Human Parechovirus and Enterovirus Initiate Divergent Innate Immune Responses in the CNS: Pathogenic and Diagnostic Implications

The picornaviruses human parechovirus (HPeV) and enterovirus (EV) cause a wide range of diseases, including CNS infections, which can be severe and potentially fatal. EV causes most cases of pediatric meningoencephalitis worldwide, and HPeV type 3 (HPeV3) is the most common cause of viral meningitis in young infants. Each year in the United States, there are over 75,000 cases of aseptic meningitis. Despite reassuring short-term outcomes, negative neurodevelopmental sequalae are increasingly associated with HPeV and EV. The pathogenesis and severity of HPeV and EV infections are undoubtedly linked to the innate and adaptive immune responses elicited by these viruses. Until this work, the innate immune response mounted against HPeV was largely unknown. Pattern recognition receptors in the CNS, including a number of Toll-like receptors located in different cells and subcellular compartments, detect invading pathogens and cause the release of cytokines and chemokines almost immediately into the CSF compartment at measurable levels. Essentially, this allows for determination of an amplified, infectious agent-specific pattern. These virus specific patterns of innate immune activation may provide insight into the pathogenesis of the corresponding disease states. Also, since these infections have similar clinical presentations, the immune profiles may be useful for rapid pathogen diagnosis in the clinical setting

Dynamic Duo: Glioblastoma and IDH-1

Presentation: 20:2

ATRX mutation in Pineal Parenchymal Tumor of Intermediate Differentiation

Objectives Based on our identification of an ATRX mutation in a PPTID of a 22 year old female, we analyzed the frequency of ATRX loss in pineal parenchymal tumors using ATRX immunohistochemical staining.https://jdc.jefferson.edu/pacbposters/1013/thumbnail.jp

Quantification of CSF chemokines and cytokines allows for rapid laboratory detection of CNS infections and further discrimination between viral and non-viral pathogens

Background: Prompt diagnosis of central nervous system (CNS) disease is critical to guide intervention and appropriate therapy. Development of novel laboratory approaches to rapidly classify acute-onset CNS disease is in great demand. Serious microbial pathogens, especially viruses, are quickly expanding beyond their historic geographic range and may not even be considered in the clinician’s differential diagnosis. Unlike bacterial cultures, current viral testing targets a limited number of viruses. Additionally, despite diversity in etiology, signs and symptoms of both infectious and non-infectious CNS disorders can be remarkably similar, which can confuse the clinical picture and delay treatment. Bacterial, viral, fungal and protozoan CNS pathogens are sensed by pattern recognition receptors of the immune system, stimulating immediate release of measurable levels of chemokines and cytokines into the CSF. Our objective is to use pathogen-specific chemokine/ cytokine profiles to classify CNS disease as infectious versus non-infectious and further discriminate between viral and non-viral infections. Methods: Levels (pg/ml) of chemokines and cytokines were determined in the CSF of 45 patients with documented infectious meningitis or meningoencephalitis (mean age 19.2 years) and in the CSF of 25 patients who were negative for CNS infection (mean age 27.4 years). MILLIPLEX MAP Human Cytokine/Chemokine Magnetic Bead Panels (Millipore) were used to measure CSF chemokines and cytokines levels (pg/ml). Innate immune analytes quantified included IP-10 (CXCL10), IFNg, IL-15, MDC (CCL22), MCP-1 (CCL2), Fractalkine, and FLT3L. Samples were analyzed in duplicate by a FlexMAP 3D (Luminex). Standard curves were generated for each cytokine and median fluorescent intensities were transformed into concentrations by 5-point, non-linear regression. For univariate analysis, comparisons between groups were made using the Mann-Whitney test. We utilized receiver operating characteristic (ROC) curve analysis to calculate areas under the ROC curve (AUC) for each analyte to access the utility of chemokine/cytokine levels as discriminating tests. The ROC generated sensitivity and specificity values were then used to determine clinically optimal cutoff values for the informative analytes. Results: Univariate analysis utilizing Mann-Whitney tests demonstrated that median values (pg/ml) of IP-10 (CXCL10), IFNg, IL-15, MDC (CCL22), MDC (CCL22), MCP-1 (CCL2), Fractalkine, and FLT3L were all significantly higher in CSF from patients with infectious brain disorders than in CSF from patients with non-infectious disorders (p-value \u3c 0.05). MDC (CCL22) demonstrated statistical significance, when comparing viral infections versus non-viral infections (with the non-viral infection group having higher analyte levels). IP10 (CXCL10) can reliably distinguish between an infectious versus non-infectious CNS process (AUC 0.9778) with an optimal cut-off value of 2023 pg/ml (sensitivity, specificity; 93.0%, 92.0%). In the infectious group, MDC (CCL22) can reliably differentiate between viral and non-viral CNS infection (AUC 0.9545) with an optimal cut-off value of 194 pg/ml (sensitivity, specificity; 91.67%, 87.88%). Conclusion: CSF levels (pg/ml) of IP-10 (CXCL10) can reliably distinguish infectious versus noninfectious CNS disorders, and in the infectious group, MDC (CCL22) can reliably distinguish between viral and non-viral CNS infections. These results suggest that CSF chemokine/cytokine quantification can serve as a useful laboratory tool for the rapid triage of CNS diseases to help guide prompt therapy and further testing

Two Cases of Spinal, Extraosseous, Intradural Ewing\u27s sarcoma/Peripheral Neuroectodermal Tumor: Radiologic, Pathologic, and Molecular Analysis.

Extraosseous Ewing\u27s sarcoma/peripheral neuroectodermal tumors (ES/PNETs) are rare neoplasms that account for approximately 10%-15% of soft tissue sarcomas in children and 5% of soft tissue sarcomas in adults. Primary spinal, extraosseous, intradural ES/PNETs are even less common. The diagnosis of ES/PNET is extremely challenging, because the tumor can have a nonspecific radiologic appearance, and the histologic features are shared by many other small round cell tumors. Thus, ES/PNET should be included in the radiologic and pathologic differential diagnosis, even in older patients and in unusual tumor sites. We report two cases of spinal, extraosseous, intradural ES/PNETs in adults who presented with back pain. Magnetic resonance imaging revealed contrast enhancing, intradural lesions in the area of the conus medullaris. The tumor in Case 1 was partially intramedullary, while the tumor in Case 2 was exclusively extramedullary. In both cases, the radiologic and intraoperative surgical impression favored ependymoma. The diagnosis of ES/PNET was established in both cases by histopathologic, immunohistochemical, and molecular analysis

BCL2 Expression and BCL2/MYC Dual Expression Predicts Inferior Survival in Primary Central Nervous System Lymphoma

Background Primary CNS lymphoma (PCNSL) is a rare type of diffuse large B-cell lymphoma (DLBCL) arising from and usually confined to CNS. Understating of the pathogenesis and prognostic markers is a challenge due to rarity of this neoplasm and paucity of the material available to study. Recent studies have shown that dual expression of MYC and BCL2 in DLBCL contributes to inferior overall survival. The prognostic value of MYC and BCL2 in PCNSL is not well studied