bs_bs_banner
doi:10.1111/jpc.12639
ORIGINAL ARTICLE
Frequency of coeliac disease in children with breath-holding spells Sedat Is¸ikay1 and S¸amil Hızlı2 1
Department of Pediatric Neurology, Gaziantep Children’s Hospital and 2Department of Pediatric Gastroenterology, Gaziantep University, Gaziantep, Turkey
Aim: Iron deficiency anaemia (IDA), which is reported very commonly among patients with breath holding spells (BHS), is the most common presentation of coeliac disease (CD). In that aspect, IDA may be a common pathway linking these two diseases. The aim of this study was to evaluate the frequency of CD in patients with BHS. Methods: We studied 348 children with BHS, and 470 age- and sex-matched controls with no known disease. Serological screening for CD was performed in all patients by searching for serum tissue transglutaminase immunoglobulin A. Results: The first group consisted of 348 children with BHS (231 males, 117 females; mean age 2.23 ± 1.84 years), and the second group consisted of 470 healthy children (284 males, 186 females; mean age 2.11 ± 1.98 years). A total of 300 (86.2%) patients had cyanotic type of BHS only, 27 (7.8%) had pallid type of BHS only and 21 (6%) had mixed type of BHS. The prevalence of IDA was statistically significantly higher in BHS patients compared with controls. Tissue transglutaminase immunoglobulin A was not detected as positive in any patients in either group; therefore, endoscopic and histopathological examinations were not performed. Conclusions: Our report is the first to describe the frequency of tissue transglutaminase immunoglobulin A positivity in patients with BHS. There was no evidence of a relationship between CD and BHS, but IDA seems to be an important risk factor in the development of BHS. Therefore, serological screening for CD in patients with BHS does not seem to be necessary. Key words:
breath-holding spells; coeliac disease; child; iron deficiency anaemia.
What is already known on this topic
What this paper adds
1 Iron deficiency anaemia (IDA), which is one of the most common presentations of coeliac disease (CD), may be a common pathway linking CD with breath holding spells (BHS). 2 Although the exact association of IDA with BHS is not known. 3 IDA is one of the conditions mostly associated with BHS. In that aspect, patients with CD can be suggested to have an increased risk of BHS or in other words IDA triggering BHS may be the result of CD that suggests an increased prevalence of CD among patients with BHS.
1 To the best of our knowledge, our report is the first to describe the frequency of tissue transglutaminase immunoglobulin A positivity in patients with BHS. 2 Although the study included a small number of cases, the results suggest that the ratio of tTg IgA positivity is not increased among patients with BHS. However, consistent with the previous literature, IDA seems to be an important risk factor in the development of BHS. 3 Though IDA seems to be a common pathway present in both CD and BHS, the results of the present study suggest that serological screening for CD in BHS is not necessary. Further large-scale studies are warranted to elucidate the relationship of CD with BHS, if present.
Coeliac disease (CD) is a chronic autoimmune disease determined in predisposed individuals, which is associated with gluten-containing cereals. The prevalence in European countries is reported as between 1/99 and 1/133.1,2 In Turkey, the prevalence of CD in the healthy child population (demonstrated by normal biopsy) is reported as 0.47%.3 In recent years, it has been clear that CD presents more frequently with non-classical Correspondence: Dr Sedat Is¸ikay, Department of Pediatric Neurology, Gaziantep Children’s Hospital, S¸ehitkamil, Gaziantep 27500, Turkey. Fax: +90 (342) 360 39 28; email: [email protected] Accepted for publication 5 May 2014.
signs than the classical form.4 Neurological complications and iron deficiency anaemia (IDA) have been reported in 6–11% of patients with CD;5–8 however, the pathophysiology of those neurological disorders that develop during the course of CD is not clear.9–11 Breath-holding spells (BHS) in children are characterised by a change in skin colour, involuntary awake state apnea and a change in or loss of consciousness. The presence of an underlying dysfunction of the autonomic nervous system in children with BHS has been proposed by many authors. BHS have also been associated with IDA. Several studies have reported abatement of BHS with iron treatment, which may suggest a
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
1
Coeliac disease and breath-holding spells
S Is¸ikay and S¸ Hızlı
Table 1 Patient characteristics of BHS and control group
Age, y Sex Male Female
BHS, n = 348 mean ± SD
Control, n = 470 mean ± SD
P value
2.23 ± 1.84 – 231 117
2.11 ± 1.98 – 284 186
0.092 0.081 – –
BHS, breath-holding spells; SD, standard deviation.
relationship between IDA and BHS.12–15 IDA, which is one of the most common presentations of CD, may be a common pathway linking CD with BHS. Although the exact association of IDA with BHS is not known, IDA is one of the conditions mostly associated with BHS. In that aspect, patients with CD can be suggested to have an increased risk of BHS or in other words IDA triggering BHS may be the result of CD that suggests an increased prevalence of CD among patients with BHS. The literature includes studies of neurological disorders and IDA in patients with CD, but there is no data about the prevalence of CD in children with BHS. We aimed to determine the frequency of CD in children diagnosed with BHS.
Materials and Methods The study was approved by the Ethics Committee at Gaziantep University Faculty of Medicine, Turkey. Additionally, the parents of all participating children gave informed consent prior to their inclusion in the study.
Patients and Methods This prospective case-control study included 348 children between the ages 6 months and 11 years, who were diagnosed as having BHS at a child neurology outpatient clinic between September 2012 and March 2013. Diagnosis of BHS was made clinically, based on the history given by the mothers and observation of the spells. Spells were defined as the stopping of child’s breathing in expiration after a deep inspiration during crying. The spells were classified as cyanotic, pallid and mixed (when there was no clear distinction between cyanosis and pallor according to the skin colour change during episodes).12,13 A detailed medical and family history was taken before inclusion in the study. We recorded the type of attacks. Initial blood values were recorded for haemoglobin concentration, mean corpuscular volume, serum iron, total iron binding capacity and ferritin levels. Electroencephalography (EEG) and electrocardiography were carried out in all cases. All of the patients agreed to participate and none left the study. A control group comprised 470 sex- and age-matched children, who were evaluated at paediatric clinics for mild upper respiratory tract infection. Demographic characteristics, medication histories and clinical findings of all of participants were recorded. None of the patients had any other disorders. Tissue transglutaminase immunoglobulin A (tTg IgA) was studied with micro-enzyme-linked immunosorbent assay method 2
Table 2 Number and percentage of patients with iron deficiency anaemia in study and control groups
Breath-holding spells group (n = 348) Control group (n = 470)
Iron deficiency anaemia
P value
312 (89.7%)
0.0001*
148 (31.5%)
–
*Chi-square test (P < 0.05).
(ImmuLisa, Immco Diagnostics Inc., Buffalo, NY, USA). Cases with a value of tTg IgA >15 U/mL were considered positive. There was not any cases with indeterminate values. Serum IgA was determined in all patients to rule out selective IgA deficiency. We performed upper gastrointestinal endoscopy with a flexible endoscope and multiple biopsies (at least 1 from bulb and 4 from the second part of the duodenum) were taken in tTg IgA-positive cases in order to confirm the diagnosis of CD.16,17 Iron deficiency was regarded as the ferritine 450 μg/dL.18
Statistical analysis Statistical analysis used SPSS software (version 16.0 for Windows, Statistical Package for the Social Sciences (SPSS), Inc., Chicago, IL, USA). Student t-test and χ2 were used.
Results The first group consisted of children with BHS (231 males, 117 females; mean age 2.23 ± 1.84 years (6 months–11 years) ), and the second group consisted of healthy children (284 males, 186 females; mean age 2.11 ± 1.98 years (5 months–11 years) ). There were no statistically significant differences between the two groups in terms of sex and age (P = 0.081 and P = 0.092, respectively) (Table 1). A total of 300 (86.2%) children had cyanotic type of BHS only, 27 (7.8%) had pallid type of BHS only and 21 (6%) had the mixed type of BHS. IDA was statistically significantly higher in patients with BHS compared with the control group (P = 0.0001, P < 0.05) (Table 2). The neurological examinations of all of the children were normal. Each child under clinical seizure suspicion had normal EEG, and all children exhibited normal developmental levels. Electrocardiography and
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
S Is¸ikay and S¸ Hızlı
serum IgA levels were normal in all patients. Both groups were seronegative for tTg IgA. Tissue transglutaminase immunoglobulin A was not detected as positive in any patients in either group. Therefore, endoscopic and histopathological examinations were not performed in any patients.
Discussion We investigated the frequency of CD among patients with BHS and compared this frequency with that of healthy children in this study. Interestingly, any of the cases neither in patient group nor in control group, totally 818 cases, were not positive for tTg IgA. In that aspect the present study did not determine any increased frequency of CD among patients with BHS. However, it is also interesting not to determine any tTg IgA positivity in all those patients. In a study of Ertekin et al., the seropositivity of healthy school children between the ages of 6–17 was determined as 0.87% in our region.19 However, this difference was attributed to the difference in age groups of studies. In ESPHGAN guidelines, it has been clearly defined that false negativity of tTg IgA increases in patients younger than 2 years of age and in our study 67% of patients were younger than the 2 years of age.18 IDA is frequently seen in CD and BHS patients. The question of whether there is a relationship between CD, BHS and IDA arises from the observation that most patients with BHS have IDA (69%).20 In addition, most patients with CD (12–69%) are diagnosed with IDA,21 and 4.4% of children with IDA are diagnosed with CD.22 Anaemia develops in CD as a result of malabsorbtion of nutritional elements such as iron, folic acid and/or B12 vitamin, due to inflammatory involvement of proximal intestine or as a result of iron loss due to concealed bleeding.20,23 In addition, a relationship between IDA and BHS has been established, and attacks in these cases decrease upon iron treatment.14,20,24 IDA observed in BHS resulted mostly from physiological anaemia and developed in CD due to malabsorbtion of iron. The results of the present study indicated no physiopathological relationship between CD and BHS. It was also determined that the iron deficiency observed in the coeliac patient group was less serious compared with the physiopathological anaemia group. This resulted from the fluctuations in iron absorption in parallel to the inflammation in coeliac patients caused by differing gluten intakes during different periods. This opinion is supported by the finding that iron deficiency was more frequent and serious in the physiologic anaemia group (serum ferritin level decreased to 0 and 1 in some patients) compared with the coeliac patients group. BHS are paroxysmal non-epileptic disorders that occur in approximately 5% of overall healthy children. The frequency of occurrence increases at age 2.23,24 In a study of 933 children performed in Turkey, 34 children (3.6%) was reported to have BHS.25 Male children exhibit earlier inclination peak levels (at age 13–18 months) compared with females (18–24 months).12 In 50% of cases, the condition disappears at approximately age 4.27,28 It occurs rarely after age 6.12,15,26 The youngest case in the literature is a 3-day-old infant with positive family history,29 whereas the oldest case involved a patient aged of 11 years and 8 months.30 The mean age in the present study was 2.24 ± 1.85 years, and the oldest patient was 11 years old. We found a
Coeliac disease and breath-holding spells
similar distribution between cyanotic, pallid and mixed types of BHS to that reported in previous studies.27 Although the pathogenesis and the triggering factors of the disease are not fully understood, some studies report that IDA is frequently observed in children with spells that respond well to iron therapy.14,15 It is well known that children with iron deficiency cry more frequently, become easily depressed and are more irritable.12 Similarly, in the present study, IDA was more common in patients with BHS subjects compared with controls. Although there are no data indicating that treatment or resolution of anaemia corresponds to decrease or resolution of the spells, treatment of these children with iron has been determined to result in a significant reduction in the frequency of BHS.14,15 In the same way with our results, in a meta-analysis of two studies, iron supplementation has been determined as useful in reducing the frequency and severity of breath-holding attacks.31 Calik et al. studied 31 patients with BHS and 35 healthy control cases and reported that the value of oxidative stress was significantly higher in patients with BHS than in the controls. They concluded that conditions associated with increased oxidative stress such as IDA may be a risk factor for the development of BHS.32 The measurement of IgA anti-tissue transglutaminase antibodies by the enzyme-linked immunosorbent assay (ELISA) is universally accepted in the screening of CD. Samas¸ça et al. aimed to evaluate tTG IgA using the gold standard represented by IgA anti-endomysium antibodies in a group of 890 children and they determined the sensitivity, positive predictive value, specificity and negative predictive value of tTG IgA as 77.3%, 55.2%, 93.1%, 97.3%, respectively.33 However, the increase in the false negativity of tTg IgA among cases lower than the age of 2 is one of the main limitations of this study. In our study, tissue transglutaminase immunoglobulin A was not detected as positive in any patients in either group and that may be attributed to the low number of study participants. However, in small populations, the specificity and sensitivity of the tissue transglutaminase IgA test is also high.34 HLA-DQ2 and HLA-DQ8 coeliac gene testing are the other popular ways in diagnosis of CD but since they are expensive and not widely available; these tests are used as confirmatory tools in our country. If any of the cases included in this study was positive for tTg IgA, then those tests were planned to be used for confirmation. In conclusion, to the best of our knowledge, our report is the first to describe the frequency of tTg IgA positivity in patients with BHS. Although the study included a small number of cases, the results suggest that the ratio of tTg IgA positivity is not increased among patients with BHS. However, consistent with the previous literature, IDA seems to be an important risk factor in the development of BHS. Though IDA seems to be a common pathway present in both CD and BHS, the results of the present study suggest that serological screening for CD in BHS is not necessary. Further large-scale studies are warranted to elucidate the relationship of CD with BHS, if present.
References 1 Fasano A, Berti I, Gerarduzzi T et al. Prevalence of celiac disease in at risk and non-at-risk groups in the United States: a large multicenter study. Arch. Intern. Med. 2003; 163: 286–92.
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
3
Coeliac disease and breath-holding spells
S Is¸ikay and S¸ Hızlı
2 Maki M, Mustalahti K, Kokkonen J et al. Prevalence of celiac disease among children in Finland. N. Engl. J. Med. 2003; 348: 2517–24. 3 Dalgic B, Sari S, Basturk B et al. Prevalence of celiac disease in healthy Turkish school children. Am. J. Gastroenterol. 2011; 106: 1512–17. 4 Fasano A, Catassi C. Coeliac disease in children. Best Pract. Res. Clin. Gastroenterol. 2005; 19: 467–78. 5 Chin RL, Sander HV, Brannagan TH et al. Celiac neuropathy. Neurology 2003; 60: 1581–5. 6 Cakır D, Tosun A, Polat M et al. Subclinical neurological abnormalities in children with celiac disease receiving a gluten-free diet. J. Pediatr. Gastroenterol. Nutr. 2007; 45: 366–9. 7 Hadjvassiliou M, Gibson A, Davies-Jones GA, Lobo AJ, Stephenson TJ, Milford-Ward A. Does criptic gluten sensitivity play a part in neurological illness? Lancet 1996; 347: 369–71. 8 Ruggieri M, Incorpora G, Polizzi A, Parano E, Spina M, Pavone P. Low prevalence of neurologic and psychiatric manifestations in children with gluten sensitivity. J. Pediatr. 2008; 152: 244–9. 9 Zelnik N, Pacht A, Obeid R, Lerner A. Range of neurologic disorders in patients with celiac disease. Pediatrics 2004; 113: 1672–6. 10 Lionetti E, Francavilla R, Pavone P et al. The neurology of coeliac disease in childhood: what is the evidence? A systematic review and meta-analysis. Dev. Med. Child Neurol. 2010; 52: 700–7. 11 Briani C, Zara G, Alaedini A et al. Neurological complications of celiac disease and autoimmune mechanisms: a prospective study. J. Neuroimmunol. 2008; 195: 171–5. 12 DiMario FJ Jr. Breath holding spells in childhood. Am. J. Dis. Child. 1992; 146: 125–31. 13 Di Mario FJ Jr, Bauer L, Volpe J, Baxter D. Respiratory sinus arrhythmia in children with severe cyanotic breath holding spells. J. Child Neurol. 1997; 12: 260–2. 14 Colina KF, Abelson HT. Resolution of breath-holding spells with treatment of concomitant anaemia. J. Pediatr. 1995; 126: 395–7. 15 Daoud AS, Batieha A, Al-Sheyyab M, Abuekteish F, Hijazi S. Effectiveness of iron therapy on breath-holding spells. J. Pediatr. 1997; 130: 547–50. 16 Marsh MN. Gluten, major histocompatibility complex, and the small intestine: a molecular and immunobiologic approach to the spectrum of gluten sensitivity (celiac sprue). Gastroenterology 1992; 102: 330–54. 17 Husby S, Koletzko S, Korponay-Szabó IR, ESPGHAN Working Group on Coeliac Disease Diagnosis; ESPGHAN Gastroenterology Committee; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J. Pediatr. Gastroenterol. Nutr. 2012; 54: 136–60.
4
18 Cook JD. Diagnosis and management of iron-deficiency anemia. Best Pract. Res. Clin. Hematol. 2005; 18: 319–32. 19 Ertekin V, Selimog˘lu MA, Kardas¸ F, Aktas¸ E. Prevalence of celiac disease in Turkish children. J. Clin. Gastroenterol. 2005; 39: 689–91. 20 Mocan H, Yildiran A, Orhan F, Erduran E. Breath holding spells in 91 children and response to treatment with iron. Arch. Dis. Child. 1999; 81: 261–2. 21 Carroccio A, Iannitto E, Cavataio F et al. Sideropenic anemia and celiac disease: one study, two points of view. Dig. Dis. Sci. 1998; 43: 673–8. 22 Fisgin T, Yarali N, Duru F, Usta B, Kara A. Hematologic manifestation of childhood celiac disease. Acta Haematol. 2004; 111: 211–14. 23 Halfdanarson TR, Litzow MR, Murray JA. Hematologic manifestations of celiac disease. Blood 2007; 109: 412–21. 24 Bhatia MS, Singhal PK, Dhar NK, Nigam VR, Malik SC, Mullick DN. Breath holding spells: an analysis of 50 cases. Indian Pediatr. 1990; 27: 1073–9. 25 Carman KB, Ekici A, Yimenicioglu S, Arslantas D, Yakut A. Breath holding spells: point prevalence and associated factors among Turkish children. Pediatr. Int. 2013; 55: 328–31. 26 Lombroso CT, Lerman P. Breathholding spells (cyanotic and pallid infantile syncope). Pediatrics 1967; 39: 563–81. 27 Di Mario FJ Jr. Prospective study of children with cyanotic and pallid breath-holding spells. Pediatrics 2001; 107: 265–9. 28 Bridge M, Livengston S, Tietze C. Breathholding spells: their relationship in syncope, convulsions and other phenomena. J. Pediatr. 1943; 23: 539–63. 29 Breukels MA, Pholtz FB, van Nieuwenhuizen O, van Diemen-Steenvoorde JA. Breath holding spells in a 3-day-old neonate: an unusual early presentation in a family with a history of breath holdingspells. Neuropediatrics 2002; 33: 41–2. 30 Low NL, Gibbs EL, Gibbs FA. Electroencephalographic findings in breath holding spells. Pediatrics 1955; 15: 595–9. 31 Zehetner AA, Orr N, Buckmaster A, Williams K, Wheeler DM. Iron supplementation for breath-holding attacks in children. Cochrane Database Syst. Rev. 2010; 12 (5): CD008132. 32 Calik M, Abuhandan M, Aycicek A, Taskin A, Selek S, Iscan A. Increased oxidant status in children with breath-holding spells. Childs Nerv. Syst. 2013; 29: 1015–19. 33 Samas¸ca G, Iancu M, Farca˘u D et al. IgA anti-tissue transglutaminase antibodies, first line in the diagnosis of celiac disease. Clin. Lab. 2011; 57: 695–701. 34 Health Quality Ontario. Clinical utility of serologic testing for celiac disease in Ontario: an evidence-based analysis. Ont. Health Technol. Assess. Ser. 2010; 10: 1–111.
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
doi:10.1111/jpc.12639
ORIGINAL ARTICLE
Frequency of coeliac disease in children with breath-holding spells Sedat Is¸ikay1 and S¸amil Hızlı2 1
Department of Pediatric Neurology, Gaziantep Children’s Hospital and 2Department of Pediatric Gastroenterology, Gaziantep University, Gaziantep, Turkey
Aim: Iron deficiency anaemia (IDA), which is reported very commonly among patients with breath holding spells (BHS), is the most common presentation of coeliac disease (CD). In that aspect, IDA may be a common pathway linking these two diseases. The aim of this study was to evaluate the frequency of CD in patients with BHS. Methods: We studied 348 children with BHS, and 470 age- and sex-matched controls with no known disease. Serological screening for CD was performed in all patients by searching for serum tissue transglutaminase immunoglobulin A. Results: The first group consisted of 348 children with BHS (231 males, 117 females; mean age 2.23 ± 1.84 years), and the second group consisted of 470 healthy children (284 males, 186 females; mean age 2.11 ± 1.98 years). A total of 300 (86.2%) patients had cyanotic type of BHS only, 27 (7.8%) had pallid type of BHS only and 21 (6%) had mixed type of BHS. The prevalence of IDA was statistically significantly higher in BHS patients compared with controls. Tissue transglutaminase immunoglobulin A was not detected as positive in any patients in either group; therefore, endoscopic and histopathological examinations were not performed. Conclusions: Our report is the first to describe the frequency of tissue transglutaminase immunoglobulin A positivity in patients with BHS. There was no evidence of a relationship between CD and BHS, but IDA seems to be an important risk factor in the development of BHS. Therefore, serological screening for CD in patients with BHS does not seem to be necessary. Key words:
breath-holding spells; coeliac disease; child; iron deficiency anaemia.
What is already known on this topic
What this paper adds
1 Iron deficiency anaemia (IDA), which is one of the most common presentations of coeliac disease (CD), may be a common pathway linking CD with breath holding spells (BHS). 2 Although the exact association of IDA with BHS is not known. 3 IDA is one of the conditions mostly associated with BHS. In that aspect, patients with CD can be suggested to have an increased risk of BHS or in other words IDA triggering BHS may be the result of CD that suggests an increased prevalence of CD among patients with BHS.
1 To the best of our knowledge, our report is the first to describe the frequency of tissue transglutaminase immunoglobulin A positivity in patients with BHS. 2 Although the study included a small number of cases, the results suggest that the ratio of tTg IgA positivity is not increased among patients with BHS. However, consistent with the previous literature, IDA seems to be an important risk factor in the development of BHS. 3 Though IDA seems to be a common pathway present in both CD and BHS, the results of the present study suggest that serological screening for CD in BHS is not necessary. Further large-scale studies are warranted to elucidate the relationship of CD with BHS, if present.
Coeliac disease (CD) is a chronic autoimmune disease determined in predisposed individuals, which is associated with gluten-containing cereals. The prevalence in European countries is reported as between 1/99 and 1/133.1,2 In Turkey, the prevalence of CD in the healthy child population (demonstrated by normal biopsy) is reported as 0.47%.3 In recent years, it has been clear that CD presents more frequently with non-classical Correspondence: Dr Sedat Is¸ikay, Department of Pediatric Neurology, Gaziantep Children’s Hospital, S¸ehitkamil, Gaziantep 27500, Turkey. Fax: +90 (342) 360 39 28; email: [email protected] Accepted for publication 5 May 2014.
signs than the classical form.4 Neurological complications and iron deficiency anaemia (IDA) have been reported in 6–11% of patients with CD;5–8 however, the pathophysiology of those neurological disorders that develop during the course of CD is not clear.9–11 Breath-holding spells (BHS) in children are characterised by a change in skin colour, involuntary awake state apnea and a change in or loss of consciousness. The presence of an underlying dysfunction of the autonomic nervous system in children with BHS has been proposed by many authors. BHS have also been associated with IDA. Several studies have reported abatement of BHS with iron treatment, which may suggest a
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
1
Coeliac disease and breath-holding spells
S Is¸ikay and S¸ Hızlı
Table 1 Patient characteristics of BHS and control group
Age, y Sex Male Female
BHS, n = 348 mean ± SD
Control, n = 470 mean ± SD
P value
2.23 ± 1.84 – 231 117
2.11 ± 1.98 – 284 186
0.092 0.081 – –
BHS, breath-holding spells; SD, standard deviation.
relationship between IDA and BHS.12–15 IDA, which is one of the most common presentations of CD, may be a common pathway linking CD with BHS. Although the exact association of IDA with BHS is not known, IDA is one of the conditions mostly associated with BHS. In that aspect, patients with CD can be suggested to have an increased risk of BHS or in other words IDA triggering BHS may be the result of CD that suggests an increased prevalence of CD among patients with BHS. The literature includes studies of neurological disorders and IDA in patients with CD, but there is no data about the prevalence of CD in children with BHS. We aimed to determine the frequency of CD in children diagnosed with BHS.
Materials and Methods The study was approved by the Ethics Committee at Gaziantep University Faculty of Medicine, Turkey. Additionally, the parents of all participating children gave informed consent prior to their inclusion in the study.
Patients and Methods This prospective case-control study included 348 children between the ages 6 months and 11 years, who were diagnosed as having BHS at a child neurology outpatient clinic between September 2012 and March 2013. Diagnosis of BHS was made clinically, based on the history given by the mothers and observation of the spells. Spells were defined as the stopping of child’s breathing in expiration after a deep inspiration during crying. The spells were classified as cyanotic, pallid and mixed (when there was no clear distinction between cyanosis and pallor according to the skin colour change during episodes).12,13 A detailed medical and family history was taken before inclusion in the study. We recorded the type of attacks. Initial blood values were recorded for haemoglobin concentration, mean corpuscular volume, serum iron, total iron binding capacity and ferritin levels. Electroencephalography (EEG) and electrocardiography were carried out in all cases. All of the patients agreed to participate and none left the study. A control group comprised 470 sex- and age-matched children, who were evaluated at paediatric clinics for mild upper respiratory tract infection. Demographic characteristics, medication histories and clinical findings of all of participants were recorded. None of the patients had any other disorders. Tissue transglutaminase immunoglobulin A (tTg IgA) was studied with micro-enzyme-linked immunosorbent assay method 2
Table 2 Number and percentage of patients with iron deficiency anaemia in study and control groups
Breath-holding spells group (n = 348) Control group (n = 470)
Iron deficiency anaemia
P value
312 (89.7%)
0.0001*
148 (31.5%)
–
*Chi-square test (P < 0.05).
(ImmuLisa, Immco Diagnostics Inc., Buffalo, NY, USA). Cases with a value of tTg IgA >15 U/mL were considered positive. There was not any cases with indeterminate values. Serum IgA was determined in all patients to rule out selective IgA deficiency. We performed upper gastrointestinal endoscopy with a flexible endoscope and multiple biopsies (at least 1 from bulb and 4 from the second part of the duodenum) were taken in tTg IgA-positive cases in order to confirm the diagnosis of CD.16,17 Iron deficiency was regarded as the ferritine 450 μg/dL.18
Statistical analysis Statistical analysis used SPSS software (version 16.0 for Windows, Statistical Package for the Social Sciences (SPSS), Inc., Chicago, IL, USA). Student t-test and χ2 were used.
Results The first group consisted of children with BHS (231 males, 117 females; mean age 2.23 ± 1.84 years (6 months–11 years) ), and the second group consisted of healthy children (284 males, 186 females; mean age 2.11 ± 1.98 years (5 months–11 years) ). There were no statistically significant differences between the two groups in terms of sex and age (P = 0.081 and P = 0.092, respectively) (Table 1). A total of 300 (86.2%) children had cyanotic type of BHS only, 27 (7.8%) had pallid type of BHS only and 21 (6%) had the mixed type of BHS. IDA was statistically significantly higher in patients with BHS compared with the control group (P = 0.0001, P < 0.05) (Table 2). The neurological examinations of all of the children were normal. Each child under clinical seizure suspicion had normal EEG, and all children exhibited normal developmental levels. Electrocardiography and
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
S Is¸ikay and S¸ Hızlı
serum IgA levels were normal in all patients. Both groups were seronegative for tTg IgA. Tissue transglutaminase immunoglobulin A was not detected as positive in any patients in either group. Therefore, endoscopic and histopathological examinations were not performed in any patients.
Discussion We investigated the frequency of CD among patients with BHS and compared this frequency with that of healthy children in this study. Interestingly, any of the cases neither in patient group nor in control group, totally 818 cases, were not positive for tTg IgA. In that aspect the present study did not determine any increased frequency of CD among patients with BHS. However, it is also interesting not to determine any tTg IgA positivity in all those patients. In a study of Ertekin et al., the seropositivity of healthy school children between the ages of 6–17 was determined as 0.87% in our region.19 However, this difference was attributed to the difference in age groups of studies. In ESPHGAN guidelines, it has been clearly defined that false negativity of tTg IgA increases in patients younger than 2 years of age and in our study 67% of patients were younger than the 2 years of age.18 IDA is frequently seen in CD and BHS patients. The question of whether there is a relationship between CD, BHS and IDA arises from the observation that most patients with BHS have IDA (69%).20 In addition, most patients with CD (12–69%) are diagnosed with IDA,21 and 4.4% of children with IDA are diagnosed with CD.22 Anaemia develops in CD as a result of malabsorbtion of nutritional elements such as iron, folic acid and/or B12 vitamin, due to inflammatory involvement of proximal intestine or as a result of iron loss due to concealed bleeding.20,23 In addition, a relationship between IDA and BHS has been established, and attacks in these cases decrease upon iron treatment.14,20,24 IDA observed in BHS resulted mostly from physiological anaemia and developed in CD due to malabsorbtion of iron. The results of the present study indicated no physiopathological relationship between CD and BHS. It was also determined that the iron deficiency observed in the coeliac patient group was less serious compared with the physiopathological anaemia group. This resulted from the fluctuations in iron absorption in parallel to the inflammation in coeliac patients caused by differing gluten intakes during different periods. This opinion is supported by the finding that iron deficiency was more frequent and serious in the physiologic anaemia group (serum ferritin level decreased to 0 and 1 in some patients) compared with the coeliac patients group. BHS are paroxysmal non-epileptic disorders that occur in approximately 5% of overall healthy children. The frequency of occurrence increases at age 2.23,24 In a study of 933 children performed in Turkey, 34 children (3.6%) was reported to have BHS.25 Male children exhibit earlier inclination peak levels (at age 13–18 months) compared with females (18–24 months).12 In 50% of cases, the condition disappears at approximately age 4.27,28 It occurs rarely after age 6.12,15,26 The youngest case in the literature is a 3-day-old infant with positive family history,29 whereas the oldest case involved a patient aged of 11 years and 8 months.30 The mean age in the present study was 2.24 ± 1.85 years, and the oldest patient was 11 years old. We found a
Coeliac disease and breath-holding spells
similar distribution between cyanotic, pallid and mixed types of BHS to that reported in previous studies.27 Although the pathogenesis and the triggering factors of the disease are not fully understood, some studies report that IDA is frequently observed in children with spells that respond well to iron therapy.14,15 It is well known that children with iron deficiency cry more frequently, become easily depressed and are more irritable.12 Similarly, in the present study, IDA was more common in patients with BHS subjects compared with controls. Although there are no data indicating that treatment or resolution of anaemia corresponds to decrease or resolution of the spells, treatment of these children with iron has been determined to result in a significant reduction in the frequency of BHS.14,15 In the same way with our results, in a meta-analysis of two studies, iron supplementation has been determined as useful in reducing the frequency and severity of breath-holding attacks.31 Calik et al. studied 31 patients with BHS and 35 healthy control cases and reported that the value of oxidative stress was significantly higher in patients with BHS than in the controls. They concluded that conditions associated with increased oxidative stress such as IDA may be a risk factor for the development of BHS.32 The measurement of IgA anti-tissue transglutaminase antibodies by the enzyme-linked immunosorbent assay (ELISA) is universally accepted in the screening of CD. Samas¸ça et al. aimed to evaluate tTG IgA using the gold standard represented by IgA anti-endomysium antibodies in a group of 890 children and they determined the sensitivity, positive predictive value, specificity and negative predictive value of tTG IgA as 77.3%, 55.2%, 93.1%, 97.3%, respectively.33 However, the increase in the false negativity of tTg IgA among cases lower than the age of 2 is one of the main limitations of this study. In our study, tissue transglutaminase immunoglobulin A was not detected as positive in any patients in either group and that may be attributed to the low number of study participants. However, in small populations, the specificity and sensitivity of the tissue transglutaminase IgA test is also high.34 HLA-DQ2 and HLA-DQ8 coeliac gene testing are the other popular ways in diagnosis of CD but since they are expensive and not widely available; these tests are used as confirmatory tools in our country. If any of the cases included in this study was positive for tTg IgA, then those tests were planned to be used for confirmation. In conclusion, to the best of our knowledge, our report is the first to describe the frequency of tTg IgA positivity in patients with BHS. Although the study included a small number of cases, the results suggest that the ratio of tTg IgA positivity is not increased among patients with BHS. However, consistent with the previous literature, IDA seems to be an important risk factor in the development of BHS. Though IDA seems to be a common pathway present in both CD and BHS, the results of the present study suggest that serological screening for CD in BHS is not necessary. Further large-scale studies are warranted to elucidate the relationship of CD with BHS, if present.
References 1 Fasano A, Berti I, Gerarduzzi T et al. Prevalence of celiac disease in at risk and non-at-risk groups in the United States: a large multicenter study. Arch. Intern. Med. 2003; 163: 286–92.
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
3
Coeliac disease and breath-holding spells
S Is¸ikay and S¸ Hızlı
2 Maki M, Mustalahti K, Kokkonen J et al. Prevalence of celiac disease among children in Finland. N. Engl. J. Med. 2003; 348: 2517–24. 3 Dalgic B, Sari S, Basturk B et al. Prevalence of celiac disease in healthy Turkish school children. Am. J. Gastroenterol. 2011; 106: 1512–17. 4 Fasano A, Catassi C. Coeliac disease in children. Best Pract. Res. Clin. Gastroenterol. 2005; 19: 467–78. 5 Chin RL, Sander HV, Brannagan TH et al. Celiac neuropathy. Neurology 2003; 60: 1581–5. 6 Cakır D, Tosun A, Polat M et al. Subclinical neurological abnormalities in children with celiac disease receiving a gluten-free diet. J. Pediatr. Gastroenterol. Nutr. 2007; 45: 366–9. 7 Hadjvassiliou M, Gibson A, Davies-Jones GA, Lobo AJ, Stephenson TJ, Milford-Ward A. Does criptic gluten sensitivity play a part in neurological illness? Lancet 1996; 347: 369–71. 8 Ruggieri M, Incorpora G, Polizzi A, Parano E, Spina M, Pavone P. Low prevalence of neurologic and psychiatric manifestations in children with gluten sensitivity. J. Pediatr. 2008; 152: 244–9. 9 Zelnik N, Pacht A, Obeid R, Lerner A. Range of neurologic disorders in patients with celiac disease. Pediatrics 2004; 113: 1672–6. 10 Lionetti E, Francavilla R, Pavone P et al. The neurology of coeliac disease in childhood: what is the evidence? A systematic review and meta-analysis. Dev. Med. Child Neurol. 2010; 52: 700–7. 11 Briani C, Zara G, Alaedini A et al. Neurological complications of celiac disease and autoimmune mechanisms: a prospective study. J. Neuroimmunol. 2008; 195: 171–5. 12 DiMario FJ Jr. Breath holding spells in childhood. Am. J. Dis. Child. 1992; 146: 125–31. 13 Di Mario FJ Jr, Bauer L, Volpe J, Baxter D. Respiratory sinus arrhythmia in children with severe cyanotic breath holding spells. J. Child Neurol. 1997; 12: 260–2. 14 Colina KF, Abelson HT. Resolution of breath-holding spells with treatment of concomitant anaemia. J. Pediatr. 1995; 126: 395–7. 15 Daoud AS, Batieha A, Al-Sheyyab M, Abuekteish F, Hijazi S. Effectiveness of iron therapy on breath-holding spells. J. Pediatr. 1997; 130: 547–50. 16 Marsh MN. Gluten, major histocompatibility complex, and the small intestine: a molecular and immunobiologic approach to the spectrum of gluten sensitivity (celiac sprue). Gastroenterology 1992; 102: 330–54. 17 Husby S, Koletzko S, Korponay-Szabó IR, ESPGHAN Working Group on Coeliac Disease Diagnosis; ESPGHAN Gastroenterology Committee; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J. Pediatr. Gastroenterol. Nutr. 2012; 54: 136–60.
4
18 Cook JD. Diagnosis and management of iron-deficiency anemia. Best Pract. Res. Clin. Hematol. 2005; 18: 319–32. 19 Ertekin V, Selimog˘lu MA, Kardas¸ F, Aktas¸ E. Prevalence of celiac disease in Turkish children. J. Clin. Gastroenterol. 2005; 39: 689–91. 20 Mocan H, Yildiran A, Orhan F, Erduran E. Breath holding spells in 91 children and response to treatment with iron. Arch. Dis. Child. 1999; 81: 261–2. 21 Carroccio A, Iannitto E, Cavataio F et al. Sideropenic anemia and celiac disease: one study, two points of view. Dig. Dis. Sci. 1998; 43: 673–8. 22 Fisgin T, Yarali N, Duru F, Usta B, Kara A. Hematologic manifestation of childhood celiac disease. Acta Haematol. 2004; 111: 211–14. 23 Halfdanarson TR, Litzow MR, Murray JA. Hematologic manifestations of celiac disease. Blood 2007; 109: 412–21. 24 Bhatia MS, Singhal PK, Dhar NK, Nigam VR, Malik SC, Mullick DN. Breath holding spells: an analysis of 50 cases. Indian Pediatr. 1990; 27: 1073–9. 25 Carman KB, Ekici A, Yimenicioglu S, Arslantas D, Yakut A. Breath holding spells: point prevalence and associated factors among Turkish children. Pediatr. Int. 2013; 55: 328–31. 26 Lombroso CT, Lerman P. Breathholding spells (cyanotic and pallid infantile syncope). Pediatrics 1967; 39: 563–81. 27 Di Mario FJ Jr. Prospective study of children with cyanotic and pallid breath-holding spells. Pediatrics 2001; 107: 265–9. 28 Bridge M, Livengston S, Tietze C. Breathholding spells: their relationship in syncope, convulsions and other phenomena. J. Pediatr. 1943; 23: 539–63. 29 Breukels MA, Pholtz FB, van Nieuwenhuizen O, van Diemen-Steenvoorde JA. Breath holding spells in a 3-day-old neonate: an unusual early presentation in a family with a history of breath holdingspells. Neuropediatrics 2002; 33: 41–2. 30 Low NL, Gibbs EL, Gibbs FA. Electroencephalographic findings in breath holding spells. Pediatrics 1955; 15: 595–9. 31 Zehetner AA, Orr N, Buckmaster A, Williams K, Wheeler DM. Iron supplementation for breath-holding attacks in children. Cochrane Database Syst. Rev. 2010; 12 (5): CD008132. 32 Calik M, Abuhandan M, Aycicek A, Taskin A, Selek S, Iscan A. Increased oxidant status in children with breath-holding spells. Childs Nerv. Syst. 2013; 29: 1015–19. 33 Samas¸ca G, Iancu M, Farca˘u D et al. IgA anti-tissue transglutaminase antibodies, first line in the diagnosis of celiac disease. Clin. Lab. 2011; 57: 695–701. 34 Health Quality Ontario. Clinical utility of serologic testing for celiac disease in Ontario: an evidence-based analysis. Ont. Health Technol. Assess. Ser. 2010; 10: 1–111.
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
