Background: There are an estimated 1.5 million children living with human immunodeficiency virus (CLHIV), most residing in sub-Saharan Africa. A common hospital presentation of CLHIV is new-onset seizure, for which imaging is helpful but not routinely performed due to scarce resources. We present imaging findings and their association with clinical risk factors and outcomes in a cohort of Zambian CLHIV presenting with new-onset seizure. Methods: In this prospective cohort study, participants were recruited at the University Teaching Hospital in Lusaka, Zambia. Various clinical and demographic characteristics were obtained. Computed tomography (CT), magnetic resonance imaging (MRI), or both were obtained during admission or shortly after discharge. If both studies were available, MRI data was used. Two neuroradiologists interpreted images using REDCap-based NeuroInterp, a tool that quantifies brain imaging findings. Age-dependent neuropsychologic assessments were administered. Results: Nineteen of 39 (49%) children had a brain MRI, 16 of 39 (41%) had CT, and four of 39 (10%) had both. Mean age was 6.8 years (S.D. 1 / 4 4.8). Children with advanced HIV disease had higher odds of atrophy (odds ration [OR] 7.2, 95% confidence interval [CI] 1.1 to 48.3). Focal abnormalities were less likely in children receiving antiretroviral therapy (ART) (OR 0.22, 95% CI 0.05 to 1.0). Children with neurocognitive impairment were more likely to have atrophy (OR 8.4, 95% CI 1.3 to 55.4) and less likely to have focal abnormalities (OR 0.2, 95% CI 0.03 to 0.9). Conclusions: Focal brain abnormalities on MRI were less likely in CLHIV on ART. Brain atrophy was the most common imaging abnormality, which was linked to severe neurocognitive impairment. (c) 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).

BACKGROUND Stroke incidence is increasing in sub-Saharan African (SSA), especially due to intracerebral hemorrhage (ICH). We sought to describe the clinical and radiological characteristics of stroke due to ICH in people living with HIV (PLWH) in Malawi. METHODS Using a cross-sectional design, we compared the clinical and radiological characteristics of ICH in PLWH and HIV negative patients. We rated ICH location as deep, or lobar, using the Cerebral Haemorrhage Anatomical RaTing inStrument (CHARTS), and radiological features, including periventricular and deep white matter hyperintensities (PVWM and DWM). We compared characteristics using parametric t-tests or non-parametric Mann-Whitney U tests. RESULTS We included 39 participants with ICH (10 PLWH; 29 HIV-negative). The median age was 60 (IQR 48-68); 22 (56%) were female. Among PLWH, the median (IQR) CD4 count was 364 cells/mm3 (164,411) and 7 (70%) were naïve to HIV treatment. Compared with HIV-negative controls, HIV-positive patients were younger (median (IQR) 49.5 years (35, 60) v 62 years (54,69)), and hypertension was common in both groups (PLWH [8,80%] v HIV-negative [26,90%]). PLWH often had lobar haematoma ICH (40% v 0%, p<0.003 and p=0.002 after controlling for age). White matter hyperintensity was prevalent (PVWM 77% v 79%; DWM 60% v 69%) and similar in both groups despite the age disparity. CONCLUSIONS In PLWH, we found an association with lobar location ICH-Stroke. Hypertension and cerebral small vessel disease markers were common in both groups, suggesting that better screening and treatment of hypertension could reduce the burden of stroke due to ICH regardless of HIV status.

A central challenge of medical imaging studies is to extract biomarkers that characterize disease pathology or outcomes. Modern automated approaches have found tremendous success in high-resolution, high-quality magnetic resonance images. These methods, however, may not translate to low-resolution images acquired on magnetic resonance imaging (MRI) scanners with lower magnetic field strength. In low-resource settings where low-field scanners are more common and there is a shortage of radiologists to manually interpret MRI scans, it is critical to develop automated methods that can augment or replace manual interpretation, while accommodating reduced image quality. We present a fully automated framework for translating radiological diagnostic criteria into image-based biomarkers, inspired by a project in which children with cerebral malaria (CM) were imaged using low-field 0.35 Tesla MRI. We integrate multiatlas label fusion, which leverages high-resolution images from another sample as prior spatial information, with parametric Gaussian hidden Markov models based on image intensities, to create a robust method for determining ventricular cerebrospinal fluid volume. We also propose normalized image intensity and texture measurements to determine the loss of gray-to-white matter tissue differentiation and sulcal effacement. These integrated biomarkers have excellent classification performance for determining severe brain swelling due to CM.

Background In cerebral malaria, the retina can be used to understand disease pathogenesis. The mechanisms linking sequestration, brain swelling, and death remain poorly understood. We hypothesized that retinal vascular leakage would be associated with brain swelling. Methods We used retinal angiography to study blood-retinal barrier integrity. We analyzed retinal leakage, histopathology, brain magnatic resonance imaging (MRI), and associations with death and neurological disability in prospective cohorts of Malawian children with cerebral malaria. Results Three types of retinal leakage were seen: large focal leak (LFL), punctate leak (PL), and vessel leak. The LFL and PL were associated with death (odds ratio [OR] = 13.20, 95% confidence interval [CI] = 5.21-33.78 and OR = 8.58, 95% CI = 2.56-29.08, respectively) and brain swelling (P < .05). Vessel leak and macular nonperfusion were associated with neurological disability (OR = 3.71, 95% CI = 1.26-11.02 and OR = 9.06, 95% CI = 1.79-45.90). Large focal leak was observed as an evolving retinal hemorrhage. A core of fibrinogen and monocytes was found in 39 (93%) white-centered hemorrhages. Conclusions Blood-retina barrier breakdown occurs in 3 patterns in cerebral malaria. Associations between LFL, brain swelling, and death suggest that the rapid accumulation of cerebral hemorrhages, with accompanying fluid egress, may cause fatal brain swelling. Vessel leak, from barrier dysfunction, and nonperfusion were not associated with severe brain swelling but with neurological deficits, suggesting hypoxic injury in survivors. Fluorescein angiography provides evidence that in cerebral malaria severe brain swelling and death are due to fluid egress from multiple small cerebral hemorrhages. In contrast, neurological deficits in survivors are associated with vessel leak and capillary nonperfusion.

CASE PRESENTATION: A 34-year-old man presented to Queen Elizabeth Central Hospital in Blantyre, Malawi with multiple enlarged right cervical lymph nodes. He had no associated constitutional symptoms. Fine-needle aspirate (FNA) of one of the lymph nodes was negative for acid-fast bacilli (AFB) by smear microscopy. The FNA specimen was not sent for histological examination. Mycobacterial culture and Xpert MTB/RIF were not available at the time. He tested positive for HIV but CD4 T-cell count was not requested at the time of HIV diagnosis, and he did not start antiretroviral therapy (ART) pending confirmation of the cause of lymphadenopathy. Excision biopsy of the lymph nodes was planned; however, the patient was lost to follow-up before the procedure was performed.

Background Managing HIV-associated cryptococcal meningitis (CM) can become challenging in the presence of concurrent unusual central nervous system infections. Case presentation A 58-year old HIV infected woman new ART starter, who was being treated effectively for cryptococcal meningitis, represented with worsening of neurological symptoms. Brain MRI revealed a multicystic lesion in the left temporal lobe. Anti-fungal treatment was escalated for a suspected cryptococcoma, but post-mortem CSF serological test confirmed racemose neurocysticercosis. Conclusion Patients with HIV-associated CM are highly immunocompromised and may have multiple pathologies simultaneously. In endemic countries, neurocysticercosis should be considered in the differential diagnosis where there is central nervous system deterioration despite effective therapy for CM.

Background: Cerebral malaria (CM) remains a leading cause of mortality and morbidity in children in sub-Saharan Africa. Recent studies using brain magnetic resonance imaging have revealed increased brain volume as a major predictor of death. Similar morphometric predictors of morbidity at discharge are lacking. The aim of this study was to investigate the utility of serial cranial cisternal cerebrospinal fluid (CSF) volume measurements in predicting morbidity at discharge in pediatric CM survivors. Methods: In this case-control study, 54 Malawian pediatric CM survivors with neurologic sequelae evident at discharge who underwent serial magnetic resonance imaging scans while comatose were matched to concurrently admitted children with serial imaging who made full recoveries. Serial cranial cisternal CSF volume quantified by radiologists blinded to outcome was evaluated as a predictor of neurologic deficits at discharge. The probability of neurologic sequelae was determined using a model that included coma duration and changes in cisternal CSF volume over time. Results: Coma duration before admission was similar between cases and controls (16.1 vs. 15.3; P = 0.81), but overall coma was longer among children with sequelae (60 vs. 38 hours; P < 0.01). Lower initial CSF volumes and decreased volumes over time were both associated with a higher probability of neurologic sequelae at discharge. Conclusions: Among pediatric CM survivors with prolonged coma, lower initial CSF volume and decreasing volume during coma is associated with neurologic sequelae at discharge. These findings suggest that cerebral edema is an underlying contributor to both morbidity and mortality in pediatric CM.

A central challenge of medical imaging studies is to extract quantitative biomarkers that characterize pathology or predict disease outcomes. In high-resolution, high-quality magnetic resonance images (MRI), state-of-the-art approaches have performed well. However, such methods may not translate to low resolution, lower quality images acquired on MRI scanners with lower magnetic field strength. Therefore, in low-resource settings where low field scanners are more common and there is a shortage of available radiologists to manually interpret MRI scans, it is essential to develop automated methods that can accommodate lower quality images and augment or replace manual interpretation. Motivated by a project in which a cohort of children with cerebral malaria were imaged using 0.35 Tesla MRI to evaluate the degree of diffuse brain swelling, we introduce a fully automated framework to translate radiological diagnostic criteria into image-based biomarkers. We integrate multi-atlas label fusion, which leverages high-resolution images from another sample as prior spatial information, with parametric Gaussian hidden Markov models based on image intensities, to create a robust method for determining ventricular cerebrospinal fluid volume. We further propose normalized image intensity and texture measurements to determine the loss of gray-to-white matter tissue differentiation and sulcal effacement. These integrated biomarkers are found to have excellent classification performance for determining severe cerebral edema due to cerebral malaria.

The hallmark of pediatric cerebral malaria (CM) is sequestration of parasitized red blood cells in the cerebral microvasculature. Malawi-based research using 0.35 Tesla (T) magnetic resonance imaging (MRI) established that severe brain swelling is associated with fatal CM, but swelling etiology remains unclear. Autopsy and clinical studies suggest several potential etiologies, but limitations of 0.35 T MRI precluded optimal investigations into swelling pathophysiology. A 1.5 T MRI in Zambia allowed for further investigations including susceptibility-weighted imaging (SWI). SWI is an ideal sequence for identifying regions of sequestration and microhemorrhages given the ferromagnetic properties of hemozoin and blood. Using 1.5 T MRI, Zambian children with retinopathy-confirmed CM underwent imaging with SWI, T2, T1 pre- and post-gadolinium, diffusion-weighted imaging (DWI) with apparent diffusion coefficients and T2/fluid attenuated inversion recovery sequences. Sixteen children including two with moderate/severe edema were imaged; all survived. Gadolinium extravasation was not seen. DWI abnormalities spared the gray matter suggesting vasogenic edema with viable tissue rather than cytotoxic edema. SWI findings consistent with microhemorrhages and parasite sequestration co-occurred in white matter regions where DWI changes consistent with vascular congestion were seen. Imaging findings consistent with posterior reversible encephalopathy syndrome were seen in children who subsequently had a rapid clinical recovery. High field MRI indicates that vascular congestion associated with parasite sequestration, local inflammation from microhemorrhages and autoregulatory dysfunction likely contribute to brain swelling in CM. No gross radiological blood brain barrier breakdown or focal cortical DWI abnormalities were evident in these children with nonfatal CM.

BACKGROUND:Increased brain volume (BV) and subsequent herniation are strongly associated with death in pediatric cerebral malaria (PCM), a leading killer of children in developing countries. Accurate noninvasive measures of BV are needed for optimal clinical trial design. Our objectives were to examine the performance of six different magnetic resonance imaging (MRI) BV quantification measures for predicting mortality in PCM and to review the advantages and disadvantages of each method.METHODS:Receiver operator characteristics were generated from BV measures of MRIs of children admitted to an ongoing research project with PCM between 2009 and 2014. Fatal cases were matched to the next available survivor. A total of 78 MRIs of children aged 5 months to 13 years (mean 4.0 years), of which 45% were males, were included.RESULTS:Areas under the curve (AUC) with 95% confidence interval on measures from the initial MRIs were: Radiologist-derived score = 0.69 (0.58-0.79; P = 0.0037); prepontine cistern anteroposterior (AP) dimension = 0.70 (0.56-0.78; P = 0.0133); SamKam ratio [Rt. parietal lobe height/(prepontine AP dimension + fourth ventricle AP dimension)] = 0.74 (0.63-0.83; P = 0.0002); and global cerebrospinal fluid (CSF) space ascertained by ClearCanvas = 0.67 (0.55-0.77; P = 0.0137). For patients with serial MRIs (n = 37), the day 2 global CSF space AUC was 0.87 (0.71-0.96; P < 0.001) and the recovery factor (CSF volume day 2/CSF volume day 1) was 0.91 (0.76-0.98; P < 0.0001). Poor prognosis is associated with radiologist score of ≥7; prepontine cistern dimension ≤3 mm; cisternal CSF volume ≤7.5 ml; SamKam ratio ≥6.5; and recovery factor ≤0.75.CONCLUSION:All noninvasive measures of BV performed well in predicting death and providing a proxy measure for brain volume. Initial MRI assessment may inform future clinical trials for subject selection, risk adjustment, or stratification. Measures of temporal change may be used to stage PCM.

Cryptococcal meningitis remains the leading cause of adult meningitis in Sub-Saharan Africa. Immune Reconstitution Inflammatory Syndrome (IRIS) following anti-retroviral therapy (ART) initiation is an important complication. Here we report the first documented case of a IRIS reaction presenting as an ischemic stroke.

Abstract Objective To assess differences in cognition functions and gross brain structure in children seven years after an episode of severe acute malnutrition (SAM), compared with other Malawian children. Design Prospective longitudinal cohort assessing school grade achieved and results of five computer-based (CANTAB) tests, covering three cognitive domains. A subset underwent brain MRI scans which were reviewed using a standardized checklist of gross abnormalities and compared with a reference population of Malawian children. Setting Blantyre, Malawi. Participants Children discharged from SAM treatment in 2006 and 2007 (n 320; median age 9·3 years) were compared with controls: siblings closest in age to the SAM survivors and age/sex-matched community children. Results SAM survivors were significantly more likely to be in a lower grade at school than controls (adjusted OR = 0·4; 95 % CI 0·3, 0·6; P < 0·0001) and had consistently poorer scores in all CANTAB cognitive tests. Adjusting for HIV and socio-economic status diminished statistically significant differences. There were no significant differences in odds of brain abnormalities and sinusitis between SAM survivors (n 49) and reference children (OR = 1·11; 95 % CI 0·61, 2·03; P = 0·73). Conclusions Despite apparent preservation in gross brain structure, persistent impaired school achievement is likely to be detrimental to individual attainment and economic well-being. Understanding the multifactorial causes of lower school achievement is therefore needed to design interventions for SAM survivors to thrive in adulthood. The cognitive and potential economic implications of SAM need further emphasis to better advocate for SAM prevention and early treatment.

Cerebral malaria (CM) causes a rapidly developing coma, and remains a major contributor to morbidity and mortality in malaria-endemic regions. This study sought to determine the relationship between cerebrospinal fluid (CSF) Plasmodium falciparum histidine rich protein-2 (PfHRP-2) and clinical, laboratory and radiographic features in a cohort of children with retinopathy-positive CM.

PURPOSE:To investigate the reliability of diffusion weighted image (DWI) measurements obtained on a 0.35T MR scanner in Malawi for malaria research. MATERIALS AND METHODS:The same healthy volunteers (n=6) were scanned on a 0.35T MR scanner in Malawi and a 3T scanner in the US. Three subjects had two repeated DWI scans at 0.35T. Due to scanner constraints, only three diffusion gradient directions for DWI on 0.35T could be obtained. An apparent diffusion coefficient (ADC) map was reconstructed from the 0.35T and the result was compared to standard DWI acquisition on the 3T scanner. The mean ADC from 15 different regions and the voxel-wise coefficient of variation (CV) were calculated to investigate the intra-scanner and inter-scanner variability. Reproducibility was calculated using intra-class correlation coefficient (ICC). RESULTS:The 0.35T intra-scanner ADC repeatability was high for all three subjects with repeated scans (ICC>0.7). The intra-scanner correlation between repeated scans was also high (r>0.67, p< 0.01). Comparing the ADC findings from the 0.35T and 3T MRs, the high inter-scanner correlation suggested that the 0.35T ADC results were valid (ICC>0.7, r>0.5, p<0.01). Voxel-wise CV revealed a few regions with larger variation (CV>20%), which were primarily located in peripheral regions and the boundary of lateral ventricles, and likely due to partial volume effects in low field scans. CONCLUSION:These findings support the validity of DWI obtained from low field MR scanners used in many low income countries.

Background Cerebral malaria (CM) remains a significant cause of morbidity and mortality in children in sub-Saharan Africa. CM mortality has been associated with increased brain volume, seen on neuroimaging studies. Methods To examine the potential role of blood metabolites and inflammatory mediators in increased brain volume in Malawian children with CM, an association study was performed between plasma metabolites, cytokine levels and phospholipase A 2 (PLA 2 ) activity with brain volume. Results The metabolomics analysis demonstrated arachidonic acid and other lysophospholipids to be positively associated with brain swelling. These lipids are products of the PLA 2 enzyme and an association of plasma PLA 2 enzymatic activity with brain swelling was confirmed. TNFα, which can upregulate PLA 2 activity, was associated with brain volume. In addition, CCL2 and IL-8 were also associated with brain volume. Some of these cytokines can alter endothelial cell tight junction proteins and increase blood brain barrier permeability. Conclusions Taken together, paediatric CM brain volume was associated with products of the PLA 2 pathway and inflammatory cytokines. Their role in causality is unknown. These molecules will need to undergo testing in vitro and in animal models to understand their role in processes of increased brain volume. These observations provide novel data on host physiology associated with paediatric CM brain swelling, and may both inform pathogenesis models and suggest adjunct therapies that could improve the morbidity and mortality associated with paediatric CM.

BACKGROUNDCase 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.METHODSWe 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.RESULTSOf 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.CONCLUSIONSIncreased 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.).