Search Results (13)

Background: Intrathecal IgG synthesis is a well-established hallmark of multiple sclerosis (MS), yet the roles of other immunoglobulin isotypes remain under investigated. This study aimed to comprehensively profile immunoglobulin distributions in cerebrospinal fluid (CSF) and plasma from MS patients and neurological controls. Methods: Paired CSF and plasma samples from 23 MS patients and 20 neurological controls were analyzed using a multiplex Luminex-based immunoassay targeting IgG1–4, IgA, and IgM. The findings were validated using commercial ELISA kits and Western blot analysis. Results: Multiplex analysis revealed a selective intrathecal enrichment of IgA and IgM in MS CSF, with significantly higher levels compared to both matched plasma and control CSF. IgG1 was modestly elevated in MS CSF by ELISA but not by multiplex assay. Western blotting confirmed a robust elevation of IgA in MS CSF, providing qualitative support for intrathecal enrichment rather than definitive proof of synthesis. Conclusions: These findings uncover previously underappreciated selective enrichment of IgA and IgM in the MS CNS compartment, complementing, rather than replacing, the established IgG-centric paradigm. The results suggest alternative antibody-mediated mechanisms in MS and highlight the importance of assay selection in biomarker discovery, which suggests IgA as an emerging component of MS immunopathology. Full article

Encephalitis is a potentially life-threatening condition with long-term neurological sequelae. However, data on early clinical, demographic, and diagnostic predictors of functional outcomes remain limited. We performed a retrospective monocentric study including 98 patients diagnosed with infectious encephalitis of various etiologies treated in the University Hospital Ulm between January 2014 and December 2024. Ordinal logistic regression models were applied to evaluate associations between admission characteristics and functional outcome at discharge, as measured by the modified Rankin Scale. Three multivariate models incorporating clinical, demographic, and MRI/EEG variables explained up to 53% of the variance in mRS at discharge (p < 0.001), outperforming models based solely on CSF parameters. Key predictors of poor functional outcome included ‘altered consciousness’ (OR 7.08, p < 0.001), higher ‘mRS at admission’ (OR 0.03–0.07 across categories, p < 0.001), ‘focal/generalized EEG slowing’ (OR 9.97, p < 0.001), ‘epileptiform EEG activity’ (OR 17.49, p < 0.001), ‘MRI: myelitis’ (OR 16.44, p = 0.004), and ‘intrathecal IgM synthesis’ (OR 8.93, p = 0.018). Conversely, ‘longer hospitalization’ (OR 0.13–0.17 for different intervals, p < 0.006) and ‘intrathecal IgG synthesis’ (OR 0.05, p = 0.03) were associated with more favorable outcomes. Despite the single-center and retrospective aspects of this study, our findings underscore a multifactorial pattern of outcome determinants in infectious encephalitis, highlighting the prognostic relevance of initial neurological status, electrophysiological abnormalities, and neuroimaging features. Full article

The combined use of serum and CSF biomarkers for prognostic stratification in multiple sclerosis (MS) remains underexplored. This multicenter observational study investigated associations between serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), and CSF lipid-specific IgM oligoclonal bands (LS-OCMB) with different forms of disability worsening, such as relapse-associated worsening (RAW), active progression independent of relapse activity (aPIRA), and non-active PIRA (naPIRA). A total of 535 patients with MS were included, all sampled within one year of disease onset. Biomarkers were quantified using single-molecule array and immunoblotting techniques, and CSF cell subsets were analyzed by flow cytometry. High sNfL z-scores and LS-OCMB positivity were independently associated with increased risk of RAW and aPIRA, collectively termed inflammatory-associated worsening (IAW), while elevated sGFAP levels predicted naPIRA. Patients with both high sNfL and LS-OCMB positivity had the highest risk of IAW. Among LS-OCMB–positive patients, higher regulatory T cell percentages were associated with lower sNfL levels, suggesting a protective role. Conversely, in LS-OCMB–negative patients, sNfL levels correlated with CSF C3 concentrations. These findings support the complementary role of sNfL, sGFAP, and LS-OCMB in identifying distinct mechanisms of disease worsening and may inform early personalized management strategies in MS. Full article

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. Full article

The kappa index is a well-established marker of intrathecal synthesis (IS) of immunoglobulin (Ig). Routinely used for diagnostic aims, IgG IS, which can be assessed quantitatively (ad hoc formulas) or qualitatively (oligoclonal bands, OCBs), may fail in detecting a humoral immune response within the central nervous system (CNS). The main aim of this study was to evaluate the kappa index for its ability to detect the presence of CNS humoral immunity and to associate it with a distinct group of disorders, in the absence of IgG IS/OCBs. Within the kappa index-positive, IgG OCB-negative (Kappa+OCB-) patient group, we also examined whether IgM/IgA IS, determined with the IgM/IgA index and CSF IgM OCBs, could contribute to disease group stratification. Diagnoses were classified as multiple sclerosis (MS), or other inflammatory (INFL), infectious (INFECT), or non-inflammatory (Other) central/peripheral nervous system disorders. Sixty-nine Kappa+OCB- patients and 50 controls (24 Kappa-OCB- and 26 Kappa+OCB+ patients) were included in this study. The most frequent diagnosis in the Kappa+OCB- group was MS (27/69), followed by INFECT (16/69). Additional evidence of IS was demonstrated through an elevated IgG/IgM/IgA index or by the presence of IgM OCBs in 59%, and through only IgM/IgA IS in 52% of cases. In INFECT patients, the median IgM/IgA indexes were higher (p < 0.001) than in other groups, with 18 patients (95%) presenting an elevated IgM index, 11 patients (58%) presenting CSF IgM OCBs, and 10 patients (53%) presenting an elevated IgA index. The vast majority of all INFECT (16/19) belonged to the Kappa+OCB- group. Our data confirm that the kappa index performs at the highest level in assessing intrathecal humoral immunity and supporting the diagnosis of both MS and CNS infectious disorders, which are also characterized by the intrathecal production of IgM and IgA. Full article

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. Full article

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. Full article

(1) Background: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) that mainly affects young adults and females more than males. The detection of intrathecal IgG synthesis (IIS) on cerebrospinal fluid (CSF) analysis supports the diagnosis of MS. A sexual dimorphism has recently been described in CSF protein content. (2) Methods: Clinical and laboratory data from 340 MS patients (F = 231, M = 99) and 89 people with clinically isolated syndrome (CIS) (F = 57, M = 32) were retrospectively analyzed to assess the presence of variables affected by sex and age. (3) Results: In MS, the albumin quotient (QAlb), reflecting the blood–CSF barrier (BCSFB) function, was higher in males (5.6 vs. 4.34) and correlated to age with a constant difference between sexes (F = 41.71). In CIS patients, QAlb increased with age only in males (r = 0.3567). Age was positively correlated to disease duration and severity in MS (r = 0.3502, r = 0.2986, respectively). No differences emerged for quantitative and qualitative IIS determinations. (4) Discussion: Although the main difference between males and females concerns the function of BCSFB assessed by QAlb, this sexual dimorphism does not affect the determination of the IIS evaluated both by quantitative and qualitative methods. Full article

The presence of intrathecal IgM synthesis (ITMS) has been associated with an aggressive multiple sclerosis (MS) clinical course. In the present systematic review, we aimed at assessing the prevalence of ITMS among different MS phenotypes. Moreover, we aimed at quantifying the risk of a second relapse in ITMS positive and oligoclonal IgG bands (OCGBs)-positive patients. We selected clinical studies reporting the ITMS prevalence assessed as oligoclonal IgM Bands (OCMBs), lipid-specific OCMBs (LS-OCMBs), and/or as an intrathecal IgM production > 0% (IgMLoc, Reiber formula). The overall prevalence of ITMS was higher in relapsing-remitting (RR) than clinically isolated syndrome (CIS) patients (40.1% versus 23.8%, p < 0.00001), while was in line with that detected in primary progressive MS (PPMS, 26.7%). Almost all patients (98%) with ITMS had also OCGBs. The risk of having a second relapse was higher in OCGBs positive patients (HR = 2.18, p = 0.007) but much higher in ITMS positive patients (HR = 3.62, p = 0.0005). This study revealed that the prevalence of ITMS is higher in RRMS patients. It suggests that the risk of having a second relapse, previously ascribed to OCGBs, may, to a certain extent, be related to the presence of intrathecal IgM. Full article

Background: Tick-borne encephalitis (TBE) is inflammation of the central nervous system (CNS) caused by a viral infection which may be associated with increased synthesis of immunoglobulins. It can lead to inter alia, breakdown of the blood-brain barrier (BBB), or even death and, unfortunately, treatment is only symptomatic. Therefore, the aim of the present study was assessment of the concentrations of free light chains (FLC) kappa (κ) and lambda (λ in the cerebrospinal fluid (CSF) and serum of patients with TBE. Methods: A total of 58 cerebrospinal fluid and serum sample pairs were analyzed. Samples were collected from patients with TBE before and after treatment. FLC were measured using the turbidimetric method. The values of κIgG-index, λIgG-index, κFLC-index and λFLC-index were calculated using relevant formulas. Results: Pre-treatment serum λFLC concentrations were higher in comparison to post-treatment levels. Moreover, it was observed that CSF λFLC, TBEV IgM, TBEV IgG, and serum TBEV IgG, as well as the values of λFLC-index, κFLC-index, and λIgG-index were elevated after treatment. In the total study group, the concentrations of CSF κFLC and λFLC, and values of four indexes: κFLC-index, λFLC-index, κIgG-index, and λIgG-index correlated with each other and with CSF TBEV IgM and IgG antibodies. The CSF level of TBEV IgG was also associated with serum IgG TBEV and CSF IgM TBEV antibodies. Additionally, serum κFLC correlated with serum and CSF λFLC. Conclusion: This is the first study that demonstrates statistically significant differences in serum and CSF λFLC, as well as in the calculated values of three algorithms: λIgG-index, κFLC-index, and λIgG-index prior to and following treatment of TBE. Our findings may indicate that these differences reflect the intrathecal synthesis of immunoglobulins and increased permeability of BBB in patients with TBE. Moreover, it could provide the basis for developing new therapeutic strategies. Full article

In this retrospective, monocentric cohort study, we tested if an intrathecal free light chain kappa (FLC-k) synthesis reflects not only an IgG but also IgA and IgM synthesis. We also analysed if FLC-k can help to distinguish between an inflammatory process and a blood contamination of cerebrospinal fluid (CSF). A total of 296 patient samples were identified and acquired from patients of the department of Neurology, University Medicine Greifswald (Germany). FLC-k were analysed in paired CSF and serum samples using the Siemens FLC-k kit. To determine an intrathecal FLC-k and immunoglobulin (Ig) A/-M-synthesis we analysed CSF/serum quotients in quotient diagrams, according to Reiber et al. Patient samples were grouped into three cohorts: cohort I (n = 41), intrathecal IgA and/or IgM synthesis; cohort II (n = 16), artificial blood contamination; and the control group (n = 239), no intrathecal immunoglobulin synthesis. None of the samples had intrathecal IgG synthesis, as evaluated with quotient diagrams or oligoclonal band analysis. In cohort I, 98% of patient samples presented an intrathecal synthesis of FLC-k. In cohort II, all patients lacked intrathecal FLC-k synthesis. In the control group, 6.5% presented an intrathecal synthesis of FLC-k. The data support the concept that an intrathecal FLC-k synthesis is independent of the antibody class produced. In patients with an artificial intrathecal Ig synthesis due to blood contamination, FLC-k synthesis is lacking. Thus, additional determination of FLC-k in quotient diagrams helps to discriminate an inflammatory process from a blood contamination of CSF. Full article

To investigate whether and how cerebrospinal fluid (CSF) findings can contribute to distinguish tick-borne encephalitis (TBE) from herpes simplex virus (HSV) and varicella zoster virus (VZV) induced central nervous system (CNS) infections (HSV-I, VZV-I). Chart review and identification of TBE, HSV- I, and VZV-I was carried out, fulfilling the following criteria: (1) clinical signs of encephalitis and/or meningitis, (2) complete CSF analysis and confirmed viral etiology by either PCR or antibody testing in CSF, (3) hospitalized patients, and (4) available brain magnetic resonance imaging (MRI). Fifty-nine patients with 118 CSF/serum pairs were included. These comprised 21 with TBE (35 CSF/serum pairs), 20 (40 CSF/serum pairs) with HSV-I, and 18 (43 CSF/serum pairs) with VZV-I. In contrast to HSV-I and VZV-I, CSF cell differentiation in TBE showed more often an increased (>20%) proportion of granulocytes (p < 0.01) and a more frequent quantitative intrathecal IgM synthesis (p = 0.001 and p < 0.01, respectively), while the second was even more pronounced when follow-up CSF analyses were included (p < 0.001). CSF findings help to distinguish TBE from other viral infections. In cases with CSF pleocytosis and a positive history for a stay in or near an endemic area, TBE antibodies in CSF and serum should be determined, especially if granulocytes in CSF cell differentiation and/or an intrathecal IgM synthesis is present. Full article

Dengue infection is a leading cause of illness and death in tropical and subtropical regions of the world. Forty percent of the world’s population currently lives in these areas. The clinical picture resulting from dengue infection can range from relatively minor to catastrophic hemorrhagic fever. Recently, reports have increased of neurological manifestations. Neuropathogenesis seems to be related to direct nervous system viral invasion, autoimmune reaction, metabolic and hemorrhagic disturbance. Neurological manifestations include encephalitis, encephalopathy, meningitis, Guillain-Barré syndrome, myelitis, acute disseminated encephalomyelitis, polyneuropathy, mononeuropathy, and cerebromeningeal hemorrhage. The development of neurological symptoms in patients with positive Immunoglobulin M (IgM) dengue serology suggests a means of diagnosing the neurological complications associated with dengue. Viral antigens, specific IgM antibodies, and the intrathecal synthesis of dengue antibodies have been successfully detected in cerebrospinal fluid. However, despite diagnostic advancements, the treatment of neurological dengue is problematic. The launch of a dengue vaccine is expected to be beneficial. Full article