The Impact of Omicron Wave on Pediatric Febrile Seizure

The coronavirus disease 2019 (COVID-19) before emergence of the omicron variant demonstrated low rate of infectivity and mortality in children compared to that in adults.1 However, a new severe acute respiratory coronavirus 2 (SARS-CoV-2) omicron variant (B.1.1.529) has been reported in South Africa.2 In South Korea, this variant, also referred to as COVID-19 omicron, began to spread from November 25th, 2021. The omicron variant reduced the risk of severe disease compared with the original strain and other variants, but it appeared to be highly infectious, which resulted in an exponential increase in confirmed cases in South Korea.3 As the number of confirmed cases increased, so did the number of pediatric patients’ hospitalization.2

A febrile seizure is characterized by a neurologic event associated with a fever that usually occurs between 6 months and 5 years of age without evidence of a central nervous system infection. Most cases are benign, but some progress to encephalitis and meningitis and thus require differentiation from other diseases.4 Some studies have reported that the correlation between COVID-19 and febrile seizure associated with their ability to affect the central nervous system.5, 6, 7

To the best of our knowledge, the relationship between an increase in the number of febrile seizures in pediatric patients with identified omicron variant infection is unknown and has not been evaluated so far. Thus, this study aims to compare the frequency and clinical features of febrile seizure before and after the emergence of the omicron variant. We also aim to compare the clinical characteristics of febrile seizure between patients with and without COVID-19.

This retrospective analysis found that the number of febrile seizures with SARS-CoV-2 infection increased in February 2022, correlating with emergence of the omicron period. Data shows that children with febrile seizure who were COVID-19 positive were of a higher age group and had longer seizure time, multiple seizure episodes, and higher prevalence of complex febrile seizure than COVID-19 negative children.

In the COVID-19 era, many countries practiced social distancing measures to prevent transmission of COVID-19.12 With the help of social distancing and hygiene precautions, the prevalence of febrile seizure decreased by 38% in 2020 compared to that in 2010-2019 in South Korea.13 In a Hong Kong-based study, seizure-related accidental ED visits significantly decreased in 2020 (relative risk, 0.379; 95% confidence interval [CI], 0.174–0.526; P < 0.001); in addition, the rate of febrile seizure-related admissions dropped to less than 20% compared to the previous year, in children aged 0–6 years.7

In a previous study conducted in children aged 0 to 5 years in the pre-omicron period (from March 1, 2020 to April 19, 2021), only 0.5% (44/8,854) of the COVID-19 patients were diagnosed with febrile seizure.6 The median age was 1.5 years, and 68.2% (30/44) were cases of simple febrile seizure. Prognosis of febrile seizure patients was good, and only 25% of the cases required hospitalization and few required critical care. A meta-analysis comparing 20 studies with 3,051 hospitalized patients aged under 18 years with COVID-19 reported that only 4% (95% CI, 2–6%; 2 studies) of the patients presented with seizure from December 31, 2019 to December 15, 2020.14

In the omicron period, the high infectivity and an ensuing rapid increase in the number of both adult and pediatric COVID-19 patients put a large burden on the medical infrastructure of many countries. Especially, hospitalization associated with pediatric COVID-19 rapidly increased.2 In South Africa, convulsion was a symptom in 25/139 (20%) hospitalized patients. In addition, seizure accounted for 20% of clinical diagnosis for hospitalization, which was the most frequent diagnosis along with gastroenteritis.15 In our study, the number and rate of ED visit associated with COVID-19 rapidly increased in omicron period. During this period, the number of COVID-19 associated febrile seizures was increased and 7.0% of COVID-19 positive patients were diagnosed with febrile seizure.

In our study, febrile seizure in the COVID-19 positive group was shown to occur in patients with a higher mean age than that of the COVID-19 negative group. The peak age of incidence of febrile seizure in children is 12 to 18 months.4, 16 In this study, the mean age of febrile seizure in the COVID-19 positive group was 33.0 months, and 15 patients were more than 6 years of age. In a previous study in South Africa, 6 of 25 patients with seizure were outside the typical age range for simple febrile seizure.2 In a Swedish case report, 3 patients were hospitalized for COVID-19 with febrile seizure, and 2 of them were aged 3 months and 14 years, respectively, which was outside the typical age range for simple febrile seizure.5

Based on the observations, we suggest several potential causes for an increase in the number of patients with febrile seizure during the omicron period. First, it is possible that the increase in the total number of COVID-19 positive pediatric patients during the omicron period contributed to the increase in the total number of febrile seizure patients. However, considering the ratio of febrile seizure to the total patients, there are certain features of the omicron variant that may explain why it causes more febrile seizures. Second, the COVID-19 positive group had significantly higher peak body temperature than the negative group. Since febrile seizure is associated with viruses that cause high fever such as human herpes virus and influenza,17 the higher peak body temperature caused by SARS-CoV-2 infection in the omicron period may have potentially caused the increase in prevalence of febrile seizure. Third, the febrile seizures most commonly occurring in fall and winter18 are associated with viruses such as influenza and respiratory syncytial virus, which mainly cause upper respiratory tract infections.4, 16, 19, 20 The omicron variant was found to cause more croup in previous studies.3, 21 Emergence of the omicron variant in 2022 may have resulted in an increase in the prevalence of febrile seizure due to more upper respiratory tract infections than that of other variants.

In the general population, complex febrile seizure accounts for approximately 20–30% of febrile seizures.22, 23 Although statistically insignificant, our study has shown that COVID-19 positive group had a higher ratio of complex febrile seizure (41.0%) and multiple seizure episodes than the negative group. Based on these characteristics, it is important to inform caregivers of seizure recurrence and to educate patients’ caretakers on emergency seizure management at home.

The potential mechanism of COVID-19 causing seizure, as introduced in many studies, is associated with direct viral injury to neural cell and inflammation. The neurotropic and neuroinvasive nature of COVID-19 cause neuronal infection through angiotensin converting enzyme 2 in brain endothelial cells leading to a cascade of inflammation.24, 25, 26 The inflammation is mediated by cytokines such as IL (interleukin)-1β, IL-6, tumor necrosis factor-α, and IL-17. The cytokines activate glial cells leading to a hyper-inflammatory response causing increased neurologic excitability and putting children at a higher susceptibility to experience febrile seizure.27, 28 The different prevalence of febrile seizure between adults and children due to COVID-19 is related to the difference in blood-brain barrier and neurovascular unit.29 Owing to the age-based changes in the blood-brain barrier and neurovascular unit, children and adults respond differently to direct neural injury by COVID-19.30 However, it is uncertain whether the omicron variant is more neurotropic and neuroinvasive than the other variants and would require further research to elucidate these results.

In this study, most patients were discharged without neurologic sequelae and no deaths occurred in the hospital. Although excluded from this study, one patient showed a notable clinical course. A boy aged 16 months, presented to the ED with 4 episodes of generalized seizures continuing for a total of 183 minutes. Other complaints were upper respiratory symptoms and respiratory distress. The patient was clinically diagnosed with status epilepticus and severe croup. Despite being treated with an anticonvulsant drug, the seizures continued and caused respiratory suppression which led to intubation and admission to the ICU. The patient received midazolam coma therapy and intravenous remdesivir. During the hospitalization, the patient showed multiple episodes of focal seizure and was finally diagnosed with post COVID-19 autoimmune encephalopathy on brain magnetic resonance imaging and treated with intravenous immunoglobulin. After discharge from the ward, the patient had an episode of focal seizure, motor dysfunction, and blindness. Recently his motor weakness and visual acuity have recovered. The patient undergoes follow-up visit in the outpatient clinic and is on anticonvulsant for partial seizure. Neurological involvement in most patients was known to be transient. Although rare, life threatening COVID-19 related neurological conditions such as encephalopathy, cerebral edema, and Guillain-Barre syndrome must be considered during management.29

This study has several limitations. First, given the single-center and retrospective design, the results might not be widely applicable. Second, not all children who visited the ED were tested for COVID-19 using PCR. Although this might be a potential bias, it is likely to be negligible because the ratio of children tested for COVID-19 PCR was similar in both, the pre-omicron and omicron, periods. Finally, as not all patients undergo complicated tests to diagnose viruses in the ED, we cannot rule out the coinfection with other viruses along with COVID-19 that may have caused febrile seizure. Considering these multiple potential causes, it is difficult to assess the true incidence of febrile seizure in COVID-19 patients. More studies may be needed to delineate the mechanism for occurrence of omicron variant associated multiple febrile seizure episodes in a higher age.

In conclusion, the frequency of COVID-19 associated febrile seizure has increased in the omicron periods. Among children with febrile seizure, those who tested positive for COVID-19 were older and had a higher peak body temperature than the negative group in the omicron period. Clinicians and caregivers must consider the possibility of complex febrile seizure and multiple seizure episodes in patients tested positive for COVID-19.