responses accompa- REFERENCES nying fever in rabbits. J Physiol 1989;416:645-57. 23. Van Miert AS, Van Duin CT, Verheijden JH, Schotman AJ, Nieuwenhuis 1. Martindale JL, Goldstein JN, Pallin DJ. Emergency department seizure J. Fever and changes in plasma zinc and iron concentrations in the epidemiology. Emerg Med Clin North Am 2011;29:15-27. goat: the role of leukocytic pyrogen. J Comp Pathol 1984;94:543-57. 2. Siqueira LF. Febrile seizures: update on diagnosis and management. 24. Gündüz Z, Yavuz I, Koparal M, Kumanda S, Saraymen R. Serum and Rev Assoc Med Bras 2010;56:489-92. cerebrospinal fl uid zinc levels in children with febrile convulsions. Acta 3. Liscák R, Vladyka V, Simonová G, Vymazal J, Novotny J Jr. Gamma knife Paediatr Jpn 1996;38:237-41 surgery of brain cavernous hemangiomas. J Neurosurg 2005;102(S):207- 25. Amiri M, Farzin L, Moassesi ME, Sajadi F. Serum trace element levels in 13. febrile convulsion. Biol Trace Elem Res 2010;135:38-44. 4. Guerreiro MM. Treatment of febrile seizures. J Pediatr 2002;78(S1):S9-13. 26. Tütüncüo lu S, Kütükçüler N, Kepe L, Coker C, Berdeli A, Tekgül H. 5. Consensus statement. Febrile seizures: long-term management of chil- Proinfl ammatory cytokines, prostaglandins and zinc in febrile convul- dren with fever-associated seizures. Pediatrics 1980;66:1009-12. sions. Pediatr Int 2001;43:235-9. 6. Mollah MA, Dey PR, Tarafdar SA, Akhter S, Ahmed S, Hassan T, et al. 27. Lin CN, Wilson A, Church BB, Ehman S, Roberts WL, McMillin GA. Pe- Zinc in CSF of patients with febrile convulsion. Indian J Pediatr 2002; diatric reference intervals for serum copper and zinc. Clin Chim Acta 69:859-61. 2012;413:612-5. 7. Millichap JG, Millichap JJ. Role of viral infections in the etiology of fe- 28. Macours P, Aubry JC, Hauquier B, Boeynaems JM, Goldman S, More- brile seizures. Pediatr Neurol 2006;35:165-72. no-Reyes R. Determination of urinary iodine by inductively coupled 8. Nakayama J and Arinami T. Molecular genetics of febrile seizures. Epi- plasma mass spectrometry. J Trace Elem Med Biol 2008;22:162-5. lepsy Res 2006;70(S1):S190-8. 29. Caldwell KL, Maxwell CB, Makhmudov A, Pino S, Braverman LE, Jones 9. Haspolat S, Mihçi E, Co kun M, Gümüslü S, Ozben T, Ye in O. Interleu- RL, et al. Use of inductively coupled plasma mass spectrometry to mea- kin-1beta, tumor necrosis factor-alpha, and nitrite levels in febrile sei- sure urinary iodine in NHANES 2000: comparison with previous meth- zures. J Child Neurol 2002;17:749-51. od. Clin Chem 2003;49:1019-21. 10. Castilla-Guerra L, del Carmen Fernández-Moreno M, López-Chozas JM, 30. May SL, May WA, Bourdoux PP, Pino S, Sullivan KM, Maberly GF. Vali- Fernández-Bolaños R. Electrolytes disturbances and seizures. Epilepsia dation of a simple, manual urinary iodine method for estimating the 2006;47:1990-8. prevalence of iodine-defi ciency disorders, and interlaboratory compari- 11. Vallee BL and Falchuk KH. Zinc and gene expression. Philos Trans R son with other methods. Am J Clin Nutr 1997;65:1441-5. Soc Lond B Biol Sci 1981;294:185-97. 31. Miksa IR, Buckley CL, Carpenter NP, Poppenga RH. Comparison of se- 12. Frederickson CJ. Neurobiology of zinc and zinc-containing neurons. Int lenium determination in liver samples by atomic absorption spectrosco- Rev Neurobiol 1989;31:145-238. py and inductively coupled plasma-mass spectrometry. J Vet Diagn In- 13. Buhl EH, Otis TS, Mody I. Zinc-induced collapse of augmented inhibi- vest 2005;17:331-40. tion by GABA in a temporal lobe epilepsy model. Science 1996;271:369- 32. Barnes RM. Analytical plasma source mass spectrometry in biomedical 73. research. Anal Bioanal Chem 1996;355:433-41. 14. Gibbs JW 3rd, Shumate MD, Coulter DA. Differential epilepsy-associat- 33. Lee SY, Oh HJ, Choi YH, Kim JW, Kim SH. Trace metal analysis using ed alterations in postsynaptic GABA(A) receptor function in dentate inductively coupled plasma-mass spectrometry (ICP-MS). Korean J Lab granule and CA1 neurons. J Neurophysiol 1997;77:1924-38. Med 2004;24:362-70. 15. Shumate MD, Lin DD, Gibbs JW 3rd, Holloway KL, Coulter DA. GABA(A) 34. Maret W and Sandstead HH. Zinc requirements and the risks and ben- receptor function in epileptic human dentate granule cells: comparison efi ts of zinc supplementation. J Trace Elem Med Biol 2006;20:3-18. to epileptic and control rat. Epilepsy Res 1998;32:114-28. http://dx.doi.org/10.3343/alm.2012.32.3.190 www.annlabmed.org 193 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Laboratory Medicine Pubmed Central

Comparison of Serum Zinc Levels Measured by Inductively Coupled Plasma Mass Spectrometry in Preschool Children with Febrile and Afebrile Seizures

Lee, Jun-Hwa; Kim, Jeong Hyun
Annals of Laboratory Medicine , Volume 32 (3) – Apr 18, 2012
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Abstract

Original Article Clinical Chemistry Ann Lab Med 2012;32:190-193 http://dx.doi.org/10.3343/alm.2012.32.3.190 I IS SS SN N 2 22 23 34 4- -3 38 80 06 6 • • e eI IS SS SN N 2 22 23 34 4- -3 38 81 14 4 Comparison of Serum Zinc Levels Measured by Inductively Coupled Plasma Mass Spectrometry in Preschool Children with Febrile and Afebrile Seizures 1 2 Jun-Hwa Lee, M.D. and Jeong Hyun Kim, M.D. 1 2 Departments of Pediatrics and Laboratory Medicine , Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea Received: August 26, 2011 Background: Changes in levels of trace elements have been proposed to underlie febrile Revision received: January 16, 2012 seizures. Particularly, low zinc levels have been proposed as related factor of febrile sei- Accepted: February 8, 2012 zure. In this study, we investigated whether mean serum zinc levels differed between chil- Corresponding author: Jeong Hyun Kim dren with febrile seizure and afebrile seizure. Department of Laboratory Medicine, Methods: Using inductively coupled plasma mass spectrometry, serum zinc levels were Samsung Changwon Hospital, Sungkyunkwan University School of measured in 288 children who had been diagnosed with febrile seizures (N = 248) and Medicine, 50 Hapsung-dong, Masan afebrile seizures (N = 40). Mean serum zinc levels were compared between the 2 groups. Hoewon-gu, Changwon 630-522, Korea Tel: +82-55-290-6095 Results: Mean serum zinc level was 60.5 ± 12.7 μg/dL in the febrile seizure group and 68.9 Fax: +82-55-290-6498 ± 14.5 μg/dL in the afebrile seizure group. A signifi cant difference in serum zinc levels was E-mail: [email protected] observed between the febrile and afebrile seizure groups (P < 0.001). © The Korean Society for Laboratory Medicine. Conclusions: Zinc levels in children with febrile seizure were signifi cantly lower than those This is an Open Access article distributed under the terms of the Creative Commons Attribution in children with afebrile seizure. Non-Commercial License (http://creativecom- mons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the Key Words: Zinc, Febrile seizure, Mass spectrometry original work is properly cited. electrolyte disturbances, reduction in serum and cerebrospinal INTRODUCTION fl uid (CSF) zinc levels, and low gamma-aminobutyric acid (GABA) Febrile seizure is one of the most common neurological problems levels are thought to play a role in the pathogenesis of febrile during childhood [1]. Approximately 2-5% of children are esti- seizure [6-10]. Among these factors, low zinc levels in both the mated to experience at least 1 epileptic seizure during a febrile CSF and serum have attracted interest, and studies on the cor- illness before they are 5 yr old. The incidence of febrile seizures relation between low serum zinc levels and febrile seizures are varies between 2% and 4% in Western countries, whereas the being currently conducted. incidence is 7% in Japan and higher in developing countries [2-4]. We compared serum zinc levels in preschool children with fe- Febrile seizures occur during infancy or childhood, typically brile seizures and those with afebrile seizures using inductively between 3 months to 5 yr of age. Seizures occurring with fever coupled plasma mass spectrometry (ICP-MS). in children who have suffered a previous non-febrile seizure are excluded from the defi nition of febrile seizures. Febrile seizures METHODS should also be distinguished from epilepsy, which is character- ized by recurrent non-febrile seizures [5]. We enrolled 288 children who were admitted to the Department The etiology and pathogenesis of febrile seizure remain un- of Pediatrics at the Samsung Changwon Hospital between Janu- known. However, several factors such as vitamin B6 defi ciency, ary 1, 2009 and February 28, 2011. Medical records were retro- 190 www.annlabmed.org http://dx.doi.org/10.3343/alm.2012.32.3.190 Lee J-H, et al. Serum zinc in children with febrile seizure spectively reviewed following approval for the study by the hos- 4), generalized tonic-clonic (N = 261), or myoclonic (N = 2). pital Institutional Review Board. To avoid probable confounding Mean serum zinc levels in the febrile seizure and afebrile sei- ± μ ± μ factors, only the specimen of the fi rst episode was considered zure groups were 60.5 12.7 g/dL and 68.9 14.5 g/dL, re- for a case of multiple seizure attacks in a child, and children spectively. An independent t-test showed that the mean serum older than 60 months were excluded. zinc levels in the febrile seizure group were signifi cantly different Febrile seizures were defi ned as seizures accompanied with (P < 0.001) from those in the non-febrile seizure group. The dif- fever ( ≥ 38 C) without central nervous system (CNS) infection, ference was significant even after correcting for age using an while afebrile seizures were defi ned as seizures due to non-fe- ANCOVA test (P < 0.001; Fig. 1). brile illness. Serum specimens were acquired from the febrile Mean serum CRP levels in the febrile seizure and afebrile sei- ± ± seizure and afebrile seizure group within the first 2 hr after a zure groups were 11.8 19.6 mg/L and 2.1 3.2 mg/L, respec- seizure attack. The specimens were stored at -20 C until analy- tively; the intergroup difference in mean serum CRP levels was sis. Serum zinc levels were analyzed using an Agilent 7500ce signifi cant (P < 0.001; Table 1). After correcting for serum CRP ICP-MS (Agilent Technologies, Inc., Tokyo, Japan). In addition, levels, the intergroup difference in the mean serum zinc levels the serum C-reactive protein (CRP) level in each patient was was statstically signifi cant (P = 0.003). measured for comparing serum zinc levels after correcting for The most common cause of fever in the febrile seizure group acute infl ammatory protein. was respiratory infections (62.5%) such as acute pharyngoton- Statistical analyses were performed using the Statistical Pack- sillitis, bronchitis, pneumonia, and infl uenza (Table 2). age for the Social Sciences (SPSS) 12.0 software (SPSS, Inc., Chicago, IL, USA) for Windows and Medcalc v11.2 (Mariakerke, DISCUSSION Belgium). Statistical signifi cance was estimated using indepen- dent t-tests and an analysis of covariance (ANCOVA) test. P val- Zinc is one of the most abundant trace elements in the body ues less than 0.05 were considered signifi cant. and is found at a high level in the CNS where it infl uences cell division and differentiation, which are required for normal CNS development [11, 12]. Most of the zinc in the brain is bound to RESULTS zinc-binding proteins that have functional and structural roles. A Characteristics of the patients included in this study are shown small portion of the zinc is present in the ion form; ionic zinc in Table 1. Mean temperatures of children in the febrile seizure ± ° ± ° and afebrile seizure groups were 38.3 0.9 C and 36.5 0.3 C, P < 0.001 respectively. Seizure was classifi ed as atonic (N = 21), focal (N = 120 Table 1. Clinical and laboratory characteristics of 288 children with febrile seizure and afebrile seizure Febrile seizure Afebrile seizure P value* Number 248 40 Age in months 26.8 ± 12.7 22.2 ± 15.4 < 0.001 Female sex (%) 115 (46.4) 21 (52.5) 0.499 Seizure type Atonic 13 8 Focal 3 1 GTC 231 30 Febrile seizures (N = 248) Afebrile seizures (N = 40) Myoclonic 1 1 Temperature (˚C) 38.3 ± 0.9 36.5 ± 0.3 < 0.001 Fig. 1. Comparison of serum zinc levels in children with febrile sei- zures and afebrile seizures. Mean serum zinc levels in the febrile Serum zinc (μg/dL) 60.5 ± 12.7 68.9 ± 14.5 < 0.001 seizure and afebrile seizure groups were 60.5 ± 12.7 μg/dL and Serum CRP (mg/L) 11. 8 ± 19.6 2.1 ± 3.2 < 0.001 68.9 ± 14.5 μg/dL, respectively. Mean serum zinc levels were signif- icantly different between these groups, according to an independent *The P value was calculated using independent t-tests. Abbreviations: GTC, generalized tonic seizure; CRP, C reactive protein. t-test (P < 0.001). http://dx.doi.org/10.3343/alm.2012.32.3.190 www.annlabmed.org 191 Serum zinc level (μg/dL) Lee J-H, et al. Serum zinc in children with febrile seizure Table 2. Causes of fever in the febrile seizure group children with febrile convulsions showed signifi cantly lower se- Cause of fever Male Female Total (%) rum zinc levels [6, 25]. In contrast to these previous studies, we analyzed data from a Acute pharyngotonsillitis 45 32 77 (31.0) large number of children with febrile seizures and considered Fever without localized signs 29 33 62 (25.0) confounding factors such as age and CRP levels. Although the Bronchitis 28 19 47 (19.0) correlation between zinc levels and aging or acute phase status Pneumonia 8 11 19 (7.7) is still debatable, zinc levels are known to increase with age until Inu fl enza 5 7 12 (4.8) adulthood, and the acute phase response has been associated Urinary tract infection 7 4 11 (4.4) with depressed serum zinc level in some studies [26, 27]. How- Acute gastroenteritis 5 3 8 (3.2) ever, in our study, zinc levels were signifi cantly different between Other 6 6 12 (4.8) the febrile and afebrile seizure groups after correcting for age or Total 133 115 248 serum CRP levels. We used ICP-MS, which is an effective technique for deter- has been suggested to be involved in specifi c physiologic mech- mining trace element levels [28-31]. Unlike inductively coupled anisms including synaptic neurotransmission. The mechanism plasma atomic emission spectrometry, ICP-MS can be used for underlying the role of zinc levels in seizures has been examined direct analysis of solution samples, can be used to measure in studies on mouse models and in vitro studies. A series of re- most elements, and provides much lower detection limits and ports have suggested that zinc modulates specifi c GABA recep- reliable isotopic analysis [32]. tors, and this mechanism is known to contribute to seizure inhi- One limitation of our study is the lack of a simple febrile or bition [13-15]. However, studies on humans have shown that healthy control group. Furthermore, ICP-MS has been recently the febrile seizure group has lower zinc level than the control developed, and reference ranges for zinc levels have not yet group with simple fever, although there is some disagreement been established. However, various analysis methods used in [16, 17]. previous studies have shown that serum zinc levels in healthy In febrile seizure, hypozincemia has been suggested as a children are higher than those in children with febrile seizure. possible change during the rising phase of body temperature in Ganesh et al. reported that the mean serum zinc level as mea- patients. Fever is thought to be mediated by an endogenous py- sured using atomic absorption spectrometry in samples from rogen. The infection state exhibits a non-specifi c host responses, healthy children between 3 months and 5 yr of age was 87.6 g/ including immune responses such as changes in the concen- dL, and the corresponding value in children with simple febrile trations of some plasma proteins. Many studies have shown that seizures was 32.17 g/dL [16]. Another study using plasma injecting infectious materials or cytokines such as tumor necro- emission spectrometry reported that serum zinc levels in pa- sis factor, interleukin-1, interleukin-6, and interferon causes hy- tients with simple febrile seizure and acute febrile illness were μ μ pozincemia accompanied by fever [18-23]. These results sug- 112.5 g/dL and 154.1 g/dL, respectively. A recent study of gest that infection leads to hypozincemia through endogenous mean serum zinc levels in healthy adults using ICP-MS reported pyrogenic substances. a similar result (80.45 g/dL) [33]. Although the difference in the In our study, the febrile seizure group had signifi cantly lower zinc levels in febrile seizure and afebrile seizure groups obtained serum zinc levels than the afebrile group. We analyzed differ- in our study is smaller than that reported in previous studies, it ences in serum zinc levels between the 2 groups after correct- is difficult to compare the serum zinc levels measured in the ing for age and CRP levels and observed that the difference re- present study with those of the previous studies because the mained signifi cant. Several reports have suggested that low se- analysis methods used were different. However, on the basis of rum levels of zinc may result in febrile seizures, but this is still previous studies, serum zinc levels in healthy and simple fever debated. Gündüz et al. [24] compared serum and CSF zinc lev- groups were presumed to be higher than those in the febrile els in patients with febrile and afebrile convulsions and healthy seizure group. controls; they concluded that compared to patients with afebrile In this study, the serum zinc level in patients with febrile sei- convulsions and healthy controls, patients with febrile convul- zure and afebrile seizure groups showed large overlap. Serum sions had lower serum zinc levels. According to previous stud- zinc levels are infl uenced by the time of day, the specifi c dis- ies, compared to a control group with fever but no convulsions, ease, or the presence of other trace elements [34]. Therefore, a 192 www.annlabmed.org http://dx.doi.org/10.3343/alm.2012.32.3.190 Lee J-H, et al. Serum zinc in children with febrile seizure 16. Ganesh R and Janakiraman L. Serum zinc levels in children with simple study design considering these effects is needed to further ex- febrile seizure. Clin Pediatr 2008;47:164-6. plain hypozincemia in febrile seizure children. 17. Garty BZ, Olomucki R, Lerman-Sagie T, Nitzan M. Cerebrospinal fl uid In conclusion, we showed that children with febrile seizures zinc concentrations in febrile convulsions. Arch Dis Child 1995;73:338-41. 18. Yamashiro O, Morimoto A, Sakata Y, Watanabe T, Murakami N. Febrile had signifi cantly lower serum zinc levels than those with afebrile and metabolic tolerance to endotoxin and human recombinant interleu- seizures. However, the mechanism of this altered serum zinc kin-1 beta in rabbits. Am J Physiol 1993;264:R1180-5. level in the febrile seizure group is poorly understood. Further 19. van Miert AS, van Duin CT, Wensing T. Fever and acute phase response induced in dwarf goats by endotoxin and bovine and human recombi- studies are needed to identify the cause of this observation. nant tumour necrosis factor alpha. J Vet Pharmacol Ther 1992;15:332- Authors’ Disclosures of Potential Conifl cts of 20. 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Annals of Laboratory Medicine – Pubmed Central

Published: Apr 18, 2012

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