Neurotropic mechanisms in COVID-19 and their potential influence on neuropsychological outcomes in children

Abstract

Children have shown more physical resilience to COVID-19 than adults, but there is a cohort of vulnerable infants and young children who may experience disease burden, both in the acute phase and chronically. Children may have had early undocumented exposure to COVID-19. Even when the risk of exposure was known, developmental variables may have made the avoidance of physical proximity difficult for children. Preliminary hypotheses concerning neurotropic factors have been documented by researchers. Children with COVID-19 and comorbid physical or mental disorders may be vulnerable to exacerbations of neurotropic factors and comorbidities, the neural impact of which has been documented for other coronaviruses. Researchers are investigating COVID-19 symptom descriptions, neurotropic mechanisms at the genomic and transcriptomatic levels, neurological manifestations, and the impact of comorbid health complications. Neuropsychologists need information concerning the likely impact of COVID-19 on children. With a view toward that goal, this article provides recommendations for relevant for some initial updates in neuropsychology practice.

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Child Neuropsychology
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Neurotropic mechanisms in COVID-19 and
their potential influence on neuropsychological
outcomes in children
Lois O. Condie
To cite this article: Lois O. Condie (2020): Neurotropic mechanisms in COVID-19 and their
potential influence on neuropsychological outcomes in children, Child Neuropsychology, DOI:
10.1080/09297049.2020.1763938
To link to this article: https://doi.org/10.1080/09297049.2020.1763938
Published online: 13 May 2020.
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Neurotropic mechanisms in COVID-19 and their potential
influence on neuropsychological outcomes in children
Lois O. Condie
Department of Neurology, Harvard Medical School, Boston, MA, USA
ABSTRACT
Children have shown more physical resilience to COVID-19 than
adults, but there is a cohort of vulnerable infants and young children
who may experience disease burden, both in the acute phase and
chronically. Children may have had early undocumented exposure to
COVID-19. Even when the risk of exposure was known, developmen-
tal variables may have made the avoidance of physical proximity
difficult for children. Preliminary hypotheses concerning neurotropic
factors have been documented by researchers. Children with COVID-
19 and comorbid physical or mental disorders may be vulnerable to
exacerbations of neurotropic factors and comorbidities, the neural
impact of which has been documented for other coronaviruses.
Researchers are investigating COVID-19 symptom descriptions, neu-
rotropic mechanisms at the genomic and transcriptomatic levels,
neurological manifestations, and the impact of comorbid health
complications. Neuropsychologists need information concerning
the likely impact of COVID-19 on children. With a view toward that
goal, this article provides recommendations for some initial updates
in neuropsychology practice.
ARTICLE HISTORY
Received 5 April 2020
Accepted 27 April 2020
KEYWORDS
COVID-19; pediatric;
neuropsychology;
assessment; disease burden
It is important to begin gathering data concerning the potential impact of COVID-19
(also called SARS-CoV-2) on the integrity of brain functioning in children.
Neuropsychologists need to be prepared for a possible uptick in referrals of children
who have suffered from COVID-19. This article represents an initial attempt to under-
stand the potential ramifications of COVID-19 in children referred for neuropsycholo-
gical assessment. The clinical symptoms of COVID-19 infection in children are not
typical and tend to show a more benign clinical course in comparison to adolescent
and adult patients. Nonetheless, concern remains about the health and wellbeing of
infants and young children during the COVID-19 crisis, some of whom have become
seriously ill. From the beginning, children were vulnerable to the early spread of the virus
and it later spread via familial clustering (Shen et al., 2020). Concern about children is
based on the knowledge that coronaviruses can affect the developing nervous systems of
infants, children, and adolescents (Bale, 2012).
Coronaviruses have both an acute and a lasting effect on the central nervous system
(CNS). Initial efforts to document COVID-19 impact have focused on the acute phase of the
CONTACT Lois O. Condie lois.condie@childrens.harvard.edu Department of Neurology, Boston Children’s
Hospital, HMS, 300 Longwood Avenue, Fegan 11, BCH 3213, Boston, MA, 02115, USA
CHILD NEUROPSYCHOLOGY
https://doi.org/10.1080/09297049.2020.1763938
© 2020 Informa UK Limited, trading as Taylor & Francis Group

illness but data concerning other coronaviruses raises the likelihood of persisting impact.
Based on predictors relevant to other coronaviruses, coronaviruses have the potential to
cause nerve damage via diverse pathways (Y. Wu et al., 2020). Likely outcomes include
encephalitis due to viral infections in the CNS, toxic encephalopathy caused by severe viral
infections, and severe acute demyelinating lesions developed after viral infections (Saad
et al., 2014). The virus may be neurotropic and may invade nervous tissue and cause
infections of immune system cells (macrophages, microglia, astrocytes) in the CNS (Y.
Wu et al., 2020). Neurological diseases may be caused or exacerbated by coronavirus
invasion. If SARS-CoV is a valid exemplar of other coronaviruses, expected outcomes
may include polyneuropathy, encephalitis, aortic ischemic stroke activity, cerebral edema,
meningeal vasodilation, and demyelination of nerve fibers (Gu et al., 2005), all of which are
known to affect neuropsychological functioning. If MERS-CoV is a valid exemplar, it adds
to concern that COVID-19 is potentially neuroinvasive (Kim et al., 2017;Saadetal.,2014).
To briefly review key terms and mechanisms, encephalitis refers to inflammatory lesions
in the brain parenchyma caused by pathogens (neuronal damage, nerve tissue lesions). It
causes headache, fever, vomiting, convulsions, and consciousness disorders. Early diagnosis
is critical. Infectious toxic encephalopathy, or acute toxic encephalitis, refers to reversible
brain dysfunction during acute infection. It causes a diverse and complex array of symp-
toms that may include headache, dysphoria, delirium, disorientation, loss of consciousness,
coma, and paralysis. Respiratory-related infection is an independent risk factor for acute
cerebrovascular disease. COVID-19 can aggravate ischemic brain injury by triggering
a cytokine cascade, particularly in young children (Dong et al., 2020), increasing the risk
of cerebral hemorrhage (Y. Wu et al., 2020). Indeed, a primary mechanism by which
chronic outcomes are potentiated is the induction of an over-activation of the immune
system, in part due to the activation of autoreactive immune cells associated with auto-
immunity in susceptible individuals. (Desforges et al., 2014).
Mechanisms of COVID-19 infections on nervous system damage include direct
infection, blood circulation pathway, neuronal pathway, hypoxia injury, immune injury,
angiotensin-converting enzyme-2 (ACE2), and other possible mechanisms. It currently is
believed that COVID-19, in concert with host immune mechanisms, may turn acute
infection into a persistent process that may lead to neurological diseases (Y. Wu et al.,
2020). ACE2 serves an important function in the introduction of COVID-19 to the CNS.
Receptors on the human cells which spike glycoproteins (S proteins) on the COVID-19
surface binds to ACE2, similar to SARS-CoV. ACE2 is mainly expressed in the human
lungs, but it also is expressed in the gastrointestinal tract, kidneys, and heart. Human cells
are infected by the entrance of COVID-19 via S proteins binding to ACE2. After the virus
enters into the cells, the viral ribonucleic acid (RNA) genome is released into the
cytoplasm and is translated into viral proteins. That process is followed by fusion
between the vesicles containing the virus particles and the plasma membrane in order
to release the virus (Haşlak et al., 2020). It is through these cellular-level processes that
researchers are beginning to explore the neurotropic mechanisms of COVID-19.
Neurotropic mechanisms of COVID-19 in the acute phase
There is an urgent need to understand the neurotropic potential of COVID-19, particu-
larly in children due to their active neurodevelopment statuses. ACE2 is the mechanism
2L. O. CONDIE

by which the virus gains entry to cells. In only a short time following the outbreak,
researchers illustrated that, similar to SARS-CoV, COVID-19 exploits ACE2 receptors to
gain entry inside the cells. This finding raises concerns about the expression of ACE2 in
neural tissue. There is preliminary evidence that COVID-19 targets the CNS via tissue
distribution, host–virus interaction, and proposed neurotropic mechanisms (Baig et al.,
2020). The brain has been reported to express ACE2 receptors detected over glial cells
and neurons, which makes them a potential target of COVID-19. Researchers must
determine its possible contribution to neural tissue damage to COVID-19 morbidity
and mortality.
ACE2, the functional receptor for COVID-19, is present in multiple human organs. It
is the same receptor used in SARS-CoV (also known as SARS). Coronavirus has been
isolated in cerebrospinal fluid (CSF) and brain tissue on autopsy in individuals with
SARS-CoV and MERS-CoV. COVID-19 has 10 to 20 times the receptor affinity to ACE2
receptors, compared to SARS CoV or SARS (Baig et al., 2020). The movement of the virus
to the brain via the cribriform plate close to the olfactory bulb may serve as an additional
pathway that could enable the virus to reach neural tissue (Netland et al., 2008) in the
acute phase.
1
Some coronaviruses have been demonstrated to spread via the synapse-
connected route from mechanoreceptors and chemoreceptors in the lung and lower
respiratory airways (Li et al., 2020). The invasion of COVID-19 via the ACE2 receptors in
the human airway epithelia, lung parenchyma, vascular endothelia, kidney cells, and
small intestine cells could serve as a portal for neurotropic mechanisms. The exact
COVID-19 route remains to be determined in empirical studies.
The systemic circulation of COVID-19 during an early or later phase of infection may
lead to cerebral involvement comparable to that reported for individuals with SARS-
CoV. The presence of the virus in the general circulation likely enables it to pass into the
cerebral circulation. Once within the setting of neuronal tissues, its interaction with
ACE2 receptors expressed in neurons may initiate a cycle of viral budding that leads to
neuronal damage. The endothelial ruptures in the cerebral capillaries can lead to brain
bleeding within the cerebral tissue that can result in fatality (Netland et al., 2008). Other
mechanisms involve the body’s stress reaction to illness. Individuals with the underlying
neurological disease may be more vulnerable to neurological manifestations of COVID-
19 via the exacerbation of the typical stress-response mechanisms (Servick, 2020).
Following the acute phase of illness, there is reason to believe that neurotropic effects
may lead to persisting problems.
Chronicity of neurotropic mechanisms of COVID-19
COVID-19 is a particularly virulent strain of coronavirus and careful monitoring of
chronic CNS outcomes is needed. The clinical effects of other coronaviruses have been
studied since the late 1960s. Coronavirus circulates throughout the world, predomi-
nantly during the winter in temperate regions, and they affect younger children and
individuals with underlying severe chronic diseases (Principi et al., 2010). Several
recognized respiratory coronavirsues have a neuroinvasive capacity. They can spread
1
The neuroinvasive potential of COVID-19 may play a role in respiratory failure and cardiorespiratory control (Netland
et al., 2008).
CHILD NEUROPSYCHOLOGY 3

from the respiratory tract to the CNS. Once there, infection of CNS cells can lead to
encephalitis and long-term neurological diseases (Desforges et al., 2014). When they
infect infants and young children, the results can be severe (Principi et al., 2010).
Initial concern about the impact of coronaviruses centered upon upper respiratory
tract infections in children, particularly those born prematurely or with a chronic under-
lying disease. Combined information from epidemiological and cellular studies later
highlighted CNS involvement. Epidemiologists illustrated that children were vulnerable
to coronaviruses that have been in continuous circulation since their initial identification
and isolation (e.g., HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1). These
coronaviruses have been identified in both hospitalized and non-hospitalized children
(Principi et al., 2010).
Clinical manifestations of coronaviruses initially include respiratory problems. Other
symptoms follow. Coronaviruses have been found in CSF, which suggests that pathogens,
once in the lungs, can spread throughout the body and eventually reach the CNS. There is
a relationship between coronavirus infections and (a) CNS damage related to encepha-
lopathies and encephalitis, (b) status epilepticus (Bohmwald et al., 2018), (c) the devel-
opment of multiple sclerosis, (d) brain damage associated with inflammatory processes,
(e) brain damage associated with febrile seizures (Principi et al., 2010) and afebrile
seizures (Bohmwald et al., 2018), and (f) progressive multifocal leukoencephalopathy
(Desforges et al., 2014). Children with compromised lung function associated with other
conditions are particularly vulnerable to these chronic outcomes.
Pediatric patients
Children are a unique population due to developmental factors that may make it difficult
for them to adhere to guidelines designed to prevent person-to-person spread of COVID-
19. Guidelines include preventing close contact with other individuals by keeping at least
6 ft. between individuals, covering one’s mouth when coughing, remaining clear of
regions that might contain droplets that could be inhaled into the lungs, and spread
that can occur in asymptomatic individuals. In the U.S., state by state stay-at-home
policies have been put into place, but elementary and high schools were somewhat late to
move to remote platforms in comparison to college campuses. Daycare closings occurred
even later than elementary school closings. Children of essential personnel remained
in day care settings or were placed with extended family members and friends. Indeed,
the U.S. healthcare sector has some of the highest child care obligations, with 28.8% of the
healthcare workforce needing to provide care for children between ages 3–12 (Bayham &
Fenichel, 2020). Those children may remain vulnerable to person-to-person transmission
due to the difficulty of establishing within-day-care social distancing norms to which
children can adhere. Additionally, unless key family members situate themselves else-
where temporarily, living with family members who are health care providers poses
a person-to-person transmission risk to children. Other children who face risk are those
whose caretakers are confused by conflicting governmental directives and advisories and
may be non-adherent to advisories.
With these potential person-to-person transmission factors in mind, researchers have
begun to examine direct COVID-19 impact in pediatric populations. Concern stems
from the fact that other coronaviruses are responsible for high rates of mortality and
4L. O. CONDIE

morbidity, mainly in young children, elderly individuals, and immunocompromised
individuals (Bohmwald et al., 2018). In pediatric patients with COVID-19, among the
171 children (age 10 or younger; the median age of 6.7 years) who tested positive (of 1391
tested) for COVID-19 in Wuhan, China, between January 28 and February 26, 2020 (Lu
et al., 2020), the most commonly reported symptoms included fever (41.5%), cough
(48.5%), pharyngeal erythema (46.2%), tachycardia (42.1%, and tachypnea (28.7%). Less
common symptoms (5.8%) included diarrhea, fatigue, emesis, nasal congestion, and
rhinorrhea. Of the children who tested positive, 15.8% were asymptomatic, 19.3% had
an upper respiratory infection, and 64.9% had pneumonia. Most infected children had
a milder clinical course than adults. Asymptomatic infections were not uncommon. Only
three of the children required admission to the intensive care unit and mechanical
intubation (one patient with leukemia, one with hydronephrosis, and one with intussus-
ception). There was one death in this population.
2
No neurological symptoms were reported in this small sample pediatric population of
children with COVID-19 (Lu et al., 2020), as was similarly seen in the Dong et al. (2020)
study cited above. Nonetheless, there is possible concern about the use of ACE inhibitors in
pediatric populations because of cytokine storm in younger children. Cytokine expression
profiles in hospitalized children with other coronaviruses have revealed relevant antibodies
in children with acute encephalitis-like syndrome and respiratory tract infection. The level
of serum granulocyte colony-stimulating factor (G-CSF) and the serum level of granulo-
cyte-macrophage colony-stimulating factor (GM-CSF) were significant higher in children
with coronavirus infections that children without it, illustrating the importance of host-
immune responses in disease progression (Li et al., 2016).
3
The high level of CSF seen in the
study was consistent with the fact that CNS viral infection might induce proliferation of
microgliaand astrocytes, resulting in the release of interleukin-8 (IL-8) serum. IL-8, known
as a neutrophil chemotactic factor, causes granulocytes to migrate toward the site of
infection. It plays an important mediator role in the immune reaction.
4
IL-8, in combina-
tion with other accumulated cytokines
5
may play a role in immune damage of the CNS of
individuals with coronavirus infections (Li et al., 2016).
Thus, if COVID-19 proves to have persisting effects on the CNS, pediatric populations
may carry the risk of neuropsychological impact. Furthermore, children may face medical
coping difficulties that tax their levels of resilience. A life-threatening illness can lead to
medical coping difficulties both during and well after the illness (K. Wu et al., 2005).
Predictors of medical coping difficulties in previous studies included the illness itself, the
level of emotional support provided to the individual, and the invasiveness of medical
procedures. Children, like adults,have facedCOVID-19 fear, uncertainty, and physical and
social isolation. They may miss school for a prolonged period of time. Researchers, using
symptom checklist data, have illustrated an increase in children’s clingy behavior, worrying,
compulsive update requests, sleep and appetite disturbances, fatigue, distractibility, irrit-
ability, inattention, and fear of asking questions (Jiao et al., 2020).
2
A 10-month-old infant with intussusception and resultant multi-organ failure passed away (Lu et al., 2020).
3
The cytokine expression differences in this sample of 419 hospitalized children, 12% of which showed this described
outcome, could not be attributable to other factors such as age or severity of the condition (Li et al., 2016).
4
In mouse studies, it plays a role in inflammatory responses involving injury to the brain (Li et al., 2016).
5
IL-6, MCP-1, transmigration of monocytes across the blood-brain barrier, recruitment of inflammatory cells into the CNS.
CHILD NEUROPSYCHOLOGY 5

For children, the impact related to hospitalization and associated risk factors may also
be relevant. After any severe case of pneumonia, a combination of underlying chronic
diseases and prolonged inflammation increases the risk of future illnesses, including
heart attack, stroke, and kidney disease. Individuals who spend time in an intensive care
unit, regardless of the reason why, are prone to physical, cognitive, and mental health
problems. Those who survive a long period on a ventilator are prone to muscle atrophy
and weakness. Upon leaving the intensive care unit, many individuals still have the virus
and must remain quarantined at home before receiving any relevant rehabilitation
services. The threat of infection has dampened efforts by others to provide social and
emotional support to recovering children. Researchers are trying to look ahead to the
neuropsychological, social, and emotional impact of the virus (Servick, 2020), along with
the hidden impact of deteriorating diets and remaining sedentary during the COVID-
19 period of stay-at-home advisories (Barnett, 2020). These data highlight the need to
foster resilience in children as they learn to cope in novel ways.
Understanding how COVID-19 affects children, in terms of both neurotropic and
medical coping impact, is critical for accurately assessing the global impact of the
epidemic. Although children may be less likely to develop severe COVID-19, a small
number of children are more vulnerable to the disease and its complications. Younger
children with underlying pulmonary pathology and immunocompromising conditions
are likely to have more severe outcomes. Some young children have been ill enough to
require hospitalization. A small percentage of children have become seriously ill
(Heimdal. et al., 2019)
6
Comorbidities
Comorbid conditions are less common in children than adults, but some children face
added risk due to comorbid conditions. Comorbidities are of concern because they may be
directly caused or exacerbated by COVID-19. Comorbidities cannot be underestimated. In
New York state, about 86% of reported COVID-19 deaths involved at least one comorbidity
(Frankl, 2020). Of the 5489 early April 2020 fatalities in New York, leading comorbidities
included hypertension, diabetes, and hyperlipidemia. Similar figures are seen elsewhere.
Among laboratory-confirmed cases of COVID-19, patients with any comorbidity yielded
poorer clinical outcomes than those without. A greater number of comorbidities also
correlated with poorer clinical outcomes (Guan et al., 2020). Comorbidities may exacerbate
already existing symptoms and ultimately tax medical coping capacities and result in
functioning deficits. It is well known that illness, adversity, stress, and trauma can have
a negative impact on the developing brain (Heilman et al., 2003).
Most coronavirus infections are self-limited and the virus is cleared by immunity with
minimal resultant clinical consequences. Unfortunately, in more vulnerable individuals,
viruses can also reach the lower respiratory tract where they cause more severe illnesses.
Examples include bronchitis, pneumonia, exacerbations of asthma, chronic obstructive
6
The attributable risk factors from COVID-19 are difficult to detect because children with severe cases have viral co-
infections in up to two-thirds of cases (Heimdal. et al., 2019). We do not fully understand the role children may play in
community-based viral transmission and impact, even when children remain asymptomatic. Studies of the reasons why
children are affected differently than adults, if it indeed turns out to be true in the long term, will clarify our
understanding of the disease and ways to treat or prevent it.
6L. O. CONDIE

pulmonary disease (COPD), and different types of severe respiratory distress syndromes
(Desforges et al., 2019). Although cerebral damage may result from COVID-19, it is likely
that widespread dysregulation of homeostasis caused by pulmonary, circulatory cardiac,
and renal damage contributes to fatalities.
The first sign of that dysregulation is seen in the acute phase. COVID-19 causes acute and
potentially lethal pneumonia, with clinical symptoms similar to those reported in severe
acute respiratory syndrome caused by (SARS-CoV) and Middle East respiratory syndrome
coronavirus (MERS-CoV). Indeed, the most characteristic symptom of individuals with
COVID-19 is respiratory distress. Some children have been admitted to intensive care units
due to pneumonia and respiratory distress. Most patient admissions to intensive care result
from their difficulty breathing spontaneously. These symptoms may be accompanied by
nonspecific neurologic signs that include headache, nausea, fatigue, and emesis.
Other specific symptoms, present in a small portion of COVID-19 cases, include
seizures, coma, acute ischemic stroke, abnormally increased blood pressure, and coagu-
lation dysfunctions. Those symptoms occur more often in elderly populations of indivi-
duals with COVID-19 than in children. Conditions already present in individuals may be
exacerbated by the binding of ACE2 receptors in vascular endothelial and other cells.
Children and adults with autoimmune diseases are at high risk of severe COVID-19 and
exacerbations of their autoimmune diseases (Zhang, 2020).
The impact of comorbidities are not easily separated from preliminary data concern-
ing neurotropic factors, but it is well known that physical illness comorbidities increase
the odds of a variety of adverse health outcomes, both physically and psychosocially. The
psychosocial impact is as extensive for children and adolescents as it is for adults, but
with the added neurodevelopmental influence of the seeming permanency of a subjective
sense of loss of wellness (Seng et al., 2005).
Preliminary data comparing COVID-19 to other coronaviruses
Awiderangeofvirusesfromdifferent families of the virus, and from different geographic
regions, have been demonstrated to cause immediate and delayed neuropathology. When
infections and neurotropic mechanisms, the resulting immune response can disrupt complex
structural and functional features of the CNS, sometimes irreversibly. The ability of a virus to
cause immediate or lasting infection impact in the CNS typically is due to a complex range of
factors that include host genetics, specific interaction with the host immune system, capacity
to spread to the brain, and unique modalities of neuron-to-neuron spread within the CNS.
Those interactions collectively determine the speed and severity of CNS impact. (Ludlow et al.,
2016). Before the onslaught of COVID-19, a better understand was needed of the character-
istics of those infections and the mechanisms that underlie their clinical manifestations. Below
is a description of what we know about the impact of other coronaviruses.
Case reports of the physical impact of COVID-19
More information is needed about the epidemiology, pathophysiology, and clinical manifes-
tations of COVID-19. Preliminary data about the physical impact of COVID-19 and other
coronaviruses are summarized in Table 1. This section begins with a description of pre-
liminary data concerning COVID-19 impact and it is followed by a comparison to the impact
CHILD NEUROPSYCHOLOGY 7

of other coronaviruses. COVID-19 is primarily a respiratory virus, but it has a potential
impact on other organs that includes mild acute kidney injury, liver (mild transaminitis), and
Table 1. COVID-19 Synopsis.
The Epidemiology, Pathophysiology, and Clinical Manifestations of COVID-19
7
Virology
(1) COVID-19 is a betacoronavirus in the same subgenus as a severe acute respiratory syndrome (SARS).
(2) The structure of the receptor-binding gene is has been shown to use the angiotensin-converting enzyme 2 (ACE2)
for cell entry.
(3) The Middle East respiratory syndrome (MERS) virus is another betacoronavirus but it is more distantly related.
Epidemiology
(1) There are more than 3.6 million confirmed cases of COVID-19.
(2) Cases have been reported on all continents except Antarctica. Cases have been steadily rising worldwide.
Pathophysiology
(1) COVID-19 can be transmitted on a person-to-person basis prior to the development of symptoms and throughout
the course of the illness.
(2) Transmission from asymptomatic individuals has been described.
(3) Transmission from environmental contamination has been described.
(4) The incubation period for COVID-19 is described as 14 days, with most symptom manifestations occurring within
4–5 days following exposure.
(5) The acute phase of COVID-19 may last as little as 1 week or as long as 6 weeks. Serious symptoms typically
develop after 8 days.
(6) The spectrum of clinical manifestation ranges from asymptomatic to critical.
(7) Severe manifestations may occur in otherwise healthy individuals of any age, but it occurs predominantly in
infants, young children, and elderly individuals.
(8) Comorbidities associated with severe morbidity and mortality include cardiovascular disease, diabetes mellitus,
hypertension, chronic lung disease, cancer, chronic kidney disease, immunocompromising conditions, liver
disease, and obesity.
(9) Lab features associated with worse outcomes include lymphopenia, elevated liver enzymes, elevated lactate
dehydrogenase, elevated inflammatory markers, elevated D-dimer, elevated prothrombin time, elevated tropo-
nin, elevated creatine phosphokinase, and acute kidney injury.
(10) Higher viral RNA levels in respiratory specimens are associated with worse outcomes.
(11) The virus may be neurotropic and may invade nervous tissue and cause infections of immune system cells
(macrophages, microglia, astrocytes) in the CNS.
(12) ACE2 is the functional receptor for COVID-19. It is the mechanism by which the virus gains entry into cells. ACE2 is
present in multiple human organs, including the nervous system.
(13) The presence of the virus in the general circulation likely enables it to pass into the cerebral circulation.
(14) The endothelial ruptures in the cerebral capillaries can lead to brain bleeding within the cerebral tissue that can
result in fatality.
(15) The movement of the virus to the brain via the cribriform plate close to the olfactory bulb, may serve as an
additional pathway that could enable the virus to reach neural tissue.
(16) There is a relationship between other coronavirus infections and CNS damange related to encephalitis, ence-
phalopathies, and other CNS outcomes.
(17) Individuals with the underlying neurological disease may be more vulnerable to neurological manifestations of
COVID-19 via the exacerbation of the typical stress-response mechanisms. Children with compromised lung
function associated with other conditions are particularly vulnerable to CNS outcomes.
(18) Particularly for children, one mechanism by which chronic outcomes are potentiated is the induction of an over-
activation of the immune system
Clinical Manifestations
(1) Pneumonia is the most frequent serious manifestation of COVID-19, characterized by fever, dry or productive
cough, dyspnea, and bilateral infiltrates on chest imaging.
(2) Other common symptoms include fatigue, anorexia, myalgias, emesis, headache, sore throat, rhinorrhea, anosmia,
dysgeusia. There have been rare reports of dermatologic findings.
(3) Complications include arrhythmias, acute cardiac injury, shock, cardiomyopathy, pulmonary embolism, acute
stroke, lymphopenia, leudopenia, leukocytosis, and extubation inflammatory response.
(4) Psychosocial manifestations may include disruption of corticolimbic pathways, with resultant acute and lasting
medical coping difficulties, trauma reactions, anxiety, depression, somatization, and other emotional and beha-
vioral changes.
(5) Examples of psychosocial impact may include affect lability, episodic rage, depression, and anxiety. Examples
stemming from prefrontal involvement may include impulsive conduct, apathy, rigidity, deficits in self-awareness,
reduced judgment, and memory deficits.
7
The epidemiology, pathophysiology, and clinical manifestations of COVID-19 have been summarized by McIntosh et al.
(2020). Information in this table is drawn from their summary and from other sources as cited in the text of this article
(Anderson et al., 2001; Baig et al., 2020; Bohmwald et al., 2018; Desforges et al., 2014; Gu et al., 2005; Netland et al.,
2008; Spreen et al., 1995; Y. Wu et al., 2020).
8L. O. CONDIE

cardiomyopathy that occurs later in the course of illness–typically post-extubation after the
patient shows respiratory improvement. Preliminary data are complicated by the difficulty of
recording symptoms in the range of mild to severe cases, with severe cases getting the most
attention. Reports of neurological impact have been limited but there is concern about
encephalitis (present of the virus in CSF), and meningitis (Ando et al., 2020).
8
Case studies have revealed some early data. In a retrospective case series from three
designated COVID-19 hospitals in Wuhan, China (January 16-February 19 2020, not peer-
reviewed), 70 out of 214 individuals (36.4%) with lab-confirmed COVID-19 showed neuro-
logical manifestations (Mao et al., 2020).Thesymptomswereidentified by retrospective chart
reviews conducted by two trained neurologists. Individuals with severe diseases (as defined by
neurological guidelines) were more likely to have neurological manifestations (cases with
neurology inter-rater reliability were counted as having those manifestations). Three cate-
gories were defined and included: (a) CNS symptoms (24.8%; headaches, dizziness, impaired
consciousness, ataxia, acute cerebrovascular disease such as ischemic stroke or hemorrhage,
and seizure), (b) peripheral nervous system (PNS) symptoms (8.9%; hypogeusia, hyposmia,
and neuralgia), and (c) skeletal muscle symptoms (10.7%; myalgia and CK>200 U/L).
Statistical p-values were significant across many symptoms when comparing individuals
with severe symptoms to those with non-severe symptoms. Because nuanced analyses were
not possible, it was unclear from the data whether individuals with stroke had vascular risk
factorsorifthestrokeswereafunctionofviralvasculitis.Theindividualsintheseveregroups
were more likely to have comorbidities of hypertension and diabetes, so it remains unclear
whether the comorbidities and not direct COVID-19 impact put those individuals at higher
risk of vasculitis and other complications.
Lab outcomes were reviewed by those same researchers. Individuals with severe
disease coupled with CNS symptoms had lab differences. They had lower lymphocyte
and platelet counts, and higher BUNs. Individuals without severe disease showed no lab
differences between those with and without CNS symptoms. Lymphopenia has been
identified in many individuals with COVID-19, so it interesting that those individuals
with CNS symptoms had lower lymphocyte counts. Immunosuppression may be the
agonist for CNS involvement in individuals with severe COVID-19. There were no
differences in the labs of individuals with and without PNS symptoms. Individuals
with muscle injury had higher absolute neutrophil count (ANC), lower alamine amino-
transferase (ALT), higher C-reactive protein (CRP), higher D dimer (indicative of an
inflammatory response), and more severe liver (higher LDH, AST, and ALT) and kidney
(higher BUN and Cr) abnormalities. Only one person had a seizure and it was unknown
whether that patient had comorbid epilepsy.
In a more extended study that was specific to children, researchers used a retrospective
analytical approach to study 2143 pediatric patients with COVID-19. Children of all ages,
and regardless of gender, were susceptible to COVID-19. Clinical manifestations in pedia-
tric populations generally were less severe than adults, but young children, particularly
infants, were quite vulnerable to the infection. There were 731 (34.1%) laboratory-
confirmed cases and there were 1412 (65.9%) suspected cases among those reported to
8
Early data have been gleaned from descriptive analyses and news reports more than peer-reviewed publication data.
Thus, the typical peer-review standards are pending but they have not been feasible or possible during this time of
crisis.
CHILD NEUROPSYCHOLOGY 9

the Chinese Center for Disease Control and Prevention (January 16-February 8 2020). Most
of the children likely were exposed to family members and/or other children with COVID-
19, and contracted it in the form of person-to-person transmission (Dong et al., 2020).
The less severe impact on children in these preliminary studies may be related to
both exposure and host factors. Children are usually well cared for at home. They
likely have relatively less chance to expose themselves to severely ill individual.
Children may be less sensitive to COVID-19 because the maturity and function, or
binding ability, of ACE2 in children may be lower in children in comparison to
adults. Additionally, children typically experience respiratory infections in winter
and thus may have higher wintertime virusantibodylevelscomparedtoadults
(Dong et al., 2020). Radiography illustrates that even when children develop pneu-
monia, they have less severe lung inflammation than adults (B. Li et al., 2020).
Unfortunately, if lessons are taken from other coronaviruses, these protective factors
will not apply uniformly to children.
In children and adults, COVID-19 targets the lungs but a lack of oxygen and wide-
spread inflammation may also damage the heart, liver, kidneys, other organs, and the
brain. A study posted online in medRxiv reported COVID-19 neurological manifesta-
tions in 78 of 214 individuals (36.4%).
9
The reported symptoms are interesting, as is the
ACE2 receptor entry port into cells, a potential mechanism for neurotropism. As
described earlier, ACE2 is present in the nervous system, particularly in the olfactory
system, one of the several possible links with implications for symptoms of hyposmia and
hypogeusia. Researchers studying other coronaviruses have described the route of neu-
ropropagation from the nasal cavity to the olfactory bulb and piriform cortex and then
the brain stem. They have identified neuron-to-neuron propagation as one underlying
mode of human coronavirus OC43 spreading in cell culture. Both passive diffusions of
released viral particles and axonal transport are valid propagation strategies used by the
virus, which is present along axons of viral platforms. Coronaviruses have static dyna-
mism that produces viral assembly sites (Dubé et al., 2018).
The impact of COVID-19 on infants and young children is of particular concern.
It is too early to determine whether COVID-19 will have a lasting impact, but clues
come from similar coronaviruses and from pneumonia impact. Coronaviruses cause
critical public health crises, especially in young children, elderly individuals, and
immunocompromised individuals. Viruses are the most prevalent pathogens con-
tained in the respiratory tract. About 200 different viruses can infect the human
airway. Infants and children are counted among the vulnerable populations, in
which viruses cause 95% and 40% of all respiratory diseases, respectively
(Desforges et al., 2019). Children may have protections that adults lack in terms
of ACE2 implications and transport of the virus to the brain. Although children
may be more resilient in terms of overall impact, infants and young children may be
at risk of ongoing neurodevelopmental impact. Infant and preschool patient popula-
tions should be monitored closely.
10
9
The 36.4% figure reported could prove to be an overestimate due to the small and hospital-based sample size, or an
underestimate due to undetected cases in tracking systems.
10
Worldwide, viral infections of the respiratory tract represent a major problem for human health, imposing a tremendous
economic burden (Desforges et al., 2019). Respiratory infections are a leading cause of morbidity and mortality in
humans worldwide.
10 L. O. CONDIE

Comparing COVID-19 to other coronaviruses
Preliminary information casts some light on how COVID-19 resembles and differs from
other coronaviruses, particularly severe acute respiratory syndrome coronavirus (SARS-
CoV). Case reports concerning other coronaviruses have been described.
11
They illus-
trate that children, elderly individuals, and immunocompromised individuals exhibit
CNS symptoms and conditions (febrile and afebrile seizures, loss of consciousness,
convulsion, ataxia, status epilepticus, encephalitis, myelitis, neuritis, and multiple sclero-
sis). Moreover, the detection of genetic material and even viral proteins
12
in CNS
samples, such as CSF or brain, is a recurrent fact described in several case reports of
other coronaviruses (Bohmwald et al., 2018). These data highlight the urgency of
characterizing COVID-19 neurotropic and neuroinvasive capacities.
For proper functioning, it is essential for the CNS to maintain homeostasis. The
blood-brain and the blood-cerebrospinal fluid barriers play roles in protecting the
brain of free passage of unwanted molecules, pathogens, and cells. The blood-brain
barrier prevents the entry of pathogens into the brain, and it is composed of cerebral
microvascular endothelium, astrocytes, pericytes, and extracellular matrix. The brain
microvascular endothelium cells are a cell type found in significant proportions in the
blood-brain barrier. Between those cells are tight junctions that control barrier perme-
ability (Bohmwald et al., 2018).
Researchers know that coronaviruses may enter the CNS through two distinct routes:
hematogenous dissemination or neuronal retrograde dissemination. Hematogenous
spread involves the presence of a coronavirus in the bloodstream. Retrograde viral spread
toward the CNS occurs when the virus infects neurons in the periphery and uses the
transport machinery within those cells to gain access to the CNS. Monocytes and
macrophages cells are used to disseminate human coronaviruses to other tissues, includ-
ing the CNS, where they may be associated with other types of pathologies. Viral spread
may occur through neuronal dissemination, where the virus infects neurons in periphery
and uses the machinery of active transport within those cells to gain access to the CNS.
This process moves a lung infection through a neuroinvasive process via a neuronal route
to the CNS. In encephalitis, viral replication occurs in the brain tissue itself, possibly
causing destructive lesions in the gray matter. Coronavirsues may play a triggering role in
demyelinating CNS diseases (Desforges et al., 2014).
Hematogenous spread involves the presence of a given virus in the bloodstream and
retrograde viral spread toward the CNS occurs when a virus infects neurons in the
11
Coronaviruses are a family of enveloped positive-stranded RNA viruses. They have a characteristic crown-shaped
appearance. They are widespread in nature, causing mainly respiratory and enteric pathologies, with neurotropic and
neuroinvasive properties in humans. Taxanomically, they are grouped in the family Coronaviridai, within the order
Nidovirales. They form four groups of enveloped viruses that have the largest genome among RNA viruses (Desforges et
al., 2014).
12
The spike protein (S) is a type-1 glycosylated transmembrane protein. It is responsible for the recognition of the cellular
receptor that the virus uses to infect susceptible cells. The envelope (E) protein is a small structural protein anchored in
the viral envelope. It has a role in the assembly of the virion, responsible for the adequate curving of the viral envelope.
The membrane (M) protein helps to shape and maintain the virion structure. The nucleocapsid (N) protein facilitates the
encapsulation of the virus. The hemagglutin-estrase (HE) is a transmembrane protein that possesses an acetyl esterase
function that may be important during an early phase or during the release of viral particles from infected cells
(Desforges et al., 2014). The detection of human coronavirus RNA in autopsied human brain samples clearly demon-
strates that these respiratory pathogens are neuroinvasive in humans and that they establish a persistent infection in
the human CNS (Desforges et al., 2014).
CHILD NEUROPSYCHOLOGY 11

periphery and uses the transport machinery within those cells in order to gain access to
the CNS (Desforges et al., 2014). The hematogenous route involves the presence of
a given virus in the blood where it can either remain free for a period of time before it
infects endothelial cells of the blood–brain barrier, or infect leukocytes that will become
a viral reservoir for dissemination toward the CNS. In the human airways, it is still
unclear what type of damage may be induced by coronaviruses in epithelial cells of the
respiratory tract after infection. Coronaviruses may, under certain circumstances, pass
through the epithelium barrier and gain access to the bloodstream or lymph, where they
can infect leukocytes and consequently disseminate toward other tissues, including the
CNS. Infection of human monocytes/macrophages may facilitate proliferation by manip-
ulating the immune system or may use axonal or dendritic cells to disseminate to the
CNS, where they could be associated with other type of pathologies. Human corona-
viruses are naturally neuroinvasive and neurotropic. They are potentially neurovirulent
as a result of misdirected host immune responses that directly induce damage to CNS
cells (Desforges et al., 2016). The increased cytokine production may induce direct
damage to neurons. It may disturb glutamate homeostasis by down-regulating the
glutamate transporter GLT-1 on astrocytes that should recapture the excess of glutamate.
This mechanism may generate glutamate excitotoxicity and thereby contribute to neu-
ronal degeneration. The outcome of the observed degeneration of neurons may even-
tually be the death of these essential cells. Infection of neurons may induce cell death by
directly generating a cytotoxic insult related to viral replication and/or to the induction of
different cell death pathways (Desforges et al., 2014).
Coronaviruses have potential neuropathological consequences in genetically or other-
wise susceptible individuals. Although the incidence of severe impact may be low in
children, vulnerable children are at risk. Collecting new data will be instrumental to our
understanding of CNS impact. Much remains to be learned about potential neuropsycho-
logical impact. In these very preliminary results, one can appreciate the physical ramifica-
tions of COVID-19. Modern neuropsychology recognizes that even when there are no
direct neurological implications, physical disease can carry a psychological burden for
individuals through compromised stress tolerance, stamina, attention, and concentration.
Concern for direct and psychosocial neuropsychological implications is reviewed below.
Anticipating a neuropsychological caseload surge
When the COVID-19 crisis fades, neuropsychologists will be faced with a surge of
returning children who need non-virtual sessions to initiate or complete their evalua-
tions. Few non-virtual outpatient visits are taking place currently. Neuropsychologists
instead are using virtual platforms to administer evaluations (or partial evaluations) that
are conducive to online administration. In addition to the surge of returning patients
whose face-to-face evaluations have been delayed due to stay-at-home advisories, neu-
ropsychologists are likely to see new referrals of children who were affected by COVID-
19. Whether COVID-19 impact will cascade out into neuropsychological caseloads in
compelling numbers remains to be seen, but it will be important to anticipate a possible
increase in caseloads. Determination of the neuropsychological impact for both asymp-
tomatic and symptomatic patients is important for guiding the development of assess-
ment protocols to document the neuropsychological impact of COVID-19.
12 L. O. CONDIE

Viral infections of the brain at an early age may lead to a variety of outcomes ranging
from developmental delay to typical development (Nichols et al., 2013). Viral CNS
infections may lead to encephalitis, which is a generalized inflammation of the cerebral
tissue with possible associate neuronal damage, loss of neuronal connectivity, or neuro-
nal necrosis (Anderson et al., 2001). The four forms of encephalitis are acute viral
encephalitis, postinfectious encephalomyelitis, chronic degeneration disease of the
CNS, and slow viral CNS infection. As with other infectious diseases (Smith &
Wilkins, 2015), it is likely the sequelae from COVID-19 will depend upon the age of
onset, the severity of the infection, comorbid seizures prior to onset, longer duration of
illness, severity and duration of high fever, and the treatment used (Ludlow et al., 2016).
It is likely that poor cognitive, language, and motor outcomes will be linked to these
variables. Vulnerable infants and young children likely are at the highest risk for
morbidity and mortality (Starza-Smith et al., 2007).
Social and environmental factors have been found to be predictive of later sequelae from
early infections. Constraints on development related to viral CNS infection may be com-
pounded or tempered by social and environmental factors. Risks are related to limited
resource access and proximal social factors such as child-rearing practices and family size
(Yeates et al., 2000). Behavioral changes associated with encephalitis are consistent with
disruption of the corticolimbic pathways responsible for emotional regulation. The frontal
lobes have strong limbic connections. Frontal lobe dysfunction may lead to emotional
changes. The direct CNS effect of viral illness can lead to resultant emotional and behavioral
changes, receptive and expressive communication disorders, changes in emotional experience
and mood, and changes in emotional memory (Heilman et al., 2003). Other ways in which
illnesses may affect individuals relates to their emotional response to the illness, and the
presence of emotional states that may enhance or induce neurological symptoms (Heilman
et al., 2003). In addition to any illness effects, children have faced concomitant disruptions that
include separation from friends and extended family members, school closures, suboptimal
access to teachers and school curricula, suboptimal accessto opportunities for exercise, illness
of family members and friends, schedule disruptions, home confinement, and other contain-
ment approaches. Children may not have sufficient life experience to understand why
containment measures are necessary. Children need security, comfort, and a sense of safety.
They may not understand the anxious responses of family members.
Preexisting family tension may have been exacerbated in some families. Not all homes
are safe places, and some children may face increased exposure to intrafamilial violence.
Even in benign situations, some parents may lack the skill set necessary to remain calm
and reassuring, to maintain a normal routine in a time of crisis, or to shield children from
media coverage or over-exposure to media. Young children may not understand the
illness and may think of themselves as responsible for the illness and associated disrup-
tions. They may show regressions. Older children may ask questions, some of which have
no clear answers. Parents may feel helpless to provide direct and honest answers to
questions, and they may themselves fear for the future. COVID-19 has affected the
grounding of many individuals in their conceptions of justice, personal agency, and
personal control. Parents may need support as they try to understand and show respect
for their children’s feelings, discuss opinions, talk about information in the medial, shore
up their own coping resources, and try to preserve family relationships and friendships in
a socially distanced manner.
CHILD NEUROPSYCHOLOGY 13

In addition to psychosocial and familial factors, disparities are of concern in the spread
and treatment of COVID-19. The Federal Emergency Management Agency (2020) has
recognized some civil rights concerns for minority populations, persons with disabilities,
and impoverished groups. They have documented and are working to address concerns
related to the disparate impact of COVID-19 based on racial, economic, and age-related
factors. They have worked on language access for non-English speaking populations, and
general access for individuals related to nationality and immigration status. They are
working on disability access for COVID-19 testing locations. Other conditions histori-
cally have necessitated the development of cognitive evaluations that require minimal
literacy, time to administer, and administrator training (Chan et al., 2019). It is likely that
neuropsychologists will need to take similar measures to ensure there is equal access to
service provision. It will be important to gather data relevant to psychosocial factors,
familial factors, and access to COVID-19 testing and treatment.
With respect to the immediate support of children, health service providers who work with
children may be in a position to reduce the psychosocial toll of COVID-19 even if available
efforts are only supportive. Novel approaches to social and emotional support are needed in
the era of social distancing. Procedures that acknowledge broad impact (physical, social,
emotional, cognitive) are most likely to be affective. COVID-19 specific techniques are needed
that address the impact of isolation during hospitalization, and mental confusion associated
with recovery from delirium. Measures are needed to acknowledge and address children’s
relative lack of a frame of reference concerning illness and hospitalization. Children need age-
appropriate explanations of the names and roles health service providers. They need verbal
and visual guidance in how to relate to a health service provider draped in personal protective
equipment. Children need technological proxies for the role of sitters and child life profes-
sionals. They need ways to cope with the physical and psychological trauma associated with
illness and treatment variables and with separation from family members.
In addition to the aforementioned immediate adaptations in how to approach chil-
dren, explain their circumstances and the environment, and explain containment mea-
sures, other measures will be needed. Neuropsychological interview, evaluation, and
technological adaptations will be needed. What follows are some suggestions concerning
updates to clinical interview techniques.
Clinical interview questions
Neuropsychologists will need to develop COVID-19 specificclinical history and course of
illness questions, and relevant assessment methodologies that address the range of subtle to
the severe impact of the virus. This manuscript contains a table of proposed interview
questions. Section 1 of Table 2 contains questions relevant to the physical impact of
COVID-19. Section 2 of Table 3 contains relevant to the psychosocial impact of COVID-
19. Because the most severe impact is likely to be seen in infants and young children, interview
questions for parents are contained in Table 2. Should researchers ultimately reveal the impact
on older children, questions will need to be adapted to language that is age-appropriate for
interviews of children. In summary, the field needs solid evidence of the direct impact of the
disease, but anticipatory preparation will be key in addressing the potential impact on
assessment caseloads.
14 L. O. CONDIE

Table 2. COVID-19 Synopsis.
Section 1: Clinical Interview Questions Relevant to the Physical Impact of COVID-19
(1) How old was your child when you learned your child had COVID-19?
(2) How was it diagnosed?
(3) Was there laboratory confirmation of COVID-19?
(4) How long was your child ill?
(5) What symptoms did your child show?
(6) Does your child have any siblings?
(7) Did anyone else in your family contract COVID-19?
(8) Did you keep your child at home or did you seek healthcare outside the home.
(9) If your child was at home during the illness, did you consult with the child’s pediatrician or other healthcare providers?
(10) If your child sought healthcare outside the home, what type of care did you seek?
(11) Was your child hospitalized? If so, for how long?
(12) Was your child placed on a ventilator?
(13) Were there any post-extubation complications?
(14) Does your child have any other health conditions? Did your child have that/those conditions at the time of the
COVID-19 symptoms?
(15) Did any of those other conditions worsen during or after the child’s COVID-19 symptoms?
(16) Has your child had any follow-up care concerning COVID-19?
(17) Did your child see any specialists during the illness or after recovery from COVID-19?
(18) Has your child seen a neurologist?
(19) Has your child undergone any imaging studies?
(20) Tell me about your child’s health right now.
(21) Have there been any recent changes in your child’s health?
(22) Having you noticed any differences in your child in comparison to how your child felt or functioned before the
child contracted COVID-19?
(23) Tell me about those differences, if any. (Follow up with specific queries that cover the domains of cognitive,
language, memory, and motor functions).
(24) Have there been any changes in your child’s ability to learn new information?
(25) Have there been any changes in your child’s listening or comprehension skills?
(26) Have there been any changes in your child’s expressive communication skills or articulation?
(27) Have there been any changes in your child’s memory?
(28) Have there been any changes in your child’s gross or fine motor skills?
(29) Have there been any changes in your child’s organizational skills?
(30) Are you confident that your child received good healthcare during the illnesss?
(31) What are your concerns, if any?
(32) Do you have anything else you want to tell me about your child’s COVID-19 illness and adaptation?
Section 2: Clinical Interview Questions Relevant to the Psychosocial Impact of COVID-19
(1) What was your child’s reaction to learning that your child had COVID-19?
(2) From a social and emotional point of view, how did your child fare when your child was symptomatic with COVID-19.
(3) How did your child react to the medical procedures that were used during your child’s illness?
(4) How did your child react to the healthcare providers?
(5) How did your child react to the hospital environment?
(6) How did your child react to healthcare providers’use of personal protective equipment?
(7) From a social and emotional point of view, how is your child faring now?
(8) Were there any acute or lasting changes in your child’s emotional functioning?
(9) Were there any acute or lasting changes in your child’s social functioning?
(10) Were there any acute or lasting behavioral changes in your child?
(11) Have there been any changes in your child’s attention and concentration skills?
(12) Have there been any changes in your child’s organizational skills?
(13) Have there been any changes in your child’s academic engagement in school?
(14) Have there been any changes in your child’s social engagement in school?
(15) Have there been any changes in your child’s sensory skills?
(16) Have there been any changes in your child’s ability to be patient and flexible?
(17) Have you noticed any mood changes in your child?
(18) Have there been any changes in your child’s ability to notice and respond socially to other individuals?
(19) Have there been any changes in your child’s self-awareness or self care?
(20) Has anything changed in your family relationships?
(21) How did the child’s parents (and grandparents) respond to the child’s illness?
(22) How did the child’s siblings respond to the child’s illness?
(23) Was there any intentional or unintentional blame, anger, or hostility toward the child or within the family system?
(24) What did family members do to socially and emotionally support the child through the illness?
(25) What did healthcare professionals do to socially and emotionally support the child through the illness?
(26) Are you confident that your child received social and emotional support during the illnesss?
(27) What have you or others done to continue to show support to your child?
(28) How has your child been functioning in school?
(29) How has your child been functioning with friends?
(30) How has your child been functioning at home?
(31) Do you have anything else you want to tell me about your child’s social and emotional response to COVID-19.
CHILD NEUROPSYCHOLOGY 15

Evaluation methodology
Adjustments must be made to evaluation methodology but characterizing the nature of
those adjustments may not be possible. Because of the potential for both regionalized and
diffuse CNS impact, neuropsychologists will need to rely upon the traditional convention
of flexible batteries that are drawn from referral questions, the main concerns of parents,
interview data, and data gleaned from records. Depending upon how protracted stay-at-
home advisories might become, parallel technological adjustments may need to be
extended. Methodologies will need to be used or developed that allow for greater use
of technology and less reliance upon person-to-person evaluations. Neuropsychologists
are already relying upon updated informed consent forms, synchronous telehealth,
paper-mailed symptom checklists, emailed electronic entry ports to online assessment
symptom checklists and independent functioning measures, administration of measures
virtually when those measures are conducive to it, and use of trained and socially
distanced proxy administrators and materials (American Academy of Neurology, 2020;
American Psychological Association [APA], 2020a,2020b). As long as those strategies
adhere to the fidelity of the measures and methodologies, consensus has been built that
deems it appropriate to use these measures during this time of crisis. Telepsychology
guidelines, best practice, and preparatory strategies are described on the website of the
(APA, 2020a,2020b).
In terms of assessment content, adjustments will involve the use of key measures that are
relevant to both the physical and psychosocial impact of COVID-19. Children who have
recovered from COVID-19 likely will need a comprehensive neuropsychological battery to
monitor their progress. Serial evaluations may be needed in order to detect any difficulties.
Chronic forms of encephalitis can take months to show symptom manifestations. The
clinical outcome often emerges slowly. Common symptoms at the peak of viral infections
include nonspecific symptoms of fever, headache, emesis, loss of energy, lethargy, irrit-
ability, clouding of consciousness, neck stiffness, mental confusion, and disorientation
(Anderson et al., 2001). Speech organization and output may be affected. Muscle weakness
may be seen. If other infectious processes can validly serve as exemplars, outcome differ-
ences are less likely to be seen on general measures such as intellectual or achievement
indices and more likely to be seen on specific indices (Anderson et al., 2001). Differences
may be subtle and are likely to affect attention, concentration, organization, capacity for
new learning, gross and fine motor skills, motor planning and integration, receptive and
expressive communication, auditory discrimination, mental fluency and flexibility, other
executive skills, and sensory integration. Children will need to be monitored for subtle
deficits and regressions. Specific neuropsychological evaluation methodology will need to
be adapted to the child’s presenting concerns.
Psychosocial variables amplify the consequences of early childhood illnesses. Examples
of encephalitis impact include affect lability, episodic rage, depression, and anxiety. When
damage extends to the prefrontal cortex, examples may include impulsive conduct, apathy,
rigidity, deficits in self-awareness, reduced judgment, and memory deficits (Anderson et al.,
2001;Spreenetal.,1995). Psychosocial evaluations should supplement the child’sneurop-
sychological assessment. Specific methodology and measurement inclusion will depend
upon the child’s presenting concerns.
16 L. O. CONDIE

Conclusion
Should the precursory information presented in this article prove to be valid and reliable, it
seems reasonable to expect there will be COVID-19 implications for neuropsychological
functioning that include changes in cognitive, motor, and language abilities, executive
functioning impact, medical coping difficulties, psychosocial impact, and independent func-
tioning impact. Evaluation methodology also will need to address any of these domains that
are relevant for a particular child. COVID-19 impact data, and generalizability from other
coronaviruses, are admittedly preliminary.
13
The integrity of neuropsychological functioning
and the prevalence of psychiatric disorders in children and adults who have recovered from
COVID-19 will need to be determined.
The mechanisms described in this study have implications for eventuating in disorders
such as attention deficit hyperactivity disorder, executive functioning weaknesses, other
neurodevelopmental disorders, somatic symptom disorders (medical coping difficulties),
and neurocognitive disorders. The clinical characteristics and disease burden of COVID-
19 will need special attention as researchers work to highlight the pathophysiology of
neuropsychological processes that is implicated in COVID-19 outcomes. Children who
contracted COVID-19 in infancy and early childhood will need special attention.
COVID-19 is rapidly becoming a highly prevalent disorder with neuropsychological
implications. More time is needed to fully understand the neuropsychological implica-
tions of COVID-19, but the need for rapid ramping up of research efforts is urgent.
Disclosure statement
No potential conflict of interest was reported by the author(s).
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