Falciparum malaria is a leading cause of mortality and morbidity worldwide. In 2016, over 216 million people were infected with malaria, resulting in 435,000 deaths, most of which occurred in children <5 years of age in sub-Saharan Africa.1 A subset of children develop cerebral malaria (CM), the most severe form of the disease, defined as unarousable coma, presence of asexual forms of parasites in peripheral blood on light microscopy and the absence of other causes of coma (such as hypoglycemia or meningitis).2–5 Malarial retinopathy increases the specificity of this clinical case definition6–8 as it correlates with the presence of cerebral microvascular sequestration with parasitized erythrocytes, the pathologic hallmark of the disease.9 Mortality from pediatric CM is 15%–25%, with neurologic sequelae (NSQ) in survivors estimated to be 9%–23% at discharge and 25%–50% on long-term follow-up.10–14
NSQ from pediatric CM include epilepsy, mental health disorders, behavioral problems, learning disabilities and both motor and sensory deficits. These have significant adverse impacts on children and their communities, in terms of capacity to learn at school, and the need for managing motor deficits, seizures and behavioral problems. The pathophysiology leading to NSQ in pediatric CM is not fully known and accurate quantitative predictors of NSQ at discharge are lacking. Such biomarkers would shed light into the pathophysiology of CM. In addition, they would assist in planning the allocation of limited resources for assessing and caring for children who are neurologically impaired by this disease. A previous cohort study of children with retinopathy-positive CM in Malawi revealed that higher maximum temperatures, seizures and male gender were risk factors for long-term epilepsy.15 Studies have shown that chronic NSQ are related to HIV co-infection, short stature, prolonged fever and coma in the acute illness, and severe atrophy or multifocal abnormalities on brain magnetic resonance imaging (MRI) performed months after the index illness. The presence of NSQ at discharge is another significant predictor of long-term deficit, even though some patients recover from the acute deficits during the first 6 months. Several clinical factors have been identified to be associated with NSQ at discharge including depth of coma, prolonged coma duration and multiple seizures during admission.14,15
Recent studies have used MRI to evaluate correlates with mortality in pediatric CM.16–18 These have revealed brain swelling as the major predictor of death. Abnormalities on T2 and diffusion-weighted imaging signal in various brain structures are also extremely common in pediatric CM. T2 changes in the thalamus, posteriorly predominant T2 changes and diffusion-weighted imaging abnormalities in the supratentorial gray matter are predictive of death.19 There have not been parallel radiologic studies evaluating structural predictors of neurologic morbidity.
Because brain swelling expels cisternal cerebrospinal fluid (CSF) into the spinal theca to maintain intracranial pressure, cisternal CSF volume can be used as a proxy measure for brain volume, cerebral edema and thus increased intracranial pressure.20–22 In this study, we used MRI to investigate whether the brain swelling during coma in pediatric CM as determined by serial cisternal CSF volume can predict the presence of NSQ at discharge.
MATERIALS AND METHODS
The study took place at Queen Elizabeth Central Hospital, a tertiary referral hospital in Blantyre, Malawi, as part of an ongoing clinicopathologic correlates study utilizing MRI to elucidate the pathogenesis of CM.
The study was approved by the ethics committees of Michigan State University and the University of Malawi College of Medicine. Informed consent was obtained from parents or guardians before enrollment.
In this case–control study, children admitted with retinopathy confirmed CM from 2009 to 2016 who underwent serial MRI studies and survived with NSQ at discharge were matched to concurrently admitted children who made a full recovery. Each pediatric CM survivor with sequelae who underwent at least 2 MRI scans was matched to the next admitted retinopathy confirmed pediatric CM survivor with at least 2 MRI scans that had full recovery (ie, no sequelae at discharge).
Children were eligible for inclusion in this analysis if they met World Health Organization criteria for CM2,6: Blantyre coma score (BCS) of ≤2, presence of asexual forms of Plasmodium falciparum on light microscopy examination of a peripheral blood film and no other cause of coma. All children underwent fundoscopy by an ophthalmologist to ascertain the presence of malarial retinopathy. Weight, height and age were recorded at admission and serial temperature measurements were taken. Blood was drawn for full blood count, blood culture, glucose and lactate, HIV test, parasite count and species determination. Hypoglycemia was corrected, if present; and meningitis was ruled out by lumbar puncture. Antimalarials were given according to national guidelines and anticonvulsants administered, as clinically indicated. The presence of NSQ was determined by a research clinician at discharge.
Brain MRI was performed on a General Electric Signa Ovation Excite 0.35T Magnet (GE Healthcare, Milwaukee, WI) using protocols that have been published before. Scans were performed on admission and daily while coma persisted.
Coma duration before admission was ascertained by parental interview at the time of admission. The BCS was ascertained every 2 hours until recovery. Coma duration after admission was coma duration from admission until BCS reached at least 3.
Quantification of CSF Volumes
The volume of CSF in the infratentorial cisterns was determined using Clear Canvas on Sagittal T1 Flair scans using a method described previously (Fig. 1).22
Demographic and clinical characteristics between cases and controls were compared using t test and χ2 analyses. We used a model comprising coma duration, presence/absence of NSQ at discharge and cisternal CSF volume to first compute a probability score for the presence of NSQ at discharge. For a given coma duration, a graph of probability of having NSQ at discharge (y axis) against cisternal CSF volume (log-CSF) (x axis) was generated. A tailor-made app (DS Small, Bo Zhang) was employed to compute probability scores for each patient. Details of the statistical analysis are in Supplementary Digital Content 1, http://links.lww.com/INF/D746. A second model including sex and age as covariates was also considered and resulted in qualitatively similar results. Details of this analysis are included as Supplementary Digital Content 2, http://links.lww.com/INF/D747.
A total of 108 children were included in the study, 54 controls (age 50 ± 28 months, 27 males) and 54 cases, these being children with NSQ at discharge (age 42 ± 28 months, 31 males). See Table 1 for clinical and demographic details.
Clinical Predictors of NSQ at Discharge
Three clinical features predicted the presence of NSQ at discharge (Table 1): initial parasitemia, coma duration during hospitalization and time to resolve fever. Age, sex, depth of coma, duration of fever before admission, duration of coma before admission, serum glucose and lactate, white cell count, seizures, maximal temperature and stunting (height or weight for age) were not predictors of sequelae.
Relationship Between Intracranial Cisternal CSF Volume and NSQ at Discharge
Children with low baseline cisternal CSF volume and/or progressively increasing brain edema leading to minimal residual cisternal CSF volume have higher probabilities of NSQ at discharge; conversely, there is a lower probability of sequelae among children with higher cisternal CSF volume (milder brain edema) (Fig. 2, Supplementary Digital Content 1, http://links.lww.com/INF/D746). A model including sex and age as covariates was also considered and resulted in qualitatively similar results (Supplementary Digital Content 2, http://links.lww.com/INF/D747).
This case–control study included only children who remained in coma long enough to undergo at least 2 MRI images, so findings here may not be generalizable to children with briefer periods of coma. Nonetheless, the findings offer important insights into mechanisms of neurologic injury among survivors.
Among the clinical factors evaluated in this case–control study of pediatric CM survivors, parasitemia, time to reach BCS = 3 and time to resolve fever emerged as predictors of neurologic injury evident at discharge. Previous work with long-term follow-up has identified maximal fever as predictive of NSQ in pediatric CM survivors.14 Fever is a well-established, causal mechanism for the worsening of an initial brain injury after a wide range of neurologic insults.23–25 In this instance, another explanation for extended fever resolution time in the children with NSQ could be the presence of co-infections in this subset. If children in this group were harboring not only Plasmodium, but another pathogen, they might be more likely to develop NSQ.
Most notably, in this study, we determined that serial cisternal CSF volume as determined by MRI during coma is an objective predictor of NSQ at discharge among pediatric CM survivors. According to the Monro-Kellie principle, cisternal CSF is expelled into the spinal theca to maintain intracranial pressure in the presence of brain swelling.20 We have shown that children who develop NSQ expel more cranial CSF into the spinal theca, indicating more and progressive brain swelling compared with children who recover fully. The brain edema is from various CM pathologic processes that conspire to cause neuronal damage leading to NSQ. These include sequestration of parasitized erythrocytes in capillaries and postcapillary venules, vessel occlusions, local ischemia, breakdown of the blood-brain barrier, microhemorrhages, myelin and axon damage, vasogenic edema and cytotoxic edema (Fig. 3).
Brain swelling has been shown to be a major contributor to mortality in pediatric CM and has also been shown to be reversible.2226 However, previous adjunctive therapies aimed at reducing cerebral edema have failed to decrease mortality.27–30 These included steroid treatment as well as direct osmotic therapy. Explanations as to why these trials failed to decrease mortality include misclassification (up to 25% of patients meeting the World Health Organization criteria for CM have other etiologies of coma11), inappropriate therapy timing, and lack of power. We feel that the definitive clinical trial to test the utility of an osmotic agent has yet to be performed. A trial testing the utility of treating pediatric CM with hypertonic saline is currently underway in Blantyre, Malawi (ClinicalTrials.gov NCT03300648).
Among pediatric CM survivors with prolonged coma, cerebral edema is a contributor to long-term neurologic disability. Interventions that decrease cerebral edema in CM may reduce both morbidity and mortality and measures of cerebral edema may assist in anticipating neurologic injury among survivors.
The authors thank the children and mothers of children who participated in the study; Ifunyana Dallah for research assistance; Dr. Simon Glover for his assistance with retinal assessments in this study population.
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