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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 aected 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 inammatory 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 signicance in sub- Saharan Africa (Kihara et al., 2006, 2009). Holding and Boivin, in their review of the neuropsychological eects of CM in sur­viving children, concluded that CM is one of the most common childhood enceph­alopathies, accounting for a signicant 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 eects of CM are embedded within a complex web of poverty, contributing more distal neuropsycho­logical risk (malnutrition) and protective (education) factors to the proximal neuro­pathological eects 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 eects of cerebral malaria and neurocognitive rehabilitation
In the rst prospective studies of the persisting neuropsychological eects of CM in surviving school- age African children, Boivin, John, and colleagues demonstrated that attention and working memory decits 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 eects (Abubakar et al., 2007) or neurocognitive rehabil­itative treatment programs available in low- resource settings for aected children. Because of this, Bangirana, Boivin, and colleagues piloted a computerized cognitive rehabilitation therapy (CCRT) intervention to specically improve attention, visu­ospatial learning, and psychosocial adjustment (domains shown most aected 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 aected 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 benet 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 decit/ 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 aer at least 2 years of follow- up aer 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 aer the completion of training.