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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
Eects 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 inammation 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 inammation is much more complicated and the outcomes more diverse than Bucknill envisioned in the mid- nineteenth century, the observation of signicant cerebral eects associated with brain inammation seems remarkably prescient, including the eects 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 signicant health burden on much of the world’s population. In 2000, infectious diseases accounted for an es­timated 22 percent of all deaths globally, particularly aecting 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 aect fetal development, children in low- and middle- income nations may be particularly aected 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 aect how infectious diseases impact child devel­opment and the brain. e toxins peruoroalkyl and polyuoroalkyl 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 peruoroalkyl and polyuoroalkyl 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 immunodeciency virus and the parasites Toxoplasma gondii and To xo c ar a species. e association was particularly strong in adolescents. e authors argued that peruoroalkyl and polyuoroalkyl toxins sup­pressed the immune system, which in turn enabled infection from a variety of or­ganisms (Bulka et al., 2021).
Climate change, too, aects exposure of children to infectious diseases through a variety of pathways. Although multiple factors inuence exposure to infectious diseases including changes in land use, climate change aects 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 (Branseld 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 aect vulnerable groups such as children and the elderly and those living in less auent 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 aect 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 aect brain development. In this chapter,
Infectious Diseases and Development 445
we explore rst how infectious diseases can aect 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 aect brain development and function.
Exposure to prenatal and childhood infections and brain development
Maternal prenatal infections and inammation (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 ospring (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
Inammatory markers during pregnancy
Maternal genital infections Schizophrenia in ospring 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 Branseld 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 ospring and in altered brain growth in the male ospring (Bauman et al., 2013). While these ndings do not directly implicate maternal infection with abnormal ospring 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 ospring 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 aect fetal brain de­velopment. Other infectious diseases in addition to the classic TORCH infections
Infectious Diseases and Development 447
also appear to aect 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 dierent 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 calcication. Other outcomes of congenital toxoplasmosis aecting 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 decits, as indicated by the Zika epidemic in 2015 and 2016 (Wheeler et al., 2020), when maternal infections during gestation severely aected brain development in some fetuses and ospring, 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 aect 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 aect brain development. One- year- old children whose mothers were exposed to SARS- CoV- 2 during pregnancy were more likely than unexposed controls to have decits in neurodevelopment (Edlow et al., 2022). Maternal, fetal, and placental immune activation during maternal SARS- CoV- 2 infection could