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Intrathecal synthesis of immunoglobulins (Igs) is a key hallmark of multiple sclerosis (MS). B cells are known to accumulate in the leptomeninges of MS patients and associate with pathology in the underlying cortex and a more severe disease course. However, the role of locally produced antibodies in MS brain pathology is poorly understood. Here, we quantified the protein levels of IgA, IgM, IgG and albumin in serum and cerebrospinal fluid (CSF) samples of 80 MS patients and 28 neurological controls to calculate Ig indices. In addition, we quantified presence of meningeal IgA + , IgM + and IgG + B cells in post-mortem brain tissue of 20 MS patients and 6 controls using immunostainings. IgM and IgG, but not IgA, indices were increased in CSF of MS patients compared to controls, with no observed differences between MS disease types. Both IgM and IgG indices correlated significantly with neurofilament light (NfL) levels in CSF, but not with clinical or radiological parameters of disease. Similarly, IgG + and IgM + B cells were increased in MS meninges compared to controls, whereas IgA + B cells were not. Neuronal loss did not differ between sections with low or high IgA + , IgM + and IgG + B cells, but was increased in sections with high numbers of all CD19 + meningeal B cells. Similarly, high presence of CD19 + meningeal B cells and IgG + meningeal B cells associated with increased microglial density in the underlying cortex. Taken together, intrathecal synthesis of IgG and IgM is elevated in MS, which corresponds to an increased number of IgG + and IgM + B cells in MS meninges. The significant correlation between intrathecal IgG and IgM production and NfL levels, and increased microglial activation in cortical areas adjacent to meningeal infiltrates with high levels of IgG + B cells indicate a role for intrathecal IgM- and IgG-producing B cells in neuroinflammatory and degenerative processes in MS., (© 2024. The Author(s).)

Background and Objectives: Japanese encephalitis (JE) is fatal endemic viral encephalitis and is common in India and other parts of the world. It has a mortality rate of around 20-30%, and most of the survivors are left with neurological deficits. Studies related to JE in India, including Jharkhand, are focused on the pediatric population. This study aims to evaluate the presentation and prognosis of JE among adults., Materials and Methods: In this observational and prospective study, 116 patients aged 18 years or above with features of encephalitis were investigated. JE was confirmed in 32 adults by detection of immunoglobulin M (IgM) antibody in cerebrospinal fluid (CSF) through the National Institute of Virology (NIV) Pune kit. Detailed demographic profile, clinical picture, fatality rate, and prognosis were evaluated., Results: Out of the 32 patients we enrolled for the study, 75% (24) were male and 75% (24) were between 18 and 40 years of age. The mean age of presentation was 29.81 ± 14.14. Most of the patients (87.5%) belonged to rural areas; also, most of them presented between August and November. In our study, the most common symptom was fever, seen in all patients, followed by altered sensorium in 24 (75%), seizure in 10 (31.25%), and headache in 8 (25%). Around 14 (43.75%) patients succumbed to death, and out of all patients who were discharged, 88.88% had neurological deficits and 11.11% of patients were healthy. The most common neurological deficit among discharged patients was an inability to speak (44.44%)., Conclusion: We found high mortality and neurological deficits among adults. Detailed epidemiological surveys, awareness programs, and targeted use of vaccination can be helpful., (© Journal of the Association of Physicians of India 2024.)

Neurological involvement has been widely reported in SARS-CoV-2 infection. However, viral identification in the cerebrospinal fluid (CSF) is rarely found. The aim of this study is to evaluate the accuracy of virological and immunological biomarkers in CSF for the diagnosis of neuroCOVID-19. We analyzed 69 CSF samples from patients with neurological manifestations: 14 with suspected/confirmed COVID-19, with 5 additional serial CSF samples (group A), and as a control, 50 non-COVID-19 cases (group B-26 with other neuroinflammatory diseases; group C-24 with non-inflammatory diseases). Real-time reverse-transcription polymerase chain reaction (real-time RT-PCR) was used to determine SARS-CoV-2, and specific IgG, IgM, neopterin, and protein 10 induced by gamma interferon (CXCL-10) were evaluated in the CSF samples. No samples were amplified for SARS-CoV-2 by real-time RT-PCR. The sensitivity levels of anti-SARS-CoV-2 IgG and IgM were 50% and 14.28%, respectively, with 100% specificity for both tests. CXCL-10 showed high sensitivity (95.83%) and specificity (95.83%) for detection of neuroinflammation. Serial CSF analysis showed an association between the neuroinflammatory biomarkers and outcome (death and hospital discharge) in two cases (meningoencephalitis and rhombencephalitis). The detection of SARS-CoV-2 RNA and specific immunoglobulins in the CSF can be used for neuroCOVID-19 confirmation. Additionally, CXCL-10 in the CSF may contribute to the diagnosis and monitoring of neuroCOVID-19.

Background: Our objective was to explore various biomarkers for predicting suboptimal responses to disease-modifying treatments (DMTs) in patients with MS (pwMS)., Methods: We conducted a longitudinal, bicentric study with pwMS stratified based on their DMTs responses. Treatment failure (TF) was defined as the onset of a second relapse, presence of two or more T2 new lesions, or disability progression independent of relapse during the follow-up period. We evaluated intrathecal synthesis (ITS) of IgG and IgM using OCB, linear indices, and Reibergrams. Free kappa light chains ITS was assessed using the linear index (FKLCi). NfL and GFAP in serum and CSF, and CHI3L1 in CSF were quantified. Quantitative variables were dichotomized based on the third quartile. Predictive efficacy was assessed through bivariate and multivariate analyses, adjusting for age, sex, EDSS, acute inflammatory activity (AI) -defined as the onset of a relapse or gadolinium-enhancing lesions within a 90-day window of lumbar puncture-, treatment modality, study center, and time from disease onset to treatment initiation. In case of collinearity, multiple models were generated or confounding variables were excluded if collinearity existed between them and the biomarker. The same methodology was used to investigate the predictive potential of various combinations of two biomarkers, based on whether any of them tested positive or exceeded the third quartile., Results: A total of 137 pwMS were included. FKLCi showed no differences based on AI, no correlation with EDSS and was significantly higher in pwMS with TF (p = 0.008). FKLCi>130 was associated with TF in bivariate analysis (Log-Rank p = 0.004). Due to collinearity between age and EDSS, two different models were generated with each of them and the rest of the confounding variables, in which FKLCi>130 showed a Hazard Ratio (HR) of 2.69 (CI: 1.35-5.4) and 2.67 (CI: 1.32-5.4), respectively. The combination of either FKLC or sNfL exceeding the third quartile was also significant in bivariate (Log-Rank p = 0.04) and multivariate (HR=3.1 (CI: 1.5-6.5)) analyses. However, when analyzed independently, sNfL did not show significance, and FKLCi mirrored the pattern obtained in the previous model (HR: 3.04; CI: 1.51-6.1). Treatment with highefficacy DMTs emerged as a protective factor in all models., Discussion: Our analysis and the fact that FKLCi is independent of EDSS and AI suggest that it might be a valuable parameter for discriminating aggressive phenotypes. We propose implementing high-efficacy drugs in pwMS with elevated FKLCi., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest related to this research. There are no financial, personal, or professional relationships that could potentially bias or influence the interpretation of the results presented in this study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Purpose: Antiganglioside antibodies (AGAs) might be involved in the etiopathogenesis of many neurological diseases, such as Miller-Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS). Available comprehensive reference data regarding AGA positivity rates and cross-responsiveness among AGAs (where one line immunoblot is positive for ≥1 AGA) during routine clinical care are scant., Methods: In this 10-year monocentric retrospective study, 3560 immunoglobulin (Ig) G and IgM line blots (GA Generic Assays' Anti-Ganglioside Dot kit) obtained using cerebrospinal fluid (CSF) and serum samples from 1342 patients were analyzed for AGA positivity in terms of 14 diagnosis categories and AGA cross-responsiveness., Results: Of all 3560 line blots 158 (4.4%) and of all CSF samples 0.4% (4/924) CSF line blots were AGA positive. For serum IgG, blots with positivity rates higher than the standard deviation of 15.6% were associated with MFS (GD3, GD1a, GT1a and GQ1b) and acute motor axonal neuropathy (AMAN) (GM1, GD1a and GT1a). For serum IgM, blots with positivity rates higher than the standard deviation of 8.1% were associated with AMAN (GM2, GT1a and GQ1b), MFS (GM1, GT1a and GQ1b), multifocal motor neuropathy (MMN) (GM1, GM2 and GQ1b) and chronic inflammatory demyelinating polyneuropathy (CIDP) (GM1). Cross-responsiveness was observed in 39.6% of all positive serum AGA., Conclusions: Testing for AGAs during routine clinical care rarely led to positive findings, both in serum and even less in CSF, except for the diagnoses AMAN, MFS, MMN and CIDP. Nonspecific findings found as cross-responsiveness between different AGA samples occur frequently, impacting the positivity of most AGA subtypes., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: A case-control study was conducted to analyze the role of cerebrospinal fluid immunoglobulin in the differential diagnosis of autoimmune encephalitis and viral encephalitis in children., Methods: One hundred and twenty patients with autoimmune encephalitis (AE) treated in our hospital from February 2021 to February 2022 were included as the observation group (AE group). 100 patients with viral encephalitis (VE group) were selected as the control group. The clinical data of all patients were collected and analyzed retrospectively. Immunoglobulin G (IgG) and immunoglobulin A (IgA)in cerebrospinal fluid of the two patients were measured by immune turbidimetry. Immunoglobulin M (IgM), and the diagnostic value of immunoglobulin in cerebrospinal fluid (CSF) in patients with AE was analyzed by receiver working curve (ROC)., Results: The level of IgG in the cerebrospinal fluid of the AE group was higher than that of the VE group, and the level of IgM was lower than that of the VE group, and the difference was statistically significant (P < 0.05). There was no significant difference in IgA levels between the two groups (P > 0.05). In terms of Magnetic Resonance (MR) features, the paraventricular, hippocampal, occipital and parietal lobes were more involved in AE patients, frontal and temporal lobes were more involved in VE patients, and paraventricular and occipital lobes were involved in MS. The proportion of bilateral extensive lesions in both groups was significantly higher than 50%. The proportions of patients in the AE group involving the lateral ventricle, insula, and parietal lobes were significantly higher than those in the VE group, and the proportions involving the basal ganglia, temporal lobes, and frontal lobes were significantly lower than those in the VE group, and the differences were statistically significant (All P < 0.05). The Area Under Curve (AUC) of IgG, IgA and IgM alone in the diagnosis of AE were 0.795(0.587-0.762), 0.602(0.502-0.631) and 0.627(0.534-0.708), respectively with the sensitivity values of 81.24% and 65.608, respectively and the specificity values of 65.08%, 57.54% and 75.01% respectively. The AUC of IgA + IgM in the diagnosis of AE was 0.733(0.617-0.849), and the sensitivity and specificity are 62.58% and 75.07% respectively. The AUC of IgA + IgG in the diagnosis of AE was 0.823(0.730-0.917), and the sensitivity and specificity were 81.24% and 67.54% respectively. The AUC of IgG + IgM in the diagnosis of AE was 0.886(0.814 ~ 0.958), and the sensitivity and specificity were 84.48% and 77.59% respectively. The AUC of IgA + IgM + IgG in the diagnosis of AE was 0.924 (0.868-0.981) with the sensitivity of 93.82%, and the specificity of 77.56%., Conclusion: The level of immunoglobulin in cerebrospinal fluid can be used as an effective reference index for the diagnosis of AE. The combined detection of IgA, IgM and IgG can improve the accuracy, sensitivity and specificity of AE., (© 2024. The Author(s).)

This article aims to study the value of cerebrospinal fluid (CSF) immunoglobulin in differential diagnosis, prediction, and prognosis of tuberculous meningitis (TBM). The clinical data of 65 patients with TBM in our hospital were collected, and 65 patients with cryptococcal meningitis (CM) were enrolled in 1:1 matching. Relevant data were collected for comparison. CSFs IgG [331.51 (164.85, 645.00) vs 129.00 (55.05, 251.00) ng/mL], IgM [22.38 (8.52, 40.18) vs 6.08 (2.19, 23.30) ng/mL], and IgA [64.11 (21.44, 115.48) vs 16.55 (4.76, 30.36) ng/mL] in the TBM group were higher than those in the CM group ( P < 0.001). In the TBM group, after 24 weeks of treatment, the CSFs IgG, IgM, and IgA were significantly decreased, and the difference was statistically significant ( P < 0.05). The predictive results of CSF immunoglobulin for TBM showed that IgG, IgM, and IgA all had some predictive value for TBM, and the combined predictive value of the three was the highest, with an area under the curve of 0.831 (95% CI: 0.774-0.881). Logistic regression analysis of CSF immunoglobulins and TBM prognosis showed that IgG [odds ratio (OR) = 4.796, 95% confidence interval (CI): 2.575-8.864], IgM (OR = 3.456, 95% CI: 2.757-5.754), and IgA (OR = 4.371, 95% CI: 2.731-5.856) were TBM risk factors for poor prognosis in patients. The levels of IgG, IgM, and IgA in CSF were positively correlated with the severity of cranial magnetic resonance imaging (MRI) in TBM patients ( R 2 = 0.542, F = 65.392, P < 0.05). CSFs IgG, IgM, and IgA can be used as a routine monitoring index for TBM patients, which has a certain reference value in differential diagnosis and efficacy evaluation., Importance: In clinical practice, physicians can determine the physical conditions of patients based on the levels of cerebrospinal fluids (CSFs) IgG, IgM, and IgA. Higher levels of CSFs IgG, IgM, and IgA suggest more possibility of tuberculous meningitis and worse prognosis and magnetic resonance imaging manifestations., Competing Interests: The authors declare no conflict of interest.

For CNS lymphomas (CNSL), there is a high need for minimally invasive and easily obtainable diagnostic markers. Intrathecal IgM synthesis can easily be determined in routine CSF diagnostics. The aim of this study was to systematically investigate the diagnostic potential of intrathecal IgM synthesis in primary and secondary CNSL (PCNSL and SCNSL). In this retrospective study, patients with a biopsy-proven diagnosis of PCNSL or SCNSL were compared with patients with other neurological diseases in whom CNSL was initially the primary radiological differential diagnosis based on MRI. Sensitivity and specificity of intrathecal IgM synthesis were calculated using receiver operating characteristic curves. Seventy patients with CNSL were included (49 PCNSL and 21 SCNSL) and compared to 70 control patients. The sensitivity and specificity for the diagnosis of CNSL were 49% and 87%, respectively, for the entire patient population and 66% and 91% after selection for cases with tumor access to the CSF system and isolated intrathecal IgM synthesis. In cases with MRI-based radiological suspicion of CNSL, intrathecal IgM synthesis has good specificity but limited sensitivity. Because of its low-threshold availability, analysis of intrathecal IgM synthesis has the potential to lead to higher diagnostic accuracy, especially in resource-limited settings, and deserves further study., (© 2024 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Background: Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the CNS. An intrathecal IgM synthesis is associated with a more rapid progression of MS and the intrathecal immune response to measles -, rubella -and varicella zoster virus (MRZR) which, if present, increases the likelihood of a diagnosis of MS in adults., Objective: To evaluate the frequency of an intrathecal IgM synthesis and MRZR in children with MS. MethodsChildren with MS and a data set including clinical and treatment history, MRI at onset, in addition to a CSF analysis, and determination of antibody index (AI) of measles, rubella, and zoster antibodies, were eligible. The presence of an intrathecal IgM synthesis and/or a positive MRZ reaction were compared to biomarkers of a more progressive disease course., Results: In 75 children with MS, OCBs were present in 93.3 %). 49,2 % experienced their first relapse within 6 months. 50.7 % had a total lesion load of more than 10 lesions in the first brain MRI. Spinal lesions were identified in 64 %. 23.5 % had a positive MRZR and 40.3 % an intrathecal IgM synthesis. No significant associations were detected between the presence of an intrathecal IgM synthesis and MRZR and parameters including the relapse rate in the first two years., Conclusion: An intrathecal IgM synthesis and a positive MRZR are found in a subset of MS children but are not associated with markers associated with a poor prognosis., (© 2024 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

West Nile virus (WNV) is an arbovirus spread primarily by Culex mosquitoes, with humans being a dead-end host. WNV was introduced to Florida in 2001, with 467 confirmed cases since. It is estimated that 80 percent of cases are asymptomatic, with mild cases presenting as a non-specific flu-like illness. Currently, detection of WNV in humans occurs primarily in healthcare settings via RT-PCR or CSF IgM when patients present with severe manifestations of disease including fever, meningitis, encephalitis, or acute flaccid paralysis. Given the short window of detectable viremia and requirement for CSF sampling, most WNV infections never receive an official diagnosis. This study utilized enzyme-linked immunosorbent assay (ELISA) to detect WNV IgG antibodies in 250 patient serum and plasma samples collected at Tampa General Hospital during 2020 and 2021. Plaque reduction neutralization tests were used to confirm ELISA results. Out of the 250 patients included in this study, 18.8% of them were IgG positive, consistent with previous WNV exposure. There was no relationship between WNV exposure and age or sex.

Intrathecal IgM production in multiple sclerosis is associated with a worse disease course. To investigate pathogenic relevance of autoreactive IgM in multiple sclerosis, CSF from two independent cohorts, including multiple sclerosis patients and controls, were screened for antibody binding to induced pluripotent stem cell-derived neurons and astrocytes, and a panel of CNS-related cell lines. IgM binding to a primitive neuro-ectodermal tumour cell line discriminated 10% of multiple sclerosis donors from controls. Transcriptomes of single IgM producing CSF B cells from patients with cell-binding IgM were sequenced and used to produce recombinant monoclonal antibodies for characterization and antigen identification. We produced five cell-binding recombinant IgM antibodies, of which one, cloned from an HLA-DR + plasma-like B cell, mediated antigen-dependent complement activation. Immunoprecipitation and mass spectrometry, and biochemical and transcriptome analysis of the target cells identified the iron transport scavenger protein SCARA5 as the antigen target of this antibody. Intrathecal injection of a SCARA5 antibody led to an increased T cell infiltration in an experimental autoimmune encephalomyelitis (EAE) model. CSF IgM might contribute to CNS inflammation in multiple sclerosis by binding to cell surface antigens like SCARA5 and activating complement, or by facilitating immune cell migration into the brain., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Forest encephalitis is a natural focal disease transmitted through the bite of hard ticks, and its pathogen is the tick-borne encephalitis virus from the Flaviviridae family. The mortality rate of forest encephalitis is relatively high, making laboratory testing significant in diagnosing this disease. This article elaborates on the etiological diagnostic methods and recent research progress in forest encephalitis. Laboratory tests for forest encephalitis mainly include routine examinations, serological tests, virus isolation, and molecular biological testing. The detection of serum-specific IgM antibodies against the forest encephalitis virus is of great importance for early diagnosis, and specific IgG antibodies serve as a "gold standard" for differentiation from other diseases. Techniques such as enzyme-linked immunosorbent assay (ELISA) or indirect immunofluorescence assay for detecting specific IgM antibodies in serum and/or cerebrospinal fluid, the serum hemagglutination inhibition test or serum complement fixation test, and the double serum hemagglutination inhibition test or complement fixation test all contribute to the early diagnosis. The development of molecular testing methods is rapid, and techniques such as metabolomics, digital PCR, and matrix metalloproteinases are also applied in the early diagnosis of forest encephalitis.

Background: Annual outbreaks of acute encephalitis syndrome pose a major health burden in India. Although Japanese encephalitis virus (JEV) accounts for around 15% of reported cases, the aetiology of most cases remains unknown. We aimed to establish an enhanced surveillance network and to use a standardised diagnostic algorithm to conduct a systematic evaluation of acute encephalitis syndrome in India., Methods: In this large-scale, systematic surveillance study in India, patients presenting with acute encephalitis syndrome (ie, acute onset of fever with altered mental status, seizure, or both) to any of the 18 participating hospitals across Uttar Pradesh, West Bengal, and Assam were evaluated for JEV (serum and cerebrospinal fluid [CSF] IgM ELISA) per standard of care. In enhanced surveillance, JEV IgM-negative specimens were additionally evaluated for scrub typhus, dengue virus, and West Nile virus by serum IgM ELISA, and for Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, dengue virus, herpes simplex virus, and enterovirus by CSF PCR across five referral laboratories. In 2017, chikungunya and Leptospira serum IgM by ELISA and Zika virus serum and CSF by PCR were also tested., Findings: Of 10 107 patients with acute encephalitis syndrome enrolled in enhanced surveillance between Jan 1, 2014, and Dec 31, 2017, 5734 (57·8%) of 9917 participants with available data were male and 6179 (62·7%) of 9856 were children aged 15 years and younger. Among patients who provided a sample of either CSF or serum in enhanced surveillance, an aetiology was identified in 1921 (33·2%) of 5786 patients enrolled between 2014 and 2016 and in 1484 (34·3%) of 4321 patients enrolled in 2017. The most commonly identified aetiologies were JEV (1023 [17·7%] of 5786 patients), scrub typhus (645 [18·5%] of 3489), and dengue virus (161 [5·2%] of 3124). Among participants who provided both CSF and serum specimens, an aetiology was identified in 1446 (38·3%) of 3774 patients enrolled between 2014 and 2016 and in 936 (40·3%) of 2324 enrolled in 2017, representing a 3·1-times increase in the number of patients with acute encephalitis syndrome with an identified aetiology compared with standard care alone (299 [12·9%]; p<0·0001)., Interpretation: Implementation of a systematic diagnostic algorithm in an enhanced surveillance platform resulted in a 3·1-times increase in identification of the aetiology of acute encephalitis syndrome, besides JEV alone, and highlighted the importance of scrub typhus and dengue virus as important infectious aetiologies in India. These findings have prompted revision of the national testing guidelines for this syndrome across India., Funding: US Centers for Disease Control and Prevention., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The purpose of this study was to describe the epidemiology of Lyme neuroborreliosis (LNB) in Kalmar County, in southern Sweden, between 2008 and 2019, and to analyse the relationship between the LNB incidence and climate factors. Data containing cerebrospinal fluid (CSF) cell counts and borrelia CSF/serum antibody index results was received from the departments of clinical chemistry and microbiology at Kalmar County hospital. For this study, we defined LNB as a case with a positive borrelia antibody CSF/serum index and CSF leukocytes > 5 × 10 6 /L. Climate data including mean temperature, humidity and precipitation covering Kalmar County was collected from the Swedish Meteorological and Hydrological Institute. A total of 5051 paired serum-CSF samples from 4835 patients were investigated of which 251 laboratory LNB cases were found. The average annual LNB incidence in Kalmar County 2008-2019 was 8.8 cases per 100,000 inhabitants. Positive relationships were observed between mean temperature and LNB incidence (p < 0.001) as well as precipitation and LNB incidence (p = 0.003), both with a one calendar month delay. The results suggest an association between climate factors such as mean temperature and precipitation and LNB incidence, presumably through increased/decreased human-tick interactions. This calls for increased awareness of LNB in both the short perspective after periods of warmth and heavy precipitation as well as in a longer perspective in relation to possible climate change. Further studies with larger study groups, covering other geographical areas and over longer periods of time are needed to confirm these findings., (© 2021. The Author(s).)

Background: An association has been found between the presence of lipid-specific oligoclonal IgM bands (LS-OCMB) in cerebrospinal fluid and a more severe clinical multiple sclerosis course., Objective: To investigate lipid-specific oligoclonal IgM bands as a prognostic biomarker of cognitive impairment in the early stages of multiple sclerosis., Methods: Forty-four patients underwent neuropsychological assessment at baseline and 4 years. Cognitive performance at follow-up was compared adjusting by age, education, anxiety-depression, and baseline performance., Results: LS-OCMB+ patients only performed worse for Long-Term Storage in the Selective Reminding Test (p = .018)., Conclusion: There are no remarkable cognitive differences between LS-OCMB- and LS-OCMB+ patients in the early stages of MS., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

IgM oligoclonal bands (OCMBs) against myelin-specific lipids have been identified as a marker for poor prognosis in multiple sclerosis (MS). The aim is to examine the relation between lipid-specific OCMBs (LS-OCMBs) and the evolution of MS. An analytical, ambispective and individual-based study was conducted. We selected 116 patients, out of whom 95 had LS-OCMBs. The predominant lipid recognized was phosphatidylcholine. The positive gangliosides OCMB group reached better scores in the 9HPT, and the phosphatidylcholine, sphingolipids and phosphatidylethanolamine OCMB groups showed statistical differences in the magnetic resonance parameters. In conclusion: some LS-OCMBs showed statistically significant differences with functional or imaging tests., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Tick-borne encephalitis (TBE) is an acute disease caused by the tick-borne encephalitis virus. Due to the viral nature of the condition, there is no effective causal treatment for full-blown disease. Current and nonspecific TBE treatments only relieve symptoms. Unfortunately, the first phase of TBE is characterized by flu-like symptoms, making diagnosis difficult during this period. The second phase is referred to as the neurological phase as it involves structures in the central nervous system-most commonly the meninges and, in more severe cases, the brain and the spinal cord. Therefore, it is important that early markers of TBE that will guide clinical decision-making and the choice of treatment are established. In this review, we performed an extensive search of literature reports relevant to biomarkers associated with TBE using the MEDLINE/PubMed database. We observed that apart from routinely determined specific immunoglobulins, free light chains may also be useful in the evaluation of intrathecal synthesis in the central nervous system (CNS) during TBEV infection. Moreover, selected metalloproteinases, chemokines, or cytokines appear to play an important role in the pathogenesis of TBE as a consequence of inflammatory reactions and recruitment of white blood cells into the CNS. Furthermore, we reported promising findings on tau protein or Toll-like receptors. It was also observed that some people may be predisposed to TBE. Therefore, to understand the role of selected tick-borne encephalitis biomarkers, we categorized these factors and discussed their potential application in the diagnosis, prognosis, monitoring, or management of TBE.

Objective: We aimed to determine in relapsing multiple sclerosis (MS) whether intrathecal synthesis of immunoglobulin (Ig) M and IgG is associated with outcomes reflecting inflammatory activity and chronic worsening., Methods: We compared cerebrospinal fluid analysis, clinical and magnetic resonance imaging data, and serum neurofilament light chain (sNfL) levels at baseline and follow-up in 530 patients with relapsing MS. Patients were categorized by the presence of oligoclonal IgG bands (OCGB) and intrathecal synthesis of IgG and IgM (intrathecal fraction [IF]: IgG IF and IgM IF ). Relationships with the time to first relapse, sNfL concentrations, T2-weighted (T2w) lesions, MS Severity Score (MSSS), and time to initiation of high-efficacy therapy were analyzed in covariate-adjusted statistical models., Results: By categorical analysis, in patients with IgM IF the median time to first relapse was 28 months shorter and MSSS on average higher by 1.11 steps compared with patients without intrathecal immunoglobulin synthesis. Moreover, patients with IgM IF had higher sNfL concentrations, more new/enlarging T2w lesions, and higher total T2w lesion counts (all p ≤ 0.01). These associations were absent or equally smaller in patients who were positive for only OCGB or OCGB/IgG IF . Furthermore, quantitative analyses revealed that in patients with IgM IF  ≥ median, the time to first relapse and to initiation of high-efficacy therapy was shorter by 32 and by 203 months, respectively (both p < 0.01), in comparison to patients with IgM IF  < median. Dose-dependent associations were also found for IgM IF but not for IgG IF with magnetic resonance imaging-defined disease activity and sNfL., Interpretation: This large study supports the value of intrathecal IgM synthesis as an independent biomarker of disease activity and severity in relapsing MS. ANN NEUROL 2021;90:477-489., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose: We investigated the prevalence of ocular abnormalities in infants vertically exposed to Toxoplasma gondii infection during an outbreak in Santa Maria City, Brazil., Design: Consecutive case series., Participants: A total of 187 infants were included., Methods: The infants were recruited from January 2018 to November 2019. All mothers were screened for syphilis and human immunodeficiency virus before delivery. Toxoplasmosis infection was confirmed in all mothers and infants based on the presence of serum anti-T. gondii immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies. All infants underwent an ophthalmologic examination; ocular abnormalities were documented using a wide-field digital imaging system. Neonatal cranial sonography or head computed tomography was performed in 181 infants, and the cerebrospinal fluid (CSF) was screened for anti-T. gondii IgG and IgM antibodies in 159 infants. Peripheral blood samples from 9 infants and their mothers were analyzed for the presence of T. gondii DNA by real-time polymerase chain reaction., Main Outcome Measures: Ocular abnormalities associated with congenital toxoplasmosis., Results: A total of 187 infants were examined. Twenty-nine infants (15.5%) had congenital toxoplasmosis, of whom 19 (10.2%) had ocular abnormalities, including retinochoroiditis in 29 of 38 eyes (76.3%), optic nerve abnormalities in 5 eyes (13.2%), microphthalmia in 1 eye (2.6%), and cataract in 2 eyes (5.3%). Bilateral retinal choroidal lesions were found in 10 of 19 infants (52.6%). Nine eyes of 6 infants had active lesions, with retinal choroidal cellular infiltrates at the first examination. Thirteen (7.2%) of 181 infants screened presented with cerebral calcifications. Eighty-three percent of the screened infants were positive for anti-T. gondii IgG and negative for IgM antibodies in the CSF. Congenital toxoplasmosis was higher in mothers infected during the third pregnancy trimester, and maternal treatment during pregnancy was not associated with a lower rate of congenital toxoplasmosis., Conclusions: High prevalence rates of clinical manifestations were observed in infants with congenital toxoplasmosis after a waterborne toxoplasmosis outbreak, the largest yet described. Cerebral calcifications were higher in infants with ocular abnormalities, and maternal infection during the third pregnancy trimester was associated with a higher rate of congenital toxoplasmosis independent of maternal treatment., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the best method to measure intrathecal immunoglobulin (Ig) M synthesis (ITMS), a biomarker of worse prognosis in multiple sclerosis (MS). We compared the ability for predicting a poor evolution of 4 methods assessing ITMS (IgM oligoclonal bands [OCMBs], lipid-specific OCMBs [LS-OCMBs], Reibergram, and IgM index) in patients with a clinically isolated syndrome (CIS)., Methods: Prospective study with consecutive patients performed at a referral MS center. We used unadjusted and multivariate Cox regressions for predicting a second relapse, Expanded Disability Status Scale (EDSS) scores of 4 and 6, and development of secondary progressive MS (SPMS)., Results: A total of 193 patients were included, with a median (interquartile range) age of 31 (25-38) years and a median follow-up of 12.9 years. Among all methods, only OCMB, LS-OCMB, and Reibergram significantly identified patients at risk of some of the pre-established outcomes, being LS-OCMB the technique with the strongest associations. Adjusted hazard ratio (aHR) of LS-OCMB for predicting a second relapse was 2.50 (95% CI 1.72-3.64, p < 0.001). The risk of reaching EDSS scores of 4 and 6 and SPMS was significantly higher among patients with LS-OCMB (aHR 2.96, 95% CI 1.54-5.71, p = 0.001; aHR 4.96, 95% CI 2.22-11.07, p < 0.001; and aHR 2.31, 95% CI 1.08-4.93, p = 0.03, respectively)., Conclusions: ITMS predicts an aggressive MS at disease onset, especially when detected as LS-OCMB., Classification of Evidence: This study provides Class II evidence that lipid-specific IgM oligoclonal bands can predict progression from CIS to MS and a worse disease course over a follow-up of at least 2 years., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

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.

Among the new biomarkers to propose therapeutic decisions in patients suffering from multiple sclerosis (MS) are the IgM oligoclonal bands (OCBs) in cerebrospinal fluid (CSF). At the current time, however, IgM OCBs are detected in laboratories at investigation level and not in the routine practice due to their complexity. For this, we have applied a semi-automated method based on an isoelectrofocusing platform from Sebia of wide availability in clinical laboratories. The IgM OCBs results were validated in paired samples of CSF and serum from patients with MS previously carried out in a reference laboratory. We found a sensitivity of 91.67%, in agreement with previous data obtained with the reference method for IgM OCBs., (Copyright © 2020. Published by Elsevier B.V.)

Japanese encephalitis (JE) is a clinical disease caused by inflammation of the central nervous system. The symptoms of this disease range broadly in severity from mild febrile illness to acute meningomyeloencephalitis. JE has been associated with a variety of neurological abnormalities, such as altered sensorium, seizures, focal neurological deficit, and acute flaccid paralysis (AFP). However, to date, AFP has never been reported as an initial manifestation of JE. Here, we present a case of AFP manifesting as the initial symptom of JE in a Chinese patient. A 30-year-old Chinese man was admitted to the West China Hospital of Sichuan University after experiencing AFP in the right upper limb, followed by hyperpyrexia and unconsciousness. Assay of cerebrospinal fluid from a lumbar puncture revealed high levels of proteins and anti- JE virus IgM antibodies. Intravenous acyclovir was administered; however, the weakness persisted and more extensive muscle wasting from the proximal to distal right upper limb occurred over 7 months. This case report highlights that JE needs to be added to the differential diagnosis of AFP in adults, especially in JE endemic seasons and areas.

Human herpesvirus-6A (HHV-6A) and -6B (HHV-6B) might be involved in the etiopathogenesis of multiple sclerosis (MS), especially the HHV-6A. We aim at assessing, for the first time in the scientific literature, the HHV-6A/B microRNAs in MS patients. We analyzed the miRNAs of HHV-6A: miR-U86, and -6B: hhv6b-miR-Ro6-1, -2, -3-3p, -3-5p, and -4 in paired samples of serum and CSF of 42 untreated MS patients and 23 patients with other neurological diseases (OND), using Taqman MicroRNA Assays. Intrathecal HHV-6A/B antibody production and anti-HHV-6A/B IgG/IgM levels in serum were measured. MS clinical data were available. We detected the following miRNAs: hhv6b-miR-Ro6-2 (serum: MS:97.7%, OND:95.7%; CSF: MS:81%, OND:86.4%), 3-3p (serum: MS:4.8%, OND:0%; CSF: MS:2.4%, OND:4.5%), -3-5p (serum: MS:95.2%, OND:91.3%; CSF: MS:50%, OND:54.5%), and miR-U86 (serum: MS:54.8%, OND:47.8%; CSF: MS:11.9%, OND:9.1%). In the serum of the whole population (MS and OND patients) we found a significant correlation between the levels of hhv6b-miR-Ro6-2 and -3-5p (Spearman r = 0.839, pcorr = 3E-13), -2 and miR-U86 (Spearman r = 0.578, pcorr = 0.001) and -3-5p and miR-U86 (Spearman r = 0.698, pcorr = 1.34E-5); also in the CSF, between hhv6b-miR-Ro6-2 and -3-5p (Spearman r = 0.626, pcorr = 8.52E-4). These correlations remained statistically significant when both populations were considered separately. The anti-HHV-6A/B IgG levels in CSF and the intrathecal antibody production in positive MS patients for hhv6b-miR-Ro6-3-5p were statistically significant higher than in the negative ones (pcorr = 0.006 and pcorr = 0.036). The prevalence of miR-U86 (30.8%) in the CSF of individuals without gadolinium-enhancing lesions was higher ( p = 0.035) than in the ones with these lesions (0%); however, the difference did not withstand Bonferroni correction (pcorr = 0.105). We propose a role of HHV-6A/B miRNAs in the maintenance of the viral latency state. Further investigations are warranted to validate these results and clarify the function of these viral miRNAs., (Copyright © 2020 Domínguez-Mozo, Nieto-Guerrero, Pérez-Pérez, García-Martínez, Arroyo and Álvarez-Lafuente.)

Introduction: Coronavirus disease (COVID-19) is spreading worldwide. The reported possible neurological symptoms are varied and range from subtle neurologic deficits to unconsciousness. Knowledge regarding the detection, diagnosis, treatment, and follow-up of COVID-19-associated neurological damage is still limited. We report a case of serious neurological damage and mental abnormalities in a patient who was finally confirmed to have COVID-19 based on IgM and IgG antibodies in the cerebrospinal fluid (CSF)., Patient Concerns: A 68-year-old man had slight flu-like symptoms and transient loss of consciousness in early February. Exaggerated unconsciousness and deteriorating mental abnormalities occurred over the next month without severe respiratory symptoms. Craniocerebral computed tomography showed normal results, but antibodies against severe acute respiratory syndrome coronavirus 2 were 100 times higher in the CSF than in the serum; tests for viral ribonucleic acid showed negative results with both a nasopharyngeal swab and CSF sample., Diagnosis: COVID-19 pneumonia was diagnosed based on symptoms and positive results for IgM and IgG in the CSF., Interventions: Antiviral, fluid, and nutritional support were administered for 30 days before admission without obvious improvement. A further 18 days of routine antiviral therapy, immunoglobulin therapy (10 g per day for 5 days), and antipsychotic drug treatment were administered., Outcomes: The patient's neurological and mental abnormalities were greatly ameliorated. He was discharged with mild irritability, slight shaking of the hands, and walking fatigue. These symptoms have persisted up to our last follow-up (May 4, 2020)., Conclusion: We believe this is the first case involving neural system injury in a patient who confirmed COVID-19 based on CSF antibody test results. Negative ribonucleic acid test results, strong positivity for antibodies, and high protein levels in the CSF suggest the possibility of autoimmune encephalitis secondary to COVID-19. This case highlights additional novel symptoms of COVID-19, and these data are important for the assessment and follow-up of COVID-19 patients.

Progressive multi-focal leukoencephalopathy (PML) is a potentially fatal encephalitis caused by JC polyomavirus (JCV). PML principally affects people with a compromised immune system, such as patients with multiple sclerosis (MS) receiving treatment with natalizumab. However, intrathecal synthesis of lipid-reactive IgM in MS patients is associated with a markedly lower incidence of natalizumab-associated PML compared to those without this antibody repertoire. Here we demonstrate that a subset of lipid-reactive human and murine IgMs induce a functional anti-viral response that inhibits replication of encephalitic Alpha and Orthobunyaviruses in multi-cellular central nervous system cultures. These lipid-specific IgMs trigger microglia to produce IFN-β in a cGAS-STING-dependent manner, which induces an IFN-α/β-receptor 1-dependent antiviral response in glia and neurons. These data identify lipid-reactive IgM as a mediator of anti-viral activity in the nervous system and provide a rational explanation why intrathecal synthesis of lipid-reactive IgM correlates with a reduced incidence of iatrogenic PML in MS.

Autoantibodies to beta amyloid (Aβ) have been suggested to be involved in the pathogenesis of Alzheimer's disease (AD). However, data from clinical studies were inconsistent on autoantibody to Aβ levels in patients with AD. Therefore, we systematically searched the literature and performed meta-analysis to summarize the data of autoantibodies to Aβ in AD patients. The systematic search from PubMed and Web of Science included thirty case-control studies with a total of 2901 individuals (1311 AD patients and 1590 healthy control subjects). Random-effect meta-analysis showed a significant increased endogenous IgG autoantibody to Aβ levels in blood when compared with controls (Hedges' g = 0.337, 95% CI = 0.020 to 0.654, P = 0.03). In contrast, blood IgM autoantibody to Aβ levels was significantly decreased in patients with AD relative to control subjects (Hedges' g = - 0.962, 95% CI = - 1.797 to - 0.126, P = 0.024). Furthermore, cerebrospinal fluid Aβ levels were not significantly different between AD patients and control subjects (Hedges' g = - 0.446, 95% CI = - 2.357 to 1.464, P = 0.647). Subgroup analysis revealed that detection method contributed to the heterogeneity for studies measuring blood IgG autoantibody to Aβ levels in AD patients. Meta-regression analyses suggested that sex is a confounder for the outcome of the meta-analysis. Taken together, the results of this meta-analysis clarified circulating autoantibodies to Aβ levels in AD patients and suggested that endogenous IgG and IgM-class antibodies to Aβ may play a role in the pathogenesis of AD.

Background: Japanese encephalitis (JE) occurs in fewer than 1% of JE virus (JEV) infections, often with catastrophic sequelae including death and neuropsychiatric disability. JEV transmission in Pakistan was documented in 1980s and 1990s, but recent evidence is lacking. Our objective was to investigate JEV as a cause of acute encephalitis in Pakistan., Methods: Persons aged ≥1 month with possible JE admitted to two acute care hospitals in Karachi, Pakistan from April 2015 to January 2018 were enrolled. Cerebrospinal fluid (CSF) or serum samples were tested for JEV immunoglobulin M (IgM) using the InBios JE DetectTM assay. Positive or equivocal samples had confirmatory testing using plaque reduction neutralization tests., Results: Among 227 patients, testing was performed on CSF in 174 (77%) and on serum in 53 (23%) patients. Six of eight patient samples positive or equivocal for JEV IgM had sufficient volume for confirmatory testing. One patient had evidence of recent West Nile virus (WNV) neurologic infection based on CSF testing. One patient each had recent dengue virus (DENV) infection and WNV infection based on serum results. Recent flavivirus infections were identified in two persons, one each based on CSF and serum results. Specific flaviviruses could not be identified due to serologic cross-reactivity. For the sixth person, JEV neutralizing antibodies were confirmed in CSF but there was insufficient volume for further testing., Conclusions: Hospital-based JE surveillance in Karachi, Pakistan could not confirm or exclude local JEV transmission. Nonetheless, Pakistan remains at risk for JE due to presence of the mosquito vector, amplifying hosts, and rice irrigation. Laboratory surveillance for JE should continue among persons with acute encephalitis. However, in view of serological cross-reactivity, confirmatory testing of JE IgM positive samples at a reference laboratory is essential., Competing Interests: The authors have declared that no competing interests exist.

One of the great challenges related to multiple sclerosis (MS) research is the identification of markers of prognosis and treatment response. In the last couple of decades, an association between intrathecally produced immunoglobulin M (IgM) and a more severe course of the disease has been suggested. Therefore, the objective of this literature review was to gather and review evidence from studies on intrathecally produced IgM as a prognostic marker of clinically isolated syndrome (CIS) converting to clinically definite MS (CDMS), the prognosis of MS and treatment response in patients with MS. This was accomplished through a systematic literature search of the PubMed database, which resulted in 719 hits that were then systematically assessed with well-defined inclusion and exclusion criteria. This process resulted in 29 relevant research articles. The combined evidence from the current literature suggests that intrathecal IgM is a negative prognostic marker that identifies patients with CIS who have a higher risk of converting to CDMS and patients with relapsing-remitting MS (RRMS) with a higher risk of a more aggressive disease course. However, a few studies, some with large studied populations, have reported conflicting results regarding MS prognosis. Further research is needed to establish a more accurate estimate of the effect of intrathecal IgM on the disease course of MS. Further research is also necessary to evaluate the potential prognostic value of intrathecal IgM in treatment response.

Case Report: A 10-year-old male with T1DM and recent travel to North Carolina presented to an ED with 1 day of fever, vomiting, and headaches. He was discharged home with the presumptive diagnosis of viral gastroenteritis but returned nine hours later, agitated, and unable to speak. CSF showed pleocytosis. MRI brain was normal, and EEG showed intermittent seizures. He was started on antiepileptics. Antibiotics were discontinued after negative bacterial work-up. Repeat MRI brain one week later showed enhancement in the left cerebral cortex. IVIG was started due to concern for autoimmune encephalitis. Repeat lumbar puncture was positive for La Crosse virus IgM., Discussion: This is the first case of La Crosse encephalitis (LACe) reported in Rhode Island.1 La Crosse virus (LACv) is a ssRNA Bunyavirus transmitted by the eastern tree-hole mosquito typically between July and September. LACv is endemic to the upper Midwestern US and Appalachia. In 2018, 81 of 86 total cases reported by the CDC were pediatric. Children are more likely to present with vomiting, seizures, and focal cortical inflammation or cerebral edema on brain imaging. IgM may be negative early in the disease course. Treatment is antiepileptics and supportive care.

Objective: The use of alemtuzumab, a humanized monoclonal anti-CD52 antibody has changed the therapy of highly active relapsing-remitting MS (RRMS). Alemtuzumab infusion depletes most lymphocytes in peripheral blood, whereas differential recovery of immune cells, probably those with a less CNS-autoreactive phenotype, is supposed to underlie its long-lasting effects. To determine whether alemtuzumab significantly reduces immunoglobulin levels in blood and CSF of treated patients, we analyzed blood and CSF samples of 38 patients with MS treated with alemtuzumab regarding changes in immunoglobulin levels., Methods: Blood and CSF samples of patients were collected at the beginning of alemtuzumab treatment and at 12, 24, and 36 months after the first administration of the drug. Specimens were analyzed regarding immunoglobulin concentrations in blood and CSF., Results: We observed significant and dose-dependent reductions of immunoglobulin levels (IgG, IgM, and IgA) in serum and CSF 12 and 24 months following 2 courses of alemtuzumab. Patients with persistent or returning disease activity who were treated with a third course of alemtuzumab exhibited even further decrease in IgG levels compared with matched controls treated twice. Here, alemtuzumab-treated patients with IgG levels below the lower limits of normal were more susceptible to pneumonia, sinusitis, and otitis, whereas upper respiratory tract and urinary tract infections were not associated therewith., Conclusions: Our results suggest to monitor IgG levels for safety reasons in patients treated with alemtuzumab-in particular when additional treatment courses are required-and to consider preventive action in critical cases., Classification of Evidence: This study provides Class IV evidence that for patients with RRMS alemtuzumab reduces immunoglobulin levels., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Tick-borne encephalitis (TBE) is an infectious disease endemic to large parts of Europe and Asia. Diagnosing TBE often relies on the detection of TBEV-specific antibodies in serum and cerebrospinal fluid (CSF) as viral genome is mostly not detectable once neurological symptoms occur., Objectives: We evaluated the performance of TBEV IgM and IgG ELISAs in both serum and CSF of confirmed TBEV patients and discuss the role of (CSF) serology in TBEV diagnostics., Study Design: For the assay evaluation we collected specimen from confirmed TBEV patients. Assay specificity was assessed using sera from patients with a related flavivirus infection or other acute infection. A selected ELISA assay was used to analyze TBEV-specific antibodies in CSF and to evaluate the use in confirming TBE diagnosis., Results: In this study the overall sensitivity of the IgM TBEV ELISAs was acceptable (94 -100 %). Four out of five IgM ELISA's demonstrated an excellent overall specificity from 94 -100% whereas a low overall specificity was observed for the IgG TBEV ELISAs (30-71%). Intrathecal antibody production against TBEV was demonstrated in a subset of TBE patients., Conclusions: In four out of five ELISAs, IgM testing in serum and CSF of TBE patients is specific and confirmative. The lack of IgG specificity in all ELISAs emphasizes the need of confirmatory testing by virus neutralisation, depending on the patient's background and the geographic location of exposure to TBEV. A CSF-serum IgG antibody index can support the diagnosis specifically in chronic disease or once IgM has disappeared., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Coccidioides spp. are dimorphic fungi endemic to Central America, regions of South America and southwestern USA. Two species cause most human disease: Coccidioides immitis (primarily California isolates) and Coccidioides posadasii. Coccidioidomycosis is typically acquired through inhalation of soil or dust containing spores. Coccidioidal meningitis (CM), most common in the immunocompromised host, can also affect immunocompetent hosts., Case Presentation: We report a case of C. posadasii meningoencephalitis in a previously healthy 42-year-old Caucasian male who returned to Canada after spending time working in New Mexico. He presented with a 3-week history of headache, malaise and low-grade fevers. He developed progressive confusion and decreasing level of consciousness following hospitalization. Evidence of hydrocephalus and leptomeningeal enhancement was demonstrated on magnetic resonance imaging (MRI) of his brain. Serologic and PCR testing of the patient's CSF confirmed Coccidioides posadasii. Despite appropriate antifungal therapy he continues to have significant short-term memory deficits and has not returned to his full baseline functional status., Conclusions: Travel to endemic regions can result in disease secondary to Coccidioides spp. and requires physicians in non-endemic areas to have a high index of suspicion. Effective therapeutic options have reduced the mortality rate of CM, however, it is still associated with significant morbidity and requires life-long therapy.

Importance: Reliable biomarkers associated with disability worsening in multiple sclerosis (MS) are still needed., Objective: To determine a possible association of intrathecal IgG synthesis and early disability worsening as measured by Expanded Disability Status Scale (EDSS) scoring in patients with relapsing-remitting MS or clinically isolated syndrome., Design, Setting, and Participants: Cerebrospinal fluid measurements and clinical data from the observational longitudinal German national multiple sclerosis cohort were analyzed. Patients were recruited between August 2010 and November 2015 from 18 centers. Data analysis was completed from August 2018 to December 2018., Exposure: Patients were offered standard immunotherapies per national treatment guidelines., Main Outcomes and Measures: A possible association between intrathecal IgG synthesis and risk of EDSS worsening 4 years after study inclusion was tested as the primary end point by multivariable binomial regression analysis. Kaplan-Meier analysis with a log-rank test was used to assess the association of intrathecal IgG synthesis with the time to EDSS worsening. Associations between intrathecal IgM or IgA synthesis and other cerebrospinal fluid parameters and EDSS worsening were analyzed as exploratory end points. Data collection began before the hypotheses were formulated., Results: Of all 1376 patients in the German Competence Network of Multiple Sclerosis cohort, 703 patients were excluded owing to missing cerebrospinal fluid or EDSS data. Of the 673 included patients, 459 (68.2%) were women. The mean (SD) age at baseline was 34 (10) years. Intrathecal IgG synthesis was associated with a higher risk of EDSS worsening after 4 years (odds ratio, 2.02 [95% CI, 1.15-3.58]; P = .01), independent of the occurrence of relapses and disease-modifying therapy. Additionally, intrathecal IgG synthesis was associated with earlier EDSS worsening; 4 years after study entry, worsening occurred in 28.4% (95% CI, 22.7%-34.1%) and 18.1% (95% CI, 12.4%-23.9%) of patients with and without intrathecal IgG synthesis, respectively. No association of other routine cerebrospinal fluid parameters with EDSS worsening was found., Conclusions and Relevance: Patients with new diagnoses of relapsing-remitting multiple sclerosis or clinically isolated syndrome with intrathecal IgG synthesis had a higher risk of and shorter time to EDSS worsening across a 4-year period of follow-up. Intrathecal IgG synthesis is a potentially useful marker for disability worsening in patients with multiple sclerosis and may be useful for early treatment decisions.

Objective: To identify CSF parameters at diagnosis of clinically isolated syndrome (CIS) and MS that are associated with early inflammatory disease activity as measured by standardized cerebral MRI (cMRI)., Methods: One hundred forty-nine patients with newly diagnosed CIS and MS were included in the retrospective study. cMRI at onset and after 12 months was analyzed for T2 and gadolinium-enhancing lesions. CSF was tested for oligoclonal bands and intrathecal synthesis of immunoglobulin G (IgG), A (IgA), and M (IgM) before initiation of disease-modifying therapy (DMT). In a subgroup of patients, CSF and serum samples were analyzed for sCD27, neurofilament light chain, and IgG subclasses 1 and 3. Association between CSF parameters and cMRI activity was investigated by univariable and multivariable regression analysis in all patients, DMT-treated patients, and untreated patients., Results: IgG index, sCD27 levels in CSF, and to a lesser extent IgM index were associated with the occurrence of new cMRI lesions. IgG index and sCD27 levels in CSF were highly correlated. In a multivariable analysis, IgG index and to a lesser extent IgM index together with DMT treatment status and gender were strongest predictors of future cMRI activity., Conclusions: CSF parameters such as IgG and IgM index are independently associated with future MRI activity and thus might be helpful to support early treatment decisions in patients newly diagnosed with CIS and MS.

Background: Hand, foot, and mouth disease (HFMD) is an acute viral infection occurring mostly in infants and children. Enterovirus 71 (EV71) infection mostly occurs in children < 5 years of age. Severe cases, however, are usually encountered in children under the age of 3 years, and exceedingly rare in teenagers > 14 years and adults., Case Presentation: We report a rare case of HFMD in a 16-year-old male teenager residing in Chonqing, China. The clinical presentation was typical of HFMD and included vesicular lesions and oral mucosal ulcers, macular and vesicular lesions on palms and soles. He developed severe neurological complications that were suggestive of brainstem encephalitis. EV71 RNA was detected in the patient's faecal samples by reverse transcription-polymerase chain reaction. Specific IgM antibody to EV71 was detected in both serum and cerebrospinal fluid by ELISA. Gamma immunoglobulin therapy at 25 g/day was administered for 2 days, along with methylprednisolone, mannitol, ganglioside, and creatine phosphate sodium. The patient showed neurological improvement and recovered completely in 1 month., Conclusions: This case indicates that EV71 infection may cause HFMD in teenagers with potentially severe neurological involvement. Clinicians should be aware of the possibility of HFMD occurring in adults and teenagers as prompt treatment could be life-saving in these patients.

The aims of the study were to determine the frequency of borrelial infection in patients with peripheral facial palsy (PFP) and to compare clinical and laboratory characteristics of patients with borrelial PFP and patients with PFP of unknown etiology. Adult patients with PFP who presented at our department between January 2006 and December 2013 qualified for the study if they had undergone lumbar puncture and also been tested for the presence of borrelial IgM and IgG antibodies in serum and cerebrospinal fluid (CSF) in indirect chemiluminescence immunoassay. Patients with PFP who had obvious signs/symptoms indicating a disease other than Lyme borreliosis (LB) were excluded. Patients who qualified for the study were classified into three groups according to the clinical and microbiological criteria: those having confirmed LB, those with possible LB, and those with PFP of unknown etiology. Of 589 patients diagnosed with PFP during the eight-year period, 436 patients (240 males, 196 females) with median age 42.5 years (15-87 years) qualified for the study. Among these patients, 64 (14.7%) fulfilled criteria for confirmed LB, 120 (27.5%) had a diagnosis of possible LB, and in 252 (57.8%) the cause of their PFP remained unknown. When compared with patients with unknown cause of PFP, the patients with confirmed LB were older, more often presented in summer, more often reported tick bites, more frequently had LB in the past, more often complained of constitutional symptoms and radicular pain, and more often had bilateral palsy and CSF pleocytosis. Among the patients with possible LB and patients with unknown cause of PFP there were no differences in frequency of constitutional symptoms, radicular pain, bilateral palsy or CSF pleocytosis. Presentation in summer, tick bites, constitutional symptoms and radicular pain, bilateral palsy, and CSF pleocytosis strongly suggest borrelial etiology of PFP., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

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.

Background: West Nile virus (WNV) is a mosquito-borne RNA virus belonging to the Flaviviridae family. Symptomatic infection happens in only about 20% of the cases, while WNV neuroinvasive disease (WNND) is rare and accounts for less than 1%. There is insufficient information about natural history and clinical course in children, because underdiagnosis is common, and reports are scarce. On the other hand, Europe has seen a dramatic increase of WNV infections in the last decades, and the Po valley itself, in Northern Italy, has become an endemic region since 2013., Case Presentation: We hereby report a case of West-Nile virus neuroinvasive disease in a 12-year-old boy. This is one of the very few cases diagnosed in the Italian pediatric population. The clinical presentation was compatible with acute encephalitis. Diagnosis was made by detection of specific IgM in both serum and cerebrospinal fluid. He finally was discharged with complete recovery, and no neurologic sequelae after a 12-months follow up period., Conclusions: Given its non-specific clinical presentation, the diffusion of WNV constitutes a crucial and emerging concern. Even though rare, neuroinvasive WNV infection should always be suspected in pediatric patients, living or traveling in endemic areas, presenting with meningitis, encephalitis or acute flaccid paralysis during the WNV transmission season.

Rabies is a fatal encephalitic disease in humans and animals caused by lyssaviruses, most commonly rabies virus (RABV). Human antemortem diagnosis of rabies is a complex process involving multiple sample types and tests for the detection of antibodies, antigen (protein), and nucleic acids (genomic RNA). Serological diagnosis of human rabies includes the detection of either neutralizing or binding antibodies in the cerebrospinal fluid (CSF) or serum samples from unimmunized individuals without prior rabies vaccination or passive immunization with purified immunoglobulins. While neutralizing antibodies are targeted against the surface-expressed glycoprotein (G protein), binding antibodies to viral antigens are predominantly against the nucleoprotein (N protein), although there can be antibodies against all RABV-expressed proteins. To determine N protein-specific antibody responses in the CSF and serum during RABV infection, we developed an enzyme-linked immunosorbent assay (ELISA) with purified recombinant N protein expressed in E. coli. N protein-specific immunoglobulin (Ig) subtypes IgG and IgM were detected in the CSF or serum of previously diagnosed human rabies cases. In addition, anti-N protein seroconversion was demonstrated over the course of illness in individual rabies cases. We compared the N protein ELISA results to those of an indirect fluorescent antibody (IFA) test, the current binding antibody assay used in diagnosis, and show that our ELISA is consistent with the IFA test. Sensitivity and specificity of the N protein ELISA ranged from 78.38-100% and 75.76-96.77% with respect to the IFA results. Our data provide evidence for the use of an N protein ELISA as an additional option for the detection of RABV-specific IgG or IgM antibodies in human CSF or serum specimens., Competing Interests: The authors have declared that no competing interests exist.

Background: Melioidosis is endemic in Southeast Asia and northern Australia. Infection usually follows percutaneous inoculation or inhalation or ingestion of the causative bacterium, Burkholderia pseudomallei, which is present in soil and surface water in endemic regions. Japanese encephalitis (JE) is a vector-borne viral zoonosis caused by Japanese encephalitis virus (JEV), leading to epidemic encephalitis in Southeast Asia. Both B. pseudomallei and JEV have spread dominantly in the Hainan and Guangdong provinces in China. Here we reported the first case of co-infection of B. pseudomallei and JEV, which was discovered in Huizhou in the Guangdong province in June 2016., Case Presentation: A 52-year-old man was admitted to the hospital with acute febrile illness and headache, diagnosed as respiratory infection, central nervous system (CNS) infection, septicemia, and hepatic dysfunction. Based on B. pseudomallei-positive blood and cerebrospinal fluid (CSF) cultures, the patient was diagnosed with melioidosis and treated aggressively with antibiotics. However, the patient failed to make a full recovery. Further laboratory tests focused on CNS infection were conducted. The co-infection of B. pseudomallei and JEV was confirmed after the positive IgM antibodies of JEV were detected in both CSF and blood. After diagnosis of co-infection with B. pseudomallei and JEV, the patient was provided supportive care in hospital and recovered after approximately 3 weeks., Conclusion: Given the possibility of co-infection of B. pseudomallei and JEV, as well as variable case presentations, it is critical to enhance the awareness, detection, and treatment of co-infection in regard to melioidosis.

Objective: To study the efficacy of interferon beta (IFNβ) and glatiramer acetate (GA) related to the presence of oligoclonal M bands (OCMB) in the cerebrospinal fluid in relapsing-remitting multiple sclerosis (RRMS)., Method: This is an observational, multicenter and retrospective study with prospectively collected data of patients that started treatment with IFNβ or GA. Treatment decision was made blinded to the OCMB status. Time to first attack after starting therapy was compared by using Kaplan-Meier curves, and adjustment by Cox regression analysis was performed., Results: Two hundred and fifty-six patients entered in the study (141-55% received IFNβ; 115-45% received GA). After a mean follow-up of 41 and 65 months, 54.7% of patients remained free from further attacks (RF). The proportion of RF patients was higher in the GA group than in the IFNβ group (72.2 vs. 40.4%, p < 0.001). The IFNβ patients with OCMB+ presented the poorest response, 31.3% RF vs. 48.1% in IFNβ without OCMB, p = 0.03., Conclusion: OCMB in CSF could be a biomarker of treatment response in multiple sclerosis.

The present paper described the immunomodulatory potential of novel nanocurcumin-based formulation enriched with trace elements and vitamins on cyclophosphamide-induced immunosuppression in rat model. Major immune-related assays were monitored such as hemagglutination assay, delayed-type hypersensitivity (DTH) reaction, cellular immune response, IgG, IgE, IgM, cerebrospinal fluid biomarkers, hematological study, antioxidant profile, and lipid biomarkers. Chemical characterization of novel formulation showed retention time (R t ) 18.98 of curcumin, while LC-MS data revealed the presence of the curcumin mass at m/z 369.01 [M + H] + (calculated for C 21 H 21 O 6 + , 369.13). This novel formulation exhibited significantly (p ≤ 0.001) increased primary and secondary antibody titer by 72.41% and 33.25%, respectively, while DTH response being improved by 87.50% (p ≤ 0.01). However, CD4 + , CD8 + , and CD28 + counts were significantly (p ≤ 0.05) increased by 76.46%, 68.21%, and 19.29%, respectively, while the concentrations of IgE, IgM, and IgG were significantly (p ≤ 0.05) increased by 40%, 28.43%, and 38.75%, respectively. CSF biomarkers analysis showed a decreased level of corticosterone, dopamine, serotonin, and tau protein by 29.38%, 51.73%, 29.93%, and 4.87%, respectively. Antioxidant enzymes such as CAT, GPx, and SOD were increased by 43.74%, 49.00%, and 40.84%, respectively, and non-enzymatic component, GSH, was increased by 55.52%. Similarly, free radical LPO was significantly (p ≤ 0.05) decreased by 40.37%, and acute inflammatory marker, MPO concentration, was reduced by 31.14%, compared with the disease control group. In addition, supportive hematology and lipid profile analysis showed promising results with improved overall animal profile. Thus, trace elements in novel formulation can be used in the various pharmacological activities and as dietary supplement due to its wide properties.