The Relation Between Febrile Seizure and Serum Iron and Zinc Levels in Children

doi:10.21203/rs.3.rs-1952482/v1

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The Relation Between Febrile Seizure and Serum Iron and Zinc Levels in Children

https://doi.org/10.21203/rs.3.rs-1952482/v1

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Purpose: Febrile seizures (FS) are the most commonly seen seizure type in children and its etiology is not fully understood. It is seen in 2-4% of all children. The most common factors contributing the etiopathogenesis of FS are fever, genetic predisposition and age. Other triggering factors include deficiency of iron, zinc and immunoglobulins as well as cytokine and interferon mechanisms.

Methods: This prospective and sectional study includes children between the ages 5 months to 5 years, who came to the outpatient pediatric clinic of Health Sciences University Bagcilar Research and Education Hospital between August 2020 and May 2021. The patient group includes 53 patients who came to the emergency service with febrile seizures and came for a follow-up within the following month and the control group includes 53 healthy children who came for a routine checkup with no prior history of seizures or other illnesses.

Results: The age of first time FS ranged from 7 months to 60 months with an average age of 19.6 months. 15.1% of patients had a first degree relative with a history of FS and 7.5% of patients had a family member with a history of epilepsy. Serum iron and serum zinc levels were statistically meaningfully lower in the FS group compared to the control group. (p:0.000; p:0.000; p<0.05 respectively)

Conclusion: The occurrence of febrile seizures is closely related to serum iron and zinc levels. We can say that FS is triggered once these parameters are below a threshold.

Febrile Seizure

Iron Deficiency

Zinc Deficiency.

Febrile seizures (FS) are the most commonly seen convulsions in the pediatric population (4–5%) [1]. In 2011, American Academy of Pediatrics defined FS as "a type of seizure happening during an inflammatory disease; seen in children between the ages of 6 months to 5 years with no history of epilepsy, without an electrolyte disorder, a metabolic disorder, trauma or intoxication and no symptom of a central nervous system infection” [2]. At least one occurrence of FS in children younger than five years old is reported to be 2–5% [3]. Prevalence of FS in boys is higher than girls with a ratio of 1.4/1 [4].

In literature, it is thought that multiple factors contribute to the etiopathogenesis of FS. The main factors include fever, genetic predisposition and age. Other triggering factors include iron, zinc and immunoglobulin deficiency and cytokine and interferon mechanisms [5, 6].

It is known that iron deficiency causes developmental abnormalities in both motor and mental retardation as well as other neurological problems such as venous thrombosis, ischemic stroke and breath holding spells [5, 7, 8]. Iron is one of the key components of neurotransmitter metabolism by participating in multiple enzyme structures in the central nervous system (CNS). With proper treatment of iron deficiency, possible neurologic problems can be averted [6, 9]. Recent studies show that low serum iron levels, lower the seizure threshold and fever facilitates this phenomenon [10].

Studies on trace elements and their functions on CNS show that these elements play an important role in neurotransmitters and their aerobic metabolisms. Zinc is found in nucleic acids which are necessary for the production of neurotransmitters in the brain as well as the structure of metalloenzymes and in proteins in gene regulation. Therefore, zinc is important in neuronal functioning and in regulation of synaptic excitability and membrane stability. Due to its specific importance, zinc deficiency is thought to have an important role in FS etiopathogenesis [11].

Even though FS is the most common type of convulsion in children, its etiopathogenesis is yet to be understood. Current literature shows that iron deficiency and zinc deficiency play an important role in occurrence of FS. The aim of our study is to investigate the relationship between serum iron and zinc levels and febrile seizures.

In this prospective and cross-sectional study, children between the ages 5 months to 5 years who came to xxxx Hospital Pediatrics Clinic from August 2020 to May 2021. 53 children who came to the emergency service with febrile seizure who then came to outpatient clinic within the following month were included in the patient group and 53 healthy children who came to the outpatient clinic for a routine check-up with no history of seizures or chronic diseases were included in the control group.

All patients were thoroughly informed and written consent was obtained from the legal guardians of all patients included in the study during their first visits. A detailed physical and neurological examination were performed and demographic information such as age and sex we well as their primary complaint, history, medical background (history and/or presence of prior seizures, etc.), family history (history of FS and/or epilepsy, etc.), prescribed medications, fever at the time of admission, neurologic and other physical examination findings were noted on the case report documents. All patients were then called back to the outpatient clinic in the following month for a complete blood count, serum iron, iron binding capacity, ferritin, serum zinc and other routine blood work to be performed. All findings were analyzed using statistical methods.

Diagnosis of FS was given based on the criteria reported by American Academy of Pediatrics (AAP). It is defined as a type of seizure in children between the ages of 6 months to 5 years with presence of fever without an acute intracranial infection, meningitis, history of epilepsy, long term brain disease, an electrolyte imbalance and other metabolic problems. In the control group, children in a similar age group with no medical or family history of seizures or epilepsy, with normal neuromotor development and growth as well as a normal physical examination and without an abnormality in their complete blood count, glucose, aspartate transaminase, alanine transaminase, calcium, potassium, sodium, C-reactive protein, urea and creatinine levels were included. The inclusion criteria are listed below:

Recent febrile seizure

Children of 5 months to 5 years without any complaint who came for a routine check-up.

The exclusion criteria were as follows:

Younger than 5 months or older than 5 years,

Afebrile seizure,

Complex febrile seizure

Those receiving antiepileptic treatment,

Patients with neurological disorders such as cerebral palsy or mental retardation,

Presence of congenital heart disease or severe heart failure at the time of admission,

Presence of severe kidney disease (creatinine > 1mg/dl)

Presence of metabolic disease,

Presence of genetic disease,

Patients with acute or chronic inflammatory disease,

Presence of CNS infection,

Patients receiving zinc or iron supplements were excluded from the study.

Collection Of Blood Samples

All blood samples were collected in the morning between 08:00 am and 10:00 am following twelve-hour fasting. Hemoglobin, hematocrit, serum iron, iron binding capacity, ferritin and zinc levels were measured. All samples were kept in refrigerators at -80°C in Eppendorf tubes after the serums were separated by centrifuging at 4000g for 15 minutes until the day of the study. Zinc levels were studied using an Agilent 7700 mass spectrometer using ICP-MS (Inductively coupled plasma mass spectrometry) method. The manufacturer reported the CV values for the study and cross-study were lower than 5%. Serum iron and iron binding capacity test were studied using Roche Cobas c503 clinical chemistry analyzer using reactivators manufactured by Roche Diagnostics International AG Rotkreuz, Switzerland. FerroZine method was used for iron tests. CV values reported by the manufacturer for the study and cross-study was lower than 2%. Iron binding capacity testing was done using FerroZine direct appointment method using the same firm's kit. CV values reported by the manufacturer for the study and cross-study was lower than 2%. Ferritin measurement tests were performed on Roche Cobas e801 immunoassay analyzer using reactivators manufactured by Roche Diagnostics International AG Rotkreuz, Switzerland. CV values reported by the manufacturer for the study and cross-study was lower than 2%. Complete blood count and other biochemical parameters were studied at Health Sciences University Istanbul Bagcilar Research and Education Hospital’s biochemistry laboratories.

For the study, approval was received by Health Sciences University Bagcilar Research and Education Hospital’s Clinical Studies and Ethics Board on September 25th, 2020 with the number 2020.09.2.16.143.

Statistical Evaluation:

IBM SPSS Statistics 22 (IBM SPSS, Turkey) program was used for statistical analysis while evaluating the data for the study. Shapiro Wilks test was used for determining the appropriateness of study parameters to normal distribution. Student t-test was used along with identifying statistical methods (mean, standard deviation and frequency) for comparing parameters with normal distribution and Mann Whitney U test for those without normal distribution for both groups. Chi-Square test and Continuity (Yates) correction was used in comparing the quantitative data. Significance was determined as p < 0.05.

The study included 106 children between the ages of 5 months to 60 months of whom 61 (57.5%) were males and 45 (42.5%) females from August 2020 to May 2021. Average age of participants is 25.89 ± 16.38 months.

The study has two groups; the control group with 53 patients (50%) and study group with 53 patients (50%). Average age of the study group is 20.90 ± 10.86 months with 54.7% males and 45.3% females. Average fever is 38.31 ± 0.2 degrees Celsius (Table 1).

Table 1

Demographic data of children with febrile seizure
		Ave ± SD
Age (mont		20.9 ± 10.86
Fever (°C)		38.31 ± 0.2
		n (%)
Gender	Male	29 (54.7)
	Female	24 (45.3)
FS history	First time	44 (83)
	2 or more	9 (17)
Consanguineous marriage	Yes	4 (7.5)
	No	49 (92.5)
Family history of FS	Yes	8 (15.1)
	No	45 (84.9)
Family history of epilepsy	Yes	4 (7.5)
	No	49 (92.5)

Ratio of first time FS was 83% whereas those with 2 or more FS was 17%. Consanguineous marriage was seen in 7.5% of patients and 92.5% had no such history. 15.1% of patients had family history of FS and 84.9% did not have a family member with history of FS. 7.5% of patients had a family member with history of epilepsy and 92.5% did not have such history. (Table 1).

71.1% of children were diagnosed with acute upper respiratory system infection, 17% had acute gastroenteritis, 9.4% had acute lower respiratory tract infection and 1.9% had urinary tract infection (Table 2).

Table 2

Distribution of cause of fever in patients with febrile seizure (patient group)
Infection present at the time of FS	n (%)
Acute Upper Respiratory Tract Infection	38 (71.7)
Acute Gastroenteritis	9 (17)
Acute Lower Respiratory Tract Infection	5 (9.4)
Urinary Infection	1 (1.9)

Average serum iron level of the study group was 44.53 ± 30.51 µg/dL, average iron binding capacity was 312.51 ± 68,15, average serum ferritin level was 29,28 ± 19,35 ng/mL, average serum zinc level was 1,03 ± 0,29 µg/mL, average hemoglobin level was 11,72 ± 1,33 µg/dL and average hematocrit level was %35,38 ± 3,37 (Table 3.1)

Table 3.1

Information on parameters of all groups
	Ort ± SS
Iron(µg/dL)	44.53 ± 30.51
Iron Binding Capacity(µg/dL)	312.51 ± 68.15
Ferritin (ng/mL)	29.28 ± 19.35
Zinc (µg/mL)	1.03 ± 0.29
Hemoglobin (g/dL)	11.72 ± 1.33
Hematocrit (%)	35.38 ± 3.37

Serum iron level of the study group was found to be statistically meaningfully lower

compared to the control group (p:0.000; p < 0.05).

Serum zinc level of the study group was found to be statistically meaningfully lower compared to the control group (p:0.000; p < 0.05).

There are no statistically meaningful differences between both groups in iron binding capacity, ferritin, hemoglobin and hematocrit levels (p > 0.05) (Table 3.2)

Table 3.2

Evaluation of study parameters amongst groups
	Control Group	Patient Group	p
	Ave ± SD	Ave ± SD	p
Iron (µg/dL)	62.62 ± 28.77	26.45 ± 19.64	¹0.000*
Iron binding capacity (µg/dL)	302.68 ± 65.32	322.33 ± 70.12	²0.138
Ferritin (ng/mL)	26.54 ± 17.11	32.02 ± 21.16	¹0,200
Zinc (µg/mL)	1.13 ± 0.34	0.93 ± 0.2	¹0,000*
Hemoglobin (g/dL)	11.87 ± 1.28	11.57 ± 1.37	¹0,376
Hematocrit (%)	35.79 ± 3.09	34.98 ± 3.62	¹0,448
¹Mann Whitney U Test ²Student t Test *p < 0.05

Serum iron level lower than 22 µg/dL was seen in 1.9% of patients in the control group and was statistically meaningfully lower than the study group (49.1%) (p:0.000; p < 0.05). There is no statistically meaningful difference between both groups for ferritin levels being lower than 30ng/mL (p > 0.05). There is no statistically meaningful difference between both groups in hemoglobin values of 10.5 g/dL for children 6–24 months and 11.5 g/dL for children 1–5 years (p > 0.05) (Table 4).

Table 4

Evaluation of major index ratios for iron status between groups
		Control group	Patient group	Total	p
		n(%)	n(%)	n(%)	p
Those with iron levels < 22 µg/dL	Yes	1 (%1.9)	26 (%49.1)	27 (%25.5)	¹0.000*
	No	52 (%98.1)	27 (%50.9)	79 (%74.5)
Those with Ferritin < 30 ng/mL	Yes	30 (%56.6)	27 (%50.9)	57 (%53.8)	²0.559
	No	23 (%43.4)	26 (%49.1)	49 (%46.2)
Hb < 10,5 g/dL for 6–24 months < 11,5 g/dL for 2–5 years	Yes	14 (%26.4)	11 (%20,8)	25 (%23,6)	¹0.647
	No	39 (%73.6)	42 (%79.2)	81 (%76.4)
¹Continuity (Yates) Correction ²Chi-Square Test *p < 0.05

Serum Zinc levels of patients who had FS for the first time was statistically meaningfully higher than those who had FS two or more times (p: 0.040). Hemoglobin levels of patients who had FS for the first time was statistically meaningfully higher than those who had FS two or more times (p: 0.027). Hematocrit levels of patients who had FS for the first time was statistically meaningfully higher than those who had FS two or more times (p:0.042) (Table 5).

Table 5

Evaluation of study parameters based on the recurrence of FS between patient groups
	İlk kez	2 ve üzeri	p
	Ort ± SS	Ort ± SS	p
Iron (µg/dL)	26.88 ± 19.73	24.36 ± 20.21	¹0.302
Iron binding capacity (µg/dL)	328.05 ± 71.96	294.4 ± 55.39	²0.138
Ferritin (ng/mL)	32.37 ± 20.67	30.31 ± 24.71	¹0.554
Zinc (µg/mL)	0.95 ± 0.21	0.84 ± 0.11	¹0.040*
Hemoglobin (g/dL)	11.71 ± 1.4	10.89 ± 1.04	¹0.027*
Hematocrit (%)	35.34 ± 3.67	33.2 ± 2.96	¹0.042*
¹Mann Whitney U Test ²Student t Test *p < 0.05

When comparing those who had FS for the first time and those who had FS two or more times, there is no statistically meaningful difference in serum iron, iron binding capacity and ferritin levels (p > 0.05) (Table 5).

Febrile seizure is the most commonly seen type of convulsion in the pediatric population (4–5%) [1]. American Academy of Pediatrics defined FS in 2011. According to the definition; FS is a type of seizure happening during an inflammatory disease; seen in children between the ages of 6 months to 5 years with no history of epilepsy, without an electrolyte disorder, a metabolic disorder, trauma or intoxication and no symptom of a central nervous system infection" [2]. 2–5% of children younger than 5 years are diagnosed with FS. [3].

Recent studies show that FS prevalence shows difference among communities, 2.3% in US, 1% in China, 3.4–9.3% in Japan, 5–10% in India and 14% in Pacific Island of Guam [12, 13]. Canpolat et al. reported the ratio to be 4.3% in Turkish population [14]. It is thought that this changing ratio of prevalence is due to differences in genetic background, exposure to different infectious agents, cultural differences and differences in socioeconomic backgrounds [15, 16].

Prevalence of FS is higher in male children compared to females with a ratio of 1.4/1 [4]. A study by Okumura et al reports this ratio as 1.3/1 whereas a study by Knudsen et al reports it as 1.4/1 [17, 18]. In our country, FS is seen more commonly in male children compared to females [19]. Findings of our study is similar to those of literature, with male-to-female ratio of 1.21/1.

Febrile seizures are commonly seen between the ages of 6 months to 5 years, most common being 6 months to 3 years with a peak at 18 months [20]. The study by Okumura et al, report the age of first time FS as 7–69 months with an average of 25 months [17]. Another study by Jang H. et al report the age interval of first time FS as 6–60 months with an average of 27.1 months [21]. A study by Ling reports the age interval for first time FS as 7–60 months with an average of 19.6 months. FS being seen in the first two years of life is 58.9%. Our findings are in coherence with current literature.

Okamura et al. reported the average body temperature of patients who had febrile seizures as 39.4°C [17], whereas Knudsen's study reported as 39.5°C [23] and Jang H et al. reported as 39.5°C [21]. In our study, the average body temperature of patients at the time of arrival ranged between 38°C and 38.8°C with an average of 38.3°C.

It is known that genetic factors play an important role in developing FS. Family history is one of the main risk factors in FS. 25–40% of patients with FS have positive family history. A study by Shinnar et al. states that seizure incidence of parents of patients with febrile seizure is 17% and seizure incidence of siblings is 19.9–24.4% [25]. The study by Wallace et al shows that FS history of first degree relatives is 17% [35[, a study by Offringa and Moyer state family history of FS as 24% [26], a study by Kölfen reports as 16.3% [27] and study by Ling reports as 26.6% [22]. A study by Ozaydin et al. shows that 34% of patients out of 471, had positive first degree family history of FS (mother, father and/or siblings) [28], a study by Kilic shows 51% of 345 patients had positive family history [29] and a study by Yilmaz et al. show 20.8% of 269 patients had positive family history of FS [30]. Our study had a similar finding to current literature with 15.1% of patients having positive family history of FS.

Family history of epilepsy is more common in children with history of FS compared to normal population. According to a study by Ozaydın et al., 9.2% of 1385 patients with FS had a first degree relative with epilepsy [28]. A study by Abuekteis et al showed 3% [31], a study by Yılmaz et al. showed 22.5% [30], a study by Kölfen showed 7.5% [27] and a study by Pavlidou showed 10.3% positivity for a family member having history of epilepsy. Our study showed that 7.5% of cases had family history of epilepsy, which is in coherence with literature.

In febrile seizures, convulsions are mostly seen during the first few days of the inflammatory disease caused by an infection. The most common triggers are viral infections. The most common cause of fever is reported to be upper respiratory system infections, however lower respiratory tract infections, urinary system infections, intestinal infections and viral exanthematous infections can also cause fever [33]. Fever may also appear without an infectious cause [34]. A study by Fukuyama et al. showed that 54% of patients with FS had upper respiratory tract infection as a cause of fever [35] while Millichap et al.'s study showed 78.6% [36] and Abuekteis et al. stated 53% [31] of patients had upper respiratory tract infection at the time of FS. A study conducted in South Korea stated that 61.9% of the case group had upper respiratory tract infection and 43.1% of the control group had pneumonia [21] and a study by Sumengen et al. showed that 66% of their patients had upper respiratory tract infection as a source of fever [37]. In our study, 71.7% had upper respiratory tract infection, 17% had acute gastroenteritis, 9.4% had lower respiratory tract infection and 1.9% had urinary tract infection as the cause of fever.

Aside from genetic factors, iron deficiency, deficiency of trace elements (zinc, selenium, copper, etc.), infections, cytokines, changes in amino acid levels, diseases of central thermoregulation and delay in CNS maturation are listed under FS etiology [38, 39]. Low serum selenium and zinc levels as well iron deficiency is found to be more common in children with FS [40, 41]. Recent studies show that iron deficiency anemia is more common in children with FS compared to general pediatric population. It is reported that seizure threshold lowers with iron deficiency since it plays a part in functioning of neurotransmitters like monoamine and aldehyde oxidase [42, 43].

In literature, it is seen that iron deficiency is very common in children with history of FS. A study by Hartfield et al. shows that iron deficiency is twice more common in children with FS history [44]. In another study children with FS was compared to control group, 30% of patients in FS group, 12% of healthy control group and 14% of patients with fever who are in control group ad iron deficiency anemia, resulting the understanding of iron deficiency being a facilitator in seizures [45]. In a study comparing patients with FS and patients with fever and no seizures, serum ferritin levels in FS group was found to be statistically meaningfully lower [46]. A study by Yigit et al. showed no statistically meaningful difference in serum ferritin levels and iron binding capacity when comparing patients with history of FS and healthy children. Also, it is reported that children with both simple febrile seizure and complex seizure had statistically meaningfully lower serum iron levels compared to healthy control group [47]. A study in Canada showed that the probability of children with febrile seizure having iron deficiency is twice more common compared to those with a febrile illness, however there is no significant difference between groups regarding the rate of anemia [44]. A study conducted by Nalbantoglu in 2019 showed a significant difference in serum iron and ferritin levels between children with history of FS and healthy population [48]. Our study found that iron levels of those in the FS group was statistically meaningfully lower compared to the control group. This is in coherence with current literature. Ferritin levels are found to be higher in the study group, however it is not statistically significant. We believe that, even though the blood samples were collected one month after the occurrence of febrile seizure, ferritin levels were higher in the study group due to the fact that ferritin is an acute phase reactant.

A study conducted in Iran in 2014 by Fallah et al. showed that when compared to healthy control group, hemoglobin levels of children with FS are statistically meaningfully lower [49]. Choudhury et al. compared hemoglobin levels of children with FS and children with fever but no history of FS and found that children with FS had statistically significantly low hemoglobin levels [46]. On the other hand, Daoud et al. reported research on hemoglobin levels of children who had FS for the first time versus children with fever and no history of seizures and found that even though the hemoglobin levels were lower in the FS group; the difference was not statistically meaningful [42]. Ozaydın et al. compared hemoglobin, hematocrit and MCV levels of children with complex febrile seizure (CFS) and simple febrile seizure (SFS) and reported that children with CFS had statistically meaningfully lower levels on all parameters [50]. A study by Aziz et al. found that children with SFS had statistically meaningfully lower levels of hemoglobin and hematocrit levels compared to children with fever but no seizures. In this study, hemoglobin and hematocrit levels of children with CFS were statistically meaningfully lower compared to both healthy control group and children with SFS [51]. In our study, the hemoglobin and hematocrit levels of FS group was lower compared to the control group, however the difference was not statistically meaningful.

A study reported in South Korea that low ferritin levels (< 30ng/mL) without the presence of iron deficiency anemia or iron deficiency defined as low serum iron level (< 22µg/dL) is related to an increased risk of febrile seizure [21]. In our study, in coherence with current literature, we defined iron deficiency as iron levels lower than 22µg/dL, ferritin levels lower than 30ng/mL and hemoglobin levels lower than 10.5g/dL for 6–24 months and 11.5g/dl for 2–5 years old. Low iron levels without presence of anemia was statistically meaningfully lower in FS group compared to control group. Ferritin levels were also low in the FS group; however, the difference was not statistically significant. Variations in the relationship between febrile seizures and anemia/iron deficiency can be attributed to ethnicity, socio-economic status, the number of people participating in the study, and the differences in concomitant nutritional status, as well as the definitions of anemia and iron deficiency status used in different studies.

Amiri et al.’s study compared zinc levels of 30 patients with FS and 30 patients with fever but no seizures. Serum zinc levels of FS group was statistically meaningfully lower compared to control group [52]. A study in Iran, compared serum zinc levels of 50 patients with FS and 50 patients with fever but no seizures. They reported that serum zinc levels of FS group was statistically meaningfully lower compared to control group [54]. A study by Ehsanipour et al. reported statistically significant low serum zinc levels in FS group compared to control group [55]. Similarly, a study by Ganesh et al. found that serum zinc levels were significantly low in patients with febrile seizures when compared to control group and reported that zinc deficiency may be a risk factor for febrile seizures and by proper zinc supplementation, incidence of FS may decrease [56]. In our study, serum zinc levels of FS group was statistically meaningfully lower compared to control group. Reference values for serum zinc level was 0.6-1.2ug/ml for 0–28 days old and 0.7-1.3ug/ml for patients older than 28 days. Based on our findings, it is possible to say that zinc deficiency plays a role in developing febrile seizures. However, to clarify the role of zinc levels in pathophysiology of febrile seizures, more comprehensive studies are required. We believe that serum and cerebrospinal fluid zinc levels must be studied comparatively to obtain more accurate findings.

Following repetitive febrile seizures, specific cell organelles (mitochondria and endoplasmic reticulum) go through certain changes and these changes result in brain damage. Increase in lipid peroxidation and changes in anti-oxidative enzyme levels trigger neuronal damage during febrile seizures. As a result, as the number of repetitive febrile seizures increase, the balance of oxidants and antioxidants further deteriorates in children, and the risk of recurrence increases significantly [57]. In addition, in a study, the serum iron level was found to be statistically significantly lower in the group with recurrent FS compared to the control group and it was emphasized that the cases with FS should be examined for iron deficiency anemia [58]. Based on these findings, we concluded that deficiencies of iron and zinc levels play an important role in developing recurrent FS since they have significance in functioning of antioxidant enzymes. In order to investigate this, we compared serum iron, iron binding capacity, ferritin, hemoglobin, hematocrit and zinc levels of patients who had FS for the first time and those with recurrent FS. Based on the data gathered, we found that both groups had lower than normal iron and ferritin levels, however the difference was not significant. Average hemoglobin and hematocrit levels of either group was anemic. Nonetheless, the hemoglobin and hematocrit levels of the group with recurrent FS was statistically meaningfully lower than first time FS patients group. Even though there is no linkage found in literature about serum zinc levels and recurrence of FS [29, 59], in our study, serum zinc levels of recurrent FS group was statistically significantly lower compared to first time FS patient group. Average serum zinc level was below normal for both groups. In addition, further deterioration in serum zinc levels trigger FS recurrence.

Limitations of the Study;

Based on current literature, it is expected that ferritin levels should be lower in FS group, whereas in our study, we found ferritin to be higher in FS group. We believe that ferritin being an acute phase reactant causes this difference. Main purpose of calling back of patients within the following month, was to eliminate the effects of infections on ferritin levels, however, continuation of the previous infection or developing a new infection may have contributed to high ferritin levels. Therefore, we were unable to determine the relationship between ferritin levels and FS.

Our study was conducted in a limited time frame with low number of patients. This

situation affects the level of significance of obtained data. Especially due to limited time, whether a recurrence occurred in a first-time FS patient was not followed up. As a result, FS recurrence was explained based on comparing first-time FS patient and those with history of 2 or more seizures. However, in literature it is stated that in order for FS recurrence rates to be better understood, FS patients should be followed up for at least 1 year and study parameters should be investigated separately for each seizure. We believe that our study contributes to future prospective studies with wider series.

Based on the findings of our study, we believe that low serum iron and serum zinc levels may facilitate febrile seizures and these parameters being lower than a certain threshold may trigger FS. Determination of these thresholds may play a role in prevention of seizures in patients with FS risk and FS risk factors may change drastically. Early diagnosis and treatment of iron deficiency, without waiting for hemoglobin to drop, may become a significant prevention method. Anxiety of families will decrease and by close monitoring of children, unnecessary prophylactic treatments may be averted. We believe that a wide randomized prospective and multi-centered study is needed in order to determine the threshold values of FS triggering parameters.

As the number of risk factors increase so does FS recurrence. Serum iron, zinc, ferritin, etc. levels of children (especially those with family history) should be monitored closely and be kept within the normal range. Over-prescription of anti-seizure medication can be averted by doing so.

Families should be informed about FS and its risk factors in order to prevent anxiety of families and usage of prophylactic drugs which are mostly prescribed due to family pressure.

Ethical approval The study was approved by the Institutional Ethics Committee of the hospital on September 9, 2020. (Registration Number: 2020.09.2.16.143). The study was conducted in accordance with the ethical principles of the Declaration of Helsinki.

Funding

The current work receives no funds, grants, or other support.

Acknowledgments

We are grateful to all participating children and their parents for their cooperation and willingness, as well as health physicians for their great help.

Conflict of interest

The authors have no conflicts of interest to declare that are relevant to the content of this article

Author contribution

OB, AO and OBG analyzed the data and drafted the manuscript. OBG and ME critically reviewed the analyses. OB, OBG, ME, SMI, OB and AO reviewed and commented on initial and final drafts of the manuscript. All authors have participated in drafting of the manuscript and/or critical revision of the manuscript for important intellectual content. All authors read and approved the final manuscript.

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No competing interests reported.

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The Relation Between Febrile Seizure and Serum Iron and Zinc Levels in Children

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