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Background and Purpose: Validation of diffusion-weighted images obtained on 0.35T MR imaging in Malawi has facilitated meaningful review of previously unreported findings in cerebral malaria. Malawian children with acute cerebral malaria demonstrated restricted diffusion on brain MR imaging, including an unusual pattern of restriction isolated to the subcortical white matter. We describe the patterns of diffusion restriction in cerebral malaria and further evaluate risk factors for and outcomes associated with an isolated subcortical white matter diffusion restriction., Materials and Methods: Between 2009 and 2014, comatose Malawian children admitted to the hospital with cerebral malaria underwent admission brain MR imaging. Imaging data were compiled via NeuroInterp, a RedCap data base. Clinical information obtained included coma score, serum studies, and coma duration. Electroencephalograms were obtained between 2009 and 2011. Outcomes captured included death, neurologic sequelae, or full recovery., Results: One hundred ninety-four/269 (72.1%) children with cerebral malaria demonstrated at least 1 area of diffusion restriction. The most common pattern was bilateral subcortical white matter involvement (41.6%), followed by corpus callosum (37.5%), deep gray matter (36.8%), cortical gray matter (17.8%), and posterior fossa (8.9%) involvement. Sixty-one (22.7%) demonstrated isolated subcortical white matter diffusion restriction. These children had lower whole-blood lactate levels (OR, 0.9; 95% CI, 0.85-0.98), were less likely to require anticonvulsants (OR, 0.6; 95% CI, 0.30-0.98), had higher average electroencephalogram voltage (OR, 1.01; 95% CI, 1.00-1.02), were less likely to die (OR, 0.09; 95% CI, 0.01-0.67), and were more likely to recover without neurologic sequelae (OR, 3.7; 95% CI, 1.5-9.1)., Conclusions: Restricted diffusion is common in pediatric cerebral malaria. Isolated subcortical white matter diffusion restriction is a unique imaging pattern associated with less severe disease and a good prognosis for full recovery. The underlying pathophysiology may be related to selective white matter vulnerability., (© 2019 by American Journal of Neuroradiology.)

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.ParticipantsChildren 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.

: media-1vid110.1542/5972295739001PEDS-VA&#95;2018-1026 Video Abstract BACKGROUND AND OBJECTIVES: Cerebral malaria (CM) causes significant mortality and morbidity in sub-Saharan African children. Reliable morbidity estimates are scarce because of methodological variability across studies. We describe the incidence, course, and severity of neurodevelopmental impairments in survivors of CM and the associated patient characteristics to inform epidemiologic estimates of malaria morbidity rates and prevention and treatment efforts., Methods: We conducted an exposure-control study of 85 survivors of CM and 100 age-matched patients in a control group who were enrolled at hospital discharge and assessed after 1, 6, and 12 months using caregiver interviews and standardized developmental, cognitive, and behavioral measures., Results: Developmental or cognitive impairment (<10th percentile of the control distribution) and/or new onset of caregiver-reported behavior problems occurred in 53% of case patients compared with 20% of the patients in the control group (odds ratio 4.5; 95% CI: 2.4 to 8.6; P < .001). In case patients, developmental or cognitive impairment at the 12-month assessment was associated with HIV-positive status and short stature at presentation, more prolonged fever and coma during admission, and severe atrophy or multifocal abnormalities being found on MRI at the 1-month assessment., Conclusions: One-half of survivors of CM were neurodevelopmentally impaired at the 1-year assessment. With these results, we support prevention trials of acute, neuroprotective interventions and the allocation of resources to evaluation, education, and rehabilitation efforts to reduce the significant long-term burden of CM-associated impairments on families and their communities., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

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., Competing Interests: There are no conflicts of interest.

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.

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Brain swelling is a major predictor of mortality in pediatric cerebral malaria (CM). However, the mechanisms leading to swelling remain poorly defined. Here, we combined neuroimaging, parasite transcript profiling, and laboratory blood profiles to develop machine-learning models of malarial retinopathy and brain swelling. We found that parasite var transcripts encoding endothelial protein C receptor (EPCR)-binding domains, in combination with high parasite biomass and low platelet levels, are strong indicators of CM cases with malarial retinopathy. Swelling cases presented low platelet levels and increased transcript abundance of parasite PfEMP1 DC8 and group A EPCR-binding domains. Remarkably, the dominant transcript in 50% of swelling cases encoded PfEMP1 group A CIDRα1.7 domains. Furthermore, a recombinant CIDRα1.7 domain from a pediatric CM brain autopsy inhibited the barrier-protective properties of EPCR in human brain endothelial cells in vitro. Together, these findings suggest a detrimental role for EPCR-binding CIDRα1 domains in brain swelling., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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.).

Our goals were to understand the brain magnetic resonance imaging (MRI) findings in children with retinopathy-negative cerebral malaria (CM) and investigate whether any findings on acute MRI were associated with adverse outcomes. We performed MRI scans on children admitted to the hospital in Blantyre, Malawi with clinically defined CM. Two hundred and seventeen children were imaged during the study period; 44 patients were malarial retinopathy-negative; and 173 patients were retinopathy-positive. We compared MRI findings in children with retinopathy-negative and retinopathy-positive CM. In children who were retinopathy-negative, we identified MRI variables that were associated with death and adverse neurologic outcomes. On multivariate analysis, cortical diffusion weighted imaging (DWI) abnormality and increased brain volume were strongly associated with neurologic morbidity in survivors. Investigations to explore the underlying pathophysiologic processes responsible for these MRI changes are warranted., (© The American Society of Tropical Medicine and Hygiene.)

Objective: To collect normative MRI data for effective clinical and research applications. Such data may also offer insights into common neurological insults., Methods: We identified a representative, community-based sample of children aged 9-14 years. Children were screened for neurodevelopmental problems. Demographic data, medical history and environmental exposures were ascertained. Eligible children underwent the Neurologic Examination for Subtle Signs (NESS) and a brain MRI. Descriptive findings and analyses to identify risk factors for MRI abnormalities are detailed., Results: One hundred and two of 170 households screened had age-appropriate children. Two of 102 children had neurological problems - one each with cerebral palsy and epilepsy. Ninety-six of 100 eligible children were enrolled. Mean age was 11.9 years (SD 1.5), and 43 (45%) were boys. No acute MRI abnormalities were seen. NESS abnormalities were identified in 6 of 96 children (6%). Radiographic evidence of sinusitis in 29 children (30%) was the most common MRI finding. Brain abnormalities were found in 16 (23%): mild diffuse atrophy in 4 (4%), periventricular white matter changes/gliosis in 6 (6%), multifocal punctuate subcortical white matter changes in 2 (2%), vermian atrophy in 1 (1%), empty sella in 3 (3%) and multifocal granulomas with surrounding gliosis in 1 (1%). Having an abnormal MRI was not associated with age, sex, antenatal problems, early malnutrition, febrile seizures, an abnormal neurological examination or housing quality (all P values >0.05). No predictors of radiographic sinusitis were identified., Conclusion: Incidental brain MRI abnormalities are common in normal Malawian children. The incidental atrophy and white matter abnormalities seen in this African population have not been reported among incidental findings from US populations, suggesting Malawi-specific exposures may be the cause., (© 2013 Blackwell Publishing Ltd.)

Abstract. A prospective cohort study of retinopathy-confirmed cerebral malaria (CM) survivors identified 42 of 132 with neurologic sequelae. The 38 survivors with sequelae who were alive when magnetic resonance imaging (MRI) technology became available underwent brain MRIs. Common MRI abnormalities included periventricular T2 signal changes (53%), atrophy (47%), subcortical T2 signal changes (18%), and focal cortical defects (16%). The χ(2) tests assessed the relationship between chronic MRI findings, acute clinical and demographic data, and outcomes. Children who were older at the time of CM infection (P = 0.01) and those with isolated behavioral problems (P = 0.02) were more likely to have a normal MRI. Acute focal seizures were associated with atrophy (P = 0.05). Acute papilledema was associated with subcortical T2 signal changes (P = 0.02). Peripheral retinal whitening (P = 0.007) and a higher admission white blood cell count (P = 0.02) were associated with periventricular T2 signal changes. Chronic MRI findings suggest seizures, increased intracranial pressure, and microvascular ischemia contribute to clinically relevant structural brain injury in CM.

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.

Background: Salmonella enterica serovar Typhi causes an estimated 22 million cases of typhoid fever and 216 000 deaths annually worldwide. We investigated an outbreak of unexplained febrile illnesses with neurologic findings, determined to be typhoid fever, along the Malawi-Mozambique border., Methods: The investigation included active surveillance, interviews, examinations of ill and convalescent persons, medical chart reviews, and laboratory testing. Classification as a suspected case required fever and ≥1 other finding (eg, headache or abdominal pain); a probable case required fever and a positive rapid immunoglobulin M antibody test for typhoid (TUBEX TF); a confirmed case required isolation of Salmonella Typhi from blood or stool. Isolates underwent antimicrobial susceptibility testing and subtyping by pulsed-field gel electrophoresis (PFGE)., Results: We identified 303 cases from 18 villages with onset during March-November 2009; 214 were suspected, 43 were probable, and 46 were confirmed cases. Forty patients presented with focal neurologic abnormalities, including a constellation of upper motor neuron signs (n = 19), ataxia (n = 22), and parkinsonism (n = 8). Eleven patients died. All 42 isolates tested were resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole; 4 were also resistant to nalidixic acid. Thirty-five of 42 isolates were indistinguishable by PFGE., Conclusions: The unusual neurologic manifestations posed a diagnostic challenge that was resolved through rapid typhoid antibody testing in the field and subsequent blood culture confirmation in the Malawi national reference laboratory. Extending laboratory diagnostic capacity, including blood culture, to populations at risk for typhoid fever in Africa will improve outbreak detection, response, and clinical treatment.

As part of an NIH-funded study of malaria pathogenesis, a magnetic resonance (MR) imaging research facility was established in Blantyre, Malaŵi to enhance the clinical characterization of pediatric patients with cerebral malaria through application of neurological MR methods. The research program requires daily transmission of MR studies to Michigan State University (MSU) for clinical research interpretation and quantitative post-processing. An intercontinental satellite-based network was implemented for transmission of MR image data in Digital Imaging and Communications in Medicine (DICOM) format, research data collection, project communications, and remote systems administration. Satellite Internet service costs limited the bandwidth to symmetrical 384 kbit/s. DICOM routers deployed at both the Malaŵi MRI facility and MSU manage the end-to-end encrypted compressed data transmission. Network performance between DICOM routers was measured while transmitting both mixed clinical MR studies and synthetic studies. Effective network latency averaged 715 ms. Within a mix of clinical MR studies, the average transmission time for a 256 × 256 image was ~2.25 and ~6.25 s for a 512 × 512 image. Using synthetic studies of 1,000 duplicate images, the interquartile range for 256 × 256 images was [2.30, 2.36] s and [5.94, 6.05] s for 512 × 512 images. Transmission of clinical MRI studies between the DICOM routers averaged 9.35 images per minute, representing an effective channel utilization of ~137% of the 384-kbit/s satellite service as computed using uncompressed image file sizes (including the effects of image compression, protocol overhead, channel latency, etc.). Power unreliability was the primary cause of interrupted operations in the first year, including an outage exceeding 10 days.

Purpose: To describe brain CT findings in retinopathy-confirmed, paediatric cerebral malaria., Materials and Methods: In this outcomes study of paediatric cerebral malaria, a subset of children with protracted coma during initial presentation was scanned acutely. Survivors experiencing adverse neurological outcomes also underwent a head CT. All children had ophthalmological examination to confirm the presence of the retinopathy specific for cerebral malaria. Independent interpretation of CT images was provided by two neuroradiologists., Results: Acute brain CT findings in three children included diffuse oedema with obstructive hydrocephalus (2), acute cerebral infarctions in multiple large vessel distributions with secondary oedema and herniation (1), and oedema of thalamic grey matter (1). One child who was reportedly normal prior to admission had parenchymal atrophy suggestive of pre-existing CNS injury. Among 56 survivors (9-84 months old), 15 had adverse neurologic outcomes-11/15 had a follow-up head CT, 3/15 died and 1/15 refused CT. Follow-up head CTs obtained 7-18 months after the acute infection revealed focal and multifocal lobar atrophy correlating to regions affected by focal seizures during the acute infection (5/11). Other findings were communicating hydrocephalus (2/11), vermian atrophy (1/11) and normal studies (3/11)., Conclusions: The identification of pre-existing imaging abnormalities in acute cerebral malaria suggests that population-based studies are required to establish the rate and nature of incidental imaging abnormalities in Malawi. Children with focal seizures during acute cerebral malaria developed focal cortical atrophy in these regions at follow-up. Longitudinal studies are needed to further elucidate mechanisms of CNS injury and death in this common fatal disease., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Infection with human immunodeficiency virus (HIV) may affect the clinical presentation of pulmonary tuberculosis (TB). To investigate the association between sputum smear status at presentation and local pulmonary immune responses in HIV-infected patients with pulmonary TB, we compared the cellular and cytokine profiles in bronchoalveolar lavage (BAL) fluid obtained from the site of lung disease in 22 sputum smear- and culture-positive, and 17 sputum smear-negative but culture-positive pulmonary TB patients. Smear-positive patients had significantly higher BAL fluid concentrations of IL-6 (p=0.007), IL-8 (p=0.02), IL-10 (p=0.03) and IFN-gamma (p=0.008) than smear-negative patients. No significant differences in the proportions of examined BAL cells were found. We concluded that sputum smear-positive TB was associated with greater pro-inflammatory and immunomodulatory cytokine responses at the site of lung disease than sputum smear-negative disease. The local immune responses may affect the clinical presentation of active pulmonary TB in HIV-infected patients.