Search

A fraction of patients with antibody-mediated autoimmune diseases remain unresponsive to first-/second-line and sometimes even to escalation immunotherapies. Because these patients are still affected by poor outcome and increased mortality, we investigated the safety and efficacy of the plasma cell-depleting anti-CD38 antibody daratumumab in life-threatening, antibody-mediated autoimmune diseases.In this retrospective, single-center case series, seven patients with autoantibody-driven neurological autoimmune diseases (autoimmune encephalitis, n = 5; neurofascin antibody-associated chronic inflammatory demyelinating polyneuropathy associated with sporadic late onset nemaline myopathy, n = 1; seronegative myasthenia gravis, n = 1) unresponsive to a median of four (range = 4-9) immunotherapies were treated with four to 20 cycles of 16 mg/kg daratumumab.Daratumumab allowed a substantial clinical improvement in all patients, as measured by modified Rankin Scale (mRS; before treatment: mRS =5, n = 7; after treatment: median mRS =4, range = 0-5), Clinical Assessment Scale in Autoimmune Encephalitis (from median 21 to 3 points, n = 5), Inflammatory Neuropathy Cause and Treatment disability score (from 7 to 0 points, n = 1), and Quantitative Myasthenia Gravis score (from 16 to 8 points, n = 1). Daratumumab induced a substantial reduction of disease-specific autoreactive antibodies, total IgG (serum, 66%, n = 7; cerebrospinal fluid, 58%, n = 5), and vaccine-induced titers for rubella (50%) and tetanus toxoid (74%). Treatment-related toxicities Grade 3 or higher occurred in five patients, including one death.Our findings suggest that daratumumab provided a clinically relevant depletion of autoreactive long-lived plasma cells, identifying plasma cell-targeted therapies as promising escalation therapy for highly active, otherwise treatment-refractory autoantibody-mediated neurological diseases.

Background Fibrin deposition is a fundamental pathophysiological event in the inflammatory component of various CNS disorders, such as multiple sclerosis (MS) and Alzheimer’s disease. Beyond its traditional role in coagulation, fibrin elicits immunoinflammatory changes with oxidative stress response and activation of CNS-resident/peripheral immune cells contributing to CNS injury. Purpose To investigate if CNS fibrin deposition can be determined using molecular MRI, and to assess its capacity as a non-invasive imaging biomarker that corresponds to inflammatory response and barrier impairment. Materials and methods Specificity and efficacy of a peptide-conjugated Gd-based molecular MRI probe (EP2104-R) to visualise and quantify CNS fibrin deposition were evaluated. Probe efficacy to specifically target CNS fibrin deposition in murine adoptive-transfer experimental autoimmune encephalomyelitis (EAE), a pre-clinical model for MS (n = 12), was assessed. Findings were validated using immunohistochemistry and laser ablation inductively coupled plasma mass spectrometry. Deposition of fibrin in neuroinflammatory conditions was investigated and its diagnostic capacity for disease staging and monitoring as well as quantification of immunoinflammatory response was determined. Results were compared using t-tests (two groups) or one-way ANOVA with multiple comparisons test. Linear regression was used to model the relationship between variables. Results For the first time (to our knowledge), CNS fibrin deposition was visualised and quantified in vivo using molecular imaging. Signal enhancement was apparent in EAE lesions even 12-h after administration of EP2104-R due to targeted binding (M ± SD, 1.07 ± 0.10 (baseline) vs. 0.73 ± 0.09 (EP2104-R), p = .008), which could be inhibited with an MRI-silent analogue (M ± SD, 0.60 ± 0.14 (EP2104-R) vs. 0.96 ± 0.13 (EP2104-La), p = .006). CNS fibrin deposition corresponded to immunoinflammatory activity (R2 = 0.85, p 2 = 0.81, p M ± SD, 6.6 ± 1 (EP2104-R) vs. 2.7 ± 0.4 (gadobutrol), p = .004) than clinically used contrast media, which increases sensitivity for lesion detection. Conclusions Molecular imaging of CNS fibrin deposition provides an imaging biomarker for inflammatory CNS pathology, which corresponds to pathophysiological ECM remodelling and disease activity, and yields high signal-to-noise ratio, which can improve diagnostic neuroimaging across several neurological diseases with variable degrees of barrier impairment.

We congratulate Guasp et al.1 for this study, which includes the complex task of neurologic investigation for patients with psychosis. It is encouraging to see neurologists engaging with this important issue.

Brain : a journal of neurology (2022). doi:10.1093/brain/awac119, Published by Oxford Univ. Press, Oxford

Autoimmune obsessive-compulsive disorder (OCD) in the context of pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) has been observed for decades. The first cases of autoimmune OCD in adulthood were recently described. An association between obsessive-compulsive symptoms (OCS) and systemic autoimmune diseases in the form of connective tissue disease has also been reported. However, whether an association exists between OCD and sarcoidosis is unknown.Here, the authors present an end 20-year-old female patient with symptoms of OCD in whom an advanced diagnostic work-up revealed inflammatory cerebrospinal fluid (CSF) changes (elevated IgG index, CSF-specific oligoclonal bands, intrathecal IgG synthesis, and a positive MRZ reaction). In tissue-based assays using unfixed mouse brain sections, both serum and CSF showed a distinct antinuclear antibody pattern with perinuclear staining. Electroencephalography identified frontocentral theta spindles. Upon endobronchial-guided lymph node biopsy demonstrating non-caseating lymph nodes in further work-up, sarcoidosis was diagnosed. Levels of the sarcoidosis parameters IL-2-R and neopterin were increased. Under immunotherapy for sarcoidosis, the OCS seemed to improve.This case study is paradigmatic, as an association between sarcoidosis and OCD has not been previously reported. After exclusion of alternative causes, the inflammatory CSF changes would be compatible with an inflammatory brain involvement of sarcoidosis. Autoimmune OCD may occur more frequently than is thought, probably also in the context of neurosarcoidosis. This could open up new opportunities through immunotherapies in rare cases with OCD.

SARS-CoV-2 Beta variant of concern (VOC) resists neutralization by major classes of antibodies from non-VOC COVID-19 patients and vaccinated individuals. Here, serum of Beta variant infected patients revealed reduced cross-neutralization of non-VOC virus. From these patients, we isolated Beta-specific and cross-reactive receptor-binding domain (RBD) antibodies. The Beta-specificity results from recruitment of novel VOC-specific clonotypes and accommodation of VOC-defining amino acids into a major non-VOC antibody class that is normally sensitive to these mutations. The Beta-elicited cross-reactive antibodies share genetic and structural features with non-VOC-elicited antibodies, including a public VH1-58 clonotype targeting the RBD ridge independent of VOC mutations. These findings advance our understanding of the antibody response to SARS-CoV-2 shaped by antigenic drift with implications for design of next-generation vaccines and therapeutics.One sentence summarySARS-CoV-2 Beta variant elicits lineage-specific antibodies and antibodies with neutralizing breadth against wild-type virus and VOCs.

Autoantibodies targeting the GABAA receptor (GABAAR) hallmark an autoimmune encephalitis presenting with frequent seizures and psychomotor abnormalities. Their pathogenic role is still not well-defined, given the common overlap with further autoantibodies and the lack of patient-derived mAbs. Five GABAAR mAbs from cerebrospinal fluid cells bound to various epitopes involving the α1 and γ2 receptor subunits, with variable binding strength and partial competition. mAbs selectively reduced GABAergic currents in neuronal cultures without causing receptor internalization. Cerebroventricular infusion of GABAAR mAbs and Fab fragments into rodents induced a severe phenotype with seizures and increased mortality, reminiscent of encephalitis patients' symptoms. Our results demonstrate direct pathogenicity of autoantibodies on GABAARs independent of Fc-mediated effector functions and provide an animal model for GABAAR encephalitis. They further provide the scientific rationale for clinical treatments using antibody depletion and can serve as tools for the development of antibody-selective immunotherapies.

Objectives:Autoimmune mechanisms are related to disease development in a subgroup of patients with psychosis. The contribution of immunoglobulin G (IgG) antibodies against myelin oligodendrocyte glycoprotein (MOG) is mainly unclear in this context.Methods:Therefore, two patients with psychosis and anti-MOG antibodies – detected in fixed cell-based and live cell-based assays – are presented.Results:Patient 1 suffered from late-onset psychosis with singular white matter lesions in magnetic resonance imaging (MRI) and intermittent electroencephalography (EEG) slowing. Patient 2 suffered from a chronic paranoid–hallucinatory disorder with intermittent confusional states, non-specific white matter alterations on MRI, a disorganised alpha rhythm on EEG, and elevated cerebrospinal fluid protein. Both patients had anti-MOG antibody titres of 1 : 320 in serum (reference < 1 : 20).Conclusions:The arguments for and against a causal role for anti-MOG antibodies are discussed. The antibodies could be relevant, but due to moderate titres, they may have caused a rather ‘subtle clinical picture’ consisting of psychosis instead of ‘classical’ MOG encephalomyelitis.

Seizures are a prominent feature in N-Methyl-D-Aspartate receptor antibody (NMDAR antibody) encephalitis, a distinct neuro-immunological disorder in which specific human autoantibodies bind and crosslink the surface of NMDAR proteins thereby causing internalization and a state of NMDAR hypofunction. To further understand ictogenesis in this disorder, and to test a potential treatment compound, we developed an NMDAR antibody mediated rat seizure model that displays spontaneous epileptiform activity in vivo and in vitro. Using a combination of electrophysiological and dynamic causal modelling techniques we show that, contrary to expectation, reduction of synaptic excitatory, but not inhibitory, neurotransmission underlies the ictal events through alterations in the dynamical behaviour of microcircuits in brain tissue. Moreover, in vitro application of a neurosteroid, pregnenolone sulphate, that upregulates NMDARs, reduced established ictal activity. This proof-of-concept study highlights the complexity of circuit disturbances that may lead to seizures and the potential use of receptor-specific treatments in antibody-mediated seizures and epilepsy., Sukhvir Wright et al. present a NMDAR antibody-induced model of encephalitis in rats and use in vitro, in vivo, and in silico electrophysiology to examine alterations in neural circuit behavior. Their results suggest that reduction of NMDARs leads to increased excitability and seizure activity, and highlights the potential use of receptor-specific treatments in antibody-mediated seizures and epilepsy.

Objective Autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is a steroid-responsive meningoencephalomyelitis, sometimes presenting with atypical clinical signs such as movement disorders or psychiatric and autonomic features. Diagnosis relies on clinical presentation, detection of GFAP autoantibodies in CSF as well as ancillary MRI biomarkers. We aimed to characterize two patients seropositive for GFAP antibodies in CSF presenting with a highly atypical clinical picture of isolated neurocognitive and autonomic features resembling neurodegenerative dementia in absence of cranial MRI abnormalities.Methods Semiquantitative, clinicoradiological, serologic and immunohistochemical analysis of two cases with longitudinal observation over a time course of 18–24 months.Results Both patients had rapidly progressive amnestic syndromes in absence of other focal neurologic signs. Cranial MRI was grossly unremarkable while functional neuroimaging showed cortical and subcortical metabolic changes. Tissue-based assays (TBA) of CSF confirmed GFAP-specific astrocytic binding patterns in rat corpus callosum and hippocampus in both cases. Incomplete steroid response prompted therapy escalation to B-cell depletion, which improved or stabilized disease courses over the observation time.Conclusions These cases suggest that rapidly progressive amnestic syndromes with psychiatric and autonomic features may be a novel phenotype of GFAP astrocytopathy as well as a potentially underrecognized mimic of neurodegenerative dementia amenable to immunomodulation. We recommend including GFAP-AB screening using TBA in the work-up of rapidly progressive dementias especially when autoimmune etiologies are suspected.

ObjectiveThe contemporary diagnosis of paraneoplastic neurologic syndromes (PNSs) requires an increasing understanding of their clinical, immunologic, and oncologic heterogeneity. The 2004 PNS criteria are partially outdated due to advances in PNS research in the last 16 years leading to the identification of new phenotypes and antibodies that have transformed the diagnostic approach to PNS. Here, we propose updated diagnostic criteria for PNS.MethodsA panel of experts developed by consensus a modified set of diagnostic PNS criteria for clinical decision making and research purposes. The panel reappraised the 2004 criteria alongside new knowledge on PNS obtained from published and unpublished data generated by the different laboratories involved in the project.ResultsThe panel proposed to substitute “classical syndromes” with the term “high-risk phenotypes” for cancer and introduce the concept of “intermediate-risk phenotypes.” The term “onconeural antibody” was replaced by “high risk” (>70% associated with cancer) and “intermediate risk” (30%–70% associated with cancer) antibodies. The panel classified 3 levels of evidence for PNS: definite, probable, and possible. Each level can be reached by using the PNS-Care Score, which combines clinical phenotype, antibody type, the presence or absence of cancer, and time of follow-up. With the exception of opsoclonus-myoclonus, the diagnosis of definite PNS requires the presence of high- or intermediate-risk antibodies. Specific recommendations for similar syndromes triggered by immune checkpoint inhibitors are also provided.ConclusionsThe proposed criteria and recommendations should be used to enhance the clinical care of patients with PNS and to encourage standardization of research initiatives addressing PNS.

The anti-CD38 antibody daratumumab is approved for treatment of refractory multiple myeloma and acts by depletion of plasma cells and modification of various T-cell functions. Its safety, immunological effects and therapeutic potential was evaluated in a 60-year old patient with life-threatening and treatment-refractory anti-CASPR2 encephalitis requiring medical care and artificial ventilation in an intensive care unit. His autoimmune dysfunction was driven by exceptional high anti-CASPR2 autoantibody titers combined with an abnormally increased T-cell activation. As he remained unresponsive to standard and escalation immunotherapies (methylprednisolone, plasma exchange, immunoadsorption, immunoglobulins, rituximab and bortezomib), therapy was escalated to 13 cycles of 16 mg/kg daratumumab. During the treatment period, clinical, radiological, histological and laboratory findings, including quantification of autoreactive and protective antibody levels and FACS-based immune phenotyping, were analyzed. Daratumumab treatment was associated with significant clinical improvement, substantial reduction of anti-CASPR2 antibody titers, especially in CSF, decrease of immunoglobulin levels and protective vaccine titers, as well as normalization of initially increased T-cell activation markers. However, the patient died of Gram-negative septicemia in a neurorehabilitation center. In conclusion, our findings suggest that daratumumab induces not only depletion of autoreactive long-lived plasma cells associated with improvements of neurological sequelae, but also severe side effects requiring clinical studies investigating efficacy and safety of anti-CD38 therapy in antibody-driven autoimmune encephalitis.

Zusammenfassung Bei einem nicht einwilligungsfähigen Patienten mit schwerer psychischer Störung besteht zwar häufig die Notwendigkeit einer raschen Diagnostik und Therapie, das Symptombild führt jedoch nicht selten zu einer Ablehnung solcher Maßnahmen. In der täglichen Praxis stellt sich dann die Frage, inwieweit der geäußerte Wille des Patienten die Behandlungsschritte vorgibt oder ob eine Entscheidung gegen den Willen des Patienten medizinisch sinnvoll, ethisch vertretbar oder sogar geboten und rechtlich zulässig ist. Autoimmune Enzephalitiden – wie die N‑Methyl-D-Aspartat-Rezeptor(NMDAR)-Enzephalitis – sind aufgrund ihrer relativen Häufigkeit, vielgestaltigen Symptomatik und guten Therapierbarkeit neuerdings wichtige Differenzialdiagnosen, da die zugrunde liegenden Autoantikörper besonders häufig zu organischen Psychosen führen. Am Beispiel eines komplexen Falles einer Patientin mit im Verlauf gesicherter NMDAR-Enzephalitis erläutern wir die praxisrelevanten ethisch-juristischen Abwägungen von der initialen invasiven Diagnostik bis zur Unterbringung und Zwangsbehandlung. Die Bewertung soll konkrete Hilfestellungen geben, die Autonomie des Patienten zu respektieren, potenzielle Widersprüche zwischen dem freien Willen und dem geäußerten Willen zu ermessen, individuelle ärztliche Überzeugungen (hinsichtlich Autonomiefähigkeit und Zwangsbehandlung) anhand der Rechtslage zu überprüfen, die Indikation für eine vorübergehende Behandlung gegen den natürlichen Willen zu stellen, Analogien zu anderen schweren Hirnerkrankungen herzustellen und erfolgreich gegenüber dem Betreuungsgericht zu argumentieren.

Primar psychotische Storungen aus dem schizophrenen Formenkreis sind nach heutigem Verstandnis Erkrankungen, die durch eine komplexe Interaktion zwischen Genen und Umwelt bedingt sind. Sekundaren psychotischen Storungen liegt eine zumindest mit Wahrscheinlichkeit benennbare organische Ursache im Sinne einer Erstverursachung (Atiologie) oder einer benennbaren Sekundarursache (Pathogenese) zugrunde. In diesem Kontext spielen Autoantikorper(AK)-assoziierte Autoimmunenzephalitiden (AEs) bzw. Autoimmunpsychosen eine zunehmend wichtige Rolle. Innerhalb der Gruppe AK-assoziierter AEs mit neuropsychiatrischer Symptomatik kommt die Anti-N-Methyl-D-Aspartat-Rezeptor-Enzephalitis am haufigsten vor. Psychopathologisch werden bei AEs zu Beginn oft polymorphe psychotische Symptome beobachtet, im Verlauf oder bereits initial treten jedoch meist weitere neurologisch-internistische Phanomene hinzu. Im Rahmen des heterogenen Syndroms einer steroidresponsiven Enzephalopathie mit Schilddrusen-AK (Hashimoto-Enzephalopathie) sind auch klassische psychotische Storungsbilder beschrieben.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis related to autoantibody-mediated synaptic dysfunction. Cerebrospinal fluid-derived human monoclonal NR1 autoantibodies showed low numbers of somatic hypermutations or were unmutated. These unexpected germline-configured antibodies showed weaker binding to the NMDAR than matured antibodies from the same patient. In primary hippocampal neurons, germline NR1 autoantibodies strongly and specifically reduced total and synaptic NMDAR currents in a dose- and time-dependent manner. The findings suggest that functional NMDAR antibodies are part of the human naïve B cell repertoire. Given their effects on synaptic function, they might contribute to a broad spectrum of neuropsychiatric symptoms. Ann Neurol 2019;85:771-776.

Autoantibodies targeting neuronal membrane proteins can cause encephalitis, seizures, and severe behavioral abnormalities. While antibodies for several neuronal targets have been identified, structural details on how they regulate function are unknown. Here we determined cryo-electron microscopy structures of antibodies derived from an encephalitis patient bound to the γ-aminobutyric acid type A (GABA(A)) receptor. These antibodies induced a severe encephalitis by directly inhibiting GABA(A) function, resulting in nervous system hyperexcitability. The structures reveal mechanisms of GABA(A) inhibition and pathology. One antibody directly competes with neurotransmitter and locks the receptor in a resting-like state. The second antibody targets the subunit interface involved in binding benzodiazepines and antagonizes diazepam potentiation. We identify key residues in these antibodies involved in specificity and affinity and confirm structure-based hypotheses for functional effects using electrophysiology. Together these studies define mechanisms of direct functional antagonism of neurotransmission underlying autoimmune encephalitis in a human patient.

Traditional static functional connectivity analyses have shown distinct functional network alterations in patients with anti

ObjectiveTo investigate the genetic determinants of the most common type of antibody-mediated autoimmune encephalitis, anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis.MethodsWe performed a genome-wide association study in 178 patients with anti-NMDAR encephalitis and 590 healthy controls followed by a colocalization analysis to identify putatively causal genes.ResultsWe identified two independent risk loci harboring genome-wide significant variants (P < 5 × 10−8, OR ≤ 2.2), one on chromosome 15, harboring only the LRRK1 gene, and one on chromosome 11 centered on the ACP2 and NR1H3 genes in a larger region of high linkage-disequilibrium. Colocalization signals with expression quantitative trait loci (eQTL) for different brain regions and immune cell types suggested ACP2, NR1H3, MADD, DDB2, and C11orf49 as putatively causal genes. The best candidate genes in each region are LRRK1, encoding Leucine-Rich Repeat Kinase 1, a protein involved in B-cell development, and NR1H3 liver x receptor alpha, a transcription factor whose activation inhibits inflammatory processes.ConclusionThis study provides evidence for relevant genetic determinants of antibody-mediated autoimmune encephalitides outside the HLA-region. The results suggest that future studies with larger sample sizes will successfully identify additional genetic determinants and contribute to the elucidation of the pathomechanism.

Introduction Although the link between autoimmune thyroiditis and mental illnesses is well established, the precise underlying pathophysiology and the influence of anti-thyroid antibodies on diagnostic findings require further research. Patients and Methods A total of 530 patients with schizophreniform and affective syndromes were screened for anti-thyroid antibodies against thyroid peroxidase (TPO), thyroglobulin (TG), and thyroid-stimulating hormone receptor (TSH-R). The patient group analyzed here is a patient subgroup of a previously published cohort (Endres et al., 2020, Translational Psychiatry). The anti-thyroid antibody positive (N = 91) and negative (N = 439) patients were compared in terms of various clinical parameters, routine cerebrospinal fluid (CSF) findings, and the number of positive anti-neuronal antibodies in serum and/or CSF, as well as electroencephalography (EEG), magnetic resonance imaging (MRI), and [18 F]fluorodeoxyglucose positron emission tomography (FDG-PET) findings. Results Anti-TPO antibodies were increased in 17%, anti-TG antibodies in 15%, and anti-TSH-R antibodies in 2% of all patients. In CSF, higher protein concentrations (p = 0.018) and albumin quotients (p = 0.008) were found in the anti-thyroid antibody positive patient group. Also, there were more patients with elevated age-corrected albumin quotients in this group (p = 0.031). FDG-PET hypometabolism was significantly more frequent and the number of positive anti-neuronal intracellular antibodies was significantly higher in patients with anti-thyroid antibodies (p = 0.048, N = 29 and p = 0.032, N = 497 respectively). In addition, there was a trend for higher white blood cell (WBC) counts in all patients with anti-thyroid antibodies (p = 0.090). In the patient subgroup with anti-TPO antibodies this difference was statistically significant (p = 0.027). No relevant differences were found in the other CSF routine parameters, the number of anti-neuronal antibodies against cell surface antigens in serum and/or CSF, EEG and MRI findings. Discussion The present study provides evidence of impaired blood CSF barrier (BCSFB) function in patients with anti-TPO and anti-TG antibodies. An influence of anti-TG antibodies on BCSFB structures has been shown in previous laboratory studies, which reported that the antibodies bind to vascular smooth muscle cells. Due to BCSFB breakdown anti-thyroid antibodies might lead to increased autoimmune susceptibility. The alterations in the FDG-PET, WBC count, and anti-neuronal antibody findings against intracellular structures indicate that it could be useful to extend diagnostic investigations in patients with anti-thyroid antibodies. Further studies should investigate whether anti-thyroid antibodies can also act as “drivers of disease”.

Many neuroimmunological diseases, such as encephalopathy, encephalitis, myelitis and acute disseminated encephalomyelitis (ADEM) have occurred more frequently after infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which indicates a parainfectious or postinfectious association. The most likely underlying mechanisms include virus-triggered overactivation of the immune system with hyperinflammation and cytokine storm but potentially also the development of specific autoantibodies against central nervous system (CNS) tissue. These were predominantly detected in the cerebrospinal fluid of severely ill coronavirus disease 2019 (COVID-19) patients. In contrast, direct damage after invasion of SARS-CoV‑2 into the brain and spinal cord does not seem to play a relevant role. Susceptibility to infection with SARS-CoV‑2 in patients with multiple sclerosis, myasthenia or other neuroimmunological diseases including the risk for severe disease courses, is not determined by the administered immunotherapy but by known risk factors, such as age, comorbidities and the disease-related degree of disability. Therefore, immunotherapy in these patients should not be delayed or discontinued. The contribution of neuroimmunological mechanisms to long-term sequelae after survival of a COVID-19 illness, such as fatigue, impairment of memory, sleep dysfunction or anxiety, will require long-term clinical follow-up, preferentially in COVID-19 register studies.Zahlreiche neuroimmunologische Krankheitsbilder wie Enzephalopathien, Enzephalitiden, Myelitiden oder ADEM (akute disseminierte Enzephalomyelitis) sind nach einer Infektion mit SARS-CoV‑2 („severe acute respiratory syndrome coronavirus 2“) gehäuft aufgetreten, was für einen para- oder postinfektiösen Zusammenhang spricht. Ursächlich ist wahrscheinlich eine virusgetriggerte Überaktivierung des Immunsystems mit Hyperinflammation und Zytokin-Sturm, aber möglicherweise auch die Bildung spezifischer Autoantikörper gegen Gewebe des Zentralnervensystems, die sich vor allem im Liquor schwerkranker COVID-19(„coronavirus disease 2019“)-Patienten finden lassen. Eine direkte Schädigung durch die Invasion von SARS-CoV‑2 ins Gehirn oder Rückenmark scheint keine relevante Rolle zu spielen. Bei Patienten mit Multipler Sklerose, Myasthenie oder anderen neuroimmunologischen Krankheitsbildern wird die Anfälligkeit für eine SARS-CoV-2-Infektion sowie das Risiko eines schweren Verlaufs nicht durch die immunmodulierende Therapie bestimmt, sondern durch bekannte Risikofaktoren wie Alter, Komorbiditäten und den krankheitsbedingten Grad der Behinderung. Immuntherapien sollten bei diesen Patienten daher nicht verschoben oder pausiert werden. Inwieweit neuroimmunologische Mechanismen auch für Langzeitfolgen nach überstandener COVID-19-Erkrankung – wie Fatigue, Gedächtnis‑, Schlaf- oder Angststörungen – verantwortlich sind, werden klinische Verlaufsuntersuchungen u. a. in COVID-19-Registerstudien zeigen.

Objective Cognitive dysfunction is a core symptom of anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis, but detailed studies on prevalence, characteristics of cognitive deficits, and the potential for recovery are missing. Here, we performed a prospective longitudinal study to assess cognitive long‐term outcome and identify clinical predictors. Methods Standardized comprehensive neuropsychological assessments were performed in 43 patients with NMDAR encephalitis 2.3 years and 4.9 years (median) after disease onset. Cognitive assessments covered executive function, working memory, verbal/visual episodic memory, attention, subjective complaints, and depression and anxiety levels. Cognitive performance of patients was compared to that of 30 healthy participants matched for age, sex, and education. Results All patients had persistent cognitive deficits 2.3 years after onset, with moderate or severe impairment in >80% of patients. Core deficits included memory and executive function. After 4.9 years, significant improvement of cognitive function was observed, but moderate to severe deficits persisted in two thirds of patients, despite favorable functional neurological outcomes (median modified Rankin Scale = 1). Delayed treatment, higher disease severity, and longer duration of the acute phase were predictors for impaired cognitive outcome. The recovery process was time dependent, with greater gains earlier after the acute phase, although improvements were possible for several years after disease onset. Interpretation Cognitive deficits are the main contributor to long‐term morbidity in NMDAR encephalitis and persist beyond functional neurological recovery. Nonetheless, cognitive improvement is possible for several years after the acute phase and should be supported by continued cognitive rehabilitation. Cognition should be included as an outcome measure in future clinical studies. ANN NEUROL 2021;90:949–961 Bundesministerium für Bildung und Forschung http://dx.doi.org/10.13039/501100002347 Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659

Anti-NMDA receptor (NMDAR) encephalitis (NMDARE) is an important treatable cause of autoimmune psychosis in all age-groups, which is sometimes associated with tumors, especially ovarian teratomas. Tuberous sclerosis complex (TSC) is an autosomal dominant inherited neurocutaneous disease predisposing for development of benign tumors. We present a case of a 35-year-old woman with recurrent episodes of schizophrenia-like symptoms. Accidentally, MRI revealed TSC-related brain tumors. NMDAR antibody titers were strongly positive in serum and cerebrospinal fluid. This is the first case describing an overlap of NMDARE and TSC-related brain tumors. A review of brain tumors and NMDARE is given in the supplementary material. Although a causal link seems interesting from a pathophysiological point of view, we are in favor of a coincidence.

ZusammenfassungZahlreiche neuroimmunologische Krankheitsbilder wie Enzephalopathien, Enzephalitiden, Myelitiden oder ADEM (akute disseminierte Enzephalomyelitis) sind nach einer Infektion mit SARS-CoV‑2 („severe acute respiratory syndrome coronavirus 2“) gehäuft aufgetreten, was für einen para- oder postinfektiösen Zusammenhang spricht. Ursächlich ist wahrscheinlich eine virusgetriggerte Überaktivierung des Immunsystems mit Hyperinflammation und Zytokin-Sturm, aber möglicherweise auch die Bildung spezifischer Autoantikörper gegen Gewebe des Zentralnervensystems, die sich vor allem im Liquor schwerkranker COVID-19(„coronavirus disease 2019“)-Patienten finden lassen. Eine direkte Schädigung durch die Invasion von SARS-CoV‑2 ins Gehirn oder Rückenmark scheint keine relevante Rolle zu spielen. Bei Patienten mit Multipler Sklerose, Myasthenie oder anderen neuroimmunologischen Krankheitsbildern wird die Anfälligkeit für eine SARS-CoV-2-Infektion sowie das Risiko eines schweren Verlaufs nicht durch die immunmodulierende Therapie bestimmt, sondern durch bekannte Risikofaktoren wie Alter, Komorbiditäten und den krankheitsbedingten Grad der Behinderung. Immuntherapien sollten bei diesen Patienten daher nicht verschoben oder pausiert werden. Inwieweit neuroimmunologische Mechanismen auch für Langzeitfolgen nach überstandener COVID-19-Erkrankung – wie Fatigue, Gedächtnis‑, Schlaf- oder Angststörungen – verantwortlich sind, werden klinische Verlaufsuntersuchungen u. a. in COVID-19-Registerstudien zeigen.

Significance This study addresses a fundamental question in neuroscience, namely how does the presynaptic component of the synapse precisely align with the postsynaptic component? This is essential for the proper transmission of signals across the synapse. This paper focuses on a set of transsynaptic, epilepsy-related proteins that are essential for this alignment. We show that the LGI1–ADAM22–MAGUK complex is a key player in the nanoarchitecture of the synapse, such that the release site is directly apposed to the nanocluster of glutamate receptors., Physiological functioning and homeostasis of the brain rely on finely tuned synaptic transmission, which involves nanoscale alignment between presynaptic neurotransmitter-release machinery and postsynaptic receptors. However, the molecular identity and physiological significance of transsynaptic nanoalignment remain incompletely understood. Here, we report that epilepsy gene products, a secreted protein LGI1 and its receptor ADAM22, govern transsynaptic nanoalignment to prevent epilepsy. We found that LGI1–ADAM22 instructs PSD-95 family membrane-associated guanylate kinases (MAGUKs) to organize transsynaptic protein networks, including NMDA/AMPA receptors, Kv1 channels, and LRRTM4–Neurexin adhesion molecules. Adam22ΔC5/ΔC5 knock-in mice devoid of the ADAM22–MAGUK interaction display lethal epilepsy of hippocampal origin, representing the mouse model for ADAM22-related epileptic encephalopathy. This model shows less-condensed PSD-95 nanodomains, disordered transsynaptic nanoalignment, and decreased excitatory synaptic transmission in the hippocampus. Strikingly, without ADAM22 binding, PSD-95 cannot potentiate AMPA receptor-mediated synaptic transmission. Furthermore, forced coexpression of ADAM22 and PSD-95 reconstitutes nano-condensates in nonneuronal cells. Collectively, this study reveals LGI1–ADAM22–MAGUK as an essential component of transsynaptic nanoarchitecture for precise synaptic transmission and epilepsy prevention.

Highlights • COVID-19 patients show a broad spectrum of neurological manifestations. • SARS-CoV-2 is scarcely detected in cerebrospinal fluid. • Viral-triggered autoimmune responses may lead to neurological symptoms. • Immunotherapy should be considered in CSF autoantibody-positive Covid-19 patients., Background COVID-19 intensive care patients can present with neurological syndromes, usually in the absence of SARS-CoV-2 in cerebrospinal fluid (CSF). The recent finding of some virus-neutralizing antibodies cross-reacting with brain tissue suggests the possible involvement of specific autoimmunity. Design Blood and CSF samples from eleven critically ill COVID-19 patients presenting with unexplained neurological symptoms including myoclonus, oculomotor disturbance, delirium, dystonia and epileptic seizures, were analyzed for anti-neuronal and anti-glial autoantibodies. Results Using cell-based assays and indirect immunofluorescence on unfixed murine brain sections, all patients showed anti-neuronal autoantibodies in serum or CSF. Antigens included intracellular and neuronal surface proteins, such as Yo or NMDA receptor, but also various specific undetermined epitopes, reminiscent of the brain tissue binding observed with certain human monoclonal SARS-CoV-2 antibodies. These included vessel endothelium, astrocytic proteins and neuropil of basal ganglia, hippocampus or olfactory bulb. Conclusion The high frequency of autoantibodies targeting the brain in the absence of other explanations suggests a causal relationship to clinical symptoms, in particular to hyperexcitability (myoclonus, seizures). Several underlying autoantigens and their potential molecular mimicry with SARS-CoV-2 still await identification. However, autoantibodies may already now explain some aspects of multi-organ disease in COVID-19 and can guide immunotherapy in selected cases.

To determine long-term seizure outcome, use of antiseizure medication (ASM) and seizure recurrence risk after its withdrawal in patients with autoimmune encephalitis (AE) due to neuronal surface and GAD antibodies.In patients from a specialized AE outpatient clinic, we assessed seizure manifestation, ASM and immunotherapy at onset of AE as well as seizure occurrence, development of autoimmune-associated epilepsy (AAE) and use of ASM in the long-term. Data were collected from patients via telephone interviews and medical records.Out of 94 AE patients, 75 were analyzed; 47 patients had NMDAR, 17 LGI1, 7 GAD, 3 CASPR2 and 1 mGluR5 antibodies. Fifty-three of the 75 patients (71 %) experienced seizures, all of which for the first time occurred at AE onset. After a median follow-up of 6 years (range, 1-15), 47 of the 53 AE patients had 1-year terminal seizure remission, median duration of terminal seizure freedom was 5 years. Rate of 1-year terminal seizure remission was significantly higher in patients with neuronal surface antibodies (NMDAR 97 %, LGI1 93 %, CASPR2 100 %) compared to patients with GAD antibodies (20 %, p < 0.001). In seizure-free patients, ASM was withdrawn after 13 months (median) without any relapse seizures.Seizures are common in most forms of AE manifesting at disease onset in all cases. However, the development of AAE is rare and typically occurs in patients with GAD antibodies. Thus, in most AE cases with neuronal surface antibodies, ASM can be withdrawn after the acute phase of AE with low risk of seizure relapse.

Seizures are a prominent feature in N-Methyl-D-Aspartate receptor antibody (NMDAR-Ab) encephalitis, a distinct neuro-immunological disorder in which specific human autoantibodies bind and crosslink the surface of NMDAR proteins thereby causing internalization and a state of NMDAR hypofunction. To further understand ictogenesis in this disorder, and to test a novel treatment compound, we developed an NMDAR-Ab mediated rat seizure model that displays spontaneous epileptiform activity in vivo and in vitro. Using a combination of electrophysiological and dynamic causal modelling techniques we show that, contrary to expectation, reduction of synaptic excitatory, but not inhibitory, neurotransmission underlies the ictal events through alterations in the dynamical behaviour of microcircuits in brain tissue. Moreover, in vitro application of an NMDAR-specific neurosteroid, pregnenolone sulfate, that upregulates NMDARs, reduced established ictal activity. This proof-of-concept study highlights the complexity of circuit disturbances that may lead to seizures and the potential use of receptor-specific treatments in antibody-mediated seizures and epilepsy.

Highlights • We performed a hippocampal shape analysis in 4 different neuroimmunological diseases. • MS, anti-NMDAR & LGI1 encephalitis show surface deformations, while NMOSD does not. • Surface deformations covered the hippocampus head and subicular areas. • These inversions revealed a similar spatial pattern across the different diseases. • Shape deformations contribute to the pathophysiology of cognitive symptoms., Hippocampal damage and associated cognitive deficits are frequently observed in neuroimmunological disorders, but comparative analyses to identify shared hippocampal damage patterns are missing. Here, we adopted a transdiagnostic analytical approach and investigated hippocampal shape deformations and associated cognitive deficits in four neuroimmunological diseases. We studied 120 patients (n = 30 in each group), including patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), anti-NMDAR and anti-LGI1 encephalitis. A control group was matched to each patient sample from a pool of 79 healthy participants. We performed an MRI-based vertex-wise hippocampal shape analysis, extracted hippocampal volume estimates and scalar projection values as a measure of surface displacement. Cognitive testing included assessment of verbal memory and semantic fluency performance. Our cross-sectional analyses revealed characteristic patterns of bilateral inward deformations covering up to 32% of the hippocampal surface in MS, anti-NMDAR encephalitis, and anti-LGI1 encephalitis, whereas NMOSD patients showed no deformations compared to controls. Significant inversions were noted mainly on the hippocampal head, were accompanied by volume loss, and correlated with semantic fluency scores and verbal episodic memory in autoimmune encephalitis and MS. A deformation overlap analysis across disorders revealed a convergence zone on the left anterior hippocampus that corresponds to the CA1 subfield. This convergence zone indicates a shared downstream substrate of immune-mediated damage that appears to be particularly vulnerable to neuroinflammatory processes. Our transdiagnostic morphological view sheds light on mutual pathophysiologic pathways of cognitive deficits in neuroimmunological diseases and stimulates further research into the mechanisms of increased susceptibility of the hippocampus to autoimmunity.

ObjectiveTo determine whether neuronal and neuroaxonal injury, neuroinflammation, and synaptic dysfunction associate with clinical course and outcomes in antibody-mediated encephalitis (AME), we measured biomarkers of these processes in CSF from patients presenting with AME and cognitively normal individuals.MethodsBiomarkers of neuronal (total tau, VILIP-1) and neuroaxonal damage (neurofilament light chain [NfL]), inflammation (YKL-40), and synaptic function (neurogranin, SNAP-25) were measured in CSF obtained from 45 patients at the time of diagnosis of NMDA receptor (n = 34) or LGI1/CASPR2 (n = 11) AME and 39 age- and sex-similar cognitively normal individuals. The association between biomarkers and modified Rankin Scale (mRS) scores were evaluated in a subset (n = 20) of longitudinally followed patients.ResultsBiomarkers of neuroaxonal injury (NfL) and neuroinflammation (YKL-40) were elevated in AME cases at presentation, whereas markers of neuronal injury and synaptic function were stable (total tau) or decreased (VILIP-1, SNAP-25, neurogranin). The log-transformed ratio of YKL-40/SNAP-25 optimally discriminated patients from cognitively normal individuals (area under the receiver operating characteristic curve 0.99; 95% confidence interval 0.97, >0.99). Younger age (ρ = −0.56; p = 0.01), lower VILIP-1 (ρ = −0.60; p < 0.01) and SNAP-25 (ρ = −0.54; p = 0.01), and higher log10(YKL-40/SNAP-25) (ρ = 0.48; p = 0.04) associated with greater disease severity (higher mRS score) in prospectively followed patients. Higher YKL-40 (ρ = 0.60; p = 0.02) and neurogranin (ρ = 0.55; p = 0.03) at presentation were associated with higher mRS scores 12 months following hospital discharge.ConclusionsCSF biomarkers suggest that neuronal integrity is acutely maintained in AME, despite neuroaxonal compromise. Low levels of biomarkers of synaptic function may reflect antibody-mediated internalization of cell surface receptors and may represent an acute correlate of antibody-mediated synaptic dysfunction, with the potential to inform disease severity and outcomes.

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from ten COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb CV07-209 neutralized authentic SARS-CoV-2 with IC50 of 3.1 ng/ml. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 Å revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2 neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy., HIGHLIGHTS • Characterization of potent human monoclonal SARS-CoV-2 neutralizing antibodies • Some SARS-CoV-2 antibodies reacted with mammalian self-antigens in different organs • Crystal structures of two antibodies in complex with SARS-CoV-2 RBD at 2.55/2.70 Å • Post-exposure antibody treatment protected from lung damage in infected hamsters, Kreye et al. report the isolation and characterization of monoclonal antibodies isolated from COVID-19 patients, some of which were found to display autoreactivity with mammalian self-antigens in different organs. Crystal structures of two antibodies in complex with SARS-CoV-2 Spike RBD reveal antibody engagement with the ACE2 binding site from different approach angles. One antibody is further evaluated for in vivo efficacy and was found to be both protective and efficacious post-challenge in a hamster infection model.

Background Anti-neuronal autoantibodies have been reported as the cause of several neurologic disorders other than encephalitis. Unfortunately, data are mostly based on serum analysis. Predictions about pathogenicity are thus limited. To determine the presence of so far unidentified autoantibody-derived neuroreactivity we analyzed cerebrospinal fluid (CSF) of children with neurological disorders other than encephalitis. Patients and methods We did a retrospective analysis of CSF from 254 children with various neurologic diseases other than encephalitis and searched for reactivity against neuronal surface antigens by immunofluorescence on unfixed murine brain sections (tissue-based assay, TBA) and by commercial cell-based assays (CBA). A semi-quantitative fluorescence score classified our results and we described the clinical course of all positive patients with strong neuroreactivity. Results Strong anti-neuronal IgG immunoreactivity of unknown antigen specificity was detected in CSF samples of 10 pediatric patients (4%, n = 10/254) with unsolved neurological disorders. CSF inflammatory markers were elevated. Most patients did not or only partly recover. Five screening-positive patients presented with a combination of headache and visual impairment due to optic nerve atrophy. Our data suggest to consider inflammatory, autoantibody-related etiologies, especially in cases without definite diagnoses. Conclusions We present an overview of CSF neuroreactivity in children with neurological disorders other than encephalitis, indicating the presence of unidentified anti-neuronal autoantibodies. As TBA enables screening for unknown autoantibodies, we suggest this method as a second step if commercial CBAs do not yield a result. Further studies are necessary to characterize such antibodies, evaluate pathogenicity, and answer the question whether positive CSF neuroreactivity should prompt an immunotherapeutic approach.

Background: agonistic autoantibodies (agAABs) against G protein-coupled receptors (GPCR) have been linked to cardiovascular disease. In dementia patients, GPCR-agAABs against the &alpha, 1- and &szlig, 2-adrenoceptors (&alpha, 1AR- and &szlig, 2AR) were found at a prevalence of 50%. Elimination of agAABs by immunoadsorption (IA) was successfully applied in cardiovascular disease. The IMAD trial (Efficacy of immunoadsorption for treatment of persons with Alzheimer dementia and agonistic autoantibodies against alpha1A-adrenoceptor) investigates whether the removal of &alpha, 1AR-AABs by a 5-day IA procedure has a positive effect (improvement or non-deterioration) on changes of hemodynamic, cognitive, vascular and metabolic parameters in patients with suspected Alzheimer&rsquo, s clinical syndrome within a one-year follow-up period. Methods: the IMAD trial is designed as an exploratory monocentric interventional trial corresponding to a proof-of-concept phase-IIa study. If cognition capacity of eligible patients scores 19&ndash, 26 in the Mini Mental State Examination (MMSE), patients are tested for the presence of agAABs by an enzyme-linked immunosorbent assay (ELISA)-based method, followed by a bioassay-based confirmation test, further screening and treatment with IA and intravenous immunoglobulin G (IgG) replacement. We aim to include 15 patients with IA/IgG and to complete follow-up data from at least 12 patients. The primary outcome parameter of the study is uncorrected mean cerebral perfusion measured in mL/min/100 gr of brain tissue determined by magnetic resonance imaging with arterial spin labeling after 12 months. Conclusion: IMAD is an important pilot study that will analyze whether the removal of &alpha, 1AR-agAABs by immunoadsorption in &alpha, 1AR-agAAB-positive patients with suspected Alzheimer&rsquo, s clinical syndrome may slow the progression of dementia and/or may improve vascular functional parameters.

Background Antibody-mediated and paraneoplastic autoimmune encephalitides (AE) present with a broad spectrum of clinical symptoms. They often lead to progressing inflammatory changes of the central nervous system with subacute onset and can cause persistent brain damage. Thus, to promptly start the appropriate and AE-specific therapy, recognition of symptoms, initiation of relevant antibody diagnostics and confirmation of the clinical diagnosis are crucial, in particular as the diseases are relatively rare. Aim This standard operating procedure (SOP) should draw attention to the clinical presentation of AE, support the diagnostic approach to patients with suspected AE and guide through the necessary steps including therapeutic decisions, tumour screening and exclusion of differential diagnoses. Method Based on existing diagnostic algorithms, treatment recommendations and personal experiences, this SOP gives an overview of clinical presentation, diagnostic procedures and therapy in AE. Additional information is provided within an accompanying text and a table describing the most important autoantibodies and their characteristics. Results The initial steps of the AE flow chart are based on clinical symptoms and the patient’s history. Assignment to paraneoplastic or antibody-mediated AE is sometimes clinically possible. Diagnostics should include MRI, EEG and CSF analysis with antibody panel diagnostic. Definite AE can be diagnosed if the underlying antibody is compatible with the clinical presentation. Classification of probable AE may be possible even with negative anti-neuronal autoantibodies if the clinical presentation and laboratory abnormalities are highly suggestive of AE. The confirmed AE diagnosis requires immediate initiation of immunotherapy. Conclusion The SOP facilitates the recognition of patients with AE and presents the necessary diagnostic and therapeutic steps.

There is increasing recognition in the neurological and psychiatric literature of patients with so-called isolated psychotic presentations (ie, with no, or minimal, neurological features) who have tested positive for neuronal autoantibodies (principally N-methyl-D-aspartate receptor antibodies) and who have responded to immunotherapies. Although these individuals are sometimes described as having atypical, mild, or attenuated forms of autoimmune encephalitis, some authors feel that that these cases are sufficiently different from typical autoimmune encephalitis to establish a new category of so-called autoimmune psychosis. We briefly review the background, discuss the existing evidence for a form of autoimmune psychosis, and propose a novel, conservative approach to the recognition of possible, probable, and definite autoimmune psychoses for use in psychiatric practice. We also outline the investigations required and the appropriate therapeutic approaches, both psychiatric and immunological, for probable and definite cases of autoimmune psychoses, and discuss the ethical issues posed by this challenging diagnostic category.

Patients with severe mental illnesses who are unable to give consent often need a rapid diagnosis and treatment but due to the psychiatric symptoms they often reject such measures. In the routine practice, the question arises to what extent the patient's expressed will should dictate the treatment steps and whether a decision against the patient's will is medically reasonable, ethically justifiable or even demanded and legally permissible. Autoimmune encephalitides, such as N‑methyl-D-aspartate receptor (NMDAR) encephalitis, have recently become important differential diagnoses due to their relative frequency, manifold symptoms and good treatability, as the underlying autoantibodies frequently cause organic psychoses. Using a complex case of a patient with NMDAR encephalitis, which was confirmed in the course of treatment, this article discusses the ethical and legal issues that are relevant in practice, from initial invasive diagnostics to involuntary confinement and compulsory treatment. The article discusses how physicians can respect the autonomy of such patients in the best way and how they can identify and resolve potential contradictions between the free will and the expressed will. Various convictions of physicians about autonomy and coercive treatment are discussed on the basis of the legal situation. Finally, it is discussed how the indications for a short compulsory treatment can be justified before the court of protection on the grounds of an analogy of autoimmune encephalitis to other severe brain diseases.

BackgroundRepertoire analysis of patient-derived recombinant monoclonal antibodies is an important tool to study the role of B cells in autoimmune diseases of the human brain and beyond. Current protocols for generation of patient-derived recombinant monoclonal antibody libraries are time-consuming and contain repetitive steps, some of which can be assisted with the help of software automation.ResultsWe developed BASE, an easy-to-use software for complete data analysis in single cell immunoglobulin cloning. BASE consists of two modules: aBASE for immunological annotations and cloning primer lookup, and cBASE for plasmid sequence identity confirmation before expression. Comparing automated BASE analysis with manual analysis we confirmed the validity of BASE output: identity between manual and automated aBASE analysis was 100% for all outputs, except for immunoglobulin isotype determination. In this case, aBASE yielded correct results in 96% of cases, whereas 4% of cases required manual confirmation. cBASE automatically concluded expression recommendations in 89.8% of cases, 91.8% of which were identical to manually derived results and none of them were false-positive.ConclusionsBASE offers an easy-to-use software solution suitable for complete Ig sequence data analysis and tracking during recombinant mcAB cloning from single cells. Plasmid sequence identity confirmation by cBASE offers functionality not provided by existing software solutions in the field and will help to reduce time-consuming steps of the monoclonal antibody generation workflow.

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from ten COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb CV07-209 neutralized authentic SARS-CoV-2 with IC50of 3.1 ng/ml. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 Å revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2 neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy.

Since the detection of autoantibodies against neuronal surface antigens, autoimmune encephalitis (AE) has been more frequently diagnosed, especially in patients with symptoms typical of limbic encephalitis, such as seizures, short-term memory deficits, or psychosis. However, the clinical spectrum of AE may be much wider, making correct clinical diagnosis difficult. We retrospectively analysed symptoms and admission diagnoses at first clinical presentation in 50 AE patients. We included patients with a clinical diagnosis of AE for whom a FDG-PET imaging was available. Final diagnoses were re-evaluated by a blinded investigator according to the most recent consensus suggestions published in 2016 for AE diagnostic criteria. We additionally describe two patients with Morvan syndrome who showed CASPR2 antibodies. In 40 patients (80.0%), the clinical presentation at first admission was typical for AE. Ten patients (20.0%) initially suffered from atypical symptoms; among these patients, isolated headache and cerebellar dysfunction were most frequent (three patients each). However, an initial diagnosis of suspected encephalitis was only reached in 16 patients (32.0%), nine (18.0) of which were suspected to have infectious encephalitis, and seven (14.0%) patients were suspected to have AE. In 34 patients (68.0%), a diagnosis other than encephalitis was considered, (e.g., epilepsy, psychiatric diseases, transient ischemic attack, dementia, meningitis, and cerebellitis). These data show the broad spectrum of initial symptoms of AE; the correct initial diagnosis of AE is often missed or delayed. Hence, clinicians in neurological and psychiatric hospitals should consider AE in the differential diagnosis of cases with atypical clinical presentations.

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a common autoimmune encephalitis presenting with psychosis, dyskinesias, autonomic dysfunction and seizures. The underlying autoantibodies against the NR1 subunit are directly pathogenic by disrupting synaptic NMDAR currents. However, antibody titers correlate only partially with the clinical outcome, suggesting the relevance of other factors such as antibody affinity. We thus determined the binding curves of human monoclonal autoantibodies and patients’ cerebrospinal fluid (CSF) against NR1-expressing HEK293 cells using flow cytometry. Antibody affinity was highly variable with binding constants (half-maximal concentration, c50) ranging from 1 to 74 µg/ml for monoclonal antibodies. Comparing values of individual monoclonal antibodies with human CSF samples suggested that the CSF signal is predominantly represented by higher-affinity antibodies, potentially in a concentration range of NR1 antibodies between 0.1 and 5 µg/ml, roughly reflecting 1–10% of total CSF IgG in NMDAR encephalitis. Binding curves further depended on the CSF composition which must be considered when interpreting established clinical routine assays. Normalization of measurements using reference samples allowed high reproducibility. Accurate and reproducible measurement of NR1 antibody binding suggested that biophysical properties of the antibody might contribute to disease severity. Normalization of the data can be an elegant way to allow comparable inter-laboratory quantification of CSF NR1 antibody titers in autoimmune encephalitis patients, a prerequisite for use as surrogate markers in clinical trials. Based on our calculations, low-affinity antibodies can easily remain undetected in routine cell-based assays, indicating that their relation to clinical symptoms should be analyzed in future studies.

Background There is a need to assess promising biomarkers for diagnosis and treatment response in real-life settings. Despite the important role of vascular risk factors, cardiovascular biomarkers have played a minor role in dementia research. Agonistic autoantibodies (agAAB) directed against G-protein-coupled receptors (GPCR) are discussed as modulators of pathology and clinical manifestation. Objective 1) Describe prevalence of agAAB directed against GPCR, especially agABB against α1-adrenergic receptors (α1-AR-agAAB) and agABB directed against β2-adrenergic receptors (β2-AR-agAAB) and 2) identify factors associated with agAAB in people with dementia during routine care. Methods Blood samples and data from 95 subjects who screened positive for dementia from a primary care cohort, analyzed using an enzyme-linked immunosorbent assay (ELISA) for detecting agAAB. Sociodemographic and clinical data were assessed, and medical records checked. Results In 40 (42%) samples, agAAB was detected, with n = 29 (31%) representing α1-AR-agAAB and n = 21 (22%) β2-AR-agAAB. There was no association between the presence of any antibody and a formal diagnosis of dementia. However, patients with coronary heart disease were more likely (OR = 4.23) to have α1-AR-agAAB than those without coronary heart disease. There were no associations between agAAB and age, sex, education, or cognitive impairment. Discussion For the first time, we show that autoantibodies have a significant prevalence in people with dementia in a routine care setting. Previous findings were restricted to highly selective samples. We replicated the association between α1-AR-agAAB in patients with coronary heart diseases but were not able to find other factors associated with the presence of agAAB.

ObjectiveTo report the clinical features of 11 patients with metabotropic glutamate receptor 5 (mGluR5) antibody–associated encephalitis, immunoglobulin G (IgG) subclass, and effects of the antibodies on neuronal mGluR5 clusters.MethodsClinical information was retrospectively obtained from referring physicians. Antibodies to mGluR5 and IgG subclasses were determined with brain immunohistochemistry and cell-based assays. The effects of the antibodies were examined on rat hippocampal neurons with reported techniques.ResultsFrom January 2005 to May 2017, 11 patients (median age 29 years, range 6–75 years, 5 female) were identified. The main clinical features were psychiatric (10), cognitive (10), movement disorders (7), sleep dysfunction (7), and seizures (6). Median modified Rankin Scale score at the peak of the disease was 4; 4 patients required intensive care. Five patients had Hodgkin lymphoma, and 1 had small cell lung cancer. CSF showed pleocytosis (median white blood cell count 22 mm3) in all patients; brain MRI was abnormal in 5, involving limbic (1) or extralimbic (4) regions. Treatments included immunotherapy and/or oncologic therapy; at the last follow-up (median 48 months), 6 patients had complete and 5 had partial recovery. Neurologic relapse occurred in 2 patients. Antibodies were IgG1 alone (4 of 9) or in combination with IgG2 (1 of 9), IgG3 (3 of 9), or both (1). Patients' IgG caused a significant and specific decrease of cell-surface synaptic and extrasynaptic mGluR5 without altering the levels of postsynaptic density protein 95.ConclusionsAnti-mGluR5 encephalitis associates with a complex neuropsychiatric syndrome, not restricted to limbic encephalitis, and can occur without tumor. Patients respond to treatment, but relapses can occur. The antibodies have pathogenic effects altering the levels of cell-surface mGluR5.

We performed a genome-wide association study in 1,194 controls and 150 patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR, n = 96) or anti-leucine-rich glioma-inactivated1 (anti-LGI1, n = 54) autoimmune encephalitis. Anti-LGI1 encephalitis was highly associated with 27 single-nucleotide polymorphisms (SNPs) in the HLA-II region (leading SNP rs2858870 p = 1.22 × 10-17 , OR = 13.66 [7.50-24.87]). Potential associations, below genome-wide significance, were found with rs72961463 close to the doublecortin-like kinase 2 gene (DCLK2) and rs62110161 in a cluster of zinc-finger genes. HLA allele imputation identified association of anti-LGI1 encephalitis with HLA-II haplotypes encompassing DRB1*07:01, DQA1*02:01 and DQB1*02:02 (p < 2.2 × 10-16 ) and anti-NMDAR encephalitis with HLA-I allele B*07:02 (p = 0.039). No shared genetic risk factors between encephalitides were identified. Ann Neurol 2018;83:863-869.

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.