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Infectious Disease and Neurocognition
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PART VI
GLOBAL ISSUES OF INFECTIOUS DISEASE
AND NEUROPSYCHOLOGICAL AND
NEUROPSYCHIATRIC FUNCTION


24
Eects of Infectious Diseases on Child and
Brain Development and Their Association
with Poverty
Shawn D. Gale and Dawson W. Hedges
Introduction
In 1857, the physician J. C. Bucknill wrote, “In the brain the state of inammation
itself either very quickly ceases or very soon causes death; but when it does cease
it leaves behind consequences which are frequently the causes of insanity, and the
causes of cerebral atrophy” (Bucknill, 1857, as quoted in Brown & Meyer, 2018).
Although brain inammation is much more complicated and the outcomes more
diverse than Bucknill envisioned in the mid- nineteenth century, the observation of
signicant cerebral eects associated with brain inammation seems remarkably
prescient, including the eects of infectious diseases during gestation and childhood
on neurodevelopment. Despite advances in public health and disease prevention
since the 1800s, infectious diseases continue to impose a signicant health burden
on much of the world’s population. In 2000, infectious diseases accounted for an estimated 22 percent of all deaths globally, particularly aecting children (Saker et al.,
2004). Even in a high- income nation, fully 50 percent of pregnant women experience an infectious disease (Zerbo et al., 2015). However, many infectious diseases are
closely associated with low income and poverty (Besnier et al., 2019; Hotez, 2014),
resulting in an increased risk of exposure. Furthermore, because infectious diseases
can adversely aect fetal development, children in low- and middle- income nations
may be particularly aected by this adverse outcome (Waldorf & McAdams, 2013).
A variety of factors including globalization, climate change, deforestation, urbanization, and socioeconomic conditions can converge to result in exposure to
infectious diseases in children in low- income nations and those living in poverty
(Saker et al., 2004). Fewer public health resources are available in low- income regions, which additionally increases exposure to infectious diseases in children living
in low- income areas (Saker et al., 2004) and in poverty. Finally, infectious diseases
can interact with other factors related to child development such as poor nutrition
(Krebs et al., 2017).
Shawn D. Gale and Dawson W. Hedges,
In: Infectious Diseases in Neurocognitive and Neuropsychiatric Medicine
Oxford University Press. © Oxford University Press 2024. DOI: 10.1093/ oso/

Infectious Disease and Neurocognition
Multiple pathways can result in childhood exposure to infectious diseases in children throughout the world including those living in poverty and in low- income nations. In one pathway, for example, interactions between environmental pollutants
and infectious diseases also might aect how infectious diseases impact child development and the brain. e toxins peruoroalkyl and polyuoroalkyl are widely distributed throughout the environment and are known immunosuppressants (Bulka
et al., 2021). In a study based on data from the United States Centers for Disease
Control and Prevention, increased peruoroalkyl and polyuoroalkyl concentrations were associated with an infectious disease burden measure based on antibodies
against cytomegalovirus, herpes simplex virus types 1 and 2, Epstein– Barr virus,
hepatitis C and E viruses, and human immunodeciency virus and the parasites
Toxoplasma gondii and To xo c ar a species. e association was particularly strong in
adolescents. e authors argued that peruoroalkyl and polyuoroalkyl toxins suppressed the immune system, which in turn enabled infection from a variety of organisms (Bulka et al., 2021).
Climate change, too, aects exposure of children to infectious diseases through
a variety of pathways. Although multiple factors inuence exposure to infectious
diseases including changes in land use, climate change aects the ranges of vectors,
hosts, and diseases reservoirs of infectious diseases (Louis et al., 2023). For example,
changes in the ranges of vectors transmitting malaria, dengue, Zika virus, and Lyme
disease are increasing the numbers of children exposed to these diseases (Perera
& Nadeau, 2022), all of which have been associated with cognitive and brain abnormalities in children (Branseld et al., 2008; Carod- Artal et al., 2013; Sahu et al.,
2021; Wheeler et al., 2020). Mathematical modeling suggests that without adequate
steps to curtail atmospheric carbon dioxide, the Aedes aegypti mosquito, which can
transmit Zika and dengue viruses, could increase its range and invade European
cities (Liu- Helmersson et al., 2019), potentially resulting in exposures to infectious
disease not previously experienced in those cities. Climate change can worsen water
quality, which also can increase exposure to infectious diseases (Perera & Nadeau,
2022). Moreover, increasing exposure to infectious diseases associated with climate
change is likely to disproportionately aect vulnerable groups such as children and
the elderly and those living in less auent areas (Atwoli et al., 2021). Climate change
is increasing viral transmission from animals to humans including in Southeast Asia
and in Africa (Carlson et al., 2022), and climate change will likely increase exposure
to over half of the known human infectious diseases (Mora et al., 2022) including the
bacterium Helicobacter pylori (Khalifa et al., 2010), factors that likely will dispropor-
tionately aect children living in low- income regions.
In addition to increasing risk of death such as from diarrhea, exposure to infectious diseases during gestation and childhood has been associated with mental
illness in both children and adults (Green et al., 2021). Further, the burden of infectious disease is higher in low- income than in high- income regions (Besnier et al.,
2019; Saker et al., 2004), increasing the risk of exposure to children living in poverty
to many of the infectious diseases that can aect brain development. In this chapter,

Infectious Diseases and Development 445
we explore rst how infectious diseases can aect child and brain development and
then discuss how children and adults living in low- income regions and poverty have
elevated risks of exposures to infectious diseases that can aect brain development
and function.
Exposure to prenatal and childhood infections and
brain development
Maternal prenatal infections and inammation (al- Haddad et al., 2019b) have
been associated with a variety of adverse fetal outcomes in fetal and brain development (Waldorf & McAdams, 2013) that can lead to later neuropsychiatric disease in the ospring (al- Haddad et al., 2019b). Table 24.1 provides a sampling
Table 24.1 A sampling of maternal infectious diseases and infectious diseases of childhood
associated with abnormal fetal or childhood brain development and neuropsychiatric or
cognitive outcome
Infectious disease Neuropsychiatric or cognitive outcome Authors
Any maternal infection Autism spectrum disorders, depression Atladóttir et al., 2010
al- Haddad et al., 2019a
Cerebral malaria Reversible cytotoxic edema in white matter Sahu et al., 2021
Common childhood
infections
Cytomegalovirus Autism spectrum disorders in those with
Depression and psychotic features in
adolescence
tuberous sclerosis complex
Chaplin et al., 2022
Yang et al., 2022
Enterovirus Poor developmental outcome do Valle, et al., 2020
Epstein– Barr virus Poor developmental outcome do Valle, et al., 2020
Exposure to infectious
diseases in early childhood
Inammatory markers
during pregnancy
Maternal genital infections Schizophrenia in ospring Babulas et al., 2006
Neonatal or childhood
Lyme disease
Prenatal and childhood
infections
Shorter time to rst diagnosis for
externalizing disorders and developmental
disorders including autism spectrum
disorders
Externalizing and internalizing symptoms
in childhood, increasing risk for mental
disorders
Autism spectrum disorders Branseld et al., 2008
Autism spectrum disorders Sabourin et al., 2019
Green et al., 2021
Mac Giollabhui et al.,
2019
(continued)

Infectious Disease and Neurocognition
Table 24.1 Continued
Infectious disease Neuropsychiatric or cognitive outcome Authors
Rubella Sensorineural hearing loss, behavioral
abnormalities
Intellectual disability Waldorf & McAdams, 2013
SARS- CoV- 2 Prenatal exposure associated with adverse
brain development
Streptococcus (invasive
group B)
Toxocariasis Reduced cognitive function Walsh & Haseeb, 2012
Toxoplasma gondii Seizures, microcephaly, intellectual
Treponema pallidum
(syphilis)
Zika virus Cortical and corpus callosum
Infant infection: increased risk for
internalizing problems, withdrawal,
anxiety, and attention problems
disability
Decreased cognitive function Mendy et al., 2015
Hydrocephalus, brain infarcts Neu et al., 2015
Seizures, intellectual disability Waldorf & McAdams,
abnormalities, ventriculomegaly, severely
decreased brain volume
Profound cognitive, motor, and language
delays
Neu et al., 2015
Edlow et al., 2022
Shook et al., 2022
Chandna et al., 2022
Neu et al., 2015
2013
Sanz Cortes et al., 2018
Wheeler et al., 2020
of papers on various infectious diseases and developmental outcomes. Providing
support for the notion that maternal infections during gestation could result in
altered brain development are ndings from a primate model that found that maternal immunoglobulin G anti- brain protein antibodies from women with a child
who has an autism spectrum disorder when given to pregnant rhesus monkeys
can result in abnormal social behavior in ospring and in altered brain growth
in the male ospring (Bauman et al., 2013). While these ndings do not directly
implicate maternal infection with abnormal ospring brain development, the
association between antibodies found in women who have had a child with an
autism spectrum disorder and abnormal social behavior and abnormal brain
growth in the ospring of rhesus monkeys exposed to these antibodies suggests a
plausible means whereby maternal infection could result in abnormal fetal brain
development.
Maternal infection from the protozoal parasite Toxoplasma gondii, the rubella
virus, cytomegalovirus, and herpes simplex virus, and others collectively known as
TORCH infections are among the infectious diseases that can aect fetal brain development. Other infectious diseases in addition to the classic TORCH infections

Infectious Diseases and Development 447
also appear to aect fetal brain development and can result in neuropsychiatric disease (al- Haddad et al., 2019b).
In addition to their associations with stillbirth and perinatal death, the
TORCH infections cause numerous dierent types of abnormal brain development. Congenital toxoplasmosis from maternal infection with Toxoplasma gondii
or reactivation of maternal latent Toxoplasma gondii can result in various forms
of congenital toxoplasmosis (Neu et al., 2015). Although rare, the classic triad of
congenital toxoplasmosis consists of chorioretinitis, hydrocephalus, and intracranial calcication. Other outcomes of congenital toxoplasmosis aecting the brain
include seizures, microcephaly, and intellectual disability (Neu et al., 2015). In addition to stillbirth, maternal infection with the rubella virus can result in the congenital rubella syndrome, which is characterized by, in addition to eye and cardiac
abnormalities, sensorineural hearing loss, later behavioral abnormalities (Neu et al.,
2015), and intellectual disability (Waldorf & McAdams, 2013). Maternal infection
from Treponema pallidum can be associated with hydrocephalus, brain infarcts,
stillbirth in the child (Neu et al., 2015), seizures, and intellectual disability (Waldorf
& McAdams, 2013). Central nervous system abnormalities associated with parvovirus B19 can include rare meningoencephalitis (Neu et al., 2015) and abnormal
neurodevelopment. Congenital infections with cytomegalovirus are associated
with sensorineural hearing loss and abnormal intellectual development (Waldorf &
McAdams, 2013). Although not considered a TORCH infection, the Zika virus can
result in profound developmental decits, as indicated by the Zika epidemic in 2015
and 2016 (Wheeler et al., 2020), when maternal infections during gestation severely
aected brain development in some fetuses and ospring, including microcephaly,
decreased brain volumes, abnormal corpus collosum, and cortical abnormalities
(Sanz Cortes et al., 2018). In a series of 121 children with congenital Zika syndrome
in Brazil, the majority at a mean age of approximately two and a half years had developmental ages of 2– 3 months, with substantial impairment in all developmental
domains. While no longer considered an epidemic, congenital Zika syndrome continues to occur in endemic regions such as parts of Brazil (Wheeler et al., 2020).
Viral encephalitis in childhood continues to occur and can aect brain development. In a study from southern Brazil, the most common cause of viral encephalitis in young children was enterovirus followed by Epstein– Barr virus. In this study
of children hospitalized with meningoencephalitis, approximately 87 percent of the
children had recovered by the time of discharge, but the authors found poor outcomes in children who had had seizures, abnormal electroencephalography, and
focal neurological signs (do Valle et al., 2020).
e severe acute respiratory syndrome coronavirus 2 (SARS- CoV- 2) pandemic,
which began in late 2019, has added additional evidence to how infectious diseases
can adversely aect brain development. One- year- old children whose mothers
were exposed to SARS- CoV- 2 during pregnancy were more likely than unexposed
controls to have decits in neurodevelopment (Edlow et al., 2022). Maternal, fetal,
and placental immune activation during maternal SARS- CoV- 2 infection could
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