Biological and structural phenotypes associated with neurodevelopmental outcomes in congenital heart disease.

Neurodevelopmental disability (NDD) is recognised as one of the most common comorbidities in children with congenital heart disease (CHD) and is associated with altered brain structure and growth throughout the life course. Causes and contributors underpinning the CHD and NDD paradigm are not fully understood, and likely include innate patient factors, such as genetic and epigenetic factors, prenatal haemodynamic consequences as a result of the heart defect, and factors affecting the fetal-placental-maternal environment, such as placental pathology, maternal diet, psychological stress and autoimmune disease. Additional postnatal factors, including the type and complexity of disease and other clinical factors such as prematurity, peri-operative factors and socioeconomic factors are also expected to play a role in determining the final presentation of the NDD. Despite significant advances in knowledge and strategies to optimise outcomes, the extent to which adverse neurodevelopment can be modified remains unknown. Understanding biological and structural phenotypes associated with NDD in CHD are vital for understanding disease mechanisms, which in turn will advance the development of effective intervention strategies for those at risk. This review article summarises our current knowledge surrounding biological, structural, and genetic contributors to NDD in CHD and describes avenues for future research; highlighting the need for translational studies that bridge the gap between basic science and clinical practice.

Differential Expression of Interferon-Alpha Protein Provides Clues to Tissue Specificity Across Type I Interferonopathies.

Whilst upregulation of type I interferon (IFN) signaling is common across the type I interferonopathies (T1Is), central nervous system (CNS) involvement varies between these disorders, the basis of which remains unclear. We collected cerebrospinal fluid (CSF) and serum from patients with Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), presumed monogenic T1Is (pT1I), childhood systemic lupus erythematosus with neuropsychiatric features (nSLE), non-IFN-related autoinflammation (AI) and non-inflammatory hydrocephalus (as controls). We measured IFN-alpha protein using digital ELISA. Eighty-two and 63 measurements were recorded respectively in CSF and serum of 42 patients and 6 controls. In an intergroup comparison (taking one sample per individual), median CSF IFN-alpha levels were elevated in AGS, SAVI, pT1I, and nSLE compared to AI and controls, with levels highest in AGS compared to all other groups. In AGS, CSF IFN-alpha concentrations were higher than in paired serum samples. In contrast, serum IFN was consistently higher compared to CSF levels in SAVI, pT1I, and nSLE. Whilst IFN-alpha is present in the CSF and serum of all IFN-related diseases studied here, our data suggest the primary sites of IFN production in the monogenic T1I AGS and SAVI are, respectively, the CNS and the periphery. These results inform the diagnosis of, and future therapeutic approaches to, monogenic and multifactorial T1Is.

Acute Hemorrhagic Leukoencephalopathy: Pathological Features and Cerebrospinal Fluid Cytokine Profiles.

BACKGROUND: Acute hemorrhagic leukoencephalopathy is a rare encephalopathy of unknown etiology, causing fulminant, hemorrhagic central nervous system demyelination with high mortality. It is unclear whether acute hemorrhagic leukoencephalopathy is an entirely distinct entity from acute disseminated encephalomyelitis. PATIENTS AND METHODS: We report two patients with rapidly progressive neurological illness resulting in raised intracranial pressure and coma, with biopsy-proven acute hemorrhagic leukoencephalopathy (perivascular hemorrhages and demyelination, predominantly neutrophil infiltrates). RESULTS: Acute cerebrospinal fluid showed pronounced T cell-associated cytokine elevation (interleukins 6, 8, and 17A) and CCL2 or CCL3, higher than in patients with acute disseminated encephalomyelitis, but no B cell-associated cytokine elevation. CONCLUSION: Improved understanding of the immune process may provide rationale for use of anticytokine biologic agents.

Author Correction: Neuroimmune disorders of the central nervous system in children in the molecular era.

In the original version of this Review published online and in print, the contribution of attendees of the International Neuroimmune Meeting to the content of the Review was not acknowledged. The author list has been corrected in the PDF and HTML versions of this article to acknowledge that the Review was written on behalf of attendees of the International Neuroimmune Meeting, and the names of the attendees have been added to the HTML version.

Neuroimmune disorders of the central nervous system in children in the molecular era.

Immune-mediated disorders of the CNS in children are a complex group of demyelinating, inflammatory, parainfectious and postinfectious disorders with heterogeneous pathobiological mechanisms and clinical manifestations, often associated with fundamental derangement in immune regulation. In this Review, we aim to provide an update on our knowledge of neuroimmune disorders and highlight areas of research that are priorities for improving clinical management. We outline the clinical features of neuroimmune disorders, the current approaches to their treatment and new approaches in development. We then consider the pathological features, including biomarkers, pathological mechanisms and genetics, and discuss the value of immune assays in clinical investigation and basic research. On the basis of current knowledge and techniques, we propose four research priorities: rigorous and consistent collection of core clinical data, cooperative investigation of treatments, development of biological assays and genetic studies. These priorities should help us to achieve the shared goal of precision medicine for neuroimmune disorders. However, multicentre research and the creation of clinical consortia for these rare disorders will be necessary, and we hope that this Review serves as a call to action that is timely given current exciting advances in neuroimmune therapeutics.