Brain swelling and death in children with cerebral malaria

Abstract

Background: Case fatality rates among African children with cerebral malaria remain in the range of 15 to 25%. The key pathogenetic processes and causes of death are unknown, but a combination of clinical observations and pathological findings suggests that increased brain volume leading to raised intracranial pressure may play a role. Magnetic resonance imaging (MRI) became available in Malawi in 2009, and we used it to investigate the role of brain swelling in the pathogenesis of fatal cerebral malaria in African children.

Methods: We enrolled children who met a stringent definition of cerebral malaria (one that included the presence of retinopathy), characterized them in detail clinically, and obtained MRI scans on admission and daily thereafter while coma persisted.

Results: Of 348 children admitted with cerebral malaria (as defined by the World Health Organization), 168 met the inclusion criteria, underwent all investigations, and were included in the analysis. A total of 25 children (15%) died, 21 of whom (84%) had evidence of severe brain swelling on MRI at admission. In contrast, evidence of severe brain swelling was seen on MRI in 39 of 143 survivors (27%). Serial MRI scans showed evidence of decreasing brain volume in the survivors who had had brain swelling initially.

Conclusions: Increased brain volume was seen in children who died from cerebral malaria but was uncommon in those who did not die from the disease, a finding that suggests that raised intracranial pressure may contribute to a fatal outcome. The natural history indicates that increased intracranial pressure is transient in survivors. (Funded by the National Institutes of Health and Wellcome Trust U.K.).

Figure 1. Brain Features on MRI in Children with Cerebral Malaria

Panel A shows normal brain volume in a 14-month-old girl at the time of a 1-month follow-up image series. This sagittal T₁-weighted MRI scan, obtained on a 0.35-T Signa Ovation Excite MRI scanner, shows how the prepontine cistern (straight arrow) and the fourth ventricle (curved arrow) are measured. Dotted lines indicate the anterior– posterior dimension of the postpontine cistern, which quantifies cerebrospinal fluid (CSF) in the fourth ventricle, and the anterior–posterior dimension of the prepontine space, which represents CSF in the subarachnoid space. The axial T₂-weighted fast spin–echo image in Panel B shows the normal appearance of the sulcal markings (white arrows), junction of gray and white matter (red arrows), and the ambient cisterns (yellow arrows). Panel C shows severely increased brain volume in a 19-month-old girl with retinopathy-positive cerebral malaria. This sagittal T₁-weighted MRI image shows downward herniation of the cerebellar tonsils (circle), effacement of the prepontine cistern (yellow arrow), and compression of the fourth ventricle (curved white arrow). There is also downward displacement of the diaphragmatic sella (straight white arrow). In Panel D, an axial T₂-weighted fast spin–echo image of the same patient shows complete effacement of all sulcal markings (white arrows) and effacement of the ambient cisterns (yellow arrows). Marked cortical thickening and increased signal are seen diffusely throughout the visualized cortexes (black arrows). The patient survived but had a protracted recovery and was blind and deaf at discharge. The posterior predominant pattern is shown in the axial T₂-weighted fast spin–echo image in Panel E. Panel F shows an increased T₂-weighted signal in the thalami bilaterally (red arrows).

Figure 2. MRI Features Associated with a Fatal Outcome in Children with Retinopathy-Positive Cerebral Malaria

This model identified brain swelling, a decreased level of CSF in the prepontine space, and a predominantly posterior pattern of involvement as independent predictors of death. Panel A shows data for 144 patients without the posterior predominant pattern; in this group, 13 of 17 deaths occurred in patients with severely increased brain volume, and all 13 of these patients had decreased prepontine CSF. The 4 patients who died without brain swelling did not have a decreased level of prepontine CSF. Panel B shows data for the 24 patients with predominantly posterior involvement on MRI: 8 of these patients died, all of whom had increased brain volume. None of the 8 patients had decreased prepontine CSF. Solid lines indicate medians, and the boxes show interquartile ranges. Whiskers extend to 1.5 times the interquartile range, and outliers are represented individually by circles beyond the whiskers. P values comparing the prepontine CSF level between patients who survived and those who died in each subgroup were estimated by means of Wilcoxon rank-sum tests.

Figure 3. Distribution of Prepontine CSF Measurements on First and Second MRIs

Second MRI scans were obtained 16 to 30 hours after the first scans. Dashed black lines indicate patients who survived, and solid yellow lines patients who died. The postadmission change in the mean prepontine CSF measurement in the 30 patients with retinopathy-positive cerebral malaria who recovered and were discharged (dashed red line) was significantly different from that in the 5 patients who died (solid red line) (P = 0.02). The means and P values in the test of differences in the trajectory of the measure between the two scans were estimated with the use of a mixed model that included a random intercept to account for within-participant correlation.