Добавил:
kiopkiopkiop18@yandex.ru t.me/Prokururor I Вовсе не секретарь, но почту проверяю Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз: Предмет: Файл:
Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5221_Библиотеки_им_академика_М_И_Перельмана.pdf
Скачиваний:
0
Добавлен:
31.08.2026
Размер:
21 Мб
Скачать
 Infectious Disease and Neurocognition
neurocognitive impairment and found that CSF TNF- α levels were associated with neurologic decits at hospital discharge as well as with longer coma duration during acute illness and neuropsychological decits in school- age survivors at 6- month follow- up post discharge (Shabani et al., 2017). In a follow- up study, this group conrmed that elevated CSF tau protein concentrations on admission were asso­ciated with long- term neurologic and cognitive impairment in Ugandan children with CM (Datta et al., 2020). Other biomarkers contributing to the pathogenesis of CM by promoting endothelial activation and parasite sequestration, such as von Willebrand factor (vWF) and angiopoietin- 2, have also been related to long- terms neurocognitive sequelae in Ugandan children surviving CM by this group (Ouma et al., 2020, 2021; Park et al., 2008, 2012).
Boivin and colleagues demonstrated that the level of vWF during acute CM illness was predictive of the degree of improvement from CCRT in terms of at­tention and maze learning performance (unpublished data; see Figure 13.3). Holding and Boivin in their review of the neuropsychological eects of CM in Ugandan school- age survivors (Boivin et al., 2007) also documented that vWF, CSF Regulated on Activation, Normal T- cell Expressed and Secreted (RANTES), and granulocytes colonizing factor levels during acute illness were predictive of long- terms decits in vigilance attention and working memory (Holding & Boivin, 2013). John and colleagues had documented earlier that lower levels of CSF RANTES during acute illness was predictive of mortality in CM children (John et al., 2006). Based on these ndings, Boivin and colleagues proposed that these three biomarkers— TNF- α, vWF, and RANTES— would be predictive of the extent to which SMA and CM survivors would benet from a neurocognitive rehabilitation intervention as presented in their CCRT RCT study (Figure 1 in Boivin et al., 2019a).
In their study, TNF- α, vWF, and RANTES were assayed from plasma and CSF of Ugandan children during the acute illness phase of SMA or CM (Boivin et al., 2019b). Two years aer acute malaria illness, 150 surviving children 6– 12 years old entered a three- arm RCT (KABC), the TOVA and the CBCL were admin­istered before and aer 24 CCRT sessions over a 3- month period and at 1- year follow- up. Using linear mixed- eects models, Boivin and colleagues determined that severe malaria survivors with lower levels of vWF, lower CSF levels of TNF- α, and higher levels of plasma and CSF RANTES had better KABC cognitive per­formance aer both titrating and non- titrating CCRT, compared to no CCRT. For the CBCL (total psychiatric symptoms), high plasma RANTES was associ­ated with no benet from either the titrating or non- titrating CCRT, while high plasma TNF- α was predictive of the benet for both interventions. is was the rst evidence in the published literature that severe malaria immunopathogenic biomarkers may be related to poorer long- term brain and behavior function as evidenced by diminished benet from a CCRT intervention administered in an RCT (Boivin et al., 2019b).
Cerebral Malaria 199
Using machine learning algorithms to model neurodevelopmental outcomes in cerebral malaria survivors
Using our well- characterized cohort of Ugandan CM survivors who were then en­rolled into our later CCRT follow- up studies, Leonenko et al. (2023) explored the use of machine learning algorithms to model their neurodevelopmental outcomes using a new strictly stationary time series model with marginal generalized Gaussian distribu­tions. e EEG data previously prepared for their prior automated stochastic analyses (Veretennikova et al., 2018) also were used in these exploratory analyses. eir gen­eralized Gaussian time series modeling for EEG increments, however, was expanded to include clinical biomarkers during acute illness (Blantyre coma score, hemoglobin level, white blood cell count), CSF proinammatory biomarkers, and other immune­pathogenic regulators (interleukin (IL)- 10, IL- 1α, IL- 1α receptor levels (plasma), IL- 6, and vWF). eir analyses also included quality of the Home Environment Measurement Evaluation (HOME) assessments done at the child/ caregiver’s home. is measure was used to evaluate the child’s developmental milieu to control for the quality of the home environment as developmental and neuropsychological outcomes at 6- and 12- month follow- up aer hospital discharge. We could then also better gauge the extent to which CCRT neuropsychological benets were modied by CM acute illness severity based on acute illness biomarker levels in any subsequent CCRT in­tervention studies. Veretennikova and colleagues concluded that the addition of sto­chastic EEG modeling improved the prediction of children’s brain function 6 months following coma and that it can be used prognostically during the acute phase of illness for longer- term neurocognitive outcomes for CM survivors (Leonenko et al., 2023).
Again, this can of great benet in resource- constrained settings where a thorough EEG and immunopathogenic interpretive workup and evaluation may not always be readily available on site but for which the EEG study and biomarker data can be ac­cessed for machine- learning analyses. Dynamic neurocognitive learning outcomes, such as those provided by CCRT, along with a comprehensive prognostic machine­learning analysis of clinical and immunopathogenic biomarkers can be applied in the evaluation of outcomes of new generations of adjuvant therapies being con­sidered to enhance the ecacy of CM and SMA treatment during the acute phase. One such very promising treatment is considered in the nal portion of this review.
Protective role of neuregulin- 1 against cerebral malaria- induced neuronal injury and behavioral sequelae
e remaining sections of this chapter review will be dedicated to an overview of the aims and potential benets of parental artemisinins in providing CM and SMA
 Infectious Disease and Neurocognition
survivors with the opportunity for a life free of long- terms neurodevelopmental and behavioral decits. Furthermore, we hope that behavioral interventions such as CCRT can be used as sensitive dynamic and culture- fair neurodevelopmental measures of brain and behavioral integrity in the aermath of more eective combination treat­ment during the acute phases of SMA and CM as well as for other infectious disease of the brain for which children in tropical regions can be especially at risk (Bangirana et al., 2013a; Boivin & Giordani, 2009, 2013). Brain- powered game apps for admin­istering CCRT on tablet devices are presently being evaluated for this purpose with Ugandan and Malawian school- age children aected by HIV (Boivin, 2019).
ere is still a need for eective combination treatments that can further diminish the long- term risk of neurological, neurocognitive, and behavioral sequelae in CM survivors. Professor Jonathan Stiles is presently leading a translational science ini­tiative that is evaluating the protective role of neurogelin- 1 as an adjuvant therapy for CM that could be used during the acute phase to further improve long- term neurocognitive and behavioral outcomes (Stiles, 2021). Presently no other proven treatments exist for the pathogenic pathways that Professor Stiles and his team have identied as being critical to the mortality and morbidity caused by CM.
Results from previous studies show that heme and Plasmodium falciparum an­tigen histidine- rich protein 2 (HRP2) by- products of parasitized red blood cell lysis during severe P. falciparum infection are major causes of brain inammation, blood– brain barrier (BBB) dysfunction, and brain tissue injury (Harbuzariu et al., 2022). Studies conducted in Ghanaian children dying of CM, severe malarial anemia, and non- malarial causes identied several biomarkers that could potentially predict CM severity and mortality (Armah et al., 2005a, 2005b). e study found CSF and serum biomarkers that were signicantly elevated in the CM mortality group when com­pared to severe malarial anemia and non- malarial deaths. eir ndings revealed additional biomarkers beyond those reported in Uganda that could be used to pre­dict severity and mortality of CM. ey included IL- 1 receptor antagonist, IL- 8, interferon gamma- induced protein 10 (IP- 10), platelet- derived growth factor BB (PDGF- BB), macrophage inammatory protein- 1 beta (MIP- 1β), Fas- ligand (Fas­L), soluble tumor necrosis factor receptor 1 (sTNF- R1), and soluble tumor necrosis factor receptor 2 (sTNF- R2). Additionally, the CSF IP- 10/ PDGF- BB median ratio was statistically signicantly higher in the CM group compared to severe malarial anemia and non- malarial groups.
It is important to note that the pathogenesis of CM and other forms of severe ma­laria is multifactorial and appears to involve cytokine and chemokine homeostasis, inammation, oxidative stress, lipid peroxidation and apoptosis, as well as neuronal and vascular injury/ repair. Further research is needed to identify more prognostic markers and development of algorithms that can predict CM severity and enable the development of better interventions.
Further work in this area has concluded that heme- mediated apoptosis in human brain vascular endothelial cells (HBVEC) was mediated through tumor protein p73 and that it induces apoptosis of BeWo cells, a trophoblast- derived cell line,
Cerebral Malaria 201
by activating the STAT3/ caspase 3/ PARP signaling pathway and reducing troph­oblast cell fusion. Interestingly, neuregulin- 1, an 8 kDa anti- inammatory pep­tide currently undergoing clinical trials against traumatic brain injury, attenuated heme- induced injury of endothelial and neuronal cells in vitro and in vivo (M. Liu et al., 2018). In their mouse model of CM infection, they showed that adjunctive infusion of neuroregulin- 1 during administration of conventional anti- malarial therapy signicantly reduced brain injury and BBB permeability and increased sur­vival. Further, neuroregulin- 1 treatment stimulated phosphorylation of its receptor ErbB4, activated AKT, and inactivated STAT3 in hCMEC/ D3 brain microvascular endothelial cells (Harbuzariu et al., 2022).
In a mouse model, CM resistant (BALB/ c) mice constitutively expressed higher levels of neuroregulin- 1 in brain tissue than CM susceptible (C57BL/ 6) mice during Plasmodium berghei ANKA (PbA) infection, indicating a key role for neuroregulin­1 in susceptibility to CM- associated mortality (M. Liu et al., 2018). In human CM studies at their two eld sites in India and Ghana, the authors observed signi­cantly lower serum neuroregulin- 1 in fatal disease than in mild malaria and healthy controls, indicating a correlation of serum neuroregulin- 1 levels with severity of human CM. is team proceeded to employ a human brain organoid model to test the hypothesis that exogenous neuroregulin- 1 treatment could abrogate heme and HRP2- induced elevation of key markers of brain inammation (CXCL10, TNF­α, IL- 8, IL- 10, Fas- L, and others), neuronal injury (neurolaments), as well as a heme- induced scavenger markers (heme oxygenase- 1 (HO- 1), haptoglobin, and hemopexin). Utilizing urine- derived cells reprogrammed to induced pluripotent stem cells, they have developed a brain chip model of the neurovascular unit that will be used in conjunction with human and murine CM studies to determine the eects of heme and HRP2 on BBB function in vitro (Harbuzariu et al., 2022).
Further recent studies indicate that enhancement of the programmed death- 1 (PD­1/ PD- L1) signaling pathway using a PDL1– IgGFc fusion protein led to amelioration of BBB dysfunction and increased CM survival. Antibody- mediated blockade of PD­1/ PD- L in experimental CM- resistant BALB/ c mice resulted in increased T- cell acti­vation, enhanced IFN- gamma production, increased recruitment of both pRBC and CD8+ T cells in the brain, and augmented experimental CM in experimental CM susceptible (C57BL/ 6) mice (Wang et al., 2024). us, the availability of the novel mu­rine and three- dimensional tissue culture models provides new opportunities to test new interventions (repurposed drugs, or small molecules) in a noninvasive manner.
Potential for impact in the adjuvant treatment of cerebral malaria to improve survival and reduce morbidity
Understanding the role of neuoregulin- 1 in the pathogenesis of CM will enable de­termining whether neuroregulin- 1 will improve survival in children with CM. Most
 Infectious Disease and Neurocognition
adjunctive treatments developed to date against CM have not reduced fatal out­comes in part because treatments have focused on clearance of circulating parasites but have neglected the involvement of damaging parasite and host factors appearing early in infection or remaining aer treatment.
Conclusion
CM is a common childhood encephalopathy in areas where malaria is endemic in­cluding sub- Saharan Africa. A variety of cognitive and neurodevelopmental adverse eects are associated with CM. Clinical and immunopathogenic biomarkers during acute malaria can aect the overall course of the cognitive and neurodevelopmental decits associated with CM. Further, a variety of interventions might improve the cognitive and neurodevelopmental decits associated with CM, including neuroregulin- 1, although proximal neuropathological mechanisms of CM must be disentangled from the more distal eects of long- term neurodevelopmental and neurocognitive outcomes that implicate a variety of pathways for at- risk children. e development of novel and innovative treatments to prevent and remediate neurocognitive sequelae for CM survivors and other brain infections prevalent in regions where malaria is endemic are desperately needed.
Acknowledgments
Funding support for original ndings presented in this review was provided by R01 HD064416 (principal investigators: Boivin and Nakasujja) and R01 NS055349 (prin­cipal investigator: John). Funding support for the evaluation of the protective role of neurogolin- 1 adjuvant therapy research program is provided by 2R01 NS091616 (principal investigator: Stiles). e funders had no role in the conceptualization and content of this chapter review.
References
ABUBAKAR, A., VAN DE VIJVER, F. J., MITHWANI, S., OBIERO, E., LEWA, N., KENGA, S.,
KATANA, K. & HOLDING, P. 2007. Assessing developmental outcomes in children from Kili, Kenya, following prophylaxis for seizures in cerebral malaria. J Health Psychol, 12, 417– 430.
AKPALU, B., AE- NGIBISE, K., AGBOKEY, F., ADJEI, G. & ENUAMEH, Y. 2012. Association between
Plasmodium falciparum malaria and the mental health of children between ve years and nineteen years in sub- Saharan Africa: A systematic review. JBI Libr Syst Rev, 10, 1– 14.
AMERICAN PSYCHIATRIC ASSOCIATION. 1994. Diagnostic and Statistical Manual of Mental
Disorders. 4th ed. Washington, DC: American Psychiatric Association.
ARMAH, H., DODOO, A. K., WIREDU, E. K., STILES, J. K., ADJEI, A. A., GYASI, R. K. & TETTEY,
Y. 2005a. High- level cerebellar expression of cytokines and adhesion molecules in fatal, paediatric, cerebral malaria. Ann Trop Med Parasitol, 99, 629– 647.
Cerebral Malaria 203
ARMAH, H., WIRED, E. K., DODOO, A. K., ADJEI, A. A., TETTEY, Y. & GYASI, R. 2005b. Cytokines
and adhesion molecules expression in the brain in human cerebral malaria. Int J Environ Res Public Health, 2, 123– 131.
BANGIRANA, P., ALLEBECK, P., BOIVIN, M. J., JOHN, C. C., PAGE, C., EHNVALL, A. & MUSISI, S.
2011. Cognition, behaviour and academic skills aer cognitive rehabilitation in Ugandan children surviving severe malaria: A randomised trial. BMC Neurol, 11, 96.
BANGIRANA, P., BIRABWA, A., NYAKATO, M., NAKITENDE, A. J., KROUPINA, M., SSENKUSU,
J. M., NAKASUJJA, N., MUSISI, S., JOHN, C. C. & IDRO, R. 2021. Use of the creating opportunities for parent empowerment programme to decrease mental health problems in Ugandan children sur­viving severe malaria: A randomized controlled trial. Malar J, 20, 267.
BANGIRANA, P., BOIVIN, M. J. & GIORDANI, B. 2013a. Computerized cognitive rehabilitation
therapy (CCRT) for African children: Evidence for neuropsychological benet and future direc­tions. In: BOIVIN, M. J. & GIORDANI, B. (Eds.), Neuropsychology of Children in Africa: Perspectives on Risk and Resilience. New York: Springer Science+ Business Media, pp. 277– 297.
BANGIRANA, P., GIORDANI, B., JOHN, C. C., PAGE, C., OPOKA, R. O. & BOIVIN, M. J. 2009a.
Immediate neuropsychological and behavioral benets of computerized cognitive rehabilitation in Ugandan pediatric cerebral malaria survivors. J Dev Behav Pediatr, 30, 310– 318.
BANGIRANA, P., IDRO, R., JOHN, C. C. & BOIVIN, M. J. 2006. Rehabilitation for cognitive impair-
ments aer cerebral malaria in African children: Strategies and limitations. Trop Med Int Health, 11, 1341– 1349.
BANGIRANA, P., JOHN, C. C., IDRO, R., OPOKA, R. O., BYARUGABA, J., JUREK, A. M. & BOIVIN,
M. J. 2009b. Socioeconomic predictors of cognition in Ugandan children: Implications for commu­nity interventions. PLoS One, 4, e7898.
BANGIRANA, P., MENK, J., JOHN, C. C., BOIVIN, M. J. & HODGES, J. S. 2013b. e association be-
tween cognition and academic performance in Ugandan children surviving malaria with neurolog­ical involvement. PLoS One, 8, e55653.
BANGIRANA, P., NAKASUJJA, N., GIORDANI, B., OPOKA, R. O., JOHN, C. C. & BOIVIN, M. J.
2009c. Reliability of the Luganda version of the Child Behaviour Checklist in measuring behavioural problems aer cerebral malaria. Child Adolesc Psychiatry Ment Health, 3, 38.
BANGIRANA, P., OPOKA, R. O., BOIVIN, M. J., IDRO, R., HODGES, J. S. & JOHN, C. C. 2016.
Neurocognitive domains aected by cerebral malaria and severe malarial anemia in children. Learn Individ Dier, 46, 38– 44.
BANGIRANA, P., OPOKA, R. O., BOIVIN, M. J., IDRO, R., HODGES, J. S., ROMERO, R. A., SHAPIRO,
E. & JOHN, C. C. 2014. Severe malarial anemia is associated with longterm neurocognitive impair­ment. Clin Infect Dis, 59, 336– 344.
BARRERA, V., HISCOTT, P. S., CRAIG, A. G., WHITE, V. A., MILNER, D. A., BEARE, N. A.,
MACCORMICK, I. J., KAMIZA, S., TAYLOR, T. E., MOLYNEUX, M. E. & HARDING, S. P. 2015. Severity of retinopathy parallels the degree of parasite sequestration in the eyes and brains of Malawian children with fatal cerebral malaria. J Infect Dis, 211, 1977– 1986.
BARRERA, V., MACCORMICK, I. J. C., CZANNER, G., HISCOTT, P. S., WHITE, V. A., CRAIG, A. G.,
BEARE, N. A. V., CULSHAW, L. H., ZHENG, Y., BIDDOLPH, S. C., MILNER, D. A., KAMIZA, S., MOLYNEUX, M. E., TAYLOR, T. E. & HARDING, S. P. 2018. Neurovascular sequestration in paedi­atric P. falciparum malaria is visible clinically in the retina. Elife, 7, e32208.
BIRBECK, G. L., MOLYNEUX, M. E., KAPLAN, P. W., SEYDEL, K. B., CHIMALIZENI, Y. F.,
KAWAZA, K. & TAYLOR, T. E. 2010. Blantyre Malaria Project Epilepsy Study (BMPES) of neurolog­ical outcomes in retinopathy- positive paediatric cerebral malaria survivors: A prospective cohort study. Lancet Neurol, 9, 1173– 1181.
BOIVIN, M. J. 2002. Eects of early cerebral malaria on cognitive ability in Senegalese children. J Dev
Behav Pediatr, 23, 353– 364.
BOIVIN, M. J. 2019. R01 HD098027: Culture- specic neurodevelopmental assessment of HIV- aected children,
2019– 2024. [National Institute of Child Health and Human Development (NICHD) grant $3,887,339].
BOIVIN, M. J., BANGIRANA, P., BYARUGABA, J., OPOKA, R. O., IDRO, R., JUREK, A. M. & JOHN,
C. C. 2007. Cognitive impairment aer cerebral malaria in children: A prospective study. Pediatrics, 119, e360– e366.
 Infectious Disease and Neurocognition
BOIVIN, M. J., BANGIRANA, P., NAKASUJA, N., PAGE, C. F., SHOHET, C., GIVON, D., BASS,
J. K., OPOKA, R. O. & KLEIN, P. S. 2013a. A year- long caregiver training program to im­prove neurocognition in preschool Ugandan HIV- exposed children. J Dev Behav Pediatr, 34, 269– 278.
BOIVIN, M. J., BANGIRANA, P., NAKASUJJA, N., PAGE, C. F., SHOHET, C., GIVON, D., BASS,
J. K., OPOKA, R. O. & KLEIN, P. S. 2013b. A year- long caregiver training program improves cognition in preschool Ugandan children with human immunodeficiency virus. J Pediatr, 163, 1409– 1416.
BOIVIN, M. J. & GIORDANI, B. 1993. Improvements in cognitive performance for schoolchildren in
Zaire, Africa, following an iron supplement and treatment for intestinal parasites. J Pediatr Psychol, 18, 249– 264.
BOIVIN, M. J. & GIORDANI, B. 2009. Neuropsychological assessment of African children: Evidence
for a universal basis to cognitive ability. In: CHIAO, J. Y. (ed.) Cultural Neuroscience: Cultural Inuences on Brain Function. New York: Elsevier Publications, pp. 113– 135.
BOIVIN, M. J. & GIORDANI, B. (Eds.) 2013. Neuropsychology of Children in Africa: Perspectives on
Risk and Resilience. New York: Springer.
BOIVIN, M. J., GIORDANI, B., NDANGA, K., MAKY, M. M., MANZEKI, K. M., NGUNU, N. &
MUAMBA, K. 1993. Eects of treatment for intestinal parasites and malaria on the cognitive abilities of schoolchildren in Zaire, Africa. Health Psychol, 12, 220– 226.
BOIVIN, M. J., GLADSTONE, M. J., VOKHIWA, M., BIRBECK, G. L., MAGEN, J. G., PAGE, C.,
SEMRUD- CLIKEMAN, M., KAUYE, F. & TAYLOR, T. E. 2011. Developmental outcomes in Malawian children with retinopathy- positive cerebral malaria. Trop Med Int Health, 16, 263– 271.
BOIVIN, M. J., NAKASUJJA, N., SIKORSKII, A., RUISENOR- ESCUDERO, H., FAMILIAR- LOPEZ, I.,
WALHOF, K., VAN DER LUGT, E. M., OPOKA, R. O. & GIORDANI, B. 2019a. Neuropsychological benets of computerized cognitive rehabilitation training in Ugandan children surviving severe ma­laria: A randomized controlled trial. Brain Res Bull, 145, 117– 128.
BOIVIN, M. J., SIKORSKII, A., FAMILIAR- LOPEZ, I., RUISENOR- ESCUDERO, H., MUHINDO, M.,
KAPISI, J., BIGIRA, V., BASS, J. K., OPOKA, R. O., NAKASUJJA, N., KAMYA, M. & DORSEY, G.
2016. Malaria illness mediated by anaemia lessens cognitive development in younger Ugandan chil­dren. Malar J, 15, 210.
BOIVIN, M. J., SIKORSKII, A., NAKASUJJA, N., RUISENOR- ESCUDERO, H., FAMILIAR- LOPEZ,
I., OPOKA, R. O. & GIORDANI, B. 2019b. Evaluating immunopathogenic biomarkers during severe malaria illness as modiers of the neuropsychologic benets of computer cognitive games rehabili­tation in Ugandan children. Pediatr Infect Dis J, 38, 840– 848.
BOIVIN, M. J., VOKHIWA, M., SIKORSKII, A., MAGEN, J. G. & BEARE, N. A. 2014. Cerebral malaria
retinopathy predictors of persisting neurocognitive outcomes in Malawian children. Pediatr Infect Dis J, 33, 821– 824.
BRIM, R., MBOMA, S., SEMRUD- CLIKEMAN, M., KAMPONDENI, S., MAGEN, J., TAYLOR, T. &
LANGFITT, J. 2017. Cognitive outcomes and psychiatric symptoms of retinopathy- positive cerebral malaria: Cohort description and baseline results. Am J Trop Med Hyg, 97, 225– 231.
CONROY, A. L., OPOKA, R. O., BANGIRANA, P., NAMAZZI, R., OKULLO, A. E., GEORGIEFF, M.
K., CUSICK, S., IDRO, R., SSENKUSU, J. M. & JOHN, C. C. 2021. Parenteral artemisinins are asso­ciated with reduced mortality and neurologic decits and improved long- term behavioral outcomes in children with severe malaria. BMC Med, 19, 168.
DATTA, D., CONROY, A. L., CASTELLUCCIO, P. F., SSENKUSU, J. M., PARK, G. S., OPOKA, R. O.,
BANGIRANA, P., IDRO, R., SAYKIN, A. J. & JOHN, C. C. 2020. Elevated cerebrospinal uid tau protein concentrations on admission are associated with long- term neurologic and cognitive im­pairment in Ugandan children with cerebral malaria. Clin Infect Dis, 70, 1161– 1168.
FAMILIAR, I., RUISENOR- ESCUDERO, H., GIORDANI, B., BANGIRANA, P., NAKASUJJA, N.,
OPOKA, R. & BOIVIN, M. 2015. Use of the Behavior Rating Inventory of Executive Function and Child Behavior Checklist in Ugandan children with HIV or a history of severe malaria. J Dev Behav Pe diat r, 36, 277– 284.
GIOIA, G. A., ISQUITH, P. K., GUY, S. C. & KENWORTHY, L. 2003. Behavior Rating Inventory of
Executive Function® (BRIEF®). Lutz, FL: Psychological Assessment Resources (PAR).
Cerebral Malaria 205
HARBUZARIU, A., NTI, A., HARP, K. O., CESPEDES, J. C., DRISS, A. & STILES, J. K. 2022.
Neuregulin- 1/ ErbB4 signaling modulates Plasmodium falciparum HRP2- induced damage to brain cortical organoids. iScience, 25, 104407.
HOLDING, P. & BOIVIN, M. J. 2013. e assessment of neuropsychological outcomes in pedi-
atric severe malaria. In: BOIVIN, M. J. & GIORDANI, B. (Eds.), Specialty Topics in Pediatric Neuropsychology. New York: Springer, pp. 235– 275.
IDRO, R., KAKOOZA- MWESIGE, A., ASEA, B., SSEBYALA, K., BANGIRANA, P., OPOKA, R. O.,
LUBOWA, S. K., SEMRUD- CLIKEMAN, M., JOHN, C. C. & NALUGYA, J. 2016. Cerebral malaria is associated with long- term mental health disorders: A cross sectional survey of a long- term cohort. Malar J, 15, 184.
IDRO, R., KAKOOZA- MWESIGE, A., BALYEJJUSA, S., MIREMBE, G., MUGASHA, C.,
TUGUMISIRIZE, J. & BYARUGABA, J. 2010a. Severe neurological sequelae and behaviour prob­lems aer cerebral malaria in Ugandan children. BMC Res Notes, 3, 104.
IDRO, R., MARSH, K., JOHN, C. C. & NEWTON, C. R. 2010b. Cerebral malaria: Mechanisms of brain
injury and strategies for improved neurocognitive outcome. Pediatr Res, 68, 267– 274.
JOHN, C. C., BANGIRANA, P., BYARUGABA, J., OPOKA, R. O., IDRO, R., JUREK, A. M., WU, B. &
BOIVIN, M. J. 2008a. Cerebral malaria in children is associated with long- term cognitive impair­ment. Pediatrics, 122, e92– e99.
JOHN, C. C., OPIKA- OPOKA, R., BYARUGABA, J., IDRO, R. & BOIVIN, M. J. 2006. Low levels of
RANTES are associated with mortality in children with cerebral malaria. J Infect Dis, 194, 837– 845.
JOHN, C. C., PANOSKALTSIS- MORTARI, A., OPOKA, R. O., PARK, G. S., ORCHARD, P. J., JUREK,
A. M., IDRO, R., BYARUGABA, J. & BOIVIN, M. J. 2008b. Cerebrospinal uid cytokine levels and cognitive impairment in cerebral malaria. Am J Trop Med Hyg, 78, 198– 205.
JOHN, C. C., PARK, G. S., SAM- AGUDU, N., OPOKA, R. O. & BOIVIN, M. J. 2008c. Elevated serum
levels of IL- 1ra in children with Plasmodium falciparum malaria are associated with increased se­verity of disease. Cytokine, 41, 204– 208.
KAMPONDENI, S., SEYDEL, K. B., ZHANG, B., SMALL, D. S., BIRBECK, G. L., HAMMOND, C. A.,
CHILINGULO, C., TAYLOR, T. E. & POTCHEN, M. J. 2020. Amount of brain edema correlates with neurologic recovery in pediatric cerebral malaria. Pediatr Infect Dis J, 39, 277– 282.
KAMPONDENI, S. D., BIRBECK, G. L., SEYDEL, K. B., BEARE, N. A., GLOVER, S. J., HAMMOND,
C. A., CHILINGULO, C. A., TAYLOR, T. E. & POTCHEN, M. J. 2018. Noninvasive measures of brain edema predict outcome in pediatric cerebral malaria. Surg Neurol Int, 9, 53.
KARIUKI, S. M., ABUBAKAR, A., HOLDING, P. A., MUNG’ALA- ODERA, V., CHENGO, E.,
KIHARA, M., NEVILLE, B. G. & NEWTON, C. R. 2012. Behavioral problems in children with epi­lepsy in rural Kenya. Epilepsy Behav, 23, 41– 46.
KARIUKI, S. M., ABUBAKAR, A., NEWTON, C. R. & KIHARA, M. 2014. Impairment of executive
function in Kenyan children exposed to severe falciparum malaria with neurological involvement. Malar J, 13, 365.
KIHARA, M. 2013. Measurement of cognitive outcomes of at- risk children using novelty processing
in rural Kenyan children. In: BOIVIN, M. J. & GIORDANI, B. (Eds.), Specialty Topics in Pediatric Neuropsychology. New York: Springer, pp. 299– 312.
KIHARA, M., CARTER, J. A., HOLDING, P. A., VARGHA- KHADEM, F., SCOTT, R. C., IDRO, R.,
FEGAN, G. W., DE HAAN, M., NEVILLE, B. G. & NEWTON, C. R. 2009. Impaired everyday memory associated with encephalopathy of severe malaria: e role of seizures and hippocampal damage. Malar J, 8, 273.
KIHARA, M., CARTER, J. A. & NEWTON, C. R. 2006. e eect of Plasmodium falciparum on cogni-
tion: A systematic review. Trop Med Int Health, 11, 386– 397.
KIHARA, M., DE HAAN, M., GARRASHI, H. H., NEVILLE, B. G. & NEWTON, C. R. 2010. Atypical
brain response to novelty in rural African children with a history of severe falciparum malaria. J Neurol Sci, 296, 88– 95.
LARRIVEY, V., NEVA, J., FINN, K., SIKORSKII, A., FAMILIAR- LOPEZ, I., UCHEAGWU, V., EZEAMAMA,
A., RUISENOR- ESCUDERO, H., NAKASUJJA, N., BOIVIN, M. & GIORDANI, B. 2022. Daily training eciency during computerized cognitive rehabilitation training (CCRT): An analysis from a randomized trial in Ugandan children with and without severe malaria. Child Neuropsychol, 28, 197– 211.
 Infectious Disease and Neurocognition
LEONENKO, N. N., SALINGER, Z., SIKORSKII, A., SUVAK, N. & BOIVIN, M. 2023. Generalized
Gaussian time series model for increments of EEG data. Stat Interface, 16, 17– 29.
LIU, M., SOLOMON, W., CESPEDES, J. C., WILSON, N. O., FORD, B. & STILES, J. K. 2018.
Neuregulin- 1 attenuates experimental cerebral malaria (ECM) pathogenesis by regulating ErbB4/ AKT/ STAT3 signaling. J Neuroinammation, 15, 104.
LIU, Q., JING, W., KANG, L., LIU, J. & LIU, M. 2021. Trends of the global, regional and national in-
cidence of malaria in 204 countries from 1990 to 2019 and implications for malaria prevention. J Travel Med, 28, taab046.
MACCORMICK, I. J. C., BARRERA, V., BEARE, N. A. V., CZANNER, G., POTCHEN, M.,
KAMPONDENI, S., HEYDERMAN, R. S., CRAIG, A. G., MOLYNEUX, M. E., MALLEWA, M., WHITE, V. A., MILNER, D., HISCOTT, P., TAYLOR, T. E., SEYDEL, K. B. & HARDING, S. P. 2022. How does blood- retinal barrier breakdown relate to death and disability in pediatric cerebral ma­laria? J Infect Dis, 225, 1070– 1080.
MACCORMICK, I. J. C., BEARE, N. A. V., TAYLOR, T. E., BARRERA, V., WHITE, V. A., HISCOTT, P.,
MOLYNEUX, M. E., DHILLON, B. & HARDING, S. P. 2014. Cerebral malaria in children: Using the retina to study the brain. Brain, 137, 2119– 2142.
MAGEN, J. G., KAUYE, F., VOKHIWA, M., SEMRUD- CLIKEMAN, M., TAYLOR, T. & BOIVIN, M.
J. 2011. Adapting the Achenbach Child Behavior Checklist (CBCL) as a psychiatric screening tool for DSM IV diagnosis in Malawian children. 1st Annual Malawi Mental Health Research and Practice Development Conference. Blantyre, Malawi.
MILLER, K., LORI, J., LIU, X., BOIVIN, M. & GIORDANI, B. 2022. e cognitive burden of severe
malaria in the Ugandan classroom and the eects of a computerized intervention. Appl Nurs Res, 63,
151551.
MIREKU, M. O., DAVIDSON, L. L., BOIVIN, M. J., ZOUMENOU, R., MASSOUGBODJI, A., COT,
M. & BODEAU- LIVINEC, F. 2016. Prenatal iron deciency, neonatal ferritin, and infant cognitive function. Pediatrics, 138, e20161319.
MONTEIRO, M. C., OLIVEIRA, F. R. D., OLIVEIRA, G. B., ROMÃO, P. R. T., SOCORRO, C. D. &
MAIA, F. 2014. Neurological and behavioral manifestations of cerebral malaria: An update. World J Transl Med, 3, 9– 16.
NESAYAN, A., AMANI, M. & ASADI GANDOMANI, R. 2019. Cognitive prole of children and its
relationship with academic performance. Basic Clin Neurosci, 10, 165– 174.
OPOKA, R. O., BANGIRANA, P., BOIVIN, M. J., JOHN, C. C. & BYARUGABA, J. 2009. Seizure ac-
tivity and neurological sequelae in Ugandan children who have survived an episode of cerebral ma­laria. Afr Health Sci, 9, 75– 81.
OUMA, B. J., BANGIRANA, P., SSENKUSU, J. M., DATTA, D., OPOKA, R. O., IDRO, R., KAIN, K. C.,
JOHN, C. C. & CONROY, A. L. 2021. Plasma angiopoietin- 2 is associated with age- related decits in cognitive sub- scales in Ugandan children following severe malaria. Malar J, 20, 17.
OUMA, B. J., SSENKUSU, J. M., SHABANI, E., DATTA, D., OPOKA, R. O., IDRO, R., BANGIRANA,
P., PARK, G., JOLOBA, M. L., KAIN, K. C., JOHN, C. C. & CONROY, A. L. 2020. Endothelial activa­tion, acute kidney injury, and cognitive impairment in pediatric severe malaria. Crit Care Med, 48, e734– e743.
PARK, G. S., IRELAND, K. F., OPOKA, R. O. & JOHN, C. C. 2012. Evidence of endothelial activation
in asymptomatic Plasmodium falciparum parasitemia and eect of blood group on levels of von Willebrand factor in Malaria. J Pediatric Infect Dis Soc, 1, 16– 25.
PARK, G. S., MIN, M., OPIKA- OPOKA, R., BOIVIN, M. J. & JOHN, C. C. 2008. von Willebrand factor,
but not sVCAM- 1 or sICAM- 1, eectively discriminates between cerebral and uncomplicated malaria in Ugandan children. Keystone Conference on Infectious Disease. Vienna, Austria.
PATEL, A. A., JANNATI, A., DHAMNE, S. C., SAPUWA, M., KALANGA, E., MAZUMDAR, M.,
BIRBECK, G. L. & ROTENBERG, A. 2020. EEG markers predictive of epilepsy risk in pediatric cere­bral malaria— A feasibility study. Epilepsy Behav, 113, 107536.
POSTELS, D. G., WU, X., LI, C., KAPLAN, P. W., SEYDEL, K. B., TAYLOR, T. E., KOUSA, Y. A., IDRO,
R., OPOKA, R., JOHN, C. C. & BIRBECK, G. L. 2018. Admission EEG ndings in diverse paediatric cerebral malaria populations predict outcomes. Malar J, 17, 208.
Cerebral Malaria 207
SCHIESS, N., VILLABONA- RUEDA, A., COTTIER, K. E., HUETHER, K., CHIPETA, J. & STINS, M.
F. 2020. Pathophysiology and neurologic sequelae of cerebral malaria. Malar J, 19, 266.
SEYDEL, K. B., KAMPONDENI, S. D., VALIM, C., POTCHEN, M. J., MILNER, D. A., MUWALO, F. W.,
BIRBECK, G. L., BRADLEY, W. G., FOX, L. L., GLOVER, S. J., HAMMOND, C. A., HEYDERMAN, R. S., CHILINGULO, C. A., MOLYNEUX, M. E. & TAYLOR, T. E. 2015. Brain swelling and death in children with cerebral malaria. N Engl J Med, 372, 1126– 1137.
SHABANI, E., OPOKA, R. O., IDRO, R., SCHMIDT, R., PARK, G. S., BANGIRANA, P.,
VERCELLOTTI, G. M., HODGES, J. S., WIDNESS, J. A. & JOHN, C. C. 2015. High plasma erythro­poietin levels are associated with prolonged coma duration and increased mortality in children with cerebral malaria. Clin Infect Dis, 60, 27– 35.
SHABANI, E., OUMA, B. J., IDRO, R., BANGIRANA, P., OPOKA, R. O., PARK, G. S., CONROY, A.
L. & JOHN, C. C. 2017. Elevated cerebrospinal uid tumour necrosis factor is associated with acute and long- term neurocognitive impairment in cerebral malaria. Parasite Immunol, 39, 10.1111/ pim.12438.
SSENKUSU, J. M., HODGES, J. S., OPOKA, R. O., IDRO, R., SHAPIRO, E., JOHN, C. C. &
BANGIRANA, P. 2016. Long- term behavioral problems in children with severe malaria. Pediatrics, 138, e20161965.
STILES, J. K. 2021. 2R01 NS091616: Protective role of Neuregulin- 1 against cerebral malaria- induced
neuronal injury and behavioral sequelae, 2021– 2026. [National Institute of Neurological Disorders and Stroke (NINDS), $3,120,836.]
VERETENNIKOVA, M. A., SIKORSKII, A. & BOIVIN, M. J. 2018. Parameters of stochastic models for
electroencephalogram data as biomarkers for child’s neurodevelopment aer cerebral malaria. J Stat Distrib Appl, 5, 8.
WANG, J., ZHU, Q., SHEN, Y., LIANG, J., WANG, Y., HUANG, Y., TONG, G., WANG, X., ZHANG, N.,
YU, K., LI, Y. & ZHAO, Y. 2024. CD8(+ ) T cell inltration and proliferation in the brainstem during experimental cerebral malaria. CNS Neurosci er, 30, e14431.