Simon J. Glover

Brain Swelling and Death in Children with Cerebral Malaria

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.).

Endothelium-Based Biomarkers Are Associated with Cerebral Malaria in Malawian Children: A Retrospective Case-Control Study

Background Differentiating cerebral malaria (CM) from other causes of serious illness in African children is problematic, owing to the non-specific nature of the clinical presentation and the high prevalence of incidental parasitaemia. CM is associated with endothelial activation. In this study we tested the hypothesis that endothelium-derived biomarkers are associated with the pathophysiology of severe malaria and may help identify children with CM. Methods and Findings Plasma samples were tested from children recruited with uncomplicated malaria (UM; n = 32), cerebral malaria with retinopathy (CM-R; n = 38), clinically defined CM without retinopathy (CM-N; n = 29), or non-malaria febrile illness with decreased consciousness (CNS; n = 24). Admission levels of angiopoietin-2 (Ang-2), Ang-1, soluble Tie-2 (sTie-2), von Willebrand factor (VWF), its propeptide (VWFpp), vascular endothelial growth factor (VEGF), soluble ICAM-1 (sICAM-1) and interferon-inducible protein 10 (IP-10) were measured by ELISA. Children with CM-R had significantly higher median levels of Ang-2, Ang-2:Ang-1, sTie-2, VWFpp and sICAM-1 compared to children with CM-N. Children with CM-R had significantly lower median levels of Ang-1 and higher median concentrations of Ang-2:Ang-1, sTie-2, VWF, VWFpp, VEGF and sICAM-1 compared to UM, and significantly lower median levels of Ang-1 and higher median levels of Ang-2, Ang-2:Ang-1, VWF and VWFpp compared to children with fever and altered consciousness due to other causes. Ang-1 was the best discriminator between UM and CM-R and between CNS and CM-R (areas under the ROC curve of 0.96 and 0.93, respectively). A comparison of biomarker levels in CM-R between admission and recovery showed uniform increases in Ang-1 levels, suggesting this biomarker may have utility in monitoring clinical response. Conclusions These results suggest that endothelial proteins are informative biomarkers of malarial disease severity. These results require validation in prospective studies to confirm that this group of biomarkers improves the diagnostic accuracy of CM from similar conditions causing fever and altered consciousness.

Angiopoietin-2 levels are associated with retinopathy and predict mortality in Malawian children with cerebral malaria: a retrospective case-control study

Objective:To investigate the relationship among the angiopoietin–Tie-2 system, retinopathy, and mortality in children with cerebral malaria. Design:A case–control study of retinopathy-positive vs. retinopathy-negative children with clinically defined cerebral malaria. Setting:Queen Elizabeth Central Hospital in Blantyre, Malawi. Subjects:One hundred fifty-five children presenting with severe malaria and meeting a strict definition of clinical cerebral malaria (Blantyre Coma Score ⩽2, Plasmodium falciparum parasitemia, no other identifiable cause for coma) were included in the study. Interventions:None. Measurements and Main Results:Clinical and laboratory parameters were recorded at admission and funduscopic examinations were performed. Admission levels of angiopoietin-1, angiopoietin-2, and a soluble version of their cognate receptor were measured by enzyme-linked immunosorbent assay. We show that angiopoietin-1 levels are decreased and angiopoietin-2 and soluble Tie-2 levels are increased in children with cerebral malaria who had retinopathy compared with those who did not. Angiopoietin-2 and soluble Tie-2 were independent predictors of retinopathy (adjusted odds ratio [95% CI], angiopoietin-2, 4.3 [1.3–14.6], p = .019; soluble Tie-2, 9.7 [2.1–45.8], p = .004). Angiopoietin-2 and soluble Tie-2 were positively correlated with the number of hemorrhages, the severity or retinal whitening, and the extent of capillary whitening observed on funduscopic examination (p < .05 after adjustment for multiple comparisons). Angiopoietin-2 and soluble Tie-2 levels were elevated in children with cerebral malaria who subsequently died and angiopoetin-2 was an independent predictor of death (adjusted odds ratio: 3.9 [1.2–12.7], p = .024). When combined with clinical parameters, angiopoetin-2 improved prediction of mortality using logistic regression models and classification trees. Conclusions:These results provide insights into mechanisms of endothelial activation in cerebral malaria and indicate that the angiopoietin–Tie-2 axis is associated with retinopathy and mortality in pediatric cerebral malaria.

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

BACKGROUND AND PURPOSE: There have been few neuroimaging studies of pediatric CM, a common often fatal tropical condition. We undertook a prospective study of pediatric CM to better characterize the MRI features of this syndrome, comparing findings in children meeting a stringent definition of CM with those in a control group who were infected with malaria but who were likely to have a nonmalarial cause of coma. MATERIALS AND METHODS: Consecutive children admitted with traditionally defined CM (parasitemia, coma, and no other coma etiology evident) were eligible for this study. The presence or absence of malaria retinopathy was determined. MRI findings in children with ret+ CM (patients) were compared with those with ret− CM (controls). Two radiologists blinded to retinopathy status jointly developed a scoring procedure for image interpretation and provided independent reviews. MRI findings were compared between patients with and without retinopathy, to assess the specificity of changes for patients with very strictly defined CM. RESULTS: Of 152 children with clinically defined CM, 120 were ret+, and 32 were ret−. Abnormalities much more common in the patients with ret+ CM were markedly increased brain volume; abnormal T2 signal intensity; and DWI abnormalities in the cortical, deep gray, and white matter structures. Focal abnormalities rarely respected arterial vascular distributions. Most of the findings in the more clinically heterogeneous ret− group were normal, and none of the abnormalities noted were more prevalent in controls. CONCLUSIONS: Distinctive MRI findings present in patients meeting a stringent definition of CM may offer insights into disease pathogenesis and treatment.

Identification of Malaria Retinopathy Improves the Specificity of the Clinical Diagnosis of Cerebral Malaria: Findings from a Prospective Cohort Study

The diagnosis of cerebral malaria (CM) is difficult to confirm in endemic regions with limited neurodiagnostics. Accurate diagnoses are critical for trials and outcomes studies. Findings from an autopsy-based study suggest that identifying malaria retinopathy in children satisfying the standard clinical case definition of CM improves our ability to accurately diagnose CM in vivo. In a post hoc analysis of a prospective exposure-control study to evaluate CM as a risk factor for epilepsy, we stratified children meeting the standard case definition by their retinopathy status (presence versus absence) and compared these groups for pre-existing risk factors for epilepsy. We also compared them to the concurrently enrolled, non-comatose controls. Children meeting the standard case definition of CM who lacked malaria retinopathy had a higher prevalence of pre-existing developmental problems and family history of epilepsy. This subset of patients may represent children with a pre-existing propensity to adverse neurologic symptoms and outcomes.

Plasma Concentrations of Parasite Histidine-Rich Protein 2 Distinguish Between Retinopathy-Positive and Retinopathy-Negative Cerebral Malaria in Malawian Children

BACKGROUND Brain histology and ophthalmoscopy suggest that approximately 25% of children with World Health Organization-defined cerebral malaria (CM) have a nonmalarial cause of death. Misclassification complicates clinical care, confounds studies of association, and may obfuscate successes in malaria control. Retinopathy predicts intracerebral parasite sequestration with >90% sensitivity and specificity, but detecting retinopathy requires well-trained personnel and expensive equipment. METHODS We investigated the utility of plasma concentrations of parasite histidine-rich protein 2 (pHRP2), a Plasmodium-specific protein, as a predictor of intracerebral parasite sequestration at autopsy and of malaria retinopathy on clinical examination in patients with clinically defined CM. RESULTS In 64 autopsy cases, 47 of whom had histological evidence of sequestration, the sensitivity and specificity of a plasma pHRP2 level of >1700 ng/mL were 98% and 94%, respectively, and the area under the receiver operating characteristic (AUROC) curve was 0.98. In a separate, prospectively studied group of 101 children with clinically defined CM, of whom 71 had retinopathy, the same pHRP2 cutoff predicted retinopathy-positivity with a sensitivity of 90% and specificity of 87% (AUROC, 0.90). CONCLUSIONS Elevated plasma pHRP2 concentrations can identify Malawian children with histologically confirmed or retinopathy-positive CM and is a more field-friendly approach to confirming the diagnosis than post mortem sampling or ophthalmoscopy.

Detection of raised intracranial pressure by ultrasound measurement of optic nerve sheath diameter in African children

Objective  To evaluate optic nerve sheath (ONS) ultrasound as a non‐invasive method of detecting raised intracranial pressure (ICP) and to establish normal ONS diameter data for African children.

Prevalence of diabetic retinopathy, cataract and visual impairment in patients with diabetes in sub-Saharan Africa.

Background/aims There are few published data on the prevalence of diabetic retinopathy in sub-Saharan Africa. We report the prevalence of all grades of retinopathy and associations with systemic parameters in patients attending a secondary care diabetes clinic in Blantyre, Malawi. Methods Cross-sectional study of all patients attending for diabetes care in a hospital setting. Clinical examination and biochemical testing was performed to assess visual acuity (VA), grade of retinopathy (slit lamp biomicroscopy), microvascular complications, glycaemic control, hypertension and HIV status. Sight-threatening diabetic retinopathy (STDR) was defined as moderate preproliferative retinopathy or worse, circinate maculopathy or exudates within one disc diameter of the foveal centre or clinically significant macular oedema. Results In patients with type 2 diabetes (n=249) the prevalence (95% CI) of any retinopathy, STDR and proliferative diabetic retinopathy (PDR) was 32.5% (26.7 to 38.3%), 19.7% (14.7 to 24.6%) and 4.8% (2.2 to 7.5%), respectively. The presence of STDR was associated with albuminuria (OR 2.6; p=0.02), the presence of neuropathy (OR 3.4; p=0.005) and insulin use (OR 5.3; p=0.0004), but not with HIV status. In patients with type 1 diabetes (n= 32), the prevalence of any retinopathy, STDR and PDR was 28.1% (12.5 to 43.7%), 18.8% (5.2 to 32.2%) and 12.5% (1.0 to 24.0%), respectively. 12.1% of study subjects had VA worse than 6/18 (20/60). Conclusion This study provides baseline information on prevalence of all grades of retinopathy and STDR in consecutive cases attending an urban/semi-urban diabetes clinic in sub-Saharan Africa. Prevalence of STDR was high and in type 2 diabetes was associated with albuminuria, neuropathy and insulin use.

A Survey of the Management, Control, and Complications of Diabetes Mellitus in Patients Attending a Diabetes Clinic in Blantyre, Malawi, an Area of High HIV Prevalence

The aim of this study was to describe the current status of diabetes care in an urban diabetes clinic in Malawi and the prevalence of human immunodeficiency virus (HIV) in this population, investigating possible associations between HIV and diabetes. A systematic prospective survey of patients attending the diabetes clinic at a teaching hospital in Blantyre, Malawi was conducted. Six hundred twenty patients were assessed. Seventy-four percent had glycosylated hemoglobin (HbA1C) > 7.5%. Systolic blood pressure was > 140 mm Hg in 52% of patients. Hypertension was more common in patients with raised creatinine (P < 0.003), retinopathy (P = 0.01), and stroke (P < 0.0002). Microvascular complication rates were high, specifically nephropathy (34.7%), retinopathy (34.7%), and neuropathy (46.4%). HIV seroprevalence was 13.7%. HIV-positive subjects had a lower body mass index (BMI) and lower fasting blood sugar, and they were more likely to have albuminuria (48.0% versus 33.3%; P < 0.05). Control of glycemia and hypertension were poor, and microvascular complications were common. Nephropathy in diabetic patients may be affected by HIV status.

Histidine-Rich Protein 2 Plasma Levels Predict Progression to Cerebral Malaria in Malawian Children With Plasmodium falciparum Infection

Some children with uncomplicated malaria progress to cerebral malaria despite appropriate treatment; identifying them in advance might improve their care. The objective of this study was to determine if plasma concentrations of a malaria protein, HRP2 (histidine-rich protein 2) would serve this purpose. Cases and controls were children presenting with uncomplicated malaria; the cases (n = 25) developed cerebral malaria, and the controls (n = 125) did not. Mean plasma HRP2 concentrations were significantly higher in the cases, and an HRP2 cutoff was identified that could predict disease progression (sensitivity and specificity, 88% for each). Quantitative measurements of HRP2 may be a useful screening tool.