Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes

The contemporary diagnosis of paraneoplastic neurologic syndromes (PNSs) requires an increasing understanding of their clinical, immunologic, and oncologic heterogeneity. The 2004 PNS criteria are partially outdated due to advances in PNS research in the last 16 years leading to the identification of new phenotypes and antibodies that have transformed the diagnostic approach to PNS. Here, we propose updated diagnostic criteria for PNS.A panel of experts developed by consensus a modified set of diagnostic PNS criteria for clinical decision making and research purposes. The panel reappraised the 2004 criteria alongside new knowledge on PNS obtained from published and unpublished data generated by the different laboratories involved in the project.The panel proposed to substitute "classical syndromes" with the term "high-risk phenotypes" for cancer and introduce the concept of "intermediate-risk phenotypes." The term "onconeural antibody" was replaced by "high risk" (>70% associated with cancer) and "intermediate risk" (30%-70% associated with cancer) antibodies. The panel classified 3 levels of evidence for PNS: definite, probable, and possible. Each level can be reached by using the PNS-Care Score, which combines clinical phenotype, antibody type, the presence or absence of cancer, and time of follow-up. With the exception of opsoclonus-myoclonus, the diagnosis of definite PNS requires the presence of high- or intermediate-risk antibodies. Specific recommendations for similar syndromes triggered by immune checkpoint inhibitors are also provided.The proposed criteria and recommendations should be used to enhance the clinical care of patients with PNS and to encourage standardization of research initiatives addressing PNS.Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology

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

Immunogénétique des encéphalites auto-immunes et maladies associées

Recently, several autoimmune encephalitides and related disorders have been described thanks to the discovery of autoantibodies targeting different neuroglial antigens of the central and peripheral nervous system. Although these antibodies have allowed for more accurate diagnoses and better understanding of some of the underlying mechanisms of these diseases, the exact processes leading to the immune tolerance breakdown are still unknown, but are likely the result of a complex interaction between environmental triggers and genetic traits. The human leukocyte antigen (HLA) is the main genetic factor related to autoimmunity, with plenty of disease associations and some already deciphered pathogenic roles. However, few studies have so far been carried out in autoimmune encephalitis and several questions remain unsolved. Thus, this PhD project aimed to study the importance of HLA in the genetic predisposition to autoimmune encephalitis, the genotype-phenotype correlation, and the peptide-binding affinities of the HLA found to be linked to these disorders. To do so, we selected four different entities defined by the presence of antibodies against glutamic acid decarboxylase 65 (GAD65), contactin-associated protein-like 2 (CASPR2), leucine-rich glioma-inactivated 1 (LGI1), and adenylate kinase 5 (AK5). Our results sustain the existence of a strong association between specific HLA alleles and non-paraneoplastic LE with IgG4 antibodies (LGI1 and CASPR2), while a weaker association is observed between the haplotype DQA1*05:01-DQB1*02:01-DRB1*03:01 and other types of encephalitis with IgG1 antibodies (GAD65 and AK5). In this second group, the neurological disorders are not associated with cancer and T-cells seem to play a major role in the pathophysiology. Finally, there is likely an absence of HLA involvement in the genetic predisposition to paraneoplastic neurological syndromes. In conclusion, the results of this PhD project support a significant role of HLA in the pathogenesis of autoimmune encephalitis and related disorders, based on a better characterization of previously reported associations as well as the description of new ones, highlighting the importance of precise clinical and biological classifications of autoimmune encephalitides to better understand the mechanisms of these diseases that seem to be different according to the subgroups.Récemment, plusieurs types d´encéphalites auto-immunes et d´autres maladies associés ont été décrites grâce à la découverte d'autoanticorps ciblant différents antigènes neurogliaux du système nerveux central et périphérique. Bien que la découverte de ces anticorps ait permis des diagnostics plus précis et une meilleure compréhension de certains mécanismes pathogéniques sous-jacents, les processus exacts menant à la rupture de tolérance immune sont encore inconnus. Ceux-ci sont probablement le résultat d'une interaction complexe entre des facteurs environnementaux et des caractéristiques génétiques. L'antigène leucocytaire humain (human leukocyte antigen, HLA) est le principal facteur génétique lié à l'auto-immunité. De nombreuses associations avec différentes maladies autoimmunes ont été décrites et dans certains cas, un rôle dans la pathogenèse a été démontré. Cependant, peu d'études ont été menées à ce jour sur les encéphalites auto-immunes et plusieurs questions restent en suspens. Notre travail visait à étudier l'importance du système HLA dans la prédisposition génétique des encéphalites auto-immunes, la corrélation génotype-phénotype, et les affinités de liaison aux peptides des HLA qui sont associés à ces encéphalites. Nous avons sélectionné quatre sous-types d’encéphalites autoimmunes définies par la présence d'anticorps contre glutamic acid decarboxylase 65 (GAD65), contactin-associated protein-like 2 (CASPR2), leucine-rich glioma-inactivated 1 (LGI1), et adenylate kinase 5 (AK5). Nos résultats mettent en évidence plusieurs point importants. Premièrement, il existe dans certains sous-groupes une forte association entre un allèle HLA spécifique et une EL non-paranéoplasique (LGI1 et CASPR2). Ces patients ont des anticorps de sous-type IgG4. Deuxièmement, une association plus faible avec l´haplotype DQA1*05:01-DQB1*02:01-DRB1*03:01 est observée dans d’autres cas (GAD et AK5). Chez ces patients, les troubles neurologiques ne sont pas liés au cancer, les patients ont des anticorps de sous-type IgG1, et les lymphocytes T semblent jouer un rôle majeur dans la pathogenèse des troubles neurologiques. Troisièmement, l´implication du système HLA dans la prédisposition génétique aux syndromes neurologiques paranéoplasiques semble faible. En conclusion, les résultats de cette thèse soutiennent un rôle significatif de l´HLA dans la pathogenèse des encéphalites auto-immunes. Notre travail a permis une meilleure caractérisation des associations précédemment rapportées ainsi que la description de nouveaux haplotypes, soulignant l'importance d’une classification clinique et biologique précise des encéphalites autoimmunes pour mieux comprendre les mécanismes pathogéniques qui semblent être différents suivant les entités étudiées

Associations between HLA and autoimmune neurological diseases with autoantibodies

International audienceRecently, several autoimmune neurological diseases have been defined by the presence of autoantibodies against different antigens of the nervous system. These autoantibodies have been demonstrated to be specific and useful biomarkers, and most of them are also pathogenic. These aspects have increased the value of autoantibodies in neurological practice, as they enable to establish more accurate diagnosis and to better understand the underlying mechanisms of the autoimmune neurological diseases when they are compared to those lacking them. Nevertheless, the exact mechanisms leading to the autoimmune response are still obscure. Genetic predisposition is likely to play a role in autoimmunity, HLA being the most reported genetic factor. Herein, we review the current knowledge about associations between HLA and autoimmune neurological diseases with autoantibodies. We report the main alleles and haplotypes, and discuss the clinical and pathogenic implications of these findings

Current Status of Biomarkers in Anti-N-Methyl-D-Aspartate Receptor Encephalitis

The discovery of biomarkers in rare diseases is of paramount importance to allow a better diagnosis, improve predictions of outcomes, and prompt the development of new treatments. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a rare autoimmune disorder associated with the presence of antibodies targeting the GluN1 subunit of the NMDAR. Since it was discovered in 2007, large efforts have been made towards the identification of clinical, paraclinical, and molecular biomarkers to better understand the immune mechanisms that govern the course of the disease as well as to define predictors of treatment response and long-term outcomes. However, most of these biomarkers are still in an exploratory phase, with only a few candidates reaching the final phases of the always-complex process of biomarker development, mainly due to the low incidence of the disease and its recent description. Clinical and paraclinical markers are probably the most widely explored in anti-NMDAR encephalitis, five of them combined in a clinical score to predict 1 year outcome. On the contrary, soluble molecules, such as persistent antibody positivity, antibody titers, cytokines, and other inflammatory mediators, have been proposed as biomarkers of clinical activity, inflammation, prognosis, and treatment response, but further studies are required for their clinical validation including larger and more homogenous cohorts of patients. Similarly, genetic susceptibility biomarkers are still in the exploratory phase and, therefore, weak conclusions can for now only be achieved. Thus, further studies are warranted to define biomarkers and unravel the underlying mechanisms driving rare diseases such as anti-NMDAR encephalitis. Future international collaborative studies with prospective designs that enable the enrollment of large cohorts will allow for the identification and validation of novel biomarkers for clinical decision-making.This work was developed within the BETPSY project, which was supported by a public grant overseen by the Agence Nationale de la Recherche (ANR), as part of the second Investissements d’Avenir program (ANR-18-RHUS-0012), and was performed within the framework of the LABEX CORTEX (ANR-11-LABX-0042) of the Université de Lyon operated by the ANR. N.L.C.P. received a grant from the Biomedical Research Institute of Málaga (IBIMA).Ye

Cytokine dynamics and targeted immunotherapies in autoimmune encephalitis.

Autoimmune encephalitides constitute a diverse group of immune-mediated central nervous system disorders mainly characterized by the presence of antibodies targeting neuronal or glial antigens. Despite the notable contribution of antibody discovery to the understanding of their physiopathology, the specific immune cells and inflammatory mediators involved in autoimmune encephalitis are still poorly defined. However, cytokines have recently emerged as crucial signalling molecules in the pathogenesis of autoimmune encephalitis. Cytokines are biologically active, soluble, low-molecular-weight proteins or glycoproteins involved in a wide variety of physiological functions, including central nervous system development and homeostasis, immune surveillance, as well as proliferation and maturation of immune cells. Since unbalanced cytokine expression is considered a hallmark of many autoimmune central nervous system disorders, their identification and quantification has become an essential element in personalized medicine applied to the field of neuroimmunology. Several studies have explored the cytokine profile of autoimmune encephalitis, but their interpretation and comparison is challenging due to their small sample sizes and extremely high heterogeneity, especially regarding the cytokines analysed, type of sample used, and associated neural antibody. Only the cytokine profile of anti-N-methyl-D-aspartate receptor encephalitis has extensively been investigated, with findings suggesting that, although humoral immunity is the main effector, T cells may also be relevant for the development of this disorder. A better understanding of cytokine dynamics governing neuroinflammation might offer the opportunity of developing new therapeutic strategies against specific immune cells, cytokines, antibodies, or intracellular signalling cascades, therefore leading to better outcomes and preventing undesired side effects of the presently used strategies. In this review, we first summarize the current knowledge about the role of cytokines in the pathogenesis of autoimmune encephalitis, combining theoretical analysis with experimental validations, to assess their suitability as clinical biomarkers. Second, we discuss the potential applicability of the novel targeted immunotherapies in autoimmune encephalitis depending on the immunobiology of the associated antibody, their limitations, as well as the main limitations that should be addressed in future studies

Epidemiology of paraneoplastic neurologic syndromes and autoimmune encephalitides in France

International audienceObjective: To determine the observed and expected incidence rates of paraneoplastic neurologic syndromes (PNSs) and autoimmune encephalitides (AEs) diagnosed in France between 2016 and 2018, we conducted a population-based epidemiologic study.Methods: Observed incidence rates were stratified by sex, age groups, region of care, year of diagnosis, and disease subgroups. National expected incidence rates were calculated based on rates obtained in the area directly adjacent to the Reference Center using a mixed Poisson model and compared with observed incidence rates.Results: Six hundred thirty-two patients with definite PNS or AE met the inclusion criteria. The observed incidence rate of definite PNS and AE in France was 3.2 per million person-years (CI95%: 2.9-3.4) compared with an expected incidence rate of 7.1 per million person-years (CI95%: 3.9-11.4). The national observed incidence rate for the antibody-positive AE subgroup increased from 1.4 per million person-years (CI95%: 1.2-1.7) in 2016 to 2.1 per million person-years (CI95%: 1.7-2.4) in 2018, thus surpassing the incidence rate of classical PNS (1.2 per million person-years [CI95%: 1.0-1.5]) of 2018.Conclusions: There was a significant widespread year-to-year increase in the incidence of diagnoses registered with the Reference Center for all subgroups of PNS and AE studied. The national observed incidence rate is likely underestimated due to underdiagnosis and underreporting

Progressive fibrosing interstitial lung disease: a clinical cohort (the PROGRESS study)

International audienceIn patients with chronic fibrosing interstitial lung disease (ILD), a progressive fibrosing phenotype (PF-ILD) may develop, but information on the frequency and characteristics of this population outside clinical trials is lacking. We assessed the characteristics and outcomes of patients with PF-ILD other than idiopathic pulmonary fibrosis (IPF) in a real-world, single-centre clinical cohort. The files of all consecutive adult patients with fibrosing ILD (2010–2017) were examined retrospectively for pre-defined criteria of ≥10% fibrosis on high-resolution computed tomography and progressive disease during overlapping windows of 2 years. Baseline was defined as the date disease progression was identified. Patients receiving nintedanib or pirfenidone were censored from survival and progression analyses. In total, 1395 patients were screened; 617 had ILD other than IPF or combined pulmonary fibrosis and emphysema, and 168 had progressive fibrosing phenotypes. In 165 evaluable patients, median age was 61 years; 57% were female. Baseline mean forced vital capacity (FVC) was 74±22% predicted. Median duration of follow-up was 46.2 months. Annualised FVC decline during the first year was estimated at 136±328 mL using a linear mixed model. Overall survival was 83% at 3 years and 72% at 5 years. Using multivariate Cox regression analysis, mortality was significantly associated with relative FVC decline ≥10% in the previous 24 months (p<0.05), age ≥50 years (p<0.01) and diagnosis subgroup (p<0.01). In this cohort of patients with PF-ILD not receiving antifibrotic therapy, the disease followed a course characterised by continued decline in lung function, which predicted mortality

Argonaute Autoantibodies as Biomarkers in Autoimmune Neurologic Diseases

International audienceObjective To identify and characterize autoantibodies (Abs) as novel biomarkers for an autoimmune context in patients with central and peripheral neurologic diseases. Methods Two distinct approaches (immunoprecipitation/mass spectrometry\textendash based proteomics and protein microarrays) and patients' sera and CSF were used. The specificity of the identified target was confirmed by cell-based assay (CBA) in 856 control samples. Results Using the 2 methods as well as sera and CSF of patients with central and peripheral neurologic involvement, we identified Abs against the family of Argonaute proteins (mainly AGO1 and AGO2), which were already reported in systemic autoimmunity. AGO-Abs were mostly of immunoglobulin G 1 subclass and conformation dependent. Using CBA, AGO-Abs were detected in 21 patients with a high suspicion of autoimmune neurologic diseases (71.4% were women; median age 57 years) and only in 4/856 (0.5%) controls analyzed by CBA (1 diagnosed with small-cell lung cancer and the other 3 with Sjögren syndrome). Among the 21 neurologic patients identified, the main clinical presentations were sensory neuronopathy (8/21, 38.1%) and limbic encephalitis (6/21, 28.6%). Fourteen patients (66.7%) had autoimmune comorbidities and/or co-occurring Abs, whereas AGO-Abs were the only autoimmune biomarker for the remaining 7/21 (33.3%). Thirteen (61.9%) patients were treated with immunotherapy; 8/13 (61.5%) improved, and 3/13 (23.1%) remained stable, suggesting an efficacy of these treatments. Conclusions AGO-Abs might be potential biomarkers of autoimmunity in patients with central and peripheral nonparaneoplastic neurologic diseases. In 7 patients, AGO-Abs were the only biomarkers; thus, their identification may be useful to suspect the autoimmune character of the neurologic disorder. Classification of Evidence This study provides Class III evidence that AGO-Abs are more frequent in patients with autoimmune neurologic diseases than controls