Neuropsychology

In the public domain 2021, Vol. 35, No. 4, 335–351

ISSN: 0894-4105 https://doi.org/10.1037/neu0000731

Neuropsychology of COVID-19: Anticipated Cognitive

and Mental Health Outcomes
Erin K. Bailey, Kayla A. Steward, Alicia B. VandenBussche Jantz, Joel E. Kamper,
Elaine J. Mahoney, and Jennifer J. Duchnick
James A Haley Veterans’ Hospital, Tampa, Florida, United States

Objective: Discuss anticipated patterns of cognitive and emotional dysfunction, prognostic indicators, and
treatment considerations based on review of (a) neuroinvasive properties of prior human coronaviruses and
(b) extensively researched disorders which share similar neurological mechanisms. Method: A web-based
comprehensive search of peer-reviewed journals was conducted based on a variety of key terms (and
variants of) including coronavirus, neuroinvasion, cognitive dysfunction, viral pandemics, respiratory
illness, critical illness, and metabolic disease. Articles were chosen based on relevance to the current topic
and ability to provide unique thematic information. Historical articles were included if these added scientific
merit to recent literature. Review of information in widely disseminated news articles was followed-up with
direct review of cited scientific literature. Databases searched included Google Scholar, PubMed, and Ovid
Medline. Results: Based on neuroinvasive properties of prior coronaviruses and existing research on similar
neurophysiological conditions with detrimental cognitive effects, COVID-19—especially those with severe
symptoms—are at risk for cognitive decline and significant psychiatric/behavioral sequela. Conclusions:
There are few studies examining cognitive outcomes in COVID-19. This review argues that neuropsycho-
logical sequelae are to be expected in patients with COVID-19. Considerations for clinicians working with
this unique population are discussed.

Key Points
Question: There is limited research describing cognitive and psychiatric outcomes in COVID-19
patients. Findings: We reviewed available literature from prior pandemics, emerging COVID-19
research, and studies describing outcomes in similar medical conditions to hypothesize concerns when
working with this population. Importance: Based on existing literature, we anticipate a wide range of
cognitive and psychiatric symptoms in COVID-19 patients. Next Steps: Neuropsychologists play a vital
role in comprehensive care for these patients and should be included on interdisciplinary treatment
teams. Longitudinal data will help clarify risk of cognitive and psychiatric sequalae among COVID-19
patients.

Keywords: coronavirus infections, neurobehavioral manifestations, cognitive dysfunction,

mental health

Coronaviruses (CoVs) are a group of viruses containing genetic
material encoded in ribonucleic acid (RNA). These RNA viruses are
particularly prone to rapid mutation and adaptation, allowing for
greater propagation within and across species (Carrasco-Hernandez
et al., 2017). Prior to 2019, six coronavirus strains emerged in
humans (Desforges et al., 2020). These are subclassified into
alphacoronavirus (HCoV-NL63, HCoV-229E) and betacoronavirus
(HCoV-OC43, HCoV-HKU1, MERS-CoV, and SARS-CoV).
While the first four boast relatively mild symptoms, Middle East
Respiratory Syndrome (MERS-CoV), and Severe Acute Respira-
tory Syndrome (SARS-CoV)—identified in 2003 and 2012, respec-
tively—augmented into epidemics with high rates of morbidity,

other federal agency, policy, or decision unless designated by other official

Erin K. Bailey https://orcid.org/0000-0002-9390-0678 documentation. No work resembling the enclosed article has been published
Joel E. Kamper https://orcid.org/0000-0001-5098-5176
or is being submitted for publication elsewhere.
Jennifer J. Duchnick https://orcid.org/0000-0002-2050-9272
Correspondence concerning this article should be addressed to Erin K.
This material is the result of work supported by resources and the use of
facilities at the James A. Haley Veterans’ Hospital. The views, opinions, and/ Bailey, Outpatient Neuropsychology and Memory Disorder Clinics, James
or findings contained here are those of the authors and may not represent the A. Haley Veterans’ Hospital, 13000 Bruce B Downs Blvd, 116A, Tampa,
views of the Department of Veterans Affairs, Department of Defense, or FL 33612, United States. Email: Erin.Bailey@va.gov

335
336 BAILEY ET AL.
mortality, and economic loss (Corman et al., 2018; Perlman, 1998).
Believed to have originated from bats by way of an intermediary
host (Algahtani et al., 2016; Li et al., 2005), these two zoonotic
respiratory infections demonstrate greater virulence and severity of
symptoms (Desforges et al., 2020) than their predecessors. In
addition to respiratory illnesses (pneumonia, bronchitis, respira-
tory distress syndrome, etc.), these infections are associated with
organ failure, gastrointestinal symptoms, and central nervous
system (CNS) dysfunction (Algahtani et al., 2016),—especially
among vulnerable populations such the elderly, children, or pa-
tients with comorbid conditions, and those who are immunocom-
promised (Desforges et al., 2020). Although existing literature
describes both the direct, neuroinvasive potential of the human
coronavirus (Bédard et al., 1991; Dubé et al., 2018; Perlman,
1998) as well as the indirect immunoresponse to CoVs
(Algahtani et al., 2016; Hung et al., 2003; Lau et al., 2004;
Wang et al., 1990; Yeh et al., 2004), prospective analysis regard-
ing anticipated patterns of cognitive dysfunction in these patients,
and considerations for the field of neuropsychology, is lacking.
Given the recent emergence of a seventh, and more pervasive
human coronavirus: SARS-CoV-2, synthesis of existing knowl-
edge and clinical recommendations for best health practices is
vital. Here, we will provide an overview of neurological compli-
cations observed during prior endemics/epidemics and in emerging
COVID-19 research. We will also discuss three mechanisms which
inform our understanding of the possible cognitive impact of
COVID-19: respiratory illnesses, metabolic disorders, and critical
illness/delirium. Mental health and treatment considerations will
also be briefly discussed.
The Human Coronavirus
The Novel Coronavirus
The human coronavirus disease 2019 (COVID-19) was first
identified in Wuhan, China in late December 2019 among a group
of patients with idiopathic pneumonia (Wang, Hu, et al., 2020; Zhu
et al., 2020). Severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2)—the virus causing COVID-19, is an airborne novel
betacoronavirus, assumed to transmit via fomites, droplets, aerosols
(Kutter et al., 2018; Sizun et al., 2000; van Doremalen et al., 2020).
It is postulated that SARS-CoV-2 binds to the angiotension-con-
verting enzyme 2 (ACE2; Wang, Wang, et al., 2020), gaining access
to cells. According to the European Centre for Disease Prevention
and Control, COVID-19 has officially reached the level of a
pandemic, infecting approximately 16.5 million people worldwide
and causing an estimated 650,000 deaths (European Centre for
Disease Prevention and Control [ECDC], 2020)—a likely underes-
timation has given lack of available and efficient widespread testing
means. Mortality is estimated at 1%–2% depending on country
(Cascella et al., 2020). Common symptoms include fever and cough,
with a mean incubation period of 4 days. Many patients also
demonstrate compromised immune functioning and metabolic dis-
turbance (Águila-Gordo et al., 2020; Portincasa et al., 2020).
Finally, as SARS-CoV-2 primarily affects pulmonary functioning,
it is not surprising that patients overwhelmingly present in respi-
ratory distress (Guan et al., 2020; Liu et al., 2020).
In a Chinese Center for Disease Control (Chinese CDC) epide-
miological study of 72,314 COVID-19 cases, 81% of patients were
classified as mild (i.e., non-pneumonia and mild pneumonia;
Surveillances, 2020). In contrast, approximately 14% demonstrated
severe respiratory symptoms such as dyspnea (shortness of breath),
respiratory frequency ≥30/min, lung infiltrates >50% within
24–48 hr, and/or hypoxemia (i.e., low levels of oxygen in the
blood). In these cases, hypoxemia is usually defined by blood
oxygen saturation (SpO2) ≤93% or ratio of partial pressure of
arterial oxygen (PaO2) to the percentage of oxygen supplied (i.e.,
fraction of inspired oxygen, FiO2), also known as PaO2/FiO2 or the
PF ratio, <300. Five percent of cases were considered critical, as
they demonstrated acute hypoxemic respiratory failure (i.e., severe
hypoxemia that is refractory to supplemental oxygen), septic shock,
and/or multiple organ dysfunction (Wu & McGoogan, 2020).
Interestingly, COVID-19 pneumonia appears to have a unique
phenotype characterized by severe hypoxemia with relative preser-
vation of respiratory mechanics (i.e., normal pulmonary compli-
ance; Gattinoni, Chiumello, et al., 2020; Negri et al., 2020). Some
studies indicate that this unique form of acute respiratory distress
syndrome (ARDS) may present in up to 60%–80% of COVID-19
cases admitted to ICU settings (Wu, Chen, & Cai, 2020). Respira-
tory treatment in COVID-19 patients with severe hypoxemia gen-
erally includes high-flow nasal cannula (HFNC), non-invasive
positive pressure ventilation (NIPPV), and in critical cases, ICU
admission and invasive mechanical ventilation (Alhazzani et al.,
2020). In a case series of hospitalized patients with COVID-19-
associated pneumonia, the overall case-fatality rate from confirmed
COVID-19 cases was 2.3%; however, the fatality rate for those
classified as critical, particularly those with premorbid health con-
ditions, was 49% (Novel Coronavirus Pneumonia Emergency
Response Epidemiology Team, 2020). Unsurprisingly, severe
hypoxemia (SpO2 < 90.5% despite oxygen supplementation) is one
of the best predictors of mortality rate in those with moderate to severe
COVID-19 pneumonia (Xie et al., 2020). Other risk factors for
increased mortality include older age, neutrophilia, organ dysfunction,
and coagulation dysfunction (Wu, Chen, & Cai, 2020). In addition to
respiratory distress, neuroinfection is speculated to contribute to other
clinical manifestations in COVID-19 patients (Steardo et al., 2020).
Potential Mechanisms of Neuroinvasion
Human coronaviruses, such as HCoV-OC43, demonstrate neu-
roinvasive properties (Bergmann et al., 2006; Cheng et al., 2020;
Jacomy & Talbot, 2001, 2003; St-Jean et al., 2004). In humans,
infection of neural and glial cells among patients with HCoV-229E
and HCoV-OC43, as well as presence of SARS-CoV in CSF, have
also been described (Arbour, Côté, et al., 1999; Arbour, Ekandé,
et al., 1999; Bonavia et al., 1997; Lau et al., 2004). Several possible
neuroinvasive mechanisms are outlined in existing literature
(Bohmwald et al., 2018; Cheng et al., 2020; Zubair et al., 2020).
In humans, Dubé et al. (2018) proposed possible neuronal-to-
neural CNS invasion of previous human CoVs from the nasal
neuroepithelium tissue to the olfactory bulb, a previously iden-
tified mechanism of CNS infection among other viruses in
humans (Koyuncu et al., 2013; Swanson & McGavern, 2015)
and in mice (Barthold et al., 1990; Perlman et al., 1990).
As betacoronaviruses share similar viral structure, several possi-
ble mechanisms for neuroinvasion by SARS-CoV-19, are discussed
in recent literature (Das et al., 2020). Angiotensin-converting
enzyme 2 (ACE2) receptors appear to be a point of entry for
 ANTICIPATED COGNITIVE OUTCOMES OF COVID-19
SARS-CoV-2 into the host cell (Chen et al., 2020; Hoffmann et al.,
2020). As ACE2 receptors are detected in neural tissue, there is
possibility of direct neuroinvasion of SARS-CoV-2, in addition to
immune (Wan et al., 2020) or respiratory-mediated (Sasannejad
et al., 2019) neurological syndromes. Like prior HCoVs, the olfac-
tory epithelium is also implicated as a possible point of SARS-CoV-
2 infiltration into the CNS (Baig et al., 2020), possibly accounting
for anosmia reported by patients. Other discussed possibilities
include neuronal transsynaptic transfer and infiltration across the
blood–brain barrier (Zubair et al., 2020). Interestingly, anosmia is
reported in COVID-19 confirmed patients in the absence of tradi-
tional respiratory symptoms, providing some support to possible
differential pulmonary versus CNS infectious processes and/or
presentation (Hopkins et al., 2020).
Central Nervous System Manifestations
Central nervous system manifestations documented among
HCoVs prior to COVID-19 are diverse (Cheng et al., 2020). Reports
of CNS complications include a pediatric patient with presumed
acute disseminated encephalomyelitis (ADEM; Yeh et al., 2004),
patients with seizures (SARS-CoV; Hung et al., 2003; Lau et al.,
2004), and a case of fatal encephalitis (HCoV-OC43; Morfopoulou
et al., 2016). In a Saudi Arabian case series, Arabi et al. (2015)
discovered notable neuroimaging findings in three patients with
MERS-CoV confirmed using reverse transcription-polymerase
chain reaction (RT-PCR), a method of detecting viral genetic
material on tracheal aspirate. Brain magnetic resonance imaging
(MRI) performed during ICU hospitalizations showed extensive
T2-weighted hyperintensities in areas such as the bilateral frontal,
parietal, and temporal lobes, periventricular white matter, basal
ganglia, corpus callosum, midbrain structures, cerebellum, pons,
and cervical cord. Two of the three patients were administered
antiviral medication (peginterferon alpha-2b and ribavirin). One
patient also suffered an anterior cerebral artery (ACA) stroke.
Although all patients presented with pre-existing cerebrovascular
risk factors (e.g., diabetes, hypertension, ischemic heart disease,
dyslipidemia), neuroimaging findings were not believed to be
secondary to comorbid conditions alone. For example, rapid hypo-
dense interval changes observed on serial computerized tomography
(CT) were incompatible with the typical indolent progression of
white matter changes most often seen with chronic conditions
(e.g., cerebrovascular disease, etc.). Further, the patient with an
ACA infarct was found to have patent ACAs on cerebral angiogram;
an unusual finding in ischemic stroke, but compatible with the non-
occlusive pathophysiology seen with viral vasculopathy. Although
all patients suffered respiratory distress, the authors concluded that
the nature and extent of both MRI and CT findings were inconsistent
with typical findings seen in cases of hypoxic brain injury and were
more consistent with findings expected in viral encephalitis. How-
ever, this study was limited by its observational nature and negative
CSF and parenchymal RT-PCR assays.
Unsurprisingly, emerging COVID-19 Literature also describes
symptoms of neurological dysfunction secondary in patients with
confirmed SARS-CoV-2 infection. Li et al. (2020a, 2020b) suggest
that the respiratory failure in COVID-19 may, in part, be due to
infection of medullary-mediated cardiorespiratory centers resulting
in loss of involuntary respiration. Neurologic symptoms, such as
anosmia (Hopkins et al., 2020; Klopfenstein et al., 2020; Marinosci
337
et al., 2020), encephalopathy (Poyiadji et al., 2020), myelitis (Zhao
et al., 2020), and seizures (Karimi et al., in press) have been
reported. In one such study, a female airline worker with
COVID-19 developed acute necrotizing encephalopathy (ANE), a
neurological condition of high morbidity and mortality most
reported in pediatric patients (Poyiadji et al., 2020). ANE is
believed to be due to cytokine storms, a catastrophic inflammatory
response to pathogens.
In a case series, Mao et al. (2020) reviewed neurological symp-
toms of 214 laboratory-confirmed COVID-19 cases. Of importance
to this article, patients with severe COVID-19 infection had signifi-
cantly greater incidence of acute cerebrovascular disease, skeletal-
muscle injury, and disturbance of consciousness. These patients
were less likely to present with traditional symptoms of fever and
cough than their non-severe peers, though more likely to have
comorbidities such as hypertension, which may predispose cere-
brovascular vulnerability. Unsurprisingly, lab results revealed
greater immune and metabolic disturbance among severe patients
with CNS manifestations, as compared to severe patients without
CNS symptoms. Additional research supports increased cerebro-
vascular risk in COVID-19. In a Dutch study of 184 ICU patients,
researchers found increasing incidence of venous and arterial
thrombotic events throughout the course of admission (Klok
et al., 2020b), ultimately reporting 49% cumulative incidence in
follow-up analyses (Klok et al., 2020a). Of this sample, five
COVID-19 patients suffered ischemic strokes. In a recent case
study, five COVID-19 confirmed patients under the age of 50
presented to a New York hospital during a 2-week period with
large-vessel strokes (Oxley et al., 2020). Yet another study of
almost 1700 hospital admissions with confirmed cases of
COVID-19 described an overall cerebrovascular disease incidence
in 1.4% of the total sample (Hernández-Fernández et al., 2020).
Further, neuroimaging-confirmed cerebrovascular disease was asso-
ciated with worse morbidity and mortality in these patients.
In pediatric populations, SARS-CoV-2 infection is temporally
associated with a novel inflammatory disorder called Multisystem
Inflammatory Syndrome in Children (MIS-C; Cheung et al., 2020;
Godfred-Cato et al., 2020), a hyperinflammatory disorder similar to
toxic shock syndrome and Kawasaki Disease (Chiotos et al., 2020;
Riphagen et al., 2020; Toubiana et al., 2020; Verdoni et al., 2020).
Hameed et al. (2020) described fever and gastrointestinal upset as
the most reported initial symptoms in a study of 35 children with
identified MIS-C. Yet, like the adult studies described above, many
children also presented with cardiovascular-related disorders,
namely pancarditis (43%), as well as septic shock (60%). Additional
literature describes cases of pediatric myocarditis, coronary artery
dilatation, aneurysm (Godfred-Cato et al., 2020), and acute heart
failure (Belhadjer et al., 2020). Interestingly, one recent study
proposed MIS-C as a potential pathologically distinct syndrome
from COVID-19 based on differential cytokine panels and periph-
eral blood smears (Diorio et al., 2020). Although more research is
needed, this may explain initial reports of lower COVID-19 preva-
lence in children (Choi et al., 2020), who may initially present with
milder respiratory distress and lower mortality rates compared
to adult populations (Dong et al., 2020; Ludvigsson, 2020;
Zimmermann & Curtis, 2020), with a conversely increased risk
of secondary inflammatory syndrome (Abdel-Mannan et al., 2020).
Given the potential for organ failure in MIS-C (Whittaker et al.,
2020), patients secondary neurologic and neurocognitive outcomes
338 BAILEY ET AL.
are possible, such as neurologic injury secondary to cerebrovascular
changes or metabolic encephalopathy (Hameed et al., 2020). Post-
infectious autoimmune responses may also incite immune-mediated
neuronal damage in pediatric—as well as adult—populations.
Another atypical presentation of COVID-19 may occur in pa-
tients with pre-existing dementia. Already vulnerable to deleterious
cognitive, psychiatric, and medical outcomes (Brown, Kumar, et al.,
2020; Wang, Li, et al., 2020), COVID-19 patients with dementia
have higher rates of mortality that non-dementia COVID-19
patients. Furthermore, these patients have a greater likelihood of
initially presenting with delirium, in contrast to anticipated respira-
tory symptoms (Bianchetti et al., 2020). The nonspecific nature of
delirium may result in late diagnosis or misdiagnosis of COVID-19,
delaying appropriate treatment for these patients. Given this,
COVID-19 should be considered an etiological rule-out in patients
with acute deterioration of cognitive or functional status.
There is also evidence that neurological complications may
present after acute CoV symptoms in adults. In a retrospective
study, Kim et al. (2017) reviewed 23 cases of patients hospitalized
for MERS-CoV. Detailed neurological follow-up was described for
four cases from the original sample who exhibited neurological
manifestations during or after the treatment. Researchers found that
initial manifestation of neurological symptoms extended up to
24 days following initial diagnosis. Symptoms included hypersom-
nolence, paresis, hyporeflexia, paresthesia, ptosis, and ophthalmo-
plegia. In one patient with severe respiratory dysfunction requiring
mechanical ventilation, these neurologic symptoms did not resolve
until day 60. Pharmacological side-effects of antiviral drugs
Interferon alpha-2a, ribavirin, and lopinavir/ritonavir were acknowl-
edged as potential moderating factors. Interestingly, 21.7% (n = 5)
of participants demonstrated confusion during the study period,
which is consistent with a prior study by Saad et al. (2014) describing
initial confusion in approximately 25% of their study sample.
In addition, coronavirus-mediated neuropathological findings,
there is also supposition regarding the potential etiological or
exacerbating role of coronavirus infections among known neuro-
logical diseases (Jacomy & Talbot, 2001, 2003). In animal studies,
mouse hepatitis virus (MHV) exhibits demyelinating, encephalitic,
and paretic properties, mediated by the immune system (Houtman &
Fleming, 1996), and spread through neurons, glial cells, cerebro-
spinal fluid (CSF), and blood (Bédard et al., 1991; Perlman, 1998;
Lavi et al., 1987). Extending from investigations of demyelination in
mice, several studies have assessed the presence of coronavirus in
human patients with multiple sclerosis (MS; Arbour et al., 2000;
Burks et al., 1980; Cook et al., 1995; Murray et al., 1992; Stewart
et al., 1992). One recent study described demyelination in an
immunocompromised child with HCoV-OC43 (Nilsson et al.,
2020). Other research examined the HCoV-229E and the HCoV-
OC43 in 90 human brain samples (Arbour et al., 2000). Forty-four
percent of the total sample tested positive for HCoV-229E, while 3%
of the sample tested positive for HCoV-OC43. However, when
compared across groups, HCoV-OC43 was preferentially detected
in samples from patients with MS compared to those with other
neurological disease and healthy controls. This is consistent with a
prior study where researchers observed HCoV-OC43, but not
HCoV-229E, in tissue samples from MS patients (Murray et al.,
1992). However, the differentiation between HCoV strains regard-
ing impact on development multiple sclerosis remains imprecise.
Contradictory evidence from Stewart et al. (1992) found the
presence of HCoV-229E in brain tissue samples of patients with
MS in the absence of any detectible HCoV-OC43 RNA.
Ultimately, many individuals with COVID-19—even those who
experience severe symptoms—will survive. Therefore, it is essential to
understand possible cognitive outcomes in this population. Despite
rapidly emerging research, the short- and long-term neuropsychological
impacts of COVID-19 remain largely unknown at present, although
early research suggests that cognitive symptoms may occur in patients
even after recovery from COVID-19 (Zhou et al., 2020). Fortunately,
there is a depth of literature on the immediate and long-term effects
of similar, neurologically impactful medical conditions. These include
chronic health conditions (e.g., obstructive sleep apnea, chronic
obstructive pulmonary disease, metabolic disease), respiratory syn-
dromes (e.g., anoxic brain injury, hypoxemia, acute respiratory
distress syndrome), and delirium. From this, we can theorize expected
cognitive and mental health outcomes in COVID-19.
Medical Conditions Impacting the Central Nervous
System: A Map for Cognitive Impairment in
COVID-19 Patients
Respiratory and Pulmonary Illness
Although the terms hypoxemia and cerebral hypoxia are often
used interchangeably, the former refers specifically to low blood
oxygen levels, whereas the latter refers to poor oxygenation at the
tissue level (Samuel & Franklin, 2008). These two conditions can
occur independently; however, hypoxemia generally causes hyp-
oxia, such as in cases of pneumonia, hypoventilation, heart failure,
and acute respiratory distress syndrome (Samuel & Franklin, 2008).
Of particular interest to this review is that hypoxemia can cause
cerebral hypoxia, which induces disruption of central nervous
system (CNS) biochemistry and hemodynamics through several
mechanisms including reperfusion and reoxygenation injury,
inflammation, excitotoxic cell damage, and glucose dysregulation
(Hoiland et al., 2016; Oechmichen & Meissner, 2006). Lang et al.
(2020) describe vascular and perfusion abnormalities in patients
with COVID-19. Thus it is important to review existing literature in
this area in order to fully understand the relationship between
oxygenation disorders and COVID-19. Below we examine rela-
tively common disorders characterized by hypoxemia and hypoxia
with evidence to support CNS involvement in these conditions, such
as cognitive sequelae and evidence from neuroimaging studies.
Obstructive Sleep Apnea and Chronic Obstructive
Pulmonary Disease
Obstructive sleep apnea (OSA) is a disorder characterized by brief
cessations of breathing during sleep, leading to reduced airflow,
recurrent hypoxemia, and excessive daytime sleepiness. According
to the comprehensive neuroimaging reviews conducted by Ferini-
Strambi et al. (2013) and Gagnon et al. (2014), OSA is correlated
with widespread reductions in gray matter volume, white matter
abnormalities, and hypometabolism and hypoperfusion across a
number of brain regions, including the prefrontal cortex, tempor-
oparietal lobes, hippocampi, amygdala, cingulate cortex, corpus
callosum, basal ganglia, and cerebellum. It is estimated that 24%–
89% of individuals with OSA experience some degree of cognitive
impairment (Antonelli-Incalzi et al., 2004; Findley et al., 1986).
 ANTICIPATED COGNITIVE OUTCOMES OF COVID-19
Findley et al. (1986) found that adults with OSA performed signifi-
cantly worse on measures of executive function, attention, psychomo-
tor speed, and verbal memory when compared to those without
hypoxemia. Moreover, the degree of daytime and nighttime hypox-
emia was directly related to the extent of cognitive impairment in these
individuals. The elderly are particularly vulnerable to the cognitive
sequelae of OSA and are more likely to develop dementia than older
adults without this condition (Caselli, 2008; Kim et al., 2011). Inter-
estingly, following treatment with continuous positive airway pressure
(CPAP), attention/vigilance, executive function, and memory
improved, while in contrast, there was no improvement on tests of
psychomotor functioning (Aloia et al., 2004; Gagnon et al., 2014).
Chronic Obstructive Pulmonary Disease (COPD) refers to a group
of progressive lung diseases, with the most common being emphy-
sema and chronic bronchitis. In comparison to OSA, in which
individuals often only experience intermittent nighttime hypoxemia,
those with COPD have continuous daily hypoxemia. Although COPD
is generally not related to global atrophy, reductions in gray matter
are found in the cingulate cortex, hippocampi, and amygdala, which
are partially related to disease duration (Esser et al., 2016). Similarly,
Zhang et al. (2012) found that, compared to healthy controls, those
with COPD have decreased gray matter volume primarily in limbic
and paralimbic structures, and density of gray matter was positively
correlated with PaO2 and negatively associated with disease duration.
In a study examining the relationship between hypoxemia and
cerebral perfusion using SPECT, those with nonhypoxemic COPD
showed decreased perfusion in the left frontal lobe, while hypoxemic
COPD patients had more widespread declines in perfusion across
bilateral frontoparietal regions (Ortapamuk & Naldoken, 2006). An
estimated 77% of patients with COPD have some degree of global
cognitive impairment, with 42% falling within the moderately-to-
severely impaired range (Grant et al., 1982). In a large, population-
based, longitudinal study, older adults with COPD experienced a more
rapid rate of cognitive decline over the course of 6 years when
compared to healthy controls, and this effect was more pronounced
in those with severe COPD when compared to those with milder
COPD (Hung et al., 2009). The most frequently observed deficits
include moderate-to-severe impairments in executive functioning,
attention, psychomotor speed, and memory (see Dodd et al., 2010
for review). The severity and overall profile of cognitive impairment
are similar to those with OSA; however, those with COPD perform
better on tasks of sustained attention and worse on psychomotor
tasks (Roehrs et al., 1995). Others have found that those with COPD
on oxygen therapy perform similarly to health controls across a
variety of cognitive domains (Kozora et al., 1999).
Anoxic Brain Injury
To produce significant anoxic brain injury, the brain must be
deprived of oxygen for approximately 4–8 min (Caine & Watson,
2000). Common causes of cerebral anoxia include cardiac arrest,
drowning, severe asthma/respiratory arrest, hanging/strangulation,
narcotics overdose, and carbon monoxide poisoning (Garcia-
Molina et al., 2006; Peskine et al., 2004). Given that anoxic brain
injury can occur through a variety of different mechanisms, it is
challenging to pin down the precise neuroimaging profile of this
condition. In a review of neuroimaging findings in those with
anoxic brain injury due to carbon monoxide (CO) poisoning
(Hopkins & Woon, 2006), the most frequently reported findings
339
are lesions in the basal ganglia, cerebellum, thalamus, substantia
nigra, and hippocampus. In addition, periventricular and deep
white matter hyperintensities, along with white matter atrophy
in the corpus callosum and temporal, parietal, and occipital
regions, are also quite common (Hopkins & Woon, 2006). Patients
often show some degree of generalized atrophy and ventricular
enlargement following CO poisoning. Anoxic brain injury due to
cardiac arrest is linked to deep white matter lesions, but not related
to leukoariosis or degree of brain atrophy (Roine et al., 1993).
Overall, the basal ganglia, hippocampi, and cerebellum appear to
be particularly vulnerable to anoxic brain damage, and widespread
white matter lesions are commonly found (Caine & Watson, 2000).
The neuropsychological profile of anoxic brain injury is well
documented (Armengol, 2000; Caine & Watson, 2000; Garcia-
Molina et al., 2006). In summary, these studies found that approxi-
mately half of all cases demonstrate moderate-to-severe anterograde
amnesia. Executive dysfunction is also commonly noted, with
patients exhibiting significantly impaired planning, abstraction,
and increased distractibility. Approximately one-third of cases
have visuospatial impairments, particularly when the lateral
occipitoparietal cortex is affected. Language skills are generally
preserved in this population, although some cases demonstrate
reduced spontaneous speech, perseveration, and dysnomia. Armengol
(2000) also found that motor functioning is frequently impaired, with
subjects often presenting with decreased strength, coordination,
psychomotor speed, dyspraxia, and dysarthria. Similarly, Peskine
et al. (2004) documented dystonia and extra-pyramidal syndrome
affecting a minority of their patients who experienced anoxia due to
cardiac arrest. Notably, this study also found that approximately half
of anoxic patients had significant functional dependence and were
unable to live independently following discharge. Interestingly, this
study was unable to find any relationships between acute medical
variables and long-term outcome.
Acute Respiratory Distress Syndrome
ARDS is an often-fatal condition in which fluid collects within the
air sacs of the lungs, causing extreme shortness of breath and severe
hypoxemia (Acute Respiratory Distress Syndrome Definition Task
Force, 2012). Those with ARDS often require aggressive treatment
options, such as use of a ventilator to breathe, and mortality rate
from ARDS is approximately 25%–40% (Acute Respiratory
Distress Syndrome Definition Task Force, 2012). Approximately
60%–80% of individuals with COVID-19 admitted to the ICU are
diagnosed with a unique form of ARDS known as “COVID-19
ARDS,” and the mortality rate for those with this condition is
between 26% and 94% (see Gibson et al., 2020 for review). Wu,
Chen, Cai, Zhou, et al. (2020) identified older age and high fever
contributed to increased risk of ARDS in a COVID-19 population.
Although some features of ARDS may vary in a COVID-19
population (Gattinoni, Coppola, et al., 2020), literature on neuro-
logical and cognitive outcomes following ARDS should be consid-
ered as one of the primary models when hypothesizing cognitive
outcomes for survivors of more critical forms of COVID-19.
In a small neuroimaging study of patients with ARDS (n = 15),
approximately one-half of the sample had normal head CT
scans, while the other half demonstrated mild-to-moderate diffuse
cerebral atrophy and ventricular enlargement compared to age- and
sex-matched healthy controls. Interestingly, these neuroimaging
340 BAILEY ET AL.
findings were not significantly related to hypoxemia or other
medical/health-related factors or cognitive outcome (Hopkins
et al., 2006). A case study of a 49-year-old woman with ARDS
(Jackson et al., 2009) found white matter hyperintensities in both
cerebral hemispheres and the left cerebellum on MRI one-month
post-discharge, and substantial atrophy and ventricular enlargement
3.5 years following hospital discharge.
Survivors of ARDS often experience poor long-term outcomes
(Wilcox & Herridge, 2010). In Hopkins et al.'s (1999) longitudinal
study following 55 individuals with ARDS, 100% of cases demon-
strated cognitive impairments at the time of hospital discharge,
including impaired memory, attention, and processing speed. When
followed up a year later, many subjects saw mild improvements;
however, 78% of these individuals continued to exhibit impairment
in at least one of the aforementioned domains. Notably, PaO2 at
baseline was significantly related to long-term outcomes on mem-
ory, attention, and processing speed tasks. In the ARDS Cognitive
Outcomes Study (ACOS; Mikkelsen et al., 2012), a prospective,
multicenter cohort study which included 122 subjects with ARDS,
subjects were administered a telephone-based battery assessing
cognitive and psychological function. A year post-discharge,
55% of the sample demonstrated cognitive impairment, and the
following percentages had impairment in each cognitive domain:
vocabulary and reasoning (3%), memory (13%), verbal fluency
(16%), and executive function (49%). Those with lower PaO2, those
who enrolled in conservative fluid-management strategies, and
those with lower central venous pressure exhibited worse cognitive
outcomes. Notably, participants’ fatigue often interfered completion
of a full neuropsychological testing battery in one session. Across
both studies, the evaluation was divided across multiple testing
days. Finally, in Needham et al. (2013) longitudinal ARDS Net-
work Long Term Outcomes Study (ALTOS) examining cognitive
outcomes in 174 individuals with acute lung injury, they found that
36% of cases demonstrated some degree of cognitive impairment at
6 months following illness onset, with the following % impaired in
each cognitive domain: verbal fluency: 32%, executive function:
24%, immediate verbal memory: 17%, delayed verbal memory:
16%, verbal abstraction: 15%, and auditory attention: 5%, by
12 months, only 25% demonstrated cognitive impairment (verbal
fluency: 24%, executive function: 14%, immediate verbal memory:
15%, delayed verbal memory: 12%, verbal abstraction: 10%, and
auditory attention: 7%). Overall, there was a significant improve-
ment across all domains aside from attention.
In a review by Sasannejad et al. (2019), the authors identified a
number of risk factors for cognitive decline following ARDS,
including delirium, mechanical ventilation, extended exposure to
sedatives, systemic inflammation, sepsis, pre-existing cognitive
impairment, and environmental factors related to the intensive
care unit (ICU).
Metabolic Dysfunction and Delirium
As this virus is primarily a respiratory condition with potential,
chronic lung dysfunction, reduced cerebral oxygenation should be
considered as one of the primary mechanisms of cognitive dysfunc-
tion in these patients. However, other likely mechanisms include
metabolic dysregulation and long-term sequelae of delirium and
treatment of critical illness, of which are described below.
Toxic-Metabolic Encephalopathy
Emerging research also demonstrates that the lungs are not the
only organ at risk of damage from COVID-19. Patients diagnosed
with this virus are also at risk of experiencing acute liver and kidney
dysfunction (Águila-Gordo et al., 2020; Portincasa et al., 2020)
which, in some cases, can have chronic effects. Although typically
seen in more severe infections, rates of hepatic dysfunction in
particular range from 15% to 53% (AASLD). Therefore, an explo-
ration of the known neurological impact of metabolic dysfunction in
these organ systems is critical when considering the potential
neuropsychological effects of this virus.
Acute metabolic dysfunction is a well-known cause of delirium
but is often discussed in as a quasi-separate entity termed toxic-
metabolic encephalopathy (TME; Chen & Young, 1996). Like any
delirium, TME is theoretically reversable, and involves impaired
attention and arousal, sleep/wake dysfunction, and a waxing/waning
course (Earnest & Parker, 1993; Maldonado, 2008). Attentional
impairments can range from full coma all the way to mild inattention
(Earnest & Parker, 1993). While TME can present typical to other
causes of delirium, one semi-specific finding is the presence of
asterixis (Earnest & Parker, 1993; Young & DeRubeis, 1998), a
postural tremor characterized by difficulty keeping the hands bent
upright at the wrists. TME is also much more likely to yield
myoclonus, and other symptoms of so-called hyperactive delirium
(Earnest & Parker, 1993; Maldonado, 2008).
Hepatic encephalopathy (HE) is a well-known neurobehavioral
syndrome that falls under the umbrella of TME. Metabolically, HE
results from an accumulation of ammonia, a biproduct of digestion,
due to impaired hepatic function. Ammonia is both directly and
indirectly neurotoxic; increasing cerebral edema and depressing
action potentials while also increasing brain glutamate leading to
indirect disruption in brain metabolism. While classically associated
with chronic liver disease (e.g., cirrhosis, hepatocellular carcinoma,
hepatitis c), individuals with decreased oxygen perfusion, as is
common in patients with SARS-CoV-2 and other respiratory dis-
eases, may be more likely to develop HE with relatively less severe
preexisting hepatic dysfunction (Tian & Ye, 2020).
Acute renal failure can result in uremic encephalopathy, the onset
of which is hastened in patients of advanced age (Bleck et al., 1993).
While the pathophysiology of uremic encephalopathy is not as well
elucidated as that for HE, infusion of parathyroid hormones has been
implicated in animal models and brain metabolism, particularly for
amino acids, has also been proposed (Bolton & Young, 1990;
Young & DeRubeis, 1998). Equally important is consideration of
potential long-term neuropsychological effects of delirium and other
critical illnesses.
TME can also present due to systemic involvement of multiple
organ systems, as is seen in sepsis. Sepsis refers to a harmful
systemic bodily response to an infection and has been observed
to occur in patients with COVID (Li, Liu, et al., 2020; Munford &
Suffredini, 2014). While the rate in COVID patients is unknown,
early estimates suggest that up to 20%–35% of hospitalized
patients will experience sepsis (Alhazzani et al., 2020). Further,
up to 70% of patients with sepsis will experience septic encepha-
lopathy (Bolton et al., 1993), the presence of which is associated
with increased mortality rates (Young & DeRubeis, 1998). The
pathophysiology of septic encephalopathy is complex and
beyond the scope of this article, but involves circulatory changes,
 ANTICIPATED COGNITIVE OUTCOMES OF COVID-19
increased inflammatory factors, neurotransmitter derangements,
and altered blood-brain barrier functioning (Bolton et al., 1993;
Papadopoulos et al., 2000).
Hypoxic-Ischemic Encephalopathy
One type of TME of relevance to COVID is hypoxic-ischemic
encephalopathy (HIE). While cases of anoxia or hypoxia can cause
acquired brain injury as described above, the presence of hypoxemia
can also lead to a transient delirium (Chen & Young, 1996).
Individuals with HIE resemble other types of TME, although the
presence of preexisting pulmonary comorbidities can render a more
severe syndrome (Earnest & Parker, 1993). While cases of HIE
typically follow the natural course of delirium (i.e., acute onset, with
gradual resolution following resolution of the underlying medical
cause), given the unique role of oxygen in cerebral functioning,
severe or prolonged hypoperfusion can lead to coma (Earnest &
Parker, 1993). Minimally conscious state, persistent vegetative
state, and other Disorders of Consciousness are also clinical syn-
dromes seen at the more severe end of the spectrum (Bernat, 2010).
While individuals experiencing a Disorder of Consciousness can
recover or improve to a normative state of arousal, those with
hypoxic or anoxic injuries tend to have overall worse outcomes
compared with those who suffer a traumatic injury (Bernat, 2010;
Whyte & Nakase-Richardson, 2013). Finally, HIE can lead to
stroke, particularly watershed infarcts, in which hypoperfusion of
cortex at the terminal ends of the three major cerebral vascular
distributions causes a characteristic infarct and radiographic pattern
(Earnest & Parker, 1993; Young & DeRubeis, 1998). While a cause
of neurocognitive impairment, these types of infarcts can also lead to
so-called “man in a barrel syndrome” (bilateral arm weakness),
cortical blindness, myoclonus, seizures, and other focal neurobe-
havioral and neurologic signs (Earnest & Parker, 1993; Young &
DeRubeis, 1998).
Long-Term Effects of Delirium
Management and resolution of TME and other causes of delirium
during the treatment of a primary infectious is an important aspect of
care for these patients. Further, discharge from the hospital repre-
sents an important prognostic indicator of recovery following
critical illness. As survival rates increase, a large proportion of
patients continue to experience physical, cognitive, and mental
health impairments months to years following hospitalization
(Griffiths et al., 2013; Needham et al., 2013, Pandharipande
et al., 2013). Although previously observed, this constellation of
symptoms was first described as a discrete entity at a 2012 stake-
holder’s conference, describing it as Post-Intensive Care Syndrome
(PICS; Needham et al., 2012). Based on these guidelines, any
patient that presents with at least one new or worsening physical,
cognitive, or mental health symptom following hospitalization for a
critical illness meets criteria for PICS, although large-scale studies
have demonstrated that many of these patients experience impair-
ments in multiple domains (Bienvenu et al., 2012; Hopkins et al.,
2012; Marra et al., 2018; Mikkelsen et al., 2012). The stakeholder’s
conference also hypothesized about potential illness-related me-
chanisms, including hypoxia, glucose dysregulation, nutritional
deficiencies, and hypotension, as well as treatment-related mechan-
isms, including use of sedatives and analgesics, immobilization,
341
disruption of the sleep-wake cycle, and intubation/ventilation
(Needham et al., 2012).
Neuroimaging studies of survivors of critical illness reveal neu-
rological abnormalities, which might account for reported cognitive
symptoms (Hopkins et al., 2016). These investigations demonstrate
that cerebral atrophy, increased white matter lesions, and even acute
infarcts and hemorrhages, are more common both during and
following ICU stays (Purmer et al., 2012; Rafanan et al., 2000;
Suchyta et al., 2010). Several studies established a relationship
between these abnormalities on neuroimaging and the presence
of cognitive impairment; they found factors such as hippocampal
atrophy, ventricular enlargement, and increased white matter lesions
were related to cognitive impairment on neuropsychological assess-
ments (Brown et al., 2015; Semmler et al., 2013).
The rates of cognitive symptoms following critical illness vary
widely across studies but have been documented to be as high as
79% (Girard et al., 2010). In one large study, 821 survivors of
critical illness were assessed at 3- and 12-months post-injury
(Pandharipande et al., 2013). While only 6% of these patients
had cognitive impairment at baseline, 40% scored at least 1.5
SD, and 26% scored at least 2 SD below the mean on a measure
of global cognition at 3 months post-discharge. For many of these
patients, cognitive impairments persisted at the 12-month follow-up
(36% below 1.5 SD, 24% below 2 SD). In this study, they also
demonstrated that it was not solely older patients who experience
cognitive symptoms after critical illness; in fact, patients under the
age of 50 with no baseline comorbidities demonstrated cognitive
impairment at 12-month follow-up in similar rates to the overall
sample (34% below 1.5 SD, 20% below 2 SD). In a separate, large
case-control study examining over 20,000 critically ill patients,
22.3% were found to have cognitive dysfunction during their
ICU hospitalization, and 2.5% developed new and persistent cog-
nitive impairment within 2 years post-ICU discharge (Sakusic et al.,
2018). Many investigations into PICS cognitive symptoms use brief
measures of global cognition (e.g., Pfoh et al., 2015, Woon et al.,
2012). However, several have utilized more comprehensive neuro-
psychological assessment to better characterize the types of deficits
these patients commonly experience. Results indicate a diffuse
pattern of findings, buy with most significant deficits in attention,
memory, and executive functioning (Jackson et al., 2003;
Pandharipande et al., 2013; Sukantarat et al., 2005). Risk factors
for prolonged cognitive impairments include number of ICU hos-
pitalizations (Sakusic et al., 2018), length of delirium (Girard et al.,
2010, Pandharipande et al., 2013), exposure to severe hypotension
(Sakusic et al., 2018), experience of hypoxemia (Mikkelsen et al.,
2012; Sakusic et al., 2018), and experience of acute stress while
hospitalized (Davydow et al., 2013). Longer mechanical ventilation
was not associated with onset of cognitive dysfunction in critically
ill patients after control for other factors (Sakusic et al., 2018).
Anticipated Cognitive Outcomes
As described above, studies of CoVs, including COVID-19,
demonstrate neuroinvasive properties which can directly impact
the CNS and—in some cases—contribute to exacerbation of,
or vulnerability to, other conditions with known cognitive
sequelae. Further, the propensity of detrimental cognitive outcomes
among these patients is amplified by secondary and tertiary
systemic dysfunction, such as renal failure, hypoxemia, cytokine
342 BAILEY ET AL.
inflammatory storms, or cardiovascular compromise. Given the
breadth of systemic dysfunction in COVID-19 cases, it is unsur-
prising that anticipated cognitive outcomes are varied. In sum, the
expected CNS impact in milder COVID-19 cases is likely minimal;
however, survivors of severe and critical COVID-19 may have more
short- and long-term neuropsychological sequelae. Based upon
similar disorders with established cognitive detriment (e.g., ARDS,
renal failure), a generalized, or global, pattern of deficits is to be
expected. This includes hypothetical declines in attention, proces-
sing speed, learning, memory retrieval, as well as executive dys-
function. However, seizures and cerebrovascular events may result
in focal areas of deficit. Depending on the area of injury, this could
include localized cortical signs, such as hemispheric neglect,
apraxia, or dysnomia. Those who are premorbidly compromised
from a medical or cognitive standpoint are likely to demonstrate a
greater and prolonged neurocognitive impact. Lastly, it is expected
that this population, particularly in the acute and post-acute phase,
will demonstrate significant fatigue effects, which should be con-
sidered when developing a neuropsychological assessment battery
for COVID-19.
Neuropsychiatric Considerations
Neuropsychiatric manifestations of COVID-19 are not yet wholly
understood and will likely continue to evolve for years to come.
Currently, there are limited studies describing the prevalence, etiology,
and clinical features of neuropsychiatric symptoms correlated with
COVID-19. However, given extensive literature following previous
pandemics of acute respiratory illness (i.e., ARDS, MERS, SARS),
we can deduct anticipated consequences on mental health.
Mental Health Outcomes of Prior Pandemics
Neuropsychiatric sequelae following epidemics and pandemics is
well-established in existing literature (Brown, Gray, et al., 2020;
Cheng & Wong, 2005; Hawryluck et al., 2004; Lam et al., 2009;
Lurie et al., 2015; Luyt et al., 2012; Mak et al., 2009; Sheng et al.,
2005; Shin et al., 2019). Similarly, there is evidence that certain
groups may be more susceptible to detrimental psychosocial effects
than others; in particular, individuals who develop the disease, those
at increased risk (i.e., older adults, immunocompromised indivi-
duals, those in group settings) people with preexisting medical,
psychiatric, or substance use problems and healthcare workers
(Cheng & Wong, 2005; Gardner & Moallef, 2015). To ascertain
neuropsychiatric symptoms following pandemics, Mak et al. (2009)
evaluated a sample of SARS survivors (N = 90) 30 months post-
outbreak and found that prevalence for any psychiatric diagnosis
was 33.3%; 25% of participants met criteria for PTSD; and 15.6%
for a depressive disorder. In another investigation, SARS survivors
in Hong Kong were evaluated to establish the presence of neuro-
psychiatric syndromes and chronic fatigue (N = 233); over 40% of
patients met criteria for psychiatric diagnoses, 40.3% endorsed
chronic fatigue, and 27.1% met CDC criteria for chronic fatigue
syndrome (Lam et al., 2009). Another prospective and observa-
tional study (Tansey et al., 2007) evaluated 117 SARS survivors
1-year post epidemic. Results indicated that some patients and
caregivers reported a significant reduction in mental health 1-year
post exposure, specifically due to social stigmatization, loss of
anonymity through the media, death of close loved ones,
overwhelming fear for their physical health and transmission of
disease to others. In a literature review by Gardner and Moallef
(2015), 20 articles relating to the neuropsychiatric sequelae of SARS
survivors revealed prominent symptoms in the acute and early
recovery stages, including: (a) psychotic symptomatology, (b)
fear of survival, and (c) fear of infecting others. The following
were demonstrated across all timeframes: (a) stigmatization, (b)
decreased quality of life, and (c) psychological distress. Further-
more, symptoms of PTSD were prevalent across all stages of the
disease process (Gardner & Moallef, 2015).
Respiratory compromise while hospitalized is shown to correlate
with symptoms of PTSD (Jiang et al., 2013). Survivors of H1N1-
associated ARDS requiring ICU care in 2009 were assessed for
psychological well-being 1 year post-illness; over 50% had symp-
toms of anxiety, more than 25% had symptoms of depression, and
40% were at risk for PTSD (Luyt et al., 2012). Similarly, 63 MERS
survivors were recruited from a prospective cohort study at 6
hospitals 1-year post-outbreak (Shin et al., 2019); 63.5% met
criteria for a psychiatric diagnosis. Psychiatric diagnoses from
this study included: PTSD (36.5%), sleep disorders (36.5%), anxiety
(34.9%), and depression (30.2%). Survivors with a history of
ventilator treatment, the death of a family member from MERS,
and past psychiatric history showed higher PTSD, anxiety, and
suicidality than those without these risk factors.
A tendency for the increase of neuropsychiatric symptoms can
also be correlated with the treatment of infectious outbreaks. In a
study by Lurie et al. (2015), chronic antibiotic exposure, pre-
dominantly to penicillins and quinolones, is associated with
heightened risk for anxiety and depression (Lurie et al., 2015).
Additionally, treatment with some antiretroviral agents can also
lead to neuropsychiatric complications. For example, the use of
agents such as oseltamivir recommended by World Health Orga-
nization and utilized for the prevention of flu outbreaks (World
Health Organization, 2009), resulted in a notable neuropsychiat-
ric complications (Kang et al., 2019). Furthermore, Sheng et al.
(2005) studied the outcomes of corticosteroids, disease severity,
and social factors on neuropsychiatric symptoms in SARS suf-
ferers, both during acute and recovering stages and found that use
of pulse steroid and total doses of pulse steroid during hospitali-
zation were predictive of neuropsychiatric symptoms, specifi-
cally anxiety, depression, psychosis, and behavioral symptoms in
the acute phase and that the effects persisted into the recover-
ing phase.
Psychiatric Disorders in Other Medical Conditions
In addition to human CoVs, there are several psychiatric con-
siderations for the medical disorders listed above. For example,
around half of individuals with cerebral anoxia have alterations in
personality and behavior, including increased depression, emotional
lability, impulsivity, irritability, emotional shallowness, lack of
empathy, impaired judgment, anosognosia, restricted affect, cogni-
tive rigidity, and/or apathy (Armengol, 2000; Caine & Watson,
2000). Individuals with OSA can also experience changes in mood
and behavior, including increased irritability, depression, and anxi-
ety (Saunamäki & Jehkonen, 2007). Children with OSA appear to be
especially prone to mood and behavior changes, particularly
increased irritability, emotional lability, hyperactivity, and poorer
academic performance (Brockmann et al., 2012; Owens, 2009).
 ANTICIPATED COGNITIVE OUTCOMES OF COVID-19
Depression and anxiety can also co-occur in patients with COPD.
Depression is found in approximately 10%–42% of milder cases and
37%–71% of more severe cases. Similarly, anxiety is reported in
10%–19% of milder cases, and 50%–75% in those with severe
COPD (Maurer et al., 2008). In a small intervention study in older
adults with COPD, 10 weeks of exercise, education, and stress
management was associated with a boost in performance on verbal
fluency measures and a reduction in anxiety when compared to
education and stress management alone (Emery et al., 1998). Psy-
chiatric symptoms in post-intensive care syndrome are also quite
prevalent. In a large survey-based study of almost 5,000 patient’s
discharged from the ICU in the United Kingdom, 55% reported
significant symptoms of depression (40%), anxiety (46%), or PTSD
(22%) at 3 or 12 months post-discharge (Hatch et al., 2018).
A multi-center study in the US reported similar rates of depression
(37% at 3 months, 33% at 12 months) and furthermore showed that
rates were high even for individuals with no premorbid depressive
symptoms reported by collateral (30% and 29% for 3 and 12-month
follow-up, respectively; Jackson et al., 2014). However, preexisting
psychiatric symptoms have been shown to increase the risk of
worsening symptoms post-discharge from ICU (Patel et al., 2016;
Wunsch et al., 2014). Other factors associated with post-discharge
psychiatric symptoms include younger age, female gender, hypo-
glycemia during ICU stay, and use of sedatives and high-dose
benzodiazepines during hospitalization (Dowdy et al., 2008;
Girard et al., 2007; Hopkins et al., 2010; Nelson et al., 2000).
Ultimately, there is limited research on the impact of COVID-19
on psychological functioning as this pandemic is still ongoing.
Recently, rare cases of COVID-19 patients developing psychotic
symptoms have been described in the literature (Chacko et al., 2020;
Varatharaj et al., 2020). In their recent review, Florino and Gorwood
(2020) proposed that the mental health and psychosocial conse-
quences of COVID-19 could be particularly serious for at least four
groups of people: (a) those who have been directly or indirectly in
contact with the virus, (b) those who are already vulnerable to
biological or psychosocial stressors (e.g., people affected by mental
health symptoms), (c) health professionals (due to higher levels of
exposure), and (d) people who follow the news through numerous
media channels. Zhang & Ma (2020) investigated the immediate
impact of COVID-19 on mental health and quality of life among
Chinese individuals. Overall, 52.1% of participants felt horrified and
apprehensive due to the pandemic. In a recent literature review
predicting the impact of COVID-19 on mental health, researchers
found that previous epidemics and pandemics reported incident
cases of psychosis in people infected with a range of 0.9%–4% and
psychosis diagnosis was associated with viral exposure, treatments
used to manage infection, and psychosocial stressors (Brown, Gray,
et al., 2020).
It is also imperative to bear in mind that survivors of pandemics
may be rejected by their local communities. Affected individuals
may blame themselves and be prevented from returning to their
homes or workplaces. Due to circumstances surrounding the origin
and spread of COVID-19, entire cultural groups, communities, and
geographic populations may become targets of stigmatization.
According to the Centers for Disease Control and Prevention
(CDC) (2020a), the Asian community, particularly, has been the
target of anger and fear (CDC, 2020a). Individuals from within this
group have been subjected to microaggressions, as well as aggres-
sive and overtly hostile acts. These individuals may face further
343
barriers to necessary healthcare due to isolation or fear, which can
further complicate medical outcomes. Given what is known thus far,
neuropsychiatric treatment recommendations will be of utmost
importance for clinicians and patients for years to come. Literature
describing neuropsychiatric outcomes of prior pandemics as well as
mental health considerations among similar neuropathological med-
ical conditions illustrate correlated risks of neuropsychiatric symp-
tomatology in individuals affected both directly and indirectly by
COVID-19. Globally, it will be critical for healthcare providers of
all disciplines to be aware of neuropsychiatric manifestations,
correlates, and strategies to manage them that encompass the needs
of identifiable populations (Yang et al., 2020).
Conclusions
The 2019 novel coronavirus was first discovered in humans in
Wuhan, China. In the subsequent seven months since initial identi-
fication, approximately 16.5 million patients have contracted the
illness with an estimated 650,000 deaths (ECDC, 2020). Global
response to the pandemic is unprecedented and research describing
symptom profiles and medical treatment outcomes in COVID-19 is
rapidly emerging; however, it will likely be years before a clear
picture of the long-term cognitive impact and psychological man-
ifestations of COVID-19 are fully understood. Despite this limita-
tion, we can surmise expected neuropsychological profiles and
treatment considerations of patients with COVID-19 based on prior
HCoV research and existing knowledge of neurologic and neuro-
psychological outcomes in similar mechanisms and disorders. It is
anticipated that patients—especially those with severe medical
compromise due to COVID-19—will demonstrate cognitive deficits
such as reduced attention, impaired processing speed, executive
dysfunction, and difficulties with learning and memory retrieval.
Neuroimaging studies also demonstrate cerebrovascular disease
among COVID-19 patients (Kremer et al., 2020; Radmanesh
et al., 2020); which may result in focal cognitive deficits
(Chougar et al., 2020) and worse patient outcome (Hernández-
Fernández et al., 2020; Jain et al., 2020).
In is imperative to keep in mind that the neuropsychological
impact of COVID-19 poses greater detriment in vulnerable popula-
tions, such as older adults, those with pre-existing medical condi-
tions (e.g., COPD), and those with more severe hypoxemia/
respiratory failure requiring ventilation.
Pediatric populations appear vulnerable to systemic inflammatory
processes (Chiotos et al., 2020; Riphagen et al., 2020; Toubiana
et al., 2020; Verdoni et al., 2020) which often present without
traditional respiratory symptoms. Further, the presence of HCoVs
have also been detected among asymptomatic individuals (Arbour
et al., 2000; Tin & Wiwanitkit, 2020), which may contribute to
inflammation and exacerbation of neurological conditions in the
absence of frank respiratory or more systemic syndromes. These
individuals may experience worsening of already disabling medical
conditions, and unfortunately, these additional required medical
needs likely went unmet with changes in accessibility of care during
the response to the pandemic. This issue may also result in diagnostic
challenges for health care providers and a failure to accurately detect
cognitive dysfunction secondary to HCoVs.
Like cognitive sequelae, psychiatric conditions—such as depres-
sion and anxiety—are expected to occur with higher prevalence in
COVID-19 patients (Fiorillo & Gorwood, 2020). Prolonged
344 BAILEY ET AL.
psychiatric symptoms (Mak et al., 2010) and increased suicide rates
(Cheung et al., 2008) have also been reported during prior pan-
demics. We speculate that individuals with pre-existing mental
health problems, those who required intensive care, and the presence
of specific environmental factors may place COVID-19 patients at
risk for development of psychiatric symptoms. For example, patients
with neurodegenerative disease or preexisting cognitive problems
are prone to social isolation and more likely to reside in assistive
living or nursing facilities (Wang, Li, et al., 2020). These patients
may also be less experienced with virtual care technology, more
prone to difficulties understanding treatment options, and more
reliant on social or community supports to meet functional needs.
With the disruption of services such as meal programs or provision of
wheelchair accessible transportation services, individuals have also
faced losing the ability to independently care for themselves and their
basic needs (Brown, Kumar, et al., 2020).
Fortunately, research describing psychiatric outcomes during
prior pandemics identifies several protective and/or mediating fac-
tors. For example, Cheng and Wong (2005) examined the neuro-
psychiatric manifestations in patients with SARS and documented
several neuropsychiatric manifestations during in the acute treat-
ment phase. After controlling for the effects of demographic and risk
factors, psychosocial factors (e.g., social support), perceived impact
(i.e., negative appraisal), post-traumatic growth (i.e., positive ap-
praisal), and self-efficacy accounted for significant variance of
differential outcomes including: (a) symptoms of anxiety and
depression, (b) quality of life, and (c) perceived health of sufferers
(Cheng & Wong, 2005). Patients with pre-existing cognitive com-
promise are more likely to reside in social isolated settings, such as
in assistive living or nursing facilities, Thus, they may be particu-
larly vulnerable to social isolation and loneliness (Brown, Kumar,
et al., 2020). Several published resources offer support for patients
and their caregivers (Alzheimer’s Disease International, 2020;
Hwang et al., 2020). We recommend through mental health screening
of COVID-19 patients with particular emphasis on adjustment-related
disorders, depression and anxiety, trauma, loneliness, and existential
crises. Mental health providers will also need to revisit the assessment
of suicidality and safety concerns which may arise in the setting of
acute anxiety, disability, bereavement, and significant loss during and
after the COVID-19 pandemic (Gunnell et al., 2020).
The COVID-19 pandemic has also highlighted and exacerbated
existing disparities in access to health care among ethnic and
minority groups in the U.S. (Fur-Holden et al., 2020). Multiple
factors may contribute to barriers to care in these populations,
including lack of financial ability to pay for care and/or health
insurance, lack of transportation to appointments, lack of knowledge
of locations available to obtain care, and/or lack of medical infor-
mation available in languages other than English (Fur-Holden et al.,
2020). Addressing access to care is particularly important due to
differences in health status related to underlying economic and
social disparities (Centers for Disease Control and Prevention
[CDC], 2020b) and increased risk for more severe symptoms.
For example, Hispanic and black children accounted for much of
the sample in a study of pediatric patients with COVID-19-associ-
ated MIS-C (Godfred-Cato et al., 2020).
Individuals with disabilities, another minority group who typi-
cally experience health care disparities, have also been particularly
impacted by the COVID pandemic (CDC, 2020b). Adequate plan-
ning for the needs of individuals with disability in times of
emergency is often lacking on the part of emergency planning
and response systems (Campbell et al., 2009), and has also been
noted during the current pandemic. Many individuals with disabil-
ities reside in the community only through use of support from
caregivers or community services. People with disabilities often
have significant medical needs and may have had difficulty acces-
sing medical supplies critical for their wellbeing with COVID-
related community changes and medical and equipment shortages.
Summary
Overall, there are correlated risks of neuropsychological symp-
toms in individuals affected both directly and indirectly by COVID-
19; however, the science at this time is still too sparse to make strong
conclusions. Early research suggests that cognitive change may be
present in patients who have recovered from COVID-19 (Zhou
et al., 2020). As such, it will be critical for healthcare providers of all
disciplines to be aware of possible cognitive and neuropsychiatric
manifestations, correlates, and management strategies (Yang et al.,
2020). More specific clinical practice and research is needed to
elucidate a more nuanced picture of outcomes and rehabilitation
needs for this population (Lahiri & Ardila, 2020). Neuropsychol-
ogists should be included as an essential part of post-acute treatment
teams to assess and track cognitive and psychiatric changes
over time.
Limitations
Several limitations of this review should be noted. In the above
sections, we present literature describing potential neuroinvasive
properties of human coronaviruses. However, research describing
exact mechanisms for neurological manifestations in patients with
HCoVs remains unclear. For example, histopathological examination
of brain tissue samples of patients with confirmed COVID-19 showed
hypoxic changes without evidence of any encephalitis (Solomon et al.,
2020). Secondly, we also limited our focus to human coronaviruses,
excluding outcomes of other coronavirus research in animal studies.
Finally, this article was written during a period of rapidly emerging
research and as such, not exhaustive of the numerous studies which
continue to be published in the academic literature.
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Received July 29, 2020
Revision received January 19, 2021
Accepted January 21, 2021 ▪