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  • Revisiting anti-Hu paraneoplastic autoimmunity: phenotypic characterization and cancer diagnosis. Brain communications Villagrán-García, M., Farina, A., Muñiz-Castrillo, S., Wucher, V., Dhairi, M., Timestit, N., Ciano-Petersen, N. L., Vogrig, A., Picard, G., Benaiteau, M., Psimaras, D., Petrova, A. V., Alberto, T., Aupy, J., Giry, M., Rogemond, V., Desestret, V., Joubert, B., Honnorat, J. 2023; 5 (5): fcad247


    Anti-Hu are the most frequent antibodies in paraneoplastic neurological syndromes, mainly associated with an often limited stage small cell lung cancer. The clinical presentation is pleomorphic, frequently multifocal. Although the predominant phenotypes are well characterized, how different neurological syndromes associate is unclear. Likewise, no specific study assessed the performance of new-generation CT and PET scanners for cancer screening in these patients. Herein, we aimed to describe the clinical pattern and cancer screening in a retrospective cohort of 466 patients with anti-Hu autoimmunity from the French Reference Centre on Paraneoplastic Neurological Syndromes registry. Clinical presentation, cancer screening and diagnosis were analysed. Among the 466 patients, 220 (54%) had multifocal neurological involvement. A hierarchical cluster analysis grouped the patients into (i) mainly limbic encephalitis, (ii) predominantly peripheral neuropathy and (iii) broad involvement of the nervous system (mixed group). Compared with limbic encephalitis and mixed groups, patients in the neuropathy group more frequently had a chronic onset of symptoms (29 versus 13 and 17%), elevated CSF proteins (83 versus 47 and 67%) and died from cancer progression (67 versus 15 and 28%; all P < 0.05). No significant difference in overall survival was observed between groups. Dysautonomia and brainstem signs were associated with a higher risk of death from the neurological cause; cancer diagnosis was the main predictor of all-cause death, especially when diagnosed within 2 years from clinical onset (all P < 0.05). Three hundred and forty-nine (75%) patients had cancer: in 295 (84%) neurological symptoms preceded tumour diagnosis, being lung cancer in 262 (89%), thereof small cell lung cancer in 227 (87%). First CT scan revealed lung cancer in 205/241 (85%), and PET scan shortened the interval to diagnosis when the initial CT scan was negative [7 months (1-66) in 27 patients versus 14 months (2-45) in 6; P < 0.001]. Although cancer diagnosis mostly occurred within 2 years from clinical onset, 13/295 (4%) patients exceeded that threshold. Conversely, 33 patients (7%) were 'cancer-free' after 2 years of follow-up. However, 13/33 (39%) had initial suspicious imaging findings that spontaneously regressed. In conclusion, although anti-Hu autoimmunity clinical presentation is mostly multifocal, we observed patients with a predominant limbic syndrome or isolated sensory neuropathy. Early implementation of PET scan shortens the interval to cancer diagnosis, which was the strongest predictor of death, especially if diagnosed ≤2 years from clinical onset. As cancer was diagnosed >2 years after clinical onset in few patients, screening should be extended up to 5 years. In addition, tumour regression was suspected in a substantial proportion of 'cancer-free' patients.

    View details for DOI 10.1093/braincomms/fcad247

    View details for PubMedID 37794924

    View details for PubMedCentralID PMC10546956

  • Different genetic signatures of small-cell lung cancer characterize anti-GABAB R and anti-Hu paraneoplastic neurological syndromes. Annals of neurology Vogrig, A., Pegat, A., Villagrán-García, M., Wucher, V., Attignon, V., Sohier, E., Brevet, M., Rogemond, V., Pinto, A. L., Muñiz-Castrillo, S., Peter, E., Robert, M., Picard, G., Hopes, L., Psimaras, D., Terra, A., Perrin, C., Cogne, D., Tabone-Eglinger, S., Martinez, S., Jury, D., Valantin, J., Gadot, N., Auclair-Perrossier, J., Viari, A., Dubois, B., Desestret, V., Honnorat, J. 2023


    Small-cell lung cancer (SCLC) is the malignancy most frequently associated with paraneoplastic neurological syndromes (PNS) and can trigger different antibody responses against intracellular (Hu) or neuronal surface (GABAB R) antigens. Our aim was to clarify if the genomic and transcriptomic features of SCLC are different in patients with anti-GABAB R or anti-Hu PNS compared with SCLC without PNS.A total of 76 SCLC tumor samples were collected: 34 anti-Hu, 14 anti-GABAB R, and 28 SCLC without PNS. The study consisted of four steps: (i) pathological confirmation; (ii) Next Generation Sequencing using a panel of 98 genes, including those encoding the autoantibodies targets ELAVL1-4, GABBR1-2, KCTD16; (iii) genome-wide Copy Number Variation (CNV); (iv) whole-transcriptome RNA sequencing.CNV analysis revealed that patients with anti-GABAB R PNS have commonly a gain in chromosome 5q, which contains KCTD16, while anti-Hu and control patients often harbor a loss. No significantly different number of mutations regarding any onconeural genes was observed. Conversely, transcriptomic profile of SCLC was different and the differentially expressed genes permitted to effectively cluster the samples into three groups, reflecting the antibody-based classification, with an overexpression of KCTD16 specific to anti-GABAB R PNS. Pathway analysis revealed that tumors of patients with anti-GABAB R encephalitis were enriched in B cell signatures, as opposed to those of patients with anti-Hu in which T cell and IFN-γ-related signatures were overexpressed.SCLC genetic and transcriptomic features differentiate anti-GABAB R, anti-Hu, and non-PNS tumors. The role of KCTD16 appears to be pivotal in the tumor immune tolerance breakdown of anti-GABAB R PNS. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/ana.26784

    View details for PubMedID 37638563

  • Detection of High-Risk Paraneoplastic Antibodies Against TRIM9 and TRIM67 proteins. Annals of neurology Bartley, C. M., Ngo, T. T., Do, L. D., Zekeridou, A., Dandekar, R., Muniz-Castrillo, S., Alvarenga, B. D., Zorn, K. C., Tubati, A., Pinto, A., Browne, W. D., Hullett, P. W., Terrelonge, M., Schubert, R. D., Piquet, A. L., Binxia, Y., Montalvo Perero, M. J., Kung, A. F., Mann, S. A., Shah, M. P., Geschwind, M. D., Gelfand, J. M., DeRisi, J. L., Pittock, S. J., Honnorat, J., Pleasure, S. J., Wilson, M. R. 2023


    Co-occurring anti-tripartite motif-containing protein 9 and 67 autoantibodies (TRIM9/67-IgG) have been reported in only a very few cases of paraneoplastic cerebellar syndrome. The value of these biomarkers and the most sensitive methods of TRIM9/67-IgG detection are not known. We performed a retrospective, multi-center study to evaluate the cerebrospinal fluid (CSF) and serum of candidate TRIM9/67-IgG cases by tissue-based immunofluorescence (TBIF), peptide phage display immunoprecipitation sequencing (PhIP-Seq), overexpression cell-based assay (CBA), and immunoblot. Cases in whom TRIM9/67-IgG was detected by at least two assays were considered TRIM9/67-IgG positive. Among these cases (N=13), CBA was the most sensitive (100%) and revealed that all cases had TRIM9 and TRIM67 autoantibodies. Of TRIM9/67-IgG cases with available clinical history, a subacute cerebellar syndrome was the most common presentation (N=7/10), followed by encephalitis (N=3/10). Of these ten, 70% had comorbid cancer (7/10), 85% of whom (N=6/7) had confirmed metastatic disease. All evaluable cancer biopsies expressed TRIM9 protein (N=5/5), whose expression was elevated in the cancerous regions of the tissue in 4 of 5 cases. TRIM9/67-IgG are rare but likely high-risk paraneoplastic biomarkers for which CBA appears to be the most sensitive diagnostic assay. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/ana.26776

    View details for PubMedID 37632288

  • Prognostic Value of Persistent CSF Antibodies at 12 Months in Anti-NMDAR Encephalitis. Neurology(R) neuroimmunology & neuroinflammation Ciano-Petersen, N. L., Robert, M., Muniz-Castrillo, S., Wucher, V., Klich, A., Vogrig, A., Villagran Garcia, M., Farina, A., Goncalves, D., Picard, G., Rogemond, V., Joubert, B., Oliver-Martos, B., Serrano-Castro, P. J., Maucort-Boulch, D., Honnorat, J. 2023; 10 (4)


    BACKGROUND AND OBJECTIVES: Anti-NMDA receptor (NMDAR) encephalitis is defined by the presence of antibodies (Abs) targeting the NMDAR in the CSF. This study aimed to determine the prognostic value of persistent CSF NMDAR-Abs during follow-up.METHODS: This retrospective observational study included patients diagnosed with anti-NMDAR encephalitis in the French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis and for whom CSF samples were obtained at diagnosis and >4 months of follow-up to evaluate CSF NMDAR-Ab persistence. Because patients were tested for CSF NMDAR-Abs at different time points, samples were stratified into different periods of follow-up (i.e., 12 months was considered for the 9- to 16-month follow-up period).RESULTS: Among the 501 patients diagnosed with anti-NMDAR encephalitis between January 2007 and June 2020, 89 (17%) were tested between 4 and 120 months for CSF NMDAR-Abs after clinical improvement and included in the study (75/89 women, 84%; median age 20 years, interquartile range [IQR] 16-26). During follow-up, 21 of 89 (23%) patients had a relapse after a median time of 29 months (IQR 18-47), and 20 of 89 (22%) had a poor outcome (mRS ≥3) after a median last follow-up of 36 months (IQR 19-64). Most patients (69/89, 77%) were tested at the 12-month follow-up period, and 42 of 69 (60%) of them had persistent CSF NMDAR-Abs. When comparing patients with persistent or absent CSF NMDAR-Abs at 12 months, poor outcome at the last follow-up was more frequent in the former (38% vs 8%, p = 0.01), who had relapses more often (23% vs 7%), which also appeared earlier in the course of the disease (90% during the following 4 years of follow-up vs 20%), although no significant difference was observed at long-term follow-up (p = 0.15). In addition, patients with persistent CSF NMDAR-Abs at 12 months had higher titers of CSF NMDAR-Abs at diagnosis.DISCUSSION: In this study, patients with persistent CSF NMDAR-Abs at 12 months were more likely to have subsequent relapses and a poor long-term outcome. However, these findings should be interpreted with caution because of the variability in the time of sampling of this study. Future prospective studies are required to validate these results in larger cohorts.

    View details for DOI 10.1212/NXI.0000000000200108

    View details for PubMedID 37147137

  • Anti-LGI1 Encephalitis With Co-occurring IgLON5 Antibodies: Clinical Features and Human Leukocyte Antigen Haplotypes. Neurology(R) neuroimmunology & neuroinflammation Schiff, P., Muniz-Castrillo, S., Do, L. D., Fantini, M. L., Chanson, E., Rogemond, V., Honnorat, J., Poncet-Megemont, L. 2023; 10 (4)


    OBJECTIVES: Autoimmune encephalitis (AE) with antibodies against LGI1 and IgLON5 are clinically distinctive but share some particularities such as a strong association with specific human leukocyte antigen (HLA) class II alleles.METHODS: We clinically describe a patient with double positivity for LGI1 and IgLON5 antibodies. In addition, we conducted specific immunodepletion with the patient's serum and HLA typing and investigated the presence of serum IgLON5 antibodies in a cohort of 23 anti-LGI1 patients carrying the HLA predisposing for anti-IgLON5 encephalitis.RESULTS: A 70-year-old woman with a history of lymphoepithelial thymoma presented with subacute cognitive impairment and seizures. Investigations included MRI and EEG showing medial temporal involvement, increased CSF protein content, and polysomnography with REM and non-REM motor activity, along with obstructive apnea. Neural antibody testing revealed both LGI1 and IgLON5 antibodies in serum and CSF, and serum immunodepletion ruled out cross-reactivity. The patient carried DRB1*07:01 and DQA1*01:01DQB1*05:01, but no other IgLON5-positive case was identified in a cohort of anti-LGI1 patients carrying DQA1*01DQB1*05. Nearly full therapeutic response was obtained after intensified immunosuppressive treatment.DISCUSSION: We present a case of anti-LGI1 encephalitis with concomitant IgLON5 antibodies. Co-occurring IgLON5 antibodies in anti-LGI1 encephalitis are exceptional, but may appear in genetically predisposed individuals.

    View details for DOI 10.1212/NXI.0000000000200126

    View details for PubMedID 37217310

  • Spatial and Ecological Factors Modulate the Incidence of Anti-NMDAR Encephalitis-A Systematic Review. Biomedicines Alentorn, A., Berzero, G., Alexopoulos, H., Tzartos, J., Reyes Botero, G., Morales Martinez, A., Muniz-Castrillo, S., Vogrig, A., Joubert, B., Garcia Jimenez, F. A., Cabrera, D., Tobon, J. V., Delgado, C., Sandoval, P., Troncoso, M., Galleguillos, L., Giry, M., Benazra, M., Hernandez Verdin, I., Dade, M., Picard, G., Rogemond, V., Weiss, N., Dalakas, M. C., Boelle, P., Delattre, J., Honnorat, J., Psimaras, D. 2023; 11 (6)


    Anti-NMDAR encephalitis has been associated with multiple antigenic triggers (i.e., ovarian teratomas, prodromal viral infections) but whether geographic, climatic, and environmental factors might influence disease risk has not been explored yet. We performed a systematic review and a meta-analysis of all published papers reporting the incidence of anti-NMDAR encephalitis in a definite country or region. We performed several multivariate spatial autocorrelation analyses to analyze the spatial variations in the incidence of anti-NMDA encephalitis depending on its geographical localization and temperature. Finally, we performed seasonal analyses in two original datasets from France and Greece and assessed the impact of temperature using an exposure-lag-response model in the French dataset. The reported incidence of anti-NMDAR encephalitis varied considerably among studies and countries, being higher in Oceania and South America (0.2 and 0.16 per 100,000 persons-year, respectively) compared to Europe and North America (0.06 per 100,000 persons-year) (p < 0.01). Different regression models confirmed a strong negative correlation with latitude (Pearson's R = -0.88, p < 0.00001), with higher incidence in southern hemisphere countries far from the equator. Seasonal analyses showed a peak of cases during warm months. Exposure-lag-response models confirmed a positive correlation between extreme hot temperatures and the incidence of anti-NMDAR encephalitis in France (p = 0.03). Temperature analyses showed a significant association with higher mean temperatures and positive correlation with higher ultraviolet exposure worldwide. This study provides the first evidence that geographic and climatic factors including latitude, mean annual temperature, and ultraviolet exposure, might modify disease risk.

    View details for DOI 10.3390/biomedicines11061525

    View details for PubMedID 37371620

  • Predicting Functional Outcome and Response to Therapy of Anti-NMDAR Encephalitis, Already at Diagnosis: The NEOS2 Model Brenner, J., Bastiaansen, A., de Bruijn, M., Leypoldt, F., Honnorat, J., Dalmau, J., Iizuka, T., Jansen, M., Schroder, I., Muniz-Castrillo, S., Crijnen, Y., de Vries, J., Schreurs, M., Munoz, A., Guasp, M., Smitt, P., Titulaer, M. LIPPINCOTT WILLIAMS & WILKINS. 2023
  • Consensus Paper: Latent Autoimmune Cerebellar Ataxia (LACA). Cerebellum (London, England) Manto, M., Hadjivassiliou, M., Baizabal-Carvallo, J. F., Hampe, C. S., Honnorat, J., Joubert, B., Mitoma, H., Muñiz-Castrillo, S., Shaikh, A. G., Vogrig, A. 2023


    Immune-mediated cerebellar ataxias (IMCAs) have diverse etiologies. Patients with IMCAs develop cerebellar symptoms, characterized mainly by gait ataxia, showing an acute or subacute clinical course. We present a novel concept of latent autoimmune cerebellar ataxia (LACA), analogous to latent autoimmune diabetes in adults (LADA). LADA is a slowly progressive form of autoimmune diabetes where patients are often initially diagnosed with type 2 diabetes. The sole biomarker (serum anti-GAD antibody) is not always present or can fluctuate. However, the disease progresses to pancreatic beta-cell failure and insulin dependency within about 5 years. Due to the unclear autoimmune profile, clinicians often struggle to reach an early diagnosis during the period when insulin production is not severely compromised. LACA is also characterized by a slowly progressive course, lack of obvious autoimmune background, and difficulties in reaching a diagnosis in the absence of clear markers for IMCAs. The authors discuss two aspects of LACA: (1) the not manifestly evident autoimmunity and (2) the prodromal stage of IMCA's characterized by a period of partial neuronal dysfunction where non-specific symptoms may occur. In order to achieve an early intervention and prevent cell death in the cerebellum, identification of the time-window before irreversible neuronal loss is critical. LACA occurs during this time-window when possible preservation of neural plasticity exists. Efforts should be devoted to the early identification of biological, neurophysiological, neuropsychological, morphological (brain morphometry), and multimodal biomarkers allowing early diagnosis and therapeutic intervention and to avoid irreversible neuronal loss.

    View details for DOI 10.1007/s12311-023-01550-4

    View details for PubMedID 36991252

    View details for PubMedCentralID 4641375

  • Editorial: Neuroglial antibodies: From clinical associations to pathophysiological investigations. Frontiers in neurology Vogrig, A., Valencia-Sanchez, C., Honnorat, J., Muniz-Castrillo, S. 2023; 14: 1143410

    View details for DOI 10.3389/fneur.2023.1143410

    View details for PubMedID 36816563

  • Anti-AGO1 Antibodies Identify a Subset of Autoimmune Sensory Neuronopathy. Neurology(R) neuroimmunology & neuroinflammation Moritz, C. P., Tholance, Y., Vallayer, P., Do, L., Muniz-Castrillo, S., Rogemond, V., Ferraud, K., La Marca, C., Honnorat, J., Killian, M., Paul, S., Camdessanche, J., Antoine, J. G. 2023; 10 (3)


    BACKGROUND AND OBJECTIVES: Autoantibodies (Abs) improve diagnosis and treatment decisions of idiopathic neurologic disorders. Recently, we identified Abs against Argonaute (AGO) proteins as potential autoimmunity biomarkers in neurologic disorders. In this study, we aim to reveal (1) the frequency of AGO1 Abs in sensory neuronopathy (SNN), (2) titers and IgG subclasses, and (3) their clinical pattern including response to treatment.METHODS: This retrospective multicentric case/control study screened 132 patients with SNN, 301 with non-SNN neuropathies, 274 with autoimmune diseases (AIDs), and 116 healthy controls (HCs) for AGO1 Abs through ELISA. Seropositive cases were also tested for IgG subclasses, titers, and conformation specificity.RESULTS: AGO1 Abs occurred in 44 patients, comprising significantly more of those with SNN (17/132 [12.9%]) than those with non-SNN neuropathies (11/301 [3.7%]; p = 0.001), those with AIDs (16/274 [5.8%]; p = 0.02), or HCs (0/116; p < 0.0001). Ab titers ranged from 1:100 to 1:100,000. IgG subclass was mainly IgG1, and 11/17 AGO1 Ab-positive SNN (65%) had a conformational epitope. AGO1 Ab-positive SNN was more severe than AGO1 Ab-negative SNN (e.g., SNN score: 12.2 vs 11.0, p = 0.004), and they more frequently and more efficiently responded to immunomodulatory treatments than AGO1 Ab-negative SNN (7/13 [54%] vs 6/37 [16%], p = 0.02). Regarding the type of treatments more precisely, this significant difference was confirmed for the use of IV immunoglobulins (IVIg) but not for steroids or second-line treatments. Multivariate logistic regression adjusted for potential confounders showed that AGO1 Ab positivity was the only predictor of response to treatment (OR 4.93, 1.10-22.24 95% CI, p = 0.03).DISCUSSION: Although AGO Abs are not specific for SNN, based on our retrospective data, they may identify a subset of cases with SNN with more severe features and a possibly better response to IVIg. The significance of AGO1 Abs in clinical practice needs to be explored on a larger series.

    View details for DOI 10.1212/NXI.0000000000200105

    View details for PubMedID 37072227

  • Anti-Hu Antibodies in Patients With Neurologic Side Effects of Immune Checkpoint Inhibitors. Neurology(R) neuroimmunology & neuroinflammation Farina, A., Villagran-Garcia, M., Ciano-Petersen, N. L., Vogrig, A., Muniz-Castrillo, S., Taillandier, L., Michaud, M., Lefilliatre, M., Wang, A., Lepine, Z., Picard, G., Wucher, V., Dhairi, M., Fabien, N., Goncalves, D., Rogemond, V., Joubert, B., Honnorat, J. 2023; 10 (1)


    BACKGROUND AND OBJECTIVES: To clinically characterize post-immune checkpoint inhibitor (ICI) Hu antibody (Ab) neurologic disorders, we analyzed Hu-Ab-positive patients with neurologic immune-related adverse events (n-irAEs) and compared them with patients with other n-irAEs, ICI-naive patients with Hu-Ab paraneoplastic neurologic syndromes (PNSs) identified in the same study center, and those with Hu-Ab n-irAEs reported elsewhere.METHODS: Patients whose samples were sent to the French reference center for a suspicion of n-irAE (2015-2021) were identified; those with a final diagnosis of n-irAE and Hu-Ab were included. Control groups included patients with a final diagnosis of n-irAE occurring during the same period as the patients included (2018-2021) but without Hu-Ab, and ICI-naive patients with Hu-Ab PNS diagnosed during the same period; a systematic review was performed to identify previous reports.RESULTS: Eleven patients with Hu-Ab and n-irAEs were included (median age, 66 years, range 44-76 years; 73% men). Ten patients had small cell lung cancer, and 1 had lung adenocarcinoma. The median follow-up from onset was 3 months (range 0.5-18 months). Compared with those with other n-irAEs (n = 63), Hu-Ab-positive patients had more frequently co-occurring involvement of both central and peripheral nervous systems (36% vs 8%, p = 0.02) and limbic (54% vs 14%, p < 0.01), brainstem (27% vs 5%, p = 0.02), and dorsal root ganglia (45% vs 5%, p < 0.01) involvement. The proportion of patients with severe disability (modified Rankin Scale score >3) at diagnosis was higher among Hu-Ab n-irAEs (91% vs 52%, p = 0.02). Patients with Hu-Ab had also poorer outcome (100% vs 28%, p < 0.01) and higher mortality (91% vs 46%, p < 0.01). There was no significant difference in terms of clinical features between Hu-Ab n-irAEs and ICI-naive Hu-Ab PNS (n = 92), but there was a poorer outcome (56/78, 71%, p < 0.01) and higher mortality (26%, p < 0.01) among the former. No significant difference was found between the patients reported herein and those in the literature.DISCUSSION: The presence of Hu-Ab identifies a subgroup of n-irAEs that consistently reproduce the phenotypes of Hu-Ab-related PNS, supporting the hypothesis of ICI triggering or unmasking PNS. As these patients show high disability and mortality, further studies are required to investigate the underlying immunopathogenic mechanisms and to improve the outcome of Hu-Ab n-irAEs.

    View details for DOI 10.1212/NXI.0000000000200058

    View details for PubMedID 36446613

  • SOX1 antibody-related paraneoplastic neurological syndromes: clinical correlates and assessment of laboratory diagnostic techniques. Journal of neurology Vabanesi, M., Pinto, A. L., Vogrig, A., Goncalves, D., Rogemond, V., Joubert, B., Fabien, N., Honnorat, J., Muñiz-Castrillo, S. 2022


    To describe the clinical associations of SOX1 antibodies (SOX1-Abs), determine the accuracy of various detection techniques, and propose laboratory criteria to identify definite paraneoplastic neurological syndromes (PNS) associated with SOX1-Abs.Single-center, retrospective study of patients referred to the French Reference Center between 2009 and 2019 for confirmation of SOX1-Ab positivity, without concurrent neural antibodies. Patients were classified according to the updated diagnostic PNS criteria; biological samples were systematically retested with three distinct techniques (line blot, cell-based assay, indirect immunofluorescence).Among 77 patients with isolated SOX1-Ab positivity, 23 (29.9%) fulfilled the criteria for definite PNS; all of them had lung cancer (mostly small-cell) and presented mainly with Lambert-Eaton myasthenic syndrome (10/23) and rapidly progressive cerebellar ataxia (6/23). SOX1-Ab positivity varied depending on the laboratory methods which were used, and a single technique was not sufficient to draw conclusions about the PNS diagnosis. The combination of an antigen-specific test (line blot and/or cell-based assay) and immunofluorescence showed the highest accuracy (81.5%, 95% CI 70.0-90.1) in identifying definite PNS. Moreover, when the PNS-Care score was recalculated assigning three points at the laboratory-level only to patients with positive "antigenic-specific test + immunofluorescence" and 0 points to the remaining cases, a higher certainty for definite and non-PNS was achieved (from 41/77, 53.2%, to 60/77, 77.9%; p < 0.001).SOX1-Abs should be considered high-risk antibodies only when detected with a positive antigenic-specific test and immunofluorescence. Other laboratory results and clinical associations different from Lambert-Eaton myasthenic syndrome and rapidly progressive cerebellar ataxia should be carefully reassessed to rule out false positivity and alternative diagnoses.

    View details for DOI 10.1007/s00415-022-11523-y

    View details for PubMedID 36512064

  • Post-acute anti-NMDAR encephalitis mirrors schizophrenia. Trends in molecular medicine Muniz-Castrillo, S., Vogrig, A., Honnorat, J. 2022


    The post-acute evolution of the cognitive and psychiatric features of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis has been poorly investigated so far. In recent work published in Lancet Neurology, Guasp et al. report that the neuropsychiatric symptoms of the post-acute phase mirror those observed in schizophrenia, although only patients with anti-NMDAR encephalitis showed improvements of their symptoms.

    View details for DOI 10.1016/j.molmed.2022.09.010

    View details for PubMedID 36220717

  • Rank Wise Effect of HLA-DQ5 Explains Risk for the Development of Anti-IgLON5 Disease Yogeshwar, S. M., Peris-Sempere, V., Muniz-Castrillo, S., Luo, G., Finke, C., Honnorat, J., Mignot, E. WILEY. 2022: S143
  • Genetics of Anti-NMDAR Encephalitis Muniz-Castrillo, S., Peris-Sempere, V., Fagundes-Bueno, F., Lomba, S., Honnorat, J., Mignot, E., Anti-Nmdare Collaborators Grp WILEY. 2022: S139
  • Paraneoplastic neurological syndromes associated with renal or bladder cancer: case series and PRISMA-IPD systematic review JOURNAL OF NEUROLOGY Villagran-Garcia, M., Muniz-Castrillo, S., Ciano-Petersen, N., Vogrig, A., Farina, A., Villard, M., Psimaras, D., Alentorn, A., Goncalves, D., Fabien, N., Rogemond, V., Joubert, B., Honnorat, J. 2022


    The link between paraneoplastic neurological syndromes (PNS) and renal cell and bladder cancer (RCC/BC) is rare and uncertain. Our aim was to clinically evaluate, in light of the updated PNS criteria, these uncommon associations.Retrospective nationwide cohort chart review study and systematic review of the literature.After excluding 5 patients due to the diagnosis of another co-occurrent malignancy, 10/18 patients with RCC and 8/18 patients with BC were identified. A total of 31 cases were previously published, yielding an overall series of 27/49 RCC and 22/49 BC patients. There was a predominance of cerebellar syndromes in both cancers (10/27, 37% for RCC; 9/22, 41% for BC), followed by encephalitis in 9/27 (33%) patients with RCC and encephalomyelitis/sensory neuronopathy in 5/22 (23%) patients with BC. The detection of high-risk Abs was more frequent among BC patients (16/19, 84% vs. 3/13, 23% in RCC, p = 0.0009), Ri antibodies being the most frequent thereof. After applying the updated PNS criteria, patients with BC met highest degrees (possible, probable, and definite) of certainty for PNS diagnosis (20/22, 91% vs. 16/27, 59% in RCC, p = 0.021).A second neoplasm should always be ruled out before establishing the diagnosis of PNS in patients with RCC or BC. However, while this association remains dubious for most patients with RCC, a casual role is more probable in patients with BC and high-risk antibodies presenting with cerebellar ataxia, brainstem encephalitis or encephalomyelitis/sensory neuronopathy.

    View details for DOI 10.1007/s00415-022-11356-9

    View details for Web of Science ID 000849276800002

    View details for PubMedID 36050418

  • Cerebellar Ataxia With Anti-DNER Antibodies: Outcomes and Immunologic Features. Neurology(R) neuroimmunology & neuroinflammation Peter, E., Do, L. D., Hannoun, S., Muniz-Castrillo, S., Vogrig, A., Wucher, V., Pinto, A., Chounlamountri, N., Zakaria, W., Rogemond, V., Picard, G., Hedou, J., Ambati, A., Alentorn, A., Traverse-Glehen, A., Manto, M., Psimaras, D., Mignot, E., Cotton, F., Desestret, V., Honnorat, J., Joubert, B. 2022; 9 (5)


    BACKGROUND AND OBJECTIVES: There is no report on the long-term outcomes of ataxia with antibodies against Delta and Notch-like epidermal growth factor-related (DNER). We aimed to describe the clinical-immunologic features and long-term outcomes of patients with anti-DNER antibodies.METHODS: Patients tested positive for anti-DNER antibodies between 2000 and 2020 were identified retrospectively. In those with available samples, immunoglobulin G (IgG) subclass analysis, longitudinal cerebellum volumetry, human leukocyte antigen isotyping, and CSF proteomic analysis were performed. Rodent brain membrane fractionation and organotypic cerebellar slices were used to study DNER cell-surface expression and human IgG binding to the Purkinje cell surface.RESULTS: Twenty-eight patients were included (median age, 52 years, range 19-81): 23 of 28 (82.1%) were male and 23 of 28 (82.1%) had a hematologic malignancy. Most patients (27/28, 96.4%) had cerebellar ataxia; 16 of 28 (57.1%) had noncerebellar symptoms (cognitive impairment, neuropathy, and/or seizures), and 27 of 28 (96.4%) became moderately to severely disabled. Half of the patients (50%) improved, and 32.1% (9/28) had no or slight disability at the last visit (median, 26 months; range, 3-238). Good outcome significantly associated with younger age, milder clinical presentations, and less decrease of cerebellar gray matter volumes at follow-up. No human leukocyte antigen association was identified. Inflammation-related proteins were overexpressed in the patients' CSF. In the rodent brain, DNER was enriched in plasma membrane fractions. Patients' anti-DNER antibodies were predominantly IgG1/3 and bound live Purkinje cells in vitro.DISCUSSION: DNER ataxia is a treatable condition in which nearly a third of patients have a favorable outcome. DNER antibodies bind to the surface of Purkinje cells and are therefore potentially pathogenic, supporting the use of B-cell-targeting treatments.

    View details for DOI 10.1212/NXI.0000000000200018

    View details for PubMedID 35940913

  • Cytokine dynamics and targeted immunotherapies in autoimmune encephalitis BRAIN COMMUNICATIONS Ciano-Petersen, N., Muniz-Castrillo, S., Birzu, C., Vogrig, A., Farina, A., Villagran-Garcia, M., Joubert, B., Psimaras, D., Honnorat, J. 2022; 4 (4): fcac196


    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.

    View details for DOI 10.1093/braincomms/fcac196

    View details for Web of Science ID 000842123700001

    View details for PubMedID 35999839

    View details for PubMedCentralID PMC9392471

  • Long-term evolution and prognostic factors of epilepsy in limbic encephalitis with LGI1 antibodies JOURNAL OF NEUROLOGY Guery, D., Cousyn, L., Navarro, V., Picard, G., Rogemond, V., Bani-Sadr, A., Shor, N., Joubert, B., Muniz-Castrillo, S., Honnorat, J., Rheims, S. 2022; 269 (9): 5061-5069


    To characterize the evolution of epilepsy in patients with leucine-rich glioma inactivated 1 antibody-associated (LGI1ab) limbic encephalitis, including factors associated with drug-resistant epilepsy (DRE).Retrospective analysis of patients with LGI1 encephalitis managed at two tertiary epilepsy centers between 2005 and 2019 and whose samples were confirmed by the French Reference Center of Paraneoplastic Neurological Syndromes. Raw clinical, biological, EEG, and MRI data were reviewed. Two endpoints were defined: (i) Epilepsy remission: patients seizure free and in whom anti-seizure medications (ASM) have been stopped for at least 1 year at the last follow-up visit (ii) DRE: patients with persistent seizures at the last follow-up despite at least two ASM used at efficacious daily dose.39 patients with LGI1 encephalitis were included with a median follow-up duration of 42 months (range 13-169). All of them reported seizures at the acute phase, with faciobrachial dystonic seizures (FBDS) in 23 (59%) and other focal seizures in 38 (97%), including 4 patients (10%) with de novo status epilepticus. At the last follow-up visit, 11 patients (28%) achieved epilepsy remission. Among the 28 patients with persistent epilepsy, eight (29%) fulfilled criteria of DRE. The only factor significantly associated with epilepsy remission was the time from clinical onset of the encephalitis to initiation of the first immunomodulatory treatment, with longer delay in patients with persistent epilepsy (7.5 ± 8.9 vs 2.4 ± 1.7 months, p = 0.006). Evolution to DRE was only driven by MRI evolution. Eight of the 15 patients (53%) who developed hippocampal atrophy (p = 0.007) also suffered from drug-resistant seizures at the last follow-up.In patients with LGI1 encephalitis, rapid initiation of immunomodulatory treatment favors long-term epilepsy remission. Evolution to DRE might primarily reflect the anatomical lesion of limbic structures. Determining what modalities of immune treatment may alter these outcomes requires prospective studies with long-term follow-up.

    View details for DOI 10.1007/s00415-022-11162-3

    View details for Web of Science ID 000798106800002

    View details for PubMedID 35595970

  • Paraneoplastic encephalitis: clinically based approach on diagnosis and management POSTGRADUATE MEDICAL JOURNAL Vaisvilas, M., Ciano-Petersen, N., Villagran-Garcia, M., Muniz-Castrillo, S., Vogrig, A., Honnorat, J. 2022: 669-678


    Paraneoplastic neurological syndromes (PNSs) comprise a subset of immune-mediated nervous system diseases triggered by an underlying malignancy. Each syndrome usually shows a distinct clinical presentation and outcome according to the associated neural antibodies. PNSs generally have a subacute onset with rapid progression and severe neurological disability. However, some patients may have hyperacute onset or even show chronic progression mimicking neurodegenerative diseases. Updated diagnostic criteria for PNS have been recently established in order to increase diagnostic specificity and to encourage standardisation of research initiatives related to PNS. Treatment for PNS includes oncological therapy and immunomodulation to halt neurological deterioration although current treatment options are seldom effective in reversing disability. Nevertheless, growing knowledge and better understanding of PNS pathogenesis promise better recognition, earlier diagnosis and novel treatment strategies. Considering that PNSs provide a model of effective anticancer immunity, the impact of these studies will extend far beyond the field of neurology.

    View details for DOI 10.1136/postgradmedj-2022-141766

    View details for Web of Science ID 000798754000001

    View details for PubMedID 37389581

  • Human Leukocyte Antigen Association Study Reveals DRB1*04:02 Effects Additional to DRB1*07:01 in Anti-LGI1 Encephalitis. Neurology(R) neuroimmunology & neuroinflammation Peris Sempere, V., Muniz-Castrillo, S., Ambati, A., Binks, S., Pinto, A., Rogemond, V., Pittock, S. J., Dubey, D., Geschwind, M. D., Gelfand, J. M., Dilwali, S., Lee, S., Knight, J., Elliott, K. S., Irani, S., Honnorat, J., Mignot, E. 1800; 9 (2)


    BACKGROUND AND OBJECTIVES: To study human leukocyte antigen (HLA) allele associations in anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis.METHODS: A multiethnic cohort of 269 patients with anti-LGI1 encephalitis and 1,359 controls was included. Four-digit HLA sequencing and genome wide association single-nucleotide polymorphism typing imputation (0.99 concordance) were used for HLA typing. Significance of primary and secondary associations was tested using chi2, Fisher exact tests, or logistic regression with the control of population stratification covariates when applicable.RESULTS: DRB1*07:01 and DQA1*02:01, 2 alleles in strong linkage disequilibrium, were associated with the disease (90% vs 24%, OR = 27.8, p < 10e-50) across ethnicity independent of variation at DRB3 and DQB1, 2 flanking HLA loci. DRB1*07:01 homozygosity was associated with a doubling of risk (OR = 2.1, p = 0.010), suggesting causality. DRB1*07:01 negative subjects were younger (p = 0.003) and more frequently female (p = 0.015). Three patients with malignant thymomas did not carry DRB1*07:01, whereas patients with other tumors had high DRB1*07:01 frequency, suggesting that the presence of tumors other than thymomas may be coincidental and not causal. In both DRB1*07:01 heterozygous individuals and DRB1*07:01 negative subjects, DRB1*04:02 was associated with anti-LGI1 encephalitis, indicating an independent effect of this allele (OR = 6.85, p = 4.57 * 10-6 and OR = 8.93, p = 2.50 * 10-3, respectively). DRB1*04:02 was also independently associated with younger age at onset (beta = -6.68, p = 9.78 * 10-3). Major histocompatibility complex peptide-binding predictions using LGI1-derived peptides revealed divergent binding propensities for DRB1*04:02 and DRB1*07:01 alleles, suggesting independent pathogenic mechanisms.DISCUSSION: In addition to the established primary DRB1*07:01 association in anti-LGI1 encephalitis, we observe a secondary effect of DRB1*04:02 with lower age at onset. Our study provides evidence for secondary effects within HLA locus that correlate with clinical phenotypes in anti-LGI1 encephalitis.

    View details for DOI 10.1212/NXI.0000000000001140

    View details for PubMedID 35115410

  • Clinical and Prognostic Value of Immunogenetic Characteristics in Anti-LGI1 Encephalitis. Neurology(R) neuroimmunology & neuroinflammation Muniz-Castrillo, S., Haesebaert, J., Thomas, L., Vogrig, A., Pinto, A., Picard, G., Blanc, C., Do, L., Joubert, B., Berzero, G., Psimaras, D., Alentorn, A., Rogemond, V., Dubois, V., Ambati, A., Tamouza, R., Mignot, E., Honnorat, J. 2021; 8 (3)


    OBJECTIVE: Antibodies against leucine-rich glioma-inactivated 1 (LGI1-Abs) characterize a limbic encephalitis (LE) strongly associated with HLA-DRB1*07:01, although some patients lack LGI1-Abs in CSF or do not carry this allele. Whether they represent a different subtype of disease or have different prognoses is unclear.METHODS: Retrospective analysis of clinical features, IgG isotypes, and outcome according to LGI1-Ab CSF positivity and DRB1*07:01 in a cohort of anti-LGI1 LE patients.RESULTS: Patients with LGI1-Abs detected in both CSF and serum (105/134, 78%) were compared with those who were CSF negative (29/134, 22%). Both groups had similar clinical features and serum levels, but CSF-positive patients had shorter diagnostic delay, more frequently hyponatremia, inflammatory CSF, and abnormal MRI (p < 0.05). Human leukocyte antigen (HLA) genotyping was performed in 72/134 (54%) patients and 63/72 (88%) carried DRB1*07:01. Noncarriers (9/72, 12%) were younger, more commonly women, and had less frequently psychiatric and frontal symptoms (p < 0.05). No difference in IgG isotypes according to CSF positivity or HLA was found (p > 0.05). HLA and IgG isotypes were not associated with poor outcome (mRS >2 at last follow-up) in univariate analyses; CSF positivity was only identified as a poor outcome predictor in the multivariate analysis including the complete follow-up, whereas age and female sex also remained when just the first year was considered.CONCLUSIONS: LE without CSF LGI1-Abs is clinically indistinguishable and likely reflects just a lesser LGI1-Ab production. HLA association is sex and age biased and presents clinical particularities, suggesting subtle differences in the immune response. Long-term outcome depends mostly on demographic characteristics and the intensity of the intrathecal synthesis.

    View details for DOI 10.1212/NXI.0000000000000974

    View details for PubMedID 33848259

  • Distinctive clinical presentation and pathogenic specificities of anti-AK5 encephalitis. Brain : a journal of neurology Muniz-Castrillo, S., Hedou, J. J., Ambati, A., Jones, D., Vogrig, A., Pinto, A., Benaiteau, M., de Broucker, T., Fechtenbaum, L., Labauge, P., Murnane, M., Nocon, C., Taifas, I., Vialatte de Pemille, C., Psimaras, D., Joubert, B., Dubois, V., Wucher, V., Desestret, V., Mignot, E., Honnorat, J. 2021


    Limbic encephalitis (LE) with antibodies against adenylate kinase 5 (AK5) has been difficult to characterize because of its rarity. In this study, we identified 10 new cases and reviewed 16 previously reported patients, investigating clinical features, IgG subclasses, human leukocyte antigen (HLA), and CSF proteomic profiles. Patients with anti-AK5 LE were mostly men (20/26, 76.9%) of median age 66 years old (range 48-94). Predominant symptom was severe episodic amnesia in all patients, frequently associated with depression (17/25, 68.0%). Weight loss, asthenia, and anorexia were also highly characteristic, being present in 11/25 (44.0%) patients. Although epilepsy was always lacking at disease onset, seizures developed later in a subset of patients (4/25, 16.0%). All patients presented CSF abnormalities, such as pleocytosis (18/25, 72.0%), oligoclonal bands (18/25, 72.0%), and increased Tau (11/14, 78.6%). Temporal lobe hyper-intensities were almost always present at disease onset (23/26, 88.5%), evolving nearly invariably toward a severe atrophy in subsequent MRIs (17/19, 89.5%). This finding was in line with a poor response to immunotherapy, with only 5/25 (20.0%) patients responding. IgG1 was the predominant subclass, being the most frequently detected and the one with highest titres in nine CSF-serum paired samples. Temporal biopsy from one of our new cases showed massive lymphocytic infiltrates dominated by both CD4+ and CT8+ T-cells, intense granzyme B expression, and abundant macrophages/microglia. HLA analysis in 11 patients showed a striking association with HLA-B*08:01 (7/11, 63.6%; OR=13.4, 95% CI [3.8-47.4]), C*07:01 (8/11, 72.7%; OR=11.0, 95% CI [2.9-42.5]), DRB1*03:01 (8/11, 72.7%; OR=14.4, 95% CI [3.7-55.7]), DQB1*02:01 (8/11, 72.7%; OR=13.5, 95% CI [3.5-52.0]), and DQA1*05:01 (8/11, 72.7%; OR=14.4, 95% CI [3.7-55.7]) alleles, which formed the extended haplotype B8-C7-DR3-DQ2 in 6/11 (54.5%) patients (OR=16.5, 95% CI [4.8-57.1]). Finally, we compared the CSF proteomic profile of five anti-AK5 patients with that of 40 controls and 10 cases with other more common non-paraneoplastic LE (five with antibodies against leucine-rich glioma inactivated 1 and five against contactin-associated protein-like 2), as well as 10 cases with paraneoplastic neurological syndromes (five with antibodies against Yo and five against Ma2). These comparisons revealed, respectively, 31 and seven significantly up-regulated proteins in anti-AK5 LE, mapping to apoptosis pathways and innate/adaptive immune responses. These findings suggest that the clinical manifestations of anti-AK5 LE result from a distinct T-cell mediated pathogenesis, with major cytotoxicity-induced apoptosis leading to a prompt and aggressive neuronal loss, likely explaining the poor prognosis and response to immunotherapy.

    View details for DOI 10.1093/brain/awab153

    View details for PubMedID 33843981

  • Glial Fibrillary Acidic Protein Autoimmunity: A French Cohort Study. Neurology Dumonceau, A. G., Ameli, R., Rogemond, V., Ruiz, A., Joubert, B., Muñiz-Castrillo, S., Vogrig, A., Picard, G., Ambati, A., Benaiteau, M., Rulquin, F., Ciron, J., Deiva, K., de Broucker, T., Kremer, L., Kerschen, P., Sellal, F., Bouldoires, B., Genet, R., Biberon, J., Bigot, A., Duval, F., Issa, N., Rusu, E. C., Goudot, M., Dutray, A., Devoize, J. L., Hopes, L., Kaminsky, A. L., Philbert, M., Chanson, E., Leblanc, A., Morvan, E., Andriuta, D., Diraison, P., Mirebeau, G., Derollez, C., Bourg, V., Bodard, Q., Fort, C., Grigorashvili-Coin, I., Rieul, G., Molinier-Tiganas, D., Bonnan, M., Tchoumi, T., Honnorat, J., Marignier, R. 2021


    To report the clinical, biological, imaging features, and the clinical course of a French cohort of patients with glial fibrillar acidic protein (GFAP) autoantibodies.We retrospectively included all patients tested positive for GFAP antibodies in the cerebrospinal fluid, by immunohistochemistry and confirmed by cell-based assay using cells expressing human GFAPα, since 2017, from two French referral centers.We identified 46 patients with GFAP antibodies. Median age at onset was 43 years, and 65% were men. Infectious prodromal symptoms were found in 82%. Other auto-immune diseases were found in 22% of patients, and coexisting neural autoantibodies in 11%. Tumors were present in 24%, and T cell dysfunction in 23%. The most frequent presentation was subacute meningoencephalitis (85%) with cerebellar dysfunction in 57% of cases. Other clinical presentation included myelitis (30%), visual (35%) and peripheral nervous system involvement (24%). MRI showed perivascular radial enhancement in 32%, periventricular T2 hyperintensity in 41%, brainstem involvement in 31%, leptomeningeal enhancement in 26%, and reversible splenial lesions in 4 cases. 33/40 patients had a monophasic course, associated to a good outcome at last follow-up (Rankin Score≤2: 89%), despite a severe clinical presentation. Adult and pediatric features are similar. Thirty-two patients were treated with immunotherapy. 11/22 patients showed negative conversion of GFAP antibodies.GFAP auto-immunity is mainly associated with acute/subacute meningoencephalomyelitis with prodromal symptoms, for which tumors and T cell dysfunction are frequent triggers. The majority of patients followed a monophasic course with a good outcome.

    View details for DOI 10.1212/WNL.0000000000013087

    View details for PubMedID 34799461

  • Genetics of Anti-NMDAR Encephalitis Implicates Natural Killer Cells Ambati, A., Lin, L., Muniz-Castrillo, S., Pinto, A. M., Ollila, H., Rogemond, V., Finke, C., Leypoldt, F., Titulaer, M., Honnorat, J., Mignot, E., NMDAR-Ab Working Grp WILEY. 2020: S52
  • Primary DQ effect in the association between HLA and neurological syndromes with anti-GAD65 antibodies. Journal of neurology Muniz-Castrillo, S., Ambati, A., Dubois, V., Vogrig, A., Joubert, B., Rogemond, V., Picard, G., Lin, L., Fabien, N., Mignot, E., Honnorat, J. 2020


    The primary cause of neurological syndromes with antibodies against glutamic acid decarboxylase 65 (GAD65-Ab) is unknown, but genetic predisposition may exist as it is suggested by the co-occurrence in patients and their relatives of other organ-specific autoimmune diseases, notably type 1 diabetes mellitus (T1DM), and by the reports of a few familial cases. We analyzed the human leukocyte antigen (HLA) in 32 unrelated patients and compared them to an ethnically matched sample of 137 healthy controls. Four-digit resolution HLA alleles were imputed from available Genome Wide Association data, and full HLA next-generation sequencing-based typing was also performed. HLA DQA1*05:01-DQB1*02:01-DRB1*03:01 was the most frequent class II haplotype in patients (13/32, 41%). DQB1*02:01 was the only allele found to be significantly more common in patients than in controls (20/137, 15%, corrected p=0.03, OR 3.96, 95% CI [1.54-10.09]). There was also a trend towards more frequent DQA1*05:01 among patients compared to controls (22/137, 16%; corrected p=0.05, OR 3.54, 95% CI [1.40-8.91]) and towards a protective effect of DQB1*03:01 (2/32, 6% in patients vs. 42/137, 31% in control group; corrected p=0.05, OR 0.15, 95% CI [0.02-0.65]). There was no significant demographic or clinical difference between DQ2 and non-DQ2 carriers (p>0.05). Taken together, these findings suggest a primary DQ effect on GAD65-Ab neurological diseases, partially shared with other systemic organ-specific autoimmune diseases such as T1DM. However, it is likely that other non-HLA loci are involved in the genetic predisposition of GAD65-Ab neurological syndromes.

    View details for DOI 10.1007/s00415-020-09782-8

    View details for PubMedID 32152690