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Despite intensive research, a precise cause of schizophrenic and schizoaffective disorders has not yet been identified. Therefore, psychiatric diagnoses are still made based on clinical ICD-10/DSM‑5 criteria and not on any objective markers; however, various causes or pathophysiological processes may ultimately lead to similar symptoms. An important task for the future of psychiatry is to identify disease subtypes with a distinct pathophysiology to develop more specific and causally acting therapies. A new diagnostic entity has become established in clinical neurology and psychiatry in recent years: autoimmune encephalitis with psychotic symptoms caused by specific antineuronal antibodies has been identified as a rare but potentially treatable cause of psychotic disorders; however, these inflammatory brain diseases are not reliably detected by routine psychiatric diagnostics. Therefore, this qualitative review is intended to provide structured support for clinical practice, which, guided by clinical warning signals, enables a rapid and reliable diagnosis as well as the initiation of immunotherapy. In the case of psychiatric symptoms, the additional onset of focal neurological signs, disturbances of consciousness and orientation, autonomic instability or epileptic seizures and electroencephalograph (EEG) abnormalities should always be followed by a more specific cerebrospinal fluid analysis with determination of antineuronal autoantibodies. Although the scientific evidence indicates that only a small subgroup of patients is affected, the swift and correct diagnosis is of high therapeutic and prognostic relevance for the affected individuals.

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation. Funding The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain.

Objective:We assessed the therapeutic potential of the plasma-cell-depleting proteasome inhibitor bortezomib in severe and therapy-refractory cases of anti–NMDA receptor (anti-NMDAR) encephalitis.Methods:Five severely affected patients with anti-NMDAR encephalitis with delayed treatment response or resistance to standard immunosuppressive and B-cell-depleting drugs (corticosteroids, IV immunoglobulins, plasma exchange, immunoadsorption, rituximab, cyclophosphamide) who required medical treatment and artificial ventilation on intensive care units were treated with 1–6 cycles of 1.3 mg/m2 bortezomib. Occurrence of adverse events was closely monitored.Results:Bortezomib treatment showed clinical improvement or disease remission, which was accompanied by a partial NMDAR antibody titer decline in 4 of 5 patients. With respect to disease severity, addition of bortezomib to the multimodal immunosuppressive treatment regimen was associated with an acceptable safety profile.Conclusions:Our study identifies bortezomib as a promising escalation therapy for severe and therapy-refractory anti-NMDAR encephalitis.Classification of evidence:This retrospective case series provides Class IV evidence that bortezomib reduces antibody titers and improves the clinical course of patients with severe anti-NMDAR encephalitis.

Objective Maternal autoantibodies are a risk factor for impaired brain development in offspring. Antibodies (ABs) against the NR1 (GluN1) subunit of the N-methyl-d-aspartate receptor (NMDAR) are among the most frequently diagnosed anti-neuronal surface ABs, yet little is known about effects on fetal development during pregnancy. Methods We established a murine model of in utero exposure to human recombinant NR1 and isotype-matched nonreactive control ABs. Pregnant C57BL/6J mice were intraperitoneally injected on embryonic days 13 and 17 each with 240μg of human monoclonal ABs. Offspring were investigated for acute and chronic effects on NMDAR function, brain development, and behavior. Results Transferred NR1 ABs enriched in the fetus and bound to synaptic structures in the fetal brain. Density of NMDAR was considerably reduced (up to -49.2%) and electrophysiological properties were altered, reflected by decreased amplitudes of spontaneous excitatory postsynaptic currents in young neonates (-34.4%). NR1 AB-treated animals displayed increased early postnatal mortality (+27.2%), impaired neurodevelopmental reflexes, altered blood pH, and reduced bodyweight. During adolescence and adulthood, animals showed hyperactivity (+27.8% median activity over 14 days), lower anxiety, and impaired sensorimotor gating. NR1 ABs caused long-lasting neuropathological effects also in aged mice (10 months), such as reduced volumes of cerebellum, midbrain, and brainstem. Interpretation The data collectively support a model in which asymptomatic mothers can harbor low-level pathogenic human NR1 ABs that are diaplacentally transferred, causing neurotoxic effects on neonatal development. Thus, AB-mediated network changes may represent a potentially treatable neurodevelopmental congenital brain disorder contributing to lifelong neuropsychiatric morbidity in affected children. ANN NEUROL 2019;86:656-670.

Changes in levels of cytokines or soluble receptors in biological fluids may provide information on immunological pathomechanisms underlying the respective diseases. Here, we studied cytokine patterns of patients with autoimmune encephalitis (AE) before and after immunosuppressive treatment in order to identify possible biomarker candidates and to look for putatively involved pathomechanisms. We performed measurements in Cerebrospinal fluid (CSF) and serum of 7 patients suffering from AE with antibodies (ab) against Leucine-rich glioma-inactivated-protein 1 (LGI1) and 9 AE patients with Contactin-associated protein-like 2 (Caspr2) ab recruited from two tertiary AE centers in Magdeburg and Berlin, Germany. In the Magdeburg samples before and after treatment were available for the measurements and in the Berlin cohort samples were collected after treatment was initiated. First, we used a human cytokine array comprising 36 cytokines or soluble receptors to screen for biomarkers in CSF samples of 8 AE (before and after treatment), 4 herpes-simplex virus meningoencephalitis patients and 4 controls without neuroinflammation. Next, CCL2, CXCl10, CXCl13, Il -6 and sICAM1 were chosen as candidates and measured in CSF and serum with specific ELISA systems in all 16 AE patients, 14 controls without neuroinflammation and 7 herpes-simplex virus meningitis patients. Clinical outcome was assessed via modified Rankin scale. LGI1 and Caspr2 abs from the Magdeburg cohort were purified by chromatography. IgG subclasses of these LGI1 or Caspr2 abs were identified by immunoblot analysis. The levels of most candidate parameters were higher in the CSF of Caspr2 than of LGI1 AE patients and controls, but there were no significant changes of cytokine concentrations before and after initiating treatment. Thus, these parameters seem unsuited as surrogate biomarkers of disease. Significantly higher levels were observed in the CSFs of Caspr2 AE patients (CXCL13 and sICAM1) as well as in the serum of Caspr2 (CXCL10) and LGI1 AE patients (CXCL13) in comparison to control samples. These results suggest that neuro-immunological pathomechanisms may differ between Caspr2 and LGI1 AE patients. Caspr2 AE seems to elicit a higher immune response than LGI1 AE, which has no correlation to the respective IgG subclass combination of AE specific abs involved in each type of disease.

Autoimmune encephalitis often causes acute psychiatric symptoms and epileptic seizures. However, it is becoming increasingly clear that depending on the target antigen both symptoms and disease severity may vary. Furthermore, the identification and characterization of antibody subtypes are highly relevant for personalizing the treatment and to prevent relapses. Here we present an atypical case of encephalitis with cerebellar and temporal dysfunction but without seizures associated with high levels of cerebrospinal fluid neuropil antibodies against a yet unknown epitope on the neuronal surface in the cerebellum, hippocampus, thalamus, and the olfactory bulb. We treated the patient successfully with corticosteroids, plasmapheresis, and rituximab.

Zusammenfassung Ziel der Studie In dieser Studie wurde erstmals das Riechvermögen bei Patienten mit limbischer Enzephalitis (LE) mittels olfaktorisch evozierter Potenziale (OERP) untersucht. Methodik Bei 19 LE Patienten (9 weibliche, 10 männliche Patienten, mittleres Alter 47 Jahre) und 19 gesunden Kotrollprobanden (GK) wurde das Riechvermögen mittels psychophysischer Schwellen-Diskrimination-Identifikations-Testung (SDI) und mittels OERPs bestimmt. Ergebnisse 10 LE Pat. (53%) hatten eine Hyposmie, 2 Pat. (11%) eine funktionelle Anosmie und 7 Pat. (36%) waren normosmisch. Der SDI-Mittelwert±Standardabweichung betrug bei den LE-Patienten 27,3±6,7; bei den GK 34,7±2,2. Der SDI-Wert der LE Patienten war im Vergleich zu den GK signifikant vermindert (p Schlussfolgerung Riechstörungen konnten gehäuft bei LE Patienten nachgewiesen werden. Möglicherweise sind hierfür strukturelle Schädigungen des limbischen Systems, das an der Weiterverarbeitung von olfaktorischen Informationen beteiligt ist, ursächlich. Die Ableitung von OERPs erwies sich als geeignetes objektives Untersuchungsverfahren zur Detektion von Riechstörungen bei LE Patienten.

Im Kontext der sekundaren, organisch bedingten schizophreniformen Psychosen spielen Autoantikorper (AK)-assoziierte Autoimmunenzephalitiden (AEs) eine zunehmend wichtige Rolle. Bei entsprechendem Verdacht wird eine organische Diagnostik inklusive Labor, MRT, EEG und Liquordiagnostik empfohlen. Die AK-Testung sollte zunachst ein Screening fur die haufigsten assoziierten AK gegen neuronale Oberflachenantigene (NMDA-Rezeptor[R], CASPR2, LGI1, AMPA-R, GABAB-R), intrazellulare Antigene (Hu, Ri, Yo, CV2/CRMP5, Ma2 [Ta], Amphiphysin, GAD65), Schilddrusengewebe (TG, TPO, TRAK) und antinukleare Antigene (ANAs) beinhalten. Die AK gegen Oberflachenantigene und GAD65 sollten direkt im Serum und Liquor untersucht werden. Seltenere AK konnen ggf. im zweiten Schritt erganzt werden. Mittels Immunfluoreszenz-Suchtests auf Hirnschnitten von Nagetieren lassen sich auch bisher unbekannte AK entdecken. Der Nachweis eines AK in Kombination mit pathologischen Zusatzbefunden kann zur Diagnosestellung einer AE fuhren und therapeutische Alternativen mit Immunmodulatoren ermoglichen.

The y-aminobutyric acid A receptor (GABAAR) participates in most neurophysiological processes. Mutations cause epilepsy and neuropsychiatric pathologies. Recently a severe encephalitis with refractory seizures and antibodies against GABAARs has been described. Considering the complex subunit distribution of GABAARs, binding patterns of human GABAAR antibodies will help to understand the pathophysiology underlying diverse clinical pictures. We therefore investigated the cerebrospinal fluid (CSF) reactivity of a patient with GABAAR encephalitis using immunocytochemistry on murine brain sections and compared its specificity with commercial GABAAR antibodies. The immunoreactivity of the patient's CSF showed excellent agreement with previously reported GABAAR mRNA expression. Colocalization with neuronal and glial markers verified the neuronal specificity of GABAAR. Patient antibodies strongly bound to neuropil in the external layers of the olfactory bulb, CA1 and CA2 of the hippocampus, neocortex, pallidum and granular cells of the cerebellum. Distribution patterns suggest the presence of polyclonal CSF GABAAR antibodies targeting multiple receptor subunits. The comparison with commercial antibodies revealed large overlap, but also specific differences. For example, commercial antibodies accumulated on dendrites, while CSF created a homogeneous neuropil signal. The number of GABAergic synapses stained with CSF exceeded those labeled with the commercial antibodies. In some areas, commercial antibodies and CSF even stained complementary populations of GABAergic neurons. The data indicate the presence of additional anti-neuronal autoantibodies in the CSF, which could be assessed in future studies with individual recombinant monoclonal antibodies from CSF B cells. This strategy would confirm antibody pathogenicity and likely explain variable clinical pictures in autoimmune encephalitis patients.

We investigated the pathogenic role of anti-N-Methyl-D-aspartate receptor (NMDAR) antibodies in neurons and in a mouse model of autoimmune encephalitis using LSM and super-resolution microscopy. We found a functional reduction of synaptic NMDARs.

According to present concepts, primary psychotic disorders in the schizophrenia spectrum are probably caused by a complex interaction between multigenetic vulnerability and causally relevant environmental factors. In contrast, secondary psychotic disorders are the result of likely identifiable organic factors either in terms of a first causation (etiology) or a secondary cause (pathogenesis). In this context, autoantibody(ab)-associated autoimmune encephalitis (AE) plays an increasingly important role. Within the group of ab-associated AE with neuropsychiatric symptoms, anti-N-methyl-D-aspartate receptor encephalitis is the most prevalent one. Psychopathologically, polymorphic psychotic symptoms are often observed at onset of AE; however, over the course of this condition or even initially other neuropsychiatric phenomena are also common. The ill-defined entity of a steroid-responsive encephalopathy with thyroid antibodies (Hashimoto's encephalitis) is a heterogeneous syndrome that may also comprise isolated psychotic disorders presenting as classical schizophrenia.

ObjectiveTo determine whether the gut microbiota shows overabundance of commensal bacteria species in patients with anti-NMDA receptor (NMDAR) encephalitis, similar to patients with MS or neuromyelitis optica where they potentially balance pro- and anti-inflammatory immune responses or participate in disease pathogenesis by molecular mimicry.MethodsIntestinal microbiota was characterized in patients with NMDAR encephalitis (n = 23, mean age: 34 ± 12.7 years; 21 females) and age/sex/environment-matched healthy controls (n = 24, 40 ± 14.2 years; 22 females) using stool bacteria 16S rDNA sequencing and classification in operational taxonomic units (OTUs). Statistical analyses focused on intraindividual and interindividual bacterial diversity and identification of differentially abundant taxa.ResultsPatients with NMDAR encephalitis and controls had similar microbiome profiles of the gut microbiota regarding intraindividual bacterial diversity, OTU distribution, ratio between regional and local species diversity when testing all OTUs, and genera with a relative abundance greater than 0.5%. Similarly, the subgroup of NMDAR encephalitis patients with an ovarian teratoma (n = 3) showed no differences in microbiome variation compared with controls. Patients in the acute encephalitis stage (n = 8) showed significant differences in the numbers of Clostridium XVIII, Clostridium IV, Oscillibacter, Prevotella, and Blautia; however, significance was lost after correction for multiple testing.ConclusionPatients with NMDAR encephalitis and controls both had a normal gut microbiome. The lack of overabundance of certain bacterial species in patients suggests that microbiome changes are no major contributors to the pathogenesis, disease course, or prognosis in NMDAR encephalitis. Despite the small sample size and heterogeneous groups, findings indicate differences to other neuroimmunologic diseases.

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.

In the context of secondary, possibly organic schizophreniform psychoses, autoantibody(AB)-associated autoimmune encephalitis (AE) plays an increasingly important role. If this is suspected, clinical investigations, including laboratory, magnetic resonance imaging, electroencephalography and cerebrospinal fluid (CSF) analyses are recommended. The AB screening should include the most frequent ABs against neuronal cell surface antigens (NMDA receptor [R], CASPR2, LGI1, AMPA-R, GABAB-R), intracellular antigens (Hu, Ri, Yo, CV2/CRMP5, Ma2[Ta], amphiphysin, GAD65), thyroid tissue (TG, TPO, TRAK), and antinuclear antigens (ANAs). The ABs against cell surface antigens and GAD65 should be examined directly in serum and CSF. Less frequent ABs can be looked for in a second step. Furthermore, immunofluorescence tests on brain slices of rodents may identify previously unknown ABs. The detection of ABs in combination with further findings can lead to the diagnosis of AE which implies new therapeutic opportunities with immunomodulators.

Background and Purpose— NMDAR1-abs (anti-N-Methyl-D-Aspartate receptor GluN1 antibodies), predominantly known in the context of autoimmune encephalitis, have been observed in serum of healthy individuals. A previous study found smaller stroke magnetic resonance imaging lesion growth in seropositive patients, suggesting a neuroprotective effect of these antibodies. The impact of NMDAR1-abs seropositivity on long-term functional outcome and recurrent vascular events and death after first-ever stroke remains unclear. Methods— Data from the Prospective Cohort with Incident Stroke—Berlin were used. NMDAR1-abs (ie, IgM, IgA, and IgG) were measured in serum within 7 days after first stroke. Outcomes of interest included modified Rankin Scale at one year and the time-to-event of a combined end point (recurrent stroke, myocardial infarction, and all-cause mortality) within 3 years. We calculated odds ratios from adjusted partial proportional odds models and subsequently compared outcome of patients with low titers (1:10; 1:32; and 1:100), and high titers (1:320; 1:1000) to seronegative patients. Furthermore, we estimated hazard ratios for a secondary vascular event or death in NMDAR1-abs seropositive compared to seronegative patients in models adjusted for confounders. Results— The analyses included 583 patients with antibody measurements (39% female, median National Institutes of Health Stroke Scale:2, IQR:1-4), and NMDAR1-abs were observed in 76 (13%) patients. NMDAR1-abs seroprevalence was not associated with functional outcome (odds ratio=1.27; 95% CI, 0.77–2.09); sub-group analyses, however, showed worse outcome in patients with high titers (odds ratio=3.47; 95% CI, 1.54–7.80). Seropositive patients had an increased risk for a secondary vascular event or death (hazard ratios =1.83, 95% CI, 1.10–3.05). Conclusions— In our study, NMDAR1-abs seropositivity was not associated with functional outcome at one year after stroke, however, high titers (≥1:320) were associated with poor functional outcome. Furthermore, NMDAR1-abs seropositivity was associated with increased cardiovascular risk within 3 years after first stroke, independently from other risk factors. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT01363856.

Mutations in several genes encoding ion channels can cause the long-QT (LQT) syndrome with cardiac arrhythmias, syncope and sudden death. Recently, mutations in some of these genes were also identified to cause epileptic seizures in these patients, and the sudden unexplained death in epilepsy (SUDEP) was considered to be the pathologic overlap between the two clinical conditions. For LQT-associated KCNQ1 mutations, only few investigations reported the coincidence of cardiac dysfunction and epileptic seizures. Clinical, electrophysiological and genetic characterization of a large pedigree (n = 241 family members) with LQT syndrome caused by a 12-base-pair duplication in exon 8 of the KCNQ1 gene duplicating four amino acids in the carboxyterminal KCNQ1 domain (KCNQ1dup12; p.R360_Q361dupQKQR, NM_000218.2, hg19). Electrophysiological recordings revealed no substantial KCNQ1-like currents. The mutation did not exhibit a dominant negative effect on wild-type KCNQ1 channel function. Most likely, the mutant protein was not functionally expressed and thus not incorporated into a heteromeric channel tetramer. Many LQT family members suffered from syncopes or developed sudden death, often after physical activity. Of 26 family members with LQT, seizures were present in 14 (LQTplus seizure trait). Molecular genetic analyses confirmed a causative role of the novel KCNQ1dup12 mutation for the LQT trait and revealed a strong link also with the LQTplus seizure trait. Genome-wide parametric multipoint linkage analyses identified a second strong genetic modifier locus for the LQTplus seizure trait in the chromosomal region 10p14. The linkage results suggest a two-locus inheritance model for the LQTplus seizure trait in which both the KCNQ1dup12 mutation and the 10p14 risk haplotype are necessary for the occurrence of LQT-associated seizures. The data strongly support emerging concepts that KCNQ1 mutations may increase the risk of epilepsy, but additional genetic modifiers are necessary for the clinical manifestation of epileptic seizures.

Coronaviruses have caused several human epidemics and pandemics including the ongoing coronavirus disease 2019 (COVID-19). Prophylactic vaccines and therapeutic antibodies have already shown striking effectiveness against COVID-19. Nevertheless, concerns remain about antigenic drift in SARS-CoV-2 as well as threats from other sarbecoviruses. Cross-neutralizing antibodies to SARS-related viruses provide opportunities to address such concerns. Here, we report on crystal structures of a cross-neutralizing antibody, CV38-142, in complex with the receptor-binding domains from SARS-CoV-2 and SARS-CoV. Recognition of the N343 glycosylation site and water-mediated interactions facilitate cross-reactivity of CV38-142 to SARS-related viruses, allowing the antibody to accommodate antigenic variation in these viruses. CV38-142 synergizes with other cross-neutralizing antibodies, notably COVA1-16, to enhance neutralization of SARS-CoV and SARS-CoV-2, including circulating variants of concern B.1.1.7 and B.1.351. Overall, this study provides valuable information for vaccine and therapeutic design to address current and future antigenic drift in SARS-CoV-2 and to protect against zoonotic SARS-related coronaviruses., Graphical abstract, Antibody CV38-142 from a COVID-19 patient cross-reacts with SARS-related viruses. Liu et al. reveal that CV38-142 interacts with the S309 N343 glycan site and synergizes with COVA1-16 that binds the conserved CR3022 site. Combination of the two cross-neutralizing antibodies shows enhanced neutralization to circulating variants of concern B.1.1.7 and B.1.351.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic is a challenge for all participants in the healthcare system. At the beginning of the pandemic, many physicians asked themselves what risk their patients, especially those with chronic diseases, were exposed to. We present an overview of all patients with multiple sclerosis (MS) and SARS-CoV-2 infection published in the literature so far. In total, there are publications on 873 SARS-CoV-2 positive MS patients and information on the outcome can be given for 700 patients. With regard to the different disease modifying therapies (DMTs), by far the most cases were described under anti-CD20 treatment (n = 317). The mortality rate of all MS patients was 4% and a further 3% required invasive or non-invasive ventilation. When looking at the severe and fatal cases, it is particularly noticeable that patients without DMTs, with previous cardiovascular diseases, or with a severe degree of disability are at risk. Immunosuppressive therapy itself does not appear to be a substantial risk factor. Rather, it is reasonable to assume that the therapies could be protective, either directly, by mitigating the cytokine storm, or indirectly, by reducing the disease activity of MS.

Die Moglichkeit, durch Autoantikorper verursachte und damit kausal behandelbare neuropsychiatrische Erkrankungen schnell erkennen und erfolgreich therapieren zu konnen, hat die Neurologie und Psychiatrie in den letzten Jahren immens bereichert. Neben dem haufigsten Autoantikorper, der gegen Glutamatrezeptoren vom Typ NMDA gerichtet ist, kommen etliche weitere als spezifische Ursache von Psychosen, kognitiven Storungen, emotionaler Instabilitat oder Katatonie bei Patienten aller Altersgruppen infrage. Der Fokus dieses Ubersichtsartikels richtet sich auf klinisch anwendbare Kriterien, die dabei helfen konnen, die richtige Diagnose bereits im Fruhstadium der Erkrankung zu stellen, um behandelbare Atiologien nicht zu ubersehen.

Anti-NMDA receptor encephalitis was first described about thirteen years ago and has become one of the most important differential diagnoses for new-onset psychosis. The disease is mediated by autoantibodies against the subunit 1 of the N-methyl-D-aspartate receptor (NMDA-R1) in patients presenting with variable clinical symptoms. Patients often profit from immunmodulatory therapy, independent of their individual symptoms. In this study CSF samples as well as monoclonal antibodies derived from patients diagnosed with NMDA-R1 encephalitis were applied to rat hippocampus and visualized by immunocytochemistry. This reveals at least two distinct patterns of immunoreactivity. Antibodies from "pattern group 1" display the familiar pattern of NMDA-R1 distribution in the hippocampus reported in experiments with rabbit anti-NMDA-R1 antibodies. Neurons and primary dendrites in the CA1 and CA3 region show strongly stained cell bodies, in line with the predominant postsynaptic localization of the NMDA receptor in the brain. However, autoantibodies from "pattern group 2" show an inverse pattern, with no staining of the cell bodies and primary dendrites in CA1 and CA3 regions. Electron microscopic experiments disclose that autoantibodies of "pattern group 1 patients" bind to postsynaptic NMDA receptors, while those of "pattern group 2 patients" target presynaptic NMDA receptors. We describe one NMDA-receptor antibody giving staining comparable to rabbit anti-NMDA-R1 antibodies, raised against the C-terminus. In the highly heterogenous disease anti-NMDA-receptor 1 encephalitis we found evidence for at least two different subtypes. It will be very interesting to determine whether there also are two distinct clinical phenotypes.

Structural and functional elements of biological systems are highly conserved across vertebrates. Many neurological and psychiatric conditions affect both humans and animals. A cross-species approach to the study of brain and behaviour can advance our understanding of human disorders via the identification of unrecognized natural models of spontaneous disorders, thus revealing novel factors that increase vulnerability or resilience, and via the assessment of potential therapies. Moreover, diagnostic and therapeutic advances in human neurology and psychiatry can often be adapted for veterinary patients. However, clinical and research collaborations between physicians and veterinarians remain limited, leaving this wealth of comparative information largely untapped. Here, we review pain, cognitive decline syndromes, epilepsy, anxiety and compulsions, autoimmune and infectious encephalitides and mismatch disorders across a range of animal species, looking for novel insights with translational potential. This comparative perspective can help generate novel hypotheses, expand and improve clinical trials and identify natural animal models of disease resistance and vulnerability.

ObjectiveTo assess intensive care unit (ICU) complications, their management, and prognostic factors associated with outcomes in a cohort of patients with autoimmune encephalitis (AE).MethodsThis study was an observational multicenter registry of consecutively included patients diagnosed with AE requiring Neuro-ICU treatment between 2004 and 2016 from 18 tertiary hospitals. Logistic regression models explored the influence of complications, their management, and diagnostic findings on the dichotomized (0–3 vs 4–6) modified Rankin Scale score at hospital discharge.ResultsOf 120 patients with AE (median age 43 years [interquartile range 24–62]; 70 females), 101 developed disorders of consciousness, 54 autonomic disturbances, 42 status epilepticus, and 39 severe sepsis. Sixty-eight patients were mechanically ventilated, 85 patients had detectable neuronal autoantibodies, and 35 patients were seronegative. Worse neurologic outcome at hospital discharge was associated with necessity of mechanical ventilation (sex- and age-adjusted OR 6.28; 95% CI, 2.71–15.61) tracheostomy (adjusted OR 6.26; 95% CI, 2.68–15.73), tumor (adjusted OR 3.73; 95% CI, 1.35–11.57), sepsis (adjusted OR 4.54; 95% CI, 1.99–10.43), or autonomic dysfunction (adjusted OR 2.91; 95% CI, 1.24–7.3). No significant association was observed with autoantibody type, inflammatory changes in CSF, or pathologic MRI.ConclusionIn patients with AE, mechanical ventilation, sepsis, and autonomic dysregulation appear to indicate longer or incomplete convalescence. Classic ICU complications better serve as prognostic markers than the individual subtype of AE. Increased awareness and effective management of these AE-related complications are warranted, and further prospective studies are needed to confirm our findings and to develop specific strategies for outcome improvement.

The y-aminobutyric acid A receptor (GABA

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.

Over the past few years, neurology has witnessed an unprecedented discovery of new clinical entities related to autoantibodies targeting natively expressed neuronal proteins, often at the synapse.1 In this issue of Neurology® : Neuroimmunology and Neuroinflammation, Honorat et al.2 report that they successfully dug for yet another disease. Starting with the observation in 6 patients of a specific, previously unknown antibody reaction with murine brain sections, the authors identified septin-5 as the underlying target of serum and CSF antibodies. The 4 patients with available clinical information had a rapidly progressive cerebellar syndrome, 2 had prominent oscillopsia at onset. Treated patients improved with immunotherapy; however, the disease was fatal in 1.

[This corrects the article DOI: 10.1371/journal.pone.0192778.].

Diverse neuropsychiatric diseases were recently linked to specific anti-neuronal autoantibodies targeting synaptic proteins. Symptoms can range from epileptic seizures to cognitive impairment to movement disorders, commonly responding to treatment with immunotherapy. Several of these autoantibodies target inhibitory synapses that use GABA or glycine as neurotransmitters. Despite their relatively low abundance, inhibitory neurons are extraordinarily diverse in anatomical, electrophysiological and molecular terms, reflecting the variable clinical phenotypes of affected patients. Indeed, data on the antibody effects in neuronal cultures or animals models suggest that most of these antibodies are directly pathogenic by down-regulating synaptic proteins, activating complement or antagonizing ligand binding. The present review summarizes the current achievements in the field of humoral autoimmunity related to inhibitory networks, state-of-the-art diagnostics and clinical characterization of patients. In many instances, the phenotypic spectrum of patients with GABA receptor, glycine receptor, amphiphysin or GAD65 antibodies mirror the experimental findings, suggesting that ongoing work will markedly contribute to the better understanding of pathophysiology in this exciting patient group and might pave the way for disease-specific immunotherapy.

ObjectiveHippocampal inflammation in anti-LGI1 encephalitis causes memory deficits, seizures and behavioural abnormalities. Recent findings suggest that extralimbic brain areas are additionally affected and that patients also suffer from non-limbic cognitive symptoms. Moreover, up to 60% of patients show no structural MRI abnormalities in the acute disease stage. We therefore investigated whether functional connectivity analyses can identify brain network changes underlying disease-related symptoms.MethodsWe studied 27 patients and a matched healthy control group using structural and functional MRI. Intrinsic functional networks were analysed using Independent Component Analysis and Dual Regression. Cognitive testing covered working memory, episodic memory, attention and executive function.ResultsOur analysis revealed functional connectivity alterations in several large-scale networks, including the default mode network (DMN) which showed an aberrant structure-function relationship with the damaged hippocampus. In addition, connectivity in the sensorimotor, salience and higher visual networks was impaired independent of hippocampal damage. Increased connectivity in ventral and dorsal DMN regions significantly correlated with better memory performance. In contrast, stronger connectivity of the insula with the salience network and DMN was linked to impaired memory function.ConclusionsAnti-LGI1 encephalitis is associated with a characteristic pattern of widespread functional network alterations. Increased DMN connectivity seems to represent a compensatory mechanism for memory impairment induced by hippocampal damage. Network analyses may provide a key to the understanding of clinical symptoms in autoimmune encephalitis and reveal changes of brain function beyond apparent structural damage.

BackgroundClinical brain MRI is normal in the majority of patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. However, extensive deep white matter damage wasrecently identifiedin these patients using diffusion weighted imaging. Here, our aim was to study a particularly vulnerable brain compartment, the late myelinating superficial white matter.MethodsForty-six patients with anti-NMDAR encephalitis were included. Ten out of these were considered neurologically recovered (modified Rankin scale of zero), while 36 patients were non-recovered. In addition, 30 healthy controls were studied. MRI data were collected from all subjects and superficial white matter mean diffusivity derived from diffusion tensor imaging was compared between groups in whole brain, lobar and vertex-based analyses. Patients underwent comprehensive cognitive testing, and correlation analyses were performed between cognitive performance and superficial white matter integrity.ResultsNon-recovered patients showed widespread superficial white matter damage in comparison to recovered patients and healthy controls. Vertex-based analyses revealed that damage predominated in frontal and temporal lobes. In contrast, the superficial white matter was intact in recovered patients. Importantly, persistent cognitive impairments in working memory, verbal memory, visuospatial memory and attention significantly correlated with damage of the superficial white matter in patients.ConclusionsAnti-NMDAR encephalitis is associated with extensive superficial white matter damage in patients with incomplete recovery. The strong association with impairment in several cognitive domains highlights the clinical relevance of white matter damage in this disorder and warrants investigations of the underlying pathophysiological mechanisms.

Objectives: Despite intensive research, schizophrenia and schizoaffective disorders continue to be theoretical constructs that describe clinical syndromes and no pathophysiologically defined diseases. Moreover, there are no clear biomarkers at hand. Therefore, these diagnoses are still set up based on clinical ICD-10/DSM-5 criteria and the exclusion of alcohol-/drug-associated, systemic or other brain organic causes.Methods: Recently, autoimmune encephalitis with psychotic symptoms caused by specific antineuronal antibodies has been identified as a rare, but potentially treatable differential diagnosis. However, these inflammatory brain diseases are not reliably detected by our current routine diagnostic workup in psychiatry. This qualitative review provides structured diagnostic and therapeutic support for clinical practice.Results: Disturbances of consciousness and orientation, catatonia, speech dysfunction, focal neurological signs, epileptic seizures/EEG abnormalities or autonomic dysfunction are warning signs in psychiatric patients which should always induce cerebrospinal fluid analysis with determination of antineuronal autoantibodies. Currently established immunotherapy strategies are summarised, taking into account international expert advice.Conclusions: Guided by clinical warning signs, our qualitative review enables rapid and reliable diagnosis of definite autoimmune encephalitis. This is of high relevance for the affected individuals, since early and sufficiently intense immunotherapy often leads to a good prognosis despite severe illness.

Autoantibodies of the IgG class against N-methyl-d-aspartate-receptor subunit NR1 (NMDAR1) were first described in anti-NMDAR encephalitis and seen as disease indicators. Recent work on together over 5000 individuals challenged this exclusive view by showing age-dependently up to >20% NMDAR1-autoantibody seroprevalence with comparable immunoglobulin class and titer distribution across health and disease. The key question therefore is to understand the properties of these autoantibodies, also in healthy carriers, in order to assess secondary complications and possible contributions to neuropsychiatric disease. Here, we believe we provide for human NMDAR1-autoantibodies the first comprehensive analysis of their target epitopes and functionality. We selected sera of representative carriers, healthy or diagnosed with very diverse conditions, that is, schizophrenia, age-related disorders like hypertension and diabetes, or anti-NMDAR encephalitis. We show that all positive sera investigated, regardless of source (ill or healthy donor) and immunoglobulin class, provoked NMDAR1 internalization in human-induced pluripotent stem cell-derived neurons and reduction of glutamate-evoked currents in NR1-1b/NR2A-expressing Xenopus oocytes. They displayed frequently polyclonal/polyspecific epitope recognition in the extracellular or intracellular NMDAR1 domains and some additionally in NR2A. We conclude that all circulating NMDAR1-autoantibodies have pathogenic potential regarding the whole spectrum of neuronal NMDAR-mediated effects upon access to the brain in situations of increased blood-brain-barrier permeability.

The field of autoimmune encephalitides associated with antibodies targeting cell-surface antigens is rapidly expanding and new antibodies are discovered frequently. Typical clinical presentations include cognitive deficits, psychiatric symptoms, movement disorders and seizures and the majority of patients respond well to immunotherapy. Pathophysiological mechanisms and clinical features are increasingly recognized and indicate hippocampal dysfunction in most of these syndromes. Here, we review the neuroimaging characteristics of autoimmune encephalitides, including N-methyl-d-aspartate (NMDA) receptor, leucine-rich glioma inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2) encephalitis as well as more recently discovered and less frequent forms such as dipeptidyl-peptidase-like protein 6 (DPPX) or glycine receptor encephalitis. We summarize findings of routine magnetic resonance imaging (MRI) investigations as well as (18)F-fluoro-2-deoxy-d-glucose (FDG)-positron emission tomography (PET) and single photon emission tomography (SPECT) imaging and relate these observations to clinical features and disease outcome. We furthermore review results of advanced imaging analyses such as diffusion tensor imaging, volumetric analyses and resting-state functional MRI. Finally, we discuss contributions of these neuroimaging observations to the understanding of the pathophysiology of autoimmune encephalitides.

Patients suffering from corneal neuropathy may present with photoallodynia; i.e., increased light sensitivity, frequently with a normal slit-lamp examination. This study aimed to evaluate the efficacy of autologous serum tears (AST) for treatment of severe photoallodynia in corneal neuropathy and to correlate clinical findings with corneal subbasal nerve alterations by in vivo confocal microscopy (IVCM).Retrospective case control study with 16 patients with neuropathy-induced severe photoallodynia compared to 16 normal controls. Symptom severity, clinical examination and bilateral corneal IVCM scans were recorded.All patients suffered from extreme photoallodynia (8.8±1.1) with no concurrent ocular surface disease. Subbasal nerves were significantly decreased at baseline in patients compared to controls; total nerve length (9208±1264 vs 24714±1056 μm/mm(2); P.0001) and total nerve number (9.6±1.4 vs 28.6±2.0; P.0001), respectively. Morphologically, significantly increased reflectivity (2.9±0.2 vs 1.8±0.1; P.0001), beading (in 93.7%), and neuromas (in 62.5%) were seen. AST (3.6±2.1 months) resulted in significantly decreased symptom severity (1.6±1.7; P=.02). IVCM demonstrated significantly improved nerve parameters (P.005), total nerve length (15451±1595 μm/mm(2)), number (13.9±2.1), and reflectivity (1.9±0.1). Beading and neuromas were seen in only 56.2% and 7.6% of patients.Patients with corneal neuropathy-induced photoallodynia show profound alterations in corneal nerves. AST restores nerve topography through nerve regeneration, and this correlated with improvement in patient-reported photoallodynia. The data support the notion that corneal nerve damage results in alterations in afferent trigeminal pathways to produce photoallodynia.

Paraneoplastic neurological syndromes belong to the most enigmatic and fascinating disorders. Their remarkable clinical spectrum ranges from sensory neuronopathy to cerebellar degeneration or limbic encephalitis. We retrace the clinical and pathological description of a forgotten case published by Hermann Oppenheim in 1888, which to our knowledge represents the first report of a paraneoplastic neurological syndrome. The young Oppenheim used thorough observation and good clinical judgment to suggest a causal link between the seemingly mere association of an underlying malignancy and a neurological syndrome, decades before Denny-Brown's identification of sensory neuronopathy in 1948 and a century before the discovery of 'anti-Hu' antibodies. Oppenheim anticipated that scientific progress was required to prove this link, and he indicated his finding as 'a pointer for future observers.' In this way, he leaves the reader with the fascinating question of which observations during our current neurology practice could be the next 'pointers' in medical research.

A 16-year-old boy presented with a 3-week history of back pain, insomnia, profuse sweating, and constipation following a respiratory infection. Physical examination revealed tachycardia, arterial hypertension, muscle weakness, and postural tremor. After hospital admission, he showed almost complete insomnia and massive hyperhidrosis, forcing him to change clothes every 15 minutes and drink up to 12 L/d. He deteriorated, with confusion, hallucination, and additional motor symptoms like fasciculations, areflexia, and muscle cramps/stiffness of both legs that prevented walking. His modified Rankin Scale (mRS) score was 4. Initial blood chemistry only revealed mild hyponatremia. Repeated neuroimaging and extended screening for infectious and neoplastic disease were unremarkable. Electroneurography revealed demyelinating peripheral neuropathy and EMG showed rare spontaneous discharges without the full picture of peripheral nerve hyperexcitability. Serum catecholamine levels were elevated and CSF analysis revealed high protein levels with normal cell count and without oligoclonal bands. Antineuronal antibody screening in serum detected antibodies against the voltage-gated potassium channel (VGKC) complex by radioimmunoassay (RIA, 283 pmol/L) and high titers (1:10,000) against contactin-associated protein 2 (CASPR2) by a commercial cell-based assay (CBA; indirect immunofluorescence on BIOCHIP-Mosaic, Euroimmun, Lubeck, Germany). As the CNS was strongly affected, we analyzed CSF reactivity with a tissue-based assay (TBA). CSF incubation on murine brain sections and subsequent visualization with fluorescent-labeled antihuman immunoglobulin G antibodies revealed a strong signal in the neuropil, mainly of hippocampus and cerebellum (figure, A–D). The CBA confirmed a low CSF anti-CASPR2 antibody titer (1:10) without intrathecal synthesis (table e-1, [links.lww.com/WNL/A71][1], for full diagnostic results). [1]: http://links.lww.com/WNL/A71

Autoimmune-mediated processes are the driving force behind many neurological diseases. Autoimmune encephalitis, a group of syndromes, mediated by or at least associated with autoantibodies against neuronal tissue, have gained increasing importance especially in paediatric neurology. Since the first NMDAR encephalitis was described a growing number of patients with encephalopathy, seizures and psychiatric symptoms were found to suffer from treatable autoimmune disorders. Recently a severe form of encephalitis associated with GABAWe now describe a child with catatonia and encephalopathy due to antibodies against the GABAThe report extends the phenotype of this rare disease. It demonstrates a favourable outcome after introduction of an early and aggressive immunomodulatory therapy. Due to the child's history of previous viral meningitis, the case raises questions about the unrevealed mechanisms leading to autoimmune encephalitis, including the model of a viral trigger as discussed in Herpes infection and NMDAR encephalitis. Finally, it describes in detail the neuropsychological symptoms and cognitive functions during disease flare and recovery.

Summary Background In anti-NMDA receptor (NMDAR) encephalitis, antibody-mediated dysfunction of NMDARs causes severe neuropsychiatric symptoms, including psychosis, memory deficits, and movement disorders. However, it remains elusive how antibody-mediated NMDAR dysfunction leads to these symptoms, and whether the symptoms arise from impairment in specific brain regions and the interactions between impaired regions. Methods In this observational study, we recruited 43 patients with anti-NMDAR encephalitis from a tertiary university hospital and 43 age-matched and sex-matched healthy controls without a history of neurological or psychiatric disorders, who were recruited from the general population of Berlin. We used structural and resting-state functional MRI to investigate alterations in connectivity in all participants. We did functional connectivity analyses, including large-scale network analysis, whole-brain pair-wise connectivity, and machine-learning classification, and compared the results with patients' functional impairment. Findings Although structural MRI was normal in 31 (72%) of the 43 patients, we observed widespread alterations of functional connectivity that correlated with clinical measures. These alterations included impaired hippocampal functional connectivity, decoupling of the medial temporal and the default-mode networks, and an overall impairment of frontotemporal connections. Furthermore, functional connectivity was impaired within distributed large-scale networks, including sensorimotor, frontoparietal, lateral-temporal, and visual networks. Memory impairment correlated with hippocampal and medial-temporal-lobe network connectivity, whereas schizophrenia-like symptoms were associated with functional connectivity changes in frontoparietal networks. Machine-learning analyses corroborated these findings and identified frontoparietal and frontotemporal connections as reliably discriminating features between patients and controls, yielding an overall accuracy of 81%. Interpretation This study reveals a characteristic pattern of whole-brain functional connectivity alterations in anti-NMDAR encephalitis that is well suited to explain the major clinical symptoms of the disorder. These observations advance the pathophysiological understanding of NMDAR dysfunction in the human brain and could be similarly relevant for other neuropsychiatric disorders, such as schizophrenia. Funding Deutsche Forschungsgemeinschaft, Israeli National Science Foundation, Ministry of Science and Technology of Israel, Orion Foundation, and the Agnes Ginges Center for Neurologenetics.

Autoimmune encephalitis is an increasingly recognized neuropsychiatric condition seen in patients of all ages. Herpes virus infections of the brain can antedate the development of pathogenic autoantibodies against N-methyl-D-aspartate receptors and further neuronal surface proteins, leading to neuronal dysfunction and relapsing symptoms. This review will recapitulate the recent scientific progress, clinical manifestations in children and adults, therapeutic options, and etiological concepts on how autoimmunity develops.Postviral autoimmune encephalitis has been established as disease mechanism after herpes simplex virus encephalitis. Relapsing symptoms in the absence of virus occur in up to 20% of cases. The clinical presentation is relatively stereotyped in children, consisting of choreoathetosis and reduced levels of consciousness. Adults commonly present with psychiatric abnormalities and cognitive changes. Virus-induced antibody generation seems to be a widespread mechanism not confined to Herpesviridae and N-methyl-D-aspartate receptor antibodies SUMMARY: The presence of prolonged, atypical, or relapsing symptoms after virus encephalitis must be actively determined, requiring early follow-up visits of patients, and should always prompt the search for underlying autoantibodies. Relapsing symptoms can markedly improve with immunotherapy, thus treatment, including corticosteroids, plasma separation, immunoglobulins, and rituximab is usually recommended, even if no specific antibody was detected.

Guillain-Barre syndrome (GBS) is an autoimmune disease with progressive flaccid paralysis of the extremities. Several auto-antibodies have been identified, binding to myelin, gangliosides, astrocytes or proteins at the nodes of Ranvier. Some epitopes are not confined to the peripheral nerve, suggesting that auto-antibodies may also contribute to symptoms of the central nervous system, which are common in GBS and include anxiety, depression, hallucinations, oneiroid psychosis or fatigue. This notion is supported by treating patients with plasma exchange, resulting in improvement of both central and peripheral symptoms. We analyzed binding of GBS sera to neurons of cholinergic, serotonergic, dopaminergic, nor‐adrenergic or histaminergic nuclei using immunohistochemistry of the rat brain. We hypothesized that GBS sera harbor antibodies against monoaminergic structures in the brain, as these circuits influence larger neuronal networks with relevance for multiple neuropsychiatric symptoms. Indeed, several GBS sera strongly and specifically reacted with monoaminergic neurons, in particular cholinergic nuclei of the diagonal band, neurons of the basal nucleus of Meynert, nor‐adrenergic neurons of the nucleus coeruleus, neurons in the raphe or the ambiguous nucleus. The frequency significantly exceeded those of sera from patients with multiple sclerosis, non-autoimmune neurological disorders and healthy controls. The binding to neuronal surfaces makes it conceivable that the auto-antibodies can interfere with ion channels and receptors and thus contribute to the variable clinical spectrum of neuropsychiatric and autonomic abnormalities in GBS. Future research should include the target identification of promising GBS sera and aim to determine the functional effects of these antibodies.

The recent discovery of neuronal cell-surface antibodies profoundly expanded the clinical spectrum of paraneoplastic neurological syndromes. Many of these syndromes are associated with impaired cognitive function, a clinical symptom that is of increasing concern in cancer patients. However, the frequency of these antibodies in cancer patients and their relation to clinical syndromes is currently unknown. Here, we investigated the prevalence of neuronal cell-surface antibodies and associated paraneoplastic neurological syndromes in 323 patients with different cancer types and in 105 controls. Cerebrospinal fluid and serum samples were analysed for a large panel of anti-neuronal antibodies and all patients were screened for cognitive deficits. Blood–brain barrier integrity was assessed using the age-normalized albumin cerebrospinal fluid/serum ratio. Anti-neuronal autoantibodies were observed in 24.5% of cancer patients (in contrast to 3.1% in neurological control patients without cancer and 2.5% in healthy controls) and were almost exclusively detected in serum. The majority of antibodies were directed against cell-surface antigens (75.9%), most frequently IgA/IgM isotypes targeting the N-methyl-d-aspartate (NMDA) receptor. Cognitive deficits and cerebellar syndromes were significantly more prevalent in antibody-positive in comparison with antibody-negative patients (21 vs. 7%, p = 2.7 × 10−4; 11 vs. 2%, p = 3.0 × 10−3). Antibody-positive patients with cognitive deficits had a significantly increased albumin cerebrospinal fluid/serum ratio in comparison with antibody-positive patients with other neurological deficits, indicating blood–brain barrier dysfunction (49.1 × 10−3 vs. 12.0 × 10−3; p = 0.036). Our results show that anti-neuronal antibodies have a high prevalence in a wide range of different tumour types and are associated with distinct neurological deficits. Specifically, the results suggest a so far undefined cognitive paraneoplastic syndrome in patients with antibodies targeting neuronal surface antigens and concurrent blood–brain barrier dysfunction. Anti-neuronal antibodies might thus serve as a biomarker for potentially treatment-responsive cognitive impairments in cancer patients.

Autoimmune mechanisms causing diverse psychiatric symptoms are increasingly recognized and brought about a paradigm shift in neuropsychiatry. Identification of underlying antibodies against neuronal ion channels or receptors led to the speculation that a number of patients go misdiagnosed with a primary psychiatric disease. However, there is no clear consensus which clinical signs in psychiatric patients should prompt further investigations including measurement of anti-neuronal autoantibodies. We therefore aimed to analyze the presenting symptoms in patients with autoimmune encephalitis and the time between symptom onset and initiation of antibody diagnostics. For this, we recruited 100 patients from the Charite Center for Autoimmune Encephalitis between May to October 2016, including all types of autoimmune encephalitides. Psychiatric abnormalities were the most common clinical symptoms, and were the presenting sign in 60%. One third of patients were initially hospitalized in a psychiatric ward. All patients positive for antibodies against the N-methyl-D-aspartate receptor (NMDAR) showed behavioral changes, hallucinations, memory deficits, catatonia or delusions. Patients positive for antibodies against other cell surface or intracellular antigens were often hospitalized with a psychosomatic diagnosis. The time between occurrence of first symptoms and antibody testing was often alarmingly prolonged. In patients with symptom onset between 2013 and 2016, the mean delay was 74 days, in cases diagnosed between 2007 and 2012 even 483 days, suggesting though that increased awareness of this novel disease group helped to expedite proper diagnosis and treatment. By analyzing the medical records in detail, we identified clinical signs that may help to assist in earlier diagnosis, including seizures, catatonia, autonomic instability or hyperkinesia. Indeed, re-analyzing the whole cohort using these ‘red flags’ led to a 58% reduction of time between symptom onset and diagnosis. We conclude that the timely diagnosis of an autoimmune psychiatric disease can be facilitated by use of the described clinical warning signs, likely enabling earlier immunotherapy and better prognosis. Also, the threshold for cerebrospinal fluid analysis and autoantibody testing should be low.

Acute spinal cord injury (SCI) causes systemic immunosuppression and life-threatening infections, thought to result from noradrenergic overactivation and excess glucocorticoid release via hypothalamus-pituitary-adrenal axis stimulation. Instead of consecutive hypothalamus-pituitary-adrenal axis activation, we report that acute SCI in mice induced suppression of serum norepinephrine and concomitant increase in cortisol, despite suppressed adrenocorticotropic hormone, indicating primary (adrenal) hypercortisolism. This neurogenic effect was more pronounced after high-thoracic level (Th1) SCI disconnecting adrenal gland innervation, compared with low-thoracic level (Th9) SCI. Prophylactic adrenalectomy completely prevented SCI-induced glucocorticoid excess and lymphocyte depletion but did not prevent pneumonia. When adrenalectomized mice were transplanted with denervated adrenal glands to restore physiologic glucocorticoid levels, the animals were completely protected from pneumonia. These findings identify a maladaptive sympathetic-neuroendocrine adrenal reflex mediating immunosuppression after SCI, implying that therapeutic normalization of the glucocorticoid and catecholamine imbalance in SCI patients could be a strategy to prevent detrimental infections.

Objective To study the prevalence of autoantibodies to synapsin in patients with psychiatric and neurological disorders and to describe clinical findings in synapsin antibody positive patients. Methods Sera of 375 patients with different psychiatric and neurological disorders and sera of 97 healthy controls were screened (dilution 1:320) for anti-synapsin IgG using HEK293 cells transfected with rat synapsin Ia. Positive sera were further analyzed by immunoblots with brain tissue from wild type and synapsin knock out mice and with HEK293 cells transfected with human synapsin Ia and Ib. Binding of synapsin IgG positive sera to primary neurons was studied using murine hippocampal neurons. Results IgG in serum from 23 (6.1%) of 375 patients, but from none of the 97 healthy controls (p = 0.007), bound to rat synapsin Ia transfected cells with a median (range) titer of 1:1000 (1:320–1:100,000). Twelve of the 23 positive sera reacted with a protein of the molecular size of synapsin I in immunoblots of wild type but not of synapsin knock out mouse brain tissue. Out of 19/23 positive sera available for testing, 13 bound to human synapsin Ia and 16 to human synapsin Ib transfected cells. Synapsin IgG positive sera stained fixed and permeabilized murine hippocampal neurons. Synapsin IgG positive patients had various psychiatric and neurological disorders. Tumors were documented in 2 patients (melanoma, small cell lung carcinoma); concomitant anti-neuronal or other autoantibodies were present in 8 patients. Conclusions Autoantibodies to human synapsin Ia and Ib are detectable in a proportion of sera from patients with different psychiatric and neurological disorders, warranting further investigation into the potential pathophysiological relevance of these antibodies.

Sir, We thank Professor Dalmau for the stimulating thoughts on our work (Dalmau, 2016). We fully agree that—already before our study—the fundamental experimental data acquired by his and further groups using human immunoglobulins from patients with N -methyl-d-aspartate receptor (NMDAR) encephalitis provided solid evidence that the clinical symptoms relate to dysfunction of NMDA receptors caused by the antibodies contained in human samples (Dalmau, 2008; Hughes et al. , 2010; Pruss et al. , 2010; Moscato et al. , 2014; Planaguma et al. , 2015, 2016). Effects in primary neuronal cell cultures mimicked the phenotype in laboratory animals and were thus designated as surrogate markers of the pathophysiology. Therefore, in this first paper using monoclonal human NMDAR autoantibodies, we …

Objective:To provide an extensive overview on the prevalence of antibodies against neuronal surfaces (neuronal surface antibody [NSAb]) in healthy participants and disease controls.Methods:We searched the PubMed database (1974 to October 2016) for studies that analyzed frequencies of 22 different NSAbs in serum or CSF and included controls. Antibody prevalence was calculated for patients with NSAb-mediated disease and controls, including healthy participants, and those with neurologic and nonneurologic diseases. Different assays for antibody detection were compared.Results:In 309 articles, 743,299 antibody tests for 22 NSAbs were performed, including 30,485 tests for 19 NSAbs in healthy controls (HCs). Of these, 26,423 (86.7%) were tested with current standard methods, usually cell-based assays. Prevalence was very low in HCs (mean 0.23%, absent for 9/19 antibodies), and test numbers ranged from 21 to 3,065 per antibody. One study reported >1,000 healthy participants, and the others contained 21–274 samples. CSF samples were virtually not available from HCs. NSAb prevalence was considerably higher (1.5%) in 69,850 disease controls, i.e., patients not initially suspected to have NSAb-mediated diseases. Antibody determination in controls using nonstandard assays (such as ELISA) resulted in 6% positivity.Conclusions:NSAbs are rarely found in healthy participants, particularly with standard detection methods, suggesting high disease specificity and supporting their diagnostic usefulness. Conversely, positive titers in atypical patients might point to the still expanding phenotypic spectrum. Future studies should include more CSF samples, data from HCs, and experimental evidence for antibody pathogenicity.