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BackgroundPatients suffering from neurological symptoms after COVID-19 vaccination (post-COVID-19 vaccination syndrome (PCVS)) have imposed an increasing challenge on medical practice, as diagnostic precision and therapeutic options are lacking. Underlying autoimmune dysfunctions, including autoantibodies, have been discussed in neurological disorders after SARS-CoV-2 infection and vaccination. Here, we describe the frequency and targets of autoantibodies against peripheral nervous system tissues in PCVS.MethodsSera from 50 PCVS patients with peripheral neurological symptoms after COVID-19 vaccination and 35 vaccinated healthy controls were used in this study. IgG autoreactivity was measured via indirect immunofluorescence assays on mouse sciatic nerve teased fibers. The frequencies of autoantibodies were compared between groups using Fisher’s exact test. Serum anti-ganglioside antibodies were measured in ganglioside blots. Autoantibody target identification was performed using immunoprecipitation coupled to mass spectrometry. Subsequent target confirmation was conducted via cell-based assays and ELISA.ResultsCompared with controls, PCVS patients had a significantly greater frequency of autoantibodies against peripheral nervous system structures (9/50(18%) vs 1/35(3%); p=0.04). Autoantibodies bound to paranodes (n=5), axons (n=4), Schmidt-Lanterman incisures (n=2) and Schwann cell nuclei (n=1). Conversely, antibodies against gangliosides were absent in PCVS patients. Target identification and subsequent confirmation revealed various subunits of neurofilaments as well as DFS-70 as autoantibody epitopes.ConclusionOur data suggest that autoantibodies against nervous system tissue could be relevant in PCVS patients. Autoantibodies against neurofilaments and cell nuclei with so far non-established links to this disease spectrum should be further elucidated to determine their biomarker potential.

Autoantibodies against proteins in the brain are increasingly considered as a potential cause of cognitive decline, not only in subacute autoimmune encephalopathies but also in slowly progressing impairment of memory in patients with classical neurodegenerative dementias. In this retrospective cohort study of 161 well-characterized patients with different forms of dementia and 34 controls, we determined the prevalence of immunoglobulin (Ig) G and IgA autoantibodies to brain proteins using unbiased immunofluorescence staining of unfixed murine brain sections. Autoantibodies were detected in 21.1% of dementia patients and in 2.9% of gender-matched controls, with higher frequencies in vascular dementia (42%), Alzheimer’s disease (30%), dementia of unknown cause (25%), and subjective cognitive impairment (16.7%). Underlying antigens involved glial fibrillary acidic protein (GFAP), glycine receptor, and Rho GTPase activating protein 26 (ARHGAP26), but also a range of yet undetermined epitopes on neurons, myelinated fiber tracts, choroid plexus, glial cells, and blood vessels. Antibody-positive patients were younger than antibody-negative patients but did not differ in the extent of cognitive impairment, epidemiological and clinical factors, or comorbidities. Further research is needed to understand the potential contribution to disease progression and symptomatology, and to determine the antigenic targets of dementia-associated autoantibodies.

Abstract Introduction Post-COVID-19 Syndrome (PCS) includes neurological manifestations, especially fatigue and cognitive deficits. Immune dysregulation, autoimmunity, endothelial dysfunction, viral persistence, and viral reactivation are discussed as potential pathophysiological mechanisms. The post-corona-virus immune treatment (PoCoVIT) trial is a phase 2a randomized, controlled, double-blind trial designed to evaluate the effect of methylprednisolone versus placebo on cognitive impairment in PCS. This trial is designed based on the hypothesised autoimmunological pathogenesis and positive aberrations, employing a series of off-label applications. Methods Recruitment criteria include a diagnosis of PCS, a minimum age of 18 years and self-reported cognitive deficits at screening. A total of 418 participants will be randomly assigned to either verum or placebo intervention in the first phase of the trial. The trial will consist of a first trial phase intervention with methylprednisolone versus placebo for six weeks, followed by a six-week treatment interruption period. Subsequently, an open second phase will offer methylprednisolone to all participants for six weeks. Outpatient follow-up visits will take place two weeks after each trial medication cessation. The third and final follow-up, at week 52, will be conducted through a telephone interview. The primary outcome measures an intra-patient change of 15 or more points in the memory satisfaction subscale of the Multifactorial Memory Questionnaire (MMQ) from baseline to follow-up 1 (week 8). Key secondary outcomes include long-term intra-patient changes in memory satisfaction from baseline to follow-up 2 (week 20), changes in other MMQ subscales (follow-up 1 and 2), and changes in neuropsychological and cognitive scores, along with assessments through questionnaires focusing on quality of life, fatigue, and mood over the same periods. Exploratory outcomes involve molecular biomarkers variations in serum and cerebrospinal fluid, as well as structural and functional brain magnetic resonance imaging (MRI) parameters changes related to cognition. Perspective This trial aims to contribute novel evidence for treating patients with PCS, with a primary focus on those manifesting cognitive deficits. By doing so, it may enhance comprehension of the underlying pathophysiological mechanisms, thereby facilitating biomarker research to advance our understanding and treatment of patients with PCS.

Abstract Background Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severely debilitating condition which markedly restricts activity and function of affected people. Since the beginning of the COVID-19 pandemic ME/CFS related to post-acute COVID-19 syndrome (PACS) can be diagnosed in a subset of patients presenting with persistent fatigue 6 months after a mostly mild SARS-CoV-2 infection by fulfillment of the Canadian Consensus Criteria (CCC 2003). Induction of autoimmunity after viral infection is a mechanism under intensive investigation. In patients with ME/CFS, autoantibodies against thyreoperoxidase (TPO), beta-adrenergic receptors (ß2AR), and muscarinic acetylcholine receptors (MAR) are frequently found, and there is evidence for effectiveness of immunomodulation with B cell depleting therapy, cyclophosphamide, or intravenous immunoglobulins (IVIG). Preliminary studies on the treatment of ME/CFS patients with immunoadsorption (IA), an apheresis that removes antibodies from plasma, suggest clinical improvement. However, evidence from placebo-controlled trials is currently missing. Methods In this double-blinded, randomized, sham-controlled, exploratory trial the therapeutic effect of five cycles of IA every other day in patients with ME/CFS, including patients with post-acute COVID-19 chronic fatigue syndrome (PACS-CFS), will be evaluated using the validated Chalder Fatigue Scale, a patient-reported outcome measurement. A total of 66 patients will be randomized at a 2:1 ratio: 44 patients will receive IA (active treatment group) and 22 patients will receive a sham apheresis (control group). Moreover, safety, tolerability, and the effect of IA on patient-reported outcome parameters, biomarker-related objectives, cognitive outcome measurements, and physical parameters will be assessed. Patients will be hospitalized at the clinical site from day 1 to day 10 to receive five IA treatments and medical visits. Four follow-up visits (including two visits at site and two visits via telephone call) at month 1 (day 30), 2 (day 60), 4 (day 120), and 6 (day 180; EOS, end of study visit) will take place. Discussion Although ME/CFS including PACS-CFS causes an immense individual, social, and economic burden, we lack efficient therapeutic options. The present study aims to investigate the efficacy of immunoadsorption and to contribute to the etiological understanding and establishment of diagnostic tools for ME/CFS. Trial registration Registration Number: NCT05710770 . Registered on 02 February 2023.

Neurodegenerative diseases (NDs) are characterized by abnormalities within neurons of the brain or spinal cord that gradually lose function, eventually leading to cell death. Upon examination of affected tissue, pathological changes reveal a loss of synapses, misfolded proteins, and activation of immune cells—all indicative of disease progression—before severe clinical symptoms become apparent. Early detection of NDs is crucial for potentially administering targeted medications that may delay disease advancement. Given their complex pathophysiological features and diverse clinical symptoms, there is a pressing need for sensitive and effective diagnostic methods for NDs. Biomarkers such as microRNAs (miRNAs) have been identified as potential tools for detecting these diseases. We explore the pivotal role of miRNAs in the context of NDs, focusing on Alzheimer’s disease, Parkinson’s disease, Multiple sclerosis, Huntington’s disease, and Amyotrophic Lateral Sclerosis. The review delves into the intricate relationship between aging and NDs, highlighting structural and functional alterations in the aging brain and their implications for disease development. It elucidates how miRNAs and RNA-binding proteins are implicated in the pathogenesis of NDs and underscores the importance of investigating their expression and function in aging. Significantly, miRNAs exert substantial influence on post-translational modifications (PTMs), impacting not just the nervous system but a wide array of tissues and cell types as well. Specific miRNAs have been found to target proteins involved in ubiquitination or de-ubiquitination processes, which play a significant role in regulating protein function and stability. We discuss the link between miRNA, PTM, and NDs. Additionally, the review discusses the significance of miRNAs as biomarkers for early disease detection, offering insights into diagnostic strategies.

IntroductionSubgroups of autoantibodies directed against voltage-gated potassium channel (Kv) complex components have been associated with immunotherapy-responsive clinical syndromes. The high prevalence and the role of autoantibodies directly binding Kv remain, however, controversial. Our objective was to determine Kv autoantibody binding requirements and to clarify their contribution to the observed immune response.MethodsBinding epitopes were studied in sera (n = 36) and cerebrospinal fluid (CSF) (n = 12) from a patient cohort positive for Kv1.2 but negative for 32 common neurological autoantigens and controls (sera n = 18 and CSF n = 5) by phospho and deep mutational scans. Autoantibody specificity and contribution to the observed immune response were resolved on recombinant cells, cerebellum slices, and nerve fibers.Results83% of the patients (30/36) within the studied cohort shared one out of the two major binding epitopes with Kv1.2-3 reactivity. Eleven percent (4/36) of the serum samples showed no binding. Fingerprinting resolved close to identical sequence requirements for both shared epitopes. Kv autoantibody response is directed against juxtaparanodal regions in peripheral nerves and the axon initial segment in central nervous system neurons and exclusively mediated by the shared epitopes.DiscussionSystematic mapping revealed two shared autoimmune responses, with one dominant Kv1.2-3 autoantibody epitope being unexpectedly prevalent. The conservation of the molecular binding requirements among these patients indicates a uniform autoantibody repertoire with monospecific reactivity. The enhanced sensitivity of the epitope-based (10/12) compared with that of the cell-based detection (7/12) highlights its use for detection. The determined immunodominant epitope is also the primary immune response visible in tissue, suggesting a diagnostic significance and a specific value for routine screening.

Hypertrophic pachymeningitis (HP) is a rare immune-mediated disease characterized by thickening of the dura mater with consecutive cranial neuropathy. While HP is usually treated with systemic immunotherapies, response to therapy is variable and may be limited by insufficient drug concentrations in the brain. We report on a 57-year-old patient with HP manifesting with vision and hearing loss who had sustained clinical progression despite various systemic immunotherapies. Intraventricular chemotherapy with methotrexate, cytarabine, and dexamethasone was initiated. We present clinical, imaging and cerebrospinal fluid (CSF) findings, including cytokine levels before and after intraventricular treatment: rapid decrease of cell count, lactate and profibrotic cytokine levels in the CSF following intraventricular chemotherapy was paralleled by a mild reduction of dura thickness in MRI. The already severely impaired visual acuity and hearing loss did not progress further. Treatment was complicated by exacerbation of previously subtle psychiatric symptoms. Follow-up was terminated after 6 months as the patient suffered from a fatal ischemic stroke. Autopsy revealed neurosarcoidosis as the underlying cause of HP. This case report suggests that intrathecal chemotherapy can reduce the inflammatory milieu in the CNS and should be considered for treatment-refractory HP before irreversible damage of cranial nerves has occurred.

Background: Anti-NMDA-receptor GluN1 antibodies (NMDAR1-abs) are present in an autoimmune encephalitis with severe neuropsychiatric symptoms. We aimed to estimate the impact of serum NMDAR1-abs on depressive symptoms years after first-ever ischemic stroke (IS). Methods: Data were used from the PROSpective Cohort with Incident Stroke-Berlin (PROSCIS-B; NCT01363856). Serum NMDAR1-abs (IgM/IgA/IgG) were measured within 7 days after IS using cell-based assays. We defined seropositivity as titers ≥1:10, thereof low titers as ≤1:100 and high titers as >1:100. We used the Center for Epidemiological Studies–Depression (CES-D) scale to measure depressive symptoms at year one, two and three following IS. We calculated crude and confounder adjusted weighted generalized linear models to quantify the impact of NMDAR1-abs on CES-D assessed at three annual time-points. Results: NMDAR1-abs were measured in 583 PROSCIS-B IS patients (mean age = 67 [SD = 13]; 42%female; median NIHSS = 2 [IQR = 1–4]) of whom 76 (13%; IgM: n = 49/IgA: n = 43/IgG: n = 2) were seropositive, 55 (9%) with low and 21 (4%) with high titers. CES-D regarded over all follow-up time-points was higher in seropositive patients (βcrude = 2.56 [95%CI = −0.34 to 5.45]; βadjusted = 2.26 [95%CI = −0.68 to 5.20]) and effects were highest in patients with high titer (low titers: βcrude = 1.42 [95%CI = −1.79 to 4.62], βadjusted = 0.53 [95%CI = −2.47 to 3.54]; high titers: βcrude = 5.85 [95%CI = 0.20 to 11.50]; βadjusted = 7.20 [95%CI = 0.98 to 13.43]). Conclusion: Patients with serum NMDAR1-abs (predominantly IgM&IgA) suffer more severe depressive symptoms after mild-to-moderate IS compared to NMDAR1-abs seronegative patients.

Anti-neuronal autoantibodies can be transplacentally transferred during pregnancy and may cause detrimental effects on fetal development. It is unclear whether autoantibodies against synapsin-I, one of the most abundant synaptic proteins, are associated with developmental abnormalities in humans. We recruited a cohort of 263 pregnant women and detected serum synapsin-I IgG autoantibodies in 13.3% using cell-based assays. Seropositivity was strongly associated with abnormalities of fetal development including structural defects, intrauterine growth retardation, amniotic fluid disorders and neuropsychiatric developmental diseases in previous children (odds ratios of 3–6.5). Autoantibodies reached the fetal circulation and were mainly of IgG1/IgG3 subclasses. They bound to conformational and linear synapsin-I epitopes, five distinct epitopes were identified using peptide microarrays. The findings indicate that synapsin-I autoantibodies may be clinically useful biomarkers or even directly participate in the disease process of neurodevelopmental disorders, thus being potentially amenable to antibody-targeting interventional strategies in the future.

Summary: Anti-NMDA receptor autoantibodies (NMDAR-Abs) in patients with NMDAR encephalitis cause severe disease symptoms resembling psychosis and cause cognitive dysfunction. After passive transfer of patients’ cerebrospinal fluid or human monoclonal anti-GluN1-autoantibodies in mice, we find a disrupted excitatory-inhibitory balance resulting from CA1 neuronal hypoexcitability, reduced AMPA receptor (AMPAR) signaling, and faster synaptic inhibition in acute hippocampal slices. Functional alterations are also reflected in widespread remodeling of the hippocampal proteome, including changes in glutamatergic and GABAergic neurotransmission. NMDAR-Abs amplify network γ oscillations and disrupt θ-γ coupling. A data-informed network model reveals that lower AMPAR strength and faster GABAA receptor current kinetics chiefly account for these abnormal oscillations. As predicted in silico and evidenced ex vivo, positive allosteric modulation of AMPARs alleviates aberrant γ activity, reinforcing the causative effects of the excitatory-inhibitory imbalance. Collectively, NMDAR-Ab-induced aberrant synaptic, cellular, and network dynamics provide conceptual insights into NMDAR-Ab-mediated pathomechanisms and reveal promising therapeutic targets that merit future in vivo validation.

Abstract In the revised diagnostic classification systems ICD-11 and DSM-5, secondary, organic forms of obsessive-compulsive disorder (OCD) are implemented as specific nosological entities. Therefore, the aim of this study was to clarify whether a comprehensive screening approach, such as the Freiburg-Diagnostic-Protocol for patients with OCD (FDP-OCD), is beneficial for detecting organic OCD forms. The FDP-OCD includes advanced laboratory tests, an expanded magnetic resonance imaging (MRI) protocol, and electroencephalography (EEG) investigations as well as automated MRI and EEG analyses. Cerebrospinal fluid (CSF), [18F]fluorodeoxyglucose positron emission tomography, and genetic analysis were added for patients with suspected organic OCD. The diagnostic findings of the first 61 consecutive OCD inpatients (32 female and 29 male; mean age: 32.7 ± 12.05 years) analyzed using our protocol were investigated. A probable organic cause was assumed in five patients (8%), which included three patients with autoimmune OCD (one patient with neurolupus and two with specific novel neuronal antibodies in CSF) and two patients with newly diagnosed genetic syndromes (both with matching MRI alterations). In another five patients (8%), possible organic OCD was detected (three autoimmune cases and two genetic cases). Immunological serum abnormalities were identified in the entire patient group, particularly with high rates of decreased “neurovitamin” levels (suboptimal vitamin D in 75% and folic acid in 21%) and increased streptococcal (in 46%) and antinuclear antibodies (ANAs; in 36%). In summary, the FDP-OCD screening led to the detection of probable or possible organic OCD forms in 16% of the patients with mostly autoimmune forms of OCD. The frequent presence of systemic autoantibodies such as ANAs further support the possible influence of autoimmune processes in subgroups of patients with OCD. Further research is needed to identify the prevalence of organic OCD forms and its treatment options.

IntroductionThe increasing identification of specific autoantibodies against brain structures allows further refinement of the group of autoimmune-associated epilepsies and affects diagnostic and therapeutic algorithms. The early etiological allocation of a first seizure is particularly challenging, and the contribution of cerebrospinal fluid (CSF) analysis is not fully understood.MethodsIn this retrospective study with a mean of 7.8 years follow-up involving 39 well-characterized patients with the initial diagnosis of new-onset seizure or epilepsy of unknown etiology and 24 controls, we determined the frequency of autoantibodies to brain proteins in CSF/serum pairs using cell-based assays and unbiased immunofluorescence staining of unfixed murine brain sections.ResultsAutoantibodies were detected in the CSF of 30.8% of patients. Underlying antigens involved glial fibrillary acidic protein (GFAP) and N-methyl-D-aspartate (NMDA) receptors, but also a range of yet undetermined epitopes on neurons, glial and vascular cells. While antibody-positive patients had higher frequencies of cancer, they did not differ from antibody-negative patients with respect to seizure type, electroencephalography (EEG) and cranial magnetic resonance imaging (cMRI) findings, neuropsychiatric comorbidities or pre-existing autoimmune diseases. In 5.1% of patients with seizures or epilepsy of initially presumed unknown etiology, mostly CSF findings resulted in etiological reallocation as autoimmune-associated epilepy.DiscussionThese findings strengthen the potential role for routine CSF analysis. Further studies are needed to understand the autoantibody contribution to etiologically unclear epilepsies, including determining the antigenic targets of underlying autoantibodies.

Abstract Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to COVID-19 (COrona VIrus Disease-2019). SARS-CoV-2 acute infection may be associated with an increased incidence of neurological manifestations such as encephalopathy and encephalomyelitis, ischemic stroke and intracerebral hemorrhage, anosmia and neuromuscular diseases. Neurological manifestations are commonly reported during the post-acute phase and are also present in Long-COVID (LCS) and post-COVID-19 syndrome (PCS). In October 2020, the German Society of Neurology (DGN, Deutsche Gesellschaft für Neurologie) published the first guideline on the neurological manifestations of COVID-19. In December 2021 this S1 guideline was revised and guidance for the care of patients with post-COVID-19 syndrome regarding neurological manifestations was added. This is an abbreviated version of the post-COVID-19 syndrome chapter of the guideline issued by the German Neurological society and published in the Guideline repository of the AWMF (Working Group of Scientific Medical Societies; Arbeitsgemeinschaft wissenschaftlicher Medizinischer Fachgesellschaften).

The sequela of COVID-19 include a broad spectrum of symptoms that fall under the umbrella term post-COVID-19 condition or syndrome (PCS). Immune dysregulation, autoimmunity, endothelial dysfunction, viral persistence, and viral reactivation have been identified as potential mechanisms. However, there is heterogeneity in expression of biomarkers, and it is unknown yet whether these distinguish different clinical subgroups of PCS. There is an overlap of symptoms and pathomechanisms of PCS with postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). No curative therapies are available for ME/CFS or PCS. The mechanisms identified so far provide targets for therapeutic interventions. To accelerate the development of therapies, we propose evaluating drugs targeting different mechanisms in clinical trial networks using harmonized diagnostic and outcome criteria and subgrouping patients based on a thorough clinical profiling including a comprehensive diagnostic and biomarker phenotyping.

Objective: To study the prevalence of autoantibodies to glial and neuronal antigens with a focus on glial acidic fibrillary protein (GFAP) in patients with dementia. Methods: Sera of 127 patients with different forms of dementia and sera of 82 age-matched patients with various neurological diseases except for dementia, as well as sera from 15 age-matched healthy controls were analyzed for anti-glial or anti-neuronal IgG using 1) primary murine embryonic hippocampus cell cultures, 2) murine brain sections, 3) immunoblotting on mouse brain homogenates and 4) astrocyte cultures. Sera reacting with astrocytes in hippocampus cell cultures were further analyzed using HEK293 cells transfected with human GFAP. Results: IgG in serum from 45 of 127 (35.5%) patients with dementia but only 8 of 97 (8.2%, p ≤ 0.001) controls bound to either glial or neuronal structures in cultured murine hippocampus cells. In these cultures antibodies to astrocytes were detected in 35 of 127 (27.5%) of the dementia patients, whereas in controls antibodies to astrocytes were detected in 4 sera only (4.1%, p ≤ 0.001). Among the sera exhibiting reactivity to astrocytes, 14 of 35 (40%) showed immunoreaction to HEK293 cells transfected with GFAP in dementia patients, representing 11% of all sera. Within the 4 immunoreactive control sera reacting with astrocytes one reacted with GFAP (1.0% of total immunoreactivity, p = 0.003). Conclusions: Autoantibodies to glial epitopes in general and to GFAP in particular are more frequent in patients with dementia than in age-matched controls without dementia, thus indicating the need for further investigations regarding the potential pathophysiological relevance of these antibodies.

The various clinical manifestations of autoimmune encephalitis made this disease group an exciting new field in Neurology and Psychiatry. Identification of numerous pathogenic auto-antibodies against neuronal tissue resulted in unprecedented diagnostic and therapeutic opportunities. This has led to a critical reappraisal also of symptoms in patients with psychosis and dementia, and in some instances resulted in re-classification of disease.We now increasingly generate patient-derived monoclonal auto-antibodies against neuronal surface proteins and demonstrate their direct pathogenicity to cause neuropsychiatric symptoms. This has two essential implications: First, patients with these types of pathogenic auto-antibodies harbour a clear risk factor for the development of psychiatric abnormalities. Second, given their pathogenicity, the primary goal of treatment must be the removal of auto-antibodies using state-of-the-art immunotherapy rather than symptomatic treatment including neuroleptics.The technological achievement of recombinant generation of disease-causing human auto-antibodies will allow in the future i) to clarify the specific role of a given auto-antibody for the disease mechanisms, including down-regulation of synaptic proteins; ii) to identify novel antibodies targeting yet unknown epitopes on neuronal or glial surfaces; iii) to develop novel antibody-specific treatments, such as CAAR T cells; and iv) to provide molecular tools for improved research into neuropsychiatric autoimmunity by using these human antibodies for high-resolution molecular imaging and animal models.Findings from these studies will likely change the current diagnostic concepts in patients with impairment of memory, cognition, affect and mood. It has become clear that the perpetual discovery of novel antibodies will continue and ultimately result in a better understanding of pathomechanisms and therapies in some forms of dementia and psychosis. Molecular research will be essential in Psychiatry in order to not overlook such treatable aetiologies as primary neurodegenerative or psychiatric disorders.

Background: Autoimmune psychosis may be caused by well-characterized anti-neuronal autoantibodies, such as those against the NMDA receptor. However, the presence of additional anti-central nervous system (CNS) autoantibodies in these patients has not been systematically assessed. Methods: Serum and cerebrospinal fluid (CSF) from patients with schizophreniform and affective syndromes were analyzed for immunoglobulin G anti-CNS autoantibodies using tissue-based assays with indirect immunofluorescence on unfixed murine brain tissue as part of an extended routine clinical practice. After an initial assessment of patients with red flags for autoimmune psychosis (n=30), tissue-based testing was extended to a routine procedure (n=89). Results: Based on the findings from all 119 patients, anti-CNS immunoglobulin G autoantibodies against brain tissue were detected in 18% (n=22) of patients (serum 9%, CSF 18%) following five principal patterns: 1) against vascular structures, most likely endothelial cells (serum 3%, CSF 8%); 2) against granule cells in the cerebellum and/or hippocampus (serum 4%, CSF 6%); 3) against myelinated fibers (serum 2%, CSF 2%); 4) against cerebellar Purkinje cells (serum 0%, CSF 2%); and 5) against astrocytes (serum 1%, CSF 1%). The patients with novel anti-CNS autoantibodies showed increased albumin quotients (p=.026) and white matter changes (p=.020) more frequently than those who tested negative for autoantibodies. Conclusion: The study demonstrates five novel autoantibody-binding patterns on brain tissue of patiens with schizophreniform and affective syndromes. CSF yielded positive findings more frequently than scrum analysis. The frequency and spectrum of autoantibodies in these patient groups may be broader than previously thought.

Summary: The recurrent emerging of novel viral variants of concern (VOCs) with evasion of preexisting antibody immunity upholds severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) case numbers and maintains a persistent demand for updated therapies. We selected the patient-derived antibody CV38-142 based on its potency and breadth against the VOCs Alpha, Beta, Gamma, and Delta for preclinical development into a therapeutic. CV38-142 showed in vivo efficacy in a Syrian hamster VOC infection model after post-exposure and therapeutic application and revealed a favorable safety profile in a human protein library screen and tissue cross-reactivity study. Although CV38-142 targets the same viral surface as sotrovimab, which maintains activity against Omicron, CV38-142 did not neutralize the Omicron lineages BA.1 and BA.2. These results highlight the contingencies of developing antibody therapeutics in the context of antigenic drift and reinforce the need to develop broadly neutralizing variant-proof antibodies against SARS-CoV-2.

AbstractAutoimmune 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. Beyond clinical presentation and imaging, diagnosis relies on detection of GFAP‐antibodies (AB) in CSF. Using quantitative behavioral, serologic, and immunohistochemical analyses, we characterize two patients longitudinally over 18–24 months who presented with rapidly progressive neurocognitive deterioration in the context of GFAP‐AB in CSF and unremarkable cranial MRI studies. Intensified immunotherapy was associated with clinical stabilization. The value of GFAP‐AB screening in selected cases of rapidly progressive dementias is discussed.

Abstract Obsessive-compulsive disorder (OCD) is a highly disabling mental illness that can be divided into frequent primary and rarer organic secondary forms. Its association with secondary autoimmune triggers was introduced through the discovery of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection (PANDAS) and Pediatric Acute onset Neuropsychiatric Syndrome (PANS). Autoimmune encephalitis and systemic autoimmune diseases or other autoimmune brain diseases, such as multiple sclerosis, have also been reported to sometimes present with obsessive-compulsive symptoms (OCS). Subgroups of patients with OCD show elevated proinflammatory cytokines and autoantibodies against targets that include the basal ganglia. In this conceptual review paper, the clinical manifestations, pathophysiological considerations, diagnostic investigations, and treatment approaches of immune-related secondary OCD are summarized. The novel concept of “autoimmune OCD” is proposed for a small subgroup of OCD patients, and clinical signs based on the PANDAS/PANS criteria and from recent experience with autoimmune encephalitis and autoimmune psychosis are suggested. Red flag signs for “autoimmune OCD” could include (sub)acute onset, unusual age of onset, atypical presentation of OCS with neuropsychiatric features (e.g., disproportionate cognitive deficits) or accompanying neurological symptoms (e.g., movement disorders), autonomic dysfunction, treatment resistance, associations of symptom onset with infections such as group A streptococcus, comorbid autoimmune diseases or malignancies. Clinical investigations may also reveal alterations such as increased levels of anti-basal ganglia or dopamine receptor antibodies or inflammatory changes in the basal ganglia in neuroimaging. Based on these red flag signs, the criteria for a possible, probable, and definite autoimmune OCD subtype are proposed.

Introduction: The antibody repertoire from CSF-derived antibody-secreting cells and memory B-cells in patients with encephalitis contains a considerable number of antibodies that do not target the disease-defining autoantigen such as the GABA or NMDA receptors. This study focuses on the functional relevance of autoantibodies to brain blood vessels in patients with GABAA and NMDA receptor encephalitis.Methods: We tested 149 human monoclonal IgG antibodies from the cerebrospinal fluid of six patients with different forms of autoimmune encephalitis on murine brain sections for reactivity to blood vessels using immunohistochemistry. Positive candidates were tested for reactivity with purified brain blood vessels, effects on transendothelial electrical resistance (TEER), and expression of tight junction proteins as well as gene regulation using human brain microvascular endothelial hCMEC/D3 cells as in vitro blood-brain barrier model. One blood-vessel reactive antibody was infused intrathecally by pump injection in mice to study in vivo binding and effects on tight junction proteins such as Occludin. Target protein identification was addressed using transfected HEK293 cells.Results: Six antibodies reacted with brain blood vessels, three were from the same patient with GABAAR encephalitis, and the other three were from different patients with NMDAR encephalitis. One antibody from an NMDAR encephalitis patient, mAb 011-138, also reacted with cerebellar Purkinje cells. In this case, treatment of hCMEC/D3 cells resulted in decreased TEER, reduced Occludin expression, and mRNA levels. Functional relevance in vivo was confirmed as Occludin downregulation was observed in mAb 011-138-infused animals. Unconventional Myosin-X was identified as a novel autoimmune target for this antibody.Discussion: We conclude that autoantibodies to blood vessels occur in autoimmune encephalitis patients and might contribute to a disruption of the blood-brain barrier thereby suggesting a potential pathophysiological relevance of these antibodies.

Maternal autoantibodies can be transmitted diaplacentally, with potentially deleterious effects on neurodevelopment. Synapsin 1 (SYN1) is a neuronal protein that is important for synaptic communication and neuronal plasticity. While monoallelic loss of function (LoF) variants in the SYN1 gene result in X-linked intellectual disability (ID), learning disabilities, epilepsy, behavioral problems, and macrocephaly, the effect of SYN1 autoantibodies on neurodevelopment remains unclear. We recruited a clinical cohort of 208 mothers and their children with neurologic abnormalities and analyzed the role of maternal SYN1 autoantibodies. We identified seropositivity in 9.6% of mothers, and seropositivity was associated with an increased risk for ID and behavioral problems. Furthermore, children more frequently had epilepsy, macrocephaly, and developmental delay, in line with the SYN1 LoF phenotype. Whether SYN1 autoantibodies have a direct pathogenic effect on neurodevelopment or serve as biomarkers requires functional experiments.

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.

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.

Summary: Background: Understanding how SARS-CoV-2 affects respiratory centres in the brainstem may help to preclude assisted ventilation for patients in intensive care setting. Viral invasion appears unlikely, although autoimmunity has been implicated, the responsible antigens remain unknown. We previously predicted the involvement of three epitopes within distinct brainstem proteins: disabled homolog 1 (DAB1), apoptosis-inducing-factor-1 (AIFM1), and surfeit-locus-protein-1 (SURF1). Methods: Here, we used microarrays to screen serum from COVID-19 patients admitted to intensive care and compared those with controls who experienced mild course of the disease. Findings: The results confirm the occurrence of IgG and IgM antibodies against the hypothesised epitopes in COVID-19 patients. Importantly, while IgM levels were similar in both groups, IgG levels were significantly elevated in severely ill patients compared to controls, suggesting a pathogenic role of IgG. Interpretation: The newly discovered anti-neuronal antibodies might be promising markers of severe disease and the targeted peptide epitopes might be used for targeted immunomodulation. Further work is needed to determine whether these antibodies may play a role in long-COVID. Funding: AF, CF and PR received support from the German Research Foundation (grants FL 379/22-1, 327654276-SFB 1315, FR 4479/1-1, PR 1274/8-1). SH, DR, and DB received support from the Ministry of Economy, State of Mecklenburg Western Pomerania, Germany (grant COVIDPROTECT: “Optimisation of diagnostic and therapeutic pathways for COVID-19 patients in MV”). SH received support from the Research Group Molecular Medicine University of Greifswald (FVMM, seed funding FOVB-2021-01). AV received support from the Else Kröner Fresenius Foundation and the Alzheimer Research Initiative.

Autoimmune obsessive–compulsive disorder (OCD) is rare. The case presented here is that of a female patient in her mid-thirties who developed postpartum OCD. Magnetic resonance imaging showed multiple juxtacortical hyperintensities that may have been post-inflammatory in origin. In tissue-based assays using mouse brain slices, the patient’s cerebrospinal fluid (CSF) showed novel anti-nucleoli autoantibodies in cerebellar Purkinje cells and cortical neurons. The CSF dopamine and glutamate concentrations were dysregulated. The clinical course and diagnostic findings were compatible with possible autoimmune OCD with postpartum onset.

Abstract Background The importance of cerebrospinal fluid (CSF) diagnostics for psychiatry is growing. The CSF/blood albumin quotient (QAlb) is considered to be a measure of the blood–CSF barrier function. Recently, systematically higher QAlb in males than in females was described in neurological patients. The aim of this study was to investigate whether a sex difference could also be detected in a well-characterized psychiatric cohort. Methods The patient cohort comprised 989 patients, including 545 females and 444 males with schizophreniform and affective syndromes who underwent CSF diagnostics, including QAlb measurement. The basic CSF findings and antineuronal autoantibody data of this cohort have already been published. This re-analysis employed analysis of covariance with age correction for QAlb mean values and chi2-testing for the number of increased age-corrected QAlb levels to investigate sex differences in QAlb. Results The QAlb levels were elevated above reference levels by 18% across all patients, and a comparison between male and female patients revealed a statistically significant sex difference, with increased values in 26% of male patients and a corresponding rate of only 10% in female patients (chi 2 = 42.625, p

Abstract Background Repertoire 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. Results We 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. Conclusions BASE offers an easy-to-use software solution suitable for complete Ig sequence data analysis and tracking during recombinant mAb 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. BASE can be installed locally or accessed online at Code Ocean.

Abstract Background Autoimmune encephalitis is a new spectrum of autoimmune disorders of the central nervous system (CNS), which are characterized by pathogenic autoantibodies against neuronal surface antigens. Clinical presentations range from acute to subacute encephalopathy with neurological and psychiatric symptoms, and life-threatening autonomic dysfunction in severe cases. There exist no approved therapies nor is data available from controlled clinical trials. Patients are usually treated with diverse combinations of immunotherapy. However, effect of immunotherapy on antibody-producing cells and thus on levels of pathogenic autoantibodies is insufficient. Therefore, therapeutic response is sometimes prolonged with necessity of long-time intensive care treatment and also irreversible deficits occur in severe cases. This trial will investigate the efficacy and safety of bortezomib, a proteasome inhibitor known to selectively deplete plasma cells, in patients with severe autoimmune encephalitis who have been treated with rituximab with insufficient response. Methods Generate-Boost is an investigator-initiated, multicenter, double-blinded, randomized controlled phase II trial which will be conducted in specialized neurological hospitals within the GENERATE (GErman NEtwork for Research on AuToimmune Encephalitis) network in Germany. Adult patients with severe autoimmune encephalitis (modified Rankin scale, mRS ≥ 3), autoantibodies against neuronal surface antigens, and pretreatment with rituximab are eligible for study participation. Fifty patients will be randomized 1:1 and undergo up to 3 cycles (each 21 days with 4 s. c. applications) of bortezomib or placebo. All patients will receive concomitant medication with dexamethasone, acyclovir and co-trimoxazole. The primary efficacy endpoint is the mRS score 17 weeks after first treatment application. Secondary endpoints are neurocognitive function, antibody titers, markers of neuronal cell damage, length of ICU/hospital stay, and mRS and Glasgow coma scale scores throughout the trial up to week 17. General and bortezomib-specific adverse events are monitored continuously. Discussion The expected outcome of the study is to obtain first reliable data on a hypothesis-driven therapeutic option in severe and difficult-to-treat autoimmune encephalitis. If treatment with bortezomib is beneficial in these cases, this will be the basis for implementation in the current guidelines. Trial registration Clinicaltrials.gov , NCT03993262 . Registered June 20, 2019; German Clinical Trials Register, DRKS00017497.

Abstract 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.

Glaucoma disease is characterized by an increased intraocular pressure (IOP), glaucomatous alterations of the optic disc and corresponding visual field defects. Even lowering the main risk factor IOP until an individual target level does not prevent this neurodegenerative disorder from proceeding. Several autoimmune mechanisms were discovered, partly showing a functionality. One of these autoimmune phenomena targets the ß2-adrenergic receptor (ß2-AR; i.e. agonistic autoantibodies; ß2-agAAb) and is linked to an elevated IOP and an impaired retinal microcirculation. As neurodegenerative disorder, Alzheimer’s Disease (AD) is postulated to share a common molecular mechanism with glaucoma. In the present study we investigated autoimmune phenomena targeting the ß2-AR in patients with AD. Sera of the patients were analyzed in a rat cardiomyocyte bioassay for the presence of functional autoantibodies against ß2-AR. In addition, different species of amyloid beta (Aß) monomers were tested (Aß1-14, Aß10-25, Aβ10–37 Aß1-40, Aß1-42, Aβ28–40, and Aß-[Pyr]3–43). Our results demonstrate that none of the short-chain Aß (Aß1-14, Aß10-25, or Aβ28–40) showed any agonistic or inhibitory effect on ß2-AR. Contrary, long-chain Aß-[Pyr]3–43, representing a major neurogenic plaque component, exerted an activation that after blocking by the ß2-AR antagonist ICI118.551, could be identified as that the effect was realized via the ß2-AR. Moreover, the long chain Aß1-40, Aβ1–42, and Aβ10–37, yet not the short-chain Aß peptides prevented the clenbuterol induced desensitization of the ß2-AR. In addition, we identified functional autoantibodies in the sera of AD patients, activating the ß2-AR, like the ß2-agAAb found in patients with glaucoma. As autoimmune mechanisms were reportedly involved in the pathogenesis of glaucoma and Alzheimer’s Disease, we postulate that overstimulation of the ß2-AR pathway can induce an adrenergic overdrive, that may play an important role in the multifactorial interplay of neurodegenerative disorders.

Background and Objectives: Neurological and psychiatric symptoms are frequent in patients with post-COVID-19 syndrome (PCS). Here, we report on the clinical presentation of the first 100 patients who presented to our PCS Neurology outpatient clinic ≥12 weeks after the acute infection with SARS-CoV-2. To date, PCS is only defined by temporal connection to SARS-CoV-2 infection. Identification of clinical phenotypes and subgroups of PCS is urgently needed.Design: We assessed clinical data of our first 100 ambulatory patients regarding clinical presentations; self-questionnaires focusing on daytime sleepiness, mood, and fatigue; and a screening assessment for detecting cognitive impairment.Results: A total of 89% of the patients presenting to the Neurology outpatient clinic had an initially mild course of COVID-19 and had not been hospitalized. The majority of the patients were female (67 vs. 33% male). The most frequent symptom reported was cognitive impairment (72%). There were 30% of patients who reported cognitive deficits and scored below 26 points on the Montreal Cognitive Assessment Scale. Fatigue (67%), headache (36%), and persisting hyposmia (36%) were also frequently reported; 5.5% of all patients showed signs of severe depression.Discussion: To our knowledge, this is the first report of patient data of a PCS Neurology outpatient clinic. Neurological sequelae also exist for more than 3 months after mainly mild SARS-CoV-2 acute infections. The reported symptoms are in accordance with recently published data of hospitalized patients.

Based on current implications of the SARS-CoV-2 pandemic with regards to mental health, we show that biological links exist between inflammation and mental illness in addition to psychoreactive effects. We describe key principles of the biological interaction of the immune system and the mind, as well as the possible routes of viral entry into the brain. In addition, we provide a stepwise scheme for the diagnosis and therapy of autoimmune-encephalitis with schizophrenia-like symptomatology as a general guide for clinical practice and in the specialized scenario of infections, such as those caused by the SARS-CoV-2 virus.

BackgroundAutoimmune encephalitis, such as anti-NMDA-receptor encephalitis, typically presenting with subacute onset of neuropsychiatric symptoms, can be detected by antineuronal autoantibodies or inflammatory changes in the cerebrospinal fluid (CSF), as well as pathological alterations in electroencephalography (EEG), magnetic resonance imaging (MRI), or [18F]fluorodeoxyglucose positron emission tomography (FDG PET). For patients with predominant psychotic symptoms, the term autoimmune psychosis was proposed. Here, the authors present the case of a patient with probable autoimmune psychosis associated with unknown antineuronal antibodies.Case PresentationA 18-year-old male patient with preexisting autism spectrum disorder developed a severe catatonic syndrome over 2.5 years. The MRI showed normal findings, the EEG depicted intermittent slowing, and the independent component analyses showed additional sharp spikes. However, FDG PET, the basic laboratory analysis and testing of the serum/CSF for well-characterized antineuronal autoantibodies were unsuspicious. The serum and CSF “tissue-based assay” using indirect immunofluorescence on unfixed murine brain tissue revealed antineuronal autoantibodies against an unknown epitope in granule cells in the cerebellum and to neurites of hippocampal interneurons with a somatodendritic staining pattern. The immunosuppressive treatment with high-dose glucocorticoids, plasma exchange, and rituximab led to partial improvement.ConclusionThe patient probably suffered from autoantibody-associated autoimmune psychosis. The special features of the case were that the patient (1) presented with mostly inconspicuous basic diagnostics, except for the altered EEG in combination with the detection of CSF autoantibodies directed against a currently unknown epitope, (2) experienced an isolated and long-lasting psychotic course, and (3) had pre-existing autism spectrum disorder. The detection of a probable autoimmune pathophysiology in such cases seems important, as it offers new and more causal immunosuppressive treatment alternatives.

BackgroundIn a subgroup of patients with mood disorders, clear-cut organic disorders are responsible for depressive symptoms (e.g., autoimmune diseases such as multiple sclerosis or systemic lupus erythematosus). In these cases, an organic affective disorder can be diagnosed.Case PresentationThe authors present the case of a 59-year-old male patient who developed a severe depressive episode over approximately 6 months and was, therefore, admitted to the hospital. In retrospect, he reported that, at age 39, he suffered from self-limiting sensory disturbances and muscle weakness in both legs. The current magnetic resonance imaging of his brain showed several conspicuous FLAIR-hyperintense supratentorial white matter lesions compatible with chronic inflammatory brain disease. Imaging of the spinal axis revealed no clear spinal lesions. Cerebrospinal fluid (CSF) analyses showed CSF-specific oligoclonal bands. Therefore, multiple sclerosis was diagnosed. Further CSF analyses, using tissue-based assays with indirect immunofluorescence on unfixed murine brain tissue, revealed a (peri-)nuclear signal and a strong neuritic signal of many neurons, especially on granule cells in the cerebellum, hippocampus, and olfactory bulb, as well as in the corpus callosum. Additionally, antinuclear antibody (ANA) titers of 1:12,800 and a lymphopenia were detected in blood tests. Further system clarification showed no suspicion of rheumatic or oncological disease. Anti-inflammatory treatment led to rapid and sustained improvement.ConclusionThe present patient suffered from a probable “autoimmune depression” in the context of newly diagnosed multiple sclerosis with typical MRI and CSF pathologies, alongside mild concomitant latent systemic autoimmune process (with high-titer ANAs and lymphopenia) and unknown antineuronal antibodies. The case report illustrates that a depressive syndrome suggestive of primary idiopathic depressive disorder may be associated with an autoimmune brain involvement. The detection of such organic affective disorders is of high clinical relevance for affected patients, as it enables alternative and more causal treatment approaches.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic keeps the world in suspense. In addition to the fundamental challenges for the health care system, the individual departments must decide how to deal with patients at risk. Neurologists are confronted with the question, how they should advise their patients regarding immunosuppressive treatment. In particular, the large number of different disease-modifying therapies (DMTs) in the treatment of neuroimmunological diseases such as multiple sclerosis poses a challenge. To a limited extent, it might be useful to transfer knowledge from previous SARS- and Middle East respiratory syndrome (MERS) coronavirus outbreaks in 2002/2003 and 2012 to the current situation. Overall, immunosuppressive therapy does neither seem to have a major impact on infection with SARS- and MERS-CoV nor does it seem to lead to a severe disease course in many cases. Considering the immunological responses against infections with novel coronaviruses in humans, interferons, glatiramer acetate, and teriflunomide appear to be safe. As lymphopenia seems to be associated with a more severe disease course, all DMTs causing lymphopenia, such as cladribine, alemtuzumab, and dimethyl fumarate, need to be reviewed more thoroughly. As they are, in general, associated with a higher risk of infection, depleting anti-CD20 antibodies may be problematic drugs. However, it has to be differentiated between the depletion phase and the phase of immune reconstitution. In summary, previous coronavirus outbreaks have not shown an increased risk for immunocompromised patients. Patients with severe neuroimmunological diseases should be kept from hasty discontinuation of immunotherapy.

BackgroundAnti-N-methyl-D-aspartate-receptor (NMDA-R) encephalitis is an autoimmune disease of the brain first described in 2007. The aim of this paper is to present a 10-year follow-up case history.Case PresentationThe authors present the case of a 39-year-old female patient who developed an anti-NMDA-R encephalitis in 2009 with predominant severe catatonic symptoms. Anti-inflammatory therapy led to the disappearance of catatonic symptoms and was discontinued during the course of the disease. After acute therapy, the patient achieved an almost full recovery presenting with ongoing discrete symptoms of sensory overload, subtle cognitive deficits, and fatigue/reduced energy levels. The follow-up investigation in 2019 showed inconspicuous findings in laboratory diagnostics and magnetic resonance imaging. Electroencephalography (EEG) analysis using independent component analysis detected left hemispherical spike-wave complexes and intermittent slowing. Regarding the sensory overload and reduced energy level, the patient benefited from low-dose neuroleptics (risperidone, amisulpride). In terms of sensory overload associated with experiences of panic, cognitive deficits and coping with the disease, she improved with cognitive behavioral therapy (CBT).ConclusionAnti-inflammatory treatment led to almost full recovery with persistent disappearance of catatonic symptoms; however, a dysexecutive syndrome led to ongoing relevant problems with good response to low-dose atypical neuroleptics and CBT. The patient had persistent EEG alterations that indicated continuing neuronal network instability. Therefore, the case demonstrates the importance of multidisciplinary outpatient treatment following acute therapy for anti-NMDA-R encephalitis in patients with ongoing psychiatric deficits. For the symptomatic treatment of executive dysfunctions, “classical” psychiatric treatment may be helpful in the course of the disease.

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.

Abstract 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.

Background: Anti-N-methyl D-aspartate (NMDA) receptor encephalitis is an autoimmune condition characterized by neuropsychiatric symptoms, including epileptic seizures, movement disorders, autonomic instability, disturbances of consciousness, paranoia, delusions, and catatonia. Ovarian teratomas and viral infections, typically Herpes simplex viruses, have previously been demonstrated to precipitate anti-NMDA receptor encephalitis, but in many cases, the trigger remains unclear. The detection of anti-NMDA receptor antibodies in cerebrospinal fluid (CSF), in combination with other CSF, electroencephalography (EEG), or magnetic resonance imaging (MRI) abnormalities, typically leads to diagnostic clarification.Case Presentation: We present the case of a 22-year-old female patient who developed an acute polymorphic psychotic episode 3 days after receiving a booster vaccination against tetanus, diphtheria, pertussis, and polio (Tdap-IPV). Her psychiatric symptoms were initially diagnosed as a primary psychiatric disorder. Her MRI, EEG, and CSF results were non-specific. Anti-NMDA receptor IgG antibodies against the GluN1 subunit were detected in her serum (with a maximum titer of 1:320), but not in her CSF. [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) showed pronounced relative hypermetabolism of her association cortices and a relative hypometabolism of the primary cortices, on the basis of which an anti-NMDA receptor encephalitis diagnosis was made, and treatment with a steroid pulse was initiated. The treatment led to fast and convincing clinical improvement with normalization of neuropsychological findings, considerable improvement of FDG-PET findings, and decreasing antibody titers.Conclusion: The patient's psychiatric symptoms were most likely caused by anti-NMDA receptor encephalitis. Her polymorphic psychotic symptoms first occurred after she had received a Tdap-IPV booster vaccination. Although the vaccination cannot have caused the initial antibody formation since IgG serum antibodies were detected only 3 days after administration of the vaccine, the vaccine may have exerted immunomodulatory effects. MRI, EEG, and CSF findings were non-specific; however, FDG-PET identified brain involvement consistent with anti-NMDA receptor encephalitis. This case shows the importance of implementing a multimodal diagnostic work-up in similar situations. The negative CSF antibody finding furthermore fits to the hypothesis that the brain may act as an immunoprecipitator for anti-NMDA receptor antibodies.

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.

Objective: To test the hypothesis that olfactory (OF) and gustatory function (GF) is disturbed in patients with autoimmune encephalitides (AE).Methods: The orthonasal OF was tested in 32 patients with AE and 32 age- and sex-matched healthy controls (HC) with the standardized Threshold Discrimination Identification (TDI) score. This validated olfactory testing method yields individual scores for olfactory threshold (T), odor discrimination (D), and identification (I), along with a composite TDI score. The GF was determined by the Taste Strip Test (TST).Results: Overall, 24/32 (75%) of patients with AE, but none of 32 HC (p < 0.001) had olfactory dysfunction in TDI testing. The results of the threshold, discrimination and identification subtests were significantly reduced in patients with AE compared to HC (all p < 0.001). Assessed by TST, 5/19 (26.3%) of patients with AE, but none of 19 HC presented a significant limitation in GF (p < 0.001). The TDI score was correlated with the subjective estimation of the olfactory capacity on a visual analog scale (VAS; rs = 0.475, p = 0.008). Neither age, sex, modified Rankin Scale nor disease duration were associated with the composite TDI score.Conclusions: This is the first study investigating OF and GF in AE patients. According to unblinded assessment, patients with AE have a reduced olfactory and gustatory capacity compared to HC, suggesting that olfactory and gustatory dysfunction are hitherto unrecognized symptoms in AE. Further studies with larger number of AE patients would be of interest to verify our results.

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.

Background: Atypical Parkinsonian syndromes with prominent frontal lobe involvement can occur in the 4R-taupathies progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Secondary forms of movement disorders may occur in the context of autoimmune encephalitis with antineuronal antibodies, such as anti-glycine receptor (anti-GlyR) antibodies, which are typically associated with Stiff-Person spectrum syndrome, or progressive encephalomyelitis with rigidity and myoclonus. Overlaps between neurodegenerative and immunological mechanisms have been recently suggested in anti-IgLON5 disease. In this case study, the authors describe a patient with a Parkinsonian syndrome with frontal lobe involvement and anti-GlyR antibodies. Case presentation: The patient presented was a 63-year-old female. Her symptoms had begun with insomnia at the age of 60, after which, since the age of 61, increasing personality changes developed, leading to a diagnosis of depression with delusional symptoms. Severe cognitive deficits emerged, along with a left-side accentuated Parkinsonian syndrome with postural instability. The personality changes involved frontal systems. Magnetic resonance imaging (MRI) showed low-grade mesencephalon atrophy. [18F]fluorodeoxyglucose positron emission tomography (FDG PET) depicted a moderate hypometabolism bilateral frontal and of the midbrain, while [123I]FPCIT single-photon emission computed tomography (SPECT) revealed severely reduced dopamine transporter availability in both striata, indicating pronounced nigrostriatal degeneration. In addition, anti-GlyR antibodies were repeatedly found in the serum of the patient (max. titer of 1:640, reference: Conclusion: The patient presented here was suffering from a complex Parkinsonian syndrome with frontal lobe involvement. Because of the high anti-GlyR antibody titers, the presence of an autoimmune cause of the disorder was discussed. However, since no typical signs of autoimmune anti-GlyR antibody syndrome (e.g., hyperexcitability, anti-GlyR antibodies in CSF, or other inflammatory CSF changes) were detected, the possibility that the anti-GlyR antibodies might have been an unrelated bystander should be considered. Alternatively, the anti-GlyR antibodies might have developed secondarily to neurodegeneration (most likely a 4-repeat tauopathy, PSP or CBD) without exerting overt clinical effects, as in cases of anti-IgLON5 encephalopathy. In this case, such antibodies might also potentially modify the clinical course of classical movement disorders. Further research on the role of antineuronal antibodies in Parkinsonian syndromes is needed.

Background: Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis is typically characterized by limbic encephalitis, faciobrachial dystonic seizures and hyponatremia. The frequency with which milder forms of anti-LGI1 encephalitis mimic isolated psychiatric syndromes, such as psychoses, or may lead to dementia if untreated, is largely unknown. Case presentation: Here, the authors present a 50-year-old patient who had suffered from neurocognitive deficits and predominant delusions for over one and a half years. He reported a pronounced feeling of thirst, although he was drinking 10–20 liters of water each day, and he was absolutely convinced that he would die of thirst. Due to insomnia in the last five years, the patient took Z-drugs; later, he also abused alcohol. Two years prior to admission, he developed a status epilepticus which had been interpreted as a withdrawal seizure. In his serum, anti-LGI1 antibodies were repeatedly detected by different independent laboratories. Cerebrospinal fluid analyses revealed slightly increased white blood cell counts and evidence for blood–brain-barrier dysfunction. Magnetic resonance imaging showed hyperintensities mesio-temporally and in the right amygdala. In addition, there was a slight grey–white matter blurring. A cerebral [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) examination of his brain showed moderate hypometabolism of the bilateral rostral mesial to medial frontal cortices. Treatment attempts with various psychotropic drugs remained unsuccessful in terms of symptom relief. After the diagnosis of probable chronified anti-LGI1 encephalitis was made, two glucocorticoid pulse treatments were performed, which led to a slight improvement of mood and neurocognitive deficits. Further therapy was not desired by the patient and his legally authorized parents. Conclusion: This case study describes a patient with anti-LGI1 encephalitis in the chronified stage and a predominant long-lasting psychiatric course with atypical symptoms of psychosis and typical neurocognitive deficits. The patient’s poor response to anti-inflammatory drugs was probably due to the delayed start of treatment. This delay in diagnosis and treatment may also have led to the FDG-PET findings, which were compatible with frontotemporal dementia (“state of damage”). In similar future cases, newly occurring epileptic seizures associated with psychiatric symptoms should trigger investigations for possible autoimmune encephalitis, even in patients with addiction or other pre-existing psychiatric conditions. This should in turn result in rapid organic clarification and—in positive cases—to anti-inflammatory treatment. Early treatment of anti-LGI1 encephalitis during the “inflammatory activity state” is crucial for overall prognosis and may avoid the development of dementia in some cases. Based on this case, the authors advocate the concept—long established in many chronic inflammatory diseases in rheumatology—of distinguishing between an “acute inflammatory state” and a “state of organ damage” in autoimmune psychosis resembling neurodegenerative mechanisms.

Progranulin (PGRN), Total-Tau (t-tau), and Neurofilament light chain (NfL) are well known biomarkers of neurodegeneration. The objective of the present study was to investigate whether these parameters represent also biomarkers in autoimmune-mediated Encephalitis (AE) and may give us insights into the pathomechanisms of AE. We retrospectively examined the concentration of PGRN in the cerebrospinal fluid (CSF) and serum of 38 patients suffering from AE in acute phase and/or under treatment. This AE cohort comprises patients with autoantibodies against: NMDAR (n = 18 patients), Caspr2 (n = 8), Lgi-1 (n = 10), GABAB(R) (n = 1), and AMPAR (n = 1). Additionally, the concentrations of NfL (n = 25) and t-tau (n = 13) in CSF were measured when possible. Follow up data including MRI were available in 13 patients. Several age-matched cohorts with neurological diseases besides neuroinflammation or neurodegeneration served as control groups. We observed that PGRN was significantly elevated in the CSF of patients with NMDAR-AE in the acute phase, but normalized at follow up under treatment (p < 0.01). In the CSF of other patients with AE PGRN was in the range of the CSF levels of control groups. T-tau was highly elevated in the CSF of patients with temporal FLAIR-signal in the MRI and in patients developing a hippocampal sclerosis. NfL was exceptionally high initially in Patients with AE with a paraneoplastic or parainfectious cause and also normalized under treatment. The normalizations of all biomarkers were mirrored in an improvement on the modified Rankin scale. The data suggest that the concentration of PGRN in CSF might be a biomarker for acute NMDAR-AE. Pathological high t-tau levels may indicate a risk for hippocampal sclerosis. The biomarker properties of NfL remain unclear since the levels decrease under treatment, but it could not predict severity of disease in this small cohort. According to our results, we recommend to measure in clinical practice PGRN and t-tau in the CSF of patients with AE.

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

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

Dementia in general and Alzheimer's disease in particular is increasingly seen in association with autoimmunity being causatively or supportively involved in the pathogenesis. Besides classic autoantibodies (AABs) present in dementia patients, there is the new autoantibody class called functional autoantibodies, which is directed against G-protein coupled receptors (GPCRs; GPCR-AABs) and are seen as pathogenic players. However, less is known about dementia patients' burden with functional autoantibodies. We present here for the first time a study analyzing the prevalence of GPCR-AABs in patients with different dementia forms such as unclassified, Lewy body, vascular and Alzheimer's dementia. We identified the GPCR-AABs' specific targets on the receptors and introduced a neutralization strategy for GPCR-AABs. Patients with Alzheimer’s and vascular dementia carried GPCR-AABs targeting the second loop of the alpha1- and the first loop of the beta2-adrenergic receptors (α1-AABs; β2-AABs). The majority of patients with Lewy body dementia lacked any of the GPCR-AABs. In vitro, the function of the dementia-associated GPCR-AABs could be neutralized by the aptamer BC007. Due to the presence of GPCR-AABs in dementia patients mainly in those suffering from Alzheimer's and vascular dementia, the orchestra of immune players in these dementia forms, so far preferentially represented by the classic autoantibodies, should be supplemented by functional autoantibodies. As dementia-associated functional autoantibodies could be neutralized by the aptamer BC007, the first step was taken for a new in vivo treatment option in dementia patients who were positive for GPCR-AABs.