Febrile convulsions are common in children with a febrile state (T ≥ 38˚C), without central nervous system diseases and metabolic disturbances that can cause convulsions, and most of them without history of febrile convulsions [1]. Febrile convulsions are divided into simple and complex febrile convulsion based on clinical features. The former mostly occurs in 6 months to 5 years old, with generalized seizures, duration less than 15 minutes, one attack in a febrile course, and no abnormal neurological signs; and the latter occurs in less than 6 months or more than 5 years, and the symptoms are focal or generalized seizures, neurological abnormalities before onset, seizure duration ≥ 15 min, or seizure duration ≥ 2 times in a febrile course, and neurological abnormalities after seizure, such as Todd’s palsy [1] [2]. Febrile convulsions are believed to be the result of multiple factors, including the vulnerability of the developing central nervous system to fever and potential risk factors (including environmental and genetic factors) [1] [3] [4] [5]. The prognosis of febrile convulsion is good generally, but convulsion happens repeatedly can cause organic pathological changes or functional abnormality in brain, especially in persistent convulsions [6] [7] [8] [9]. Therefore, it is very important to find out the risk factors in time, which may help to predict the progress of the disease such as recurrent convulsions.

Febrile convulsions are an age-dependent phenomenon. Although the most commonly identified risk factors of febrile convulsions include age, high fever, infection, recent immunization, and a family history of febrile convulsions [10] [11], some patients also have mild electrolyte disturbances, especially in children with complex febrile convulsions [3] [12] [13]. Whether electrolyte disturbances are a risk factor for febrile convulsions and recurrent convulsions still not clear. In addition, studies have shown that the direct effect of heat on ion channels [14], such as voltage-gated sodium channel [15], localized to the site of action potential initiation potentially causes a profound increase in neuronal excitability [14], which is likely to contribute to abnormal serum sodium levels and febrile convulsions genesis.

Although genetic susceptibility to febrile convulsions has received attention, the exact modes of inheritance are not fully understood. Susceptibility to febrile seizures has been linked to several genetic loci in different families, including the long arm of chromosome 8q13-21 (FEB1) [16], chromosome 19p (FEB2) [17] and chromosome 2q23-24 (FEB3) [18], which is transmitted in an autosomal dominant pattern with reduced penetrance or as a polygenic or multifactorial model [19]. According to Yuxin Xu et al. [20], the series of genes controlling important nodes of neural signaling, including SCN1A, SCN2A, SCN1B, SCN9A, GABRG2, STX1B, and PCDH19, which are believed to be responsible for the early identification of generalized epilepsy with febrile seizures plus (GEFS+), Dravet syndrome (DS), and PCDH19 gene-related seizures. In some patients and families, the propensity for febrile convulsions is an early manifestation of GEFS+ [21] [22], and some with severe myoclonic epilepsy of infancy DS is another genetic epilepsy with a well-known preponderance for seizures with fever in early childhood [23]. Stefania Scalise et al. [11] also investigated the role of SCN1A mutations in encoding the voltage-gated sodium channel (VGSC) NaV1.1 gene in children with thermal convulsions, suggesting that SCN1A mutations lead to immature intracellular expression, which leads to normal neuronal transmission.

In this study, we investigated whether electrolyte balance disturbances were associated with convulsions during fever and which electrolytes were associated with recurrence of convulsions. Meanwhile, the genes related to febrile convulsions in children with a family history of convulsions were also analyzed.

Febrile convulsion is the most common disease in Pediatric Emergency Department, usually occurring between 6 months and 5 years old [1]. Age, infection, vaccination, trace element deficiency, maternal states and genetic predisposition are the commonly known risk factors for febrile convulsion. [10] [11]. Studies have shown that various electrolyte disturbances occur in patients with febrile convulsion [12] [35] [36] [37]. Similarly, in our study, significant hyponatremia was found in the febrile convulsion group compared with the febrile-only group within 2 hours after the onset of convulsions. However, hyponatremia levels in children with febrile convulsion did not reach levels of severe hyponatremia that could trigger convulsion, and there was no different between Single Convulsion Group and Multiple Convulsion Group. In addition, some mutations genes with insufficient pathogenic evidence were found, which need to be further combined with clinical analysis.

In this study, the children in this study were all febrile patients, and most of them had hyponatremia, which may be related to hyponatremia caused by inappropriate ADH secretion syndrome in infected patients [38] [39] [40]. The serum sodium of the children in the febrile convulsion group was mostly lower than 133 mmol/L, and ROC curve analysis suggested that serum sodium had a certain predictive effect on febrile convulsion (serum sodium AUC0.694), and determined the critical value (serum sodium < 133 mmol/L, sensitivity 70.2%, specificity 62.1%). However, there was no correlation between serum sodium and recurrence of febrile convulsions. The additional gating defects for both R859H and R865G mutants were detected at 40˚C, and the GEFS+ mutant R859H showed a loss of function in the voltage dependence of inactivation and an increased channel use-dependency at 40˚C with no reduction in peak current density [41]. Meanwhile, the DS mutant R865G exhibited reduced peak sodium currents, enhanced entry into slow inactivation, and increased use-dependency at 40˚C [41]. These studies explain that patients with defects of R859H or R865G mutants had higher levels of hyponatremia triggering febrile convulsions than patients with nonfebrile convulsions [42], but had not shown that this mechanism was associated with repeated convulsions.

On the other hand, potassium, and calcium concentrations were lower and blood glucose concentrations higher than those in the control group, both of which were associated with febrile convulsion. However, these indicators are within the normal range and have no effect on clinical judgment. In a study of 1199 children, febrile seizures and trauma were found to be more likely to cause stress hyperglycemia than fever alone, and none of the children in the study went on to develop diabetes [43]. Raluca Maria Costea et al. suggested that the duration of febrile convulsions was longer (>15 min), repeated febrile convulsion\, focal convulsion, body temperature ≥ 39.5˚C, and higher lactate values are significantly associated with stress hyperglycemia, and stress hyperglycemia can be a predictor of recurrence of febrile convulsions [44]. In this study, although blood glucose in the MC group was significantly lower than that in SC group, the mean blood glucose in the two groups was still within the normal range, and the effect of hyperglycemia on recurrent convulsion was not reflected in this study.

Children with a family history of convulsions are more likely to develop febrile convulsions, which may be associated with multiple genes. Studies have shown that mutations in sodium channel and GABA receptor genes are found in families with syndromes associated with febrile convulsions [45]. In this study, 5 of the 15 family members of children with a family history of convulsion agreed to be tested for gene related to febrile convulsion. 189 gene loci, such as AARS, were detected, and no obvious gene mutations related to clinical phenotype of febrile convulsion were found, but mutations at other gene loci were reported in 4 of them, such as ARHG EF15, MAG12, ATP7A, GABRG2, SCN9A, SPTAN, RELN, MTOR. Patient A tested a large sample of data supporting the predisposition locus ATP7A (a gene that encodes an inherited or acquired predisposition to a disease in response to appropriate environmental stimuli). ATP7A is an important gene encoding copper pump, and its clinical phenotypes are Menkes disease, occipital Angle syndrome, and X-linked distal spinal muscular atrophy type 3 [46]. At the same time, GABRG2 mutation was also detected. Although the evidence of pathogenicity was insufficient, the possibility of pathogenicity was not excluded in combination with the clinical practice of febrile convulsion in children, which needs further follow-up. The gene GABRG2 was derived from the mother, and the disease phenotypes were generalized epilepsy with febrile seizures plus type 3 (OMIM: 611277), familial febrile epilepsy 8 (OMIM: 607681), and early infantile epileptic encephalopathy 74 (OMIM: 618396) [47]. The SCN9A mutation was detected in patient B, which originated from his mother. Combined with clinical analysis, the possibility of pathogenesis was not excluded. The clinical phenotypes consistent with clinical manifestations were generalized epilepsy with febrile convulsion type 7 (OMIM: 613863) and Dravet syndrome (OMIM: 607208) [8] (. SPTAN1 mutation was detected in Patient C. The variant originated from the father and had the clinical phenotype of early onset infant epileptic encephalopathy type 5 (OMIM: 613477), it has also been reported that SPTAN1 encephalopathy is a unique clinical syndrome caused by SPTAN1 specific mutations [31]. Although the current history of febrile convulsion in the child is not supported by clinical evidence, it is not excluded that the child will later develop corresponding epileptic encephalopathy, and need further followed up. In patient D, genetic variants of ARHGEF15 and MAGI2 were detected, both of which were of undetermined pathogenicity and of non-parental origin, and ARHGEF15 was reported to be a mutation associated with epileptic encephalopathy [26].

Hyponatremia may be a relative risk factor for febrile convulsions, which may also be a reflection of patient carrying genes involved in sodium channel regulation in febrile seizure-related genes such as R859H or R865G mutants in patients. Therefore, for children with a family history of febrile convulsion and serum sodium lower than 133 mmol/L, related gene analysis can be performed to clarify the etiological diagnosis and predict subsequent neurological diseases.

Furthermore, Gene mutations of various ion channels are closely related to the occurrence of febrile convulsions. It is expected to be further investigated by multicenter randomized controlled studies in future.

The current study has some limitations that should be noted. One of the limitations is that blood samples were collected within 2 hours after febrile convulsions and blood electrolyte indicators were measured, which could not be evaluated before the occurrence of convulsions. Future prospective cohort studies or long-term clinical follow-up studies are needed to reveal the intrinsic link between electrolytes and febrile convulsions. In addition, due to economic and family reasons, many families did not agree to complete febrile convulsions related genes, resulting in a small quantity of genetical cases. In the future, education and promotion of the conclusions in this study can be conducted to obtain more clinical data conducive to research.

Thanks all the enrolled patients and the Clinical Biological Resource Bank of Guangzhou Women and Children’s Medical Center for providing the clinical samples used in this study.

The data reported in this paper have been deposited in the OMIX, China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences. The information record number is BF2022083012025. (https://ngdc.cncb.ac.cn/omix: accession No.OMIX807).

All authors declare no conflict of interest.

Li, W.Q., Li, P.Q., Fan, X.W., Liu, G.M. and Wang, Q. (2022) Clinical Analysis of the Relationship between Convulsion and Blood Electrolyte in Children. Journal of Behavioral and Brain Science, 12, 552-568. https://doi.org/10.4236/jbbs.2022.1211033