Serial Imaging of Virus-Associated Necrotizing Disseminated Acute Leukoencephalopathy (VANDAL) in COVID-19.

BACKGROUND AND PURPOSE: Various patterns of leukoencephalopathy have been described in coronavirus disease 2019 (COVID-19). In this article, we aimed to describe the clinical and imaging features of acute disseminated leukoencephalopathy in critically ill patients with COVID-19 and the imaging evolution during a short-term follow-up. MATERIALS AND METHODS: We identified and reviewed the clinical data, laboratory results, imaging findings, and outcomes for 8 critically ill patients with COVID-19 with acute disseminated leukoencephalopathy. RESULTS: All patients demonstrated multiple areas of white matter changes in both cerebral hemispheres; 87.5% (7/8) of patients had a posterior predilection. Four patients (50%) had short-term follow-up imaging within a median of 17 days after the first MR imaging; they developed brain atrophy, and their white matter lesions evolved into necrotizing cystic cavitations. All (8/8) patients had inflammatory cytokine release syndrome as demonstrated by elevated interleukin-6, D-dimer, lactate dehydrogenase, erythrocyte sedimentation rate, C-reactive protein, and ferritin levels. Most (7/8; 87.5%) patients were on prolonged ventilator support (median, 44.5 days; interquartile range, 20.5 days). These patients had poor functional outcomes (6/8 [75%] patients were discharged with mRS 5) and high mortality (2/8, 25%). CONCLUSIONS: Critically ill patients with COVID-19 can develop acute disseminated leukoencephalopathy that evolves into cystic degeneration of white matter lesions with brain atrophy during a short period, which we dubbed virus-associated necrotizing disseminated acute leukoencephalopathy. This may be the result of COVID-19-related endothelial injury, cytokine storm, or thrombotic microangiopathy.

The Yin and Yang of pain: variability in formalin test nociception and morphine analgesia produced by the Yin Yang 1 transcription factor gene.

We recently observed a reliable phenotypic difference in the inflammatory pain sensitivity of a congenic mouse strain compared to its background strain. By constructing and testing subcongenic strains combined with gene-expression assays, we provide evidence for the candidacy of the Yy1 gene - encoding the ubiquitously expressed and multifunctional Yin Yang 1 transcription factor - as responsible. To confirm this hypothesis, we used a Cre/lox strategy to produce mutant mice in which Yy1 expression was ablated in Nav 1.8-positive neurons of the dorsal root ganglion. These mutants also displayed reduced inflammatory pain sensitivity on the formalin test. Further testing of pain-related phenotypes in these mutants revealed robustly increased sensitivity to systemic and spinal (but not supraspinal) morphine analgesia, and greatly increased endogenous (swim stress-induced) opioid analgesia. None of the known biological roles of Yin Yang 1 were suggestive of such a phenotype, and thus a novel player in pain modulatory systems has been identified.

No causative DLL4 mutations in periodic catatonia patients from 15q15 linked families.

Two well-supported theories of schizophrenia pathogenesis are the neurotransmitter theory and the neurodevelopmental theory, suggesting, respectively, that dysregulation of neurotransmitter signaling and abnormal brain development are causative in this disease. The strongest evidence of neurotransmitter involvement are suggestions of abnormal dopamine signaling in the prefrontal cortex and one of the strongest indications of developmental abnormalities contributing to this disease is an inverse layering of the prefrontal cortex. These two theories of schizophrenia pathogenesis can be united by their involvement of the prefrontal cortex, where structural abnormalities could lead to neurochemical abnormalities. Accordingly, any gene expressed in the prefrontal cortex of developing brains is a functional candidate for schizophrenia. We have previously reported strong linkage to 15q15 (LOD = 3. 57; P = 2.6 x 10(-5)) in a collection of German multiplex families segregating the periodic catatonia subtype of schizophrenia in a nearly Mendelian fashion. A gene within our 15q15 linkage region, DLL4, is expressed in developing forebrain and produces a NOTCH4 ligand. Variants of NOTCH4 are associated with schizophrenia, thus DLL4 is both a functional as well as a positional candidate for schizophrenia. We screened this gene for mutations in three affected individuals and two unrelated controls and found two previously unreported SNPs, one non-synonymous polymorphism that changed an arganine to a histadine in Exon 7 and one synonymous polymorphism in exons. The non-synonymous SNP is a rare variant in that it was not found in 100 control chromosomes; however, it did not cosegregate with the disease in the extended family so it is not causative in this pedigree. It is unlikely that mutations in DLL4 are causative in this collection of families with linkage to 15q15.