The application value of cerebrospinal fluid immunoglobulin in tuberculous meningitis.

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 (R2 = 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.

Intrathecal IgM synthesis as a diagnostic marker in patients with suspected CNS lymphoma.

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.

Cell-binding IgM in CSF is distinctive of multiple sclerosis and targets the iron transporter SCARA5.

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.

Lipid-specific IgMs induce antiviral responses in the CNS: implications for progressive multifocal leukoencephalopathy in multiple sclerosis.

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-ß in a cGAS-STING-dependent manner, which induces an IFN-α/ß-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.

CSF parameters associated with early MRI activity in patients with MS.

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.

Emergence of Orientia tsutsugamushi as an important cause of Acute Encephalitis Syndrome in India.

BACKGROUND: Acute Encephalitis Syndrome (AES) is a major seasonal public health problem in Bihar, India. Despite efforts of the Bihar health department and the Government of India, burden and mortality of AES cases have not decreased, and definitive etiologies for the illness have yet to be identified. OBJECTIVES: The present study was undertaken to study the specific etiology of AES in Bihar. METHODS: Cerebrospinal fluid and/or serum samples from AES patients were collected and tested for various pathogens, including viruses and bacteria by ELISA and/or Real Time PCR. FINDINGS: Of 540 enrolled patients, 33.3% (180) tested positive for at least one pathogen of which 23.3% were co-positive for more than one pathogen. Most samples were positive for scrub typhus IgM or PCR (25%), followed by IgM positivity for JEV (8.1%), WNV (6.8%), DV (6.1%), and ChikV (4.5%).M. tuberculosis and S. pneumoniae each was detected in ~ 1% cases. H. influenzae, adenovirus, Herpes Simplex Virus -1, enterovirus, and measles virus, each was detected occasionally. The presence of Scrub typhus was confirmed by PCR and sequencing. Bihar strains resembled Gilliam-like strains from Thailand, Combodia and Vietnam. CONCLUSION: The highlights of this pilot AES study were detection of an infectious etiology in one third of the AES cases, multiple etiologies, and emergence of O. tsutsugamushi infection as an important causative agent of AES in India.

Improvement in Diagnosis of Histoplasma Meningitis by Combined Testing for Histoplasma Antigen and Immunoglobulin G and Immunoglobulin M Anti-Histoplasma Antibody in Cerebrospinal Fluid.

Background: Central nervous system (CNS) histoplasmosis is a life-threatening condition and represents a diagnostic and therapeutic challenge. Isolation of Histoplasma capsulatum from cerebrospinal fluid (CSF) or brain tissue is diagnostic; however, culture is insensitive and slow growth may result in significant treatment delay. We performed a retrospective multicenter study to evaluate the sensitivity and specificity of a new anti-Histoplasma antibody enzyme immunoassay (EIA) for the detection of IgG and IgM antibody in the CSF for diagnosis of CNS histoplasmosis, the primary objective of the study. The secondary objective was to determine the effect of improvements in the Histoplasma galactomannan antigen detection EIA on the diagnosis of Histoplasma meningitis. Methods: Residual CSF specimens from patients with Histoplasma meningitis and controls were tested for Histoplasma antigen and anti-Histoplasma immunoglobulin G (IgG) and immunoglobulin M (IgM) antibody using assays developed at MiraVista Diagnostics. Results: A total of 50 cases and 157 controls were evaluated. Fifty percent of patients with CNS histoplasmosis were immunocompromised, 14% had other medical conditions, and 36% were healthy. Histoplasma antigen was detected in CSF in 78% of cases and the specificity was 97%. Anti-Histoplasma IgG or IgM antibody was detected in 82% of cases and the specificity was 93%. The sensitivity of detection of antibody by currently available serologic testing including immunodiffusion and complement fixation was 51% and the specificity was 96%. Testing for both CSF antigen and antibody by EIA was the most sensitive approach, detecting 98% of cases. Conclusions: Testing CSF for anti-Histoplasma IgG and IgM antibody complements antigen detection and improves the sensitivity for diagnosis of Histoplasma meningitis.

Intrathecal immunoglobulin synthesis in patients with symptomatic epilepsy and epilepsy of unknown etiology ('cryptogenic').

BACKGROUND AND PURPOSE: To compare the frequency of intrathecal immunoglobulin (Ig) synthesis in patients with symptomatic epilepsy and epilepsy of unknown etiology ('cryptogenic'). METHODS: Patients with epileptic (n = 301) and non-epileptic (n = 10) seizures were retrospectively screened for autochthonous intrathecal Ig synthesis and oligoclonal bands (OCBs) in the cerebrospinal fluid. RESULTS: Intrathecal IgG/OCBs were detected in 8% of patients with epilepsies of unknown etiology, 5% of patients with first seizures of unknown cause and 0-4% of patients with epilepsy due to brain tumors, cerebrovascular disease or other etiologies. Intrathecal IgG/OCBs were not seen in patients with psychogenic seizures. Identical OCBs in serum and cerebrospinal fluid were more common in all patient groups (10-40% depending on underlying etiology). CONCLUSIONS: Intrathecal IgG synthesis/OCBs were observed slightly more frequently in patients with 'cryptogenic' epilepsy and with first seizures of unknown etiology than in other patient groups. However, this remained an infrequent finding and thus we could not confirm humoral immunity as a leading disease mechanism in patients with epilepsy in general or with unknown etiology in particular.

A probable case of West Nile virus transfusion transmission.

BACKGROUND: Transfusion-transmitted West Nile virus (WNV) infection is infrequent as a result of minipool (MP) and individual-donation (ID) nucleic acid testing (NAT) of blood donations. ID-NAT is triggered on the basis of local WNV activity identified by MP-NAT. STUDY DESIGN AND METHODS: A 78-year-old male patient who was treated for cardiac disease received 14 blood components from 30 donors in August 2016. He was discharged 7 days after aortic valve replacement and coronary bypass surgery, but was re-admitted on Day 12 with symptoms of viral infection, and eventually was diagnosed with aseptic meningitis. The patent died on Day 51. RESULTS: The patient was positive for WNV-immunoglobulin M (IgM) antibodies in his cerebrospinal fluid on Day 14 and was positive for WNV-IgM (on Days 14 and 16) and WNV-IgG antibodies (on Day 16) in his serum. All associated donations were nonreactive by MP-NAT or ID-NAT. However, one MP-NAT was noted to have an elevated (but negative) signal-to-cutoff ratio, and one donor from that MP was subsequently found positive for WNV-IgM and IgG antibodies; the donor was diagnosed with a WNV-like viral syndrome that had an onset 3 to 5 days postdonation. The donor's plasma was transfused 12 days before the patient's onset of WNV-meningoencephalitis. Conversion to ID-NAT was triggered for the region 7 days after the implicated donation, which was associated with the region's first human WNV case. CONCLUSION: Despite the possibility of mosquito-borne transmission, this was considered to be a case of transfusion-transmitted WNV infection from an MP-NAT-nonreactive donation collected just before triggering conversion to ID-NAT; a rare event recognized once in 84 million donations.

Cerebrospinal fluid anti-Epstein-Barr virus specific oligoclonal IgM and IgG bands in patients with clinically isolated and Guillain-Barré syndrome.

Epstein-Barr virus (EBV) has been implicated in multiple sclerosis (MS) pathogenesis. We aimed to assess the frequency of EBV-specific IgG and IgM oligoclonal bands (OCB) in cerebrospinal fluid (CSF) of 50 patients with clinically isolated syndrome (CIS) and in 27 controls with Guillain-Barré syndrome (GBS). Furthermore, we assessed correlations between the presence of OCB and CIS patients' CSF, MRI, and clinical variables. There was no difference in the proportion of CIS and GB patients with positivity for anti-EBV-specific IgG/IgM OCB. There were no correlations between OCB and analyzed variables, nor were they predictive of a higher disability at 3 years.

Improvement of diagnostic approach to Lyme neuroborreliosis in children by using recombinant antigens in detection of intrathecally produced IgM/IgG.

BACKGROUND: The purpose of the study was to evaluate new 3rd-generation test kits, EIA Borrelia recombinant IgM and IgG (TestLine, Brno, Czech Republic), in serum and cerebrospinal fluid (CSF) of children with Lyme neuroborreliosis. METHODS: Comparison of three tests was used: the whole-cell EIA from Borrelia garinii (EIA 1) was compared with the EIA using recombinant antigens (EIA 2) and immunoblot. In total, 364 samples of serum and CSF were examined. Eighty-six paired sera and CSF samples were evaluated in the first group of children with Lyme neuroborreliosis. The second group consisted of 30 children with probable Lyme neuroborreliosis. Sixty-six samples from children with neuroinfections other than borrelial etiology were used as controls. RESULTS: In the first group of children with proven LNB, EIA 2 gave significantly more positive results for IgG in serum (P = 0.006; OR = 7.5) as in CSF (P < 0.001; OR = 4.5). There was no statistically significant difference in the IgM positivity of serum (P = 0.54; OR = 0.71). EIA 2 determined significantly (P = 0.001; OR = 0.06) less positive results of IgM in CSF in the LNB patients. IgG antibody index (AI) assessed by both methods revealed similar results (P = 0.646; OR = 1.38). Both methods are comparable, but IgM AI assessed by EIA 2 showed significantly less positive results (P < 0.001; OR = 0.04).The differences in the detection of positive IgM/IgG antibodies in serum and CSF did not reach statistical significance either in the groups of children with excluded LNB or in controls. CONCLUSIONS: EIA 2 showed better results than EIA 1 and western blot for the detection of positive IgG antibodies in serum and CSF. The difference in the calculation of AI IgG by EIA 1 and EIA 2 was not noticeable in the group of LNB patients. Comparing IgG and IgM AIs calculated from both tests, the sensitivity for EIA 2 was 68% for IgG and 26% for IgM. The specificity is 100% for both tests.

Clinical features and neuroimaging (CT and MRI) findings in presumed Zika virus related congenital infection and microcephaly: retrospective case series study.

OBJECTIVE: To report radiological findings observed in computed tomography (CT) and magnetic resonance imaging (MRI) scans of the first cases of congenital infection and microcephaly presumably associated with the Zika virus in the current Brazilian epidemic. DESIGN: Retrospective study with a case series. SETTING: Association for Assistance of Disabled Children (AACD), Pernambuco state, Brazil. PARTICIPANTS: 23 children with a diagnosis of congenital infection presumably associated with the Zika virus during the Brazilian microcephaly epidemic. MAIN OUTCOME MEASURES: Types of abnormalities and the radiological pattern of lesions identified on CT and MRI brain scans. RESULTS: Six of the 23 children tested positive for IgM antibodies to Zika virus in cerebrospinal fluid. The other 17 children met the protocol criteria for congenital infection presumably associated with the Zika virus, even without being tested for IgM antibodies to the virus--the test was not yet available on a routine basis. Of the 23 children, 15 underwent CT, seven underwent both CT and MRI, and one underwent MRI. Of the 22 children who underwent CT, all had calcifications in the junction between cortical and subcortical white matter, 21 (95%) had malformations of cortical development, 20 (91%) had a decreased brain volume, 19 (86%) had ventriculomegaly, and 11 (50%) had hypoplasia of the cerebellum or brainstem. Of the eight children who underwent MRI, all had calcifications in the junction between cortical and subcortical white matter, malformations of cortical development occurring predominantly in the frontal lobes, and ventriculomegaly. Seven of the eight (88%) children had enlarged cisterna magna, seven (88%) delayed myelination, and six each (75%) a moderate to severe decrease in brain volume, simplified gyral pattern, and abnormalities of the corpus callosum (38% hypogenesis and 38% hypoplasia). Malformations were symmetrical in 75% of the cases. CONCLUSION: Severe cerebral damage was found on imaging in most of the children in this case series with congenital infection presumably associated with the Zika virus. The features most commonly found were brain calcifications in the junction between cortical and subcortical white matter associated with malformations of cortical development, often with a simplified gyral pattern and predominance of pachygyria or polymicrogyria in the frontal lobes. Additional findings were enlarged cisterna magna, abnormalities of corpus callosum (hypoplasia or hypogenesis), ventriculomegaly, delayed myelination, and hypoplasia of the cerebellum and the brainstem.

[Adult-onset opsoclonus-myoclonus-ataxia syndrome revealing rubella meningoencephalitis]. / Syndrome opsoclonus-myoclonus-ataxie révélant une méningo-encéphalite rubéolique chez un adulte.

INTRODUCTION: Opsoclonus-myoclonus-ataxia (OMS) is a rare clinical syndrome, of paraneoplastic infectious, post-infectious, post-vaccinal or idiopathic origin. CASE REPORT: We report a 24-year-old young man who presented with gait disorder preceded by a febrile rash and retroauricular lymph nodes. Three days before admission, he had headache, vertigo, nausea and vomiting followed by gait unsteadiness and movement disorders of limbs and eyes. On examination, he had OMS syndrome. Brain MRI, total body scan, MIBG scintigraphy, tumor markers and onconeural antibodies were normal. Cerebro-spinal fluid (CSF) analysis showed lymphocytic meningitis. Positive serum and CSF immunoglobulin M antibody against rubella virus was demonstrated. He received acyclovir with full recovery within two weeks. We discuss the peculiarities of this association with a literature review. CONCLUSION: This observation enlarges the spectrum of neurological manifestations of rubella as well as that of OMS etiologies.

Coronavirus Infections in the Central Nervous System and Respiratory Tract Show Distinct Features in Hospitalized Children.

BACKGROUND/AIMS: Coronavirus (CoV) infections induce respiratory tract illnesses and central nervous system (CNS) diseases. We aimed to explore the cytokine expression profiles in hospitalized children with CoV-CNS and CoV-respiratory tract infections. METHODS: A total of 183 and 236 hospitalized children with acute encephalitis-like syndrome and respiratory tract infection, respectively, were screened for anti-CoV IgM antibodies. The expression profiles of multiple cytokines were determined in CoV-positive patients. RESULTS: Anti-CoV IgM antibodies were detected in 22/183 (12.02%) and 26/236 (11.02%) patients with acute encephalitis-like syndrome and respiratory tract infection, respectively. Cytokine analysis revealed that the level of serum granulocyte colony-stimulating factor (G-CSF) was significantly higher in both CoV-CNS and CoV-respiratory tract infection compared with healthy controls. Additionally, the serum level of granulocyte macrophage colony-stimulating factor (GM-CSF) was significantly higher in CoV-CNS infection than in CoV-respiratory tract infection. In patients with CoV-CNS infection, the levels of IL-6, IL-8, MCP-1, and GM-CSF were significantly higher in their cerebrospinal fluid samples than in matched serum samples. CONCLUSION: To the best of our knowledge, this is the first report showing a high incidence of CoV infection in hospitalized children, especially with CNS illness. The characteristic cytokine expression profiles in CoV infection indicate the importance of host immune response in disease progression.

Anti-N-methyl-D-aspartate receptor encephalitis with positive serum antithyroid antibodies, IgM antibodies against mycoplasma pneumoniae and human herpesvirus 7 PCR in the CSF.

We report the case of a boy with an encephalopathy associated with extrapyramidal and psychiatric symptoms and anti-N-methyl-D-aspartate receptor antibodies. He had positive serum antithyroid antibodies, IgM antibodies against Mycoplasma pneumoniae and human herpesvirus 7 polymerase chain reaction in the cerebrospinal fluid. He was successfully treated with rituximab, after steroids, intravenous immunoglobulin and plasma exchange. The pathophysiology of this disorder may be post-infectious and autoimmune.

Cerebral toxoplasmosis after umbilical cord blood transplantation diagnosed by the detection of anti-toxoplasma specific IgM antibody in cerebrospinal fluid.

Cerebral toxoplasmosis is a rare, potentially fatal, complication of hematopoietic cell transplantation. Early definitive diagnosis is very difficult and it may be associated with a poor prognosis. Herein, we describe a 60-year-old woman who developed cerebral toxoplasmosis after cord blood transplantation for myelodysplastic syndrome. During treatment with tacrolimus and methylprednisolone for relapsed grade 2 acute gut GVHD, fever and disturbance of consciousness occurred on day 210. Brain MRI showed multiple ring-enhancing nodular lesions in the thalamus, basal ganglia, brainstem, and subcortical white matter. Cerebrospinal fluid (CSF) assessment revealed elevations of both anti-to-xoplasma IgM and IgG, which were also elevated in serum, but no evidence of other infections or malignancies. Notably, the IgM level was higher in the CSF than in serum. Thus, cerebral toxoplasmosis was diagnosed. Soon after administration of oral sulfamethoxazole/trimethoprim and intravenous clindamycin in combination with short-term dexamethasone for the cerebral edema, her symptoms and signs began to improve. On day 229, both IgM and IgG titers in CSF had clearly decreased but remained essentially constant in serum. She was discharged without clinically significant neurological disorders. This case suggests that CSF specific anti-toxoplasma IgM titers might be useful for early diagnosis of cerebral toxoplasmosis after transplantation.