Association of SARS-CoV-2 Infection with Neurological Symptoms and Neuroimaging Manifestations in the Pediatric Population: A Systematic Review

Background Neurological manifestations have been widely reported in adults with COVID-19, yet the extent of involvement among the pediatric population is currently poorly characterized. The objective of our systematic review is to evaluate the association of SARS-CoV-2 infection with neurological symptoms and neuroimaging manifestations in the pediatric population. Methods A literature search of Cochrane Library; EBSCO CINAHL; Global Index Medicus; OVID AMED, Embase, Medline, PsychINFO; and Scopus was conducted in accordance with the Peer Review of Electronic Search Strategies form (October 1, 2019 to March 15, 2022). Studies were included if they reported (1) COVID-19-associated neurological symptoms and neuroimaging manifestations in individuals aged < 18 years with a confirmed, first SARS-CoV-2 infection and were (2) peer-reviewed. Full-text reviews of 222 retrieved articles were performed, along with subsequent reference searches. Results A total of 843 nonduplicate records were retrieved. Of the 19 identified studies, there were ten retrospective observational studies, seven case series, one case report, and one prospective cohort study. A total of 6,985 individuals were included, where 12.8% of hospitalized patients experienced neurocognitive impairments: MIS-C (24.2%), neuroinflammation (10.1%), and encephalopathy (8.1%) were the most common disorders; headaches (16.8%) and seizures (3.8%) were the most common symptoms. Based on pediatric-specific cohorts, children experienced more drowsiness (7.3% vs. 1.3%) and muscle weakness (7.3% vs. 6.3%) as opposed to adolescents. Agitation or irritability was observed more in children (7.3%) than infants (1.3%). Conclusion Our findings revealed a high prevalence of immune-mediated patterns of disease among COVID-19 positive pediatric patients with neurocognitive abnormalities.


Introduction
Coronaviruses usually cause respiratory illness, but the highly pathogenic SARS-CoV-2 virus-responsible for COVID-19-is also associated with peripheral and central nervous system (CNS) disorders (1). In adults, its clinical presentation is heterogenous, ranging from asymptomatic or mild respiratory tract symptoms to severe pneumonia with acute respiratory distress syndrome (ARDS) and multiorgan dysfunction (2). During the acute stage, severe neurological and psychiatric complications may also manifest, where development of cytokine storm and thrombogenic reactions result in a high incidence of ischemic stroke and intracerebral hemorrhage (3,4). Conversely, the pediatric population is much less susceptible to serious SARS-CoV-2 infection; only 0.4% of severe cases involved children (3,5). A large percentage of children are either asymptomatic or pre-symptomatic. They generally present milder symptoms of COVID-19 and are rarely hospitalized due to a lower risk of exposure, higher levels of antibodies against viruses, and maturing angiotensin-converting enzyme 2 (ACE2) (5,6). However, as the pandemic progressed, reports of immune-mediated patterns of disease began to emerge; it became evident that other systemic symptoms could develop alongside respiratory involvement (3).
of Electronic Search Strategies (PRESS) form. The full search strategies, grey literature search, and PRESS form can all be located here: https://doi.org/10.5683/SP3/VAPXLL. Subject headings and textwords related to the following concepts were included in the search: 'brain imaging,' 'brain structure/function,' 'covid,' and 'pediatrics. ' The search strategy for the concept of COVID-19 was adapted from two published search strategies while the concept of pediatrics was adapted from four published search strategies (10)(11)(12)(13)(14).
The search strategy was developed and nalized in OVID Medline and then translated to the Cochrane Library, EBSCO CINAHL, Global Index Medicus, OVID AMED, OVID Embase, OVID PsychINFO, and Scopus. The search was ltered to human participants. No language restrictions were applied. A date limit was implemented to include articles published since 2019. The searches were run on December 22, 2021 and -prior to nal analysis -rerun on March 15, 2022 in order to incorporate papers published since the review began. The search results were exported into Endnote and subsequently imported into Covidence for two rounds of deduplication prior to screening.
Relevant grey literature was identi ed by hand searching grey literature databases and catalogs, including BioRxiv, ClinicalTrials.gov, ISRCTN Registry, MedRxiv, and the World Health Organization International Trials Registry Platform. Hand searching of the reference lists of included articles and previous reviews was also performed to identify studies that may have been missed.

Screening
Two reviewers (ATHK and JSP) independently conducted title and abstract screening on the retrieved articles based on the prede ned inclusion/exclusion criteria. Full-text screening was then independently conducted by two reviewers (ATHK and JSP) to reassess their eligibility for inclusion in the data extraction stage. Any subsequent discrepancies were resolved by discussion or by cross-referencing a third reviewer (KAK). Additionally, a manual search was performed by two reviewers (ATHK and JSP) on selected references since September 2021 to ensure that additional appropriate articles published after conducting the search strategy were screened for eligibility as well.

Eligibility Criteria
Our inclusion criteria included the following: original, peer-reviewed research articles (from "2019 October" to present); all studies (e.g., case reports, casecontrol studies, cohort studies, observational studies, pilot studies, preprints, randomized controlled trials, registered clinical trials, and other study designs) that examine the impact of SARS-CoV-2 infection on brain structure and function in the pediatric population; individuals under 18 years of age; patients with a con rmed, rst SARS-CoV-2 infection; scanned for structural and functional changes using brain CT, MRI, PET scan, or other modalities; studies reporting su cient details on neuroimaging ndings; cohort studies and case-series without group control to aid with additional data; and available full-text article.
Our exclusion criteria included the following: abstracts, dissertations, editorials, guidelines, perspective papers, or review articles; uncon rmed cases of COVID-19; patients with pre-existing neurological comorbidities; studies conducted only on animals; and studies lacking explicit reporting or inclusion of su cient details on neuroimaging ndings and COVID-19 patient performances based on standard cognitive assessments.

Data Extraction
A standardized data extraction form was developed on a Microsoft Excel spreadsheet (version 2016; Microsoft, Redmond, WA, USA) and included the following headings: article title, rst author and publication year, country of study, study design and methodology, demographic information: age (including mean and median) and gender, sample size (COVID-19 positive children), COVID-19 con rmation, COVID-19 severity stage, affected sample size (COVID-19 positive children with neurological symptoms and/or neuroimaging manifestations), and neurological complications (type of disorder and time of appearance).

Assessment of Bias and Methodological Quality
Each selected article underwent risk of bias assessment according to the study design ( Table 1). The JBI Critical Appraisal Checklist for Case Series, Cohort Studies, and Cross-sectional Studies were used based on the following domains: presence of attrition bias (number of withdrawals and drop-outs), detection bias, performance bias, reporting bias, selection bias, and 'others' (15,16). Each study was awarded one ("yes") or zero ("no") points on the JBI checklist; total points along with maximum attainable points were included. Two reviewers (MYJ and ZG) independently performed this task before coming to a mutual conclusion. All discrepancies were resolved through discussion and arbitration by a third author (ATHK).

Results
A total of 19 studies were included in this systematic review, which examined the association between SARS-CoV-2 infection and neurological symptoms and atypical neuroimaging manifestations in the pediatric population. Overall, it was found that 12.8% (n = 892 of 6,985) of hospitalized patients experienced neurocognitive impairments. By order of decreasing prevalence, it is noteworthy that MIS-C (n = 216 of 892, 24.2%) was the most common disorder, followed by neuroin ammation (n = 90 of 892, 10.1%)-which includes acute disseminated encephalomyelitis (ADEM) or encephalitis or myelitis or meningism or meningitis or meningoencephalitis-and encephalopathy (n = 72 of 892, 8.1%). Moreover, headaches (n = 150 of 892, 16.8%) and seizures (n = 34 of 892, 3.8%) were among the most commonly reported neurological symptoms. When examining symptom prevalence by age group, drowsiness was found to be more prevalent among children (n = 8 of 78, 7.3%) as opposed to adolescents (n = 1 of 52, 1.3%). More children also experienced muscle weakness (n = 8 of 78, 7.3%) as compared to adolescents (n = 5 of 52, 6.3%). Agitation or irritability was observed more in children (n = 8 of 78, 7.3%) than infants (n = 1 of 6, 1.3%). These estimates along with the primary ndings of their associated articles are summarized in Table 2. • Stroke (n = 12) • ADEM (n = 8) • Guillain-Barre syndrome/variants (n = 4) • Acute motorsensory axonal neuropathy (n = 1) • Acute fulminant cerebral edema (n 4) • Head CT performed (n = 63) •      The remaining 843 were screened by title and abstract based on the inclusion and exclusion criteria-yielding 221 eligible studies for full-text assessment. Of the 221 papers, only 19 met the inclusion criteria and 202 were excluded for the following reasons: wrong patient population (n = 108), wrong study design (n = 84), incorrect outcomes (n = 5), double study (n = 3), and wrong intervention (n = 2) (Fig. 1).
Of the 19 studies, ten were retrospective observational studies, seven were case series, one was a case report, and one was a prospective cohort study. Details of study selection are illustrated in Fig. 1

Quality Assessment Results
The component studies in our systematic review consisted of case reports/series, cross-sectional studies, and cohort studies. Overall, studies were of moderate quality with some concerns across some key domains. Since JBI does not provide domain-based scoring, a numeric value was assigned to the study delineating its overall quality. Detailed information regarding the study, the tool applied, and obtained and maximum scores are presented in Table 1.

Discussion
Although children present with milder symptoms of COVID-19, 12.8% of COVID-19 positive, hospitalized pediatric patients had experienced neurocognitive impairments across the 19 included studies. Speci cally, 24.2% of patients with neurological abnormalities had MIS-C, which was found to be the most prevalent manifestation, followed by neuroin ammation (10.1%) -including ADEM or encephalitis or myelitis or meningism or meningitis or meningoencephalitis-and encephalopathy (8.1%). When the data was categorized according to age groups, we observed that drowsiness and muscle weakness were more common among children than adolescents, and that agitation or irritability was more common among children than infants.
Many mechanistic theories have been proposed to gain a better understanding of the possible associations between COVID-19 and neurological manifestations in the pediatric population. The SARS-CoV-2 virus is known to have neurotropic abilities, using the ACE2 receptor as an entry way into host cells (17)(18)(19)(20). It is suggested that the resulting disruption of intracellular neural homeostasis may lead to in ammation and disruption of the blood-brain barrier. This overarching proin ammatory phenomenon may explain why headaches and seizures were among the most commonly reported neurological symptoms-as well as in our ndings (16.8% and 3.8%, respectively) (21). A possible explanation involves the direct entry of SARS-CoV-2 through ACE2 and/or the olfactory tract (22)(23)(24). The protective blood-brain barrier becomes disrupted, resulting in endotheliopathy and an immunologically-directed assault on the CNS (25, 26). As a result, the immune system becomes exposed to novel CNS antigens (27,28). An alternative hypothesis states that there is an elevation of systemic in ammatory markers post-viral infection, causing neurological symptoms representing injury consequent to activation of the systemic autoin ammatory system (27,29,30).
Recently, multiple studies have reported a growing number of COVID-19-infected children developing this systemic in ammatory illness-now formally recognized as MIS-C (31)(32)(33)(34). It is theorized that MIS-C may manifest as part of a post-infectious immune response -similar to the mechanism involved in the COVID-19-related autoimmune meningoencephalitis observed in adults (35). Furthermore, the MIS-C-induced cytokine storm has been proposed as another probable cause of the neurologic manifestations.
Evidence is also emerging on a potential association between COVID-19 and demyelinating disorders, such as Guillain-Barré Syndrome (GBS), in postinfectious adolescents (36-38). It is hypothesized that COVID-19 can achieve molecular mimicry due to similar antigenic factors to neurons (38-41). Such similarity enables interaction between COVID-19 and myelin autoantigens -ultimately causing myelin and neurologic damage, as seen in GBS (42,43). As syndromes such as MIS-C and GBS are relatively uncommon and understudied, longitudinal studies are needed to gain greater insight into their neuropathophysiological mechanisms and association with COVID-19-especially among different age groups within the pediatric population: infants, children, and young adults.
Despite numerous studies reporting on the neurological manifestations of COVID-19 in adults, literature about the impact of COVID-19 on the brain structure and function of children and adolescents still remains limited. In the early stages of the COVID-19 pandemic, it appeared that the pediatric population was signi cantly less affected by the virus than adults were -where most were either asymptomatic, pre-symptomatic, or had mild symptoms (3). Although a number of explanations were proposed for the decreased impact of SARS-CoV-2 infection in children, there is still no signi cant evidence to support these claims (42). As the pandemic progressed, cases of children becoming seriously ill surfaced and became more widespread-among which some children acquired MIS-C requiring intensive care and the less severe, Kawasaki-like disease (27,(44)(45)(46)(47).
When comparing adult cases to pediatric cases, it was found that most adult patients did not exhibit the respiratory symptoms of the initial COVID-19 infection (35). Additionally, Monrand et al. conducted a case series of seven adolescents who displayed persistent functional complaints following a con rmed or suspected SARS-CoV-2 infection. They showed evidence of a PET hypometabolism pattern involving the olfactory gyrus and medial temporal lobes that extended to the pons and cerebellum-similar to that previously discovered in adults with long COVID (48). This data supports the possibility of long COVID in children, given that all participants-regardless of age-shared a functional brain involvement during the acute COVID-19 stage (48, 49). However, it is important to highlight that there is limited knowledge on the neurological involvement and long-term effects of the SARS-COV-2 virus on children and young adults, as there is currently no substantial research examining the subject (50).
Future research must urgently focus on identifying subsets of children who are more susceptible to developing the aforementioned autoimmune manifestations -particularly as more children are returning to school and the risk of transmission heightens. It will also be important to investigate the impact of vaccination status in preventing these neurological presentations. Additional longitudinal studies are needed to establish a stronger relationship between pediatric neurological impairment and SARS-CoV-2 infection as an underlying etiological factor, thoroughly chart the neurological presentations of COVID-19 into groups of syndromes based on observed patterns, investigate pediatric speci c cohorts at presentation along with long-term follow-up, and ascertain underlying mechanisms as well as promising therapeutic interventions. The foregoing neurological aspects associated with COVID-19 overlap with some observations in adults similarly infected with COVID-19, and add to the previously observed elevated rate of neurological and psychiatric disorders consequent to the pandemic (51-53).

Limitations
The study has certain limitations. A key limitation of this study was the primary use of case reports/series and retrospective studies. Our data showed characteristic imaging abnormalities in children with MIS-C associated with COVID-19, but its frequency among all a icted children is uncertain. Additionally, only hospital-recognized cases of COVID-19-related neurological involvement were included, which may not adequately re ect the scope and severity among the entire pediatric population. Another limitation was the lack of data available on the longitudinality of neurological presentations. Finally, speci c neurological complications-such as olfactory impairment, which was commonly reported in adults-should also be studied in the pediatric population by functional neuroimaging study (54).

Conclusion
This systematic review evaluates the association of SARS-CoV-2 infection with neurological symptoms and neuroimaging manifestations in the pediatric population and shows that, while a signi cant percentage of children and adolescents experienced MIS-C, neuroin ammation, and encephalopathy were-by comparison-moderately common. However, due to limited data on pediatric-speci c subsets, more longitudinal studies are required to characterize the heterogenous neurological presentations of COVID-19 into either 'infant,' 'children', or 'adolescent' categories. Hence, with loosening pandemic restrictions, our focus must urgently address this gap in knowledge in order to identify the demographic that is most vulnerable to developing COVID-19-associated autoimmune disorders.