Marked IDO2 expression and activity related to autophagy and apoptosis in brain tissue of fatal tuberculous meningitis.

In about 1% of tuberculosis (TB) patients, Mycobacterium tuberculosis (M. tuberculosis) can disseminate to the meninges, causing tuberculous meningitis (TBM) with mortality rate up to 60%. Chronic granulomatous inflammation (non-necrotizing and necrotizing) in the brain is the histological hallmark of TBM. The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and the generated kynurenine metabolites exert major effector functions relevant to TB granuloma functioning. Here we have assessed immunohistochemically IDO1 expression and activity and its effector function and that of its isoform, IDO2, in post-mortem brain tissue of patients that demised with neurotuberculosis. We also related these findings to brain tissue of fatal/severe COVID-19. In this study, IDO1 and IDO2 were abundantly expressed and active in tuberculoid granulomas and were associated with the presence of M. tuberculosis as well as markers of autophagy and apoptosis. Like in fatal/severe COVID-19, IDO2 was also prominent in specific brain regions, such as the inferior olivary nucleus of medulla oblongata and cerebellum, but not associated with granulomas or with M. tuberculosis. Spatially associated apoptosis was observed in TBM, whereas in fatal COVID-19 autophagy dominated. Together, our findings highlight IDO2 as a potentially relevant effector enzyme in TBM, which may relate to the symptomology of TBM.

A proposed magnetic resonance imaging grading system for the spectrum of central neonatal parasagittal hypoxic-ischaemic brain injury.

AIM: To describe the spectrum of parasagittal injury on MRI studies performed on children following severe perinatal term hypoxia-ischaemia, using a novel MRI grading system, and propose a new central pattern correlated with neuropathologic features. METHODS: MR scans of 297 patients with perinatal term hypoxia-ischaemia were evaluated for typical patterns of brain injury. A total of 83 patients that demonstrated the central/basal ganglia-thalamus and perirolandic pattern of injury were categorised according to the degree of severity. The perirolandic injury was graded by the degree of interhemispheric widening, paracentral lobule involvement and perirolandic cortex destruction leading to a tiered categorisation. Of these 83 patients, 19 had the most severe subtype of injury. A detailed analysis of the clinical data of a subset of 11 of these 19 patients was conducted. RESULTS: We demonstrated the mild subtype in 21/83(25%), the moderate subtype in 22/83(27%) and the severe subtype in 21/83(25%). A fourth pattern was identified in 19/83(23%) patients with a diamond-shaped expansion of the interhemispheric fissure, concomitant thalamic, putaminal, hippocampal and other smaller substrate involvement indicative of the most destructive subtype. CONCLUSIONS: We propose a new MR grading system of injury at the parasagittal perirolandic region related to severe, sustained central perinatal term hypoxia-ischaemia. We also introduce a previously undescribed pattern of injury, the most severe form of this spectrum, seen especially after prolongation of the second stage of labour. This constellation of high metabolic substrate, targeted tissue destruction is consistently demonstrated by MRI, termed the massive paramedian injury pattern.

The use of thalidomide to treat children with tuberculosis meningitis: A review.

Much of the morbidity and mortality caused by tuberculous meningitis (TBM) is mediated by a dysregulated immune response. Effective host-directed therapy is therefore critical to improve survival and clinical outcomes. Currently only one host-directed therapy (HDT), corticosteroids, is proven to improve mortality. However, there is no evidence that corticosteroids reduce morbidity and the mechanism of action for mortality reduction is uncertain. Further, it has no proven benefit in HIV co-infected individuals. One promising host-directed therapy approach is to restrict the immunopathology arising from tumour necrosis factor (TNF)-α excess is via TNF-α inhibitors. There are accumulating data on the role of thalidomide, anti-TNF-α monoclonal antibodies (infliximab, adalimumab) and the soluble TNF-α receptor (etanercept) in TBM treatment. Thalidomide was developed nearly seventy years ago and has been a highly controversial drug. Birth defects and toxic adverse effects have limited its use but an improved understanding of its immunological mechanism of action suggest that it may have a crucial role in regulating the destructive host response seen in inflammatory conditions such as TBM. Observational studies at our institution found low dosage adjunctive thalidomide safe in treating tuberculous mass lesions and blindness related to optochiasmatic arachnoiditis, with good clinical and radiological response. In this review, we discuss possible mechanisms of action for thalidomide, based on our clinico-radiologic experience and post-mortem histopathological work. We also propose a rationale for its use in the treatment of certain TBM-related complications.

Unusual Presentation of Atrial Myxoma: A Case Report and Review of the Literature.

BACKGROUND Although rare, atrial myxoma is the most common benign cardiac tumor. The recognized triad of presenting symptoms relates to constitutional, embolic, and obstructive effects produced by the tumor. However, the presentation may be non-specific and mimic other diseases, confounding diagnosis. CASE REPORT A middle-aged woman presented with wheezing and shortness of breath. With a strong background smoking history, the initial impression was that of acute bronchospasm. She however deteriorated rapidly, with decreased consciousness and cardiac arrest requiring resuscitation. Despite intensive care management, she died within 1 day of admission. Autopsy revealed a previously undiagnosed left atrial myxoma with coronary and systemic embolization. CONCLUSIONS This case highlights an unusual presentation of atrial myxoma, resulting in fatal simultaneous embolization to the coronary and cerebral arteries. This simultaneous embolic presentation is not common, but the potential consequences are serious. This report also demonstrates that the presentation of a left-sided atrial myxoma with cardiac asthma can mimic respiratory disease and confound diagnosis. In adult patients without a history of chronic respiratory disease, the possibility of cardiac asthma should always be entertained. Furthermore, the importance of considering atrial myxoma as a cause for cardiac asthma is emphasized. The use of transthoracic echocardiogram in aiding the rapid diagnosis of atrial myxoma is recommended. Finally, the continued acknowledgement of the important contribution the academic autopsy makes in complementing and improving clinical practice remains imperative.

Complete Clinicopathological Case Report of a Young Patient Dying of COVID-19-Related Stroke.

ABSTRACT: The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic has revealed diverse neurological manifestations of coronavirus disease 2019 (COVID-19). This case report begins with a background review of the neurological effects of COVID-19, focusing on stroke, neuroinflammation, and coagulopathy. It then describes the clinical course and autopsy findings of a young patient presenting with COVID-19-associated stroke. The formal neuropathological examination is presented, along with the systemic and brain histological features. Interesting aspects include multiterritory hemorrhagic infarctions, microinfarcts throughout the cortex and white matter, and prominent mixed inflammatory cell cuffing of intracerebral blood vessels distant from the infarcts.

Three-dimensional visualizations from a dataset of immunohistochemical stained serial sections of human brain tissue containing tuberculosis related granulomas.

This data article presents datasets associated with the research article entitled "The immunological architecture of granulomatous inflammation in central nervous system tuberculosis'' (Zaharie et al., 2020). The morphology of tuberculosis related granulomas within the central nervous system of human patients was visualized in six different three-dimensional (3D) models. Post-mortem, formalin fixed and paraffin embedded specimens from deceased tuberculous meningitis patients were immunohistochemically stained and 800 serial histologically stained sections were acquired. Images from all sections were obtained with an Olympus BX43 light microscope and structures were identified, labeled and made three-dimensional. The interactive 3D-models allows the user to directly visualize the morphology of the granulomas and to understand the localization of the granulomas. The 3D-models can be used for multiple purposes and provide both an educational source as a gold standard for further animal studies, human research and the development of in silico models on the topic of central nervous system tuberculosis.

The immunological architecture of granulomatous inflammation in central nervous system tuberculosis.

Of all tuberculosis (TB) cases, 1% affects the central nervous system (CNS), with a mortality rate of up to 60%. Our aim is to fill the 'key gap' in TBM research by analyzing brain specimens in a unique historical cohort of 84 patients, focusing on granuloma formation. We describe three different types: non-necrotizing, necrotizing gummatous, and necrotizing abscess type granuloma. Our hypothesis is that these different types of granuloma are developmental stages of the same pathological process. All types were present in each patient and were mainly localized in the leptomeninges. Intra-parenchymal granulomas were less abundant than the leptomeningeal ones and mainly located close to the cerebrospinal fluid (subpial and subependymal). We found that most of the intraparenchymal granulomas are an extension of leptomeningeal lesions which is the opposite of the classical Rich focus theory. We present a 3D-model to facilitate further understanding of the topographic relation of granulomas with leptomeninges, brain parenchyma and blood vessels. We describe innate and adaptive immune responses during granuloma formation including the cytokine profiles. We emphasize the presence of leptomeningeal B-cell aggregates as tertiary lymphoid structures. Our study forms a basis for further research in neuroinflammation and infectious diseases of the CNS, especially TB.