The Young Minds Affected: A Deep Dive into SARS-CoV-2 Neurological Manifestations in Children

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has received widespread attention from healthcare professionals and researchers worldwide. The likelihood of pediatric patients contracting SARS-CoV-2 was lower in comparison to adults, and they generally exhibited either asymptomatic or milder symptoms. Nevertheless, there were instances in which children experienced severe and atypical illnesses.

The field of neurology has generated significant interest in relation to SARS-CoV-2 infection, with over 5000 original articles and reviews published on this topic. The occurrence of neurological manifestations in coronavirus disease 2019 (COVID-19) was not surprising, as Middle East respiratory syndrome and severe acute respiratory syndrome coronavirus 1 have been associated with a variety of neurological signs and symptoms. However, SARS-CoV-2 was associated with neurological manifestations that were not commonly reported with other coronaviruses.

It was initially believed that neurological manifestations were rare in pediatric patients. As research has pointed out the range of neurological symptoms, it has become evident that these symptoms occur frequently in children as well, although their types differ substantially from those identified in adults. It is worth noting that children generally displayed a higher frequency of seizures, whereas adults were more prone to experiencing strokes.

The neurological presentations of SARS-CoV-2 variants may differ. To the best of the authors’ knowledge, there is a lack of studies investigating all variants of concern for variant-specific neurological manifestations, despite the necessity of such research. Therefore, this study aimed to provide a thorough characterization of the neurological manifestations associated with all SARS-CoV-2 variants of concern reported in the pediatric population.

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.

The neurological consequences of COVID-19 according to age have been explored in several studies with varying results. 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.

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%), but was in line with the findings of Antoon et al. (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. 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. 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. In contrast, Antoon et al. 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.

Seizures, including de novo status epilepticus, have been frequently reported in pediatric patients with COVID-19. Moreover, some studies have indicated that seizures are the most common neurological manifestations. The reported frequencies varied across studies, ranging from 0.06% to 61.9%. 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. According to Cho et al., seizure frequency decreases with age. However, our study revealed that the highest frequency of seizures was observed in the 5–9 age group (7.8%).

This study, as well as others, 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. highlighted the potential of COVID-19 to cause more severe febrile-induced seizures.

Previous studies have reported headache frequencies ranging from 10% to 20%, while this study found a frequency of 2.6%. This disparity may be attributable to the subjective nature of headaches 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. This discrepancy may be attributed to variations in clinical examination techniques.

This study had several strengths. First, although this study is not the first to evaluate the neurological manifestations 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 underreporting 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. It should also be noted that the neurological symptoms detailed in this study are not specific to acute infection with SARS-CoV-2.

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.

Further research is needed to clarify the mechanisms underlying the neurological manifestations of SARS-CoV-2, especially in pediatric patients. Understanding these mechanisms may lead to better management and treatment strategies for affected children. Additionally, exploring the long-term neurological outcomes in pediatric patients who have recovered from COVID-19 is crucial for identifying potential long-term complications and providing appropriate care.

The findings of this study have significant implications for public health policies and clinical practice. Healthcare providers should be aware of the potential for neurological manifestations in pediatric patients with COVID-19 and consider these symptoms when diagnosing and treating children with the disease. Early recognition and management of neurological symptoms can improve outcomes and reduce the risk of long-term complications.

In conclusion, the study provides valuable insights into the neurological manifestations of SARS-CoV-2 in pediatric patients, highlighting the need for further research and improved clinical awareness. The variations in neurological symptoms across different age groups and SARS-CoV-2 variants underscore the complexity of the disease and the importance of tailored approaches to diagnosis and treatment. By addressing these challenges, the medical community can enhance the care of pediatric patients affected by COVID-19 and contribute to the broader understanding of the disease’s impact on neurological health.


Table A1. Definition used for diagnosis of new-onset neurological manifestations during acute SARS-CoV-2 infection.

Neurological
Manifestation
Definition
SeizuresA paroxysmal manifestation involving sudden loss of consciousness and uncontrollable movements, or generalized hypotonia. A pediatric neurologist determined the diagnosis through medical history and clinical presentation.
Simple febrile
seizures
A single episode of generalized seizures occurring within a 24-h period and lasting less than 15 min, in the presence of focal signs accompanied by a fever (temperature above 38 °C) in children under 5 years of age without any underlying neurological diseases .
Complex febrile seizuresSeizures that occur in children with an underlying neurological disease or prolonged (over 15 min), focal, or multiple seizures in a 24-h period in children without any underlying neurological diseases. These seizures are accompanied by a fever .
Established status epilepticusContinuous seizures or recurrent seizures without consciousness recovery over a period of 30 min or more in children who do not have fever .
Febrile status
epilepticus
Continuous seizures or recurrent seizures without consciousness recovery over a period of 30 min or more, accompanied by fever .
HeadacheA clinical diagnosis was made after the exclusion of any additional underlying disorders other than SARS-CoV-2 infection in patients who reported headaches during medical examination.
Muscular
involvement
Myalgia or hypotonia reported by the patient or detected by the pediatrician during the medical examination.
Vasovagal
syncope
A temporary, non-traumatic loss of consciousness is triggered by certain factors.
ApneaInterruption of breathing for a brief period, accompanied by bradycardia, cyanosis, or pallor.
AnosmiaPartial or complete loss of smell was reported by the patient or patient guardian during the medical examination.
DysgeusiaTaste disturbances reported by the patient or patient guardian during a medical examination.
EncephalopathyA diffuse brain condition characterized by altered mental status (lethargy, reduced consciousness, or changes in personality) that persist for over 24 h. The diagnosis was established after the exclusion of any underlaying disorder other than SARS-CoV-2 infection.
Idiopathic
endocranial
hypertension
(suggested)
Signs and symptoms of increased intracranial pressure, with a normal composition of cerebrospinal fluid, and normal brain imaging.
Ischemic strokeSudden onset of neurological symptoms such as hemiplegia or any focal neurological signs, followed by the identification of ischemic stroke through cerebral imaging.
AtaxiaThe disruption of posture and movement coordination. The diagnosis was made by a pediatric neurologist through a medical history and clinical presentation .
Peripheral
neuropathy
Self-limited symptoms of peripheral motor or sensory nerve fibers were reported during a medical examination .
Sleep MyoclonusInvoluntary and benign brief movements that occur during sleep. The diagnosis was made by a pediatric neurologist based on clinical presentation after ruling out other medical conditions .

APPENDIX 1 – Long COVID Symptoms in Children

The clinical manifestations of long COVID in children encompass a broad range of symptoms affecting multiple organ systems, typically emerging 4-12 weeks after the acute phase of infection. Here’s a detailed summary of the technical data and current understanding of these manifestations, as of June 2024:

Clinical Symptoms and Prevalence

General Symptoms:

  • Fatigue: Up to 87% of children with long COVID report persistent fatigue, significantly impacting daily activities and quality of life.
  • Headaches: Reported in about 77.9% of children, often persistent and severe.
  • Musculoskeletal Pain: Commonly includes muscle pain and joint pain, contributing to overall discomfort and functional limitations.

Respiratory Symptoms:

  • Dyspnea (shortness of breath): Reported by 13.8% to 50% of affected children.
  • Cough: Persistent cough is observed in 0.5% to 5% of cases.
  • Chest Pain: Noted in 1.4% to 31.1% of children, often associated with other respiratory symptoms.

Neurocognitive Issues:

  • Brain Fog: Concentration difficulties and memory issues are prevalent, reported in 2% to 44% of cases, often affecting academic performance and daily functioning.
  • Mood Changes: Includes irritability, mood swings, and emotional instability, reported in 23.3% of children.
  • Sleep Disturbances: Insomnia and other sleep-related issues are significant, with prevalence varying across studies.

Cardiovascular Symptoms:

  • Heart Palpitations: Commonly reported, often accompanied by anxiety and other stress-related symptoms.
  • MIS-C (Multisystem Inflammatory Syndrome in Children): A severe condition associated with high immune activation, leading to heart damage, irregular heart rhythms, and other cardiovascular issues.
  • Gastrointestinal Symptoms:
  • Nausea and Diarrhea: Persistent gastrointestinal issues, including prolonged viral shedding in the gastrointestinal tract, are notable in some cases.
  • Abdominal Pain: Often reported along with other gastrointestinal symptoms.
  • Other Symptoms:
  • Anosmia (loss of smell) and Ageusia (loss of taste): Each affecting around 11.1% of children, significantly impacting their quality of life.
  • Skin Manifestations: Includes rashes and other dermatological symptoms.

Pathophysiology

  • Viral Persistence:
  • Prolonged presence of viral RNA in tissues, particularly the gastrointestinal tract, suggests ongoing immune responses even months after the initial infection.

Autoimmunity:

  • Development of autoantibodies targeting various body systems, contributing to chronic inflammation and tissue damage.

Neuroinflammation:

  • Involvement of transient receptor potential (TRP) channels, leading to neuroinflammation and symptoms such as chronic cough, gastrointestinal disturbances, and possibly neurodegeneration in severe cases.

Epidemiology

Studies have shown varying prevalence rates, with long COVID symptoms present in approximately 7% to 15% of children at 12 weeks post-infection. Factors increasing the risk include older age, severe initial infection, and the presence of multiple organ system involvement during acute COVID-19.

Current Management Strategies

Management focuses on symptom relief and supportive care, given the broad spectrum of symptoms and their impact on children’s daily lives. Multidisciplinary approaches involving pediatricians, neurologists, cardiologists, and mental health professionals are recommended to address the complex needs of these patients.

Summary Table of Long COVID Symptoms in Children

SymptomPrevalence RangeCommonly Affected Systems
Fatigue17.9% – 87%General
Headache9.1% – 77.9%Neurological
Dyspnea13.8% – 50%Respiratory
Cough0.5% – 5%Respiratory
Chest Pain1.4% – 31.1%Respiratory/Neurological
Concentration Difficulties2% – 44%Neurological
Mood Changes23.3%Neuropsychiatric
Heart PalpitationsCommonCardiovascular
Anosmia/Ageusia11.1%Sensory
Gastrointestinal SymptomsVariableGastrointestinal

This information reflects the latest research and clinical findings as of June 2024, providing a comprehensive overview of the diverse and persistent nature of long COVID in children. For more detailed data and studies, you can refer to sources like the NHLBI, Medical Xpress, and The BMJ.


reference link :

  • https://www.mdpi.com/1999-4915/16/6/967
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10626026/

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