Neural autoantibodies in cerebrospinal fluid and serum in clinical high risk for psychosis, first-episode psychosis, and healthy volunteers

The pathophysiological role of neural autoantibodies in acute psychotic disorders is receiving increased attention. However, there is still an ongoing debate, whether predominantly psychotic manifestations of autoimmune encephalitides exist that may remain undetected and, thus, untreated. Furthermore, it is discussed if such conditions can be diagnosed based on serum antibody results or if a reliable diagnosis requires additional cerebrospinal fluids (CSF) results. In this study, we screened pairs of serum and CSF samples from antipsychotic-naïve individuals with first-episode schizophrenic psychosis (FEP, n = 103), clinical high risk for psychosis (CHR, n = 47), and healthy volunteers (HV, n = 40) for eight different antibodies against various antigens that have been shown to be associated with autoimmune encephalitides: N-methyl-D-aspartate receptor (NMDAR, NR1 subunits only), glutamic acid decarboxylase (GAD65), leucine-rich glioma inactivated protein 1 (LGI1), contactin-associated protein-like 2 protein (CASPR2), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit 1, AMPAR subunit 2, γ-aminobutyric acid-B receptors (GABABR), and glycine receptors. All patients were within the norm with regards to a careful neurological examination, a magnetic resonance imaging (MRI) of the brain, an electroencephalogram (EEG), and routine blood pathology. All CSF samples were autoantibody-negative. In three serum samples of individuals with FEP, we detected low-titer CASPR2 immunoglobulin (Ig) G antibodies (≤1:160, n = 2) and non-IgG antibodies against NMDAR (n = 1) (overall serum-autoantibody prevalence in FEP: 2.91%). However, the IgG titers were below the laboratory cut-off defined for positivity, and non-IgG antibodies are of no clinical relevance. This suggests that there were no cases of autoimmune encephalitis in our cohort. Our results highlight the importance and the high specificity of CSF analysis to reliably detect autoantibodies. They confirm the hypothesis that pure psychotic manifestations of antibody-associated autoimmune encephalitides without any additional neuropsychiatric findings are very rare. However, special attention must be paid to those presenting with atypical mental illnesses with additional neurological symptoms, evidence of clinically-significant cognitive involvement, profound sleep-wake perturbations, seizures, electroencephalographic, or magnetic resonance imaging pathologies to be able to identify cases with autoimmune-mediated psychiatric syndromes

Neural Autoantibodies in Cerebrospinal Fluid and Serum in Clinical High Risk for Psychosis, First-Episode Psychosis, and Healthy Volunteers

Bien C, Rohleder C, Mueller JK, Bien CI, Koethe D, Leweke FM. Neural Autoantibodies in Cerebrospinal Fluid and Serum in Clinical High Risk for Psychosis, First-Episode Psychosis, and Healthy Volunteers. Frontiers in psychiatry. 2021;12: 654602.The pathophysiological role of neural autoantibodies in acute psychotic disorders is receiving increased attention. However, there is still an ongoing debate, whether predominantly psychotic manifestations of autoimmune encephalitides exist that may remain undetected and, thus, untreated. Furthermore, it is discussed if such conditions can be diagnosed based on serum antibody results or if a reliable diagnosis requires additional cerebrospinal fluids (CSF) results. In this study, we screened pairs of serum and CSF samples from antipsychotic-naive individuals with first-episode schizophrenic psychosis (FEP, n = 103), clinical high risk for psychosis (CHR, n = 47), and healthy volunteers (HV, n = 40) for eight different antibodies against various antigens that have been shown to be associated with autoimmune encephalitides: N-methyl-D-aspartate receptor (NMDAR, NR1 subunits only), glutamic acid decarboxylase (GAD65), leucine-rich glioma inactivated protein 1 (LGI1), contactin-associated protein-like 2 protein (CASPR2), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit 1, AMPAR subunit 2, gamma-aminobutyric acid-B receptors (GABABR), and glycine receptors. All patients were within the norm with regards to a careful neurological examination, a magnetic resonance imaging (MRI) of the brain, an electroencephalogram (EEG), and routine blood pathology. All CSF samples were autoantibody-negative. In three serum samples of individuals with FEP, we detected low-titer CASPR2 immunoglobulin (Ig) G antibodies (≤1:160, n = 2) and non-IgG antibodies against NMDAR (n = 1) (overall serum-autoantibody prevalence in FEP: 2.91%). However, the IgG titers were below the laboratory cut-off defined for positivity, and non-IgG antibodies are of no clinical relevance. This suggests that there were no cases of autoimmune encephalitis in our cohort. Our results highlight the importance and the high specificity of CSF analysis to reliably detect autoantibodies. They confirm the hypothesis that pure psychotic manifestations of antibody-associated autoimmune encephalitides without any additional neuropsychiatric findings are very rare. However, special attention must be paid to those presenting with atypical mental illnesses with additional neurological symptoms, evidence of clinically-significant cognitive involvement, profound sleep-wake perturbations, seizures, electroencephalographic, or magnetic resonance imaging pathologies to be able to identify cases with autoimmune-mediated psychiatric syndromes. Copyright © 2021 Bien, Rohleder, Mueller, Bien, Koethe and Leweke

Early immunotherapy is highly effective in IgG1/IgG4 positive IgLON5 disease

Visually induced self-motion perception (vection) relies on visual-vestibular interaction. Imaging studies using vestibular stimulation have revealed a vestibular thalamo-cortical dominance in the right hemisphere in right handers and the left hemisphere in left handers. We investigated if the behavioural characteristics and neural correlates of vection differ between healthy left and right-handed individuals. 64-channel EEG was recorded while 25 right handers and 25 left handers were exposed to vection-compatible roll motion (coherent motion) and a matched, control condition (incoherent motion). Behavioural characteristics, i.e. vection presence, onset latency, duration and subjective strength, were also recorded. The behavioural characteristics of vection did not differ between left and right handers (all p > 0.05). Fast Fourier Transform (FFT) analysis revealed significant decreases in alpha power during vection-compatible roll motion (p < 0.05). The topography of this decrease was handedness-dependent, with left handers showing a left lateralized centro-parietal decrease and right handers showing a bilateral midline centro-parietal decrease. Further time-frequency analysis, time locked to vection onset, revealed a comparable decrease in alpha power around vection onset and a relative increase in alpha power during ongoing vection, for left and right handers. No effects were observed in theta and beta bands. Left and right-handed individuals show vection-related alpha power decreases at different topographical regions, possibly related to the influence of handedness-dependent vestibular dominance in the visual-vestibular interaction that facilitates visual self-motion perception. Despite this difference in where vection-related activity is observed, left and right handers demonstrate comparable perception and underlying alpha band changes during vection

Glial Fibrillary Acidic Protein Autoimmunity After Aseptic Meningitis: A Report of 2 Cases

Bien C, Büttner T, Reichen I, et al. Glial Fibrillary Acidic Protein Autoimmunity After Aseptic Meningitis: A Report of 2 Cases. Neurology: Neuroimmunology & Neuroinflammation. 2024;11(1): e200180.OBJECTIVES: We describe 2 patients with glial fibrillary acidic protein (GFAP) autoimmunity secondary to aseptic viral meningitis or meningoencephalomyelitis.; METHODS: This study involved a retrospective chart review.; RESULTS: Two female patients, 45 and 55 years of age, developed aseptic meningoencephalomyelitis or meningitis; in one patient, it was likely caused by herpes simplex virus 2. The patients were recovering from the infectious condition when they, 51 and 5 days after onset, had new symptoms with detection of GFAP antibodies in the CSF; CSF and serum samples from the initial lumbar punctures had been negative for GFAP antibodies. Both patients recovered with steroid treatment (in one case, plus rituximab; in the other, plus azathioprine) including resolution of MRI and CSF abnormalities.; DISCUSSION: These 2 patients had GFAP autoimmunity secondary to viral meningoencephalomyelitis or meningitis. This suggests that GFAP astrocytopathy might not always be a primary disease entity; it may follow another brain injury that triggers this autoimmune response. Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology

Investigation of the presence of specific neural antibodies in dogs with epilepsy or dyskinesia using murine and human assays

Hemmeter L, Bien C, Bien CI, et al. Investigation of the presence of specific neural antibodies in dogs with epilepsy or dyskinesia using murine and human assays. Journal of Veterinary Internal Medicine . 2023.BACKGROUND: Autoimmune mechanisms represent a novel category for causes of seizures and epilepsies in humans, and LGI1-antibody associated limbic encephalitis occurs in cats.; HYPOTHESIS/OBJECTIVES: To investigate the presence of neural antibodies in dogs with epilepsy or dyskinesia of unknown cause using human and murine assays modified for use in dogs.; ANIMALS: Fifty-eight dogs with epilepsy of unknown cause or suspected dyskinesia and 57 control dogs.; METHODS: Serum and CSF samples were collected prospectively as part of the diagnostic work-up. Clinical data including onset and seizure/episode type were retrieved from the medical records. Screening for neural antibodies was done with cell-based assays transfected with human genes for typical autoimmune encephalitis antigens and tissue-based immunofluorescence assays on mouse hippocampus slices in serum and CSF samples from affected dogs and controls. The commercial human und murine assays were modified with canine-specific secondary antibody. Positive controls were from human samples.; RESULTS: The commercial assays used in this study did not provide unequivocal evidence for presence of neural antibodies in dogs including one dog with histopathologically proven limbic encephalitis. Low titer IgLON5 antibodies were present in serum from one dog from the epilepsy/dyskinesia group and in one dog from the control group.; CONCLUSION AND CLINICAL IMPORTANCE: Specific neural antibodies were not detected using mouse and human target antigens in dogs with epilepsy and dyskinesia of unknown origin. These findings emphasize the need for canine-specific assays and the importance of control groups. © 2023 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC. on behalf of the American College of Veterinary Internal Medicine

CASPR2 autoimmunity in children expanding to mild encephalopathy with hypertension

OBJECTIVE To delineate autoimmune disease in association with contactin-associated protein 2 (CASPR2) antibodies in childhood, we reviewed the clinical phenotype of children with CASPR2 antibodies. METHODS Retrospective assessment of patients recruited through laboratories specialized in autoimmune CNS disease. RESULTS Ten children with serum CASPR2 antibodies were identified (age at manifestation 18 months to 17 years). Eight children with CASPR2 antibody titers from ≥1:160 to 1:5,120 had complex autoimmune diseases with an age-dependent clinical phenotype. Two children with structural epilepsy due to CNS malformations harbored nonspecific low-titer CASPR2 antibodies (serum titers 1:80). The clinical symptoms of the 8 children with high-titer CASPR2 antibodies were general weakness (8/8), sleep dysregulation (8/8), dysautonomia (8/8) encephalopathy (7/8), neuropathic pain (7/8), neuromyotonia (3/8), and flaccid paresis (3/8). Adolescents (3/8) showed pain, neuromyotonia, and encephalopathy, whereas younger children (5/8) displayed severe hypertension, encephalopathy, and hormonal dysfunction mimicking a systemic disease. No tumors were identified. Motor symptoms remitted with immunotherapy. Mild behavioral changes persisted in 1 child, and autism spectrum disorder was diagnosed during follow-up in a young boy. CONCLUSION High-titer CASPR2 antibodies are associated with Morvan syndrome in children as young as 2 years. However, CASPR2 autoimmunity mimics systemic disease and hypertensive encephalopathy in children younger than 7 years. The outcome following immunotherapy was mostly favorable; long-term behavioral impairment may occur in younger children