ypical presentations of sarcoidosis permit ready diagnosis in a substantial proportion of individuals with this disease; however, the diagnosis is often rendered difficult by unusual clinical manifestations or diagnostic mimics, which can be organ specific. This difficulty is particularly evident in neurosarcoidosis (NS). 1 Despite numerous publications on NS, no consensus definition of the entity exists and no consensus perspective addresses the prerequisites for establishing a diagnosis. Development of criteria for diagnosis is essential for the design of clinical trials for NS and is valuable to the patient and clinician. A consortium of physicians with expertise in NS has developed consensus criteria for the diagnosis of NS. Because sarcoidosis can affect the central nervous system (CNS) and peripheral nervous system (PNS), occasionally in the absence of other organ involvement, we propose harmonized diagnostic criteria for both the CNS and PNS. MethodsThe Neurosarcoidosis Consortium Consensus Group consisted of 14 members: 10 neurologists and 4 pulmonologists. The group met 5 times in person and conducted additional work via electronic communication. The group started with the premise that a need existed for consensus diagnostic criteria for NS to improve clinical care and support research. The group agreed that diagnostic labels about NS should be based on level of certainty and provide specific guid-IMPORTANCE The Neurosarcoidosis Consortium Consensus Group, an expert panel of physicians experienced in the management of patients with sarcoidosis and neurosarcoidosis, engaged in an iterative process to define neurosarcoidosis and develop a practical diagnostic approach to patients with suspected neurosarcoidosis. This panel aimed to develop a consensus clinical definition of neurosarcoidosis to enhance the clinical care of patients with suspected neurosarcoidosis and to encourage standardization of research initiatives that address this disease.OBSERVATIONS The work of this collaboration included a review of the manifestations of neurosarcoidosis and the establishment of an approach to the diagnosis of this disorder. The proposed consensus diagnostic criteria, which reflect current knowledge, provide definitions for possible, probable, and definite central and peripheral nervous system sarcoidosis. The definitions emphasize the need to evaluate patients with findings suggestive of neurosarcoidosis for alternate causal factors, including infection and malignant neoplasm. Also emphasized is the need for biopsy, whenever feasible and advisable according to clinical context and affected anatomy, of nonneural tissue to document the presence of systemic sarcoidosis and support a diagnosis of probable neurosarcoidosis or of neural tissue to support a diagnosis of definite neurosarcoidosis.CONCLUSIONS AND RELEVANCE Diverse disease presentations and lack of specificity of relevant diagnostic tests contribute to diagnostic uncertainty. This uncertainty is compounded by the absence of a pathognomonic histologic tissue...

To date, the most effective treatment of HIV-1 is a combination antiretroviral therapy (cART), which reduces viral replication and reverses pathology. We investigated the effect of cART (RT and protease inhibitors) on the content of extracellular vesicles (EVs) released from HIV-1-infected cells. We have previously shown that EVs contain non-coding HIV-1 RNA, which can elicit responses in recipient cells. In this manuscript, we show that TAR RNA levels demonstrate little change with the addition of cART treatment in cell lines, primary macrophages, and patient biofluids. We determined possible mechanisms involved in the selective packaging of HIV-1 RNA into EVs, specifically an increase in EV-associated hnRNP A2/B1. More recent experiments have shown that several other FDA-approved drugs have the ability to alter the content of exosomes released from HIV-1-infected cells. These findings on cART-altered EV content can also be applied to general viral inhibitors (interferons) which are used to treat other chronic infections. Additionally, we describe unique mechanisms of ESCRT pathway manipulation by antivirals, specifically the targeting of VPS4. Collectively, these data imply that, despite antiretroviral therapy, EVs containing viral products are continually released and may cause neurocognitive and immunological dysfunction.

Background and Purpose Perform an investigation of the frequency and distribution of leptomeningeal enhancement on post-gadolinium magnetization-prepared FLAIR (MPFLAIR) in multiple sclerosis (MS) on 7 Tesla (7T) MRI and to relate this finding to measures of brain structure and lesion volumes. Methods Twenty-nine participants with MS underwent 7T MRI of the brain. Three healthy volunteers (HV) were scanned for comparison. Areas of post-contrast leptomeningeal enhancement were identified. Images were segmented for brain structure and lesion volumes. The relationship between leptomeningeal enhancement and clinical and volumetric data was explored. Results Two patterns of enhancement were found: “nodular” (discrete, spherical nodules at the pial surface or subarachnoid space) and “spread/fill” (appearance of contrast spread through the subarachnoid space). Twenty-six of 29 (90%) MS participants had at least one focus of leptomeningeal enhancement. Nodular foci were present in 15/29 (51%) MS participants. Spread/fill foci were present in 22/29 (76%) MS participants. Two HVs had examples of nodular foci, but none had spread/fill enhancement. MS participants with spread/fill foci were older (48.9 years (SD 8.3)) than those without (33.3 years (SD 11.5), p = 0.005). MS participants with spread/fill foci had reduced cortical gray matter volume compared to those without (p = 0.020). Conclusions Leptomeningeal enhancement on post-contrast 7T MPFLAIR is more prevalent than prior reports at 3T – occurring at frequencies closer to histopathologic data. Spread/fill foci are associated with reduced cortical GM volumes and may represent blood-meningeal barrier breakdown near sites of meningeal inflammation, whereas nodular foci may be a normal variant.

Exposure to cigarette smoke has been associated with in increased risk of neurological diseases such as stroke, Alzheimer’s disease and multiple sclerosis. In these studies, serum and brain sections from Lewis rats or those exposed to cigarette smoke and control rats were examined for evidence of increased inflammation and oxidative stress. Immunocytochemical staining of brain sections from CS-exposed rats showed increased expression of class II MHC and, in ELISA, levels of IFN-gamma and TNF-α were higher than for non-exposed rats. In polymerase chain reaction assays there was increased interferon-gamma, TNF-α, IL-1α, IL-1β, IL-23, IL-6, IL-23, IL-17, IL-10, TGF-β, T-bet and FoxP3 gene expression with CS exposure. There was also markedly elevated MIP-1α/CCL3, less prominent MCP-1/CCL2 and no elevation of SDF-1α gene expression. Analysis of samples from CS-exposed and control rats for anti-oxidant expression showed no significant difference in serum levels of glutathione and, in brain, similar levels of superoxide dismutase and decreased thioredoxin gene expression. In contrast, there was increased brain gene expression for the pro-oxidants iNOS and the NADPH components NOX4, dual oxidase 1 and p22phox. Nrf2 expression, which is typically triggered as a secondary response to oxidative stress, was also increased in brains from CS-exposed rats with nuclear translocation of this protein from cytoplasm demonstrated in astrocytes in association with increased expression of the aryl hydrocarbon receptor gene, a Nrf2 target. These studies, therefore, demonstrate that CS exposure in these animals can trigger multiple immune and oxidative responses that may be have important roles in the pathogenesis of CNS inflammatory neurological diseases.