Nicole Fortier O'BRien

Background and ObjectivesHigher CSF tau concentration is a marker of neuronal injury in cerebral malaria (CM) and has been associated with long-term neurologic deficits. However, its relationship w...

Background: Cerebral malaria (CM) impacts hundreds of thousands of African children and causes significant morbidity and mortality. Beyond supportive care and antimalarials, treatments that improve outcomes have not been identified. Methods: We conducted a randomized, open-label, phase 3 clinical trial in Blantyre, Malawi (2018–2023). Children aged 6 months to 12 years with CM (Blantyre Coma Score ≤ 2, Plasmodium falciparum parasitemia, and no alternative coma etiology) underwent magnetic resonance imaging (MRI) screening. Participants with severe brain swelling [brain volume score (BVS) 6–8] were randomized to early intubation and mechanical ventilation, 3% hypertonic saline (HTS), or usual care. The primary outcome was 7-day mortality. Secondary outcomes included neurologic morbidity in survivors, serious adverse events, and changes in transcranial Doppler (TCD)-measured cerebral blood flow velocities (CBFVs). Results: Of 206 children screened with MRI, 57 met criteria for randomization (23 mechanical ventilation, 17 HTS, and 17 usual care). Neither mechanical ventilation nor HTS reduced 7-day mortality compared with usual care (risk difference − 0.075, 95% CI − 0.27 to 0.17, p = 0.59 for ventilation; 0.002, 95% CI − 0.22 to 0.28, p = 1.0 for HTS). Neurologic morbidity at hospital discharge did not differ between intervention groups and controls. HTS administration resulted in rapid and sustained increases in CBFVs in all major cerebral vessels. Among children with baseline cerebral hyperemia, those treated with HTS had significantly worse outcomes (combined neurologic morbidity or death) than hyperemic children receiving usual care (relative risk 3.0, 95% CI 1.02 to 10.9, p = 0.04). Conclusions: In children with CM and severe brain swelling, adjunctive early mechanical ventilation or hypertonic saline does not improve survival or neurologic outcomes. Hypertonic saline increases cerebral blood flow and is associated with harm in children with baseline cerebral hyperemia. These findings demonstrate that non-phenotype-guided neuroprotective strategies are ineffective in CM and highlight the need for cerebrovascular endotype-informed therapeutic approaches.

: Lasting sequelae are identified in 50% of child survivors of cerebral malaria (CM). Rehabilitation options in malaria-endemic regions are scarce and largely focused on physical deficits, leaving children without support for cognitive recovery. Effective and accessible interventions are vital for improving outcomes. Furthermore, the assessment of brain function and recovery after CM is dependent on behavior-based tests that are time-consuming and require substantial training to administer. Objective, easy-to-use alternatives may be impactful. Children aged 3–12 years who had survived CM were recruited. Participants underwent a 6-month in-home, tablet-based neurorehabilitation program called Dino Island (DI). Participants also underwent serial assessments of brain health that were conducted by measuring event-related potentials (ERPs) using the Brain Vital Signs system. The feasibility, fidelity, acceptability, appropriateness, and affordability of the interventions were evaluated through interviews with the study nurses and the participants’ families. Both programs were feasible and easy to implement. Acceptability was demonstrated by low attrition rates (5%) and positive family ratings (100%). Appropriateness for DI was confirmed by parent reports of positive behavioral changes in their children (60%). For Brain Vital Signs, appropriateness was confirmed by adequate data acquisition for most participants. Finally, positive indicators of affordability from a healthcare perspective were identified. Neurorehabilitation using a home tablet-based program and objective brain health assessment using ERPs was feasible, well accepted, and appropriate in child CM survivors in sub-Saharan Africa. Further development and research into the program’s ability to improve and measure cognitive recovery is justified.

Background: Cerebral malaria (CM) is a common cause of febrile coma among African children. Despite treatment with highly efficacious intravenous artesunate, CM remains associated with high mortality and neurologic sequelae. In a mouse CM model, the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) demonstrated robust efficacy as a potential adjuvant therapy. Before testing DON in children with CM, we investigated tolerability in African adults, including individuals with malaria. Methods: We conducted an open-label, prospective, dose-escalation, phase 1 clinical trial of single-dose intravenous DON in Blantyre, Malawi. Participants included healthy adults and adults with uncomplicated malaria, enrolled in dose-cohorts of 10 and administered DON at 0.1, 1.0, 5.0, or 10 mg/kg. We assessed adverse events (AEs) and plasma pharmacokinetics. Results: Forty healthy adults and 38 adults with uncomplicated malaria received DON. Transient, asymptomatic creatinine elevation occurred 12 hours postinfusion in 18% of all participants. Nausea and vomiting were uncommon at 0.1 and 1.0 mg/kg but occurred more frequently at 5.0 and 10 mg/kg DON. All DON-related AEs resolved rapidly, without sequelae, and did not significantly differ between healthy and uncomplicated malaria participants. In healthy adults, maximum plasma concentrations increased proportional to dose, but adults with malaria had greater than dose-proportional increases. Terminal half-life ranged from 1.7 to 4.1 hours. Conclusions: DON was well tolerated in healthy adults and adults with uncomplicated malaria. Higher doses were associated with transient gastrointestinal AEs. Pharmacokinetics were minimally influenced by malaria disease. These results provide critical data to guide dosing strategies for adjunctive DON in children with CM. Clinical Trials Registration. NCT05478720.

Paediatric cerebral malaria (CM) kills thousands of children globally each year. Despite multiple interventional trials, no adjunctive therapy has demonstrated a survival benefit. As CM is known to cause multiple organ dysfunction syndrome (MODS), failure to consider the immediate cause of death or cause-specific mortality may partially explain these negative findings, particularly for targeted, organ specific therapies. A retrospective review of data from children with CM enrolled in interventional clinical trials at the Blantyre Malaria Project/Queen Elizabeth Central Hospital between 2018 and 2025 was performed. For participants who died during their hospitalization, the immediate cause of death was categorized into one of seven groups using a priori definitions. A total of 393 children were enrolled in the study period, and 52 (13%) died. Cerebral herniation was the most common immediate cause of death (46%) followed by status epilepticus with apnea (17%). Non-neurologic immediate causes of death occurred in 37% and included: cardiac failure/shock (13%), respiratory failure (12%), renal failure (6%), hepatic failure (4%), and other/indeterminant (2%). Admission coma score was significantly lower in children who died of cerebral herniation or hepatic failure (p = 0.001). Admission oxygen saturation was lowest in patients who died of respiratory failure (p = 0.04) and admission lactate was highest in those that died of cardiac failure/shock, hepatic failure, or other/indeterminant causes (p = 0.01). MODS was prevalent across the cohort regardless of the immediate cause of death. Multiple different immediate causes of death were identified in children with CM. This may dilute the measured impact of brain-focused therapies aimed at reducing central nervous system injury. Modifications in sample size estimates may need to be made in future clinical trials.

Background: In febrile comatose patients living in malaria-endemic areas, overlapping symptoms and limited laboratory capacity make it difficult to distinguish parasitic, bacterial, and viral central nervous system infections. We evaluated electroencephalography (EEG) as a biomarker to differentiate the microbiologic etiology of pediatric febrile coma at a major referral center in Malawi. Methods: This was a retrospective case-control study comparing EEG recordings of Malawian children with cerebral malaria to those with febrile coma of nonmalarial cause (bacterial meningitis, viral encephalitis, or unknown cause). Participants were admitted to Queen Elizabeth Central Hospital (Blantyre, Malawi) between 2013 and 2021. Inclusion criteria were fever, coma (Blantyre Coma Score ≤2), and coma etiology (malarial or nonmalarial) defined by laboratory testing. Four supervised machine learning algorithms were used to train a balanced ensemble classifier, SuperLearner, generating test characteristics of the diagnostic ability of EEG features. Results: Two hundred three children with cerebral malaria and 87 children with nonmalarial coma were included. Univariate analysis of qualitative (visual) EEG interpretations revealed higher voltage, slower background frequency, more sleep elements, less variability, more abnormal organization, and less continuity in cerebral malaria. Quantitative waveform analysis showed greater power in cerebral malaria. Both quantitative and qualitative EEG interpretation distinguished coma etiology (area under the receiver operating characteristic curve [AUROC] = 0.85 and 0.86, respectively). Combining qualitative and quantitative interpretation methods, the test characteristic improved (AUROC = 0.90). Conclusions: EEG features distinguish malarial from nonmalarial coma in febrile Malawian children. This technology may aid in distinguishing the microbiologic etiology of febrile coma in malaria-endemic areas.

BACKGROUND AND PURPOSE: Cerebral malaria is a leading cause of childhood mortality and neurological morbidity in sub-Saharan Africa and South Asia; and a strong association between diffuse brain swelling and mortality has been well established. Our goal was to characterize patterns of cortical edema on brain MRI in children with cerebral malaria and determine their association with patient outcomes. MATERIALS AND METHODS: We retrospectively reviewed admission brain MR images obtained from Malawian children with clinical cerebral malaria admitted at a single center from 2013-2019. Two neuroradiologists assessed the pattern of cortical edema on T1-, T2-, and diffusion-weighted images using a consensus approach. The overall degree of brain volume (brain volume score) and other brain imaging findings were also assessed, including focal signal changes in the basal ganglia, white matter, and posterior fossa. We evaluated the frequency and associations of these imaging findings with clinical outcomes at hospital discharge (deceased, alive with neurological sequelae, or alive without neurological sequelae). RESULTS: We included admission brain MRI scans from 190 children with clinical cerebral malaria. Cortical edema was identified in 163 MRIs. The predominant pattern of cortical edema was diffuse cortical involvement with relative sparing of the occipital and peri-Rolandic areas: 103 (63.2%) had this pattern, whereas 37 (22.7%) had sparing of the occipital cortex only and 23 (14.1%) had generalized cortical edema without focal sparing. The presence of occipital and peri-Rolandic sparing inversely correlated with brain volume score (β=-0.26, p<0.001) and outcomes (OR [95% CI]: 0.3 [0.1-0.6], p=0.002). CONCLUSIONS: Pediatric cerebral malaria is associated with a typical pattern of cortical edema that relatively spares the occipital and peri-Rolandic areas, which become progressively involved with more severe disease. ABBREVIATIONS: CM = Cerebral Malaria; BVS = Brain Volume Score; DWI = Diffusion-Weighted Imaging; PRES = Posterior Reversible Encephalopathy Syndrome.

Background: The greatest burden of sickle cell disease (SCD) globally occurs in sub‐Saharan Africa, where significant morbidity occurs secondary to SCD‐induced vasculopathy and stroke. Transcranial doppler (TCD) ultrasound grades the severity of vasculopathy, with disease modifying therapy resulting in stroke risk reduction in high‐risk children. The feasibility and utility of TCD screening in young children with SCD remains understudied.Procedure: We performed a retrospective review of TCD examination results in children ≤24 months with SCD in one of six centers in Africa. Using the time‐averaged maximum of the mean flow velocity, values 200 cm/s high risk.Results: A total of 115 children were screened, with five (4.3%) unable to complete the TCD due to agitation. A total of 110 children with a mean age of 15 ± 5 months were included. Low risk studies were identified in 95 (86.4%) and conditional risk in 15 (13.6%). No patient had a high risk study. Those with conditional risk examinations were not more anemic than those with low risk studies (p = 0.84).Conclusions: TCD screening of young children with SCD is feasible, with low technical failure rates. Many children in our cohort had a conditional risk study, suggesting cerebral vasculopathy begins at a young age in some African children. Future large cohort studies should be undertaken to determine the incidence of conditional or high risk studies in African children ≤2 years with SCD to inform future guideline development for TCD screening.

Background: Transcranial doppler ultrasound (TCD) allows for the assessment of the cerebrovascular hemodynamics in critically ill children. Given the increasing availability of machines equipped with TCD capabilities globally, it may be a useful approach to detect cerebral hypoperfusion and guide neurologic resuscitation for pediatric patients in resource limited settings where other neuromonitoring techniques are unavailable. However, the current need to evaluate waveform characteristics and to age correct values to determine if a study is abnormal decreases the feasibility of using point of care TCD in this way. The brain shock index (BSI), a repurposing of the Lindegaard Ratio, overcomes these limitations. Methods: We performed a prospective study of children with cerebral malaria (CM). On admission and daily thereafter, TCD was used to evaluate the middle cerebral (MCA) and extra-cranial carotid arteries (Ex-ICA), and the BSI was calculated bilaterally (MCA mean flow velocity ((Vm))/Ex-ICA Vm). Neurologic outcome at discharge was assessed. Results: A cohort of 291 children with CM were evaluated. BSI calculation was successful in all of them. The mean time to perform TCD and calculate the BSI was 4 ± 2 min. Overall, 222 participants (76%) had a good outcome and 69 (24%) a poor outcome. The BSI had an AUC of 0.98 (95% CI 0.97–0.99, p < 0.0001) to predict death or moderate to severe disability. The highest sensitivity and specificity of the BSI to predict adverse outcomes occurred at a cut off value ≤ 1.1. The adjusted odds ratio of poor outcome was 3.2 (95% CI 1.6–6.1, p = 0.001) if any BSI measurement during hospitalization fell below this threshold. No intracranial pressure monitoring was available to determine the relationship between the BSIs and an invasively measured cerebral perfusion pressure. Conclusion: The BSI is a rapid, feasible point of care ultrasound measurement of cerebral hypoperfusion, with values ≤ 1.1 strongly correlating with poor neurologic outcomes in children with CM. Future studies should be performed to assess the utility of BSI to detect the presence and measure the severity of reduced cerebral perfusion pressure in other populations of critically ill children.