1. Introduction

Febrile seizures (FS) occur in 2-5% of children aged 6 months to 5 years. In the vast majority, they are benign and do not require antiepileptic therapy. However, 2-10% of patients may develop afebrile seizures, including various forms of epilepsy.Early detection of risk factors for the transition of FS to epileptic syndrome makes it possible to optimize monitoring, prognosis and, if necessary, early therapy [5].

Epileptic syndrome is one of the most urgent problems of pediatric neurology. The frequency of epilepsy in the population is 0.5-0.75% of the child population, and febrile seizures (FS) - up to 5%. About half of all seizures occur before the age of 15, of which the largest number of seizures occur between the ages of 1 and 9 years. The frequent development of seizures in childhood is explained by the peculiarities of the child's nervous system and the variety of causes that cause them [1,4].

Febrile seizures often begin with a sudden increase in temperature, which is associated with hypoxia of the brain. It is known that with an increase in body temperature of only 1°C, the intensity of metabolic processes in the brain increases by 7-10%, and hence the need for oxygen. With a gradual increase in temperature, seizures are much less frequent, as there is time for the necessary increase in cerebral blood flow, which prevents hypoxia [1,3,4,6].

An important role in the occurrence of this disease in children is played by perinatal factors, in particular, cerebral hypoxia, developmental abnormalities, genetic determinations, as well as anatomical and physiological features of the child's brain, which, in certain pathological conditions, are prone to high convulsive activity and excitability of the brain, even with the smallest metabolic changes occurring in the child's body [2,5].

The aim of this study is to systematize the factors associated with an increased risk of FS transformation into afebrile seizures.

2. Materials and Methods

The analysis was based on data from 78 FS patients (the main group) and 35 healthy children (the control group). Two subgroups are identified among them:

• Subgroup A (n=58): children with single/uncomplicated FS, without subsequent transition;

• Subgroup B (n=20): children who had afebrile seizures 6-24 months after FS (epilepsy was confirmed in 80% of cases).

Methods:

• analysis of anamnestic and clinical data;

• electroencephalography (EEG) in the intercalary period;

• MRI of the brain according to the indications;

• Family history;

• Genetic screening (including SCN1A and GABRG2).

3. The Results and Their Discussion

The study examined 78 children under the age of 5 who are in the period of convalescence, i.e. recovery, characterized by the gradual disappearance of FS (up to 5-6 years) and the restoration of normal bodily functions. For several years, children with FS were under supervision, constant monitoring was carried out, recreational activities, periodic checkups, and examinations were carried out.

Figure 1. Analysis of the distribution of children by gender

High fever, genetic predisposition, and perinatal disorders significantly increase the risk of developing FS (Table 1).

Table 1. Common clinical risk factors for febrile seizures

The results of numerous clinical observations and studies confirm that, despite the relatively benign nature of most febrile seizures (FS), there are a number of well-defined factors that significantly increase the risk of their chronicity and transformation into afebrile seizures, i.e. epilepsy (Table 2).

Table 2. Risk factors for the transformation of FS into afebrile seizures (epilepsy)

The most significant prognostic factors are:

• long (>15 min) and focal FS;

• pathological changes on the EEG;

• presence of epileptogenic mutations (for example, SCN1A — Dravet syndrome);

• * structural changes in the brain, especially medial temporal sclerosis and I.

The most significant clinical markers of an unfavorable prognosis include focal (localized) and prolonged (prolonged, more than 15 minutes) seizures, as well as repeated FS during one episode of fever. These characteristics classify seizures as atypical (or complex) and identify them as the most closely associated with the further development of epileptic syndrome. Especially alarming is the occurrence of seizures against a background of subfebrile or normal temperature, which may indicate the initially epileptic nature of the attack, mistakenly regarded as febrile.

Electroencephalography (EEG) is of no small importance, which remains a key tool in assessing the risk of transition from febrile seizures to epilepsy. The detection of epileptiform (paroxysmal) activity during the inter–seizure period, especially in the form of acute and slow waves, peaks or peak-wave complexes, indicates increased convulsive readiness of the brain. Such changes can serve as a predictor of the occurrence of febrile seizures even in the absence of pronounced clinical symptoms.

At the molecular level, one of the most studied causes of increased convulsive readiness are genetic mutations that affect the functioning of ion exchange channels and neurotransmitter receptors. This is especially true for sodium channels (for example, SCN1A, SCN2A) and GABA receptors (in particular, GABRG2 and GABRA1), which play a key role in the balance of excitatory and inhibitory effects in the central nervous system. Such mutations may underlie not only febrile seizures, but also more severe forms of epilepsy, including Dravet syndrome and generalized epilepsy with febrile seizures plus (GEFS+).

Thus, when assessing the prognosis of a child with febrile seizures, it is important to take into account a combination of clinical, neurophysiological, and molecular genetic factors, since their combination significantly increases the risk of chronification of the condition and requires closer monitoring, and in some cases, preventive antiepileptic therapy.

Factors that significantly predispose to the occurrence of febrile seizures include:

• Early age of onset of seizures (up to 18 months), reflecting the increased sensitivity of the immature central nervous system to temperature and inflammatory triggers;

• High level of hyperthermia (>39.5°C) during the episode, which can serve as both a direct provoker of convulsive activity and a marker of a pronounced inflammatory response;

• Familial predisposition to FS and epilepsy, which indicates the role of inherited neuronal hyperexcitability and genetic vulnerability;

• Perinatal complications (hypoxia, asphyxia, intracranial injuries, etc.) that potentially disrupt the processes of myelination and functional maturation of the cerebral cortex.

Factors that increase the risk of transformation of febrile seizures into afebrile seizures and epilepsy:

• The focal nature of seizures, as well as their prolonged course (>15 minutes) and frequent relapses, which are associated with more pronounced convulsive activity and may indicate a latent epileptogenic zone;

• The presence of pathological changes on the EEG during the inter-seizure period, including focal epileptiform discharges and paroxysmal activity, which indicates the formation of an epileptic network;

• * Structural brain abnormalities revealed by neuroimaging (in particular, hippocampal sclerosis, cortical dysplasia), confirming the presence of an organic basis of epileptogenesis;

• The presence of mutations in epileptogenic genes (e.g., SCN1A, GABRG2) that play a key role in the regulation of neuronal excitability and ion channels.

Given the identified risk factors, special attention should be paid to children with a burdened medical history, a complex course of FS and/or abnormal EEG and MRI data. For this category of patients, it is justified:

• conducting an in-depth neurophysiological and neuroimaging examination;

• genetic counseling in the presence of familial seizures or resistant seizures;

• dynamic monitoring for early detection of signs of epilepsy;

• timely administration of neuroprotective or anticonvulsant therapy in cases of confirmed transformation of FS into epileptic syndrome.

On the other hand, the first FS in a child's life does not mean that he already suffers from epilepsy or will inevitably suffer from epilepsy in the future. Epilepsy affects only children who have the necessary pathological conditions - risk factors that determine the evolution of the disease towards epilepsy. Even in the presence of risk factors, it takes a certain amount of time for the disease to form from the first FS to well-established clinical forms of epilepsy.

4. Conclusions

The detection of these signs requires increased monitoring, in-depth examination and, if necessary, early intervention.

The analysis of clinical, neurological, neurophysiological, and molecular genetic data made it possible to identify key factors contributing to both the development of febrile seizures in children and their transformation into febrile seizures, including epilepsy.

Thus, early identification of risk factors and targeted monitoring of high-risk children makes it possible to timely intervene in a potentially unfavorable scenario of the disease and improve the neurodevelopment and quality of life of patients.