The findings of this study showed that 10% of pediatric patients with acute SARS-CoV-2 infection experienced neurological manifestations. Although the neurological manifestations were consistent across all pandemic waves, the frequency of these manifestations varied based on the wave of the pandemic and the age of the patient. The neurological manifestations described in this study have been documented in scientific literature, including rare cases [51–62].
The neurological consequences of COVID-19 according to age have been explored in several studies with varying results [63–65]. The literature review revealed inconsistencies in the classification of age and the absence of age groups used in the official WHO reports. However, this study adopted the same age groups as those presented in the WHO's global reports on COVID-19 to facilitate data comparisons that may arise in future research in this area [32].
The frequency of neurological manifestations in pediatric patients with acute SARS-CoV-2 infection was lower in this study (10%) than in most previous studies (13.5–40%) [19, 66–68], but was in line with the findings of Antoon et al. [63] (7%). The frequency of neurological manifestations in pediatric patients may vary due to differences in methodologies, such as variations in upper age limits, analyzed period, and inclusion of multisystem inflammatory syndrome.
Proust et al. [69] identified distinct patterns of central nervous system (CNS) cell invasion in Wuhan and Omicron variants, which may explain the different neurological manifestations associated with each variant. To the best of our knowledge, this is the only real-world study currently available to validate the findings of Proust et al. [69] regarding the increased neurological involvement of the Wuhan and Omicron variants compared with the Alpha and Delta variants.
Studies that analyzed the neurological manifestations during the Omicron wave and compared them with previous periods or other SARS-CoV-2 variants found evidence to support the increase in neurological symptoms [65, 70–72]. In contrast, Antoon et al. [60] noted more neurological manifestations during the Wuhan wave than during the Omicron wave. This difference may be due to the shorter Omicron spread considered by Antoon et al. [63].
Seizures, including de novo status epilepticus, have been frequently reported in pediatric patients with COVID-19 [73, 74]. Moreover, some studies have indicated that seizures were the most common neurological manifestations [65]. The reported frequencies varied across studies, ranging from 0.06–61.9% [12, 65]. The present study showed a striking increase in seizure frequency during the Omicron wave compared to prior waves. This result was unexpected as Omicron was believed to be less severe than prior variants [10]. According to Cho et al. [75], seizure frequency decreases with age. However, our study revealed that the highest frequency of seizures was observed in the 5 to 9 age group (7.8%).
This study, as well as others [63, 72], discovered that febrile seizures were the most common neurological manifestation among pediatric patients diagnosed with COVID-19. It is worth noting that Kim et al [76] highlighted the potential of COVID-19 to cause more severe febrile-induced seizures.
Previous studies have reported headache frequencies ranging from 10–20% [12, 75], while this study found a frequency of 2.6%. This disparity may be attributable to the subjective nature of headache and the inability of young children to communicate this symptom.
It is important to note that this study revealed a lower frequency of muscular involvement in patients with COVID-19 than previously reported [12, 75]. This discrepancy may be attributed to variations in the clinical examination techniques.
This study had several strengths. First, although this study is not the first to evaluate the neurotropism of SARS-CoV-2 among various waves or age groups, it has the longest study duration among similar studies. Second, this study involved a comprehensive comparison of all the prevailing SARS-CoV-2 variants in Romania. Third, although our study is limited by single center data, it has the merit of including a cohort that reflects the dissemination of COVID-19 in Romania.
This study has certain limitations. The inclusion of only inpatients may lead to under-reporting of neurological symptoms in children with mild or asymptomatic COVID-19. Furthermore, the study may underestimate the self-reported symptoms, especially in younger children who cannot communicate subjective sensations. The reported frequencies may also have been influenced by the retrospective and unicentric nature of this study. Additionally, the specific SARS-CoV-2 variant for each patient could not be determined, as they were categorized based on the prevalent variant in Romania during the corresponding period.
This study highlights the necessity of conducting multicenter studies with similar methodologies to gain a comprehensive understanding of the age- and variant-specific neurological manifestations of acute SARS-CoV-2 infection. Such studies can contribute to understanding the potential risks associated with long COVID-19 syndrome.