Febrile Convulsions in Anemic Children: A Review

Febrile convulsions are the most common type of convulsions that affect children aged 6 months to 5 years old. Iron deficiency anemia could be a risk factor for febrile convulsions as was suggested by some studies, for the reason that febrile convulsions is common in children under 5 years and iron deficiency anemia is also more common in children in the same age bracket. The prevalence of febrile convulsions is 2-5% of the total number of children. Studies discussing the association of iron deficiency anemia and febrile convulsions are contradictory. Management of cases is of great importance as there are special guidelines. Prevention is also vital as it plays a role in evading the occurrence of the convulsions.


INTRODUCTION
Children aged from 6 months to 60 months are highly susceptible to getting febrile illnesses. The peak age of febrile convulsions incidence is thought to be 14-18 months. Febrile convulsion is the most common illness in the nervous system that affect children and 2-5% of the total number of children or 4.8 out of every 1000 children become affected annually [1].

Review Article
Febrile illnesses are any disease that cause fever with rising body temperature to 38°C or more for 2-7 days with no localizing source, infection of central nervous system, metabolic disorders, or history of febrile convulsions; this definition is credited to the American Academy of Pediatrics [2][3][4][5][6][7]. Febrile convulsions occur because the brain cannot endure the rise of body temperature. Febrile convulsions are mostly benign and rarely cause brain damage, while they may lead to emotional, physical, and mental damage [8]. Many studies have tried to conduct febrile convulsions risk factors, possibility to recur (30% and 50% after the first and the second events of convulsions, respectively), socio-economic effects on families and society, susceptibility to develop epilepsy in the future in 2-4% of cases, and its relation to increased risk of hospitalization [8,9]. Some of the risk factors aggravating febrile convulsions, are previous family history of convulsions or febrile convulsions, mothers who smoke or take alcohol, viral infections, certain vaccinations, developmental delay, discharging from a neonatal unit after 28 days, nutritional deficiencies (including iron and zinc), high fevers, and head traumas [10][11][12][13][14][15][16][17][18][19]. Iron deficiency anemia could be a risk factor for febrile convulsions as was suggested by some studies, for the reason that febrile convulsions is common in children under 2 years and iron deficiency anemia is also more common in children in the same age. Simple febrile convulsions typically have a good prognosis, with no indication for increased rates of mortality, hemiplegia, or cognitive disorders [20]. Febrile convulsions are mostly benign; nevertheless, families still feel stressed about the condition of their child.
Iron deficiency anemia (IDA) is the most common and typical type of micro-nutritional deficiency in the world. It is characterized by deficiency of iron from the body, thus decreasing the production of hemoglobin. Iron is present in the hemoglobin structure, thereby playing a vital role in the transport of oxygen to different tissues of the body such as the brain [21]. IDA affects at least one third of the people in the world, also affecting more than 20% of pregnant women and more than 23% of children under five years of age. Fortunately, IDA is a condition that is remediable and could be corrected [22]. Iron is an important micro-element that is used by all the cells in the body, especially the CNS and the neurons. Iron is a co-factor for numerous enzymes in the body and plays a role in the production of neurotransmitters and their function, hormonal function and DNA duplication [23]. Iron deficiency decreases the metabolism of some neurotransmitters and works on stimulating neurons thus leading to change of the amplitude and the threshold of neurons excitation, accordingly increasing the possibility of convulsions [24][25][26][27]. IDA is related with behavioral abnormalities and impaired cognitive function in adults and children. It can cause irreversible brain damage if it happens during the most active time of brain development in young children [28]. Studies reporting the association between IDA and febrile convulsions are conflicting, as some studies demonstrate that iron deficiency with or without anemia were more predominant in children with febrile convulsions, indicating significant association [29][30][31][32][33][34][35][36], while other studies showed no association between iron deficiency and febrile convulsions in children [37][38][39][40][41].

Study Objective
In this review, we looked into the updates on the association between IDA and febrile convulsions and management of febrile convulsions in anemic children.

METHODOLOGY
The review is a comprehensive research of Medline, Google scholar, EMBASE and PubMed databases from the year 2000 to 2021.

Study Duration
Data was collected during the period from 1-31 July, 2021.

Data Collection
Medline, Google scholar, EMBASE and PubMed databases searches were performed for articles about the most important recent developments in the association between IDA and febrile convulsions and management of febrile convulsions in anemic children, published in English around the world. The keyword search headings included "Iron deficiency anemia, Febrile convulsions, Children, Fever", and a combination of these was used. References list of each included study was searched for further supportive data.

Statistical Analysis
No software was utilized to analyze the data. The data was extracted based on specific form that contains (Title of the publication, author's name, objective, summary, results, and outcomes). Double revision of each member's outcomes was applied to ensure the accuracy and minimize the mistakes.

Pathophysiology
Iron is an important micro-element that is used by mostly all the cells in the body and is especially utilized by the brain and neurons. Iron is an essential micro-nutrient for proper growth and development in children. Iron deficiency disturbs the function of many organs, leading to anemia, abnormal growth and behavior, mental retardation, altered thermoregulation, weakened physical performance and immune disorders. Iron is a co-factor for numerous enzymes in the body and plays a role in the production of neurotransmitters and their function, metabolism of some neurotransmitters such as monoamine and aldehyde oxidase, hormonal function, and DNA duplication [23-25]. IDA plays an important role in initiating of convulsions through decreasing gamma-aminobutyric acid (GABA) inhibitory neurotransmitter, increasing glutamate excitatory neurotransmitters, decrease of monoamines, altering neuron metabolism, and impairing oxygenation of the tissue [42]. Also IDA affects developing brain and mechanisms as altering development of hippocampus neurons, delaying maturing of myelin, slowing visual and auditory evoked abilities and also altering synaptic neurotransmitter systems including Norepinephrine, Dopamine, and serotonin and these may be responsible for inducing convulsions [43]. IDA effects on developing children is frustrating because iron supplementation later in life cannot cure the learning difficulties, behavioral disorders, and psychiatric problems which are associated with IDA in early life [44]. Some studies declared that the imbalance between excitatory and inhibitory synaptic activity is suspected to be associated with varied psychiatric disorders and convulsions [45][46][47].

Association of Iron Deficiency Anemia in Children with Febrile Convulsions
It is thought that there is an association between IDA and febrile convulsions but the evidence is inconclusive due to unreliable and conflicting results demonstrated in different studies. While some studies declare that there is association, some other studies report that there is no association between them. Out of the total 510 participants, IDA was detected in 133 patients amongst them 51 were in the control group and 82 were in the study group. It was detected that there was significant association found between IDA and the two groups with p≤0.05 level of significance. Moreover, odds ratio of 1.608 specified that participants in cases are more possible to be diagnosed with IDA. From this study we conclude that children with febrile convulsions are most likely to develop IDA. IDA may be considered as a risk factor that may lead to febrile convulsions in children [48].
A cross-sectional study was carried out in the pediatric hospital in Assiut University, Assiut, Egypt among 100 children; 50 children with febrile convulsions were considered as the study group and 50 febrile children without convulsions as the control group. In the study group, the age of patients ranged from 0.7 to 4.3 years, and male patients in this group were 27 (54.0%) while the female patients were 23(46.0%). In the control group, the age of patients ranged from 0.7 to 4.6 years, and male patients in this group were 35 (70.0%) while the female patients were 15 (30.0%). The variances between the study group and the control group were not significant P < 0.05. The results in the study group were as follows: the mean hemoglobin (HB) level was 10.20 ± 1.42, the mean HTC level was 32.30 ± 4.26, the mean MCV score was 72.83 ± 7.71, the mean MCH score was 23.60 ± 3.15, the mean serum iron level was 39.68 ± 18.00, and the mean serum ferritin level was 65.61 ± 86.87. While the results in the control group were as follows: the mean hemoglobin (HB) level was 12.22 ± 1.29, the mean HTC level was 37.37 ± 3.89, the mean MCV score was 82.29 ± 6.48, the mean MCH score was 26.34 ± 3.15, the mean serum iron level was 78.21 ± 42.95, and the mean serum ferritin level was 160.37 ± 105.76. The P values were significant, as the HB P=0.000, HTC P= 0.000, MCV P= 0.000, MCH P= 0.000, serum iron P= 0.000, and the serum ferritin P= 0.000. We conclude from this study that iron deficiency is predisposing factor for developing febrile convulsions [49].
An analytical case control study conducted among 100 children in Shahid Sadoughi Hospital from December 2011 to August 2012. There were 45 girls and 55 boys with mean age of 23.7 ± 14.3 months. The participants were divided into two groups; case/febrile convulsions group and control/healthy group. The results in the case group were as follows: hemoglobin level 11.46 ± 1.18 g/dl, serum iron levels 48.91 ± 22.96 μg/dl, and serum ferritin level 38.52 ± 11.38 ng/ml. While in the control group the results were as follows: hemoglobin level 11.9 ± 0.89, serum iron levels 75.13 ± 35.57, and serum ferritin level 54.32 ± 13.46. Also iron deficiency and iron deficiency anemia were evaluated; the results were as follows: iron deficiency was present in the case/febrile convulsion group with a percentage of 48%, while it was present in the control/healthy group with a percentage of 28%, and iron deficiency anemia (IDA) was present in the case/febrile convulsion group with a percentage of 22%, while it was present in the control/healthy group with a percentage of 10% and as conducted from the results that IDA was more frequent in febrile convulsions group more than the healthy group (P values<0.05). The P values were significant and stated as follows: the HB P= 0.042, serum iron P= 0.001, and the serum ferritin P= 0.001. We conclude from this study that iron deficiency is a risk factor for developing febrile convulsions [50].
On the other hand, a case control study was conducted during March 2005 to September 2006 among 200 children with a diagnosed first febrile convulsion, aged between 6 months and 5 years. Patients were divided into two groups; the control group included the febrile children without convulsions and the case group included febrile children with convulsions. The results of this study were questioning, as the RBC level, serum iron level, and plasma ferritin level were significantly higher amongst the cases with first febrile convulsions than in the controls. The level of Hb, Hct, MCV, MCH, and MCHC were also higher among case group than control group, but variances were not significant. IDA was less frequent amongst the case group with febrile convulsion, as compared to the control group, and its difference was not statistically significant. So this study suggests that IDA was less frequent amongst the case group with febrile convulsion, as compared to the control group, and there was not a protective effect of iron deficiency against febrile convulsions [51].
We observed from reviewing several studies that results were contradictory, and until now there is no accurate and sure evidence of whether or not IDA is a risk factor for febrile convulsions.

Management
Management in this case is concerning two major lines, which are managing febrile convulsions solely first and then managing IDA.
When a child is presents to the emergency department the first step to make is checking ABC (airway, breathing, circulation), then measuring blood glucose after the first febrile convulsion [52,53]. Then, the clinician should work on differentiating whether the seizures are simple or complex, and if it is the first febrile convulsion then it needs to be differentiated from acute symptomatic seizures due to high risk of CNS infection [54]. Treatment is determined after knowing the main cause of the fever and managing its symptoms. It is important to make the child drink plenty of water to assure the hydration of the body, and then administer paracetamol or ibuprofen to ease feelings of discomfort, but do not administer paracetamol together with ibuprofen [55,56].
Parents and health workers should know that antipyretic drugs are used mainly to ease the discomfort caused by the infection, not to decrease the risk of febrile convulsions [57,58]. Some parents think that long term antiepileptic drugs are given as prophylaxis for febrile convulsions, but this is wrong because side effects of antiepileptic drugs are more than their potential benefits [53,54,59,60]. Sometimes to stop seizures, benzodiazepines, such as rectal diazepam or buccal midazolam, can be given [61]. The last line of management is managing the IDA; management of IDA is partially easy and practicable as the main steps taken for convenient treatment is by using replacement therapy by using iron supplements, improving of nutrition and raising the nutritional education of patients and families, and stabilizing of environmental factors are pH as it affects the body absorption of foods containing iron [62].

CONCLUSION
IDA could be a potential risk factor for febrile convulsions, as children with febrile convulsions are more likely to develop IDA than those with febrile illness alone or healthy children. Our belief of this association is based on the physiological evidence of effects of iron deficiency on the brain.
However, we recommend doing further studies accessing the effect of IDA on the brain and whether IDA affects febrile convulsions or not. Also we recommend that iron status should be evaluated in children with febrile convulsions.

CONSENT
It is not applicable.