A new study by researchers from UPMC Children’s Hospital of Pittsburgh-USA, Johns Hopkins Children’s Center-USA, University of Washington-USA, Seattle Children’s Hospital-USA, Universidad Nacional de Colombia and Fundación Universitaria de Ciencias de la Salud-Colombia and University of Utah-USA has found that over 44 percent children hospitalized for COVID-19 had at least one neurologic manifestation including headaches and/or altered mental status.
The key findings of the study were:
-44% of hospitalized children and SARS-CoV-2 condition had neurologic manifestations
-More children with MIS-C had neurologic manifestation vs. acute SARS-CoV-2
-Headache and encephalopathy were the most common neurologic manifestations
-Older children and those with preexisting conditions were at higher risk
The study objective was to characterize the frequency, early impact, and risk factors for neurologic manifestations in hospitalized children with acute SARS-CoV-2 infection or Multisystem Inflammatory Syndrome in Children (MIS-C).
The study involved a multicenter, cross-sectional study of neurologic manifestations in children age < 18 years hospitalized with positive SARS-CoV-2 test or clinical diagnosis of a SARS-CoV-2-related condition between January 2020-April 2021. Multivariable logistic regression to identify risk factors for neurologic manifestations was performed.
The study findings were published in the peer reviewed journal: pediatric Neurology. https://www.pedneur.com/article/S0887-8994(21)00276-9/fulltext
In this preliminary report of neurologic manifestations in children hospitalized with acute SARS-CoV-2 and MIS-C: 1) neurologic manifestations were common (44%); 2) the frequency of severe neurologic conditions including stroke were uncommon, but children with neurologic manifestations were more likely to present with abnormal GCS and require ICU care; and 3) older children and those with specific pre-existing conditions and constitutional symptoms were at increased risk of neurologic manifestations, although this risk differs by acute SARS-CoV-2 vs. MIS-C diagnosis.
The frequency of neurologic manifestations in this prospective cohort of hospitalized children is lower than that reported by the GCS-NeuroCOVID Consortium – Adult study (All COVID-19 cohort, 80%)2. Our cohort had higher prevalence of neurologic manifestations than reported in a secondary analysis of the Overcoming COVID-19 study (n=1,695 children in US hospitals)6. In the latter cohort, only 22% of children hospitalized with SARS-CoV-2 infection (not reported by acute SARS-CoV-2 or MIS-C separately) had neurologic manifestations.
In that cohort, fatigue/weakness were most common, followed by altered awareness or confusion, and then headache. One explanation for the difference in neurologic manifestation type and frequency is that our study collected more granular data collection on neurologic manifestations than the Overcoming COVID-19 study, and our study did not assess fatigue/weakness11.
Finally, a meta-analysis of neurologic manifestations in SARS-CoV-2 infection in children found that fatigue/myalgia was most prevalent (14%) followed by acute encephalopathy (13%), with a lower headache and seizure prevalence than we observed at 4% and 3%, respectively15.
Differences in our study population, such as including children with pre-existing neurologic conditions and a substantial number of children with MIS-C, may account for some of the differences in reported frequency of neurologic manifestations. Many excellent reviews exist regarding potential mechanisms of neurologic manifestations with SARS-CoV-2 in children; detailed discussion of this is outside the scope of this report16.
Headache and acute encephalopathy were the predominant neurologic manifestations, especially in children with MIS-C. This differs from adults, in whom acute encephalopathy was the most commonly reported neurologic manifestation (50%), which was also associated with mortality 2.
An International Pediatric Stroke Study Group multinational study reported that of children with strokes occurring during the pandemic, fewer than half were tested for acute SARS-CoV-2 infection and that most children with stroke had underlying risk factors for stroke17.
In our study, stroke was less prevalent in children than in the adult GCS-NeuroCOVID consortium study (1% vs. 3%), but seizure/status epilepticus was more prevalent in children than adults (8% vs. 1%). Further, seizure/status epilepticus was more than twice as frequent in children with acute SARS-CoV-2 than MIS-C.
In the Overcoming COVID-19 study, seizures were more common in younger versus older children6. Other more severe conditions occurred rarely, similar to a cohort in the United Kingdom, which prospectively studied children with SARS-CoV-2-related illness who were hospitalized and received a neurology consultation7. They found more encephalopathy and neuropsychiatric manifestations occurred in the children with MIS-C versus acute SARS-CoV-2 infection.
This finding is similar to newly reported data in children with pre-existing neurologic disease with influenza18. In our study, children with SARS-CoV-2-related illness and pre-existing neurologic conditions had 3·48 higher odds for neurologic manifestation compared to children without pre-existing neurologic condition.
It is possible that children with pre-existing neurologic conditions have decreased cognitive and functional reserves and hence less tolerance to systemic insults common to hospitalized patients such as oxygen desaturation, hypotension, and fever. Children with MIS-C had more than 2 times higher odds of neurologic manifestation compared with the acute SARS-CoV-2 cohort.
This may be due in part to hyperinflammation; more research is needed19. Metabolic disease, which includes type I diabetes mellitus, was also associated with neurologic manifestations in children with acute SARS-CoV-2, with SARS-CoV-2 having mechanistic plausibility for “diabetogenic effect”, similar to other viruses20.
Clinical implications & Future
Different patterns of neurologic and non-neurologic symptoms occurred in children with acute SARS-CoV-2 versus MIS-C diagnosis, which may help identify children needing close neurologic monitoring. Consequences of critical illness and pediatric sepsis, including neurologic manifestations, functional health, and health-related quality of life impairments are increasingly recognized21, 22, 23, 24, but little is known in children with acute SARS-CoV-2 and MIS-C.
Children with life-threatening neurologic involvement (n=43) during admission in Overcoming COVID-19 study, were at risk of new neurologic deficits at hospital discharge (40%), and death (26%)6. Studies regarding treatment efficacy of interventions in children with neurologic manifestations in SARS-CoV-2-related conditions are vitally needed.
Finally, important health effects and inequalities are emerging from the SARS-CoV-2 pandemic including poor access to healthcare and education25,26, exposure to maltreatment27, developmentally important experiences28, and parental loss29,30.