Changes in Distribution of Severe Neurologic Involvement in US Pediatric Inpatients With COVID-19 or Multisystem Inflammatory Syndrome in Children in 2021 vs 2020

This case series assesses data from 55 US hospitals about neurologic involvement in children and adolescents with acute COVID-19 or multisystem inflammatory syndrome in children.

I n 2020, neurologic involvement in severe acute COVID-19 or multisystem inflammatory syndrome in children (MIS-C) was identified in 22% of pediatric patients (365 of 1695) hospitalized at 52 US sites from March to mid-December, and 12% had severe complications. 1 In June 2021, the B.1.617.2 (Delta) variant of SARS-CoV-2 became predominant, causing another surge of US pediatric hospitalizations. 2 In 2021, children became eligible for COVID-19 vaccination (May 12, 2021, for adolescents, 3 November 2, 2021, for children aged 5-11 years 4 ). This update on the extent of SARS-CoV-2-related neurologic involvement and documented hospital outcomes in US children and adolescents evaluates patients hospitalized during 2021 including their COVID-19 vaccination status. Data for the update came from active surveillance performed at hospitals participating in the Overcoming COVID-19 public health surveillance network (eAppendix in Supplement 1).

Design and Participants
We performed active surveillance at 55 hospitals in 31 states to identify US patients (<21 years) with severe acute COVID-19 (admitted to an intensive care or step-down unit at a participating site) or who met Centers for Disease Control and Prevention (CDC) criteria for MIS-C hospitalized between December 15, 2020, and December 31, 2021 (eTable 1 in Supplement 1). Patients with acute COVID-19 had a positive result on a SARS-CoV-2 respiratory test (reverse transcriptase-polymerase chain reaction [RT-PCR] or antigen) and symptoms related to COVID-19. Patients with MIS-C had a positive SARS-CoV-2 respiratory or antibody test result. Reporting guidelines for uncontrolled case series were followed. 5 The investigation was approved by the central institutional review board at Boston Children's Hospital and determined to meet the requirement of public health surveillance as defined in 45 CFR 46.102 (I)(2) by the CDC with waiver of consent.

Classification of Neurologic Involvement and Outcomes
Data were abstracted from medical records by trained staff. 1 Patients with life-threatening neurologic conditions and neurologic deficits (gross impairment in motor, cognitive, or speech and language functions) identified from medical records were adjudicated by neurology, neuroradiology, and critical care experts (K.L.L., T.Y.P., A.G.R.). Cases of encephalitis were adjudicated using standardized case report forms including the International Encephalitis Consortium criteria. 6 Race and ethnicity were extracted from medical records, and social vulnerability index 7 was calculated from home addresses. Vaccination eligibility and status were confirmed as previously reported (eMethods in Supplement 1).

Statistical Analyses
Descriptive statistics were used to report frequencies. Continuous variables included median and IQR, and categorical variables included counts and percentages. We used a χ 2 test, Fisher exact test, or Kruskal-Wallis test to evaluate betweengroup differences using R (version 4.0.2, R Project for Statis-tical Computing) with P < .05 considered statistically significant. Missing data were not imputed.

Results
Of 2168 patients (58% male; median age, 10.3 years) with acute COVID-19 (34%) or MIS-C (66%), 476 (22%) had neurologic involvement ( Table 1 and eFigure 1 in Supplement 1). Patients with neurologic involvement were older and had more underlying neurologic disorders than those without. Seizures were more common in younger children, and loss of taste and smell was more common in adolescents (eTable 2 and eFigure 2 in Supplement 1).
In patients with neurologic involvement, 91% had nonlife-threatening neurologic symptoms, most commonly fatigue/weakness, confusion, headache, and loss of taste/ smell. Among patients with non-life-threatening neurologic involvement, 90% survived without neurologic deficits, 5% died, and 4% were discharged alive with neurologic deficits related to sequelae of critical illness. A spectrum of lifethreatening neurologic conditions and outcomes were identified in 42 of 476 patients (9%) with neurologic involvement, including 23 (55%) with acute central nervous system (CNS) infection/acute disseminated encephalomyelitis (ADEM). Life-threatening neurologic conditions were more frequently reported during the Delta than pre-Delta periods (64% vs 36%). Ten of 42 patients (24%) survived with new neurologic deficits at discharge and 8 (19%) died (Table 2 and eTable 3 in Supplement 1).
There were 9 possible and 5 confirmed cases of encephalitis (eTable 4 in Supplement 1). Electroencephalography abnormalities included diffuse background slowing (n = 10) and/or focal seizures or epileptic discharges (n = 5). Brain magnetic resonance imaging (MRI) findings were mostly ADEMlike with multifocal, nonenhancing lesions with T2 prolongation and reduced diffusivity mainly in the deep juxtacortical and periventricular white matter, thalami, basal ganglia, brainstem, and posterior fossa and in 1 case cortical involvement in the supratentorium (eTable 4 in Supplement 1). One patient had low titer-positive myelin oligodendrocyte glycoprotein antibody (1:20) with involvement of the left temporal lobe on MRI that resolved on 9-month follow-up brain MRI. Of 23 patients with acute CNS infection/ADEM, outcomes were severe in 7 patients (30%) ( Table 2 and eTable 1 in Supple-ment 1). Representative brain MRI studies from 2 patients with acute encephalitis and 1 with meningitis and cerebral venous sinus thrombosis complication are shown in the Figure. Of the 155 vaccine-eligible patients with neurologic involvement and confirmed vaccination status, 147 (95%) were unvaccinated (Table 1 and eTable 5 in Supplement 1), includ- ing 15 of 16 patients (94%) with life-threatening neurologic conditions (Table 2).

Discussion
In 2168 US children and adolescents hospitalized with acute COVID-19 or MIS-C during 2021, the frequency, range, and severity of neurologic involvement were similar to the 2020 investigation. 1 However, there were 2 major differences between the 2 surveillance periods. First, acute CNS infection/ ADEM cases accounted for a higher proportion of life-threatening cases (55% in 2021 vs 19% in 2020). Many of these patients had subacute onset of encephalitis-like symptoms and ADEM-like imaging features and were discharged home, but 30% had severe outcomes. Because the adjudication methods for neurologic involvement were the same in both years, it is possible that the increased number of acute CNS infection/ADEM cases in 2021 were associated with the Delta variant 8 or due to more diagnostic investigations in 2021 identifying more cases. Second, most patients with severe COVID-19 or MIS-C associated neurologic involvement who were vaccine eligible were unvaccinated. Animal model data for SARS-CoV-2-induced encephalomyelitis support the possibility that it may contribute to the immunopathogenesis of encephalitis in humans. 9 Brain biopsies in 9 adults with fatal COVID-19 revealed extensive inflam-mation of both white and gray matter without detectable SARS-CoV-2. 10 Whether COVID-19 vaccination can prevent SARS-CoV-2-associated neurologic complications merits further study, weighing the immune-mediated vaccine-specific adverse neurologic events. 11,12 Limitations This investigation has multiple limitations. As a public health surveillance investigation, we were unable to study the immunobiology underlying severe complications, including the Delta variant, or assess reasons for low vaccine uptake. It is probable that we did not capture all patients. Fatigue, weakness, and headache are nonspecific symptoms that could lead to overreporting of milder neurologic involvement. Although data collection was standardized, potential misclassification of patients with neurologic involvement, including acute CNS infection/ADEM, may have occurred because of nonstandardized diagnostic investigations at each site, conducted using clinical discretion. ADEM was categorized based on the presence of encephalopathy and acute imaging features only and therefore is unconfirmed based on the 2013 International Pediatric Multiple Sclerosis Society Group criteria. 13 Myelin oligodendrocyte glycoprotein has been reported in pediatric patients with COVID-19, 14 but we cannot determine in the 1 patient if it represents a primary or autoimmune response to SARS-CoV-2 or is unrelated. A, Teenager presented with acute respiratory failure, fever, acute onset of altered awareness, confusion, agitation, and difficulty walking. Axial T2 images show myositis of the facial muscles with stranding of subcutaneous fat, sinusitis, and cavernous sinus thrombosis with T2 hypointense signal and reduced diffusivity (apparent diffusion coefficient [ADC] map). Coronal and axial T1 images with contrast demonstrate dural enhancement, filling defects in superior ophthalmic veins and cavernous sinuses consistent with thrombosis (arrowheads). The patient's brain injury evolved to diagnosis of death by neurologic criteria. B, Teenager with history of obesity, hypertension, and diabetes presented with 3 weeks of fever, confusion, headache, seizures, orofacial dyskinesias, agitation, slurred speech, difficulty walking, chorea, and left-sided weakness. Axial T2 fluid-attenuated inversion recovery (FLAIR) images demonstrate T2 hyperintense signal in bilateral cerebellar, bilateral temporal, and bilateral centrum semiovale white matter with reduced diffusivity. There was no enhancement, and susceptibility was present in lesions consistent with punctate blood products (not shown). The patient later died by brain death. C, Teenager presented with 3 weeks of fever, headaches, lethargy, confusion, seizure, vomiting, blurry vision, and nystagmus. Axial T2 FLAIR images demonstrate moderate enlargement of lateral and third ventricles, T2 prolongation in bilateral cerebellar hemispheres, bilateral thalami, and bifrontal white matter and cortex with reduced diffusivity on trace diffusion images and no enhancement (not shown). ADEM indicates acute disseminated encephalomyelitis.