Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, the virus has undergone mutation, leading to a shift in clinical symptoms from primarily affecting the respiratory system to involving multiple organs. Neurological manifestations, known as “neuroCOVID,” have been noted in adults. Meanwhile, children, including those with no history of febrile seizures, have presented with seizures when infected with the Omicron variant [1-3]. Febrile seizures, which typically occur in children aged 6 months to 5 years, can arise during viral infection [4-6]. Seizures induced by fever associated with COVID-19 have been linked to status epilepticus or increased seizure frequency in patients with pre-existing epilepsy [7]. Several hypotheses have been introduced regarding the impact of COVID-19 on the brain, with evidence pointing to the role of inflammatory cytokines in causing coagulopathy [8,9]. Abnormalities in electroencephalograms (EEGs) have been detected, particularly in severe cases, with prognostic implications [10,11]. Marinelli et al. [12] observed attenuated EEG patterns in adult patients with severe COVID-19 and found elevated interleukin 6 (IL-6) levels in those who died from the virus. However, the relationship between serological markers and EEG findings in pediatric patients remains to be clarified. This study was performed to investigate this correlation and to establish baseline characteristics in such patients.

We retrieved the medical chart data of 585 patients with confirmed COVID-19. We excluded a total of 544 patients aged 18 years and older, as well as those with missing data or who declined to provide laboratory measurements. Consequently, 41 patients with COVID-19 were included in the study. Among these individuals, we conducted further analysis of 17 patients who visited our clinics with seizures, as well as nine patients with available EEG results (Fig. 1). None of the study participants had a history of multisystem inflammatory syndrome in children, nor had they received treatment in intensive care units. All patients had unremarkable perinatal and birth histories, and their neurodevelopmental examinations were normal for their age.

The mean age of the patients was 3.6 years, with an average hospital stay of 3.7 days (range, 1.0 to 7.0) and a predominance of male patients. Among those with seizures, boys were also more prevalent than girls, and the mean age was higher compared to the non-seizure group. Patients with seizures experienced higher peak fever temperatures than those without seizures. Serum IL-6 concentrations were elevated in all enrolled patients, with the seizure group displaying levels about twice as high as those not exhibiting seizures. Additionally, D-dimer levels were higher in the seizure group, while both the proportion and counts of lymphocytes were lower compared to the non-seizure group. No significant difference was observed between groups in white blood cell or neutrophil counts. Similarly, no significant differences were noted in body weight proportions, although a higher percentage of patients in the seizure group were above the 75th percentile for body weight (Table 1).

Of the total patients, eight children experienced complex febrile seizures. Within this group, three children had focal seizures, two experienced seizures more than twice a day, and three exhibited prolonged seizures lasting over 30 minutes, for which they received intravenous lorazepam. Four patients had a family history of febrile seizures, three patients had previous febrile seizures, and all these patients presented simple types of febrile seizures. Seven patients underwent brain magnetic resonance imaging (MRI). Of these, two exhibited abnormal findings, namely choroidal fissure cyst and delayed myelination. The remaining MRI results were non-specific, with no evidence of encephalitis . All patients achieved complete control of seizure activity, maintained an alert mental status, and were discharged from the clinic without the need for anti-seizure medications.

Furthermore, patients with available EEG findings were categorized by the presence or absence of theta burst. The serum IL-6 level was approximately twice as high in the group with theta burst (84.2 pg/mL) compared to the group without such theta activity (42.6 pg/mL). However, this relationship was not statistically significant (Table 2).

Using the results of a linear regression model based on fever peak, we found that a high serum IL-6 level was correlated with a high fever peak (β=0.01; 95% confidence interval [CI], 0.004 to 0.016; P=0.002). However, we observed no significant correlation between fever peak and serum ferritin level (β=−0.004; 95% CI, −0.006 to 0.001; P=0.014) or total lymphocyte count (β=−0.099; 95% CI, −0.192 to −0.006; P=0.038). In the multivariate linear regression model examining the relationship between seizure duration and inflammatory markers, IL-6 levels were associated with prolonged seizure duration, although the association weakened after adjustment (crude: 0.175 [95% CI, −0.032 to 0.382; P=0.09]; adjusted: 0.131 [95% CI, −0.024 to 0.287; P=0.087]).Conversely, only lymphocyte counts were correlated with prolonged seizure duration (crude: 10.951 [95% CI, 3.490 to 18.411; P=0.007]; adjusted: 17.783 [95% CI, 5.224 to 30.341; P=0.011]).

In this study, we analyzed inflammatory markers and EEG findings associated with COVID-19, observing several changes in serological markers among patients with the disease. Notably, a significant correlation was observed between increased serum IL-6 levels and peak body temperature. C-reactive protein and IL-6 levels have been shown to be significantly elevated in patients who died from COVID-19 [16]. Furthermore, a dramatic rise in IL-6 has been associated with COVID-19-related severe pneumonia and bilateral interstitial lung disease [17]. However, previous research has also suggested that specific cytokines, including interferon-α/β/γ, tumor necrosis factor-α, and various interleukins (IL-1α/β, -2, -6, -12, -13, and -18), are implicated in the antiviral response, with IL-6 playing a pivotal role in the survival and proliferation of CD4 T cells [18,19]. Therefore, in light of our findings and a review of the literature, IL-6 can be considered a key immunological mediator involved in the COVID-19 immune response.

Additionally, our findings revealed a markedly higher level of cytokines in the group experiencing seizures, with serum IL-6 level displaying a significant correlation with seizure duration. While the exact mechanism by which COVID-19 may trigger seizures remains unconfirmed, several studies have proposed that inflammatory cytokines are crucial neuromodulators that become elevated following epileptic events, both in vivo and in vitro [8,20-22]. Specifically, the increased levels of circulating cytokines seen in patients with COVID-19 can increase the permeability of the blood-brain barrier [23,24] and activate additional inflammatory mediators, triggering a cascade of immune responses [25]. Moreover, inflammatory cytokines may stimulate activity in the developing brain, aligning with the evidence-based theory of epileptic events [26]. Animal studies of febrile seizures have demonstrated elevated cytokine levels in the hippocampus [27]. Our findings indicate that cytokines associated with COVID-19 could represent a crucial marker for understanding the mechanisms underlying fever-induced seizures in children. Additionally, our results suggested a relationship between increased total lymphocyte count and the duration of seizure. This correlation is particularly interesting in that it mirrors the early immune response to viral infection observed in studies of immunocompromised patients. For instance, a moderate rise in lymphocyte count is evident in the initial phase of human immunodeficiency virus infection, followed by a gradual decline [28]. Traditional febrile seizures in children are associated with a variety of viral infections that cause high fever [29]. Significant lymphocytopenia is indicative of an “immunological burst” involving circulating cytokines, which can influence the severity of viral infections, including COVID-19 [30]. However, our findings reveal an unexpected pattern, as lymphocytosis was significantly associated with prolonged seizures in patients with COVID-19. Thus, extended seizures induced by fever in the context of COVID-19 may be linked to lymphocytosis during the early stages of infection [31], offering a different perspective from the mechanisms associated with high fever in other viral infections.

Our findings indicate that patients exhibiting theta burst activity on EEG had IL-6 levels approximately twice as high as those without such activity. Theta burst activity is noteworthy, as it can signify focal abnormalities in brain function and is indicative of prolonged seizures in otherwise healthy children with febrile seizures [32,33]. Furthermore, the presence of theta burst activity is linked to an increased risk of recurrent febrile seizures and adverse outcomes in childhood epilepsy [34,35]. This leads us to consider the potential relationship between theta rhythm and seizure triggered by fever associated with COVID-19 in children. It is plausible that COVID-19 infection may provoke theta burst activity in the brain. Supporting this hypothesis, anosmia was a prominent and widely examined neurological symptom during the initial wave of the COVID-19 pandemic [36]. Autopsy findings suggest a direct pathway for SARS-CoV-2 entry, in which the virus interacts with angiotensin-converting enzyme 2 receptors in the olfactory mucosa [37]. Although the olfactory cortex is situated near the frontal lobe, it has anatomical connections with the hippocampus [38], a primary site of the generation of theta rhythms [39]. In vitro studies using a mouse model injected with SARS-CoV-2 RNA have demonstrated viral aggregation in the hippocampus [40]. Consequently, we propose that the mechanism underlying fever-induced seizures associated with COVID-19 may involve the neuronal invasion route through the hippocampal network.

This study had several limitations. First, the sample size was small, with relatively few patients enrolled. Second, the research was based on retrospective observational data obtained over a short period that did not include laboratory data, such as cerebrospinal fluid analysis. Lastly, the evaluation of developmental milestones relied on questionnaires completed by parents, and the study did not consider other prospective neurological outcomes, such as underlying susceptibility to epilepsy or encephalopathy. Despite these limitations, our research provides current insights into the relationship between serological markers and specific EEG features in healthy pediatric patients. Further follow-up studies should, therefore, be conducted to monitor the neurological outcomes of the enrolled patients, thereby gaining a deeper understanding of latent neurological complications. Additionally, larger populations and extended longitudinal studies are needed to investigate the long-term neurocognitive effects and the pathophysiology of seizures triggered by COVID-19-related fever. Such studies should include postmortem examinations and experimental animal models, along with cerebrospinal fluid analysis or brain biopsy.