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Autoimmune encephalitis (AE) can be classified into antibody-defined subtypes, which can manifest with immunotherapy-responsive movement disorders sometimes mimicking non-inflammatory etiologies. In the elderly, anti-leucin-rich-glioma-inactivated-1 (LGI1) and contactin-associated-protein-like-2 (CASPR2) antibody-associated diseases compose a relevant fraction of AE. Patients with LGI1 autoantibodies are known to present with limbic encephalitis and additionally faciobrachial dystonic seizures (FBDS) may occur. However, the clinical spectrum of CASPR2 autoantibody-associated disorders is more diverse including limbic encephalitis, Morvan`s syndrome, peripheral nerve hyperexcitability syndrome, ataxia, pain and sleep disorders. Reports on unusual, sometimes isolated and immunotherapy-responsive movement disorders in CASPR2-autoantibody associated syndromes have caused substantial concern regarding necessity of autoantibody-testing in patients with movement disorders. Therefore, we aimed to systematically assess their prevalence and manifestation in patients with CASPR2 autoimmunity. This international, retrospective cohort study included patients with CASPR2 autoimmunity from participating expert centers in Europe. Patients with ataxia and/or movement disorders were analyzed in detail using questionnaires and video recordings. We recruited a comparator group with anti-leucin-rich-glioma-inactivated-1 (LGI1) encephalitis from the GENERATE network. Characteristics were compared according to serostatus. We identified 164 patients with CASPR2 autoantibodies. Of these, 149 (90.8%) had only CASPR2- and 15 (9.1%) both CASPR2- and LGI1-autoantibodies. Compared to 105 patients with LGI1 encephalitis, patients with CASPR2 autoantibodies more often had movement disorders and/or ataxia (35.6% versus 3.8%; p

BackgroundNeurological immune-related adverse events (irAE-n) are severe and potentially fatal toxicities of immune checkpoint inhibitors (ICI). To date, the clinical significance of neuronal autoantibodies in irAE-n is poorly understood. Here, we characterize neuronal autoantibody profiles in patients with irAE-n and compare these with ICI-treated cancer patients without irAE-n.MethodsIn this cohort study (DRKS00012668), we consecutively collected clinical data and serum samples of 29 cancer patients with irAE-n (n = 2 pre-ICI, n = 29 post-ICI) and 44 cancer control patients without irAE-n (n = 44 pre- and post-ICI). Using indirect immunofluorescence and immunoblot assays, serum samples were tested for a large panel of neuromuscular and brain-reactive autoantibodies.ResultsIrAE-n patients and controls received ICI treatment targeting programmed death protein (PD-)1 (61% and 62%), programmed death ligand (PD-L)1 (18% and 33%) or PD-1 and cytotoxic T-lymphocyte-associated protein (CTLA-)4 (21% and 5%). Most common malignancies were melanoma (both 55%) and lung cancer (11% and 14%). IrAE-n affected the peripheral nervous system (59%), the central nervous system (21%), or both (21%). Prevalence of neuromuscular autoantibodies was 63% in irAE-n patients, which was higher compared to ICI-treated cancer patients without irAE-n (7%, p BR, -NMDAR, -myelin), intracellular (anti-GFAP, -Zic4, -septin complex), or unknown antigens were detected in 13 irAE-n patients (45%). In contrast, only 9 of 44 controls (20%) presented brain-reactive autoantibodies before ICI administration. However, seven controls developed de novo brain-reactive autoantibodies after ICI initiation, therefore, prevalence of brain-reactive autoantibodies was comparable between ICI-treated patients with and without irAE-n (p = .36). While there was no clear association between specific brain-reactive autoantibodies and clinical presentation, presence of at least one of six selected neuromuscular autoantibodies (anti-titin, anti-skeletal muscle, anti-heart muscle, anti-LRP4, anti-RyR, anti-AchR) had a sensitivity of 80% (95% CI 0.52-0.96) and a specificity of 88% (95% CI 0.76-0.95) for the diagnosis of myositis, myocarditis, or myasthenia gravis.ConclusionNeuromuscular autoantibodies may serve as a feasible marker to diagnose and potentially predict life-threatening ICI-induced neuromuscular disease. However, brain-reactive autoantibodies are common in both ICI-treated patients with and without irAE-n, hence, their pathogenic significance remains unclear.

BackgroundCity 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.MethodsWe 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.ResultsWe 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.ConclusionThe 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.

Einleitung: Kognitive Beeintr��chtigungen sind ein h��ufiges Symptom bei malignen Erkrankungen (Cancer-related cognitive impairment, CRCI). Die Pathomechanismen f��r CRCI abseits von Chemotherapie sind weitestgehend unklar. Auch unabh��ngig von der Therapie k��nnen relevante kognitive Defizite auftreten. Erste Hinweise suggerieren eine m��gliche Assoziation von CRCI mit dem Vorliegen neuronaler Autoantik��rper. Diese sind bisher vor allem bei Patienten mit paraneoplastischen neurologischen Syndromen untersucht worden, k��nnen jedoch auch bei Tumorpatienten ohne manifeste neurologische Syndrome auftreten. Das Lungenkarzinom ist die Tumorart, die am h��ufigsten mit dem Vorliegen neuronaler Autoantik��rper assoziiert ist. Ziel dieser Arbeit ist, bei Patienten mit Lungenkarzinom i) die Pr��valenz von neuronalen Autoantik��rpern, ii) die kognitive Funktion sowie iii) die Korrelation von Antik��rpern mit kognitiven Defiziten systematisch zu untersuchen. Methoden: Das Serum von 167 Patienten mit Lungenkarzinom (davon 127 Patienten mit nicht- kleinzelligem Lungenkarzinom (NSCLC) und 40 Patienten mit kleinzelligem Lungenkarzinom (SCLC)) wurde mittels indirekter Immunfluoreszenz in zellbasierten und gewebebasierten Verfahren auf das Vorliegen neuronaler Autoantik��rper untersucht. Nach dem Ausschluss von Patienten mit m��glichen St��rfaktoren auf die kognitive Funktion (z.B. Gehirnmetastasen, Ganzhirnbestrahlung) wurden 97 Patienten mit detaillierten neuropsychologischen Testverfahren in allen kognitiven Dom��nen untersucht. Das Vorliegen von CRCI wurde nach den Kriterien der International Cognition and Cancer Task Force (ICCTF) bestimmt. Ergebnisse: Neuronale Autoantik��rper fanden sich bei 60/167 (35,9%) aller Lungenkarzinompatienten: bei 31/167 (18,6%) Antik��rper mit bekannter Zielstruktur (Nachweis in zellbasierten Verfahren) und bei 29/167 (17,4%) mit bisher unbekannter Zielstruktur (Nachweis in gewebebasierten Verfahren). Die Pr��valenz von Antik��rpern mit bekannter Zielstruktur war bei SCLC-Patienten signifikant h��her als bei NSCLC-Patienten (30% vs. 15%, p=0,033), insbesondere von Antik��rpern gegen intrazellul��re Antigene (25% vs. 3,1%, p, Introduction: Cancer-related cognitive impairment (CRCI) is a frequent symptom in cancer patients. The pathomechanism apart from chemotherapy remains unknown, cognitive deficits can occur independent of any treatment. First studies suggest a possible association of CRCI with neuronal autoantibodies. These antibodies have been mainly investigated in patients with paraneoplastic neurologic syndromes, but can also be detected in cancer patients without neurologic disorders. Lung cancer is the tumor most frequently associated with neuronal autoantibodies. The aim of this study is to i) investigate the prevalence of neuronal autoantibodies in lung cancer patients, ii) examine their cognitive function and iii) analyze a possible correlation between neuronal autoantibodies and CRCI. Methods: The serum of 167 lung cancer patients (127 non-small cell lung cancer patients (NSCLC) and 40 small-cell lung cancer patients (SCLC)) was analyzed for the presence of neuronal autoantibodies using indirect immunofluorescence in cell-based assays and brain tissue sections. After exclusion of patients with potential confounders of cognitive performance (e.g. brain metastases, cranial irradiation), 97 patients were tested for cognitive deficits using a comprehensive neuropsychological test battery for all cognitive domains. Presence of CRCI was defined according to the International Cognition and Cancer Task Force (ICCTF) criteria. Results: Brain-directed autoantibodies were found in 60/167 (35.9%) of all lung cancer patients: 31/167 (18.6%) against known antigens and 29/167 (17.4%) against yet unknown antigens. Prevalence of antibodies against known antigens was significantly higher in SCLC patients than in NSCLC patients (30% vs. 15%,p=0.033), especially antibodies against intracellular antigens (25% vs. 3.1%,p

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.

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.

Background Cancer-related cognitive impairment is an important complication in cancer patients, yet the underlying mechanisms remain unknown. Over the last decade, the field of paraneoplastic neurological syndromes has been dramatically changed by the discovery of new neuronal autoantibodies, some of them associated with cognitive impairment. We aimed to assess the prevalence of neuronal autoantibodies in melanoma patients and their association with neurological and cognitive dysfunction. Patients and methods A total of 157 consecutive melanoma patients with a median age of 63 years were recruited at the Department of Dermatology, Charite—Universitatsmedizin Berlin and tested for neuronal autoantibodies. A comprehensive neuropsychological assessment was carried out in a selected subgroup of 84 patients after exclusion of patients with confounding factors for a cognitive dysfunction, including brain metastases, relevant medication, and neurological disorders. Results Neuronal autoantibodies were found in 22.3% of melanoma patients. The most frequent antibodies were IgA/IgM anti-NMDAR antibodies. Applying the International Cognition and Cancer Task Force criteria, 36.9% had cognitive impairment, however, with a threefold higher odds in antibody-positive compared with antibody-negative patients (57.1% versus 30.2%, OR = 3.1, 95% CI: 1.1 to 8.6; P = 0.037). In patients with anti-NMDAR antibodies, this impairment increased with higher antibody titers (P = 0.007). Antibody-positive patients had a significantly impaired overall cognitive performance (z-value: −0.38 ± 0.69 versus 0.00 ± 0.56; P = 0.014) as well as significant impairments in tests of memory, attention, and executive function. In a multiple linear regression analysis, autoantibodies were an independent risk factor for cognitive impairment (B = −0.282; 95% CI: −0.492 to −0.071; P = 0.009). Autoantibody seropositivity was associated with immune checkpoint inhibitor treatment and a history of autoimmune diseases. Conclusions A large number of melanoma patients harbor neuronal autoantibodies that are associated with significant cognitive impairment affecting memory, attention, and executive function. Neuronal autoantibodies might represent a pathophysiological factor and possible biomarker in the development of cancer-related cognitive impairment.

Serum neuronal autoantibodies, such as those to the NMDA receptor (NMDAR), are detectable in a subgroup of patients with psychotic disorders. It is not known if they are present before the onset of psychosis or whether they are associated with particular clinical features or outcomes. In a case–control study, sera from 254 subjects at clinical high risk (CHR) for psychosis and 116 healthy volunteers were tested for antibodies against multiple neuronal antigens implicated in CNS autoimmune disorders, using fixed and live cell-based assays (CBAs). Within the CHR group, the relationship between NMDAR antibodies and symptoms, cognitive function and clinical outcomes over 24 month follow-up was examined. CHR subjects were not more frequently seropositive for neuronal autoantibodies than controls (8.3% vs. 5.2%; OR = 1.50; 95% CI: 0.58–3.90). The NMDAR was the most common target antigen and NMDAR IgGs were more sensitively detected with live versus fixed CBAs (p p p p p

Background and Objective: Due to the increasing number of long-term survivors, cancer-related cognitive impairment is attracting growing attention in prostate cancer patients. Although primarily studied in the context of androgen deprivation therapy, cognitive impairment frequently occurs independently of cancer treatment. In recent years, new neuronal autoantibodies directed against cell-surface antigens have been identified. Specifically, antibodies targeting the NMDA receptor are highly prevalent in cancer patients and have been associated with cognitive impairment and dementia. Therefore, this study aims to assess the prevalence of these antibodies and evaluate their role as potential mediators of cancer-related cognitive impairment in prostate cancer. Patients and Methods: A total of 187 patients with prostate cancer were recruited at the Department of Urology, Charit��-Universit��tsmedizin Berlin and local outpatient clinic between February and September 2015. Neuronal autoantibody testing was performed using a well-established commercial assay. A subgroup of 102 patients without confounding factors for cognitive dysfunction underwent neurological examination and comprehensive neuropsychological assessment using a detailed neuropsychological test battery. Prevalence of cognitive impairment was assessed following the definition of the ���International Cognition and Cancer Task Force��� and compared between antibody-positive and antibody-negative patients, as well as between antibody subgroups. Results: Neuronal autoantibodies were detected in 18.2% (34/187) of prostate cancer patients. The majority of antibodies were directed against neuronal surface antigens (27/187 [14.4%]), predominantly antibodies of the IgA and IgM isotype directed against the NMDA receptor (26/187 [13.9%]). Antibodies directed against intracellular epitopes were identified in 5.3% (10/187) of patients. Forty-eight percent (49/102) of patients presented cognitive impairment. Antibody-positive patients had 4-fold higher odds to have a verbal memory deficit compared to antibody-negative patients (33.3% [6/18] vs. 10.7% [9/84]; OR 4.2, 95% CI 1.3-13.8, p=0.014). The subgroup of patients with IgA/IgM NMDA receptor antibodies similarly showed a significantly higher frequency of verbal memory deficits (46.2% [6/13] vs. 10.7% [9/84]; OR 7.1, 95% CI 2.0-26.0, p=0.001). In addition, patients with IgA NMDA receptor antibodies showed reduced performance on visuospatial memory tasks. Logistic and linear regression models confirmed IgA/IgM NMDA receptor antibodies as an independent predictor of memory impairment. Conclusion: Neuronal autoantibodies, especially antibodies targeting neuronal surface epitopes, occur in a large number of prostate cancer patients. IgA and IgM NMDA receptor antibodies are associated with increased odds for memory impairment. Therefore, these neuronal antibodies, indicative of a tumor-associated immune-response against the nervous system, may represent an important pathogenic factor in cancer-related cognitive impairment in prostate cancer., Hintergrund und Zielsetzung: Tumor-assoziierte kognitive Defizite werden zunehmend als relevante Komplikation von Tumorerkrankungen erkannt. Bei Patienten mit Prostatakarzinom spielt dies eine zunehmende Rolle aufgrund der steigenden Lebenserwartung und des hierdurch vermehrten Langzeit��berlebens. Bisher wurden kognitive Defizite bei Prostatakarzinom-Patienten vorwiegend im Rahmen einer Hormontherapie untersucht. Relevante kognitive Defizite k��nnen jedoch auch unabh��ngig von der Tumortherapie auftreten. In den letzten Jahren wurden neue neuronale Antik��rper gegen Zelloberfl��chenantigene identifiziert. Insbesondere Antik��rper gegen den NMDA-Rezeptor zeigen eine hohe Pr��valenz in Tumorpatienten und wurden im Zusammenhang mit kognitiven Defiziten und Demenz beschrieben. In dieser Studie sollen daher die Pr��valenz neuronaler Autoantik��rper und deren Assoziation mit kognitiven und neurologischen Defiziten bei Patienten mit Prostatakarzinom untersucht werden. Methoden: Insgesamt wurden 187 Patienten mit Prostatakarzinom zwischen Februar und September 2015 in der Klinik f��r Urologie, Charit��-Universit��tsmedizin Berlin und in einer urologischen Fachpraxis eingeschlossen. Die Antik��rperdiagnostik erfolgte mittels standardisierter kommerzieller Verfahren. Nach Ausschluss von Patienten mit m��glichen St��r- und Einflussfaktoren auf die kognitive Funktion, wurde eine Untergruppe von 102 Patienten neuropsychologisch und neurologisch untersucht. Die Pr��valenz kognitiver Defizite wurde nach den standardisierten Kriterien der ���International Cognition and Cancer Task Force��� bewertet und zwischen Antik��rper-positiven und Antik��rper-negativen sowie zwischen Antik��rper Subgruppen verglichen. Ergebnisse: Neuronale Antik��rper wurden im Serum von 18.2% (34/187) der Prostatakarzinom-Patienten detektiert. Der Gro��teil der Antik��rper war gegen Oberfl��chenantigene (14.4% [27/187]) gerichtet, am h��ufigsten fanden sich NMDA-Rezeptor Antik��rper (13.9% [26/187]) vom IgA- und IgM-Subtyp. Antik��rper gegen intrazellul��re Antigene wurden bei 5.3% (10/187) der Patienten nachgewiesen. Ein kognitives Defizit wurde in 48% (49/102) der Prostatakarzinom-Patienten identifiziert. Antik��rper-positive Patienten zeigten im Vergleich zu den Antik��rper-negativen Patienten signifikant h��ufiger ein Defizit im verbalen Ged��chtnis (33.3% [6/18] vs. 10.7% [9/84]; OR 4.2, CI 1.3-13.8, p=0.014). Die Subgruppe von Patienten mit IgA/IgM NMDA-Rezeptor-Antik��rpern zeigte ebenfalls signifikant h��ufiger ein Ged��chtnisdefizit im Vergleich zu den Antik��rper-negativen Patienten (46.2% [6/13] vs. 10.7% [9/84]; OR 7.1, 95% CI 2.0-26.0, p=0.001). Zudem zeigte die Patientengruppe mit IgA NMDA-Rezeptor-Antik��rpern im Vergleich zu den Antik��rper-negativen Patienten ein signifikant schlechteres Testergebnis im Bereich von verbalem und r��umlichem Ged��chtnis. IgA und IgM NMDA-Rezeptor-Antik��rper konnten mittels logistischer und linearer Regression als unabh��ngige Pr��diktoren f��r Ged��chtnisdefizite best��tigt werden. Fazit: Neuronale Autoantik��rper, insbesondere Antik��rper gegen neuronale Oberfl��chenantigene, treten in einem hohen Anteil von Prostatakarzinom-Patienten auf. IgA und IgM NMDA-Rezeptor-Antik��rper zeigen einen Zusammenhang mit Ged��chtnisdefiziten. Diese neuronalen Oberfl��chen-Antik��rper, hinweisend f��r eine tumor-induzierte Immunantwort gegen das Nervensystem, stellen deshalb m��glicherweise einen wichtigen pathogenetischen Faktor in der Entstehung von tumor-induzierten Ged��chtnisdefiziten in Prostatakarzinom-Patienten dar.

In recent years, as an increasing number of neuronal autoantibodies have been detected and used for clinical diagnosis, clinicians have become more aware of autoimmune encephalitis, causing its reported incidence to trend upward over several years. To date, however, there has been no large-scale epidemiological survey of autoimmune encephalitis in adults and children, and its epidemiological characteristics remain unclear. Six main types of antibodies are detected and used to diagnose autoimmune encephalitis in Chongqing, Southwestern China: anti-NMDA receptor antibody, anti-GABAB receptor antibody, anti-LGI1 antibody, anti-CASPR2 antibody, anti-AMPA1 receptor antibody, and anti-AMPA2 receptor antibody. From January 2012 to February 2018, 189 patients at six general hospitals in Chongqing were diagnosed with autoimmune encephalitis and were positive for neuronal autoantibodies. In this report, the epidemic situation and the antibody distribution among these patients are analyzed and described in detail. The differences in disease severity among different ages and between the sexes are evaluated, and the correlation between antibody titer and disease severity is also assessed.

Autism spectrum disorders (ASDs) are the most common neurodevelopmental disorders with unidentified etiology. The behavioral manifestations of ASD may be a consequence of genetic and/or environmental pathology in neurodevelopmental processes. In this limited study, we assayed autoantibodies to a panel of vital neuronal and glial proteins in the sera of 40 subjects (10 children with ASD and their mothers along with 10 healthy controls, age-matched children and their mothers). Serum samples were screened using Western Blot analysis to measure immunoglobulin (IgG) reactivity against a panel of 9 neuronal proteins commonly associated with neuronal degeneration: neurofilament triplet proteins (NFP), tubulin, microtubule-associated proteins (tau), microtubule-associated protein-2 (MAP-2), myelin basic protein (MBP), myelin-associated glycoprotein (MAG), &alpha, synuclein (SNCA) and astrocytes proteins such as glial fibrillary acidic protein (GFAP) and S100B protein. Our data show that the levels of circulating IgG class autoantibodies against the nine proteins were significantly elevated in ASD children. Mothers of ASD children exhibited increased levels of autoantibodies against all panel of tested proteins except for S100B and tubulin compared to age-matched healthy control children and their mothers. Control children and their mothers showed low and insignificant levels of autoantibodies to neuronal and glial proteins. These results strongly support the importance of anti-neuronal and glial protein autoantibodies biomarker in screening for ASD children and further confirm the importance of the involvement of the maternal immune system as an index that should be considered in fetal in utero environmental exposures. More studies are needed using larger cohort to verify these results and understand the importance of the presence of such autoantibodies in children with autism and their mothers, both as biomarkers and their role in the mechanism of action of autism and perhaps in its treatment.

Background In 2010 the spectrum of known antigens in autoimmune encephalitis has been expanded by GABAB receptors. Until now over 80 patients with GABAB receptor encephalitis have been described. We report the occurrence of GABAB receptor antibodies in a patient with clinically diagnosed amyotrophic lateral sclerosis (ALS). GABAB receptor antibodies have not been described previously in an ALS patient. Case presentation A 75-year-old female patient presented with cerebellar ataxia, bulbar palsy and cognitive impairment. In the later course of disease signs for affection of the second motor neuron evolved and she was diagnosed with ALS. A post-mortem analysis of cerebrospinal fluid revealed high titers of GABAB receptor antibodies. Conclusions This case provides an idea of the natural course of GABAB receptor encephalitis and demonstrates that antibody-mediated autoimmunity could be one of several pathways leading to the ALS phenotype. Furthermore this unique case stimulates the question whether neuronal antibodies might be more common in ALS than previously suspected.

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.

In recent years, as an increasing number of neuronal autoantibodies have been detected and used for clinical diagnosis, clinicians have become more aware of autoimmune encephalitis, causing its reported incidence to trend upward over several years. To date, however, there has been no large-scale epidemiological survey of autoimmune encephalitis in adults and children, and its epidemiological characteristics remain unclear. Six main types of antibodies are detected and used to diagnose autoimmune encephalitis in Chongqing, Southwestern China: anti-NMDA receptor antibody, anti-GABAB receptor antibody, anti-LGI1 antibody, anti-CASPR2 antibody, anti-AMPA1 receptor antibody, and anti-AMPA2 receptor antibody. From January 2012 to February 2018, 189 patients at six general hospitals in Chongqing were diagnosed with autoimmune encephalitis and were positive for neuronal autoantibodies. In this report, the epidemic situation and the antibody distribution among these patients are analyzed and described in detail. The differences in disease severity among different ages and between the sexes are evaluated, and the correlation between antibody titer and disease severity is also assessed.

Autoantibodies against the RhoGTPase-activating protein 26 (ARHGAP26) were originally identified in the context of subacute autoimmune cerebellar ataxia. Further studies identified a wider clinical spectrum including psychotic, affective, and cognitive symptoms. Only a few patients reported so far had evidence of a tumor association. A prospective analysis between January 2015 and December 2017 at the Dept. of Neurology at Charité—Universitätsmedizin Berlin identified 14 patients with ARHGAP26 autoantibodies on a cell-based assay, of which three patients had additional brain immunohistochemistry staining of cerebellar molecular layer and Purkinje cells, who were therefore considered antibody-positive. In all three patients, ARHGAP26 autoantibodies were associated with tumors. In two patients, an isolated cognitive impairment without additional neurological deficits was observed. These cases thus further extend the clinical spectrum associated with ARHGAP26 autoantibodies and strengthen a potential paraneoplastic context.

Background In 2010 the spectrum of known antigens in autoimmune encephalitis has been expanded by GABAB receptors. Until now over 80 patients with GABAB receptor encephalitis have been described. We report the occurrence of GABAB receptor antibodies in a patient with clinically diagnosed amyotrophic lateral sclerosis (ALS). GABAB receptor antibodies have not been described previously in an ALS patient. Case presentation A 75-year-old female patient presented with cerebellar ataxia, bulbar palsy and cognitive impairment. In the later course of disease signs for affection of the second motor neuron evolved and she was diagnosed with ALS. A post-mortem analysis of cerebrospinal fluid revealed high titers of GABAB receptor antibodies. Conclusions This case provides an idea of the natural course of GABAB receptor encephalitis and demonstrates that antibody-mediated autoimmunity could be one of several pathways leading to the ALS phenotype. Furthermore this unique case stimulates the question whether neuronal antibodies might be more common in ALS than previously suspected. Electronic supplementary material The online version of this article (10.1186/s12883-019-1269-7) contains supplementary material, which is available to authorized users.

IgG4 autoimmune diseases are characterized by the presence of antigen-specific autoantibodies of the IgG4 subclass and contain well-characterized diseases such as muscle-specific kinase myasthenia gravis, pemphigus, and thrombotic thrombocytopenic purpura. In recent years, several new diseases were identified, and by now 14 antigens targeted by IgG4 autoantibodies have been described. The IgG4 subclass is considered immunologically inert and functionally monovalent due to structural differences compared to other IgG subclasses. IgG4 usually arises after chronic exposure to antigen and competes with other antibody species, thus “blocking” their pathogenic effector mechanisms. Accordingly, in the context of IgG4 autoimmunity, the pathogenicity of IgG4 is associated with blocking of enzymatic activity or protein–protein interactions of the target antigen. Pathogenicity of IgG4 autoantibodies has not yet been systematically analyzed in IgG4 autoimmune diseases. Here, we establish a modified classification system based on Witebsky’s postulates to determine IgG4 pathogenicity in IgG4 autoimmune diseases, review characteristics and pathogenic mechanisms of IgG4 in these disorders, and also investigate the contribution of other antibody entities to pathophysiology by additional mechanisms. As a result, three classes of IgG4 autoimmune diseases emerge: class I where IgG4 pathogenicity is validated by the use of subclass-specific autoantibodies in animal models and/or in vitro models of pathogenicity; class II where IgG4 pathogenicity is highly suspected but lack validation by the use of subclass specific antibodies in in vitro models of pathogenicity or animal models; and class III with insufficient data or a pathogenic mechanism associated with multivalent antigen binding. Five out of the 14 IgG4 antigens were validated as class I, five as class II, and four as class III. Antibodies of other IgG subclasses or immunoglobulin classes were present in several diseases and could contribute additional pathogenic mechanisms.

Autoantibodies against the RhoGTPase-activating protein 26 (ARHGAP26) were originally identified in the context of subacute autoimmune cerebellar ataxia. Further studies identified a wider clinical spectrum including psychotic, affective, and cognitive symptoms. Only a few patients reported so far had evidence of a tumor association. A prospective analysis between January 2015 and December 2017 at the Dept. of Neurology at Charité-Universitätsmedizin Berlin identified 14 patients with ARHGAP26 autoantibodies on a cell-based assay, of which three patients had additional brain immunohistochemistry staining of cerebellar molecular layer and Purkinje cells, who were therefore considered antibody-positive. In all three patients, ARHGAP26 autoantibodies were associated with tumors. In two patients, an isolated cognitive impairment without additional neurological deficits was observed. These cases thus further extend the clinical spectrum associated with ARHGAP26 autoantibodies and strengthen a potential paraneoplastic context.

Autoimmune Encephalitis (AE) is a challenging diagnosis due to the similarities in the clinical, imaging and laboratory findings among many forms of infectious encephalitis. Patients generally have impaired memory and cognition and neuropsychiatric manifestations over a period of days or weeks. However, a careful history and examination may show early clues to particular autoimmune causes, such as seizures, dystonia, abnormal movements, psychosis, or the presence of particular tumours. Appropriate autoantibody testing can confirm specific diagnoses. When infectious etiology is excluded, AE must be considered which is potentially reversible with immunomodulation therapy. Here, we describe five patients with AE: four auto-antibody positive, one auto-antibody negative, treated during last 20 months, presenting with different syndromes and first ever reported from western Rajasthan. Hence, this case series highlights the importance of early diagnosis and appropriate treatment leading to significant reduction of mortality and morbidity.

AIM: To evaluate the relationship between diagnosis and clinical course of Tourette syndrome and group A Streptococcus (GAS). METHOD: GAS infections, anti-streptococcal, and anti-basal ganglia antibodies (ABGA) were compared between 168 patients (136 males, 32 females) with Tourette syndrome; (median [range] age [25th-75th centile] 10y [8-11y]); median Tourette syndrome duration (25th-75th centile), 3y (1y 3mo-5y 9mo) and a comparison group of 177 patients (117 males, 60 females) with epileptic or sleep disorders median age [25th-75th centile], 10y [8y-1y 6mo]). One hundred and forty-four patients with Tourette syndrome were followed up at 3-month intervals; exacerbations of tics, obsessive-compulsive symptoms, and other psychiatric comorbidities were defined by a bootstrap procedure. The effect of new GAS infections and identification of new ABGA upon risk of exacerbation was assessed using logistic regression analysis. RESULTS: Cross-sectionally, patients with Tourette syndrome exhibited a higher frequency of GAS infection (8% vs 2%; p=0.009), higher anti-streptolysin O (ASO) titres (246 [108-432] vs 125 [53-269]; p0.05). INTERPRETATION: Patients with Tourette syndrome might be more prone to GAS infections and develop stronger antibody responses to GAS, probably as a result of underlying immune dysregulation. New GAS infections are unlikely to exert, years after their onset, a major effect upon the severity of neuropsychiatric symptoms.

Antibodies that immunoprecipitate (125)I-alpha-dendrotoxin-labelled voltage-gated potassium channels extracted from mammalian brain tissue have been identified in patients with neuromyotonia, Morvan's syndrome, limbic encephalitis and a few cases of adult-onset epilepsy. These conditions often improve following immunomodulatory therapies. However, the proportions of the different syndromes, the numbers with associated tumours and the relationships with potassium channel subunit antibody specificities have been unclear. We documented the clinical phenotype and tumour associations in 96 potassium channel antibody positive patients (titres >400 pM). Five had thymomas and one had an endometrial adenocarcinoma. To define the antibody specificities, we looked for binding of serum antibodies and their effects on potassium channel currents using human embryonic kidney cells expressing the potassium channel subunits. Surprisingly, only three of the patients had antibodies directed against the potassium channel subunits. By contrast, we found antibodies to three proteins that are complexed with (125)I-alpha-dendrotoxin-labelled potassium channels in brain extracts: (i) contactin-associated protein-2 that is localized at the juxtaparanodes in myelinated axons; (ii) leucine-rich, glioma inactivated 1 protein that is most strongly expressed in the hippocampus; and (iii) Tag-1/contactin-2 that associates with contactin-associated protein-2. Antibodies to Kv1 subunits were found in three sera, to contactin-associated protein-2 in 19 sera, to leucine-rich, glioma inactivated 1 protein in 55 sera and to contactin-2 in five sera, four of which were also positive for the other antibodies. The remaining 18 sera were negative for potassium channel subunits and associated proteins by the methods employed. Of the 19 patients with contactin-associated protein-antibody-2, 10 had neuromyotonia or Morvan's syndrome, compared with only 3 of the 55 leucine-rich, glioma inactivated 1 protein-antibody positive patients (P < 0.0001), who predominantly had limbic encephalitis. The responses to immunomodulatory therapies, defined by changes in modified Rankin scores, were good except in the patients with tumours, who all had contactin-associated-2 protein antibodies. This study confirms that the majority of patients with high potassium channel antibodies have limbic encephalitis without tumours. The identification of leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 as the major targets of potassium channel antibodies, and their associations with different clinical features, begins to explain the diversity of these syndromes; furthermore, detection of contactin-associated protein-2 antibodies should help identify the risk of an underlying tumour and a poor prognosis in future patients.