Brain MRI and cognitive function seven years after surviving an episode of severe acute malnutrition in a cohort of Malawian children.

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.

Noninvasive measures of brain edema predict outcome in pediatric cerebral malaria.

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.

1.5 Tesla Magnetic Resonance Imaging to Investigate Potential Etiologies of Brain Swelling in Pediatric 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.

Validation of diffusion measurements obtained on a 0.35T MR in Malawi: Important insights for radiologists in low income settings with low field MRI.

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.

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.).

Magnetic resonance imaging research in sub-Saharan Africa: challenges and satellite-based networking implementation.

As part of an NIH-funded study of malaria pathogenesis, a magnetic resonance (MR) imaging research facility was established in Blantyre, Malawi 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 Malawi 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.

Association between sputum smear status and local immune responses at the site of disease in HIV-infected patients with pulmonary tuberculosis.

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.