In the Eye of Experimental Cerebral Malaria

Abstract

Cerebral malaria is the most severe complication of Plasmodium falciparum infection, accounting for 1 million deaths per year. We characterized the murine disease using in vivo magnetic resonance imaging (MRI) at 4.7 T, proving that ischemic edema is responsible for fatality. The aim of the present study was to identify early markers of experimental cerebral malaria using very high field conventional MRI (11.75 T). CBA/J mice infected with Plasmodium berghei ANKA were observed at an early stage of the disease, before the onset of detectable brain swelling and at the most acute stage of cerebral malaria. Herein, we report the first detection of damage to the optic and trigeminal nerves on T 2 -weighted MRI. The trigeminal nerves appeared hypointense, with significantly reduced diameter and cross-sectional area. The optic nerves were hypointense and often not visible. In addition, the internerve distance between the optic nerves was significantly and progressively reduced between the early and severest stages. Cranial nerve injury was the earliest anatomic hallmark of the disease, visible before brain edema became detectable. Thus, cranial nerve damage may manifest in neurologic signs, which may assist in the early recognition of cerebral malaria. Malaria is a major disease of the developing world, and cerebral malaria (CM) is the most lethal complication of infection with Plasmodium falciparum, with an estimated death toll of approximately 1 million in 2008. 1 In subSaharan Africa, children younger than 5 years account for more than 80% of malaria-related deaths, and 10% to 20% of those surviving an episode of CM develop longterm cognitive impairment. 2,3 Magnetic resonance imaging (MRI) is a powerful tool for the diagnosis and follow-up of central nervous system disease but also for the understanding of pathophysiologic processes. However, CM radiologic reports are sparse, and findings are inconsistent among patients. The small number of experimental CM (ECM) imaging studies 4 -7 conducted have identified hallmarks of the disease at its most acute stage and at an earlier stage already characterized by significant brain swelling. 4 However, the field lacks a thorough and extensive account of early MRI-detectable markers of CM visible before the onset of cerebral edema. It is essential, therefore, that early sensitive indices of disease be identified. The use of MRI in a clinically relevant animal model is an approach that allows investigation of the acute effects of parasitic infection and host immune response on the brain. Previously, we performed the first in vivo MRI studies of ECM-susceptible or ECM-resistant mice infected with Plasmodium berghei ANKA (PbA) at 4.7 T. 4,8 We showed that ECM is characterized by blood-brain barrier breakdown, hemorrhages, reduced brain perfusion, ischemia, hemodynamic dysfunction, and brain edema. We identified that a potential cause of death in CM was compression of the cerebral arteries by a swollen cerebrum, resulting in a severe reduction in cerebral blood flow. Herein, we p...

Lung endothelial cell antigen cross-presentation to CD8+T cells drives malaria-associated lung injury

“…1g), concurrently with vascular leakage. Of note, the only published data on MRI findings relate to patients with cerebral malaria 32,33 , pediatric cerebral malaria patients 34 , and ECM-susceptible and resistant mice infected with PbA 35,36 . Our data indicate that this technique may complement or replace traditional X-ray imaging of lung edema.…”

Fatal cerebral malaria: a venous efflux problem

“…Resulting damage can explain, at least in part, other major long-term sequelae such as deficits in vision, hearing, and smell. The notion that IH can be caused by sequestration of iRBC as well as leukocytes is supported by reports documenting that both HCM and ECM are associated with deafness, loss of smell, and blindness (Brewster et al, 1990 ; Schmutzhard et al, 2010 , 2011 ; Idro et al, 2010a ; Saggu et al, 2011 ; Zhao and Mackenzie, 2011 ; Zhao et al, 2014 ). Thus, IH eliminates the need to explain any selective recognition mechanism Plasmodium might use to target multiple sensitive sites in the brain (Idro et al, 2010b ).…”

MRI demonstrates glutamine antagonist-mediated reversal of cerebral malaria pathology in mice

“…MRI provided evidence in vivo that brain edema, both vasogenic and cytotoxic, as well as reduced cerebral blood flow, play dominant roles in death in ECM (14). In general, ECM brain abnormalities described by MRI have been primarily observed in the olfactory bulbs (OBs), but also more posteriorly in the corpus callosum (CC) and subcortical white matter/external capsules in more severe disease (14)(15)(16)(17)(18). Subsequent MRI studies provided similar evidence that brain swelling contributed to death in pediatric (19,20) and adult CM (21).…”