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INTRODUCTION: The role of autoimmune responses against central nervous system (CNS) antigens in encephalitis presenting with non-classified neurologic or psychiatric symptoms has been appreciated in the past decade. Paraneoplastic limbic encephalitis has a poor prognosis and is most commonly associated with lung, ovarium, and testicular neoplasms, leading to immune reactions against intracellular antigens (anti-Hu/ANNA1, anti-Ri/ANNA2, anti-CV2/CRMP5 and anti-Ma2/Ta). In contrast, the recently described autoimmune encephalitis subtypes present with a broad spectrum of symptoms, respond to autoimmune therapies well and usually associate with autoantibodies against neuronal cell surface receptors (NMDAR, GABABR, AMPAR) or synaptic proteins (LGI1, CASPR2). AIM: Our aim is to bring to awareness the increasing number of autoimmune encephalitis patients requiring neurologic, psychiatric and intensive care and to emphasize the significance of detecting various autoantibodies in diagnosing patients. METHOD: In the past 6 years, our laboratory received 836 autoimmune encephalitis diagnostic test requests from a total of 717 patients. Serum and cerebrospinal fluid (CSF) samples were analysed with indirect immunofluorescence using a BIOCHIP consisting of cell lines transfected with 6 different receptor proteins. RESULTS: IgG autoantibodies against receptor proteins were present in 7.5% of patients. The frequency of positive samples was the following: NMDAR > LGI1 > GABABR > CASPR2. CONCLUSION: Detecting autoantibodies facilitates the diagnosis of autoimmune encephalitis in an early stage. Patients diagnosed early can be effectively treated with plasmapheresis and immunosuppressive drugs. The efficiency of therapies can be monitored by autoantibody detection. Therefore, the diagnostic immune laboratory plays an important role in proper diagnosis and in the prevention of rapidly progressing symptoms. Orv Hetil. 2018; 159(3): 107-112.
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Autoanticorpos/sangue , Autoanticorpos/líquido cefalorraquidiano , Proteínas de Transporte/sangue , Proteínas de Transporte/líquido cefalorraquidiano , Encefalite/sangue , Encefalite/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Líquido Cefalorraquidiano/química , Feminino , Humanos , MasculinoRESUMO
Resting-state functional magnetic resonance imaging (rs-fMRI) has been widely utilized to investigate plasticity mechanisms and functional reorganization in multiple sclerosis (MS). Among many resting state (RS) networks, a significant role is played by the salience network (SN, ventral attention network). Previous reports have demonstrated the involvement of osteopontin (OPN) in the pathogenesis of MS, which acts as a proinflammatory cytokine ultimately leading to neurodegeneration. Concentration of serum OPN was related to MRI findings 10.22±2.84 years later in 44 patients with MS. Local and interhemispheric correlations (LCOR, IHC), ROI-to-ROI and seed-based connectivity analyses were performed using serum OPN levels as independent variable along with age and gender as nuisance variables. We found significant associations between OPN levels and local correlation in right and left clusters encompassing the central opercular- and insular cortices (p-FDR = 0.0018 and p-FDR = 0.0205, respectively). Moreover, a significant association was identified between OPN concentration and interhemispheric correlation between central opercular- and insular cortices (p-FDR = 0.00015). Significant positive associations were found between OPN concentration and functional connectivity (FC) within the SN (FC strength between the anterior insula ventral division and 3 other insular regions, F(2,13) = 7.84, p-FDR = 0.0117). Seed-based connectivity analysis using the seven nodes of the SN resulted in several positive and inverse associations with OPN level. Serum OPN level may predict FC alterations within the SN in 10 years.
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Imageamento por Ressonância Magnética , Esclerose Múltipla , Osteopontina , Humanos , Osteopontina/sangue , Feminino , Masculino , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla/sangue , Adulto , Pessoa de Meia-Idade , Rede Nervosa/fisiopatologia , Rede Nervosa/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologiaRESUMO
BACKGROUND AND OBJECTIVES: Patients with ongoing seizures are usually not allowed to drive. The prognosis for seizure freedom is favorable in patients with autoimmune encephalitis (AIE) with antibodies against NMDA receptor (NMDAR), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and the gamma-aminobutyric-acid B receptor (GABABR). We hypothesized that after a seizure-free period of 3 months, patients with AIE have a seizure recurrence risk of <20% during the subsequent 12 months. This would render them eligible for noncommercial driving according to driving regulations in several countries. METHODS: This retrospective multicenter cohort study analyzed follow-up data from patients aged 15 years or older with seizures resulting from NMDAR-, LGI1-, CASPR2-, or GABABR-AIE, who had been seizure-free for ≥3 months. We used Kaplan-Meier (KM) estimates for the seizure recurrence risk at 12 months for each antibody group and tested for the effects of potential covariates with regression models. RESULTS: We included 383 patients with NMDAR-, 440 with LGI1-, 114 with CASPR2-, and 44 with GABABR-AIE from 14 international centers. After being seizure-free for 3 months after an initial seizure period, we calculated the probability of remaining seizure-free for another 12 months (KM estimate) as 0.89 (95% confidence interval [CI] 0.85-0.92) for NMDAR, 0.84 (CI 0.80-0.88) for LGI1, 0.82 (CI 0.75-0.90) for CASPR2, and 0.76 (CI 0.62-0.93) for GABABR. DISCUSSION: Taking a <20% recurrence risk within 12 months as sufficient, patients with NMDAR-AIE and LGI1-AIE could be considered eligible for noncommercial driving after having been seizure-free for 3 months.
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Autoanticorpos , Encefalite , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana , Proteínas do Tecido Nervoso , Receptores de GABA-B , Recidiva , Humanos , Feminino , Masculino , Adulto , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Autoanticorpos/sangue , Pessoa de Meia-Idade , Encefalite/imunologia , Estudos Retrospectivos , Receptores de GABA-B/imunologia , Proteínas do Tecido Nervoso/imunologia , Adulto Jovem , Proteínas de Membrana/imunologia , Receptores de N-Metil-D-Aspartato/imunologia , Convulsões/etiologia , Convulsões/imunologia , Doença de Hashimoto/imunologia , Doença de Hashimoto/sangue , Idoso , Adolescente , Seguimentos , Proteínas/imunologia , Estudos de CoortesRESUMO
Osteopontin (OPN) is a proinflammatory marker produced by systemic immune and central nervous system (CNS) resident cells. We examined, if the level of OPN in the cerebrospinal fluid (CSF) and blood is associated with late-time regional brain volumes and white matter (WM) lesion load in MS. Concentrations of OPN in blood and CSF were related to MRI findings 10.1 ± 2.0 years later in 46 patients with MS. OPN concentration was measured by ELISA, while regional brain volumes and lesion load was assessed by magnetic resonance imaging (MRI) using 3D MPRAGE sequence and automated MR volumetry. OPN measured in the CSF was associated with several regional brain volumes and WM lesion load measured 10.1 ± 2.0 years later. CSF OPN concentration correlated with long-term enlargement of lateral- and inferior lateral ventricles and the elevation of gross CSF volume, in conjunction with the reduction of several cortical/subcortical gray matter and WM volumes. Serum OPN showed no long-term association with regional brain volumes. OPN measured from the CSF but not from the serum was associated with lower regional brain volumes measured a decade later, indicating the primary role of inflammation within the CNS in developing long-term brain related alterations.
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Encéfalo/patologia , Esclerose Múltipla/sangue , Osteopontina/metabolismo , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Osteopontina/sangue , Osteopontina/líquido cefalorraquidiano , Adulto JovemRESUMO
PURPOSE: Decreased expression of TLR homolog CD180 in peripheral blood B cells and its potential role in antibody production have been described in autoimmune diseases. Effectiveness of anti-CD20 therapy in neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) strengthens the role of B cells in the pathogenesis. Therefore, we aimed to investigate the CD180 expression of peripheral blood B cell subsets in NMOSD and MS patients and analyze the levels of natural anti-citrate synthase (CS) IgG autoantibodies and IgG antibodies induced by bacterial infections reported to play a role in the pathogenesis of NMOSD or MS. METHODS: We analyzed the distribution and CD180 expression of peripheral blood B cell subsets, defined by CD19/CD27/IgD staining, and measured anti-CS IgM/G natural autoantibody and antibacterial IgG serum levels in NMOSD, RRMS, and healthy controls (HC). RESULTS: We found decreased naïve and increased memory B cells in NMOSD compared to MS. Among the investigated four B cell subsets, CD180 expression was exclusively decreased in CD19+CD27+IgD+ nonswitched (NS) memory B cells in both NMOSD and MS compared to HC. Furthermore, the anti-CS IgM natural autoantibody serum level was lower in both NMOSD and MS. In addition, we found a tendency of higher anti-CS IgG natural autoantibody levels only in anti-Chlamydia IgG antibody-positive NMOSD and MS patients. CONCLUSIONS: Our results suggest that reduced CD180 expression of NS B cells could contribute to the deficient natural IgM autoantibody production in NMOSD and MS, whereas natural IgG autoantibody levels show an association with antibacterial antibodies.
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Antígenos CD/metabolismo , Autoanticorpos/imunologia , Subpopulações de Linfócitos B/imunologia , Citrato (si)-Sintase/imunologia , Células B de Memória/imunologia , Esclerose Múltipla/imunologia , Neuromielite Óptica/imunologia , Adulto , Idoso , Antígenos CD/genética , Células Cultivadas , Regulação para Baixo , Feminino , Humanos , Imunoglobulina M/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores Toll-Like/genética , Adulto JovemRESUMO
BACKGROUND: Osteopontin (OPN) is a proinflammatory biomarker, and neurofilament light chain (NFL) levels reflect axonal damage. Resting-state functional MRI (rs-fMRI) defines brain networks during wakeful rest. OBJECTIVE: To examine, if levels of OPN and NFL are associated on the long term with (i) lesion evolution, (ii) changes in normal-appearing white matter (NAWM) microstructure and (iii) functional connectivity in multiple sclerosis (MS). METHODS: Concentration of NFL and OPN in the blood and CSF were related to MRI findings 10.3 ± 2.8 years later in 53 patients with MS. NFL was examined by Simoa method, OPN by ELISA. Lesion volume in the brain and cervical spinal cord was examined by 3D FLAIR images. Voxel-wise images of fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) were examined by tract-based spatial statistics corrected for gender, age and lesion volume. Metabolites were examined by single-voxel MR-spectroscopy in the NAWM. Fifty-five default mode network connections were examined by rs-fMRI corrected for gender, age, MS subtype and current therapy as covariates. RESULTS: While NFL in paired serum and CSF positively correlated (p = 0.019), there was no correlation between serum and CSF OPN. Higher OPN levels in the CSF but not in the serum showed association with increased brain WM lesion volume (p = 0.009) in 10.3 ± 2.8 years. Higher OPN in the CSF was associated with reduced FA, increased MD, and reduced RD in different NAWM areas 10.3 ± 2.8 years later. Higher OPN in the serum and CSF were associated with increased connectivity strength between the medial prefrontal cortex (MPFC) and other regions except with inferior parietal lobule. NFL in the CSF and in the serum was associated with decreased connectivity strength except for ventral MPFC-hippocampal formation. Neither serum OPN nor NFL at the time of the MRI were associated with functional connectivity changes. CONCLUSION: While serum NFL levels reflects CNS production, OPN in serum and CSF may have different cellular sources. OPN within the CSF but not in the serum may forecast development of lesions and microstructural abnormalities in 10 years, indicating the detrimental role of CNS inflammation on the long-term. Although both OPN and NFL in the CSF were associated with functional connectivity changes in 10 years, NFL was associated with decreased strength possibly indicating general axonal loss. In contrast, the positive association of OPN levels in the CSF with increased connectivity strength in 10 years may point to adaptive re-organization due to inflammatory WM lesions and microstructural changes.
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Esclerose Múltipla , Substância Branca , Encéfalo/diagnóstico por imagem , Humanos , Filamentos Intermediários , Esclerose Múltipla/diagnóstico por imagem , Proteínas de Neurofilamentos , Osteopontina , Substância Branca/diagnóstico por imagemRESUMO
Background: In our previous single-center study of autoimmune encephalitis (AE) related autoantibody test results we found positivity in 60 patients out of 1,034 with suspected AE from 2012 through 2018 as part of a Hungarian nationwide program. In our current multicenter retrospective study, we analyzed the clinical characteristics and outcome of AE patients with positive neuronal cell surface autoantibody test results. Methods: A standard online questionnaire was used to collect demographic and clinical characteristics, laboratory and imaging data, therapy and prognosis of 30 definitive AE patients in four major clinical centers of the region. Results: In our study, 19 patients were positive for anti-NMDAR (63%), 6 patients (20%) for anti-LGI1, 3 patients for anti-GABABR (10%) and 3 patients for anti-Caspr2 (10%) autoantibodies. Most common prodromal symptoms were fever or flu-like symptoms (10/30, 33%). Main clinical features included psychiatric symptoms (83%), epileptic seizures (73%) and memory loss (50%). 19 patients (63%) presented with signs of central nervous system (CNS) inflammation, which occurred more frequently in elder individuals (p = 0.024), although no significant differences were observed in sex, tumor association, time to diagnosis, prognosis and immunotherapy compared to AE patients without CNS inflammatory markers. Anti-NMDAR encephalitis patients were in more severe condition at the disease onset (p = 0.028), although no significant correlation between mRS score, age, sex and immunotherapy was found. 27% of patients (n = 8) with associated tumors had worse outcome (p = 0.045) than patients without tumor. In most cases, immunotherapy led to clinical improvement of AE patients (80%) who achieved a good outcome (mRS ≤ 2; median follow-up 33 months). Conclusion: Our study confirms previous publications describing characteristics of AE patients, however, differences were observed in anti-NMDAR encephalitis that showed no association with ovarian teratoma and occurred more frequently among young males. One-third of AE patients lacked signs of inflammation in both CSF and brain MRI, which emphasizes the importance of clinical symptoms and autoantibody testing in diagnostic workflow for early introduction of immunotherapy, which can lead to favorable outcome in AE patients.
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Paraneoplastic neurologic syndromes (PNS) and autoimmune encephalitis (AE) are rare neurological disorders, which have similar symptoms, but vary in outcome and treatment strategy. In our retrospective statistical study we evaluated the autoantibody test results of serum and CSF from 2362 patients with suspected PNS and 1034 patients with suspected AE. For autoantibody testing, immunoblot assay (PNS) and cell-based indirect immunofluorescence assay (AE) were used. Autoantibodies were present in 8% of patients with suspected PNS: anti-Yo > anti-Hu > anti-Ma2 > anti-CV2 > anti-titin > anti-Zic4 > anti-amphiphysin > anti-Ri > anti-GAD65 > anti-Sox1 > anti-recoverin. Mostly elderly women were affected. Autoantibodies were present in 5.8% of patients with suspected AE: anti-NMDAR (young women) > anti-LGI1 (middle-aged men) > anti-GABABR (elderly men) > anti-Caspr2 (adult men). Our results correspond to the data described in the literature. The number of patients with suspected PNS and AE shows an increasing tendency, where the autoantibody testing with modern laboratory diagnostic methods helps in the early introduction of the appropriate therapy.
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Encefalite/diagnóstico , Encefalite/imunologia , Doença de Hashimoto/diagnóstico , Doença de Hashimoto/imunologia , Síndromes Paraneoplásicas do Sistema Nervoso/diagnóstico , Síndromes Paraneoplásicas do Sistema Nervoso/imunologia , Adulto , Idoso , Autoanticorpos/sangue , Autoanticorpos/líquido cefalorraquidiano , Autoanticorpos/imunologia , Encefalite/terapia , Feminino , Doença de Hashimoto/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Paraneoplásicas do Sistema Nervoso/terapia , Estudos RetrospectivosRESUMO
OBJECTIVE: Autoantibody detection is crucial for the early diagnosis of autoimmune encephalitis (AIE) since prompt therapy can determine the disease outcome. Here, we report a single-center 6-year retrospective study of autoantibody testing in AIE in the Hungarian population. METHODS: Serum and/or cerebrospinal fluid (CSF) autoantibody tests were performed using cell-based indirect immunofluorescence assay for AIE diagnosis. Samples were provided by neurology clinics as part of a nationwide program. Test results were analyzed for samples received during the period from 2012 to 2018. RESULTS: We tested 1,247 samples from 1,034 patients with suspected AIE. Autoantibodies were present in 60 patients (5.8% of total). The distribution of patients with different autoantibodies by age and sex was as follows: NMDAR (70%), mostly in young females, LGI1 (15%) in middle-aged males, GABAB R (12%) in elderly males, and Caspr2 (7%) in males. Long-term follow-up was conducted in 30 patients with repeated test requests, of which 17 remained positive, and 13 switched to negative. CONCLUSION: We report the most comprehensive clinical laboratory study of autoantibody testing in AIE in the Hungarian population. Our results show that the frequency of different autoantibody types in AIE corresponds to the data described in the literature.