Acute Brain MRI Findings in 120 Malawian Children with Cerebral Malaria: New Insights into an Ancient Disease

Potchen, Michael J.; Kampondeni, Samuel; Seydel, Karl B.; Birbeck, Gretchen L.; Hammond, Colleen; Bradley, William G.; DeMarco, J. Kevin; Glover, Simon J.; Ugorji, Joseph; Latourette, Matthew T.; Siebert, James E.; Molyneux, Malcolm E.; Taylor, Terrie E.

doi:10.3174/ajnr.a3035

Cited by 115 publications

(133 citation statements)

References 31 publications

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“…One of the most deadly complications of P. falciparum infection in humans is cerebral malaria (HCM) characterized by the onset of severe neurological signs such as altered consciousness, seizures, and coma (2). Autopsy and MRI analyses of brains of children with HCM indicate sequestration of infected red blood cells (iRBCs), microhemorrhaging, breakdown of the blood-brain barrier (BBB) (3), and a fatal increase in intracranial pressure resulting from edema (4,5). At present, despite effective antimalarial drug treatment, mortality for children presenting with HCM remains high, at 15-25%.…”

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confidence: 99%

Targeting glutamine metabolism rescues mice from late-stage cerebral malaria

Gordon

Hart

Tran

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The most deadly complication of Plasmodium falciparum infection is cerebral malaria (CM) with a case fatality rate of 15-25% in African children despite effective antimalarial chemotherapy. There are no adjunctive treatments for CM, so there is an urgent need to identify new targets for therapy. Here we show that the glutamine analog 6-diazo-5-oxo-L-norleucine (DON) rescues mice from CM when administered late in the infection a time at which mice already are suffering blood-brain barrier dysfunction, brain swelling, and hemorrhaging accompanied by accumulation of parasite-specific CD8 + effector T cells and infected red blood cells in the brain. Remarkably, within hours of DON treatment mice showed blood-brain barrier integrity, reduced brain swelling, decreased function of activated effector CD8 + T cells in the brain, and levels of brain metabolites that resembled those in uninfected mice. These results suggest DON as a strong candidate for an effective adjunctive therapy for CM in African children.cerebral malaria | adjunctive therapy | CD8 + T cells | glutamine metabolism | DON

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confidence: 99%

Targeting glutamine metabolism rescues mice from late-stage cerebral malaria

Gordon

Hart

Tran

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Computed tomography of Kenyan children with cerebral malaria revealed that more than 40% had brain edema (7). More recently, increased brain volume in Malawian children with cerebral malaria based on MRI was reported (8). Severe intracranial hypertension in children with cerebral malaria is often fatal (7,9).…”

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confidence: 99%

Protective role of brain water channel AQP4 in murine cerebral malaria

Promeneur

Lunde

Amiry-Moghaddam

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Tragically common among children in sub-Saharan Africa, cerebral malaria is characterized by rapid progression to coma and death. In this study, we used a model of cerebral malaria appearing in C57BL/6 WT mice after infection with the rodent malaria parasite Plasmodium berghei ANKA. Expression and cellular localization of the brain water channel aquaporin-4 (AQP4) was investigated during the neurological syndrome. Semiquantitative real-time PCR comparing uninfected and infected mice showed a reduction of brain AQP4 transcript in cerebral malaria, and immunoblots revealed reduction of brain AQP4 protein. Reduction of brain AQP4 protein was confirmed in cerebral malaria by quantitative immunogold EM; however, polarized distribution of AQP4 at the perivascular and subpial astrocyte membranes was not altered. To further examine the role of AQP4 in cerebral malaria, WT mice and littermates genetically deficient in AQP4 were infected with P. berghei. Upon development of cerebral malaria, WT and AQP4-null mice exhibited similar increases in width of perivascular astroglial endfeet in brain. Nevertheless, the AQP4-null mice exhibited more severe signs of cerebral malaria with greater brain edema, although disruption of the blood-brain barrier was similar in both groups. In longitudinal studies, cerebral malaria appeared nearly 1 d earlier in the AQP4-null mice, and reduced survival was noted when chloroquine rescue was attempted. We conclude that the water channel AQP4 confers partial protection against cerebral malaria. C erebral malaria is a dangerous complication of infection with Plasmodium falciparum, especially in children of sub-Saharan Africa, with a mortality rate of 20% (1). If untreated, cerebral malaria often causes coma and death within 24 h (2). Survivors of cerebral malaria often suffer neurological sequelae such as ataxia, hemiplegia, epilepsy, and blindness. The exact pathogenesis of cerebral malaria remains unclear. It is thought that massive sequestration of erythrocytes containing mature stages of P. falciparum within the brain microvasculature (3), as well as an excessive response of the host immune system against the malaria parasite, contribute to the disease (4).Brain edema and intracranial hypertension are common in cerebral malaria. Elevated cerebrospinal fluid pressure has been reported in more than 80% of African children with cerebral malaria (5, 6). Computed tomography of Kenyan children with cerebral malaria revealed that more than 40% had brain edema (7). More recently, increased brain volume in Malawian children with cerebral malaria based on MRI was reported (8). Severe intracranial hypertension in children with cerebral malaria is often fatal (7, 9). Autopsies of African children who died from cerebral malaria revealed brain edema (10, 11).A murine model of cerebral malaria has been established in a susceptible strain of mice (C57BL/6) infected with the rodent malaria parasite P. berghei ANKA (12). Although relevance to human cerebral malaria in adults has been questioned (13), this mo...

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“…We previously reported the MRI findings found in 120 children with retinopathy-positive CM scanned during this time interval. 11 In our previous study, scans from children with retinopathy-positive CM were compared with images from 32 children with retinopathy-negative CM.…”

Section: Introductionmentioning

confidence: 99%

“…Criteria have been established for the assessment of overall brain volume. 11 Discrepant interpretations between the radiologists were settled by consensus.…”

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confidence: 99%

Brain MRI of Children with Retinopathy-Negative Cerebral Malaria

Postels

Birbeck

et al. 2014

The American Society of Tropical Medicine and Hygiene

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Abstract. Our goals were to understand the brain magnetic resonance imaging (MRI) findings in children with retinopathy-negative cerebral malaria (CM) and investigate whether any findings on acute MRI were associated with adverse outcomes. We performed MRI scans on children admitted to the hospital in Blantyre, Malawi with clinically defined CM. Two hundred and seventeen children were imaged during the study period; 44 patients were malarial retinopathy-negative; and 173 patients were retinopathy-positive. We compared MRI findings in children with retinopathy-negative and retinopathy-positive CM. In children who were retinopathy-negative, we identified MRI variables that were associated with death and adverse neurologic outcomes. On multivariate analysis, cortical diffusion weighted imaging (DWI) abnormality and increased brain volume were strongly associated with neurologic morbidity in survivors. Investigations to explore the underlying pathophysiologic processes responsible for these MRI changes are warranted.

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Acute Brain MRI Findings in 120 Malawian Children with Cerebral Malaria: New Insights into an Ancient Disease

Cited by 115 publications

References 31 publications

Targeting glutamine metabolism rescues mice from late-stage cerebral malaria

Targeting glutamine metabolism rescues mice from late-stage cerebral malaria

Protective role of brain water channel AQP4 in murine cerebral malaria

Brain MRI of Children with Retinopathy-Negative Cerebral Malaria

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