Novel risk loci in LGI1-antibody encephalitis: genome-wide association study discovery and validation cohorts.

Encephalitis with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E) is a common form of autoimmune encephalitis, presenting with seizures and neuropsychiatric changes, predominantly in older males. More than 90% of patients carry the human leucocyte antigen (HLA) class II allele, HLA-DRB1*07:01. However, this is also present in 25% of healthy controls. Therefore, we hypothesised the presence of additional genetic predispositions. In this genome-wide association study and meta-analysis, we studied a discovery cohort of 131 French LGI1-Ab-E and a validation cohort of 126 American, British and Irish LGI1-Ab-E patients, ancestry-matched to 2613 and 2538 European controls, respectively. Outside the known major HLA signal, we found two single nucleotide polymorphisms (SNPs) at genome-wide significance (p < 5 x 10-8), implicating PTPRD, a protein tyrosine phosphatase, and LINC00670, a non-protein coding RNA gene. Meta-analysis defined four additional non-HLA loci, including the protein coding COBL gene. Polygenic risk scores with and without HLA variants proposed a contribution of non-HLA loci. In silico network analyses suggested LGI1 and PTPRD mediated interactions via the established receptors of LGI1, ADAM22 and ADAM23. Our results identify new genetic loci in LGI1-Ab-E. These findings present opportunities for mechanistic studies and offer potential markers of susceptibility, prognostics and therapeutic responses.

B cell and aquaporin-4 antibody relationships with neuromyelitis optica spectrum disorder activity.

This post hoc analysis of the randomized, placebo-controlled N-MOmentum study (NCT02200770) of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD) evaluated relationships between circulating B-cell subsets and aquaporin-4 immunoglobulin G (AQP4-lgG) titers and attacks. Among participants receiving placebo, CD20+ and CD27+ B-cell counts were modestly increased from the pre-attack visit to attack; plasmablast/plasma cell gene signature was increased from baseline to the pre-attack visit (p = 0.016) and from baseline to attack (p = 0.009). With inebilizumab treatment, B-cell subset counts decreased and did not increase with attacks. No difference in change of AQP4-IgG titers from baseline to time of attack was observed.

LGI1 Autoantibodies Enhance Synaptic Transmission by Presynaptic Kv1 Loss and Increased Action Potential Broadening.

BACKGROUND AND OBJECTIVES: Autoantibodies against the protein leucine-rich glioma inactivated 1 (LGI1) cause the most common subtype of autoimmune encephalitis with predominant involvement of the limbic system, associated with seizures and memory deficits. LGI1 and its receptor ADAM22 are part of a transsynaptic protein complex that includes several proteins involved in presynaptic neurotransmitter release and postsynaptic glutamate sensing. Autoantibodies against LGI1 increase excitatory synaptic strength, but studies that genetically disrupt the LGI1-ADAM22 complex report a reduction in postsynaptic glutamate receptor-mediated responses. Thus, the mechanisms underlying the increased synaptic strength induced by LGI1 autoantibodies remain elusive, and the contributions of presynaptic molecules to the LGI1-transsynaptic complex remain unclear. We therefore investigated the presynaptic mechanisms that mediate autoantibody-induced synaptic strengthening. METHODS: We studied the effects of patient-derived purified polyclonal LGI1 autoantibodies on synaptic structure and function by combining direct patch-clamp recordings from presynaptic boutons and somata of hippocampal neurons with super-resolution light and electron microscopy of hippocampal cultures and brain slices. We also identified the protein domain mediating the presynaptic effect using domain-specific patient-derived monoclonal antibodies. RESULTS: LGI1 autoantibodies dose-dependently increased short-term depression during high-frequency transmission, consistent with increased release probability. The increased neurotransmission was not related to presynaptic calcium channels because presynaptic Cav2.1 channel density, calcium current amplitude, and calcium channel gating were unaffected by LGI1 autoantibodies. By contrast, application of LGI1 autoantibodies homogeneously reduced Kv1.1 and Kv1.2 channel density on the surface of presynaptic boutons. Direct presynaptic patch-clamp recordings revealed that LGI1 autoantibodies cause a pronounced broadening of the presynaptic action potential. Domain-specific effects of LGI1 autoantibodies were analyzed at the neuronal soma. Somatic action potential broadening was induced by polyclonal LGI1 autoantibodies and patient-derived monoclonal autoantibodies targeting the epitempin domain, but not the leucin-rich repeat domain. DISCUSSION: Our results indicate that LGI1 autoantibodies reduce the density of both Kv1.1 and Kv1.2 on presynaptic boutons, without actions on calcium channel density or function, thereby broadening the presynaptic action potential and increasing neurotransmitter release. This study provides a molecular explanation for the neuronal hyperactivity observed in patients with LGI1 autoantibodies.

Autoimmune Encephalitis.

OBJECTIVE: This article focuses on the clinical features and diagnostic evaluations that accurately identify patients with ever-expanding forms of antibody-defined encephalitis. Forms of autoimmune encephalitis are more prevalent than infectious encephalitis and represent treatable neurologic syndromes for which early immunotherapies lead to the best outcomes. LATEST DEVELOPMENTS: A clinically driven approach to identifying many autoimmune encephalitis syndromes is feasible, given the typically distinctive features associated with each antibody. Patient demographics alongside the presence and nature of seizures, cognitive impairment, psychiatric disturbances, movement disorders, and peripheral features provide a valuable set of clinical tools to guide the detection and interpretation of highly specific antibodies. In turn, these clinical features in combination with serologic findings and selective paraclinical testing, direct the rationale for the administration of immunotherapies. Observational studies provide the mainstay of evidence guiding first- and second-line immunotherapy administration in autoimmune encephalitis and, whereas these typically result in some clinical improvements, almost all patients have residual neuropsychiatric deficits, and many experience clinical relapses. An improved pathophysiologic understanding and ongoing clinical trials can help to address these unmet medical needs. ESSENTIAL POINTS: Antibodies against central nervous system proteins characterize various autoimmune encephalitis syndromes. The most common targets include leucine-rich glioma inactivated protein 1 (LGI1), N-methyl-d-aspartate (NMDA) receptors, contactin-associated proteinlike 2 (CASPR2), and glutamic acid decarboxylase 65 (GAD65). Each antibody-associated autoimmune encephalitis typically presents with a recognizable blend of clinical and investigation features, which help differentiate each from alternative diagnoses. The rapid expansion of recognized antibodies and some clinical overlaps support panel-based antibody testing. The clinical-serologic picture guides the immunotherapy regime and offers valuable prognostic information. Patient care should be delivered in conjunction with autoimmune encephalitis experts.

Autoantibody-mediated central nervous system channelopathies.

The autoimmune channelopathies represent a rapidly evolving scientific and clinical domain. The description of channels, expressed on neurons and glia, as targets of autoantibodies in neuromyelitis optica, autoimmune encephalitis, and related syndromes have revolutionized many areas of neurologic practice. To date, tens of surface antibody specificities have been described, a number that is likely to continue to increase. A central paradigm for all these disorders is that of pathogenic autoantibodies which target extracellular epitopes accessible for binding in vivo. Hence, in these disorders, the autoantibodies are causative diagnostic tools, and provide valuable reagents to model the diseases. Their production by B-lineage cells provides opportunities to study and modulate their production. Across these syndromes, early recognition and treatment are critical since most respond to immunotherapies. Yet, several unmet medical needs persist within treated patient populations, and widespread clinical under-recognition remains a challenge. In this review, we summarize the neuroscience and immunologic basis of autoantibody-mediated central nervous system channelopathies, the molecular effects of the autoantibodies, clinical phenotypes, and treatment approaches. We describe progress since the inauguration of the field through to open questions and potential future directions.

Innovation and optimization in autoimmune encephalitis trials: the design and rationale for the Phase 3, randomized study of satralizumab in patients with NMDAR-IgG-antibody-positive or LGI1-IgG-antibody-positive autoimmune encephalitis (CIELO).

Background: Autoimmune encephalitis (AIE) encompasses a spectrum of rare autoimmune-mediated neurological disorders, which are characterized by brain inflammation and dysfunction. Autoantibodies targeting the N-methyl-d-aspartic acid receptor (NMDAR) and leucine-rich glioma-inactivated 1 (LGI1) are the most common subtypes of antibody-positive AIE. Currently, there are no approved therapies for AIE. Interleukin-6 (IL-6) signaling plays a role in the pathophysiology of AIE. Satralizumab, a humanized, monoclonal recycling antibody that specifically targets the IL-6 receptor and inhibits IL-6 signaling, has demonstrated efficacy and safety in another autoantibody-mediated neuroinflammatory disease, aquaporin-4 immunoglobulin G antibody-positive neuromyelitis optica spectrum disorder, and has the potential to be an evidence-based disease modifying treatment in AIE. Objectives: CIELO will evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics of satralizumab compared with placebo in patients with NMDAR-immunoglobulin G antibody-positive (IgG+) or LGI1-IgG+ AIE. Study design: CIELO (NCT05503264) is a prospective, Phase 3, randomized, double-blind, multicenter, basket study that will enroll approximately 152 participants with NMDAR-IgG+ or LGI1-IgG+ AIE. Prior to enrollment, participants will have received acute first-line therapy. Part 1 of the study will consist of a 52-week primary treatment period, where participants will receive subcutaneous placebo or satralizumab at Weeks 0, 2, 4, and every 4 weeks thereafter. Participants may continue to receive background immunosuppressive therapy, symptomatic treatment, and rescue therapy throughout the study. Following Part 1, participants can enter an optional extension period (Part 2) to continue the randomized, double-blind study drug, start open-label satralizumab, or stop study treatment and continue with follow-up assessments. Endpoints: The primary efficacy endpoint is the proportion of participants with a ≥1-point improvement in the modified Rankin Scale (mRS) score from study baseline and no use of rescue therapy at Week 24. Secondary efficacy assessments include mRS, Clinical Assessment Scale of Autoimmune Encephalitis (CASE), time to rescue therapy, sustained seizure cessation and no rescue therapy, Montreal Cognitive Assessment, and Rey Auditory Verbal Learning Test (RAVLT) measures. Safety, pharmacokinetics, pharmacodynamics, exploratory efficacy, and biomarker endpoints will be captured. Conclusion: The innovative basket study design of CIELO offers the opportunity to yield prospective, robust evidence, which may contribute to the development of evidence-based treatment recommendations for satralizumab in AIE.

Distinct plasma metabolomic signatures differentiate autoimmune encephalitis from drug-resistant epilepsy.

OBJECTIVE: Differentiating forms of autoimmune encephalitis (AE) from other causes of seizures helps expedite immunotherapies in AE patients and informs studies regarding their contrasting pathophysiology. We aimed to investigate whether and how Nuclear Magnetic Resonance (NMR)-based metabolomics could differentiate AE from drug-resistant epilepsy (DRE), and stratify AE subtypes. METHODS: This study recruited 238 patients: 162 with DRE and 76 AE, including 27 with contactin-associated protein-like 2 (CASPR2), 29 with leucine-rich glioma inactivated 1 (LGI1) and 20 with N-methyl-d-aspartate receptor (NMDAR) antibodies. Plasma samples across the groups were analyzed using NMR spectroscopy and compared with multivariate statistical techniques, such as orthogonal partial least squares discriminant analysis (OPLS-DA). RESULTS: The OPLS-DA model successfully distinguished AE from DRE patients with a high predictive accuracy of 87.0 ± 3.1% (87.9 ± 3.4% sensitivity and 86.3 ± 3.6% specificity). Further, pairwise OPLS-DA models were able to stratify the three AE subtypes. Plasma metabolomic signatures of AE included decreased high-density lipoprotein (HDL, -(CH2)n-, -CH3), phosphatidylcholine and albumin (lysyl moiety). AE subtype-specific metabolomic signatures were also observed, with increased lactate in CASPR2, increased lactate, glucose, and decreased unsaturated fatty acids (UFA, -CH2CH=) in LGI1, and increased glycoprotein A (GlycA) in NMDAR-antibody patients. INTERPRETATION: This study presents the first non-antibody-based biomarker for differentiating DRE, AE and AE subtypes. These metabolomics signatures underscore the potential relevance of lipid metabolism and glucose regulation in these neurological disorders, offering a promising adjunct to facilitate the diagnosis and therapeutics.

HLA and KIR genetic association and NK cells in anti-NMDAR encephalitis.

Introduction: Genetic predisposition to autoimmune encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDAR) is poorly understood. Given the diversity of associated environmental factors (tumors, infections), we hypothesized that human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptors (KIR), two extremely polymorphic gene complexes key to the immune system, might be relevant for the genetic predisposition to anti-NMDAR encephalitis. Notably, KIR are chiefly expressed by Natural Killer (NK) cells, recognize distinct HLA class I allotypes and play a major role in anti-tumor and anti-infection responses. Methods: We conducted a Genome Wide Association Study (GWAS) with subsequent control-matching using Principal Component Analysis (PCA) and HLA imputation, in a multi-ethnic cohort of anti-NMDAR encephalitis (n=479); KIR and HLA were further sequenced in a large subsample (n=323). PCA-controlled logistic regression was then conducted for carrier frequencies (HLA and KIR) and copy number variation (KIR). HLA-KIR interaction associations were also modeled. Additionally, single cell sequencing was conducted in peripheral blood mononuclear cells from 16 cases and 16 controls, NK cells were sorted and phenotyped. Results: Anti-NMDAR encephalitis showed a weak HLA association with DRB1*01:01~DQA1*01:01~DQB1*05:01 (OR=1.57, 1.51, 1.45; respectively), and DRB1*11:01 (OR=1.60); these effects were stronger in European descendants and in patients without an underlying ovarian teratoma. More interestingly, we found increased copy number variation of KIR2DL5B (OR=1.72), principally due to an overrepresentation of KIR2DL5B*00201. Further, we identified two allele associations in framework genes, KIR2DL4*00103 (25.4% vs. 12.5% in controls, OR=1.98) and KIR3DL3*00302 (5.3% vs. 1.3%, OR=4.44). Notably, the ligands of these KIR2DL4 and KIR3DL3, respectively, HLA-G and HHLA2, are known to act as immune checkpoint with immunosuppressive functions. However, we did not find differences in specific KIR-HLA ligand interactions or HLA-G polymorphisms between cases and controls. Similarly, gene expression of CD56dim or CD56bright NK cells did not differ between cases and controls. Discussion: Our observations for the first time suggest that the HLA-KIR axis might be involved in anti-NMDAR encephalitis. While the genetic risk conferred by the identified polymorphisms appears small, a role of this axis in the pathophysiology of this disease appears highly plausible and should be analyzed in future studies.

Risk of Seizure Recurrence Due to Autoimmune Encephalitis With NMDAR, LGI1, CASPR2, and GABABR Antibodies: Implications for Return to Driving.

BACKGROUND AND OBJECTIVES: Patients with ongoing seizures are usually not allowed to drive. The prognosis for seizure freedom is favorable in patients with autoimmune encephalitis (AIE) with antibodies against NMDA receptor (NMDAR), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and the gamma-aminobutyric-acid B receptor (GABABR). We hypothesized that after a seizure-free period of 3 months, patients with AIE have a seizure recurrence risk of <20% during the subsequent 12 months. This would render them eligible for noncommercial driving according to driving regulations in several countries. METHODS: This retrospective multicenter cohort study analyzed follow-up data from patients aged 15 years or older with seizures resulting from NMDAR-, LGI1-, CASPR2-, or GABABR-AIE, who had been seizure-free for ≥3 months. We used Kaplan-Meier (KM) estimates for the seizure recurrence risk at 12 months for each antibody group and tested for the effects of potential covariates with regression models. RESULTS: We included 383 patients with NMDAR-, 440 with LGI1-, 114 with CASPR2-, and 44 with GABABR-AIE from 14 international centers. After being seizure-free for 3 months after an initial seizure period, we calculated the probability of remaining seizure-free for another 12 months (KM estimate) as 0.89 (95% confidence interval [CI] 0.85-0.92) for NMDAR, 0.84 (CI 0.80-0.88) for LGI1, 0.82 (CI 0.75-0.90) for CASPR2, and 0.76 (CI 0.62-0.93) for GABABR. DISCUSSION: Taking a <20% recurrence risk within 12 months as sufficient, patients with NMDAR-AIE and LGI1-AIE could be considered eligible for noncommercial driving after having been seizure-free for 3 months.

N-Methyl-D-Aspartate Receptor-Antibody Encephalitis Impairs Maintenance of Attention to Items in Working Memory.

NMDA receptors (NMDARs) may be crucial to working memory (WM). Computational models predict that they sustain neural firing and produce associative memory, which may underpin maintaining and binding information, respectively. We test this in patients with antibodies to NMDAR (n = 10, female) and compare them with healthy control participants (n = 55, 20 male, 35 female). Patients were tested after recovery with a task that separates two aspects of WM: sustaining attention and feature binding. Participants had to remember two colored arrows. Then attention was directed to one of them. After a variable delay, they reported the direction of either the same arrow (congruent cue) or of the other arrow (incongruent cue). We asked how congruency affected recall precision and measured types of error. Patients had difficulty in both sustaining attention to an item over time and feature binding. Controls were less precise after longer delays and incongruent cues. In contrast, patients did not benefit from congruent cues at longer delays [group × congruency (long condition); p = 0.041], indicating they could not sustain attention. Additionally, patients reported the wrong item (misbinding errors) more than controls after congruent cues [group × delay (congruent condition), main effect of group; p ≤ 0.001]. Our results suggest NMDARs are critical for both maintaining attention and feature binding.

Social Vulnerability and Receipt of Neoadjuvant Chemotherapy in Patients Undergoing Radical Cystectomy for Bladder Cancer.

OBJECTIVE: To evaluate the association between a population-level measure of social determinants of health, the Centers for Disease Control and Prevention Social Vulnerability Index (SVI), and receipt of neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer (MIBC) undergoing radical cystectomy. METHODS: We queried our institutional database for patients with nonmetastatic MIBC treated with radical cystectomy between 2000 and 2022. Patients were assigned an SVI via ZIP code of residence and grouped into quintiles of SVI (ie, least vulnerable to most vulnerable). Multivariable logistic regression was performed to evaluate the association between SVI and receipt of neoadjuvant chemotherapy, adjusting for age, race, gender, and cancer stage. A sub-analysis was performed to evaluate the association between subthemes of SVI (socioeconomic status, household composition/disability, race/ethnicity/language, and housing/transportation) and receipt of neoadjuvant chemotherapy. RESULTS: Of the 978 patients identified, 490 (50.1%) received neoadjuvant chemotherapy. Patients that received neoadjuvant chemotherapy had a lower SVI, were younger, and had >cT2 stage (all, P <.05). The most vulnerable patients had lower odds of receiving neoadjuvant chemotherapy (OR 0.61, 0.39-0.95) compared to the least vulnerable patients. Analysis of subthemes of SVI demonstrated similar associations by socioeconomic status (OR 0.56, 0.36-0.86) and household composition/disability (OR 0.57, 0.33-0.99). CONCLUSION: Adverse social determinants of health, or social vulnerability, are associated with suboptimal and disparate utilization of neoadjuvant chemotherapy in patients with MIBC undergoing radical cystectomy. Strategies for identifying vulnerable populations may allow for more targeted interventions that would improve equity in bladder cancer care.

LGI1-antibody encephalitis: how to approach this highly treatable dementia mimic in memory and mental health services.

Leucine-rich glioma-inactivated 1-antibody-encephalitis is a treatable and potentially reversible cause of cognitive and psychiatric presentations, and may mimic cognitive decline, rapidly progressive dementia and complex psychosis in older patients. This aetiology is of immediate relevance given the alternative treatment pathway required, compared with other conditions presenting with cognitive deficits.

Peripherally-derived LGI1-reactive monoclonal antibodies cause epileptic seizures in vivo.

One striking clinical hallmark in patients with autoantibodies to leucine-rich glioma inactivated 1 (LGI1) is the very frequent focal seizure semiologies, including faciobrachial dystonic seizures (FBDS), in addition to the amnesia. Polyclonal serum IgGs have successfully modelled the cognitive changes in vivo but not seizures. Hence, it remains unclear whether LGI1-autoantibodies are sufficient to cause seizures. We tested this with the molecularly precise monoclonal antibodies directed against LGI1 [LGI1-monoclonal antibodies (mAbs)], derived from patient circulating B cells. These were directed towards both major domains of LGI1, leucine-rich repeat and epitempin repeat, and infused intracerebroventricularly over 7 days into juvenile male Wistar rats using osmotic pumps. Continuous wireless EEG was recorded from a depth electrode placed in hippocampal CA3 plus behavioural tests for memory and hyperexcitability were performed. Following infusion completion (Day 9), post-mortem brain slices were studied for antibody binding and effects on Kv1.1. The LGI1-mAbs bound most strongly in the hippocampal CA3 region and induced a significant reduction in Kv1.1 cluster number in this subfield. By comparison to control-Ab injected rats video-EEG analysis over 9 days revealed convulsive and non-convulsive seizure activity in rats infused with LGI1-mAbs, with a significant number of ictal events. Memory was not impaired in the novel object recognition test. Peripherally-derived human LGI1-mAbs infused into rodent CSF provide strong evidence of direct in vivo epileptogenesis with molecular correlations. These findings fulfill criteria for LGI1-antibodies in seizure causation.

Autoimmune and paraneoplastic seizures.

Seizures are a common feature of autoimmune encephalitis and are especially prevalent in patients with the commonest autoantibodies, against LGI1, CASPR2 and the NMDA, GABAB, and GABAA receptors. In this chapter, we discuss the classification, clinical, investigation, and treatment aspects of patients with these, and other autoantibody-mediated and -associated, illnesses. We highlight distinctive and common seizure semiologies which, often alongside other features we outline, can help the clinical diagnosis of an autoantibody-associated syndrome. Next, we classify these syndromes by either focusing on whether they represent underlying causative autoantibodies or T-cell-mediated syndromes and on the distinction between acute symptomatic seizures and a more enduring tendency to autoimmune-associated epilepsy, a practical and valuable distinction for both patients and clinicians which relates to the pathogenesis. We emphasize the more effective immunotherapy response in patients with causative autoantibodies, and discuss the emerging evidence for various first-, second-, and third-line immunotherapies. Finally, we highlight available clinical rating scales which can guide autoantibody testing and immunotherapy in patients with seizures of unknown etiology. Throughout, we relate the clinical and therapeutic observations to the immunobiology and neuroscience which drive these seizures.

Ultrahigh frequencies of peripherally matured LGI1- and CASPR2-reactive B cells characterize the cerebrospinal fluid in autoimmune encephalitis.

Intrathecal synthesis of central nervous system (CNS)-reactive autoantibodies is observed across patients with autoimmune encephalitis (AE), who show multiple residual neurobehavioral deficits and relapses despite immunotherapies. We leveraged two common forms of AE, mediated by leucine-rich glioma inactivated-1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies, as human models to comprehensively reconstruct and profile cerebrospinal fluid (CSF) B cell receptor (BCR) characteristics. We hypothesized that the resultant observations would both inform the observed therapeutic gap and determine the contribution of intrathecal maturation to pathogenic B cell lineages. From the CSF of three patients, 381 cognate-paired IgG BCRs were isolated by cell sorting and scRNA-seq, and 166 expressed as monoclonal antibodies (mAbs). Sixty-two percent of mAbs from singleton BCRs reacted with either LGI1 or CASPR2 and, strikingly, this rose to 100% of cells in clonal groups with ≥4 members. These autoantigen-reactivities were more concentrated within antibody-secreting cells (ASCs) versus B cells (P < 0.0001), and both these cell types were more differentiated than LGI1- and CASPR2-unreactive counterparts. Despite greater differentiation, autoantigen-reactive cells had acquired few mutations intrathecally and showed minimal variation in autoantigen affinities within clonal expansions. Also, limited CSF T cell receptor clonality was observed. In contrast, a comparison of germline-encoded BCRs versus the founder intrathecal clone revealed marked gains in both affinity and mutational distances (P = 0.004 and P < 0.0001, respectively). Taken together, in patients with LGI1 and CASPR2 antibody encephalitis, our results identify CSF as a compartment with a remarkably high frequency of clonally expanded autoantigen-reactive ASCs whose BCR maturity appears dominantly acquired outside the CNS.

Fatigue predicts quality of life after leucine-rich glioma-inactivated 1-antibody encephalitis.

Patient-reported quality-of-life (QoL) and carer impacts are not reported after leucine-rich glioma-inactivated 1-antibody encephalitis (LGI1-Ab-E). From 60 patients, 85% (51 out of 60) showed one abnormal score across QoL assessments and 11 multimodal validated questionnaires. Compared to the premorbid state, QoL significantly deteriorated (p < 0.001) and, at a median of 41 months, fatigue was its most important predictor (p = 0.025). In total, 51% (26 out of 51) of carers reported significant burden. An abbreviated five-item battery explained most variance in QoL. Wide-ranging impacts post-LGI1-Ab-E include decreased QoL and high caregiver strain. We identify a rapid method to capture QoL in routine clinic or clinical trial settings.

Fine needle aspiration of human lymph nodes reveals cell populations and soluble interactors pivotal to immunological priming.

Lymph node (LN) fine needle aspiration (LN FNA) represents a powerful technique for minimally invasive sampling of human LNs in vivo and has been used effectively to directly study aspects of the human germinal center response. However, systematic deep phenotyping of the cellular populations and cell-free proteins recovered by LN FNA has not been performed. Thus, we studied human cervical LN FNAs as a proof-of-concept and used single-cell RNA-sequencing and proteomic analysis to benchmark this compartment, define the purity of LN FNA material, and facilitate future studies in this immunologically pivotal environment. Our data provide evidence that LN FNAs contain bone-fide LN-resident innate immune populations, with minimal contamination of blood material. Examination of these populations reveals unique biology not predictable from equivalent blood-derived populations. LN FNA supernatants represent a specific source of lymph- and lymph node-derived proteins, and can, aided by transcriptomics, identify likely receptor-ligand interactions. This represents the first description of the types and abundance of immune cell populations and cell-free proteins that can be efficiently studied by LN FNA. These findings are of broad utility for understanding LN physiology in health and disease, including infectious or autoimmune perturbations, and in the case of cervical nodes, neuroscience.

Criminality in patients with autoimmune encephalitis: A case series.

BACKGROUND AND PURPOSE: Despite it being an immunotherapy-responsive neurological syndrome, patients with autoimmune encephalitis (AE) frequently exhibit residual neurobehavioural features. Here, we report criminal behaviours as a serious and novel postencephalitic association. METHODS: This retrospective cohort study included 301 AE patients. Five of who committed crimes underwent direct assessments and records review alongside autoantibody studies. RESULTS: Five of 301 patients (1.7%) with AE exhibited criminal behaviours, which included viewing child pornography (n = 3), repeated shoplifting, and conspiracy to commit murder. All five were adult males, with LGI1 autoantibodies (n = 3), CASPR2 autoantibodies, or seronegative AE. None had evidence of premorbid antisocial personality traits or psychiatric disorders. Criminal behaviours began a median of 18 months (range = 15 months-12 years) after encephalitis onset. At the time of crimes, two patients were immunotherapy-naïve, three had been administered late immunotherapies (at 5 weeks-4 months), many neurobehavioural features persisted, and new obsessive behaviours had appeared. However, cognition, seizure, and disability measures had improved, alongside reduced autoantibody levels. CONCLUSIONS: Criminal behaviours are a rare, novel, and stigmatizing residual neurobehavioural phenotype in AE, with significant social and legal implications. With caution towards overattribution, we suggest they occur as part of a postencephalitis limbic neurobehavioural syndrome.

Data accuracy, consistency and completeness of the national Swiss cystic fibrosis patient registry: Lessons from an ECFSPR data quality project.

BACKGROUND: Good data quality is essential when rare disease registries are used as a data source for pharmacovigilance studies. This study investigated data quality of the Swiss cystic fibrosis (CF) registry in the frame of a European Cystic Fibrosis Society Patient Registry (ECFSPR) project aiming to implement measures to increase data reliability for registry-based research. METHODS: All 20 pediatric and adult Swiss CF centers participated in a data quality audit between 2018 and 2020, and in a re-audit in 2022. Accuracy, consistency and completeness of variables and definitions were evaluated, and missing source data and informed consents (ICs) were assessed. RESULTS: The first audit included 601 out of 997 Swiss people with CF (60.3 %). Data quality, as defined by data correctness ≥95 %, was high for most of the variables. Inconsistencies of specific variables were observed because of an incorrect application of the variable definition. The proportion of missing data was low with <5 % for almost all variables. A considerable number of missing source data occurred for CFTR variants. Availability of ICs varied largely between centers (10 centers had >5 % of missing documents). After providing feedback to the centers, availability of genetic source data and ICs improved. CONCLUSIONS: Data audits demonstrated an overall good data quality in the Swiss CF registry. Specific measures such as support of the participating sites, training of data managers and centralized data collection should be implemented in rare disease registries to optimize data quality and provide robust data for registry-based scientific research.

Encephalitis: diagnosis, management and recent advances in the field of encephalitides.

Encephalitis describes inflammation of the brain parenchyma, typically caused by either an infectious agent or through an autoimmune process which may be postinfectious, paraneoplastic or idiopathic. Patients can present with a combination of fever, alterations in behaviour, personality, cognition and consciousness. They may also exhibit focal neurological deficits, seizures, movement disorders and/or autonomic instability. However, it can sometimes present non-specifically, and this combined with its many causes make it a difficult to manage neurological syndrome. Despite improved treatments in some forms of encephalitides, encephalitis remains a global concern due to its high mortality and morbidity. Prompt diagnosis and administration of specific and supportive management options can lead to better outcomes. Over the last decade, research in encephalitis has led to marked developments in the understanding, diagnosis and management of encephalitis. In parallel, the number of autoimmune encephalitis syndromes has rapidly expanded and clinically characteristic syndromes in association with pathogenic autoantibodies have been defined. By focusing on findings presented at the Encephalitis Society's conference in December 2021, this article reviews the causes, clinical manifestations and management of encephalitis and integrate recent advances and challenges of research into encephalitis.