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Infectious Disease and Neurocognition
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PART III
PARASITIC DISEASES
IN NEUROCOGNITIVE AND
NEUROPSYCHIATRIC MEDICINE


13
Cerebral Malaria and Its
Neuroinflammatory, Cognitive, and
Neuropsychiatric Associations
Michael J. Boivin and Jonathan K. Stiles
Significance of cognitive impairment associated
with cerebral malaria
In 2018, malaria aected 228 million people worldwide, claiming over 405,000
lives, with 67 percent of them being children under age 5 years, mostly in subSaharan Africa (Q. Liu et al., 2021). Human cerebral malaria (CM) is a severe form
of malaria characterized by sequestration of parasitized red blood cells in cerebral microcirculation and induction of inammatory mediators, which can cause
impaired consciousness with unarousable coma (MacCormick et al., 2022). Over
the past decade, there has been a transition from quinine to parenteral artemisinin as the standard of care in treating complicated malaria during the acute phase
because of the growing evidence that parenteral artemisinins are associated not
only with reduced mortality and neurologic morbidity in CM survivors but can
also improve long- term behavioral and neurocognitive outcomes in CM survivors
(Conroy et al., 2021).
Cognitive impairment following severe malaria is a well- documented problem of
great public health signicance in sub- Saharan Africa (Kihara et al., 2006, 2009).
Holding and Boivin, in their review of the neuropsychological eects of CM in surviving children, concluded that CM is one of the most common childhood encephalopathies, accounting for a signicant number of hospital admissions in endemic
malarial areas (Holding & Boivin, 2013). In their view, the neuropsychological effects of severe malaria should be considered part of a syndrome because the proposed neuropathological mechanisms and neuropsychological outcomes implicate
a variety of pathways for risk and resilience. e brain and behavior eects of CM are
embedded within a complex web of poverty, contributing more distal neuropsychological risk (malnutrition) and protective (education) factors to the proximal neuropathological eects of the disease itself (Idro et al., 2010b).
Michael J. Boivin and Jonathan K. Stiles,
Diseases in Neurocognitive and Neuropsychiatric Medicine
Oxford University Press. © Oxford University Press 2024. DOI: 10.1093/ oso/

Infectious Disease and Neurocognition
Neuropsychological eects of cerebral malaria and
neurocognitive rehabilitation
In the rst prospective studies of the persisting neuropsychological eects of CM in
surviving school- age African children, Boivin, John, and colleagues demonstrated
that attention and working memory decits persist in one out of four children with
CM (Boivin et al., 2007; John et al., 2008a). In Uganda alone, they estimated that
this results in an estimated 80,000 new pediatric cases each year with mild to severe neurocognitive impairment from this disease. Such impairment will likely compromise their school performance, impede their activities of daily living, and lessen
their future economic opportunities. eir study group then went on to document
neurodevelopment delay and neurocognitive disabilities in Ugandan toddlers and
preschool- age children from CM and from severe malaria anemia (SMA) in a series
of prospective studies (Bangirana et al., 2014, 2016), which could then go on to undermine academic performance at school age (Bangirana et al., 2013b).
At that time, there was no known treatment intervention during acute illness to
prevent CM brain- injury eects (Abubakar et al., 2007) or neurocognitive rehabilitative treatment programs available in low- resource settings for aected children.
Because of this, Bangirana, Boivin, and colleagues piloted a computerized cognitive
rehabilitation therapy (CCRT) intervention to specically improve attention, visuospatial learning, and psychosocial adjustment (domains shown most aected by
CM in their previous studies) with school- age Ugandan CM survivors (Bangirana
et al., 2009a). ey went on to establish that CCRT in school- age Ugandan CM survivors not only improved neurocognitive skills in attention and working memory
(Bangirana et al., 2009a) but also demonstrated that these improved skills were
foundational to improved academic skills (Bangirana et al., 2011).
Bangirana et al. (2013a) reviewed their principal ndings from this series of pilot
studies concluding that it was possible for these children to achieve their full potential despite the persisting neurocognitive sequelae of CM (Bangirana et al., 2013a).
However, to achieve this, they must have access to interventions like computerized
cognitive rehabilitation, speech and physical therapy, and caregiver training to enhance early childhood development when aected by severe malaria in their preschool years (Boivin & Giordani, 2009). ey believed such a study was feasible for
community- wide scale- up because almost the whole of Uganda potentially had access to the internet through mobile- phone coverage network cards that could plug
into low- cost, durable, solar- charged laptop computers. is warranted a clinical
study of CCRT with school- age survivors of CM that could establish the feasibility
of using such a system to provide neurocognitive assessment and treatment in areas
where such services are unavailable, demonstrating that such services can be delivered to multiple children simultaneously while being mediated by local healthcare workers and teachers (Bangirana et al., 2009b). Furthermore, establishing the
feasibility and benet of CCRT in the sub- Saharan African Ugandan study setting

Cerebral Malaria 187
as proposed by Boivin and colleagues could revolutionize screening assessment and
treatment options for a broad range of developmental disabilities from infectious disease and other causes of brain injury worldwide (Bangirana et al., 2006).
Boivin and colleagues then proposed a randomized control trial (RCT) to further
establish that CCRT could improve attention, working memory, aspects of executive
functioning, and psychosocial adjustment in pediatric CM survivors at school age
(Figure 13.1). Such programs were already being used extensively with children with
developmental disabilities (e.g., attention decit/ hyperactivity disorder (ADHD),
learning disorders) and brain injury in high- income countries. e evidence from
150 severe malaria and
control pairs from home
N = 150
KABC-2, TOVA, BOT2, CogState, CBCL
Captain’s Log
24 Sessions over 8 Weeks
N = 50
KABC-2, TOVA, BOT2, CogState, CBCL
1-year follow-up: academic
KABC-2, TOVA, BOT2, CogState, CBCL
Pre-test:
Random
assignment
Passive control
No computer training or
games
N = 50
Post-test:
Captain’s Log
Locked
24 Sessions over 8 Weeks
N = 50
Figure 13.1 This schematic depicts the enrollment of 150 children with severe malaria (cerebral
malaria or severe malaria anemia) enrolled at school age aer at least 2 years of follow- up
aer being enrolled during acute illness in hospital in a prospective observational study of the
immunopathology, neurology, and neurodevelopment of severe malaria follow- up study. Also,
150 control (non- malaria) children were enrolled from their households in a case– control study
design. Baseline (pre- test) assessments included the Kaufman Assessment Battery for Children,
2nd edition (KABC- 2), Tests of Variables of Attention (TOVA), Bruininks– Oseretsky Test (BOT- 2)
test for motor proficiency, Cogstate test for neuropsychological screening, and Achenbach
Child Behavior Checklist (CBCL) screening for psychiatric symptoms (answered by the primary
caregiver). Participants were randomized to one of three study arms: Captain’s Log (by BRAIN
TRAIN corporation) computerized cognitive rehabilitation training (CCRT) of 24 1- hour sessions
over 8 weeks (titrated or adaptive training), passive control arm (no training), or Captain’s Log
Locked (non- titrating CCRT or non- adaptive training). Children were evaluated again post
training and then again at 1- year follow- up aer the completion of training.
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