High frequency of cerebrospinal fluid autoantibodies in patients with seizures or epilepsies of unknown etiology.

Introduction: The 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. Methods: In 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. Results: Autoantibodies 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. Discussion: These 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.

The brain reacting to COVID-19: analysis of the cerebrospinal fluid proteome, RNA and inflammation.

Patients with COVID-19 can have a variety of neurological symptoms, but the active involvement of central nervous system (CNS) in COVID-19 remains unclear. While routine cerebrospinal fluid (CSF) analyses in patients with neurological manifestations of COVID-19 generally show no or only mild inflammation, more detailed data on inflammatory mediators in the CSF of patients with COVID-19 are scarce. We studied the inflammatory response in paired CSF and serum samples of patients with COVID-19 (n = 38). Patients with herpes simplex virus encephalitis (HSVE, n = 10) and patients with non-inflammatory, non-neurodegenerative neurological diseases (n = 28) served as controls. We used proteomics, enzyme-linked immunoassays, and semiquantitative cytokine arrays to characterize inflammatory proteins. Autoantibody screening was performed with cell-based assays and native tissue staining. RNA sequencing of long-non-coding RNA and circular RNA was done to study the transcriptome. Proteomics on single protein level and subsequent pathway analysis showed similar yet strongly attenuated inflammatory changes in the CSF of COVID-19 patients compared to HSVE patients with, e.g., downregulation of the apolipoproteins and extracellular matrix proteins. Protein upregulation of the complement system, the serpin proteins pathways, and other proteins including glycoproteins alpha-2 and alpha-1 acid. Importantly, calculation of interleukin-6, interleukin-16, and CXCL10 CSF/serum indices suggest that these inflammatory mediators reach the CSF from the systemic circulation, rather than being produced within the CNS. Antibody screening revealed no pathological levels of known neuronal autoantibodies. When stratifying COVID-19 patients into those with and without bacterial superinfection as indicated by elevated procalcitonin levels, inflammatory markers were significantly (p < 0.01) higher in those with bacterial superinfection. RNA sequencing in the CSF revealed 101 linear RNAs comprising messenger RNAs, and two circRNAs being significantly differentially expressed in COVID-19 than in non-neuroinflammatory controls and neurodegenerative patients. Our findings may explain the absence of signs of intrathecal inflammation upon routine CSF testing despite the presence of SARS-CoV2 infection-associated neurological symptoms. The relevance of blood-derived mediators of inflammation in the CSF for neurological COVID-19 and post-COVID-19 symptoms deserves further investigation.

Factors predisposing to humoral autoimmunity against brain-antigens in health and disease: Analysis of 49 autoantibodies in over 7000 subjects.

BACKGROUND: Circulating autoantibodies (AB) against brain-antigens, often deemed pathological, receive increasing attention. We assessed predispositions and seroprevalence/characteristics of 49 AB in > 7000 individuals. METHODS: Exploratory cross-sectional cohort study, investigating deeply phenotyped neuropsychiatric patients and healthy individuals of GRAS Data Collection for presence/characteristics of 49 brain-directed serum-AB. Predispositions were evaluated through GWAS of NMDAR1-AB carriers, analyses of immune check-point genotypes, APOE4 status, neurotrauma. Chi-square, Fisher's exact tests and logistic regression analyses were used. RESULTS: Study of N = 7025 subjects (55.8 % male; 41 ±â€¯16 years) revealed N = 1133 (16.13 %) carriers of any AB against 49 defined brain-antigens. Overall, age dependence of seroprevalence (OR = 1.018/year; 95 % CI [1.015-1.022]) emerged, but no disease association, neither general nor with neuropsychiatric subgroups. Males had higher AB seroprevalence (OR = 1.303; 95 % CI [1.144-1.486]). Immunoglobulin class (N for IgM:462; IgA:487; IgG:477) and titers were similar. Abundant were NMDAR1-AB (7.7 %). Low seroprevalence (1.25 %-0.02 %) was seen for most AB (e.g., amphiphysin, KCNA2, ARHGAP26, GFAP, CASPR2, MOG, Homer-3, KCNA1, GLRA1b, GAD65). Non-detectable were others. GWAS of NMDAR1-AB carriers revealed three genome-wide significant SNPs, two intergenic, one in TENM3, previously autoimmune disease-associated. Targeted analysis of immune check-point genotypes (CTLA4, PD1, PD-L1) uncovered effects on humoral anti-brain autoimmunity (OR = 1.55; 95 % CI [1.058-2.271]) and disease likelihood (OR = 1.43; 95 % CI [1.032-1.985]). APOE4 carriers (∼19 %) had lower seropositivity (OR = 0.766; 95 % CI [0.625-0.933]). Neurotrauma predisposed to NMDAR1-AB seroprevalence (IgM: OR = 1.599; 95 % CI [1.022-2.468]). CONCLUSIONS: Humoral autoimmunity against brain-antigens, frequent across health and disease, is predicted by age, gender, genetic predisposition, and brain injury. Seroprevalence, immunoglobulin class, or titers do not predict disease.

Neurofilament Levels Are Reflecting the Loss of Presynaptic Dopamine Receptors in Movement Disorders.

Aims: Neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) are biomarkers for neuroaxonal damage. We assessed whether NfL and other biomarker levels in the CSF are correlated to the loss of presynaptic dopamine transporters in neurons as detected with dopamine transporter SPECT (DaTscan). Methods: We retrospectively identified 47 patients (17 Alzheimer's dementia, 10 idiopathic Parkinson's disease, 7 Lewy body dementia, 13 progressive supranuclear palsy or corticobasal degeneration) who received a DaTscan and a lumbar puncture. DaTscan imaging was performed according to current guidelines, and z-scores indicating the decrease in uptake were software based calculated for the nucleus caudatus and putamen. The CSF biomarkers progranulin, total-tau, alpha-synuclein, NfL, and pNfH were correlated with the z-scores. Results: DaTscan results in AD patients did not correlate with any biomarker. Subsuming every movement disorder with nigrostriatal neurodegeneration resulted in a strong correlation between putamen/nucleus caudatus and NfL (nucleus caudatus right p < 0.01, putamen right p < 0.05, left p < 0.05) and between pNfH and putamen (right p < 0.05; left p < 0.042). Subdividing in disease cohorts did not reveal significant correlations. Progranulin, alpha-synuclein, and total-tau did not correlate with DaTscan results. Conclusion: We show a strong correlation of NfL and pNfH with pathological changes in presynaptic dopamine transporter density in the putamen concomitant to nigrostriatal degeneration. This correlation might explain the reported correlation of impaired motor functions in PD and NfL as seen before, despite the pathological heterogeneity of these diseases.

Mild Cognitive Impairment in Chronic Brain Injury Associated with Serum Anti-AP3B2 Autoantibodies: Report and Literature Review.

BACKGROUND: Chronic traumatic brain injury is a condition that predisposes the brain to activate B-cells and produce neural autoantibodies. Anti-adaptor protein 3, subunit B2 (AP3B2) autoantibodies have thus far been associated with diseases affecting the cerebellum or vestibulocerebellum. Through this case report, we aim to broaden the spectrum of anti-AP3B2-associated disease. CASE DESCRIPTION: We report on a 51-year-old woman with a brain injury approximately 28 years ago who recently underwent neuropsychological testing, magnetic resonance imaging of the brain (cMRI), and cerebrospinal fluid (CSF) analysis. Neural autoantibodies were determined in serum and CSF. Our patient suffered from mild cognitive impairment (amnestic MCI, multiple domains) with stable memory deficits and a decline in verbal fluency and processing speed within a two-year interval after the first presentation in our memory clinic. Brain MRI showed brain damage in the right temporoparietal, frontolateral region and thalamus, as well as in the left posterior border of the capsula interna and white matter in the frontal region. Since the brain damage, she suffered paresis of the upper extremities on the left side and lower extremities on the right side as well as gait disturbance. Our search for autoantibodies revealed anti-AP3B2 autoantibodies in serum. CONCLUSIONS: Our report expands the spectrum of symptoms to mild cognitive impairment in addition to a gait disturbance associated with anti-AP3B2 autoantibodies. Furthermore, it is conceivable that a prior traumatic brain injury could initiate the development of anti-AP3B2-antibody-associated brain autoimmunity, reported here for the first time.

Case Report: Anti-flotillin 1/2 Autoantibody-Associated Atypical Dementia.

Flotillin proteins are involved in neurodegeneration and T-cell immunity. Here, we report the case of 65-year-old woman who presented with dementia, depressive symptoms, and a patient history involving speech problems. As diagnostics methods we applied magnetic resonance imaging, clinical examination, extensive neuropsychological testing, and cerebrospinal fluid analysis. Neuropsychological testing revealed major cognitive decline in attentional, executive, and memory functions together with impaired activities of daily living. The cerebrospinal fluid showed elevated phosphorylated tau protein 181. We identified serum autoantibodies against the flotillin 1/2 complex. Immunotherapy entailing four cycles of high-dose steroids resulted in less cognitive dysfunction along with reduced depressive symptoms in the second follow-up after starting steroids. In conclusion: probable autoimmune-mediated dementia associated with anti-flotillin 1/2 complex autoantibodies expands the phenotypic spectrum of anti-flotillin 1/2 antibody disease.

Autoantibodies against NMDA receptor 1 modify rather than cause encephalitis.

The etiology and pathogenesis of "anti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis" and the role of autoantibodies (AB) in this condition are still obscure. While NMDAR1-AB exert NMDAR-antagonistic properties by receptor internalization, no firm evidence exists to date that NMDAR1-AB by themselves induce brain inflammation/encephalitis. NMDAR1-AB of all immunoglobulin classes are highly frequent across mammals with multiple possible inducers and boosters. We hypothesized that "NMDAR encephalitis" results from any primary brain inflammation coinciding with the presence of NMDAR1-AB, which may shape the encephalitis phenotype. Thus, we tested whether following immunization with a "cocktail" of 4 NMDAR1 peptides, induction of a spatially and temporally defined sterile encephalitis by diphtheria toxin-mediated ablation of pyramidal neurons ("DTA" mice) would modify/aggravate the ensuing phenotype. In addition, we tried to replicate a recent report claiming that immunizing just against the NMDAR1-N368/G369 region induced brain inflammation. Mice after DTA induction revealed a syndrome comprising hyperactivity, hippocampal learning/memory deficits, prefrontal cortical network dysfunction, lasting blood brain-barrier impairment, brain inflammation, mainly in hippocampal and cortical regions with pyramidal neuronal death, microgliosis, astrogliosis, modest immune cell infiltration, regional atrophy, and relative increases in parvalbumin-positive interneurons. The presence of NMDAR1-AB enhanced the hyperactivity (psychosis-like) phenotype, whereas all other readouts were identical to control-immunized DTA mice. Non-DTA mice with or without NMDAR1-AB were free of any encephalitic signs. Replication of the reported NMDAR1-N368/G369-immunizing protocol in two large independent cohorts of wild-type mice completely failed. To conclude, while NMDAR1-AB can contribute to the behavioral phenotype of an underlying encephalitis, induction of an encephalitis by NMDAR1-AB themselves remains to be proven.

Mild Amnestic Cognitive Impairment and Depressive Symptoms in Autoimmune Encephalitis Associated with Serum Anti-Neurexin-3α Autoantibodies.

(1) Background: autoimmune encephalitis associated with neurexin-3α antibodies is a seldom reported disease entity often accompanied by a severe clinical neuropsychiatric syndrome. (2) Method: we report on the case of a 58-year-old man diagnosed with neurexin-3α-associated autoimmune encephalitis revealing cognitive decline and depression before the proof of neurexin-3α antibodies. He underwent neuropsychological testing, peripheral blood and cerebrospinal fluid analysis, neuroimaging and electroencephalography. (3) Results: our patient's main clinical feature was amnestic cognitive decline in combination with depressive symptoms. CSF analysis showed elevated phosphorylated tau protein 181 and positive proof of serum neurexin-3α antibodies in a cell-based assay. An 18F-FDG-PET/CT of the brain initially showed bilateral cerebral hypometabolism prefrontal and parietal, which was absent in follow up. The brain MRI was unremarkable. EEG recordings showed frontotemporal slowing in the theta and delta range. (4) Conclusions: taken together, we assumed autoimmune encephalitis associated with serum neurexin-3α antibodies. To the best of our knowledge, we are the first to report on a predominantly mild clinical manifestation entailing amnestic mild cognitive impairment in addition to depression, thus broadening the clinical spectrum associated with neurexin-3α antibodies.

Neural cell-surface and intracellular autoantibodies in patients with cognitive impairment from a memory clinic cohort.

Autoantibody-associated cognitive impairment is an expanding field in geriatric psychiatry. We aim to assess the association between the presence of specific neural autoantibodies and cognitive performance in a memory clinic cohort. 154 patients with cognitive impairment were included between 2019 and 2020 presenting initially in a memory clinic. We evaluated their patient files retrospectively applying epidemiologic parameters, psychopathology, neuropsychology, intracellular and membrane-surface autoantibodies in serum and cerebrospinal fluid (CSF) and markers of neurodegeneration in CSF. In 26 of 154 patients, we searched for neural autoantibodies due to indicators for autoimmunity. In 15/26 (58%) of patients we detected serum and/or CSF autoantibodies. We identified autoantibodies against intracellular or cell-surface antigens in 7 of all 26 (27%) patients with cognitive dysfunction, although we cannot exclude patients with potential specific autoantibodies lacking autoimmune indicators. There were no significant differences between psychopathological and neuropsychological profiles in groups of patients with cognitive impairment comprising patients with autoantibodies (ABS + COG), no autoantibodies (ABS - COG), and Alzheimer's disease (ADCOG). Concerning our CSF parameters, we detected intrathecal IgG synthesis in 14% of ABS + COG and in 13% of ABS - COG patients, whereas no intrathecal IgG synthesis was found in ADCOG patients. Furthermore, CSF Aß42 was significantly diminished in the ADCOG compared to the ABS + COG group (p < 0.05). In addition, the Aß42/40 ratio was lower in ADCOG patients than in the ABS + COG or ABS - COG group (p < 0.05). Our findings reveal the underestimated occurrence and autoantibodies' potential role in patients presenting cognitive impairment. Furthermore, the patients with possible Alzheimer's disease might be differentiated from autoantibody-positive patients via a reduced Aß42 and Aß42/40 ratio in the CSF. The antibody-type varies between patients to a relevant degree, thus demonstrating the need for more research to identify subgroup-specific phenotypes. These pilot study results open an avenue for improving diagnosis and treatment in a memory clinic.

Case Report: Semantic Variant of Primary Progressive Aphasia Associated With Anti-Glial Fibrillary Acid Protein Autoantibodies.

Background: Frontotemporal lobar degeneration is a heterogeneous disorder entailing a semantic variant of primary progressive aphasia (svPPA). A subtype of frontotemporal dementia associated with glutamate receptor subunit 3 (GluA3) antibody of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) was recently identified. Here, we describe the novelty of a svPPA associated with anti-glial fibrillary acid protein (GFAP) antibodies. Methods: To diagnose this 68-year-old woman we conducted a clinical examination, neuropsychological testing, CSF analysis, MRI and 18F-fluorodeoxyglucose (18F-FDG) Positron Emission Tomography (PET)/computed tomography (CT) imaging. Results: The clinical phenotype corresponds to a svPPA based on impaired confrontation naming and single-word comprehension. In addition, we observed spared speech production, impaired object knowledge, and surface dyslexia - further supporting the diagnosis of svPPA. Additional characteristic imaging features such as anterior temporal hypometabolism in 18F-FDG PET/CT confirmed patient's svPPA diagnosis. CSF analysis revealed signs of axonal degeneration, as both tau and phosphorylated tau proteins exceeded normal levels. Her serum showed anti-GFAP autoantibodies. Conclusion: We diagnosed a svPPA in this patient and report an association between serum anti-GFAP antibodies and svPPA never reported in the literature so far, thereby expanding the clinical spectrum of svPPA and anti-GFAP-antibody related disease. Further research is needed to elucidate the underlying immunopathology of this disease entity to ultimately improve treatment.

Dysfunctional Learning and Verbal Memory in Patients with Elevated Tau Protein Levels and Serum Recoverin Autoantibodies-Case Series and Review.

Recoverin-antibody-related disease is currently restricted to late-onset ataxia and autoimmune retinopathy, which can be paraneoplastic or not. However, cognitive dysfunction associated with recoverin antibodies has not been reported so far in a homogeneous patient group. Our case series is dedicated to describing the novel phenotype of cognitive impairment associated with recoverin antibodies. We included five patients with cognitive impairment who presented serum recoverin autoantibodies detected by immunoblots in our case series investigation. We also analyzed their psychopathology, clinical data, cerebrospinal fluid (CSF), and neuroimaging data. Five patients with cognitive impairment associated with serum recoverin antibodies exhibited profound dysfunctional learning and verbal memory. In the CSF of 40% of them, we also diagnosed axonal neurodegeneration entailing elevated tau and phosphorylated tau protein levels. Psychopathologies such as affective symptoms (restlessness, depressive mood, anxiety, complaintiveness) and formal thought disorder, such as rumination, were detected in 25-75% of the patients. We hypothesized a role of recoverin autoimmunity in the pineal gland involving consecutive modulation of hippocampus-based memory caused by an altered release of melatonin. We describe a novel phenotype of possible recoverin autoimmunity in patients with cognitive impairment. However, no clear diagnostic clues can be extracted because of the low diagnostic validity of the testing strategies applied. The possibility of recoverin antibody autoimmunity in the pineal gland correlating with a modulation of hippocampus-based memory should be further investigated.

Impaired Verbal Memory Recall in Patients With Axonal Degeneration and Serum Glycine-Receptor Autoantibodies-Case Series.

BACKGROUND: Glycine receptor antibody-associated neuropsychiatric disease is currently known to be dominated by the phenotypes stiff-person syndrome and progressive encephalomyelitis entailing rigidity and myoclonus. In our case series we aim to depict the less-often reported feature of cognitive impairment associated with glycine receptor antibodies. METHODS: We investigated five patients with cognitive impairment varying from mild cognitive impairment to dementia associated with serum glycine receptor antibodies. Mild and major neurocognitive disorders were diagnosed according to the DSM-5 (fifth edition of the Diagnostic and Statistical Manual of Mental Disorders). Neuropsychology via Consortium to Establish a Registry for Alzheimer's Disease (CERAD) testing results, psychopathology data via the Manual for the Assessment and Documentation of Psychopathology in Psychiatry (AMDP), cerebrospinal fluid analysis and magnetic resonance imaging data were retrospectively analyzed from patient files. RESULTS: We identified five patients with cognitive impairment as the main neuropsychiatric feature associated with serum glycine receptor antibodies. One patient also presented akinetic rigidity syndrome. The psychopathology comprised disorders of attention and memory, orientation, formal thought, and affect. In addition to suffering deficits in verbal memory function, figural recall, phonematic fluency, and globally deteriorated cognitive function, these patients presented seriously impaired memory recall in particular. Tau protein and phosphorylated tau protein 181 were elevated in 75% of patients. CONCLUSIONS: Our results suggest that axonal neurodegeneration and especially impaired verbal memory recall in addition to deficits in verbal and figural memory characterize patients with progressive cognitive impairment associated with glycine receptor antibodies. This unresolved issue should be clarified by researchers to discover whether axonal degeneration is merely an age-related phenomenon or one related to glycine-receptor autoantibodies in old age. Cognitive impairment as a neuropsychiatric syndrome of glycine-receptor antibody disease is a potential, conceivable, but so far unproven additional feature requiring deeper large-scale investigations and consideration during differential diagnosis in memory clinics.

Multiple inducers and novel roles of autoantibodies against the obligatory NMDAR subunit NR1: a translational study from chronic life stress to brain injury.

Circulating autoantibodies (AB) of different immunoglobulin classes (IgM, IgA, and IgG), directed against the obligatory N-methyl-D-aspartate-receptor subunit NR1 (NMDAR1-AB), belong to the mammalian autoimmune repertoire, and appear with age-dependently high seroprevalence across health and disease. Upon access to the brain, they can exert NMDAR-antagonistic/ketamine-like actions. Still unanswered key questions, addressed here, are conditions of NMDAR1-AB formation/boosting, intraindividual persistence/course in serum over time, and (patho)physiological significance of NMDAR1-AB in modulating neuropsychiatric phenotypes. We demonstrate in a translational fashion from mouse to human that (1) serum NMDAR1-AB fluctuate upon long-term observation, independent of blood-brain barrier (BBB) perturbation; (2) a standardized small brain lesion in juvenile mice leads to increased NMDAR1-AB seroprevalence (IgM + IgG), together with enhanced Ig-class diversity; (3) CTLA4 (immune-checkpoint) genotypes, previously found associated with autoimmune disease, predispose to serum NMDAR1-AB in humans; (4) finally, pursuing our prior findings of an early increase in NMDAR1-AB seroprevalence in human migrants, which implicated chronic life stress as inducer, we independently replicate these results with prospectively recruited refugee minors. Most importantly, we here provide the first experimental evidence in mice of chronic life stress promoting serum NMDAR1-AB (IgA). Strikingly, stress-induced depressive-like behavior in mice and depression/anxiety in humans are reduced in NMDAR1-AB carriers with compromised BBB where NMDAR1-AB can readily reach the brain. To conclude, NMDAR1-AB may have a role as endogenous NMDAR antagonists, formed or boosted under various circumstances, ranging from genetic predisposition to, e.g., tumors, infection, brain injury, and stress, altogether increasing over lifetime, and exerting a spectrum of possible effects, also including beneficial functions.

Corrigendum: Figural Memory Impairment in Conjunction With Neuropsychiatric Symptoms in IgLON5 Antibody-Associated Autoimmune Encephalitis.

[This corrects the article DOI: 10.3389/fpsyt.2020.00576.].

Figural Memory Impairment in Conjunction With Neuropsychiatric Symptoms in IgLON5 Antibody-Associated Autoimmune Encephalitis.

BACKGROUND: IgLON5 disease is an autoimmune disorder that shares neuropathological aspects with a tauopathy. Its clinical spectrum is heterogeneous, and figural memory impairment as an initial phenomenon of IgLON5 syndrome has not yet been described. The rationale of this report is to highlight symptoms related to IgLON5 disease that have not been reported to date. This case report will thereby emphasize how important it is to initiate thorough diagnostic methods including cerebrospinal fluid analysis (CSF) before starting early immunotherapy. METHODS: We examined a 65-year-old Caucasian male via neuropsychological tests, magnetic resonance imaging (MRI), electroencephalography (EEG), neurography and polysomnography. He also underwent two lumbar punctures from which we determined specific autoantibodies in cerebrospinal (CSF) and peripheral blood (PB). RESULTS: The patient presented initially complaining of memory loss, gradual dysphagia and sleeping dysfunction. Neuropsychological testing at first presentation and follow-up revealed subtle figural and working memory impairment. At onset and at his 6-month follow-up, we detected IgLON5 antibodies in CSF and PB. Furthermore, we identified in the CSF a blood-brain barrier disturbance at disease onset and follow-up, and markers of neuroaxonal damage such as mildly elevated phosphorylated Tau-181 protein with 86 pg/ml (normal range ≤ 61 pg/ml) at onset. Three months after his initial presentation, he was suffering from axonal neuropathy and transient ataxia in the extremities. Assuming a definitive autoimmune encephalitis-associated with anti-IgLON5 antibodies, we applied high-dose steroids monthly (1g methylprednisolone i.v. for five consecutive days) and his memory complaints, ataxia of extremities and peripheral neuropathy as well as sleeping dysfunction decreased. CONCLUSIONS: Our findings broaden IgLON5 disease's clinical spectrum to include predominant and discrete figural memory impairment together with sleeping dysfunction at disease onset. In addition, our report illustrates how important taking an elaborated diagnostic approach is to assuring an accurate diagnosis and the appropriate therapy if a patient presents with a persisting figural memory impairment and sleeping abnormalities so as to avoid overlooking IgLON5 disease and a potentially poor outcome.

International multicenter examination of MOG antibody assays.

OBJECTIVE: To compare the reproducibility of 11 antibody assays for immunoglobulin (Ig) G and IgM myelin oligodendrocyte glycoprotein antibodies (MOG-IgG and MOG-IgM) from 5 international centers. METHODS: The following samples were analyzed: MOG-IgG clearly positive sera (n = 39), MOG-IgG low positive sera (n = 39), borderline negative sera (n = 13), clearly negative sera (n = 40), and healthy blood donors (n = 30). As technical controls, 18 replicates (9 MOG-IgG positive and 9 negative) were included. All samples and controls were recoded, aliquoted, and distributed to the 5 testing centers, which performed the following antibody assays: 5 live and 1 fixed immunofluorescence cell-based assays (CBA-IF, 5 MOG-IgG, and 1 MOG-IgM), 3 live flow cytometry cell-based assays (CBA-FACS, all MOG-IgG), and 2 ELISAs (both MOG-IgG). RESULTS: We found excellent agreement (96%) between the live CBAs for MOG-IgG for samples previously identified as clearly positive or negative from 4 different national testing centers. The agreement was lower with fixed CBA-IF (90%), and the ELISA showed no concordance with CBAs for detection of human MOG-IgG. All CBAs showed excellent interassay reproducibility. The agreement of MOG-IgG CBAs for borderline negative (77%) and particularly low positive (33%) samples was less good. Finally, most samples from healthy blood donors (97%) were negative for MOG-IgG in all CBAs. CONCLUSIONS: Live MOG-IgG CBAs showed excellent agreement for high positive and negative samples at 3 international testing centers. Low positive samples were more frequently discordant than in a similar comparison of aquaporin-4 antibody assays. Further research is needed to improve international standardization for clinical care.

Multicenter prospective study on multivariant diagnostics of autoimmune bullous dermatoses using the BIOCHIP technology.

BACKGROUND: The current standard in the serologic diagnosis of autoimmune bullous diseases (AIBD) is a multistep procedure sequentially applying different assays. In contrast, the BIOCHIP Mosaic technology combines multiple substrates for parallel analysis by indirect immunofluorescence. METHODS: Sera from 749 consecutive, prospectively recruited patients with direct immunofluorescence-positive AIBD from 13 international study centers were analyzed independently and blinded by using (1) a BIOCHIP Mosaic including primate esophagus, salt-split skin, rat bladder, monkey liver, monkey liver with serosa, recombinant BP180 NC16A, and gliadin GAF3X, as well as HEK293 cells expressing recombinant desmoglein 1, desmoglein 3, type VII collagen, and BP230 C-terminus and (2) the conventional multistep approach of the Department of Dermatology, University of Lübeck. RESULTS: In 731 of 749 sera (97.6%), specific autoantibodies could be detected with the BIOCHIP Mosaic, similar to the conventional procedure (725 cases, 96.8%). The Cohen κ for both serologic approaches ranged from 0.84 to 1.00. In 6.5% of sera, differences between the 2 approaches occurred and were mainly attributed to autoantigen fragments not present on the BIOCHIP Mosaic. LIMITATIONS: Laminin 332 and laminin γ1 are not represented on the BIOCHIP Mosaic. CONCLUSIONS: The BIOCHIP Mosaic is a standardized time- and serum-saving approach that further facilitates the serologic diagnosis of AIBD.

Serological Diagnosis of Autoimmune Bullous Skin Diseases.

Autoimmune bullous dermatoses (AIBD) encompass a variety of organ-specific autoimmune diseases that manifest with cutaneous and/or mucosal blisters and erosions. They are characterized by autoantibodies targeting structural proteins of the skin, which are responsible for the intercellular contact between epidermal keratinocytes and for adhesion of the basal keratinocytes to the dermis. The autoantibodies disrupt the adhesive functions, leading to splitting and blister formation. In pemphigus diseases, blisters form intraepidermally, whereas in all other disease types they occur subepidermally. Early identification of autoimmune bullous dermatoses is crucial for both treatment and prognosis, particularly as regards tumor-associated disease entities. The diagnosis is based on clinical symptoms, histopathology, direct immunofluorescence to detect antibody/complement deposits, and the determination of circulating autoantibodies. The identification of various target antigens has paved the way for the recent development of numerous specific autoantibody tests. In particular, optimized designer antigens and multiplex test formats for indirect immunofluorescence and ELISA have enhanced and refined the laboratory analysis, enabling highly efficient serodiagnosis and follow-up. This review elaborates on the current standards in the serological diagnostics for autoimmune bullous dermatoses.

Encephalopathy Associated With Neurochondrin Autoantibodies.

We determined the prevalence of autoantibodies against an extended number of established and novel neural antigens in children and adolescents with suspected autoimmune encephalitis, epilepsy, single seizures, or marked epileptiform activity in electroencephalography (EEG). Prospectively, 103 patients were recruited aged between 0 and 18 years and 104 controls. A panel of 35 autoantibodies against neural cell-surface and intracellular antigens was screened. Sixteen of 103 patients (15.5%) showed a positive result for 1 or more autoantibodies, compared to 6 of 104 controls (5.8%, P = .02). Neurochondrin was identified as a possible new target of autoantibodies in 3 patients within this cohort, but none in controls. The patients showed severe behavioral disturbances, memory and cognitive impairment, episodes of reduced responsiveness, but no seizures, and normal MRI. Clinical findings, course, and treatment response of these 3 patients are presented.

Added value of IgA antibodies against Zika virus non-structural protein 1 in the diagnosis of acute Zika virus infections.

Zika virus (ZIKV) is a mosquito-borne flavivirus posing a public health threat due to its association with neurological complications in newborns and adults. In flavivirus-endemic areas, coming mosquito seasons will require the differentiation of primary versus secondary and acute versus past ZIKV/flavivirus infections. This is complicated by two major difficulties: [i] secondary infections often present with low or undetectable titres of specific IgM and with early-positive IgG, [ii] previous flavivirus infection(s) or vaccinations cause elevated cross-reactivities. Here, we analysed the anti-ZIKV IgA, IgG, and IgM responses at different stages of infection in an endemic setting, scrutinising the diagnostic relevance of specific IgA. Anti-ZIKV antibodies were measured by ELISA based on ZIKV non-structural protein 1 (NS1) in paired sera from 31 patients with suspected primary or (flavivirus-primed) secondary ZIKV infection. The control panel comprised samples from 136 DENV-infected patients. Among ZIKV samples collected 8-16 days after symptom onset, ELISA sensitivities for detecting anti-ZIKV NS1 IgA, IgG, and IgM were 93.5%, 100%, and 48.4%, respectively. The proportion of cases with negative IgM but positive IgA was higher in suspected secondary (61.9%) than in primary (30.0%) ZIKV infections. Combined IgA/IgM detection yielded a sensitivity of 100% at a specificity of 97.1%. In conclusion, at time points after PCR can detect the virus, the determination of anti-ZIKV NS1 IgA may improve the accuracy in diagnosing acute ZIKV infection in flavivirus-endemic regions in the context of both primary and secondary infection, especially when IgM is undetectable.