Diagnostic Utility of MOG Antibody Testing in Cerebrospinal Fluid.

OBJECTIVE: The aim of this study was to assess the diagnostic utility of cerebrospinal fluid (CSF) myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) testing. METHODS: We retrospectively identified patients for CSF MOG-IgG testing from January 1, 1996, to May 1, 2023, at Mayo Clinic and other medical centers that sent CSF MOG-IgG for testing including: controls, 282; serum MOG-IgG positive MOG antibody-associated disease (MOGAD), 74; serum MOG-IgG negative high-risk phenotypes, 73; serum false positive MOG-IgG with alternative diagnoses, 18. A live cell-based assay assessed CSF MOG-IgG positivity (IgG-binding-index [IBI], ≥2.5) using multiple anti-human secondary antibodies and end-titers were calculated if sufficient sample volume. Correlation of CSF MOG-IgG IBI and titer was assessed. RESULTS: The pan-IgG Fc-specific secondary was optimal, yielding CSF MOG-IgG sensitivity of 90% and specificity of 98% (Youden's index 0.88). CSF MOG-IgG was positive in: 4/282 (1.4%) controls; 66/74 (89%) serum MOG-IgG positive MOGAD patients; and 9/73 (12%) serum MOG-IgG negative patients with high-risk phenotypes. Serum negative but CSF positive MOG-IgG accounted for 9/83 (11%) MOGAD patients, and all fulfilled 2023 MOGAD diagnostic criteria. Subgroup analysis of serum MOG-IgG low-positives revealed CSF MOG-IgG positivity more in MOGAD (13/16[81%]) than other diseases with false positive serum MOG-IgG (3/15[20%]) (p = 0.01). CSF MOG-IgG IBI and CSF MOG-IgG titer (both available in 29 samples) were correlated (Spearman's r = 0.64, p < 0.001). INTERPRETATION: CSF MOG-IgG testing has diagnostic utility in patients with a suspicious phenotype but negative serum MOG-IgG, and those with low positive serum MOG-IgG results and diagnostic uncertainty. These findings support a role for CSF MOG-IgG testing in the appropriate clinical setting. ANN NEUROL 2024;96:34-45.

Paraneoplastic Calmodulin Kinase-Like Vesicle-Associated Protein (CAMKV) Autoimmune Encephalitis.

OBJECTIVES: To report an autoimmune paraneoplastic encephalitis characterized by immunoglobulin G (IgG) antibody targeting synaptic protein calmodulin kinase-like vesicle-associated (CAMKV). METHODS: Serum and cerebrospinal fluid (CSF) samples harboring unclassified antibodies on murine brain-based indirect immunofluorescence assay (IFA) were screened by human protein microarray. In 5 patients with identical cerebral IFA staining, CAMKV was identified as top-ranking candidate antigen. Western blots, confocal microscopy, immune-absorption, and mass spectrometry were performed to substantiate CAMKV specificity. Recombinant CAMKV-specific assays (cell-based [fixed and live] and Western blot) provided additional confirmation. RESULTS: Of 5 CAMKV-IgG positive patients, 3 were women (median symptom-onset age was 59 years; range, 53-74). Encephalitis-onset was subacute (4) or acute (1) and manifested with: altered mental status (all), seizures (4), hyperkinetic movements (4), psychiatric features (3), memory loss (2), and insomnia (2). Paraclinical testing revealed CSF lymphocytic pleocytosis (all 4 tested), electrographic seizures (3 of 4 tested), and striking MRI abnormalities in all (mesial temporal lobe T2 hyperintensities [all patients], caudate head T2 hyperintensities [3], and cortical diffusion weighted hyperintensities [2]). None had post-gadolinium enhancement. Cancers were uterine adenocarcinoma (3 patients: poorly differentiated or neuroendocrine-differentiated in 2, both demonstrated CAMKV immunoreactivity), bladder urothelial carcinoma (1), and non-Hodgkin lymphoma (1). Two patients developed encephalitis following immune checkpoint inhibitor cancer therapy (atezolizumab [1], pembrolizumab [1]). All treated patients (4) demonstrated an initial response to immunotherapy (corticosteroids [4], IVIG [2]), though 3 died from cancer. INTERPRETATION: CAMKV-IgG is a biomarker of immunotherapy-responsive paraneoplastic encephalitis with temporal and extratemporal features and uterine cancer as a prominent oncologic association. ANN NEUROL 2024;96:21-33.

Elevated cerebrospinal fluid IgG index in herpes simplex encephalitis post-HSV-1 clearance: A preliminary study.

Herpes simplex encephalitis (HSE) is an acute form of encephalitis that can lead to poor neurological outcomes. Although the exact pathogenesis of HSE remains elusive, recent reports suggest a significant role for postinfectious immune-inflammatory processes in the central nervous system (CNS). This study aimed to clarify the association between CNS autoimmune responses and clinical presentation in patients with HSE, focusing on cerebrospinal fluid (CSF) characteristics, particularly the IgG index. We retrospectively analyzed 176 consecutive patients suspected of having aseptic meningitis /encephalitis for chronological changes in CSF findings and clinical presentations. These patients underwent PCR screening for herpesviruses (HV) in their CSF. We identified seven patients positive for herpes simplex virus type 1 (HSV-1), 20 patients positive for varicella-zoster virus, and 17 patients who met the criteria for aseptic meningitis but were PCR-negative for HV. Patients in the HSV-1-positive group exhibited a significant increase in the IgG index at the time of PCR-negative conversion compared with on admission (p = 0.0156), while such a change was not observed in the other two groups. Additionally, all patients in the HSV-1-positive group tested negative for anti-neural autoantibodies in CSF and serum samples collected approximately 3 weeks after onset. This study, therefore, highlights that CSF IgG index elevation occurs even after PCR-confirmed HSV-1 clearance, which might indicate immunopathogenesis that is independent of antibody-mediated mechanisms.

Diagnostic value of anti-VZV IgG in neurological diseases among varicella unvaccinated individuals.

Varicella zoster virus (VZV) is a neurotropic alphaherpesvirus that causes neurological manifestations either as a complication of primary infection or reactivation. VZV induced neurological diseases have a good prognosis when confirmed early and treated with anti-viral therapy. Myelitis, encephalitis, ventriculitis or meningitis can occur without a telltale rash in immunocompetent and immunocompromised individuals making the diagnosis difficult. We analyzed CSF and serum samples from 30 unvaccinated study participants (17 male and 13 female) to determine the presence of VZV DNA by PCR in CSF and to estimate serum and CSF anti-VZV IgG and albumin levels in participants with neurological manifestations with/without rash. Anti-VZV IgG was detected in CSF (n = 22, [73%]) and serum (n = 29, [97%]) of pediatric and adult participants. Anti-VZV IgG were detected in CSF of participants with varied clinical presentation altered sensorium (n = 8, [36%]), meningitis (n = 4, [18%]), acute febrile illness (n = 3, [14%], encephalopathy/meningoencephalitis (n = 2, [9%]), irritability (n = 2, [9%]) and each patient from cerebrovascular stroke, demyelinating disorder and febrile seizure (n = 1, [4.5%]). VZV DNA was detected from one participant and CSF serum albumin levels were elevated in 53% of study participants. VZV DNA is present up to 1-2 weeks post onset of disease, after which anti-VZV antibody may be the only indicator of disease and therefore both VZV DNA and anti-VZV IgG need to be tested for in CSF. As VZV DNA and VZV IgG antibody are both good indicators of VZV reactivation, routine testing would result in reduced morbidity and mortality by early detection of disease and antiviral treatment.

Antiganglioside antibody frequency in routine clinical care settings.

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.

Detection of intrathecal IgG antibody for varicella and measles diagnosis by evaluation and comparison of a commercial IgG chemiluminescent immunoassay with two ELISAs.

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

Spinal cord compression by cystic IgG4-related spinal pachymeningitis mimicking neurocysticercosis: a case report.

BACKGROUND: To report a case of IgG4-related pachymeningitis presenting with cystic lesions mimicking neurocysticercosis. CASE PRESENTATION: A 40-year-old female patient with tetraparesis, dysphagia and dysphonia was evaluated with clinical examination, magnetic resonance imaging, and meningeal biopsy. Magnetic resonance imaging (MRI) revealed diffuse pachymeningeal enhancement involving the cranial, cervical, thoracic, and lumbar segments with spinal cord compression and cystic lesions. CSF immunology was initially positive for cysticercus cellulosae. After disease progression a meningeal biopsy was compatible with IgG4 related disease. The patient had partial response to rituximab and needed multiple surgical procedures for spinal cord decompression and CSF shunting. CONCLUSIONS: This case highlights the possibility of IgG4-related disease in patients with diffuse pachymeningitis causing spinal cord compression, even with cystic lesions on MRI. Diagnosis of IgG4-related pachymeningitis is paramount due to the possibility of treatment response to immunotherapy, particularly to anti-CD20 agents.

IgG and kappa free light chain CSF/serum indices: evaluating intrathecal immunoglobulin production in HIV infection in comparison with multiple sclerosis.

OBJECTIVES: To study intrathecal kappa free light chain (KFLC) synthesis in people living with HIV (PLWH) in comparison with multiple sclerosis (MS). METHODS: Cross-sectional analysis including 56 untreated and 150 well treated PLWH, and compared with 58 controls, and 223 MS patients. RESULTS: Elevated serum/cerebrospinal fluid (CSF) IgG and KFLC indices were observed in untreated PLWH. Seventy percent of untreated PLWH had KFLC index above 6.1, a threshold associated with clinically isolated syndrome/MS diagnosis. No association was found between KFCL index and CSF markers of neuronal injury in either PLWH or MS patients. CONCLUSIONS: HIV-related immune system dysfunction is often associated with an elevated KFLC index akin to those observed in MS. HIV infection should be considered as a differential diagnosis for patients presenting with neurological symptoms and increased intrathecal immunoglobulin synthesis.

Diagnostic implications of MOG-IgG detection in sera and cerebrospinal fluids.

The spectrum of MOG-IgG-associated disease (MOGAD) includes optic neuritis (ON), myelitis (MY), acute disseminated encephalomyelitis (ADEM), brainstem encephalitis, cerebral cortical encephalitis (CE) and AQP4-IgG-negative neuromyelitis optica spectrum disorder (NMOSD). In MOGAD, MOG-IgG are usually detected in sera (MOG-IgGSERUM), but there have been some seronegative MOGAD cases with MOG-IgG in CSF (MOG-IgGCSF), and its diagnostic implications remains unclear. In this cross-sectional study, we identified patients with paired serum and CSF sent from all over Japan for testing MOG-IgG. Two investigators blinded to MOG-IgG status classified them into suspected MOGAD (ADEM, CE, NMOSD, ON, MY and Others) or not based on the current recommendations. The MOG-IgGSERUM and MOG-IgGCSF titres were assessed with serial 2-fold dilutions to determine end point titres [≥1:128 in serum and ≥1:1 (no dilution) in CSF were considered positive]. We analysed the relationship between MOG-IgGSERUM, MOG-IgGCSF and the phenotypes with multivariable regression. A total of 671 patients were tested [405 with suspected MOGAD, 99 with multiple sclerosis, 48 with AQP4-IgG-positive NMOSD and 119 with other neurological diseases (OND)] before treatment. In suspected MOGAD, 133 patients (33%) tested MOG-IgG-positive in serum and/or CSF; 94 (23%) double-positive (ADEM 36, CE 15, MY 8, NMOSD 9, ON 15 and Others 11); 17 (4.2%) serum-restricted-positive (ADEM 2, CE 0, MY 3, NMOSD 3, ON 5 and Others 4); and 22 (5.4%) CSF-restricted-positive (ADEM 3, CE 4, MY 6, NMOSD 2, ON 0 and Others 7). None of AQP4-IgG-positive NMOSD, multiple sclerosis or OND cases tested positive for MOG-IgGSERUM, but two with multiple sclerosis cases were MOG-IgGCSF-positive; the specificities of MOG-IgGSERUM and MOG-IgGCSF in suspected MOGAD were 100% [95% confidence interval (CI) 99-100%] and 99% (95% CI 97-100%), respectively. Unlike AQP4-IgG-positive NMOSD, the correlation between MOG-IgGSERUM and MOG-IgGCSF titres in MOGAD was weak. Multivariable regression analyses revealed MOG-IgGSERUM was associated with ON and ADEM, whereas MOG-IgGCSF was associated with ADEM and CE. The number needed to test for MOG-IgGCSF to diagnose one additional MOGAD case was 13.3 (14.3 for ADEM, 2 for CE, 19.5 for NMOSD, infinite for ON, 18.5 for MY and 6.1 for Others). In terms of MOG-IgGSERUM/CSF status, most cases were double-positive while including either serum-restricted (13%) or CSF-restricted (17%) cases. These statuses were independently associated with clinical phenotypes, especially in those with ON in serum and CE in CSF, suggesting pathophysiologic implications and the utility of preferential diagnostic testing. Further studies are warranted to deduce the clinical and pathological significance of compartmentalized MOG-IgG.

The role of immunoglobulin in cerebrospinal fluid on the differential diagnosis of autoimmune encephalitis and viral encephalitis in children.

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.

Single-cell RNA sequencing reveals diverse B cell phenotypes in patients with anti-NMDAR encephalitis.

BACKGROUNDS: Anti-N-methyl-D-aspartate receptor encephalitis (NMDAR-E) is a severe autoimmune disorder characterized by prominent psychiatric symptoms. Although the role of NMDAR antibodies in the disease has been extensively studied, the phenotype of B cell subsets is still not fully understood. METHODS: We utilized single-cell RNA sequencing, single-cell B cell receptor sequencing (scBCR-seq), bulk BCR sequencing, flow cytometry, and enzyme-linked immunosorbent assay to analyze samples from both NMDAR-E patients and control individuals. RESULTS: The cerebrospinal fluid (CSF) of NMDAR-E patients showed significantly increased B cell counts, predominantly memory B (Bm) cells. CSF Bm cells in NMDAR-E patients exhibited upregulated expression of differential expression genes (DEGs) associated with immune regulatory function (TNFRSF13B and ITGB1), whereas peripheral B cells upregulated DEGs related to antigen presentation. Additionally, NMDAR-E patients displayed higher levels of IgD- CD27- double negative (DN) cells and DN3 cells in peripheral blood (PB). In vitro, DN1 cell subsets from NMDAR-E patients differentiated into DN2 and DN3 cells, while CD27+ and/or IgD+ B cells (non-DN) differentiated into antibody-secreting cells (ASCs) and DN cells. NR1-IgG antibodies were found in B cell culture supernatants from patients. Differential expression of B cell IGHV genes in CSF and PB of NMDAR-E patients suggests potential antigen class switching. CONCLUSION: B cell subpopulations in the CSF and PB of NMDAR-E patients exhibit distinct compositions and transcriptomic features. In vitro, non-DN cells from NMDAR-E can differentiate into DN cells and ASCs, potentially producing NR1-IgG antibodies. Further research is necessary to investigate the potential contribution of DN cell subpopulations to NR1-IgG antibody production.

Oligoclonal bands.

Oligoclonal bands (OCBs) represent the presence of intrathecal immunoglobulin G (IgG) as detected by isoelectric focusing and immunofixation. Cerebrospinal fluid (CSF) analysed alongside a paired serum sample gives five different immunofixation patterns. These are: type 1-the normal physiological state with no intrathecal IgG synthesis; type 2-evidence for intrathecal IgG synthesis, with CSF-restricted OCBs; type 3-evidence for intrathecal IgG synthesis, with CSF-restricted OCBs, but with additional, identical bands in the CSF and serum; type 4-absence of intrathecal IgG synthesis, but with identical OCBs in CSF and serum; and type 5-absence of intrathecal IgG synthesis, with a monoclonal band in CSF and serum. Analysis of these patterns can help to diagnose a range of neurological conditions, including multiple sclerosis. However, it is important to interpret OCB results alongside other CSF tests and their clinical context.

[The combined application of oligoclonal bands in cerebrospinal fluid and IgG intrathecal synthesis indicators and biochemical markers in the diagnosis of multiple sclerosis].

Objective: To establish and verify a diagnostic model for distinguishing multiple sclerosis (MS) from other neurological diseases with similar symptoms by usingcerebrospinal fluid oligoclonal band (CSF-OCB)combined with IgG intrathecal synthesis indicators and biochemical markers. Methods: Multiple sclerosis (MS) patients admitted to the Neurology Department of Beijing Tiantan Hospital affiliated with Capital Medical University from January 2014 to December 2022 were selected as the case group, while patients with similar neurological symptoms were selected as the control group. Using the case-control study design, a retrospective analysis was conducted on the detection of age, gender, oligoclonal bands in cerebrospinal fluid, IgG intrathecal synthesis indicators and biochemical indicators for all study subjects. The differential diagnosis model was determined by the multiple logistic regression analysis, and the receiver operating characteristic (ROC) curve was used to analyze the diagnostic efficiency of the differential diagnosis model for neurological diseases with similar symptoms to MS and other conditions. Results: This study included 167 patients in the case group and 335 patients in the control group, of which 128 patients in the case group and 265 patients in the control group were used to construct the model, and 39 patients in the case group and 70 patients in the control group were used for model validation. The differential diagnostic model constructed by a multivariate logistic regression model was Y=0.871×CSF-OCB-0.051×CSFprotein-0.231×CSFchloride+1.183×gender-0.036×LDH+35.770. The model showed that the area under the curve, sensitivity and specificity were respectively 0.916, 87.3% and 87.6%. The Delong test results showed that the diagnostic efficacy of the model was significantly different from OCB, IgG intrathecal synthesis indicators, and OCB combined with IgG intrathecal synthesis indicators (P<0.05). The new model validation showed that the actual diagnostic consistency rate for the MS group was 84.6%, while the actual diagnostic consistency rate for the control group was 90.0%. Conclusion: This study combines OCB, IgG intrathecal synthesis indicators, and biochemical indicators to establish a diagnostic prediction model for neurological diseases with similar clinical symptoms in MS. This model may have good differential diagnostic value and can better assist clinical diagnosis in the early stages of disease progression in MS patients.

Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A consensus statement.

Cerebrospinal fluid (CSF) analysis is of utmost importance for diagnosis and differential diagnosis of patients with suspected multiple sclerosis (MS). Evidence of intrathecal immunoglobulin G (IgG) synthesis proves the inflammatory nature of the disease, increases diagnostic certainty and substitutes for dissemination in time according to current diagnostic criteria. The gold standard to determine intrathecal IgG synthesis is the detection of CSF-restricted oligoclonal bands (OCBs). However, advances in laboratory methods brought up κ-free light chains (FLCs) as a new biomarker, which are produced in excess over intact immunoglobulins and accumulate in CSF in the case of central nervous system-derived inflammation. Overwhelming evidence showed a high diagnostic accuracy of intrathecal κ-FLC synthesis in MS with sensitivity and specificity of approximately 90% similar to OCB. κ-FLCs have advantages as its detection is fast, easy, cost-effective, reliable, rater-independent and returning quantitative results which might also improve the value of predicting MS disease activity. An international panel of experts in MS and CSF diagnostics developed a consensus of all participants. Six recommendations are given for establishing standard CSF evaluation in patients suspected of having MS. The panel recommended to include intrathecal κ-FLC synthesis in the next revision of MS diagnostic criteria as an additional tool to measure intrathecal immunoglobulin synthesis.

Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Intrathecal immunoglobulin-G synthesis is a hallmark of multiple sclerosis (MS), which can be detected by oligoclonal IgG bands (OCB) or by κ-free light chains (κ-FLC) in cerebrospinal fluid. OBJECTIVE: To perform a systematic review and meta-analysis to evaluate whether κ-FLC index has similar diagnostic value to identify patients with clinically isolated syndrome (CIS) or MS compared to OCB, and to determine κ-FLC index cut-off. METHODS: PubMed was searched for studies that assessed diagnostic sensitivity and specificity of κ-FLC index and OCB to discriminate CIS/MS patients from control subjects. Two reviewers following preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines performed study eligibility assessment and data extraction. Findings from studies were analyzed with bivariate mixed models. RESULTS: A total of 32 studies were included in the meta-analysis to evaluate diagnostic value of κ-FLC index. Sensitivity and specificity ranged from 52% to 100% (weighted average: 88%) and 69% to 100% (89%) for κ-FLC index and from 37% to 100% (85%) and 74% to 100% (92%) for OCB. Mean difference of sensitivity and specificity between κ-FLC index and OCB was 2 and -4 percentage points. Diagnostic accuracy determined by mixed models revealed no significant difference between κ-FLC index and OCB. A discriminatory cut-off for κ-FLC index was determined at 6.1. CONCLUSION: The findings indicate that κ-FLC index has similar diagnostic accuracy in MS as OCB.

Oligoclonal bands: clinical utility and interpretation cues.

Oligoclonal immunoglobulin G (IgG) bands (OCBs) are a useful diagnostic tool to detect a central humoral response. In particular, cerebrospinal fluid (CSF)-restricted OCBs represent a hallmark of multiple sclerosis (MS), where they can be detected in > 90% of cases and support its diagnosis, although a specific causative agent inducing B cell activation has not yet been identified. The determination of intrathecal IgM, including IgM/lipid-specific IgM OCBs, on the other hand, seems to be of prognostic relevance and is associated with a more aggressive disease course. OCBs can also be present in other central nervous system (CNS) disorders, including antibody-mediated, inflammatory, infectious, and neurodegenerative conditions, as well as in both chronic and early disease stages, suggesting the occurrence of primary or concomitant immune-mediated processes. Finally, intrathecal humoral immune response can also occur, although rarely, in patients with peripheral neuropathies, particularly in those of inflammatory origin, as a possible consequence of blood-spinal nerve root barrier (BSNRB) damage. Isoelectric focusing (IEF) on agarose gels followed by immunoblotting is the technique recommended for OCB detection, analyzing paired undiluted CSF and serum samples. However, technical issues including blot, staining, and IEF reproducibility as well as operator-dependent pattern interpretations decrease reproducibility, causing misinterpretations of results, with significant diagnostic implications. These technical issues can lead to difficulties in distinguishing between negative results (type 1 pattern = absence of OCBs in serum and CSF and type 4 pattern = presence of identical OCBs in both serum and CSF) and results indicating intrathecal IgG synthesis (pattern 2 = presence of OCBs in CSF and type 3 = presence of OCBs in CSF and additional identical OCBs in both serum and CSF). Corrective measures and identification of specialized laboratories with expertise in the field are fundamental to applying this useful technique in clinical practice. In this context, recent research has focused on the automated assessment of CSF kappa free light Ig chains as a more sensitive, non-operator-dependent marker of intrathecal Ig synthesis. We herein review central and peripheral nervous system conditions associated with OCBs and discuss their relation with pathogenetic mechanisms.

Cerebrospinal fluid findings in COVID-19: a multicenter study of 150 lumbar punctures in 127 patients.

BACKGROUND: Comprehensive data on the cerebrospinal fluid (CSF) profile in patients with COVID-19 and neurological involvement from large-scale multicenter studies are missing so far. OBJECTIVE: To analyze systematically the CSF profile in COVID-19. METHODS: Retrospective analysis of 150 lumbar punctures in 127 patients with PCR-proven COVID-19 and neurological symptoms seen at 17 European university centers RESULTS: The most frequent pathological finding was blood-CSF barrier (BCB) dysfunction (median QAlb 11.4 [6.72-50.8]), which was present in 58/116 (50%) samples from patients without pre-/coexisting CNS diseases (group I). QAlb remained elevated > 14d (47.6%) and even > 30d (55.6%) after neurological onset. CSF total protein was elevated in 54/118 (45.8%) samples (median 65.35 mg/dl [45.3-240.4]) and strongly correlated with QAlb. The CSF white cell count (WCC) was increased in 14/128 (11%) samples (mostly lympho-monocytic; median 10 cells/µl, > 100 in only 4). An albuminocytological dissociation (ACD) was found in 43/115 (37.4%) samples. CSF L-lactate was increased in 26/109 (24%; median 3.04 mmol/l [2.2-4]). CSF-IgG was elevated in 50/100 (50%), but was of peripheral origin, since QIgG was normal in almost all cases, as were QIgA and QIgM. In 58/103 samples (56%) pattern 4 oligoclonal bands (OCB) compatible with systemic inflammation were present, while CSF-restricted OCB were found in only 2/103 (1.9%). SARS-CoV-2-CSF-PCR was negative in 76/76 samples. Routine CSF findings were normal in 35%. Cytokine levels were frequently elevated in the CSF (often associated with BCB dysfunction) and serum, partly remaining positive at high levels for weeks/months (939 tests). Of note, a positive SARS-CoV-2-IgG-antibody index (AI) was found in 2/19 (10.5%) patients which was associated with unusually high WCC in both of them and a strongly increased interleukin-6 (IL-6) index in one (not tested in the other). Anti-neuronal/anti-glial autoantibodies were mostly absent in the CSF and serum (1509 tests). In samples from patients with pre-/coexisting CNS disorders (group II [N = 19]; including multiple sclerosis, JC-virus-associated immune reconstitution inflammatory syndrome, HSV/VZV encephalitis/meningitis, CNS lymphoma, anti-Yo syndrome, subarachnoid hemorrhage), CSF findings were mostly representative of the respective disease. CONCLUSIONS: The CSF profile in COVID-19 with neurological symptoms is mainly characterized by BCB disruption in the absence of intrathecal inflammation, compatible with cerebrospinal endotheliopathy. Persistent BCB dysfunction and elevated cytokine levels may contribute to both acute symptoms and 'long COVID'. Direct infection of the CNS with SARS-CoV-2, if occurring at all, seems to be rare. Broad differential diagnostic considerations are recommended to avoid misinterpretation of treatable coexisting neurological disorders as complications of COVID-19.

The relationship between the laboratory diagnosis of Lyme neuroborreliosis and climate factors in Kalmar County Sweden - an overview between 2008 and 2019.

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 × 106/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.

Ocular Findings in Infants with Congenital Toxoplasmosis after a Toxoplasmosis Outbreak.

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.

Uncommon manifestations of a rare disease: a case of autoimmune GFAP astrocytopathy.

BACKGROUND: Manifestations of intractable hyponatremia and hypokalemia in autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy have been rarely reported. CASE PRESENTATION: A 75-year-old male patient presented as the case of syndrome of inappropriate antidiuretic hormone secretion (SIADH) and intractable hypokalemia, showed fever, fatigue, and mental disorders. Signs and symptoms of meningoencephalitis, ataxia, and cognitive abnormalities. Magnetic resonance imaging (MRI) revealed multiple white matter lesions of the central nervous system. He had GFAP-IgG in the cerebrospinal fluid (CSF). After treatment with corticosteroids, his symptoms were alleviated gradually, and the level of electrolytes was normal. However, head contrast-enhanced MRI + susceptibility-weighted imaging (SWI) showed a wide afflicted region, and the serum GFAP-IgG turned positive. Considering the relapse of the disease, ha was treated with immunoglobulin and mycophenolate mofetil (MMF) to stabilize his condition. CONCLUSION: This case showed a rare disease with uncommon manifestations, suggesting that careful examination and timely diagnosis are essential for disease management and satisfactory prognosis.