Limbic Encephalitis Research Articles

Case report: Recurring potassium channel complex autoimmunity-related neuropathic pain

Voltage-gated potassium channel (VGKC) complex autoimmunity associated with nerve hyperexcitability is an uncommon clinical spectrum. It is mostly characterized by limbic encephalitis, continuous neuromyotonia, and dysautonomia. Pain, however, has rarely been reported as the first symptom. The present study describes a case of persistent neuropathic pain as the only symptom associated with a positive serum contactin-associated protein-like 2 (CASPR2) auto-antibody in a 41-year-old female patient. Her pain was completely relieved with steroids and intravenous immunoglobulin (IVIG) therapy. Nevertheless, the pain recurred 1 year later, consistent with an immunofluorescence titer of the CASPR2 antibody. Our case shows that neuropathic pain may occur as the first and only manifestation of a VGKC complex autoimmunity disorder. VGKC antibody titers might be an indication of pain severity. Steroids coupled with IVIG are effective, but relapse may still occur.

Characteristic analysis of autoimmune encephalitis with antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

The clinical data of 7 patients with anti-α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid receptor (AMPAR) encephalitis admitted to the First Affiliated Hospital of Zhengzhou University from January 2015 to January 2024 were retrospectively collected, and 87 cases with complete literature data were included for summary analysis. Seven casess exhibited limbic encephalitis, including 3 with lung cancer and 1 with thymoma. All cases were treated with glucocorticoids and/or human immunoglobulin. Four cases with concurrent tumors were followed up for 1 to 25 months and all died. Among the 94 patients (7 admitted cases and 87 documented cases), there were 76 cases with tumor (80.9%), including 33 cases of thymoma (43.4%), 23 cases of lung cancer (30.3%), 9 cases of breast cancer (11.8%), and 6 cases of ovarian tumor (7.9%). The tumor was diagnosed in 13 cases (18.8%) before encephalitis, 40 cases (58.0%) within 1 month after encephalitis, 13 cases (18.8%) within 1-6 months, 2 case (2.9%) within 6-12 months, and 1 case (1.4%) after 1 year. Compared to the 18 patients without tumors who were followed up for>1 year, the 76 patients with tumors showed an increase in age and incidence of mental disorders (both P<0.05), while follow-up time and proportion of good prognosis were decreased (both P<0.05). Closely follow-up should be conducted within 1 year after anti-AMPAR encephalitis, especially in the lungs, thymus, breast, and ovaries. The prognosis of patients with tumors is poor, and older age and mental disorders may indicate the occurrence of tumors.

Kikuchi-Fujimoto Disease Presenting as Autoimmune Limbic Encephalitis: A Case Report with Review of Literature.

Kikuchi-Fujimoto disease (KFD) is a rare benign condition associated with fever and lymphadenopathy and was first described by Kikuchi and Fujimoto independently in 1972 as histiocytic necrotizing lymphadenitis. The diagnosis is made by histopathology with immunohistochemistry. Limbic encephalitis is an extremely rare presentation of this uncommon disease, which has been described mainly in children. Available evidence is sparse in the form of case reports and case series in the form of 10 cases published till date. We report a case of an adult female with KFD with autoimmune limbic encephalitis, who had complete clinical and radiologic recovery with treatment, and a literature review of all the cases published till date.

Humoral signatures of Caspr2-antibody spectrum disorder track with clinical phenotypes and outcomes.

Immunoglobulin (Ig) G4 auto-antibodies (Abs) against contactin-associated protein-like 2 (Caspr2), a transmembrane cell adhesion protein expressed in the central and peripheral nervous system, are found in patients with a broad spectrum of neurological symptoms. While the adoptive transfer of Caspr2-specific IgG induces brain pathology in susceptible rodents, the mechanisms by which Caspr2-Abs mediate neuronal dysfunction and translate into clinical syndromes are incompletely understood. We use a systems-level approach combined with high-dimensional characterization of Ab-associated immune features to deeply profile humoral biosignatures in patients with Caspr2-Ab-associated neurological syndromes. We identify two signatures strongly associated with two major clinical phenotypes, limbic encephalitis (LE) and predominant peripheral nerve hyperexcitability without LE (non-LE). Caspr2-IgG Fc-driven pro-inflammatory features, characterized by increased binding affinities for activating Fcγ receptors (FcγRs) and C1q, along with a higher prevalence of IgG1-class Abs, in addition to IgG4, are strongly associated with LE. Both the occurrence of Caspr2-specific IgG1 and higher serum levels of interleukin (IL)-6 and IL-15, along with increased concentrations of biomarkers reflecting neuronal damage and glial cell activation, are associated with poorer clinical outcomes at 1-year follow-up. The presence of IgG1 isotypes and Fc-mediated effector functions control the pathogenicity of Caspr2-specific Abs to induce LE. Biologics targeting FcR function might potentially restrain Caspr2-Ab-induced pathology and improve clinical outcomes. This study was funded by a German-French joint research program supported by the German Research Foundation (DFG) and the Agence Nationale de la Recherche (ANR) and by the Interdisciplinary Centre for Clinical Research (IZKF) Münster.

B-076 Detection of KLHL11 Autoantibodies Using a New Cell-based Indirect Immunofluorescence Assay

Abstract Background Autoantibodies against kelch-like protein 11 (KLHL11) were first described in 2019 as markers of paraneoplastic encephalitis. Early diagnosis and treatment are imperative to improve prognosis and outcome of affected patients. Rat brain immunohistochemistry was reported to be not useful in routine screening for KLHL11 antibodies. This study evaluates the performance of a new recombinant cell-based assay for the standardized detection of KLHL11-specific IgG and reports the characteristics of the examined patients. Methods Serum (n=9), CSF (n=5) and/or plasmapheresis (n=1) samples from 10 patients with clinical presentations compatible with anti-KLHL11 encephalitis as well as sera from 100 healthy blood donors were analyzed using a prototype indirect immunofluorescence assay (IFA; EUROIMMUN) based on recombinant HEK293 cells expressing human KLHL11. Results KLHL11 autoantibodies were detected at high titers in all samples (serum &amp;gt;1:1,000; CSF &amp;gt;1:320; plasma &amp;gt;1:100,000) from all (10/10) patients but in none (0/100) of the blood donors, indicating 100% sensitivity and specificity. Anti-KLHL11-positive patients had a median age of 52 years (range 27-71) and 80% were male. The most common reported clinical presentations were cerebellar syndrome (ataxia), brainstem diencephalic encephalitis, rhombencephalitis and limbic encephalitis. Testicular or ovarian tumors were found in 87.5% (7/8) of the cases with available results from malignancy screening. Conclusions The new cell-based IFA enables the sensitive and specific detection of KLHL11 autoantibodies, thus supporting the diagnosis of patients with predominantly paraneoplastic brainstem cerebellar syndrome. Future studies will evaluate assay performance in larger patient cohorts to address the reported association of KLHL11 autoimmunity with a wider spectrum of syndromes and tumors.

AntiSox-1 Limbic Encephalitis: When A Movement Disorder Evolves Oddly And Delirium Just Does Not Feel Right

Abstract Background A 74year old male presented to a Movement Disorder service with a 15year history of a parkinsonian syndrome with asymmetric, akinetic rigidity and prominent axial features. Motor features were stable for almost 13years. Neuropsychiatric features rapidly emerged over several months including: multimodality perceptual hallucinosis, upside down and tilt illusion, akinetopsia, intractable insomnia, emotional incontinence and Othello syndrome. A marked motor, mysaesthenic pattern, deterioration occurred in conjunction with hypoactive delirium, dysphagia, pyrexias, raised inflammatory markers and weight loss, necessitating hospitalisation. Computed tomography (CT) of chest, abdomen and pelvis did not demonstrate infective or neoplastic aetiology. CT brain did not demonstrate cerebellar atrophy. Positron emission tomography did not demonstrate a vasculitis. Drg regimen alterations brought about minor improvements, but he remained very severely frail and discharged to hospice care. Unexpectedly, cognition then markedly improved and neuropsychiatric symptoms resolved over months, and he returned home, albeit now severely frail. There was persistence of hemiparkinsonian symptoms, contralateral to which, dystonia had emerged with new bilateral upper limb ataxia and nystagmus. No mysaesthenic features persisted. Methods Cerebrospinal fluid analysis and electroencephalography were not undertaken. MRI brain was not undertaken. Results Anti Sox-1 positive. Anti Zic-4 and Recoverin were equivocal. Neuronal antibodies were negative. Conclusion Limbic encephalitis as a result of AntiSox-1 onconeural antibodies is most commonly associated with small cell cancer of the lung (prevalence of 36.5% of cases). Lambert-Eaton Mysaesthenic Syndrome is a more common presentation than paraneoplastic cerebellar degeneration. Hindsight raises the possibility of non-convulsive status epilepticus as an explanation for abrupt hypoactive delirium presentation on the background of deteriorating neuropsychiatric features. Oncological or immunotherapeutic intervention was not considered appropriate by respiratory or neurology teams respectively; nor did the patient wish for these to be pursued. Case reports indicate that an underlying neoplasm is not always identified. Non-paraneoplastic autoimmune encephalitis can have a better prognosis.

Scrub Typhus Meningoencephalitis Presenting as Generalized Convulsive Status Epilepticus with Basal Ganglia and Extra-limbic Cortical Involvement, Complicated by Cortical Multifocal Myoclonus

Background Scrub typhus is an acute febrile infectious disease highly prevalent in the Asia Pacific region, often referred to as the “tsutsugamushi triangle.” This mite-borne rickettsial zoonosis is caused by Orientia tsutsugamushi, an intracellular Gram-negative organism that primarily targets endothelial cells. The resulting vasculitis leads to multisystem involvement. In terms of neurological manifestations, meningoencephalitis is the most common presentation of scrub typhus. Other frequent neurological manifestations include cranial nerve paresis, transverse myelitis, and polyneuropathy. Status epilepticus, while reported, is a rare presenting feature of this infection. Although scrub typhus has been documented to present as limbic encephalitis, there have been no previous descriptions in the literature of neuroradiological patterns affecting the basal ganglia or extra-limbic cortices in this condition. Case Report We report a case of a 23-year-old previously healthy woman who presented with scrub typhus meningoencephalitis. The condition manifested as encephalitis with involvement of the basal ganglia and extra-limbic cortices. She presented with generalized convulsive status epilepticus, which was complicated by cortical multifocal myoclonus. Discussion Scrub typhus can be a significant diagnostic challenge, potentially presenting with generalized convulsive status epilepticus and mimicking both clinical and radiological features of arboviral encephalitides, such as those caused by West Nile and Japanese encephalitis viruses. Furthermore, as demonstrated in this case, its radiological presentation can resemble that of autoimmune encephalitis. Given that scrub typhus is amenable to treatment with antibiotics, such as doxycycline and azithromycin, which do not increase seizure risk, it should be considered in the differential diagnosis for patients presenting with seizures or encephalitis, especially in endemic areas.

FDG-PET and ASL MRI identify largely overlapping hypermetabolic and hyperperfusion changes in limbic autoimmune encephalitis.

Arterial spin labeling (ASL) MRI has been anecdotally used to assess brain perfusion in autoimmune encephalitis (AE) and its relationship with [18F]FDG-PET dysmetabolism has been scarcely investigated.Considering the physiological coupling of metabolism and perfusion, we aimed to evaluate the degree of correspondence between ASL-MRI and [18F]FDG-PET in AE. A retrospective cohort of five patients underwent ASL-MRI and [18F]FDG-PET during the acute stage and at follow-up. We assessed the presence of regions with hypermetabolism on [18F]FDG-PET and hyperperfusion on ASL-MRI and evaluated concordance and spatial overlap of these metrics. Clinical assessment scale in AE and modified Rankin Scale were obtained at baseline and follow-up. In two patients [18F]FDG-PET and ASL-MRI were unremarkable; in three patients there were anatomically overlapping areas of hypermetabolism and hyperperfusion (average DICE similarity coefficient 0.358). Following immunotherapy, metabolic and perfusion changes consistently demonstrated a progressive normalization, aligning with clinical improvement. We identified suboptimal anatomical correspondence of abnormalities assessed with [18F]FDG-PET and ASL-MRI. Hyperperfusion and hypermetabolism might reflect differently AE-related pathophysiological correlates, but they both demonstrate ability to monitor disease activity. ASL-MRI is a promising marker of disease activity in AE and a favorable alternative to [18F]FDG-PET due to its cost-effectiveness, safety, and wide availability.

Decoding Multiple Antibody Positivity: Lessons from Paraneoplastic Sensory Ataxia.

Paraneoplastic neurologic syndromes are cancer-associated, immune-mediated neurologic manifestations that may involve any part of the nervous system. They usually present with characteristic neurologic features and should be considered in high-risk phenotypes such as limbic encephalitis, encephalomyelitis, rapidly progressive cerebellar syndrome, opsoclonus-myoclonus, sensory neuronopathy, enteric neuropathy, and Lambert-Eaton myasthenic syndrome. The diagnosis is made by antibody positivity in the serum or cerebrospinal fluid, in the presence of an appropriate clinical phenotype. Findings on antibody testing by immunoblot should always be verified by immunofluorescence. We report a rare case of sensory neuronopathy with triple paraneoplastic antibody positivity (anti-Hu, anti-collapsing response-mediator protein 5, and anti-amphiphysin) on immunoblot but only anti-Hu positivity on immunofluorescence. The presence of lower facial dyskinesias should raise the possibility of an immune-mediated neurologic syndrome in the appropriate clinical context.

Difficulties in differential diagnosis of glial tumors and limbic encephalitis: literature data, clinical observations

Difficulties in differential diagnosis of glial tumors and limbic encephalitis: literature data, clinical observations

Diagnostic Performance of ASL-MRI and FDG-PET in Frontotemporal Dementia: A Systematic Review and Meta-Analysis.

While the diagnosis of frontotemporal dementia (FTD) is based mostly on clinical features, [18F]-FDG PET has been investigated as a potential imaging golden standard in ambiguous cases, with arterial spin labeling (ASL) MRI gaining recent interest. The purpose of this study is to conduct a systematic review and meta-analysis on the diagnostic performance of ASL MRI in FTD patients and compare it to that of [18F]-FDG PET. A systematic search of PubMed, Scopus and EMBASE was conducted until March 13, 2024. Inclusion criteria were: original articles, patients with FTD and/or its variants, use of ASL MR perfusion imaging with or without [18F]-FDG PET, presence of sufficient diagnostic performance data. Exclusion criteria were: meeting abstracts, comments, summaries, protocols, letters and guidelines, longitudinal studies, overlapping cohorts. The quality of eligible studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2. Pooled sensitivity, specificity, and diagnostic odds ratio (DOR) for [18F]-FDG PET and ASL MRI were calculated, and a summary receiver operating characteristic curve was plotted. Seven eligible studies were identified, which included a total of 102 FTD patients. Aside from some of the studies showing at worst an unclear risk of bias in patient selection, index test, flow and timing, all studies showed low risk of bias and applicability concerns in all categories. Data from 4 studies was included in our meta-analysis for ASL MRI and 3 studies for [18F]-FDG PET. Pooled sensitivity, specificity and DOR were 0.70 (95% CI: 0.59-0.79), 0.81 (95% CI: 0.71-0.88) and 8.00 (95% CI: 3.74-17.13) for ASL MRI, and 0.88 (95% CI: 0.71-0.96), 0.89 (95% CI: 0.43-0.99) and 47.18 (95% CI: 10.77-206.75) for [18F]-FDG PET. The number of studies was relatively small, with a small sample size. The studies used different scanning protocols as well as a mix of diagnostic metrics, all of which might have introduced heterogeneity in the data. While ASL MRI performed worse than [18F]-FDG PET in the diagnosis of FTD, it exhibited a decent diagnostic performance to justify its further investigation as a quicker and more convenient alternative. 3DPCASL, 3D pseudocontinuous ASL; AD, Alzheimer's disease; ASL, arterial spin labeling; AUC, area under the curve; CI, confidence interval; DOR, diagnostic odds ratio; FN, false negative; FP, false positive; FTD, frontotemporal dementia; LE, limbic encephalitis; NLR, negative likelihood ratio; PASL, pulsed ASL; PLD, post-label delay; PLR, positive likelihood ratio; PRISMA, PSP, progressive supranuclear palsy; Preferred Reporting Items for Systematic Reviews and Meta-Analysis; SROC, summary receiver operative characteristic; TN, true negative; TP, true positive; QUADAS-2, Quality Assessment of Diagnostic Accuracy Studies-2.

Review of Diagnostic Challenges and Literature Data in Paraneoplastic Limbic Encephalitis: A Case Presentation

Abstract Paraneoplastic limbic encephalitis is a rare condition reported in practice. It is most commonly associated with small cell lung cancer (SCLC). This case report is offered to aid physicians in making informed decisions about timing and type of treatment and is evident, that quick diagnosis is critical for both, neurologists and oncologists. The presentation reviews the case of a female patient diagnosed with limbic encephalitis. Further research is needed to establish clinical, laboratory and instrumental criteria that may be related to outcomes. The purpose of this paper is to present the potential repercussions of a delayed diagnosis and highlight the beneficial results of specific investigations and symptomatic therapy. Comprehensive familiarity with clinical presentations and the limitations of current diagnostic procedures is imperative for neurologists. Equally essential is this understanding for radiologists, serving as the basis for accurate diagnostic analyses derived from imaging findings. The intricate nature of neurological disorders sometimes necessitates the cooperation of neurologists, radiologists, and, in this particular instance, oncologists, in order to achieve precise diagnosis and develop successful treatment approaches.

Stiff Person Syndrome and GAD Antibody-Spectrum Disorders.

Antibodies against glutamic acid decarboxylase (GAD), originally associated with stiff person syndrome (SPS), define the GAD antibody-spectrum disorders that also include cerebellar ataxia, autoimmune epilepsy, limbic encephalitis, progressive encephalomyelitis with rigidity and myoclonus (PERM), and eye movement disorders, all of which are characterized by autoimmune neuronal excitability. This article elaborates on the diagnostic criteria for SPS and SPS spectrum disorders, highlights disease mimics and misdiagnoses, describes the electrophysiologic mechanisms and underlying autoimmunity of stiffness and spasms, and provides a step-by-step therapeutic scheme. Very-high serum GAD antibody titers are diagnostic for GAD antibody-spectrum disorders and also predict the presence of GAD antibodies in the CSF, increased intrathecal synthesis, and reduced CSF γ-aminobutyric acid (GABA) levels. Low serum GAD antibody titers or the absence of antibodies generates diagnostic challenges that require careful distinction in patients with a variety of painful spasms and stiffness, including functional neurologic disorders. Antibodies against glycine receptors, first found in patients with PERM, are seen in 13% to 15% of patients with SPS, whereas amphiphysin and gephyrin antibodies, seen in 5% of patients with SPS spectrum disorders, predict a paraneoplastic association. GAD-IgG from different SPS spectrum disorders recognizes the same dominant GAD intracellular epitope and, although the pathogenicity is unclear, is an excellent diagnostic marker. The biological basis of muscle stiffness and spasms is related to autoimmune neuronal hyperexcitability caused by impaired reciprocal γ-aminobutyric acid-mediated (GABA-ergic) inhibition, which explains the therapeutic response to GABA-enhancing agents and immunotherapies. It is essential to distinguish SPS spectrum disorders from disease mimics to avoid both overdiagnoses and misdiagnoses, considering that SPS is treatable if managed correctly from the outset to prevent disease progression. A step-by-step, combination therapy of GABA-enhancing medications along with immunotherapies ensures prolonged clinical benefits.

Relapsing meningitis and limbic encephalitis in anti-AQP4-Ab-associated neuromyelitis optica spectrum disorder.

neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease mainly affecting optic nerves and the spinal cord. Due to the potentially irreversible tissue damage, prevention of relapses is of utmost importance. We describe the atypical clinical course and pathology results of a patient with anti-aquaporin-4 antibody (anti-AQP4-Ab)-associated NMOSD who developed aseptic meningitis followed by limbic-encephalitis-like presentation with extensive brain lesions upon treatment with rituximab and tocilizumab. The patient developed subacute cognitive decline with magnetic resonance imaging (MRI) evidence of extensive brain white matter lesions. In the hypothesis of an opportunistic brain infection, she underwent brain biopsy of the temporal pole. Pathology results revealed typical NMOSD findings with complement activation, supporting the hypothesis of an atypical presentation of anti-AQP-Ab-associated NMOSD. Accordingly, treatment with the complement-targeting drug eculizumab was started, leading to a dramatic clinical and MRI improvement. aseptic meningitis and limbic encephalitis could represent a rare phenotype of anti-AQP4-Ab-associated NMOSD.

Diagnostic and prognostic biomarkers in immune checkpoint inhibitor-related encephalitis: a retrospective cohort study

Immune checkpoint inhibitor-related encephalitis (ICI-encephalitis) is not well characterised and diagnostic and prognostic biomarkers are lacking. We aimed to comprehensively characterise ICI-encephalitis and identify diagnostic biomarkers and outcome predictors. This retrospective observational study included all patients with ICI-encephalitis studied in the French Reference Centre on Paraneoplastic Neurological Syndromes (PNS) and Autoimmune Encephalitis (2015-2023). ICI encephalitis was considered definite in case of inflammatory findings at paraclinical tests and/or well-characterised neural antibodies. Predictors of immune-related adverse event (irAE) treatment response, defined as a Common Terminology Criteria for Adverse Events v5.0 grade<3at any time after therapeutic intervention, were assessed by logistic regression analysis, and predictors of mortality by Cox regression analysis. Neurofilament light chain (NfL) was measured by enzyme-linked immunosorbent assay. Sixty-seven patients with definite encephalitis were identified (median age, 69 years; 66% male). A focal syndrome was observed in 43/67 patients (64%; limbic encephalitis, cerebellar ataxia, and/or brainstem encephalitis), while 24/67 (36%) had meningoencephalitis, a non-focal syndrome with altered mental status (22/24 patients, 92%) and pleocytosis (24/24 patients, 100%). Patients with focal encephalitis more frequently had abnormal brain MRI (26/42, 62% versus 8/24, 33%, p=0.025), PNS-related antibodies (36/43, 84% versus 1/24, 4%, p<0.001), and neuroendocrine cancers (22/43, 51% versus 1/24, 4%; p<0.001) than patients with meningoencephalitis. Focal encephalitis patients had a lower rate of irAE treatment response (7/39, 18%) and higher mortality (27/43, 63%) compared to meningoencephalitis patients (12/22, 77% and 5/24, 21%, respectively, p<0.001 each). PNS-related antibodies were associated with less irAE treatment response, independently of age, sex, and baseline severity (adjusted OR 0.05; 95%CI [0.01; 0.19]; p<0.001) as well as higher mortality, independently of age and cancer type (adjusted HR 5.07; 95% CI [2.12; 12.12]; p<0.001). Serum NfL discriminated patients with definite ICI-encephalitis (n=27) from cancer-matched controls (n=16; optimal cut-off >273.5pg/mL, sensitivity 81%, specificity 88%, AUC 0.87, 95% CI [0.76; 0.98]) and irAE treatment responders (n=10) from non-responders (n=17, optimal cut-off >645pg/mL, sensitivity 90%, specificity 65%; AUC 0.75, 95% CI [0.55; 0.94]). ICI-encephalitis corresponds to a set of clinically-recognisable syndromes. Patients with focal encephalitis, PNS-related antibodies, and/or higher serum NfL have low irAE treatment response rates. Research is needed on the underlying immunopathogenesis to foster therapeutic innovations. Agence Nationale de la Recherche.

Human stem cell-derived neurons and astrocytes to detect novel auto-reactive IgG response in immune-mediated neurological diseases.

Up to 46% of patients with presumed autoimmune limbic encephalitis are seronegative for all currently known central nervous system (CNS) antigens. We developed a cell-based assay (CBA) to screen for novel neural antibodies in serum and cerebrospinal fluid (CSF) using neurons and astrocytes derived from human-induced pluripotent stem cells (hiPSCs). Human iPSC-derived astrocytes or neurons were incubated with serum/CSF from 99 patients [42 with inflammatory neurological diseases (IND) and 57 with non-IND (NIND)]. The IND group included 11 patients with previously established neural antibodies, six with seronegative neuromyelitis optica spectrum disorder (NMOSD), 12 with suspected autoimmune encephalitis/paraneoplastic syndrome (AIE/PNS), and 13 with other IND (OIND). IgG binding to fixed CNS cells was detected using fluorescently-labeled antibodies and analyzed through automated fluorescence measures. IgG neuronal/astrocyte reactivity was further analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMCs) were used as CNS-irrelevant control target cells. Reactivity profile was defined as positive using a Robust regression and Outlier removal test with a false discovery rate at 10% following each individual readout. Using our CBA, we detected antibodies recognizing hiPSC-derived neural cells in 19/99 subjects. Antibodies bound specifically to astrocytes in nine cases, to neurons in eight cases, and to both cell types in two cases, as confirmed by microscopy single-cell analyses. Highlighting the significance of our comprehensive 96-well CBA assay, neural-specific antibody binding was more frequent in IND (15 of 42) than in NIND patients (4 of 57) (Fisher's exact test, p = 0.0005). Two of four AQP4+ NMO and four of seven definite AIE/PNS with intracellular-reactive antibodies [1 GFAP astrocytopathy, 2 Hu+, 1 Ri+ AIE/PNS)], as identified in diagnostic laboratories, were also positive with our CBA. Most interestingly, we showed antibody-reactivity in two of six seronegative NMOSD, six of 12 probable AIE/PNS, and one of 13 OIND. Flow cytometry using hiPSC-derived CNS cells or PBMC-detected antibody binding in 13 versus zero patients, respectively, establishing the specificity of the detected antibodies for neural tissue. Our unique hiPSC-based CBA allows for the testing of novel neuron-/astrocyte-reactive antibodies in patients with suspected immune-mediated neurological syndromes, and negative testing in established routine laboratories, opening new perspectives in establishing a diagnosis of such complex diseases.

Expression of mGluR5 in Pediatric Hodgkin and Non-Hodgkin lymphoma-A Comparative Analysis of Immunohistochemical and Clinical Findings Regarding the Association between Tumor and Paraneoplastic Neurological Disease.

Autoantibodies targeting the neuronal antigen metabotropic glutamate receptor 5 (mGluR5) have been identified in patients with Ophelia syndrome, which describes a co-occurrence of paraneoplastic limbic encephalitis and Hodgkin lymphoma (HL). Little data exist regarding frequency and function of mGluR5 in HL and its potential role in causing seropositive paraneoplastic disease. We studied a representative cohort of pediatric HL and NHL patients (n = 57) using immunohistochemistry and fluorescence staining to investigate mGluR5 expression. All lymphoma tissues displayed positive mGluR5 staining, with focus on Hodgkin-Reed-Sternberg (H-RS) cells. We did not detect any mGluR5 staining in tumor-free lymph nodes, which is consistent with the absence of GRM5 transcripts in RNA-sequencing data from non-malignant B and T cells. The frequent presence in pediatric lymphoma falls in line with reports of mGluR5 expression and associated tumor progression in other malignancies. We tested for correlation with clinical features, focusing on disease progression and neurological symptoms. Low mGluR5 expression in H-RS cells correlated with young patient age (<15 years) and positive histology for EBV infection. Paraneoplastic or neurological symptoms were found exclusively in HL patients. While an impact of mGluR5 on HL severity remains possible, a prognostic value of mGluR5 expression levels requires further investigation.

(Auto)immunity in focal epilepsy: mechanisms of (auto‑)immune-inflammatory epileptogenic neurodegeneration

While the neuronal mechanisms of epileptic hyperexcitability (HE) have been studied in detail, recent findings suggest that extraneuronal, mainly immune-mediated inflammatory and vascular mechanisms play an important role in the development and progression of HE in epilepsy and the cognitive and behavioral comorbidities. Narrative review. As in autoimmune (limbic) encephalitis (ALE/AIE) or Rasmussen's encephalitis (RE), the primary adaptive and innate immune responses and associated changes in the blood-brain barrier (BBB) and neurovascular unit (NVU) can cause acute cortical hyperexcitability (HE) and the development of hippocampal sclerosis (HS) and other structural cortical lesions with chronic HE. Cortical HE, which is associated with malformation of cortical development (MCD) and low-grade epilepsy-associated tumors (LEAT), for example, can be accompanied by secondary adaptive and innate immune responses and alterations in the BBB and NVU, potentially modulating the ictogenicity and epileptogenicity. These associations illustrate the influence of adaptive and innate immune mechanisms and associated changes in the BBB and NVU on cortical excitability and vice versa, suggesting adynamic and complex interplay of these factors in the development and progression of epilepsy in general. The described concept of a neuro-immune-vascular interaction in focal epilepsy opens up new possibilities for the pathogenetic understanding and thus also for the selective therapeutic intervention.

Exploring the diverse phenotypes of anti-GAD 65 encephalitis, diagnosis and treatment challenges

Objectives. To present two cases of anti-glutamic acid decarboxylase 65 (anti-GAD65) antibody encephalitis with different clinical phenotypes. Introduction. Anti-glutamic acid decarboxylase 65 antibody encephalitis (GAD-65 AE) is a rare pathology with a high potential for severity, having multiple forms of presentation and multiple differential diagnoses. This presentation aims to exemplify the strong clinical heterogeneity that is associated with this clinical entity by putting forth two cases that were treated in our clinic, each representing a separate clinical phenotype of this pathology. Material and methods. We analyzed two cases from our clinic of autoimmune encephalitis with positive anti-GAD65 antibodies and compared the cases with the data from the literature regarding clinical presentation, differential diagnosis, treatment, and evolution. Content. The first case presented is a woman aged 71 (66 at onset) presenting with progressive cerebellar ataxia. She was diagnosed with GAD-65 AE based on clinical presentation and positive anti-GAD65 antibodies titer. She was initially treated with methylprednisolone pulse therapy and received four such courses in the first year after diagnosis, resulting in a slowing of the progression of the neurological deficit. During the COVID19 pandemic, treatment was paused and her neurological status resumed its decline, and she also developed insulin-dependent diabetes mellitus. Starting in 2021, treatment was continued, having received one course of IVIg and one course of plasma exchange in our clinic. Eventually, the treatment was switched to Mycophenolate mofetil but her status continues to decline. The second case is about a 32 years old woman, with a history of recurrent seizures and progressive memory decline that started at 28 years. She was diagnosed 11 months after the onset with limbic encephalitis with anti-GAD65 antibodies, left temporal focal epilepsy with nocturnal seizures and mild cognitive decline. She was treated with corticotherapy and IgG. She was discharged home with antiepileptic treatment with no recurring seizures, but a slow cognitive decline. She had two relapses at distance from the onset, the first one with status epilepticus and the second one with focal seizures and a generalized seizure. She developed type I diabetes with positive anti-pancreatic islet antibodies. After the first relapse, immunosuppressive therapy with Mycophenolate mofetil was initiated. The evolution was good and under immunosuppression she had only one episode of seizures in the context of a COVID-19 infection. Conclusions. Autoimmune encephalitis with positive GAD antibodies presents a very diverse clinical picture, as we can see in the presented cases.

Anti-LGI1 Autoimmune Encephalitis in a Patient with Rheumatoid Arthritis and MGUS.

Anti-leucine-rich glioma inactivated 1 limbic encephalitis (anti-LGI1 LE) is one of the most frequent autoimmune encephalitis, commonly coexisting with other autoimmune diseases. Rheumatoid arthritis (RA) and monoclonal gammopathy of unknown significance (MGUS) are commonly associated with autoimmune phenomena. However, neither RA nor MGUS have been described in the literature to date as coexisting with anti-LGI1 LE. We present the case of anti-LGI1 LE in a male patient with rheumatoid arthritis, who was also found to have an MGUS. The patient was initially treated with corticosteroids and IV immunoglobulin. After a mild relapse, his treatment was complemented with rituximab, resulting in complete regression of the disease symptoms. Our report provides evidence for the coexistence of anti-LGI1 LE with RA and/or MGUS, thus extending the differential diagnosis of patients suffering with these disease entities that present with neuropsychiatric symptoms suggestive of encephalitis. Moreover, this case raises challenges on the management of the coexistence of these diseases, given the lack of therapeutic guidelines and their potential interaction on a pathophysiological and a clinical level. In a patient with known autoimmune or malignant background who presents with neuropsychiatric symptoms, after excluding infectious encephalitis or central nervous system involvement in the primary disease condition, autoimmune limbic encephalitis (LE) should also be considered.In a patient diagnosed with anti-LGI1 LE there should be an extensive check for coexisting occult pre-malignant conditions, even for months after disease presentation.Clinical management and treatment options of anti-LGI1 LE when coexisting with other autoimmune or pre-malignant conditions can be challenging; thus, more research is needed towards that direction.