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Background: Anti-GAD65 autoantibodies (GAD65-Abs) may occur in patients with epilepsy and other neurological disorders, but the clinical significance is not clear-cut. Whereas high levels of GAD65-Abs are considered pathogenic in neuropsychiatric disorders, low or moderate levels are only considered as mere bystanders in, e.g., diabetes mellitus type 1 (DM1). The value of cell-based assays (CBA) and immunohistochemistry (IHC) for GAD65-Abs detection has not been clearly evaluated in this context., Objective: To re-evaluate the assumption that high levels of GAD65-Abs are related to neuropsychiatric disorders and lower levels only to DM1 and to compare ELISA results with CBA and IHC to determine the additional value of these tests., Methods: 111 sera previously assessed for GAD65-Abs by ELISA in routine clinical practice were studied. Clinical indications for testing were, e.g., suspected autoimmune encephalitis or epilepsy (neuropsychiatric cohort; n  = 71, 7 cases were initially tested positive for GAD65-Abs by ELISA), and DM1 or latent autoimmune diabetes in adults (DM1/LADA cohort ( n  = 40, all were initially tested positive)). Sera were re-tested for GAD65-Abs by ELISA, CBA, and IHC. Also, we examined the possible presence of GAD67-Abs by CBA and of other neuronal autoantibodies by IHC. Samples that showed IHC patterns different from GAD65 were further tested by selected CBAs., Results: ELISA retested GAD65-Abs level in patients with neuropsychiatric diseases was higher than in patients with DM1/LADA (only retested positive samples were compared; 6 vs. 38; median 47,092 U/mL vs. 581 U/mL; p  = 0.02). GAD-Abs showed positive both by CBA and IHC only if antibody levels were above 10,000 U/mL, without a difference in prevalence between the studied cohorts. We found other neuronal antibodies in one patient with epilepsy (mGluR1-Abs, GAD-Abs negative), and in a patient with encephalitis, and two patients with LADA., Conclusion: GAD65-Abs levels are significantly higher in patients with neuropsychiatric disease than in patients with DM1/LADA, however, positivity in CBA and IHC only correlates with high levels of GAD65-Abs, and not with the underlying diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zong, Vinke, Du, Hoffmann, Mané-Damas, Molenaar, Damoiseaux, Losen, Rouhl and Martinez-Martinez.)

Background: City living might lead to a higher risk of psychiatric disease, but to date there is no evidence of any correlation between an urban environment and the occurrence of neural autoantibodies in psychiatric disease. Our aim is to identify whether the number of patients with and without neural autoantibodies living in diverse rural and urban environments differ., Methods: We enrolled retrospectively a cohort of 167 psychiatric patients via a cross-sectional design from the Department of Psychiatry and Psychotherapy University Medical Center Göttingen and determined serum and/or CSF neural autoantibodies in them. The patients live in the German states of Lower Saxony, Thuringia, and Hessen. Their data were investigated in conjunction with the location of their primary residence. We categorized them into five different categories depending upon their primary residence: one rural and four different urban environments depending on their population numbers., Results: We identified 36 psychiatric patients with neural autoantibodies, and 131 psychiatric patients with none. In total, 24 psychiatric patients with neural autoantibodies were classified as sharing a possible, probable, or definitive autoimmune origin according to our recently set criteria. We observed as a non-significant trend that more psychiatric patients with neural autoantibodies and a probable or definitive autoimmune origin (45.8%) live in a major city with over 100,000 inhabitants than do psychiatric patients presenting no evidence of autoantibodies (26.4%). However, we identified no relevant differences between (1) psychiatric patients with and without neural autoantibodies or between (2) psychiatric patients with a possible, probable, or definitive autoimmune origin and those without such autoantibodies in relation to the diverse rural and urban environmental settings., Conclusion: The inherently different aspects of rural and urban environments do not appear to be relevant in determining the frequency of neural autoantibodies in psychiatric patients in Lower Saxony, Thuringia, and Hessen in Germany. Furthermore, large-scale studies involving other states across Germany should be conducted to exclude any regional differences and to examine the tendency of a higher frequency in large cities of autoimmune-mediated psychiatric syndromes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hansen, Juhl, Grenzer, Teegen, Wiltfang and Fitzner.)

Background: Anti-neural autoantibodies associated with psychiatric syndromes is an increasing phenomenon in psychiatry. Our investigation aimed to assess the frequency and type of neural autoantibodies associated with distinct psychiatric syndromes in a mixed cohort of psychiatric patients., Methods: We recruited 167 patients retrospectively from the Department of Psychiatry and Psychotherapy, University Medical Center Göttingen for this study. Clinical features including the assessment of psychopathology via the Manual for Assessment and Documentation of Psychopathology in Psychiatry (AMDP), neurological examination, cerebrospinal fluid (CSF), magnetic resonance imaging (MRI) and electroencephalography (EEG) analysis were done in patients. Serum and or CSF anti- neural autoantibodies were measured in all patients for differential diagnostic reasons., Results: We divided patients in three different groups: (1) psychiatric patients with CSF and/or serum autoantibodies [PSYCH-AB+, n = 25 (14.9%)], (2) psychiatric patients with CSF autoantibodies [PSYCH-AB CSF+, n = 13 (7.8%)] and (3) those psychiatric patients without autoantibodies in serum and/or CSF [PSYCH-AB-, n = 131]. The prevalence of serum neural autoantibodies was 14.9% (PSYCH-AB+), whereas 7.2% had CSF autoantibodies (PSYCH-AB CSF+) in our psychiatric cohort. The most prevalent psychiatric diagnoses were neurocognitive disorders (61-67%) and mood disorders (25-36%) in the patients presenting neural autoantibodies (PSYCH-AB+ and PSYCH-AB CSF+). However, psychiatric diagnoses, neurological deficits, and laboratory results from CSF, EEG or MRI did not differ between the three groups. To evaluate the relevance of neural autoantibody findings, we applied recent criteria for possible, probable, or definitive autoimmune based psychiatric syndromes in an paradigmatic patient with delirium and in the PSYCH-AB+ cohort. Applying criteria for any autoimmune-based psychiatric syndromes, we detected a probable autoimmune-based psychiatric syndrome in 13 of 167 patients (7.8%) and a definitive autoimmune-based psychiatric syndrome in 11 of 167 patients (6.6%)., Conclusions: Neural autoantibodies were detected mainly in patients presenting neurocognitive and mood disorders in our psychiatric cohort. The phenotypical appearance of psychiatric syndromes in conjunction with neural autoantibodies did not differ from those without neural autoantibodies. More research is therefore warranted to optimize biomarker research to help clinicians differentiate patients with potential neural autoantibodies when a rapid clinical response is required as in delirium states., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hansen, Juhl, Grenzer, Rentzsch, Wiltfang and Fitzner.)

Objective: The objective of the study was to determine the incidence of antibodies against neuronal surface antigens (NSA-ab) in patients with different types of epilepsy, in comparison with the subjects diagnosed with immune-mediated disorders. Methods: Forty patients with drug-resistant epilepsy (DRE) of unknown origin, 16 with post-stroke epilepsy, and 23 with systemic autoimmune disorders (SAD) with CNS involvement were included. NSA-ab were sought in serum using indirect immunofluorescence method. Relationships were analyzed between presence of NSA-ab and clinical presentation. Results: NSA-ab was detected in the sera from five patients: anti-DPPX in one patient, anti-AMPAR1/R2 in two, anti-LGI1 in one and, in one case, both anti-CASPR2 and DPPX IgG. Out of these five patients, three represented the SAD subgroup and two the DRE subgroup. None of the patients with post-stroke epilepsy was positive for NSA-ab. Significance: Autoimmune etiology is worth considering in patients with drug-resistant epilepsy of unknown origin. The presence of NSA-ab in patients with systemic autoimmune disorders may be caused by unspecifically enhanced autoimmune reactivity. NSA-ab seem not to be related to epilepsy resulting from ischemic brain injury., Competing Interests: KB-M and MJ was employed by company Euroimmun Poland. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dziadkowiak, Moreira, Buska-Mach, Szmyrka, Budrewicz, Barg, Janik and Pokryszko-Dragan.)

Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis manifests with precipitous cognitive decline, abnormal movements, and severe seizures that can be challenging to control with conventional anti-seizure medications. We previously demonstrated that intracerebroventricular (i.c.v.) administration of cerebrospinal fluid from affected patients, or purified NMDA receptor antibodies from encephalitis patients to mice precipitated seizures, thereby confirming that antibodies are directly pathogenic for seizures. Although different repertoires of anti-NMDA receptor antibodies could contribute to the distinct clinical manifestations in encephalitis patients, the role of specific antibodies in the expression of seizure, motor, and cognitive phenotypes remains unclear. Using three different patient-derived monoclonal antibodies with distinct epitopes within the N-terminal domain (NTD) of the NMDA receptor, we characterized the seizure burden, motor activity and anxiety-related behavior in mice. We found that continuous administration of 5F5, 2G6 or 3C11 antibodies for 2 weeks precipitated seizures, as measured with continuous EEG using cortical screw electrodes. The seizure burden was comparable in all three antibody-treated groups. The seizures were accompanied by increased hippocampal C-C chemokine ligand 2 (CCL2) mRNA expression 3 days after antibody infusion had stopped. Antibodies did not affect the motor performance or anxiety scores in mice. These findings suggest that neuronal antibodies targeting different epitopes within the NMDA receptor may result in a similar seizure phenotype., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Taraschenko, Fox, Eldridge, Wang, Dowd, Al-Saleem, Kattala, Dessain and Dingledine.)

The presence of autoantibodies against neuronal cell surface or synaptic proteins and their relationship to autoimmune encephalitis have recently been characterized. These autoantibodies have been also reported in other pathologic conditions; however, their role during sepsis is not known. This study detected the presence of autoantibodies against neuronal cell surface or synaptic proteins in the serum of septic patients and determined their relationship to the occurrence of brain dysfunction and mortality. This prospective, observational cohort study was performed in four Brazilian intensive care units (ICUs). Sixty patients with community-acquired severe sepsis or septic shock admitted to the ICU were included. Blood samples were collected from patients within 24 h of ICU admission. Antibodies to six neuronal proteins were assessed, including glutamate receptors (types NMDA, AMPA1, and AMPA2); voltage-gated potassium channel complex (VGKC) proteins, leucine-rich glioma-inactivated protein 1 (LGI1), and contactin-associated protein-2 (Caspr2), as well as the GABAB1 receptor. There was no independent association between any of the measured autoantibodies and the occurrence of brain dysfunction (delirium or coma). However, there was an independent and significant relationship between anti-NMDAR fluorescence intensity and hospital mortality. In conclusion, anti-NMDAR was independently associated with hospital mortality but none of the measured antibodies were associated with brain dysfunction in septic patients.