No abstract

Introduction: Pediatric convulsive status epilepticus (CSE) which is refractory to first-line benzodiazepines is a significant clinical challenge, especially within resource-limited countries. Parenteral phenobarbital is widely used in Africa as second-line agent for pediatric CSE, however evidence to support its use is limited. Purpose: This study aimed to compare the use of parenteral phenobarbital against parenteral phenytoin as a second-line agent in the management of pediatric CSE. Methodology: An open-labeled single-center randomized parallel clinical trial was undertaken which included all children (between ages of 1 month and 15 years) who presented with CSE. Children were allocated to receive either parenteral phenobarbital or parenteral phenytoin if they did not respond to first-line benzodiazepines. An intention-to-treat analysis was performed with the investigators blinded to the treatment arms. The primary outcome measure was the success of terminating CSE. Secondary outcomes included the need for admission to the pediatric intensive care unit (PICU) and breakthrough seizures during the admission. In addition, local epidemiological data was collected on the burden of pediatric CSE. Results: Between 2015 and 2018, 193 episodes of CSE from 111 children were enrolled in the study of which 144 met the study requirements. Forty-two percent had a prior history of epilepsy mostly from structural brain pathology (53%). The most common presentation was generalized CSE (65%) caused by acute injuries or infections of the central nervous system (59%), with 19% of children having febrile status epilepticus. Thirty-five percent of children required second-line management. More patients who received parenteral phenobarbital were at a significantly reduced risk of failing second-line treatment compared to those who received parenteral phenytoin ( RR = 0.3, p = 0.0003). Phenobarbital also terminated refractory CSE faster ( p < 0.0001). Furthermore, patients who received parenteral phenobarbital were less likely to need admission to the PICU. There was no difference between the two groups in the number of breakthrough seizures that occurred during admission. Conclusion: Overall this study supports anecdotal evidence that phenobarbital is a safe and effective second-line treatment for the management of pediatric CSE. These results advocate for parenteral phenobarbital to remain available to health care providers managing pediatric CSE in resource-limited settings. Attachments: CONSORT 2010 checklist Trial registration: NCT03650270 Full trial protocol available: https://clinicaltrials.gov/ct2/show/NCT03650270?recrs=e&type=Intr&cond=Status+Epilepticus&age=0&rank=1

A national multicenter study identified 17 South African children with vertically acquired HIV-1 infection and HIV-associated vasculopathy. Five of the children (all indigenous African ancestry) had progressive vascular disease, consistent with moyamoya syndrome. Median presentation age 5.8 years (range 2.2-11). The children with moyamoya syndrome presented with abnormal CD4 counts and raised viral loads. Clinical features included motor deficits, neuroregression, and intellectual disability. Neuroimaging supported progressive vascular disease with preceding clinically silent disease course. Neurologic recovery occurred in 1 patient with improved CD4 counts. Four of the 5 children presented during the era when access to antiretroviral therapy was limited, suggesting that with improved management of HIV-1, progressive vasculopathy is less prevalent. However the insidious disease course illustrated indicates that the syndrome can progress "silently," and manifest with misleading phenotypes such as cognitive delay or regression. Sub-Saharan Africa has limited access to neuroimaging and affected children may be underdiagnosed.

A B S T R A C TPurpose: The effects of antiseizure medications (ASMs) on bone metabolism is inconsistent. Most studies are in high income settings and none from sub-Saharan Africa.Methods: A hospital based cross-sectional study in a paediatric epilepsy service with a comparison group assessed vitamin D metabolism.Results: Seventy-five children with epilepsy and 75 comparison group were recruited. Median age for children with epilepsy was 9 years (range 1-17 years) and controls 3 years (range 1-12 years). Vitamin D deficiency occurred in 11(16.2%) children with epilepsy versus 6 (8.8%) control group (p = 0.29). Vitamin D insufficiency occurred in 30 (44.1%) children with epilepsy compared to 27(39.7%) control group. Children on ASMs had lower mean vitamin D levels than the control group (p = 0.02). Children on enzyme-inducing ASMs had lower mean vitamin D levels (p = 0.08), vitaminD 2 (p = 0.0018), vitaminD 3 (p = 0.004), serum phosphate levels (p = 0.000), and higher mean parathyroid hormone levels (p = 0.03) compared to controls. There was no difference in dietary intake and ancestry, although the dietary content of both groups was low in vitamin D products.Conclusions: Low vitamin D levels were common in children from both groups, but statistically lower for the children on ASMs. Children on enzyme-inducing ASMs need screening for vitamin D deficiency. The literature supports extending this for all children on ASMs. This is the first study to report that children on enzymeinducing ASMs have lower levels of Vitamin D 2 and D 3 levels, probably as result of increased destruction of vitamin D. Improved vitamin D intake for children in vulnerable settings is important.in the liver to form 25-hydroxyvitamin D 3 and subsequently 1α hydroxylation in the kidneys to form 1α, 25 dihydroxy-vitamin D 3 . The degradation of Vitamin D 3 in the kidneys occurs through an enzyme CYP24 to form the metabolites 24, 25 dihydroxy-vitamin D 3 and 1α, 24, 25 trihydroxy-vitamin D 3 [6,7]. In vitro studies support that CYP3A4 catalyzes the hydroxylation of 125 dihydroxy vitamin D 3 into inactive metabolites in the liver and small intestines, where CYP24A1 is nearly absent, which results in decreased intestinal calcium uptake. Notably, CYP3A4 also contributes to the catabolism of 25 hydroxy vitamin D 3 by catalyzing its hydroxylation into 425 dihydroxy vitamin D 3 [8].ASMs induce hepatic cytochrome P450 enzymes, especially https://doi.

DNA-RNA hybrids arise in all cell types, and are removed by multiple enzymes, including the trimeric ribonuclease, RNase H2. Mutations in human RNase H2 result in Aicardi–Goutières syndrome (AGS), an inflammatory brain disorder notable for being a Mendelian mimic of congenital viral infection. Previous studies have shown that several AGS-associated mutations of the RNase H2B subunit do not affect trimer stability or catalytic activity and are clustered on the surface of the complex, leading us to speculate that these mutations might impair important interactions of RNase H2 with so far unidentified proteins. In this study, we show that AGS mutations in this cluster impair the interaction of RNase H2 with several members of the CoREST chromatin-silencing complex that include the histone deacetylase HDAC2 and the demethylase KDM1A, the transcriptional regulators RCOR1 and GTFII-I as well as ZMYM3, an MYM-type zinc finger protein. We also show that the interaction is mediated by the zinc finger protein ZMYM3, suggesting that ZMYM3 acts as a novel type of scaffold protein coordinating interactions between deacetylase, demethylase and RNase H type enzymes, raising the question of whether coordination between histone modifications and the degradation of RNA-DNA hybrids may be required to prevent inflammation in humans.

No abstract