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Tick-borne encephalitis virus (TBEV) is the most important tick-transmitted neurotropic flavivirus in Europe and Asia. Our analysis aimed to investigate the contribution of TBEV-specific antibody detection by serological assays and TBEV RNA detection by real-time PCR to the diagnosis of tick-borne encephalitis (TBE). We analyzed data from 3713 patients from 16 years of laboratory TBEV diagnostics in an endemic area in Southern Germany. During this period, 126 cases of TBE were diagnosed. TBEV-specific IgM ELISA tests showed a high clinical sensitivity (96.8%) and a very high clinical specificity (99.7%). In immunocompetent patients, TBE was reliably diagnosed by detection of TBEV IgM antibodies in serum. Intrathecal TBEV IgG antibody synthesis was detected in 46 of 84 (55%) cases by analysis of paired serum and cerebrospinal fluid (CSF) samples. None of the 87 immunocompetent TBE patients tested had detectable TBEV RNA in serum or CSF. In contrast, in two TBE patients without TBEV-specific antibodies, diagnosis could only be made by the detection of TBEV RNA in CSF. Both patients had previously been treated with the B cell-depleting antibody rituximab. Therefore, in patients with CNS infection and humoral immunodeficiency, it is necessary to include TBEV PCR in the diagnostic approach.

Purpose Diagnosis of (European) Lyme neuroborreliosis has been based on clinical presentation, cerebrospinal fluid (CSF) pleocytosis and demonstration of intrathecal borrelial antibody synthesis (ITBAS) to document Borrelia burgdorferi s. l. infection. It is not known if other criteria to document Borrelia infection may contribute to the diagnosis. Methods We compared the sensitivity of three individual criteria (ITBAS, CSF Borrelia culture, and the presence of erythema migrans [EM]) to confirm the diagnosis of early Lyme neuroborreliosis in 280 patients ≥ 15 years of age evaluated at a Lyme borreliosis outpatient clinic in Slovenia. The patients had either radicular pain of new onset or involvement of a cranial nerve but without radicular pain, each in conjunction with CSF pleocytosis. Evaluation was of patients who had each of the three confirmatory criteria assessed, and for whom at least one criterion was positive. Results Analysis of 280 patients, 120 women and 160 men, median age 57 (range 15–84) years, revealed that ITBAS was the most frequently observed positive criterion (85.4%), followed by EM (52.9%), and by a positive CSF Borrelia culture (9.6%). Of the 280 patients, 154 (55%) met only one criterion (43.2% ITBAS only, 10.7% EM only, and 1.1% positive CSF culture only), whereas 42.1% met two criteria. Only 2.9% of patients were positive by all three criteria. Conclusion Although ITBAS was the most frequent criterion for confirmation for Borrelia infection, the presence of EM alone confirmed an additional 10.7% of patients and a positive CSF Borrelia culture alone added another 1.1%.

ObjectivesAnalyse alternative methods of intrathecal antibody detection by comparing chemiluminescent immunoassay (CLIA) and enzyme-linked immunosorbent assay (ELISA) techniques to determine if CLIA can replace ELISA in the diagnosis of CNS infections.MethodsA panel of 280 paired samples—cerebrospinal fluid (CSF) and serum—with known antibody reactivities (Varicella, n = 60; Measles, n = 120) and negative samples (n = 100) were used to evaluate the performance of six serological test kits (Enzygnost, VirClia®, and Serion ELISA (Measles and Variella).ResultsFor Measles virus IgG, the VirClia® IgG monotest revealed 97% and 94% positive and negative agreement to the Enzygnost as reference test, respectively. In contrast, Serion ELISA kits yielded values of 18% and 90%. For the Varicella Zoster virus (VZV) IgG, the VirClia® IgG monotest showed 97% and 90% positive and negative agreement compared to Enzygnost. The Serion ELISA kits showed values of 55% and 86%, respectively. ROC analysis revealed that the areas under the curve for Measles and VZV IgGs were 0.7 and 0.852, respectively, using the Serion kit, and 0.963 and 0.955, for Vircell S.L CLIA technique. VirClia® monotest values were calculated using an antibody index cut-off of 1.3.ConclusionThe findings indicate that CLIA testing can improve antibody detection in CSF samples, aiding the diagnosis of infectious neurological impairments.

Background: The presence of intrathecal total IgG production is a hallmark of cerebrospinal fluid (CSF) characteristics in multiple sclerosis (MS). Herein, we systematically analyze how the intensity (instead of mere presence) of intrathecal total IgG production relates to basic CSF parameters in MS. Methods: We retrospectively assessed clinical routine CSF findings from 390 therapy-naïve relapsing-remitting MS patients diagnosed according to 2017 revised McDonald criteria. The intensity of intrathecal total IgG synthesis according to Reiber’s formula was stratified and correlated to demographics, CSF white cell count (WCC), and diversity of MRZ reaction, defined as a polyspecific intrathecal production of IgG reactive against ≥2 of the 3 viruses; measles (M), rubella (R), and varicella zoster (Z) virus. Results: The higher intensity of intrathecal total IgG production significantly correlated with higher CSF WCC (Spearman’s ρ = 0.433, p < 0.001) and with the increasing presence and diversity of positive MRZ reaction (Spearman’s ρ = 0.600, p < 0.001). Female patients showed higher intensity of intrathecal total IgG production and higher prevalence of positive MRZ reaction than males. Conclusions: The intensity of intrathecal total IgG production correlates with the degree of CSF WCC and diversity of MRZ reaction in MS. As yet unidentified female sex-related factors increase the intensity and diversity of intrathecal IgG production in MS.

A multicenter molecular biomarker survey was conducted in Multiple Sclerosis (MS) centers across Central-Eastern European countries, encompassing a population of 107 million. Our aim was to provide a “snapshot” for future studies investigating the use of molecular biomarkers in MS. A self-report questionnaire was distributed via email to MS centers in seven Central-Eastern European countries (Croatia, Czech Republic, Poland, Romania, Serbia, Slovakia, and Slovenia) and to four reference centers (two in Austria, one in Germany, and one in Denmark), focusing on cerebrospinal fluid (CSF) analysis and molecular biomarkers in MS. Responding centers routinely request CSF oligoclonal band (OCB) testing in suspected MS cases, although no consensus exists on the number of CSF-restricted bands required to define OCB positivity, either within or between countries. More than half of the surveyed centers in the Czech Republic, Slovakia, Slovenia, and the reference centers request kappa free light chain (κFLC) testing in patients with suspected MS. Neurofilament light chain (NfL) is frequently used as a molecular biomarker for MS in Romania, Slovakia, and the reference centers. In summary, besides the use of CSF-specific OCB there is no consensus among the surveyed countries regarding the use of molecular biomarkers in MS.

Anti-IgLON5 disease is a rare chronic autoimmune disorder characterized by IgLON5 autoantibodies predominantly of the IgG4 subclass. Distinct pathogenic effects were described for anti-IgLON5 IgG1 and IgG4, however, with uncertain clinical relevance. IgLON5-specific IgG1-4 levels were measured in 46 sera and 20 cerebrospinal fluid (CSF) samples from 13 HLA-subtyped anti-IgLON5 disease patients (six females, seven males) using flow cytometry. Intervals between two consecutive serum or CSF samplings (31 and 10 intervals, respectively) were categorized with regard to the immunomodulatory treatment active at the end of the interval, changes of anti-IgLON5 IgG1 and IgG4 levels, and disease severity. Intrathecal anti-IgLON5 IgG4 synthesis (IS) was assessed using a quantitative method. The median age at onset was 66 years (range: 54-75), disease duration 10 years (range: 15-156 months), and follow-up 25 months (range: 0-83). IgLON5-specific IgG4 predominance was observed in 38 of 46 (83%) serum and 11 of 20 (55%) CSF samples. Anti-IgLON5 IgG4 levels prior clinical improvement in CSF but not serum were significantly lower than in those prior stable/progressive disease. Compared to IgLON5 IgG4 levels in serum, CSF levels in HLA-DRB1*10:01 carriers were significantly higher than in non-carriers. Indeed, IgLON5-specific IgG4 IS was demonstrated not only in four of five HLA-DRB1*10:01 carriers but also in one non-carrier. Immunotherapy was associated with decreased anti-IgGLON5 IgG serum levels. In CSF, lower anti-IgLON5 IgG was associated with immunosuppressive treatments used in combination, that is, corticosteroids and/or azathioprine plus intravenous immunoglobulins or rituximab. Our findings might indicate that CSF IgLON5-specific IgG4 is frequently produced intrathecally, especially in HLA-DRB1*10:01 carriers. Intrathecally produced IgG4 may be clinically relevant. While many immunotherapies reduce serum IgLON5 IgG levels, more intense immunotherapies induce clinical improvement and may be able to target intrathecally produced anti-IgLON5 IgG. Further studies need to confirm whether anti-IgLON5 IgG4 IS is a suitable prognostic and predictive biomarker in anti-IgLON5 disease.

The aim of this study was to evaluate the usefulness of IgM anti-Tick-Borne Encephalitis (anti-TBE) intrathecal synthesis in the diagnosis and prediction of the clinical course of the disease. Thirty-six patients were included in the study (patients reported symptoms such as fever, headache, fatigue, and nausea/vomiting). CRP, White Blood Cells (WBC), pleocytosis, Cerebrospinal Fluid (CSF) protein concentration, CSF albumin concentration, serum IgM, serum IgG, CSF IgM, CSF IgG, IgM Index, IgG Index, and IgG Index/IgM Index ratio were the parameters which were examined in the individuals. An analysis of correlation presented statistical significance between IgM Index and pleocytosis and protein concentration in CSF in the whole group of individuals. IgM Index and IgG Index/IgM Index ratio may be used in the prediction of severity of TBE. The most probable link between the IgM intrathecal production and severity of TBE may be a result of delayed seroconversion to IgG, and therefore not an adequate response to the virus presence.

Intrathecal immunoglobulin A (IgA) synthesis in multiple sclerosis (MS) has long earned little attention, despite a potential significance in disease pathogenesis and prognosis. The presence of IgA-positive plasma cells in MS lesions and along damaged axons suggests a role in disease pathogenesis. Available clinical evidence about a potential positive or negative prognostic role is scarce and inconclusive. Recent observations, however, highlight the migration of immune regulatory IgA-producing plasma cells from the gut to the central nervous system (CNS) in experimental autoimmune encephalitis models. A connection between intrathecal IgA synthesis and the gut–brain axis in MS was further corroborated by the discovery of gut microbiota-specific IgA+ B cells in human CNS during relapse. In this review, we summarize current evidence on the occurrence and immunopathology of intrathecal IgA synthesis in MS, explore its biological implications, and address methodological challenges regarding the detection of IgA as a major limitation and possible source of inconsistencies in clinical studies. By synthesizing these diverse lines of evidence, we highlight the importance of further research and the need for standardized detection methods to clarify the role of IgA in MS pathogenesis, disease progression, and as potential biomarker.

Tick-borne encephalitis (TBE) is an emerging vector-borne disease in Europe caused by tick-borne encephalitis virus (TBEV), which belongs to Flaviviridae. Although most of the patients quickly recover from TBE, some require further neurological and psychiatric treatment due to persistent symptoms. The aim of the study was to evaluate the usefulness of an antibodies index for predicting the course of the disease and potential persistent sequalae. Sixty-six patients (49 males and 17 females, mean age 45.97 ± 13.69 years) with TBE hospitalized in the Department of Infectious Diseases and Neuroinfections, Medical University of Bialystok, Poland, in years 2016–2019 were included to the study. TBE antibodies titer in serum and CSF samples were measured with an Anti-TBEV ELISA (IgM, IgG) EUROIMMUN test. Patients who developed persistent sequelae after TBE had significantly lower IgG intrathecal index at admission. Additionally, IgG2/IgG1was significantly higher in patients who developed sequelae. IgG intrathecal index might be a useful tool for the prediction of TBE sequelae development.

Background Rituximab, a monoclonal antibody against the B-cell-specific surface protein CD20, is being evaluated for treatment of multiple sclerosis and neuromyelitis optica. Both diseases are restricted to the brain and cerebrospinal fluid (CSF). Whereas the ability of rituximab to deplete B cells in peripheral blood and tissue is well known, little information is available about the ability of rituximab to penetrate the barriers separating brain and CSF from the serum compartment. Objective To measure rituximab levels in serum and CSF of rituximab-treated patients and correlate them with CSF and response markers. Methods Fourteen paired serum/CSF samples of patients with autoimmune nervous system disorder were analyzed for up to 43 weeks after rituximab application. Results Rituximab remains detectable within the CSF after i.v. application for up to 24 weeks. Furthermore, levels of rituximab in CSF correlate significantly with the integrity of the blood CSF barrier.