European Journal of Cardiovascular Medicine

Febrile seizure is one of the most common convulsive events in children younger than 5 years of age. It occurs in 2-5% of all the children worldwide. Peak incidence is around 18 months of age. It is defined as seizures occurring in infants and children with fever between 6-60 months of age without any evidence of CNS infection or other identified causes (Kwak et al, 2017; Mikati and Hani, 2016)1,2. In pediatric practice febrile seizure is a major challenge due to high prevalence in under 5 years age children and its recurrent nature.

Febrile seizures is a benign condition with an excellent prognosis, but this might be a frightening and stressful experience for parents. The awareness about complications of febrile seizure is increased in recent times (Leung et al, 2018)3.

There are many postulations put forward to explain the mechanism of febrile seizures (Sangeetha Yogana, 2018)4. Few among them are genetic susceptibility, rise in temperature, nutritional deficiency. Among this above-mentioned multifactorial etiology of febrile seizures, nutrition deficiency also plays an important role.

The National Family Health Survey-4 (NFHS-4)5 data suggests that nutritional anemia is widely prevalent among all age groups and around 58.6% per cent children under 5 years of age are anemic and according to the data in NFHS-5 shows that among all age groups, the highest prevalence of anemia was reported among children aged 6-59 months- 67% which reveal increase in prevalence. So, this age group of Iron deficiency anemia of under 5 years coincides with the common age group of children presenting with Febrile seizures.

Febrile seizures and iron deficiency anemia are two common conditions occurring in children between 6 months and 60 months (Kwak et al, 2017)6. Iron is an important micronutrient that plays a major role in many metabolic processes in our body. Anaemia is not the only consequence of Iron deficiency; its deficiency can virtually affect every organ system including the central nervous system. Several morphological and biochemical changes at the tissue level have been shown to be the result of iron deficiency. Iron deficiency anemia leads to functional impairment at various tissues such as the myocardium, peripheral cortex, liver, jejunum, and kidney (Shah et al, 2012)7. Cognitive dysfunction, psychomotor retardation, behavioral impairment, Pica, breath holding spells, restless leg syndrome are conditions that are associated with iron deficiency anemia (Sharma and Sharma, 2018). Iron deficiency anemia (IDA) leads to long term impairment of mental and psychological development in children (Shah et al, 2012)7. It is a well-known fact that iron deficiency is associated with various neurological manifestations such as irritability, poor attention span, learning difficulties and delayed developmental milestones. Iron is known to act as coenzyme in various pathways and various neurotransmitters. The effect of iron deficiency anemia on the young developing brain and also mechanisms such as altered development of hippocampus neurons, slowed visual and auditory evoked potentials, alteration in synaptic neurotransmitter systems like norepinephrine, dopamine, glutamate, delayed maturation of myelin are hypothesized to be responsible for the various symptoms stated above (Krishnan et al, 2018). IDA has been proposed as a risk factor for febrile seizures but no other types of seizures. (Krishnan et al, 2018)8. Iron deficiency reduces the metabolism of some neurotransmitters such as monoamine and aldehyde oxidase and this alters the seizure threshold of a child (Sharma and Sharma, 2018)9.

Due to these conflicting results between studies on iron deficiency with occurrence of febrile seizures and less availability of local regional studies prompted us to do this study. Here, in this study we will be observing the association of Iron deficiency status in children presenting with febrile seizures to the Department of Pediatrics, Gayathri Vidya Parishad Institute of Health care and Medical Technology, Visakhapatnam, AP, India

AIM AND OBJECTIVES

• To study the Iron Status in children with febrile seizures.
• To study the Association of Iron status with Febrile seizures
• To find out the relation between severity of Iron deficiency anemia with febrile seizures

STUDY DESIGN

Observation study

STUDY CENTRE

This study was conducted in the Department of Pediatrics, Gayathri Vidya Parishad Institute of Health care and Medical Technology, Visakhapatnam, AP, India.

STUDY PERIOD

Study was conducted over a period of 18 months from July 2023 to December 2024

STUDY GROUP

Children in the age group between 6 months to 5 years of either gender presenting with febrile seizures & febrile illness without seizures, brought to Gayathri Vidya Parishad Institute of Health care and Medical Technology, Visakhapatnam, AP, India and treated on OPD or IPD basis.

Cases: Children presenting with febrile seizures meeting inclusion criteria. Febrile seizures are characterized by convulsions occurring in relation to febrile illness, in the absence of infections of CNS (or) any other defined causes of seizures in a neurologically normal child between the age group of 6 months – 5 years.

Controls: Children matched by age with febrile illness of any etiology without convulsions and meeting the inclusion criteria

Sample size was 75 children between the age group of 6 months to 5 years in each group presenting with febrile seizures and febrile illness without seizure.

INCLUSION CRITERIA

1. Children in the age group of 6 months to 5 years.

2. Cases consist of children presenting with both simple and complex febrile seizures.

3. Children presenting with both 1st episode as well as recurrent episode of febrile seizure will be included as cases.

4. Control group consists of children matched by age, presenting with febrile illness of any aetiology without seizures. Febrile illness is defined as a rectal temperature 38.0ºC or 100.4ºF, axillary temperature is 0.3-0.6ºC lower than the rectal temperature (26).

EXCLUSION CRITERIA

1. Children of age group < 6 months and > 5 years

2. Children presenting with afebrile seizure.

3. Seizures due to metabolic derangement.

4. Known case of epilepsy.

5. Those having any clinical signs of central nervous system infection. (meningoencephalitis)

6. Those children with neurodevelopmental problem (cerebral palsy, hemiplegia, neurodegenerative disorder).

Methodology

This observation case-control study was conducted on children of age group 6 months to 5 years with febrile seizures & febrile illness without seizures presenting to Gayatri Vidhya Parishad Institute of Health care and Medical Technology, Visakhapatnam, AP, India, on Depending upon the general condition, child was given initial treatment and after stabilization, Parents/Legal guardians were asked for permission of their children to participate in the study. After written & informed consent, detailed history was taken, and physical examination was done, then blood sample was collected from the patients for evaluating Iron status and other necessary laboratory tests. All this information was noted in pre-structured proforma sheet. From the blood sample collected, Hemoglobin was analyzed by Hb- cyanide free SLS method, Serum Iron was analyzed by Iron-TPTZ method, TIBC-Nitroso- PSAP method. Pre structured proforma was used to record the details.

Iron deficiency status10 was considered as Serum Iron<50 ug/dl, Serum Ferritin < 12 ug/l, TIBC >400 ug/dl, Haemoglobin < 11 gm/dl And anemia was graded based on WHO classification intomild anaemia-10-10.9 gm/dl, moderate-9.9—7, severe <7 gm/dl

Statistical analysis

The results are presented in frequencies and percentages. The Chi-square test was used to assess the associations. The p-value<0.05 was considered significant. All the analysis was carried out on SPSS 16.0 version (Chicago, Inc., USA).

The present study was conducted in the Department of Paediatrics, Gayathri Vidya Parishad Institute of Health care and Medical Technology, Visakhapatnam, AP, India with the objective to study iron status in children presenting with febrile seizures of age group 6 months to 5 years. A total of 75 cases and 75 controls were included in the study.

Table-1: Distribution of age between cases and controls

Table-2: Distribution of gender between cases and controls

Table-3: Comparison of weight between cases and controls

Table-4: Comparison of head circumference between cases and controls

Table-5: Comparison of seizure between cases and controls

Table-6: Distribution of type of seizure among cases

Table-7: Distribution of no. of episodes of seizure among cases

Table-8: Comparison of cause of fever between cases and controls

Table-9: Comparison of temperature between cases and controls

Table-10: Comparison of family history between cases and controls

Table-11: Comparison of developmental history between cases and controls

Table-12: Comparison of Socio-Economic status between cases and controls

Table-13: Comparison of pallor between cases and controls

Table-14: Comparison of Hb between cases and controls

Table-15: Comparison of Ferritin between cases and controls

Table-16: Comparison of serum iron between cases and controls

Table-17: Comparison of TIBC between cases and controls

Febrile seizures are the most common cause of seizures in children, occurring in 2-5% of children (Johnston, 2007)11. A simple febrile seizure is generalized, tonic clonic which usually occurs within 24 hours of onset of fever, and it is usually a single episode which lasts for few seconds but may rarely extend up to 15 minutes and is followed by a brief period of post-ictal drowsiness (Mohamad and Mikati, 2013)12.

It occurs between 6 months to 5 years of age without any evidence of neuroinfection, with a peak incidence of febrile seizure around the age of 18 months. Risk of recurrence in febrile convulsions is 30-40% and half of these go on to get a second recurrence (Vestergaard et al, 2002)13.

Iron deficiency anaemia is very common among children of less than 4 years which overlaps with the high incidence of simple febrile seizure in age groups of 14 to 18 months in developing countries with an iron deficiency prevalence of 46 to 66% of children (Sudhagandhi et al, 2011)14.

The present study was conducted in the Department of Paediatrics  Gayathri Vidya Parishad Institute of Health care and Medical Technology, Visakhapatnam, AP, India gy, with the objective to study iron status in children presenting with febrile seizures of age group 6 months to 5 years. A total of 75 cases and 75 controls wereincluded in the study.

In the current study, mean age of onset of febrile seizure is 27 months. More than one third of both cases (45.3%) and controls (46.7%) were between 24-60 months of age. There was no significant (p>0.05) difference in age between cases and controls showing comparability of the groups in terms of age. This study found that more than half of both cases (68%) and controls (57.3%) were males. There was no significant (p>0.05) difference in gender between cases and controls showing comparability of the groups in terms of gender. In the study by Khan et al (2021)15, in the Group-1 (cases), mean age was 24.22+1.35 months whereas in Group-2 (controls), mean age was 23.91+1.22months (p=0.1078). In the study by Saddique et al (2021)16, out of 310 cases, 34.84 %(n=108) were between 6-30 months of age while 65.16%(n=202) were between 31-60 months of age, mean+SD was calculated as 36.14+12.99 month, 42.90% (n=133) were male and 57.1%(n=177) were females. Gopchade et al (2021)17 revealed that out of 50 studied cases 36 (72.00%) were males and 14 (28.00%) were females with a M: F ratio of 1:0.38. The mean age of patients was found to be 18.18 +/- 11.32 months.

In the present study, simple febrile seizure was among majority of cases (88%) and complex febrile seizure was in 12% cases. This study observed that first episode was among majority of cases (80%). Second and third episode was in 16% and 4% cases respectively. These results were like study by Gopchade et al (2021)17 found that majority of the cases (74%) were having first onset of febrile seizures. Second and third episode of febrile seizures was seen in 8 (16%) and 5 (10%) cases respectively. 42 (84%) patients were found to have simple febrile seizures whereas remaining 8 (16%) patients had complex febrile seizures. Rao and Kumar et al (2020)18 showed that out of 50 cases of the first episode of simple febrile seizures, 78% (39) cases of seizures lasted for < 5 mins and 22% (11) cases of seizures lasted for 5-10 mins.

In this study, LRTI was the most common cause of fever among cases (28%) and AFI was the most common cause of fever among controls (22.7%). Acute gastroenteritiswas the second most common cause of fever among cases (26.7%) and LRTI was the second most common cause of fever among controls (21.3%). Interestingly, among controls, cause of fever in (6.7%) controls were covid-19 and was zero in cases. Rao and Kumar (2020)18 showed that out of 50 cases and 50 controls, 41(82%) cases and 42(84%) controls had upper respiratory tract infections, 9(18%) cases and 8(16%) controls have acute gastroenteritis. This study revealed that temperature was between 100-1010F among 57.3% of cases and 49.3% of controls. However, temperature was <1000F in 24% of cases and in 29.3% of controls. There was no significant (p>0.05) difference in temperature at admission between cases and controls. In contrast to our study, Elkafafy et al (2021)19 found that the peak temperature was significantly elevated among the case group (P=0.03).

This study showed that family history was present among 33.3% of cases and in 12% of controls. There was significant (p=0.002) difference in family history between cases and controls. Like this study, Madavi et al (2021)20 found that compared to controls, significantly higher number of cases had a family history of FS and family history of seizure disorder (both p-values<0.05). This study was conducted in urban tertiary corporate hospital. This study showed that Socio-Economic Status was between 26-29 among majority of both cases (85.3%) and controls (89.3%). There was no significant (p>0.05). In the study by Rao and Kumar et al (2020)18, out of 50 cases, 100% (50) were of lower SES. Among 50 controls 96% (48) of controls were of lower Socio-Economic Status and 4% (2) of controls were of middle Socio-Economic Status. Krishnan et al (2018)8 found that majority of the patients in the FFC group were from lower-middle class (63.64%) and SFC group were from upper-lower class (54.55%) and a majority of controls were from upper- lower class (72.73%). However, in contrast to the present study, statistical significance was noted in the study by Krishnan et al (2018)8 between FFC and socioeconomic status with the majority belonging to lower-middle class (p=0.010).

In this study, pallor was present among 56% of cases and in 37.3% of controls. There was significant (p=0.02) difference in pallor between cases and controls.

In the present study, compared to controls, 26.7% of cases had severe anaemia. There was significant (p=0.0001) difference in Hb between cases and controls. Madavi et al (2021)20 found that as compared to controls, cases had significantly lower median hemoglobin levels (all p-values<0.05). In the study by Khan et al (2021)15, in Group-1 (cases), the mean hemoglobin (Hb) level was significantly low in comparison to Group-2 (controls) (p<0.00001). A total of 53 (29.44%) children had iron deficiency anemia (IDA). In Group-1 (cases), IDA was observed in 36 (40.0%) patients while it was seen in 17 (18.89%) children in Group-2 (controls) (p=0.0019). Saddique et al (2021)16 showed that the frequency of iron deficiency anemia in children presenting with febrile seizures in services hospital, Lahore was found out to be 14.84 %( n=46). They concluded that frequency of iron deficiency anemia was 15% in children with febrile seizures. In the study by Khatri et al (2020)21, the mean value of Hb (gm/dl) in febrile seizure group was 9.02 (SD±1.50) and in control group it was 10.57 (SD±1.40) (p<0.01).

Kumari et al (2021)22 showed that the risk of simple febrile seizure was 1.86 times more among the patients with level of hemoglobin < 11 gm/dl as compared with the patients with level of hemoglobin≥11 gm/dl [OR-1.76(1.01, 3.08); p= 0.04] and the risk was significant.

This study found that Ferritin was <12 among 54.7% of cases and in 18.7% of controls. There was significant (p=0.00001) difference in ferritin between cases and controls. In this study, Serum iron was <50 among 61.3% of cases and in 32 % of controls. There was significant (p=0.0001) difference in serum iron between cases and controls. In this study, TIBC was >400 among 61.3 % of cases and in 41.3% of controls. There was significant (p=0.01) difference in TIBC between cases and controls. Madavi et al (2021)20 observed that cases had significantly higher median red cell distribution width (p-value = 0.004). Similarly, cases had a significantly lower mean SI levels, and SI/TIBC index, as compared to controls (both p-values<0.05). However, cases had significantly higher mean TIBC (p-values<0.05). As compared to the controls, cases withIDA had 8.4 fold increased risk of developing the FS. Khan et al (2021)15 observed that in Group-1 (cases), the mean MCV level and serum ferritin level were significantly low in comparison to Group-2 (controls) (p<0.00001). Gopchade (2021)17 found that 36 (72%) patients were found to have iron deficiency anemia defined as serum ferritin level below 12 microgram/lit. Kumari et al (2021)22 found that iron deficiency anemia (IDA) was more frequently seen among children with FS than those with febrile illness alone. They concluded that iron deficiency and iron deficiency anemia were more common among children with simple febrile seizures, and they were associated with increase in the duration and frequency of seizures. Rao and Kumar (2020)18 found that the mean level of TIBC in cases was 434.86±125.18 and the mean level of TIBC in controls was 354.14±103.10.

Bharat Kumar et al (2019)23 showed a significant association between anaemia and febrile seizures (p<0.02), a significant association between Hyponatremia and febrile seizures (p< 0.001). Prevalence of anaemia was 50% whereas hyponatremia was 35.8%; as a risk factor for febrile seizure. Serum iron < 22 ng/dL (odds ratio 3.42, 95% confidence interval [CI] 1.31–8.9, P = 0.012) and ferritin < 30 ng/mL (odds ratio 6.18, 95% CI 2.32–16.42, P< 0.001) were associated with increased risk of developing febrile seizures in multivariate logistic regression analysis.

Similar to many previous studies, our study conducted in a tertiary care hospital in Gayathri Vidya Parishad Institute of Health care and Medical Technology, Visakhapatnam, AP, India also demonstrated the association of iron deficiency with febrile seizures. Thus considering the role of Iron deficiency as risk factor for febrile seizure, supplementation can be considered as a preventive approach to FS, which is a cost- effective strategy, particularly in developing countries like India.

From our current hospital based observational study we have found that Hemoglobin, Ferritin, Serum iron levels, TIBC are significantly lower in children with febrile seizures suggesting that low iron status may be a risk factor for development of febrile seizures. So, screening for Iron deficiency should be considered in all children presented with first episode of febrile seizure. Early detection and iron supplementation in these children might prevent simple febrile seizures.

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