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1 Seizure 18 (2009) Contents lists available at ScienceDirect Seizure journal homepage: Association between iron deficiency anemia and first febrile convulsion: A case control study Elham Bidabadi a, *, Mehryar Mashouf b a Guilan University of Medical Sciences, No. 15, 135 ave., Golsar, Rasht , Iran b Arya Hospital, Anzali Blv., Rasht , Iran ARTICLE INFO ABSTRACT Article history: Received 7 June 2007 Received in revised form 20 June 2008 Accepted 8 January 2009 Keywords: Febrile seizure Case control study Iron deficiency anemia Epilepsy Objective: The relationship between iron deficiency anemia and febrile convulsions has been examined in several studies with conflicting results. The authors aimed to evaluate the relation, if any, of iron status with first febrile convulsion. Methods: In this case control study, the authors assessed 200 children with a diagnosis of first febrile convulsion, aged between 6 months and 5 years, during March 2005 to September The control group consisted of febrile children without convulsion; controls were matched to the cases by gender and age. Results: The patients and controls were and months of mean age, respectively. The amount of RBC, serum iron, and plasma ferritin were significantly higher, and TIBC was significantly lower among the cases with first febrile convulsions than in the controls. The amount of Hb, Hct, MCV, MCH, and MCHC were also higher among cases than controls, but differences were not statistically significant. Iron deficiency anemia was less frequent among the cases with febrile convulsion, as compared to the controls, and its difference was not statistically significant; but there is not a protective effect of iron deficiency against development of febrile convulsion (odd ratio = 1.175). The mean of temperature peak on admission was significantly higher in the febrile convulsion group ( C) compared with the controls ( C) (P < ). Conclusions: The results of this study suggest that iron deficiency anemia was less frequent among the cases with febrile convulsion, as compared to the controls, and there is not a protective effect of iron deficiency against febrile convulsions. ß 2009 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. 1. Introduction Febrile convulsions are the most common form of childhood seizures. The peak incidence is at the age of approximately 18 months. In the United States and Western Europe, they occur 2 4% of all children 1 8 ; In Japan, however, 9 10% of all children experience febrile convulsion, 1 9 and rates as high as 14% have been reported from the Mariana Islands in Guam Febrile convulsions have been studied extensively over the past two decades, and a large body of literature now exists to help practitioners assess the risks associated with such presentations. 2,11 15 Independent risk factors for febrile convulsions were height of temperature, history of febrile convulsions in a first or in a higher degree relative, the number of fever episodes per year, maternal smoking and alcohol consumption during pregnancy, and perinatal exposure to antiretrovirals. 7,12,16,17 Genetic factors * Corresponding author. Tel.: address: mashoof@mail.com (M. Mashouf). contribute significantly to the etiology of febrile convulsions. Family studies have shown that relatives of these patients are at increased risk compared to the general population. 18 Twin studies have also indicated that genetic factors play an important role in susceptibility to febrile convulsion. 19 Segregation patterns in families with febrile convulsions suggest different modes of inheritance. Most studies have supported a polygenic or multifactorial model, with an estimated heritability of 75% However, in families of probands with multiple febrile convulsions, the inheritance pattern was consistent with a single-majorlocus model that best fit autosomal dominance with a disease penetrance of 65%. Linkage analysis studies identified five chromosomal loci for febrile convulsion: FEB1 at 8q13-q21, FEB2 at 19p, FEB3 at 2q23-q24, FEB4 at 5q14-q15 and FEB5 at 6q22-q In some families, febrile convulsion is present as part of a broader phenotypic spectrum that also includes atypical febrile seizures (FS+) and afebrile generalized and partial seizures i.e. generalized epilepsy with febrile seizures plus (GEFS+). 28 In GEFS+ families, mutations were identified in SCN1B on chromosome 19p13.1 (GEFS+1), SCN1A on chromosome 2q24 (GEFS+2) /$ see front matter ß 2009 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi: /j.seizure

2 348 E. Bidabadi, M. Mashouf / Seizure 18 (2009) and GABRG2 on chromosome 5q31-q33 (GEFS+3) The disease phenotype within the GEFS+ families with identified mutations segregated in an autosomal dominant pattern with reduced disease penetrance. Mutations in these three genes were found in several GEFS+ families, but in most families the causal gene has not yet been identified. 33 In a large family with febrile convulsion and familial temporal lobe epilepsy (TLE) a locus was found on chromosome 12q22-q Risk factors associated with a complex first febrile convulsion were age of 15 months or less, birth weight of 2 kg or less, and initial temperature of 38 8C or less 35 ; but despite these studies the risk factors remain largely unknown. 7 Iron deficiency is reported to be one of the most prevalent nutritional problem in the world today, especially in developing countries, with an estimated 5 billion people so afflicted, 36 and iron deficiency anemia is a very common nutritional insult among human infants, especially between 6 and 24 months In developing countries 46 66% of children under 4 years are anemic, with half attributed to iron deficiency anemia. In the United States, the prevalence of dietary iron deficiency has markedly declined in infants in the last 30 years, but poor, minority, and/or immigrant infants and toddlers remain at increased risk. There are no accurate statistics of prevalence of iron deficiency anemia in Iranian children, but it estimated about 20%. 42,43 Foods rich in iron are less available in the diet of poor families, especially in the developing countries. In Iran, supplemental iron in the form of ferrous sulfate recommends at the dose of 3 mg/kg/day by 6 months for all fullterm infants, as a routine dietary measure, for 1 2 years. Among the numerous biological effects of iron, there is considerable evidence that iron is also important for neurological functioning. 36,44 50 Such functions include neurotransmitter metabolism, myelin formation, 54 and brain energy metabolism In the rodent model, iron deficiency affects regional monoamine metabolism, in part through iron-dependent enzymes such as tryptophan hydroyxlase (for serotonin) and tyrosine hydroxylase (for dopamine and norepinephrine). 59 Recent research shows that iron deficiency also results in elevations in extracellular dopamine and norepinephrine and reductions in D1 and D2 receptors and all monoamine transporters Iron deficiency decreased the expression of cytochrome c oxidase, a marker of neuronal metabolic activity. 63 Serial neurometabolic assessment of the hippocampus in the iron deficient rat pup showed elevations in intracellular glutamate, phosphocreatine, and phosphoryl-ethanolamine concentrations. 64 Gestational iron deficiency induced changes in the dendritic structure, as assessed by microtubule associated protein 2 expression. The role of iron in myelination of the rodent brain has been known for several decades. 54,62 Potential explanations include fundamental changes to early preoligodendrocyte and oligodendrocyte populations and altered regulation of oligodendrocyte iron uptake via transferrin and transferrin receptors. 65,66 Most human studies on developmental and behavioral effects of iron deficiency focus on the infancy period of peak prevalence, which is 6 24 months. Iron deficiency anemia patients have shown an altered rapid eye movement density in active sleep, 67 poorer recognition memory with event-related potentials, 68 and altered electroencephalographic frontal asymmetry. 69 Affective changes in iron deficiency anemia infants, such as wariness, hesitance, decreased positive effect, and social interaction, are seen. Recent studies of auditory evoked potential changes in iron deficient infants point to possible irreversibly slowed central processing. 70,71 A basic principle of fetal/neonatal iron biology is that iron is prioritized to red cells at the expense of other tissues, including brain. When iron supply does not meet iron demand, the fetal brain may be at risk even if the infant is not anemic. 72 Evidence that iron might be important for neurological functioning has generated considerable optimism that this material might also play a role in initiation of febrile convulsions. Previous studies examining the relationship between iron deficiency anemia and febrile convulsions have been conflicting. 7,73 75 Pisacane et al. 7 reported that anemia was more common in children younger than 2 years with febrile convulsions, whereas, in contrast, Kobrinsky et al. 73 reported that iron deficiency raises the threshold for seizures. The purpose of the present study was to assess the relation, if any, of iron status with first febrile convulsion. 2. Materials and methods The study group consisted of all children with a diagnosis of first febrile convulsion (FFC), aged between 6 months and 5 years, without history of previous convulsion, developmental delay, neurological deficit, or CNS infection. Patients were treated at Rasht 17th Shahrivar Hospital, a referral pediatric center in the north of Iran associated with the Department of Child Neurology, during March 2005 to September The control group consisted of febrile children without convulsion or previous history of convulsion, visited in the outpatient pediatric clinic of the hospital, none of them needed for hospital admission on the first visit, but subsequently 26 patients of this control group needed for hospitalization in the course of their disease (25 pneumonia and 1 Kawasaki disease); controls were matched to the cases by gender and age (within 1 month for children younger than 1 year, and 2 months for children older than 1 year), family history of afebrile seizures, temperature at presentation, white blood cell count, differential, nutrition and antibiotic use. All cases and controls were with normal growth. Demographic information collected for cases and controls included age, and gender. Age (in months and years) was calculated from the date of birth. Information on birth weight and current weight, developmental milestones, body temperature upon admission, cause of fever, history of iron supplement therapy, family history of febrile convulsion, and family history of epilepsy were recorded for all cases and controls, as well as details of the seizure history, duration, frequency, type of seizure (simple or complex), and duration between initiation of fever and convulsion for cases with FFC. A single seizure of <15 min duration in the presence of fever without focal features was defined as a simple febrile convulsion, whereas seizures were defined as complex if they lasted >15 min, had focal features, or occurred more than once in 24 h. We used Acetaminophen, mg/kg/dose every 4 6 h, for its antipyretic effects, for all cases and controls with body temperature higher than C. Routine hematological investigations after collection of blood samples with 6 h of fasting were performed for all patients on 8:00 am at subsequent day of outpatient visit for controls and of hospital admission for cases, if there was not history of any iron supplement therapy for previous 3 days. Red blood cell count (RBC), hemoglobin (Hb), Hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), serum iron concentration, total iron binding capacity (TIBC), and plasma ferritin (PF) were collected for each patient. PF level was measured by using the IMx Ferritin assay in a microparticle enzyme immunoassay (MEIA) for quantitative determination of human PF. We collected MCV, MCH, and MCHC for exclusion of other types of anemia, such as thalassemia, because Iran is one of the countries that located on the thalassemic belt. On the coasts of Caspian sea, on the north of Iran, rate of carriers is about 10%; in the other parts of Iran, this rate is between 4% and 8%. 76 Iron deficiency anemia was defined as decrease of the Hb and Hct below 2 standard deviation (S.D.) of normal values for age group, as presence of Hb < 10.5 g% for 6 24 months and <11.5 g%

3 E. Bidabadi, M. Mashouf / Seizure 18 (2009) for months old, Hct < 33% for 6 24 months and <34% for months old, MCV < 70 fl for 6 24 months and <75 fl for months old, MCH < 23 pg for 6 24 months and <24 pg for months old, MCHC < 30 g% for 6 24 months and <31 g% for months old, RBC < for 6 24 months and < for months old, serum iron concentration <40 mg/dl before 1 year old and < 50 mg/dl after 1 year old, PF < 7 mg/l, and TIBC > 430 mcg/dl. 77 A pilot study on 60 patients (30 cases and 30 controls) was performed for sample size estimation. Based on a = 0.05 and study power (1 b) = 0.8, and 17 anemic patients in controls (P 1 = 0.56) and 12 anemic patients in cases group (P 2 = 0.40): n ¼ ðz 1 a=2 þ Z 1 b Þ 2 ½P 1 ð1 P 1 ÞþP 2 ð1 P 2 ÞŠ ðp 1 P 2 Þ 2 ¼ ð1:96 þ 1:28Þ2 ½ð0:56 0:44Þþð0:4 0:6ÞŠ ð0:56 0:4Þ We obtained written informed consent from all parents for inclusion in the study. The Ethics Committee at Guilan University of Medical Sciences (GUMS) approved the study. Discrete variables are expressed as counts (%) and compared using the Chi-square tests. Continuous variables are expressed as mean S.D. and compared by means of the unpaired, two-sided t- test. Adjusted odds ratios and 95% Wald confidence intervals were calculated based on these models. Statistical significance was set at P < Results There were a total of 200 patients and 200 controls. The patients and controls were and months of mean age, respectively. Both patients and the controls had a similar proportion of males (57.5% vs. 59%) and females (42.5% vs. 41%). Upper respiratory tract infections and gastroenteritis were the most frequent underlying illnesses for fever in cases and controls, respectively, which was not significantly different between underlying disease and initiation of seizure (Table 1). The distribution of seizure types between age groups in cases with FFC shows in Table 1, also. Seizure was most frequent on months of age, and simple seizure was the most frequent type of seizures in all but months of age groups. There was not statistically significant relationship between age groups and seizure types (P = 0.556). The mean of temperature peak on admission was significantly higher in the FFC group ( C) compared with the controls ( C) (P < ). Table 1 shows the time interval between initiation of the fever and the seizure attack in the patients with FFC. Simple seizure was the most frequent type of seizures in all groups, and the relationship between duration of initiation of fever and type of convulsion attacks for cases with FFC was statistically significant (P = 0.014). Data on the patient s hematologic status are provided in Table 2; as shown in the table, the amount of RBC, serum iron, and PF were significantly higher, and TIBC was significantly lower among the cases with FFC than in the controls. The amount of Hb, Hct, MCV, MCH, and MCHC were also higher among cases than controls, but differences were not statistically significant. Family history of febrile convulsion or epilepsy, iron supplement therapy, and presence of iron deficiency anemia among cases and controls are detailed in Table 2. Iron deficiency anemia was less frequent among the cases with FFC, as compared to the controls, and its difference was not statistically significant. A significantly higher proportion of children from the FFC group had a family history of epilepsy (P < ). Table 1 Baseline characteristics of two groups. 4. Discussion Cases (n = 200) Controls (n = 200) Total No. % No. % Age (months) Underlying illness Upper respiratory tract infection Pneumonia Gastroenteritis Infectious mononucleosis Vaccination Acute otitis media Mumps Kawasaki disease Urinary tract infection Unknown Simple seizure (n = %) Complex seizure (n = 68 34%) Age group (months) (17.4%) 14 (20.6%) (49.2%) 29 (42.6%) (16.7%) 10 (14.7%) (11.4%) 7 (10.3%) (5.3%) 8 (11.8%) 15 Duration <1 h 20 (15.1%) 18 (26.5%) h 96 (72.7%) 34 (50%) 130 >24 h 16 (12.1%) 16 (23.5%) 32 As dietary habits of children would have an important influence on iron intake, all of our participants had breast or formula feeding until 6 months of age; solid foods such as cereals, rice and carrot soup with meat and gradual addition of vegetables, potatoes and lentil started at this age; egg yolk added on 7 months with additional fruit juices (apple, banana, lemon, etc.). Most infants naturally adapt themselves to a schedule of three meals a day by about the end of the first year of life. There is a controversy regarding the role of iron status in the FFC. Pisacane et al. 7 in a case control study with 146 cases and 293 controls, with age of 6 24 months, reported a significantly higher rate of iron deficiency anemia among children with FFC than in Table 2 Comparison of cases and controls. Cases (n = 200) Control (n =200) P-value Mean Hb (g%) Mean Hct (%) Mean RBC Mean MCV (fl) Mean MCH (pg) Mean MCHC (g%) Mean serum iron (mg/dl) Mean TIBC (mcg/dl) Mean PF (mg/l) Iron deficiency anemia 88 (44%) 96 (48%) Family history of epilepsy 95 (47.5%) 32 (16%) < Iron supplement therapy 167 (83.5%) 169 (84.5%) 0.785

4 350 E. Bidabadi, M. Mashouf / Seizure 18 (2009) controls; Naveed-ur-Rehman and Billoo 74 suggested the same result in a case control study with 30 cases and 30 controls; whereas Daoud et al. 8 in a case control study with 75 cases and 75 controls demonstrated that only low PF level is associated with and may play a role in FFC, with lack of significant differences in Hb, MCV, and MCH; in contrast, Kobrinsky et al. 73 in a case control study with 25 cases and 26 controls, showed that anemia raises the threshold for FFC and iron deficiency may protect against the development of febrile convulsions. The results of this study demonstrated the significantly higher amount of RBC, serum iron, and PF, and significantly lower amount TIBC among the cases with FFC than in the controls. It is known that ferritin is an acute-phase reactant that increases nonspecifically in response to any febrile illness 8,73 ; fever, however, was present in all patients in the two groups, therefore differences in ferritin concentration between the two groups cannot be explained by fever. The amount of Hb, Hct, MCV, MCH, and MCHC were also higher among cases than controls, but differences failed to attain statistical significance. Iron deficiency anemia was less frequent among the cases with febrile convulsion, as compared to the controls, and its difference was not statistically significant. These results are in contrast with Pisacane et al., 7 Naveed-ur-Rehman and Billoo, 74 and Daoud et al. 8 studies, and confirmed Kobrinsky et al. 73 study results; but in contrast with the study of Kobrinsky, our study failed to demonstrate a protective effect of iron deficiency against development of febrile convulsion, based upon odd ratio = The authors believed that differences between the results of the present study and the other studies are because of difference in sample size and using different patient age groups. A threshold to febrile seizures dependent on the height of the body temperature has been demonstrated in animals of various species and in patients with febrile convulsions. The threshold varies with individuals, and according to age and maturation. Increased peak temperature upon admission has been reported to increase the risk of first febrile convulsion progressively, a finding confirmed in six additional reports reviewed in and more recently in 1995 by Berg et al. 17 ; in a study involving 110 children with febrile convulsions, the mean of body temperature at the time of the seizure was C, and the mean of 101 recordings with seizures was significantly higher than the mean of 51 highest fevers unassociated with seizures (P < 0.001) 79 ; but some other studies failed to show the relation between mean peak temperature on admission for cases and controls 8 ; our study demonstrated significantly higher mean peak temperature upon admission in the febrile convulsion group compared with the controls ( C vs C) (P < ). In our study, the majority of febrile convulsions occur between 6 months and 3 years of age, with the mean age of months, like other studies in this era; the same results obtained for the higher incidence of convulsions in boys than girls 80,81 and higher proportion of children from the febrile convulsion group with a family history of epilepsy This study has some limitations. A case control study might be misleading if cases were identified from hospital admissions and admission to hospital was influenced not only by the presence and severity of disease but also by other variables, such as social class. In general it is better to use incident rather than prevalent cases. In the present study, the 17th Shahrivar hospital is the only referral hospital for child neurology cases for a large geographic area in the north of Iran, with an exclusive clinic and only one child neurologist for these cases. 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