Diagnosis of multiple sclerosis in times of MOG and AQP4 autoantibody testing - A monocentric study.

BACKGROUND: Myelin oligodendrocyte glycoprotein-IgG-associated encephalomyelitis (MOG-EM) and neuromyelitis optica spectrum disorders are challenging differential diagnoses of multiple sclerosis (MS). Hence, there is uncertainty, whether to test all MS patients for corresponding antibodies. Our objective was to provide a systematic study on the frequency of MOG and Aquaporin-4 (AQP4) autoantibodies in MS patients to evaluate a possible risk of misclassification. METHODS: Retrospective study in MS patients (including an unselected cohort of patients diagnosed with MS, a cohort of patients with PPMS and a healthy control group) for seroprevalence of MOG and AQP4 autoantibodies by cell-based assay. RESULTS: None of 241 patients with relapsing-remitting, 19 with secondary progressive and 82 with primary progressive MS revealed MOG or AQP4 autoantibodies. CONCLUSION: General testing of MOG and AQP4 autoantibodies in MS patients seems not necessary, but should be limited to selected cases only.

Cerebrospinal Fluid Biomarkers in Relation to MRZ Reaction Status in Primary Progressive Multiple Sclerosis.

The MRZ reaction (MRZR) comprises the three antibody indices (AIs) against measles, rubella, and varicella zoster virus, reflecting an intrathecal polyspecific B cell response highly specific for multiple sclerosis (MS). Thus, MRZR can be used to confirm a diagnosis of primary progressive MS (PPMS) but its pathophysiological and wider clinical relevance is unclear. This study aimed to investigate whether PPMS patients with a positive MRZR (MRZR+) differ from those with a negative MRZR (MRZR-) according to cerebrospinal fluid (CSF) biomarkers of B cell activity, neuroaxonal damage or glial activity, and clinical features. (1) Methods: In a multicenter PPMS cohort (n = 81) with known MRZR status, we measured B cell-activating factor (BAFF), chemokine CXC ligand 13 (CXCL-13), soluble B cell maturation antigen (sBCMA), soluble transmembrane activator and CAML interactor (sTACI), and chitinase-3-like protein 1 (CHI3L1) in the CSF with enzyme-linked immunosorbent assays (ELISAs). Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were detected in serum and CSF using single molecule array (SIMOA) technology. (2) Results: MRZR+ patients (45.7% of all PPMS patients) revealed higher levels of NfL in CSF compared to MRZR- patients (54.3%). There were positive correlations between each of sBCMA, sTACI, and intrathecal immunoglobin G (IgG) synthesis. Additionally, NfL concentrations in serum positively correlated with those in CSF and those of GFAP in serum. However, MRZR+ and MRZR- patients did not differ concerning clinical features (e.g., age, disease duration, Expanded Disability Status Scale (EDSS) at diagnosis and follow-up); CSF routine parameters; CSF concentrations of BAFF, CXCL-13, sBCMA, sTACI, CHI3L1, and GFAP; or serum concentrations of GFAP and NfL. (3) Conclusions: In PPMS patients, MRZR positivity might indicate a more pronounced axonal damage. Higher levels of the soluble B cell receptors BCMA and transmembrane activator and CAML interactor (TACI) in CSF are associated with a stronger intrathecal IgG synthesis in PPMS.

Increased IL-8 concentrations in the cerebrospinal fluid of patients with unipolar depression.

INTRODUCTION: Unipolar depression is a common and debilitating disorder. Immunological explanatory approaches have become increasingly important in recent years and can be studied particularly well in the cerebrospinal fluid (CSF). Previous studies discerned alterations in interleukin (IL)-6 and IL-8 levels; however, findings regarding IL-8 were partly contradictory. The aim of the present study was to investigate the concentrations of different cytokines and chemokines, focusing on IL-8, in the CSF of patients with unipolar depression. MATERIALS AND METHODS: Participants included 40 patients with unipolar depression and 39 mentally healthy controls with idiopathic intracranial hypertension. CSF cytokine levels were measured using a magnetic bead multiplexing immunoassay. RESULTS: IL-8 levels in the CSF of the patient group with depression were significantly higher than those in the control group (Mean ± SD: 38.44 ± 6.26 pg/ml versus 21.40 ± 7.96 pg/ml; p < .001). LIMITATIONS: The significance of the results is limited by the retrospective design and methodological aspects. DISCUSSION: The main findings of this study were significantly higher concentrations of IL-8 in the CSF of patients with unipolar depression than in the control group. The detection of high CSF IL-8 levels in this study supports the idea that inflammatory processes might play a role in the pathophysiology of a subgroup of patients with depression.

Anti-Thyroid Peroxidase and Anti-Thyroglobulin Autoantibodies in the Cerebrospinal Fluid of Patients with Unipolar Depression.

INTRODUCTION: The risk of developing depression is increased in patients with autoimmune thyroiditis. Autoimmune Hashimoto thyroiditis is diagnosed using the serum markers anti-thyroid peroxidase (TPO) and anti-thyroglobulin (TG) antibodies. In rare cases, patients with autoimmune thyroiditis can also suffer from the heterogeneous and ill-defined syndrome of Hashimoto encephalopathy. Biomarkers for Hashimoto encephalopathy or for any brain involvement of autoimmune thyroiditis are currently lacking. The aim of the present descriptive study was therefore to determine whether a subgroup of seropositive patients shows intrathecal anti-thyroid antibody synthesis in the cerebrospinal fluid (CSF). PARTICIPANTS AND METHODS: Paired serum and CSF samples from 100 patients with unipolar depression were examined for anti-TPO and anti-TG antibodies using enzyme-linked immunosorbent assays. Antibody-specific indices (ASIs) were calculated for seropositive samples. These ASIs allow the differentiation between the brain-derived fraction of antibodies and antibodies which are passively diffused from the serum. ASIs >1.4 were assessed as positive for brain-derived antibodies. Additionally, for explorative evaluations, a stricter ASI limit of >2 was applied. RESULTS: Anti-TPO antibodies were increased in the serum of 16 patients (16%); increased anti-TPO ASIs (>1.4) were detected in 11 of these patients (69%). Anti-TG antibodies in the serum were detected in three patients (3%), with two of them (67%) showing increased ASIs (>1.4). Overall, the authors found increased anti-thyroid antibodies in 17 of 100 patients (17%), with 13 out of 17 patients showing increased ASIs (76%; range 1.4-4.1). Choosing ASI levels of >2 led to positive findings in six out of 16 patients (38%) with anti-TPO antibodies in their serum but no increase in ASIs in three patients (0%) who were seropositive for anti-TG antibodies. The patients with elevated ASIs (N = 13) were younger than the ASI-negative patients (N = 87; p = 0.009); no differences were noted in the frequency of CSF, electroencephalography, and/or magnetic resonance imaging alterations. DISCUSSION: A subgroup of seropositive patients showed intrathecal synthesis of anti-TPO and, more rarely, of anti-TG antibodies, which might be an indication of central autoimmunity in a subgroup of patients with unipolar depression. The confirmation of elevated ASIs as a biomarker for Hashimoto encephalopathy must await further studies. The relevance of the findings is limited by the study's retrospective and uncontrolled design.

Cerebrospinal Fluid Findings of 36 Adult Patients with Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder characterized by difficulties with social interaction, repetitive behavior, and additional features, such as special interests. Its precise etiology is unclear. Recently, immunological mechanisms, such as maternal autoantibodies/infections, have increasingly been the subject of discussion. Cerebrospinal fluid (CSF) investigations play a decisive role in the detection of immunological processes in the brain. This study therefore retrospectively analyzed the CSF findings of adult patients with ASD. CSF basic measures (white blood cell count, total protein, albumin quotient, immunoglobulin G (IgG) index, and oligoclonal bands) and various antineuronal antibody findings of 36 adult patients with ASD, who had received lumbar puncture, were compared with an earlier described mentally healthy control group of 39 patients with idiopathic intracranial hypertension. CSF protein concentrations and albumin quotients of patients with ASD were significantly higher as compared to controls (age corrected: p = 0.003 and p = 0.004, respectively); 17% of the patients with ASD showed increased albumin quotients. After correction for age and gender, the group effect for total protein remained significant (p = 0.041) and showed a tendency for albumin quotient (p = 0.079). In the CSF of two ASD patients, an intrathecal synthesis of anti-glutamate decarboxylase 65 (GAD65) antibodies was found. In total, more of the ASD patients (44%) presented abnormal findings in CSF basic diagnostics compared to controls (18%; p = 0.013). A subgroup of the patients with adult ASD showed indication of a blood-brain barrier dysfunction, and two patients displayed an intrathecal synthesis of anti-GAD65 antibodies; thus, the role of these antibodies in patients with ASD should be further investigated. The results of the study are limited by its retrospective and open design. The group differences in blood-brain barrier markers could be influenced by a different gender distribution between ASD patients and controls.