Optic nerve sheath diameter and its association with brain swelling in pediatric cerebral malaria: a retrospective study.

Introduction: Mortality in pediatric cerebral malaria (CM) in low- and middle-income countries (LMICs) is associated with brain swelling on magnetic resonance imaging (MRI); however, MRI is unavailable in most LMICs. Optic nerve sheath diameter (ONSD) measurement is an inexpensive method of detecting increased intracranial pressure compared with the invasive opening pressure (OP). Our primary objective was to determine if increased ONSD correlated with brain swelling on MRI in pediatric CM. Our secondary objective was to determine if increased ONSD correlated with increased OP and/or poor neurological outcome in pediatric CM. We hypothesized that increased ONSD would correlate with brain swelling on MRI and increased OP and that ONSD would be higher in survivors with sequelae and non-survivors. Methods: We performed a retrospective chart review of children aged 0-12 years in Blantyre, Malawi, from 2013 to 2022 with CM as defined by the World Health Organization. Brain swelling on admission MRI was characterized by brain volume scores (BVS); severe swelling was scored as 7-8, mild-to-moderate as 4-6, normal as 3. The admission ONSD was measured via ultrasound; it was defined as abnormal if it was >4.5 mm in children >1 year and >4 mm in children <1 year. Favorable outcome was defined as a normal neurological exam on discharge in survivors. The primary and secondary objectives were evaluated using Spearman's correlation; and the demographics were compared using chi-square and the Kruskal-Wallis test (Stata, College Station, TX, USA). Results: Median age of the 207-patients cohort was 50 months [interquartile range (IQR) 35-75]; 49% (n = 102) were female. Of those, 73% (n = 152) had a favorable outcome, and 14% (n = 30) died. Twenty-nine (14%) had a normal BVS, 134 (65%) had mild-to-moderate swelling, and 44 (21%) had severe swelling. ONSD was elevated in 86% (n = 178) of patients, while 12% of patients had increased OP. There was a weakly positive correlation between BVS and ONSD (r = 0.14, p = 0.05). The median ONSD was not significantly different compared by discharge outcome (p = 0.11) or by BVS (p = 0.18). Conclusion: ONSD was not a reliable tool to correlate with BVS, neurological outcome, or OP in children with CM. Future studies to identify alternative methods of early identification of CM patients at highest risk for morbidity and mortality are urgently needed.

Case report: Acute necrotizing encephalopathy: a report of a favorable outcome and systematic meta-analysis of outcomes with different immunosuppressive therapies.

Acute Necrotizing Encephalopathy (ANE) is a condition characterized by symmetric, bilateral lesions affecting the thalamus and potentially other areas of the brain following an acute febrile illness. It manifests clinically as abrupt development of encephalopathy, or alteration in mental status that often includes development of seizures and progression to coma. Treatment strategies combine immunosuppressive therapies and supportive care with varying levels of recovery, however there are no universally accepted, data-driven, treatment algorithms for ANE. We first report a case of a previously healthy 10-year-old female with acute onset diplopia, visual hallucinations, lethargy, and seizures in the setting of subacute non-specific viral symptoms and found to have bilateral thalamic and brainstem lesions on MRI consistent with ANE. She was treated with a combination of immunomodulatory therapies and ultimately had a good outcome. Next, we present a meta-analysis of 10 articles with a total of 158 patients meeting clinical and radiographic criteria for ANE. Each article reported immunosuppressive treatments received, and associated morbidity or mortality outcome for each individual patient. Through our analysis, we confirm the effectiveness of high-dose, intravenous, methylprednisolone (HD-IV-MP) therapy implemented early in the disease course (initiation within 24 h of neurologic symptom onset). There was no significant difference between patients treated with and without intravenous immunoglobulin (IVIG). There was no benefit of combining IVIG with early HD-IV-MP. There is weak evidence suggesting a benefit of IL-6 inhibitor tocilizumab, especially when used in combination with early HD-IV-MP, though this analysis was limited by sample size. Finally, plasma exchange (PLEX) improved survival. We hope this meta-analysis will be useful for clinicians making treatment decisions for patients with this potentially devastating condition.

Capacity Building in Pediatric Critical Care-Global Health Research and Education: The Blantyre Experience.

Pediatric critical care medicine (PCCM), as it is practiced in high-income countries, is focused on specialized medical care for the most vulnerable pediatric patient populations. However, best practices for provision of that care globally are lacking. Thus, PCCM research and education programming can potentially fill significant knowledge gaps by facilitating the development of evidence-based clinical guidelines that reduce child mortality on a global scale. Malaria remains a leading cause of pediatric mortality worldwide. The Blantyre Malaria Project (BMP) is a research and clinical care collaborative that has focused on reducing the public health burden of pediatric cerebral malaria in Malawi since 1986. In 2017, the requirements of a new research study led to the creation of PCCM services in Blantyre, creating the opportunity to establish a PCCM-Global Health Research Fellowship by BMP in collaboration with the University of Maryland School of Medicine. In this perspective piece, we reflect on the evolution of the PCCM-Global Health research fellowship. Although the specifics of this fellowship are out of the scope of this perspective, we discuss the context allowing for the development of this program and explore some early lessons learned to consider for future capacity-building efforts in the future of PCCM-Global Health research.

Glucocorticoid sensitizers Bag1 and Ppid are regulated by adolescent stress in a sex-dependent manner.

Early life stress precipitates dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and this effect is most pronounced in females. The mechanisms that mediate female sensitivity to stress-induced HPA axis dysregulation are unknown. The purpose of this study was to determine whether sex moderates the effects of chronic adolescent stress on glucocorticoid receptor (GR) translocation and moderators of the GR system. Female adolescent rats with a history of chronic stress exposure demonstrated a delayed resolution of the plasma corticosterone response to an acute stressor and this delay was accompanied by attenuated GR translocation compared to control adolescent females. The chronic stress-induced phenotype in females was similar to the baseline phenotype in male adolescent rats. Conversely, the expression patterns of GR moderators/co-chaperones became more sexually dimorphic following chronic stress, suggesting divergent function of the GR system between male and female adolescent rats. Gene expression of Ppid, a positive regulator of the GR, was predicted by plasma estradiol and 34% lower in control adolescent females than males, indicating that sex steroids may play a role in the sexually dimorphic response. After chronic adolescent stress, females displayed elevated hippocampal expression of Bag1 and Ppid genes that was not observed in males. Overall, the GR output to an acute stressor, illustrated by transcription of Nr3c1 (encoding the GR), Bag1, Fkbp5, Ppid, and Src1, was significantly upregulated and differed in a sex-specific and chronic stress-dependent manner. This study provides new evidence for sex differences during development and adaptation of the glucocorticoid receptor chaperone system.

Behavioral phenotypes persist after gonadal steroid manipulation in white-throated sparrows.

White-throated sparrows (Zonotrichia albicollis) exhibit a behavioral polymorphism that segregates with a plumage marker. Individuals with a white stripe (WS) on the crown engage in an aggressive strategy that involves more singing, whereas individuals with a tan stripe (TS) sing less and engage in more parental care. Previous work has shown that plasma levels of gonadal steroids differ between the morphs in both sexes, suggesting a hormonal mechanism for the polymorphic behavior in this species. Here, we eliminated morph differences in plasma levels of testosterone (T) in males and estradiol (E2) in females in order to test whether morph differences in behavior would be similarly eliminated. Males and females in non-breeding condition were treated with T or E2, respectively, so that plasma levels in the treated groups were high and equal between the WS and TS morphs. We found that despite hormone treatment, WS and TS birds differed with respect to singing behavior. WS males sang more in response to song playback than did TS males, and WS females exhibited more spontaneous song than TS females. We also found that WS males gave more chip calls, which are often used in contexts of territorial aggression. Overall, these results suggest that WS birds engage in more territorial vocalization, particularly song, than do TS birds, even when T or E2 levels are experimentally equalized. This behavioral difference may therefore be driven by other factors, such as steroid metabolism, receptor expression or function, or steroid-independent neurotransmitter systems.