Translational imaging of TSPO reveals pronounced innate inflammation in human and murine CD8 T cell-mediated limbic encephalitis.

Autoimmune limbic encephalitis (ALE) presents with new-onset mesial temporal lobe seizures, progressive memory disturbance, and other behavioral and cognitive changes. CD8 T cells are considered to play a key role in those cases where autoantibodies (ABs) target intracellular antigens or no ABs were found. Assessment of such patients presents a clinical challenge, and novel noninvasive imaging biomarkers are urgently needed. Here, we demonstrate that visualization of the translocator protein (TSPO) with [18F]DPA-714-PET-MRI reveals pronounced microglia activation and reactive gliosis in the hippocampus and amygdala of patients suspected with CD8 T cell ALE, which correlates with FLAIR-MRI and EEG alterations. Back-translation into a preclinical mouse model of neuronal antigen-specific CD8 T cell-mediated ALE allowed us to corroborate our preliminary clinical findings. These translational data underline the potential of [18F]DPA-714-PET-MRI as a clinical molecular imaging method for the direct assessment of innate immunity in CD8 T cell-mediated ALE.

Autoimmune encephalitis: recent clinical and biological advances.

In 2015, we wrote a review in The Journal of Neurology summarizing the field of autoantibody-associated neurological diseases. Now, in 2023, we present an update of the subject which reflects the rapid expansion and refinement of associated clinical phenotypes, further autoantibody discoveries, and a more detailed understanding of immunological and neurobiological pathophysiological pathways which mediate these diseases. Increasing awareness around distinctive aspects of their clinical phenotypes has been a key driver in providing clinicians with a better understanding as to how these diseases are best recognized. In clinical practice, this recognition supports the administration of often effective immunotherapies, making these diseases 'not to miss' conditions. In parallel, there is a need to accurately assess patient responses to these drugs, another area of growing interest. Feeding into clinical care are the basic biological underpinnings of the diseases, which offer clear pathways to improved therapies toward enhanced patient outcomes. In this update, we aim to integrate the clinical diagnostic pathway with advances in patient management and biology to provide a cohesive view on how to care for these patients in 2023, and the future.

Cerebrospinal fluid proteomics indicates immune dysregulation and neuronal dysfunction in antibody associated autoimmune encephalitis.

Autoimmune Encephalitis (AE) spans a group of non-infectious inflammatory conditions of the central nervous system due to an imbalanced immune response. Aiming to elucidate the pathophysiological mechanisms of AE, we applied an unsupervised proteomic approach to analyze the cerebrospinal fluid (CSF) protein profile of AE patients with autoantibodies against N-methyl-d-aspartate receptor (NMDAR) (n = 9), leucine-rich glioma-inactivated protein 1 (LGI1) (n = 9), or glutamate decarboxylase 65 (GAD65) (n = 8) compared to 9 patients with relapsing-remitting multiple sclerosis as inflammatory controls, and 10 patients with somatic symptom disorder as non-inflammatory controls. We found a dysregulation of the complement system, a disbalance between pro-inflammatory and anti-inflammatory proteins on the one hand, and dysregulation of proteins involved in synaptic transmission, synaptogenesis, brain connectivity, and neurodegeneration on the other hand to a different extent in all AE subtypes compared to non-inflammatory controls. Furthermore, elevated levels of several proteases and reduction in protease inhibitors could be detected in all AE subtypes compared to non-inflammatory controls. Moreover, the different AE subtypes showed distinct protein profiles compared to each other and inflammatory controls which may facilitate future identification of disease-specific biomarkers. Overall, CSF proteomics provides insights into the complex pathophysiological mechanisms of AE, including immune dysregulation, neuronal dysfunction, neurodegeneration, and altered protease function.

Glutamic acid decarboxylase antibody-associated neurological syndromes: Clinical and antibody characteristics and therapy response.

BACKGROUND: Antibodies against glutamic acid decarboxylase (GAD-abs) at high serum levels are associated with diverse autoimmune neurological syndromes (AINS), including cerebellar ataxia, epilepsy, limbic encephalitis and stiff-person syndrome. The impact of low serum GAD-ab levels in patients with suspected AINS remains controversial. Specific intrathecal GAD-ab synthesis may serve as a marker for GAD-ab-associated nervous system autoimmunity. We present characteristics of a multicentric patient cohort with suspected AINS associated with GAD antibodies (SAINS-GAD+) and explore the relevance of serum GAD-ab levels and intrathecal GAD-ab synthesis. METHODS: All patients with SAINS-GAD+ included in the registry of the German Network for Research on Autoimmune Encephalitis (GENERATE) from 2011 to 2019 were analyzed. High serum GAD-ab levels were defined as RIA>2000 U/mL, ELISA>1000 U/mL, or as a positive staining pattern on cell-based assays. RESULTS: One-hundred-one patients were analyzed. In descending order they presented with epilepsy/limbic encephalitis (39%), cerebellar ataxia (28%), stiff person syndrome (22%), and overlap syndrome (12%). Immunotherapy was administered in 89% of cases with improvements in 46%. 35% of SAINS-GAD+ patients had low GAD-ab serum levels. Notably, unmatched oligoclonal bands in CSF but not in serum were more frequent in patients with low GAD-ab serum levels. GAD-ab-levels (high/low) and intrathecal GAD-ab synthesis (present or not) did not impact clinical characteristics and outcome. CONCLUSIONS: Overall, immunotherapy in SAINS-GAD+ was moderately effective. Serum GAD-ab levels and the absence or presence of intrathecal GAD-ab synthesis did not predict clinical characteristics or outcomes in SAINS-GAD+. The detection of unmatched oligoclonal bands might outweigh low GAD-ab serum levels.

A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies.

Autoimmune neurological syndromes (AINS) with autoantibodies against the 65 kDa isoform of the glutamic acid decarboxylase (GAD65) present with limbic encephalitis, including temporal lobe seizures or epilepsy, cerebellitis with ataxia, and stiff-person-syndrome or overlap forms. Anti-GAD65 autoantibodies are also detected in autoimmune diabetes mellitus, which has a strong genetic susceptibility conferred by human leukocyte antigen (HLA) and non-HLA genomic regions. We investigated the genetic predisposition in patients with anti-GAD65 AINS. We performed a genome-wide association study (GWAS) and an association analysis of the HLA region in a large German cohort of 1214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1047 individuals without neurological or endocrine disease as population-based controls. Predictions of protein expression changes based on GWAS findings were further explored and validated in the CSF proteome of a virtually independent cohort of 10 patients with GAD65-AINS and 10 controls. Our GWAS identified 16 genome-wide significant (P < 5 × 10-8) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 × 10-16, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187-0.358], localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci (>90%) mapped to non-coding regions of the genome. Over 40% of the variants have known regulatory functions on the expression of 48 genes in disease relevant cells and tissues, mainly CD4+ T cells and the cerebral cortex. The annotation of epigenomic marks suggested specificity for neural and immune cells. A network analysis of the implicated protein-coding genes highlighted the role of protein kinase C beta (PRKCB) and identified an enrichment of numerous biological pathways participating in immunity and neural function. Analysis of the classical HLA alleles and haplotypes showed no genome-wide significant associations. The strongest associations were found for the DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype (P = 4.39 × 10-4, OR = 2.5, 95%CI = 1.499-4.157) and DRB1*04:01 allele (P = 8.3 × 10-5, OR = 2.4, 95%CI = 1.548-3.682) identified in our cohort. As predicted, the CSF proteome showed differential levels of five proteins (HLA-A/B, C4A, ATG4D and NEO1) of expression quantitative trait loci genes from our GWAS in the CSF proteome of anti-GAD65 AINS. These findings suggest a strong genetic predisposition with direct functional implications for immunity and neural function in anti-GAD65 AINS, mainly conferred by genomic regions outside the classical HLA alleles.

Clinical, serological and genetic predictors of response to immunotherapy in anti-IgLON5 disease.

Anti-IgLON5 disease is a newly defined clinical entity characterized by a progressive course with high disability and mortality rate. While precise pathogenetic mechanisms remain unclear, features characteristic of both autoimmune and neurodegenerative diseases were reported. Data on immunotherapy are limited, and its efficacy remains controversial. In this study, we retrospectively investigated an anti-IgLON5 disease cohort with special focus on clinical, serological and genetic predictors of the immunotherapy response and long-term outcome. Patients were recruited from the GENERATE (German Network for Research on Autoimmune Encephalitis) registry. Along with clinical parameters, anti-IgLON5 immunoglobulin (Ig)G in serum and CSF, anti-IgLON5 IgG1-4, IgA and IgM in serum, neurofilament light chain and glial fibrillary acidic protein in serum as well as human leukocyte antigen-genotypes were determined. We identified 53 patients (symptom onset 63.8 ± 10.3 years, female:male 1:1.5). The most frequent initial clinical presentations were bulbar syndrome, hyperkinetic syndrome or isolated sleep disorder [at least one symptom present in 38% (20/53)]. At the time of diagnosis, the majority of patients had a generalized multi-systemic phenotype; nevertheless, 21% (11/53) still had an isolated brainstem syndrome and/or a characteristic sleep disorder only. About one third of patients [28% (15/53)] reported subacute disease onset and 51% (27/53) relapse-like exacerbations during the disease course. Inflammatory CSF changes were evident in 37% (19/51) and increased blood-CSF-barrier permeability in 46% (21/46). CSF cell count significantly decreased, while serum anti-IgLON5 IgG titre increased with disease duration. The presence of human leukocyte antigen-DRB1*10:01 [55% (24/44)] was associated with higher serum anti-IgLON5 IgG titres. Neurofilament light chain and glial fibrillary acidic protein in serum were substantially increased (71.1 ± 103.9 pg/ml and 126.7 ± 73.3 pg/ml, respectively). First-line immunotherapy of relapse-like acute-to-subacute exacerbation episodes resulted in improvement in 41% (11/27) of patients and early initiation within the first 6 weeks was a predictor for therapy response. Sixty-eight per cent (36/53) of patients were treated with long-term immunotherapy and 75% (27/36) of these experienced no further disease progression (observation period of 20.2 ± 15.4 months). Long-term immunotherapy initiation during the first year after onset and low pre-treatment neurofilament light chain were significant predictors for a better outcome. In conclusion, subacute disease onset and early inflammatory CSF changes support the primary role of autoimmune mechanisms at least at initial stages of anti-IgLON5 disease. Early immunotherapy, prior to advanced neurodegeneration, is associated with a better long-term clinical outcome. Low serum neurofilament light chain at treatment initiation may serve as a potential biomarker of the immunotherapy response.

Neuropsychological Performance in Autoimmune Limbic Encephalitis: Evidence from an Immunotherapy-Naïve Cohort.

OBJECTIVE: Autoimmune limbic encephalitis (ALE) is characterized by memory impairment, psychiatric symptoms, and epileptic seizures. Though, the neuropsychological profile of ALE is not yet well defined. However, there is some evidence that neuropsychological impairments might exceed those related to the limbic system and that different autoantibodies (AABs) are associated with distinguishable pattern of neuropsychological impairments. We provide a comprehensive presentation of neuropsychological performance of ALE in an immune therapy-naïve sample. METHODS: We retrospectively analyzed 69 immunotherapy-naïve ALE-patients (26 seropositive-[8 LGI1-, 4 CASPR2-, 2 GABAB-R-, 3 Hu-, 4 GAD65-, 2 Ma2-, 2 unknown antigen, and 1 Yo-AABs] and 43 seronegative patients, mean age 56.0 years [21.9-78.2], mean disease duration 88 weeks [0-572]). Neuropsychological evaluations comprised of the domains memory, attention, praxis, executive functions, language, social cognition, and psychological symptoms. We compared these functions between seronegative -, seropositive patients with AABs against intracellular neural antigens and seropositive patients with AABs against surface membrane neural antigens. RESULTS: No effect of AAB group on neuropsychological performance could be detected. Overall, ALE predominantly presents with deficits in long-term memory and memory recognition, autobiographical-episodic memory loss, impairment of emotion recognition, and depressed mood. Furthermore, deficits in praxis of pantomimes and imitations, visuo-construction, and flexibility may occur. CONCLUSION: ALE shows a wide spectrum of neuropsychological impairments, which might exceed the limbic system, with no evidence of differences between AAB groups. Neuropsychological assessment for diagnosing ALE should include long-term memory, memory recognition, autobiographical-episodic memory, emotion recognition, and a detailed investigation of depression.

Increased Intrathecal B and Plasma Cells in Patients With Anti-IgLON5 Disease: A Case Series.

BACKGROUND AND OBJECTIVES: Despite detection of autoantibodies, anti-IgLON5 disease was historically considered a tau-associated neurodegenerative disease, with limited treatment options and detrimental consequences for the patients. Observations in increasing case numbers hint toward underlying inflammatory mechanisms that, early detection provided, open a valuable window of opportunity for therapeutic intervention. We aimed to further substantiate this view by studying the CSF of patients with anti-IgLON5. METHODS: We identified 11 patients with anti-IgLON5 from our database and compared clinical, MRI, and CSF findings with a cohort of 20 patients with progressive supranuclear palsy (PSP) (as a noninflammatory tauopathy) and 22 patients with functional neurologic disorder. RESULTS: Patients with anti-IgLON5 show inflammatory changes in routine CSF analysis, an increase in B-lymphocyte frequency, and the presence of plasma cells in comparison to the PSP-control group and functional neurologic disease controls. Patients with intrathecal plasma cells showed a clinical response to rituximab. DISCUSSION: Our findings indicate the importance of inflammatory mechanisms, in particular in early and acute anti-IgLON5 cases, which may support the use of immune-suppressive treatments in these cases. The main limitation of the study is the small number of cases due to the rarity of the disease.

Impact of T cells on neurodegeneration in anti-GAD65 limbic encephalitis.

OBJECTIVE: Direct pathogenic effects of autoantibodies to the 65 kDa isoform of glutamic acid decarboxylase (GAD65) in autoimmune limbic encephalitis (LE) have been questioned due to its intracellular localization. We therefore hypothesized a pathogenic role for T cells. METHODS: We assessed magnet resonance imaging, neuropsychological and peripheral blood, and CSF flow cytometry data of 10 patients with long-standing GAD65-LE compared to controls in a cross-sectional manner. These data were related to each other within the GAD65-LE group and linked to neuropathological findings in selective hippocampectomy specimen from another two patients. In addition, full-resolution human leukocyte antigen (HLA) genotyping of all patients was performed. RESULTS: Compared to controls, no alteration in hippocampal volume but impaired memory function and elevated fractions of activated HLADR+ CD4+ and CD8+ T cells in peripheral blood and cerebrospinal fluid were found. Intrathecal fractions of CD8+ T cells negatively correlated with hippocampal volume and memory function, whereas the opposite was true for CD4+ T cells. Consistently, antigen-experienced CD8+ T cells expressed increased levels of the cytotoxic effector molecule perforin in peripheral blood, and perforin-expressing CD8+ T cells were found attached mainly to small interneurons but also to large principal neurons together with wide-spread hippocampal neurodegeneration. 6/10 LE patients harbored the HLA-A*02:01 allele known to present the immunodominant GAD65114-123 peptide in humans. INTERPRETATION: Our data suggest a pathogenic effect of CD8+ T cells and a regulatory effect of CD4+ T cells in patients with long-standing GAD65-LE.

Rituximab Treatment and Long-term Outcome of Patients With Autoimmune Encephalitis: Real-world Evidence From the GENERATE Registry.

BACKGROUND AND OBJECTIVES: To determine the real-world use of rituximab in autoimmune encephalitis (AE) and to correlate rituximab treatment with the long-term outcome. METHODS: Patients with NMDA receptor (NMDAR)-AE, leucine-rich glioma-inactivated-1 (LGI1)- AE, contactin-associated protein-like-2 (CASPR2)-AE, or glutamic acid decarboxylase 65 (GAD65) disease from the GErman Network for Research on AuToimmune Encephalitis who had received at least 1 rituximab dose and a control cohort of non-rituximab-treated patients were analyzed retrospectively. RESULTS: Of the 358 patients, 163 (46%) received rituximab (NMDAR-AE: 57%, CASPR2-AE: 44%, LGI1-AE: 43%, and GAD65 disease: 37%). Rituximab treatment was initiated significantly earlier in NMDAR- and LGI1-AE (median: 54 and 155 days from disease onset) compared with CASPR2-AE or GAD65 disease (median: 632 and 1,209 days). Modified Rankin Scale (mRS) scores improved significantly in patients with NMDAR-AE, both with and without rituximab treatment. Although being more severely affected at baseline, rituximab-treated patients with NMDAR-AE more frequently reached independent living (mRS score ≤2) (94% vs 88%). In LGI1-AE, rituximab-treated and nontreated patients improved, whereas in CASPR2-AE, only rituximab-treated patients improved significantly. No improvement was observed in patients with GAD65 disease. A significant reduction of the relapse rate was observed in rituximab-treated patients (5% vs 13%). Detection of NMDAR antibodies was significantly associated with mRS score improvement. A favorable outcome was also observed with early treatment initiation. DISCUSSION: We provide real-world data on immunosuppressive treatments with a focus on rituximab treatment for patients with AE in Germany. We suggest that early and short-term rituximab therapy might be an effective and safe treatment option in most patients with NMDAR-, LGI1-, and CASPR2-AE. CLASS OF EVIDENCE: This study provides Class IV evidence that rituximab is an effective treatment for some types of AE.

Determinants of cognition in autoimmune limbic encephalitis-A retrospective cohort study.

Autoimmune limbic encephalitis (ALE) is the most common type of autoimmune encephalitis (AIE). Subacute memory disturbance, temporal lobe seizures, and psychiatric symptoms are clinical hallmarks of the disease. However, little is known on the factors contributing to cognitive functioning in ALE. Hence, we here investigate major determinants of cognitive functioning in ALE. In a retrospective analysis of 102 patients with ALE, we first compared verbal learning capacity, nonverbal learning capacity, and attentional and executive functioning by absence or presence of different types of neural autoantibodies (AABs). Subsequently we established three linear regression models including 63, 38, and 61 patients, respectively to investigate how cognitive functioning in these domains may depend on common markers of ALE such as intrathecal inflammation, blood-cerebrospinal fluid (CSF)-barrier function, mesiotemporal epileptiform discharges and slowing, determined by electroencephalography (EEG) and structural mesiotemporal changes, measured with magnetic resonance imaging (MRI). We also accounted for possible effects of cancer- and immunotherapy and other centrally effective medication. There was no effect of AAB status on cognitive functioning. Although the regression models could not predict verbal and nonverbal learning capacity, structural mesiotemporal neural network alterations on T2-/fluid attenuated inversion recovery (FLAIR)-signal-weighted MRI and mesiotemporal epileptiform discharges or slowing on EEG exerted a significant impact on memory functions. In contrast, the regression model significantly predicted attentional and executive functioning with CSF white blood cell count and centrally effective medication being significant determinants. In this cohort, cognitive functioning in ALE does not depend on the AAB status. Common markers of ALE cannot predict memory functioning that only partially depends on structural and functional alterations of mesiotemporal neural networks. Common markers of ALE significantly predict attentional and executive functioning that is significantly related to centrally effective medication and CSF white blood cell count, which may point toward inflammation affecting brain regions beyond the limbic system.

Occurrence of status epilepticus in persons with epilepsy is determined by sex, epilepsy classification, and etiology: a single center cohort study.

BACKGROUND: Status epilepticus (SE) can occur in persons with or without epilepsy and is associated with high morbidity and mortality. METHODS: This survey aimed to record self-reported frequency of SE in persons with epilepsy, its association with clinical characteristics and patient level of information on SE and rescue medication. 251 persons with epilepsy at a tertiary epilepsy center were included in the study. RESULTS: 87 (35%) had a history of SE defined as seizure duration of more than 5 min. These patients were less likely to be seizure-free, and had a higher number of present and past anti-seizure medication. Female sex, cognitive disability, younger age at epilepsy onset, defined epilepsy etiology, and focal epilepsy were associated with a history of SE. On Cox regression analysis, female sex, defined etiology and focal classification remained significant. 67% stated that they had information about prolonged seizures, and 75% knew about rescue medication. 85% found it desirable to receive information about SE at the time of initial diagnosis of epilepsy, but only 16% had been offered such information at the time. CONCLUSION: SE is frequent among persons with epilepsy and there remain unmet needs regarding patient education.

Classification of neurological diseases using multi-dimensional CSF analysis.

Although CSF analysis routinely enables the diagnosis of neurological diseases, it is mainly used for the gross distinction between infectious, autoimmune inflammatory, and degenerative disorders of the CNS. To investigate, whether a multi-dimensional cellular blood and CSF characterization can support the diagnosis of clinically similar neurological diseases, we analysed 546 patients with autoimmune neuroinflammatory, degenerative, or vascular conditions in a cross-sectional retrospective study. By combining feature selection with dimensionality reduction and machine learning approaches we identified pan-disease parameters that were altered across all autoimmune neuroinflammatory CNS diseases and differentiated them from other neurological conditions and inter-autoimmunity classifiers that subdifferentiate variants of CNS-directed autoimmunity. Pan-disease as well as diseases-specific changes formed a continuum, reflecting clinical disease evolution. A validation cohort of 231 independent patients confirmed that combining multiple parameters into composite scores can assist the classification of neurological patients. Overall, we showed that the integrated analysis of blood and CSF parameters improves the differential diagnosis of neurological diseases, thereby facilitating early treatment decisions.

An Assay to Determine Mechanisms of Rapid Autoantibody-Induced Neurotransmitter Receptor Endocytosis and Vesicular Trafficking in Autoimmune Encephalitis.

N-Methyl-D-aspartate (NMDA) receptors (NMDARs) are among the most important excitatory neurotransmitter receptors in the human brain. Autoantibodies to the human NMDAR cause the most frequent form of autoimmune encephalitis involving autoantibody-mediated receptor cross-linking and subsequent internalization of the antibody-receptor complex. This has been deemed to represent the predominant antibody effector mechanism depleting the NMDAR from the synaptic and extra-synaptic neuronal cell membrane. To assess in detail the molecular mechanisms of autoantibody-induced NMDAR endocytosis, vesicular trafficking, and exocytosis we transiently co-expressed rat GluN1-1a-EGFP and GluN2B-ECFP alone or together with scaffolding postsynaptic density protein 95 (PSD-95), wild-type (WT), or dominant-negative (DN) mutant Ras-related in brain (RAB) proteins (RAB5WT, RAB5DN, RAB11WT, RAB11DN) in HEK 293T cells. The cells were incubated with a pH-rhodamine-labeled human recombinant monoclonal GluN1 IgG1 autoantibody (GluN1-aAbpH-rhod) genetically engineered from clonally expanded intrathecal plasma cells from a patient with anti-NMDAR encephalitis, and the pH-rhodamine fluorescence was tracked over time. We show that due to the acidic luminal pH, internalization of the NMDAR-autoantibody complex into endosomes and lysosomes increases the pH-rhodamine fluorescence. The increase in fluorescence allows for mechanistic assessment of endocytosis, vesicular trafficking in these vesicular compartments, and exocytosis of the NMDAR-autoantibody complex under steady state conditions. Using this method, we demonstrate a role for PSD-95 in stabilization of NMDARs in the cell membrane in the presence of GluN1-aAbpH-rhod, while RAB proteins did not exert a significant effect on vertical trafficking of the internalized NMDAR autoantibody complex in this heterologous expression system. This novel assay allows to unravel molecular mechanisms of autoantibody-induced receptor internalization and to study novel small-scale specific molecular-based therapies for autoimmune encephalitis syndromes.

Onconeural antigen spreading in paraneoplastic neurological disease due to small cell lung cancer.

Cellular and humoral immunity towards distinct onconeural antigens is the hallmark of paraneoplastic neurological diseases (PNDs). Stable formation of immunoglobulin (Ig) G antibodies to particular onconeural antigens occurs in the majority of cases, whereas persistent coexistence of antibodies specific for multiple onconeural antigens is a relatively rare phenomenon of certain malignant tumors like small cell lung cancer (SCLC). We here describe onconeural antigen spreading in a 70-year-old Caucasian male with PND due to SCLC. Onconeural antigen spreading may be promoted by two mutually non-exclusive mechanisms: (i) a switch of antigen expression pattern of the underlying tumor tissue as a result of a mutagenic process caused by the cancer itself and (ii) a self-propagated paraneoplastic immune response with persistent neuronal destruction, liberation, processing and presentation of intracellular neural antigens. This illustrates a potential dissociation between peripheral anti-tumoral immunity and central anti-neural immunity during the course of PND.

Amygdala enlargement and emotional responses in (autoimmune) temporal lobe epilepsy.

Temporal lobe epilepsy with amygdala enlargement (TLE-AE) is increasingly recognized as a distinct adult electroclinical syndrome. However, functional consequences of morphological alterations of the amygdala in TLE-AE are poorly understood. Here, two emotional stimulation designs were employed to investigate subjective emotional rating and skin conductance responses in a sample of treatment-naïve patients with suspected or confirmed autoimmune TLE-AE (n = 12) in comparison to a healthy control group (n = 16). A subgroup of patients completed follow-up measurements after treatment. As compared to healthy controls, patients with suspected or confirmed autoimmune TLE-AE showed markedly attenuated skin conductance responses and arousal ratings, especially pronounced for anxiety-inducing stimuli. The degree of right amygdala enlargement was significantly correlated with the degree of autonomic arousal attenuation. Furthermore, a decline of amygdala enlargement following prompt aggressive immunotherapy in one patient suffering from severe confirmed autoimmune TLE-AE with a very recent clinical onset was accompanied by a significant improvement of autonomic responses. Findings suggest dual impairments of autonomic and cognitive discrimination of stimulus arousal as hallmarks of emotional processing in TLE-AE. Emotional responses might, at least partially, recover after successful treatment, as implied by first single case data.

Treating refractory post-herpetic anti-N-methyl-d-aspartate receptor encephalitis with rituximab.

Herpes simplex virus-1 has been identified as the trigger factor in certain cases of NMDA-receptor autoimmune encephalitis. We report on a 67-year-old female patient, who was severely affected by post-herpetic NMDA-receptor autoimmune encephalitis. Her symptoms did not improve under methylprednisolone pulse therapy and plasma exchange under acyclovir prophylaxis. She received protein A immunoadsorption and a long-term immunosuppression with rituximab. Under treatment, activated T-cells as well as B- and plasma cells decreased in peripheral blood and cerebrospinal fluid, and anti-NMDA-R IgG titers in serum and cerebrospinal fluid declined with near complete cessation of intrathecal autoantibody synthesis. The patient regained near complete independence and profoundly improved on formal neuropsychological assessment. Despite reduction of antiviral defense through of lowered activated T cells and concomitantly decreasing HSV-specific IgG antibodies, no evidence of viral reactivation was detected.

Neurochondrin is a neuronal target antigen in autoimmune cerebellar degeneration.

OBJECTIVE: To report on a novel neuronal target antigen in 3 patients with autoimmune cerebellar degeneration. METHODS: Three patients with subacute to chronic cerebellar ataxia and controls underwent detailed clinical and neuropsychological assessment together with quantitative high-resolution structural MRI. Sera and CSF were subjected to comprehensive autoantibody screening by indirect immunofluorescence assay (IFA) and immunoblot. Immunoprecipitation with lysates of hippocampus and cerebellum combined with mass spectrometric analysis was used to identify the autoantigen, which was verified by recombinant expression in HEK293 cells and use in several immunoassays. Multiparameter flow cytometry was performed on peripheral blood and CSF, and peripheral blood was subjected to T-cell receptor spectratyping. RESULTS: Patients presented with a subacute to chronic cerebellar and brainstem syndrome. MRI was consistent with cortical and cerebellar gray matter atrophy associated with subsequent neuroaxonal degeneration. IFA screening revealed strong immunoglobulin G1 reactivity in sera and CSF with hippocampal and cerebellar molecular and granular layers, but not with a panel of 30 recombinantly expressed established neural autoantigens. Neurochondrin was subsequently identified as the target antigen, verified by IFA and immunoblot with HEK293 cells expressing human neurochondrin as well as the ability of recombinant neurochondrin to neutralize the autoantibodies' tissue reaction. Immune phenotyping revealed intrathecal accumulation and activation of B and T cells during the acute but not chronic phase of the disease. T-cell receptor spectratyping suggested an antigen-specific T-cell response accompanying the formation of antineurochondrin autoantibodies. No such neurochondrin reactivity was found in control cohorts of various neural autoantibody-associated neurologic syndromes, relapsing-remitting multiple sclerosis, cerebellar type of multiple system atrophy, hereditary cerebellar ataxias, other neurologic disorders, or healthy donors. CONCLUSION: Neurochondrin is a neuronal target antigen in autoimmune cerebellar degeneration.