Inflammatory Cerebrospinal Fluid Research Articles

Acute encephalopathy with elevated CSF inflammatory markers as the initial presentation of COVID-19

BackgroundCOVID-19 is caused by the severe acute respiratory syndrome virus SARS-CoV-2. It is widely recognized as a respiratory pathogen, but neurologic complications can be the presenting manifestation in a subset of infected patients.Case presentationWe describe a 78-year old immunocompromised woman who presented with altered mental status after witnessed seizure-like activity at home. She was found to have SARS-CoV-2 infection and associated neuroinflammation. In this case, we undertake the first detailed analysis of cerebrospinal fluid (CSF) cytokines during COVID-19 infection and find a unique pattern of inflammation in CSF, but no evidence of viral neuroinvasion.ConclusionOur findings suggest that neurologic symptoms such as encephalopathy and seizures may be the initial presentation of COVID-19. Central nervous system inflammation may associate with neurologic manifestations of disease.

Searching for autoimmune encephalitis: Beware of normal CSF

ObjectiveTo determine the prevalence of cerebrospinal fluid (CSF) markers associated with inflammation (i.e., elevated white blood cell count, protein concentration, and CSF-specific oligoclonal bands) in patients with early active autoimmune encephalitis (AE). MethodsCSF characteristics, including WBC count, protein concentration, and oligoclonal banding, were analyzed in patients diagnosed with AE at two tertiary care centers. ResultsNinety-five patients were included in the study. CSF white blood cell counts and protein levels were within normal limits for 27% (CI95%: 19–37) of patients with AE. When results of oligoclonal banding were added, 14% (CI95%: 6–16) of patients with AE had “normal” CSF. The median CSF white blood cell count was 8 cells/mm3 (range: 0–544) and the median CSF protein concentration was 0.42 g/L (range: 0.15–3.92). ConclusionsWhite blood cell counts and protein levels were within normal limits in the CSF of a substantial proportion of patients with early active AE. Inclusion of CSF oligoclonal banding identified a higher proportion of patients with an inflammatory CSF profile, especially when CSF was sampled early in the disease process.

Glial fibrillary acidic protein (GFAP) associated autoimmune meningoencephalitis in a patient receiving nivolumab

Immune checkpoint inhibitors (ICIs) represent a major development in cancer treatment, allowing for improved survival and disease control in an expanding number of cancer types. Due to their mechanism of disrupting immunologic homeostasis, ICIs are frequently associated with adverse effects, termed immune related adverse effects (irAE). These side effects can affect any organ system, including the central and peripheral nervous systems.We present a case of a 47 year old man with stage IIIc metastatic melanoma who received 3 cycles of nivolumab (a monoclonal antibody inhibitor of programmed cell death protein 1 (PD-1)). After completing the third cycle, he presented with a meningoencephalitis clinical picture with an inflammatory cerebrospinal fluid (CSF) and normal MRI. He was found to have a positive anti-glial fibrillary acidic protein (GFAP) autoantibody in his CSF by immunofluorescent assay (IFA) and cell based assay (CBA) which confirmed a diagnosis of anti-GFAP autoimmune encephalitis. He was treated with immunotherapy and made a full recovery. In this report, we present the first reported case of anti-GFAP autoimmune encephalitis associated with ICI therapy and provide a brief review of the literature.

A Novel Highly Sensitive Method for Measuring Inflammatory Neural-Derived APC Activity in Glial Cell Lines, Mouse Brain and Human CSF.

Background: Neural inflammation is linked to coagulation. Low levels of thrombin have a neuroprotective effect, mediated by activated protein C (APC). We describe a sensitive novel method for the measurement of APC activity at the low concentrations found in neural tissue. Methods: APC activity was measured using a fluorogenic substrate, Pyr-Pro-Arg-AMC, cleaved preferentially by APC. Selectivity was assessed using specific inhibitors and activators. APC levels were measured in human plasma, in glia cell lines, in mice brain slices following mild traumatic brain injury (mTBI) and systemic lipopolysaccharide (LPS) injection, and in cerebrospinal fluid (CSF) taken from viral meningoencephalitis patients and controls. Results: Selectivity required apixaban and alpha-naphthylsulphonylglycyl-4-amidinophenylalanine piperidine (NAPAP). APC levels were easily measurable in plasma and were significantly increased by Protac and CaCl2. APC activity was significantly higher in the microglial compared to astrocytic cell line and specifically lowered by LPS. Brain APC levels were higher in posterior regions and increased by mTBI and LPS. Highly elevated APC activity was measured in viral meningoencephalitis patients CSF. Conclusions: This method is selective and sensitive for the measurement of APC activity that significantly changes during inflammation in cell lines, animal models and human CSF.

Cerebrospinal fluid challenges for the diagnosis of herpes simplex infection in the central nervous system.

The aim of the present study was to adapt a commercial kit anti-HSV IgG used for serum samples to be performed with a CSF sample. Forty CSF specimens from 38 patients with suspected CNS HSV infection were serially diluted for detecting anti-HSV IgG by enzyme immunoassay (EIA). The same samples were also analyzed with the polymerase chain reaction (PCR). The sensitivity of EIA test for HSV was 5% (dilution 1:40) and 65% (dilution 1:2) in CSF, and HSV DNA PCR was 15%. The combined analysis of EIA (dilution 1:2) and PCR increased the sensitivity up to 72.5%. The inflammatory CSF was associated with positive HSV PCR. We demonstrated the importance to adapt serological anti-HSV IgG EIA test for CSF assays to increase the accuracy of the analysis, considering the low concentration of specific antibodies in CSF.

Oligoclonal IgG antibodies in multiple sclerosis target patient-specific peptides.

IgG oligoclonal bands (OCBs) are present in the cerebrospinal fluid (CSF) of more than 95% of patients with multiple sclerosis (MS), and are considered to be the immunological hallmark of disease. However, the target specificities of the IgG in MS OCBs have remained undiscovered. Nevertheless, evidence that OCBs are associated with increased levels of disease activity and disability support their probable pathological role in MS. We investigated the antigen specificity of individual MS CSF IgG from 20 OCB-positive patients and identified 40 unique peptides by panning phage-displayed random peptide libraries. Utilizing our unique techniques of phage-mediated real-time Immuno-PCR and phage-probed isoelectric focusing immunoblots, we demonstrated that these peptides were targeted by intrathecal oligoclonal IgG antibodies of IgG1 and IgG3 subclasses. In addition, we showed that these peptides represent epitopes sharing sequence homologies with proteins of viral origin, and proteins involved in cell stress, apoptosis, and inflammatory processes. Although homologous peptides were found within individual patients, no shared peptide sequences were found among any of the 42 MS and 13 inflammatory CSF control specimens. The distinct sets of oligoclonal IgG-reactive peptides identified by individual MS CSF suggest that the elevated intrathecal antibodies may target patient-specific antigens.

Novel Surrogate Markers of CNS Inflammation in CSF in the Diagnosis of Autoimmune Encephalitis.

Background: Autoimmune encephalitis (AE) is an important cause of refractory epilepsy, rapidly progressive cognitive decline, and unexplained movement disorders in adults. Whilst there is identification of an increasing number of associated autoantibodies, patients remain with a high clinical probability of autoimmune encephalitis but no associated characterized autoantibody. These patients represent a diagnostic and treatment dilemma.Objective: To evaluate routine and novel diagnostic tests of cerebrospinal fluid (CSF) in patients with a high probability of AE to attempt to identify better biomarkers of neuroinflammation.Methods: Over 18 months (2016–2018), adult patients with a high clinical probability of AE were recruited for a pilot cross-sectional explorative study. We also included viral polymerase-chain-reaction (PCR) positive CSF samples and CSF from neurology patients with “non-inflammatory” (NI) diagnoses for comparison. CSF was examined with standard investigations for encephalitis and novel markers (CSF light chains, and cytokines).Results and Conclusions: Thirty-two AE patients were recruited over 18 months. Twenty-one viral controls, 10 NI controls, and five other autoimmune neurological disease controls (AOND) were also included in the analysis. Our study found that conventional markers: presence of CSF monocytosis, oligoclonal bands, anti-neuronal immunofluorescence, and magnetic resonance imaging (MRI) changes could be suggestive of AE, but these investigations were neither sensitive nor specific. Promising novel makers of autoimmune encephalitis were the CSF cytokines IL-21 and IP10 which may provide better delineation between viral infections and autoimmune encephalitis than conventional markers, potentially leading to more immediate diagnosis and management of these patients.

Clinicopathological characteristics of histiocytic sarcoma affecting the central nervous system in dogs.

BackgroundHistiocytic sarcoma affecting the central nervous system (CNS HS) in dogs may present as primary or disseminated disease, often characterized by inflammation. Prognosis is poor, and imaging differentiation from other CNS tumors can be problematic.ObjectiveTo characterize the clinicopathological inflammatory features, breed predisposition, and survival in dogs with CNS HS.AnimalsOne hundred two dogs with HS, 62 dogs with meningioma.MethodsRetrospective case series. Records were reviewed for results of cerebrospinal fluid (CSF) analysis, CBC, treatment, and outcome data.ResultsPredisposition for CNS HS was seen in Bernese Mountain Dogs, Golden Retrievers, Rottweilers, Corgis, and Shetland Sheepdogs (P ≤ .001). Corgis and Shetland Sheepdogs had predominantly primary tumors; Rottweilers had exclusively disseminated tumors. Marked CSF inflammation was characteristic of primary rather than disseminated HS, and neoplastic cells were detected in CSF of 52% of affected dogs. Increased neutrophil to lymphocyte ratios were seen in all groups relative to controls (P <.008) but not among tumor subtypes. Definitive versus palliative treatment resulted in improved survival times (P < .001), but overall prognosis was poor.Conclusions and Clinical ImportanceClinicopathological differences between primary and disseminated HS suggest that tumor biological behavior and origin may be different. Corgis and Shetland Sheepdogs are predisposed to primary CNS HS, characterized by inflammatory CSF. High total nucleated cell count and the presence of neoplastic cells support the use of CSF analysis as a valuable diagnostic test. Prognosis for CNS HS is poor, but further evaluation of inflammatory mechanisms may provide novel therapeutic opportunities.

Serum Neurofilament Light Polypeptide is a Biomarker for Inflammation in Cerebrospinal Fluid Caused by Fine Particulate Matter

ABSTRACT Epidemiological and toxicological evidence indicates that fine particulate matter (PM2.5, particulate matter < 2.5 µm in aerodynamic diameter) causes cardiopulmonary toxicity; however, its neurotoxic effects remain unclear. The objective of this study was to investigate the role of the neurofilament light (NEFL) serum polypeptide in neurotoxicity. 6-month-old male Sprague Dawley (SD) rats were exposed to traffic-related PM1 (< 1 µm in aerodynamic diameter; 16.3 µg m–3) and gaseous pollutants (via high-efficiency particulate air, HEPA) for 3 and 6 months through a whole-body exposure system. According to our observations, the levels of interleukin (IL)-4, IL-10, and tumor necrosis factor (TNF)-α in the serum of the rats significantly increased (p < 0.05) after 3 months of exposure to PM1, whereas that of NEFL polypeptide significantly increased (p < 0.05) after 3 and 6 months of exposure. Additionally, increases in the IL-2, IL-6, IL-10, IL-17a, TNF-α, and interferon (IFN)-γ levels after 3 and/or 6 months of exposure to this pollutant (p < 0.05) were observed in the cerebrospinal fluid (CSF). In terms of their respective levels, the IL-6 correlated well with the CSF IL-2 and IL-10; the TNF-α correlated well with the CSF IL-6, IL-17a, TNF-α, and IFN-γ; and the NEFL polypeptide correlated well with the CSF IL-2, IL-4, IL-6, IL-10, IL-17a, TNF-α, and IFN-γ. In summary, systemic neuroinflammatory and immune responses in rats occurred after chronic exposure to PM1. Hence, NEFL polypeptide in serum may be a suitable biomarker for neurotoxicity caused by chronic exposure to this pollutant.

Intrathecal, Not Systemic Inflammation Is Correlated With Multiple Sclerosis Severity, Especially in Progressive Multiple Sclerosis.

Objective: To test the hypothesis that Multiple Sclerosis (MS) patients have increased peripheral inflammation compared to healthy donors and that this systemic activation of the immune system, reflected by acute phase reactants (APRs) measured in the blood, contributes to intrathecal inflammation, which in turn contributes to the development of disability in MS.Methods: Eight serum APRs measured in a prospectively-collected cross-sectional cohort with a total of 51 healthy donors and 291 untreated MS patients were standardized and assembled into related biomarker clusters to derive global measures of systemic inflammation. The resulting APR clusters were compared between diagnostic categories and correlated to equivalently-derived cerebrospinal fluid (CSF) biomarkers of innate and adaptive immunity. Finally, correlations were calculated between biomarkers of systemic and intrathecal inflammation and MS severity measures, which predict future rates of disability progression.Results: While two blood APR clusters were elevated in MS patients, only one exhibited a weak correlation with MS severity. All CSF inflammation clusters, except CSF albumin, correlated with at least one measure of MS severity, with biomarkers of humoral adaptive immunity exhibiting the strongest correlations, especially in Progressive MS.Conclusion: Systemic inflammation does not appear to be strongly associated with intrathecal inflammation in MS. Positive correlations between markers of intrathecal inflammation, especially of humoral immunity, with MS severity measures support a pathogenic role of intrathecal (compartmentalized) inflammation in central nervous system tissue destruction, including in Progressive MS.

Synaptic, axonal damage and inflammatory cerebrospinal fluid biomarkers in neurodegenerative dementias

IntroductionSynaptic damage, axonal neurodegeneration, and neuroinflammation are common features in Alzheimer's disease (AD), frontotemporal dementia (FTD), and Creutzfeldt-Jakob disease (CJD). MethodsUnicentric cohort of 353 participants included healthy control (HC) subjects, AD continuum stages, genetic AD and FTD, and FTD and CJD. We measured cerebrospinal fluid neurofilament light (NF-L), neurogranin (Ng), 14-3-3, and YKL-40 proteins. ResultsBiomarkers showed differences in HC subjects versus AD, FTD, and CJD. Disease groups differed between them except AD versus FTD for YKL-40. Only NF-L differed between all stages within the AD continuum. AD and FTD symptomatic mutation carriers presented differences with respect to HC subjects. Applying the AT(N) system, 96% subjects were positive for neurodegeneration if 14-3-3 was used, 94% if NF-L was used, 62% if Ng was used, and 53% if YKL-40 was used. DiscussionBiomarkers of synapse and neurodegeneration differentiate HC subjects from neurodegenerative dementias and between AD, FTD, and CJD. NF-L and 14-3-3 performed similar to total tau when AT(N) system was applied.

1717. Cryptococcal Meningitis: A Comparison of Clinical Features and Outcomes by HIV Status

BackgroundCryptococcal meningitis is an opportunistic fungal infection associated with HIV and other forms of immunosuppression. We lack a clear understanding of cryptococcal meningitis (CM) among HIV-negative patients in the United States. Our aim was to compare clinical features and outcomes across HIV status in patients with laboratory-confirmed cryptococcal meningitis.MethodsWe conducted a retrospective cohort study of patients with laboratory-confirmed (positive culture or antigen test) cryptococcal disease treated at a tertiary care center from January 2000 to September 2018. Patients were identified via local laboratory and TrinetX datasets. Data were gathered on demographics, HIV status, site of infection, clinical presentation, cerebrospinal fluid (CSF) profiles, hospital course, and mortality. Organ transplant recipients and/or non-meningeal infections were excluded.ResultsSeventy patients with cryptococcal disease were identified. Our final sample included 36 CM patients with a mean age of 48.8 ± 13.2 years; 66.7% (n = 24) had HIV. Median (IQR) absolute CD4 count for the HIV group was 35/μL (10–80/μL). Non-HIV patients were significantly older (P < 0.001) and had higher rates of altered mental status (AMS) on presentation (58.3% vs. 25%, P = 0.05). There was no significant variation in temperature, blood pressure, white blood cell count, serum sodium, or CSF opening pressure. Non-HIV patients had significantly higher CSF cell count (P = 0.02) and protein (P < 0.001), and lower glucose (P = 0.005) compared with HIV patients. There was no significant variation in length of stay or rates of intensive care unit admission. Overall, 90-day all-cause mortality was 19.4%: mortality rates were significantly higher in non-HIV patients at both 90 days (P = 0.017) and one year (P = 0.047).ConclusionCompared with individuals with HIV, non-HIV cryptococcal meningitis patients have a more inflammatory CSF profile at the time of diagnosis, higher rates of AMS on presentation, and higher rates of 90-day and 1-year all-cause mortality. We postulate that reversible immunosuppression among HIV patients may partially explain these findings. Further research is needed to identify hallmarks of cryptococcal meningitis in non-HIV patients to facilitate early intervention. Disclosures All authors: No reported disclosures.

Blood and cerebrospinal fluid characteristics in neonates with a suspected central nervous system infection.

Clinical signs and symptoms of central nervous system (CNS) infections in neonates are often nonspecific. Therefore, cerebrospinal fluid (CSF) analysis is performed to diagnose CNS infections. Data on combined microbiological results and their correlation with biochemical characteristics in CSF and blood in infants younger than 90 days are limited. This study provides an overview of microbiological test results, CSF- and hematological characteristics among infants with a clinically suspected CNS infection.This retrospective study included infants younger than 90 days, with a clinically suspected CNS infection who underwent a diagnostic lumbar puncture between January 2012 and January 2014. Data on the presence of microbiological pathogens in CSF, CSF inflammation markers (white blood cell [WBC] counts, protein levels and glucose CSF/serum ratio) and blood inflammatory responses (WBC count, C-reactive protein [CRP], neutrophil percentage) were collected by reviewing patient files.We included data from 576 infants (median age 12.5 days, interquartile range, 6-27 days) of whom 383 (66.5%) were born prematurely. In total, 16 bacterial pathogens (3.0%) and 21 viruses (5.5%) were detected in CSF. Escherichia coli was detected in 5 cases (1.0%), Enterovirus was detected in 12 cases (3.1%). Leucocytosis in CSF was associated with identification of a pathogen in CSF. Increased CRP was associated with the identification of a bacterial pathogen in CSF.Bacterial or viral pathogens were only identified in a small proportion of infants with a clinically suspected CNS infection. Leucocytosis in CSF was associated with CNS infection in infants. An increased CRP was indicative of bacterial meningitis.

8.1 CSF PATHOLOGY INCLUDING BLOOD-BRAIN BARRIER DYSFUNCTION IN PSYCHOSIS AND THE POTENTIAL EFFICACY OF ANTI-INFLAMMATORY TREATMENTS – FROM REGISTER STUDIES TO META-ANALYSIS

Utilizing the nationwide Danish registers, we have shown dose-response associations between infections and general medical diseases involving inflammatory processes, such as autoimmune diseases, with the development of psychosis. In people with autoimmune diseases, infections further increased the risk, potentially due to affecting the Blood-Brain Barrier, making the brain more vulnerable to the potential detrimental effects of the autoantibodies. Hence, particularly the group of autoimmune diseases with suspected presence of brain-reactive antibodies had a further increased risk of psychosis if experiencing severe infections. The results are based on data from 1) nationwide register studies on all individuals living in Denmark after 1969, 2) a Danish population-based sample of over 80.000 individuals born after 1981 with GWAS analyses and linked to the nationwide registers, 3) systematic reviews and meta-analysis on all CSF studies conducted on psychosis and on all placebo controlled RCT’s investigating anti-inflammatory treatment response of psychosis. Conducting the first systematic review of all available studies on cerebrospinal fluid (CSF) immune alterations, we showed that the CSF/serum albumin ratio was increased in schizophrenia, compared to healthy controls, indicating Blood-Brain Barrier dysfunction. Moreover, total CSF protein and the IgG ratio was increased in schizophrenia, whereas the IgG Albumin ratio was decreased. In the CSF of people with schizophrenia there were increased levels of Interleukin-6 and IL-8 levels, compared to healthy controls. The levels of IL-6 were particularly increased during acute psychotic episodes. In the two studies investigating how often the analyzes of CSF resulted in re-diagnosis, CSF dependent re-diagnosis occurred in 3.2–6% of cases. Moreover, results from register information on specific CSF infections and associations with psychosis and mental disorders in general will be presented, including the effect on measures of cognition. Furthermore, immunogenetic and genetic findings regarding genes related to the Blood-Brain Barrier and the impact of environmental exposures on the associations with psychosis and mental disorders in general from a population-based cohort of over 80.000 Danish individuals will be presented at the session. Lastly, results on the efficacy of anti-inflammatory treatment in addition to antipsychotics will be presented based on an updated meta-analysis of all trials conducted, including associations with the ability to pass the Blood-Brain Barrier of the anti-inflammatory medication. In conclusion, current findings suggest that psychotic disorders may have CSF abnormalities including signs of blood-brain barrier impairment and inflammation. However, the available evidence does not yet allow any firm conclusion due to the lack of unbiased CSF studies and high sensitive imaging studies of the Blood-Brain Barrier during psychotic episodes. High-quality longitudinal CSF studies are indeed lacking, including impact of psychotropic medications, lifestyle factors and potential benefits of anti-inflammatory treatment in subgroups with signs of CSF inflammation.

Modification of CSF findings in multiple sclerosis in the era of rapidly expanding treatment options

ABSTRACTBackground: The detection of cerebrospinal fluid (CSF)-specific oligoclonal bands (OCB) as well as an elevated antibody production directed against neurotrophic viruses remain hallmark findings in multiple sclerosis (MS). In general, individual patients show a unique pattern of OCB, which is believed to persist over time. Here, the authors revisited this assumption and investigated to what extent common anti-inflammatory MS medications can alter the level of immunoglobulins produced within the CSF.Methods: The authors analyzed three patients and compared CSF findings longitudinally. Two of these patients received corticosteroids, either systemically or intrathecally, the third patient was treated continuously with natalizumab.Results: In line with reports from other groups, the authors observed that continuous natalizumab treatment dampened the intrathecal immunoglobulin production in our patient. Exceeding this anticipated scenario, the authors detected that the continued administration of corticosteroids similarly reduced the production of CSF immunoglobulins, down to a level at which these parameters are considered normal.Conclusion: These observations suggest that inflammatory CSF findings are more accessible to immunomodulatory MS treatment than previously thought, and that accordingly, their significance may transition from a sole diagnostic finding to a valuable therapeutic biomarker which may help to assess effective targeting of CNS-established inflammation in MS.

Mass spectrometry-based analysis of cerebrospinal fluid from arthritis patients\u2014immune-related candidate proteins affected by TNF blocking treatment

BackgroundSigns of inflammation in cerebrospinal fluid (CSF) of rheumatoid arthritis patients correlate positively with fatigue, a central nervous system (CNS)-related symptom that can be partially suppressed by TNF blockade. This suggests a possible role for CNS inflammation in arthritis that may be affected by TNF blockade. We therefore investigated the effects of TNF blockade on the arthritis CSF proteome and how candidate proteins related to clinical measures of disease activity and inflammation.MethodsMass spectrometry-based quantitative proteomic analysis was performed on CSF from seven polyarthritis patients before and during infliximab treatment. Treatment-associated proteins were identified using univariate (Wilcoxon signed rank test) and multivariate (partial least squares discriminant analysis (PLS-DA)) strategies. Relations between selected candidate proteins and clinical measures were investigated using the Spearman correlations. Additionally, selected proteins were cross-referenced to other studies investigating human CSF in a thorough literature search to ensure feasibility of our results.ResultsUnivariate analysis of arthritis CSF proteome revealed a decrease of 35 proteins, predominantly involved in inflammatory processes, following TNF blockade. Seven candidate proteins, Contactin-1 (CNTN1), fibrinogen gamma chain (FGG), hemopexin (HPX), cell adhesion molecule-3 (CADM3), alpha-1B-glycoprotein (A1BG), complement factor B (CFB), and beta-2-microglobulin (B2M), were selected for further studies based on identification by both univariate and multivariate analyses and reported detection in human CSF and known associations to arthritis. Decreased levels of FGG and CFB in CSF after treatment showed strong correlations with both erythrocyte sedimentation rate and disability scores, while CNTN1 and CADM3 were associated with pain.ConclusionSeveral immune-related proteins in the CSF of arthritis patients decreased during TNF blockade, including FGG and CFB that both correlated strongly with systemic inflammation. Our findings stress that also intrathecal inflammatory pathways are related to arthritis symptoms and may be affected by TNF blockade.

Importance of cerebrospinal fluid investigation during dengue infection in Brazilian Amazonia Region.

BACKGROUND Amazon, the largest tropical forest of the world, has suffered from dengue outbreaks since 1998. Cerebrospinal fluid (CSF) of patients, from Amazonas state, suspected of central nervous system (CNS) viral infection was studied using molecular and immunological methods. OBJECTIVE To evaluate the importance of CSF investigation in patients with acute dengue virus (DENV) infection of CNS. METHODS CSF samples of 700 patients were analysed by reverse transcription polymerase chain reaction (RT-PCR) to detect the presence of dengue virus (DENV) RNA and by enzyme-linked immunosorbent assay (ELISA) to detect presence of DENV specific IgM. FINDINGS DENV infection was detected in 4.3% of the CSF samples; 85.7% (24/28) by DENV IgM and 14.3% (4/28) by viral RNA. DENV detected by viral RNA were to be found serotypes DENV-2 (three patients) and DENV-1 (one patient). The neurological diagnosis in patients CNS infection of DENV included encephalitis (10), meningoencephalitis (10), meningitis (6), acute myelitis (1), and encephalomyelitis (1). The majority (89.3%) had intrathecal inflammation: pleocytosis, hyperproteinorrachia and DENV IgM antibodies. Hypoglycorrhachia and/or high levels of lactate in CSF were found in 36% of the patients. Co-infection (CMV, HIV, EBV, and/or Mycobacterium tuberculosis) was observed in eight (28.6%) cases. CONCLUSIONS We found intense inflammatory CSF that is unusual in CNS disorders caused by dengue infection. It may be due co-infections or the immunogenetic background of the local Amerindian Brazilian population. CSF examination is an important diagnostic support tool for neurological dengue diagnosis.

Pretreatment Cerebrospinal Fluid Bacterial Load Correlates With Inflammatory Response and Predicts Neurological Events During Tuberculous Meningitis Treatment.

The Mycobacterium tuberculosis load in the brain of individuals with tuberculous meningitis (TBM) may reflect the host's ability to control the pathogen, determine disease severity, and determine treatment outcomes. We used the GeneXpert assay to measure the pretreatment M. tuberculosis load in cerebrospinal fluid (CSF) specimens from 692 adults with TBM. We sought to understand the relationship between CSF bacterial load and inflammation, and their respective impact on disease severity and treatment outcomes. A 10-fold higher M. tuberculosis load was associated with increased disease severity (odds ratio, 1.59; P = .001 for the comparison between grade 1 and grade 3 severity), CSF neutrophil count (r = 0.364 and P < .0001), and cytokine concentrations (r = 0.438 and P < .0001). A high M. tuberculosis load predicted new neurological events after starting treatment (P = .005, by multinomial logistic regression) but not death. Patients who died had an attenuated inflammatory response at the start of treatment, with reduced cytokine concentrations as compared to survivors. In contrast, patients with high pretreatment CSF bacterial loads, cytokine concentrations, and neutrophil counts were more likely to subsequently experience neurological events. The pretreatment GeneXpert-determined M. tuberculosis load may be a useful predictor of neurological complications occurring during TBM treatment. Given the evidence for the divergent pathogenesis of TBM-associated neurological complications and deaths, therapeutic strategies to reduce them may need reassessment.

Critical Care Management of Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

Anti-N-methyl-D-aspartate receptor encephalitis is considered an immune-mediated form of encephalitis with paraneoplastic and nonparaneoplastic forms. Delay in recognition is common and patients typically present to the ICU without a diagnosis or with complications following a delayed diagnosis. The aim of this review is to provide a focused overview for the ICU clinician regarding presentation, diagnosis, and critical care management. PubMed database search with manual review of articles involving anti-N-methyl-D-aspartate receptor encephalitis. Anti-N-methyl-D-aspartate receptor encephalitis is increasingly encountered in the ICU. The cascade of events initiating anti-N-methyl-D-aspartate receptor antibody formation may involve an infectious trigger particularly in the setting of teratoma. Following a prodrome, most patients develop psychiatric symptoms followed by movement disorder. Classical, psychiatric, and catatonic phenotypes may be distinguished based on the presence and severity of symptoms. Early immunotherapy and low initial cerebrospinal fluid inflammation are independent predictors of positive outcomes in ICU patients. Concomitant organ failure, status epilepticus, and the identification of a tumor did not influence outcome in critically ill patients. Supportive care in the ICU includes management of various manifestations of dyskinesia, status epilepticus, autonomic disorders, and the need for general sedation. Common treatment strategies and limitations are discussed including the emerging role of bortezomib. Intensivists should be familiar with the presentation and management of anti-N-methyl-D-aspartate receptor encephalitis. Early diagnosis and immediate implementation of steroids, immunoglobulins, and/or plasmapheresis and immune therapy are associated with a good neurologic outcome although response may be delayed. The selection and timing of second-line immune therapy requires further study.

Peripheral and cerebrospinal fluid immune activation and inflammation in chronically HIV-infected patients before and after virally suppressive combination antiretroviral therapy (cART).

Cerebrospinal fluid (CSF)/plasma HIV-RNA ratio has been associated with residual neurocognitive impairment on cART, leading us to hypothesize a specific peripheral and/or CSF immune feature in patients with high CSF/plasma ratio (≥ 1). In patients with diverse pre-cART CSF/plasma ratio (61/70 with CSF/plasma ratio < 1, L-CSF, 9/70 with CSF/plasma ratio ≥ 1, H-CSF), we investigated the effects of 12months of effective cART on peripheral and CSF inflammatory markers, on T cell activation/maturation and HIV/CMV-specific intracellular cytokine pattern. We also studied the possible clinical association between peripheral/CSF pro-inflammatory milieu and neurocognitive screening tests (MMSE, FAB, IHDS). Prior to cART, the two groups were comparable for peripheral and CSF inflammation, T cell activation/proliferation and maturation, and HIV/CMV-specific response. Upon cART initiation, both H-CSF and L-CSF featured a significant reduction in plasma TNF-α and circulating CD8 activation, with a redistribution of memory/naïve T cell subsets in L-CSF alone. In the CSF compartment, cART seemed able to reduce pro-inflammatory cytokine/chemokine levels in both H-CSF and L-CSF patients. Interestingly, despite a reduction in the pro-inflammatory milieu, no changes were shown in neurocognitive screening tests in both patients' groups. We hereby show that 12-month cART is able to reduce intratechal and peripheral pro-inflammatory burden; a longer cART exposure and a more comprehensive neuropsychological evaluation might be necessary to gain a broader insight into the possible effects on neurocognitive performance.