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HLA association in MOG-IgG– and AQP4-IgG–related disorders of the CNS in the Dutch population | Neurology Neuroimmunology & Neuroinflammation

HLA association in MOG-IgG– and AQP4-IgG–related disorders of the CNS in the Dutch population | Neurology Neuroimmunology & Neuroinflammation | AntiNMDA | Scoop.it
Abstract Objective To investigate the possible human leukocyte antigen (HLA) association of both myelin oligodendrocyte glycoprotein (MOG-IgG)-associated diseases (MOGAD) and aquaporin-4 antibody (AQP4-IgG)-positive neuromyelitis optica spectrum disorders (NMOSDs) in the Dutch population with European ancestry to clarify similarities or differences in the immunogenetic background of both diseases. Methods Blood samples from patients in the Dutch national MS/NMOSD expert clinic were tested for MOG-IgG and AQP4-IgG using a cell-based assay. HLA Class I and II genotyping was performed in 43 MOG-IgG–seropositive and 42 AQP4-IgG–seropositive Dutch patients with European ancestry and compared with those of 5,604 Dutch healthy blood donors. Results No significant HLA association was found in MOG-IgG–seropositive patients. The AQP4-IgG–seropositive patients had a significant higher frequency of HLA-A*01 (61.9% vs 33.7%, OR 3.16, 95% CI, 1.707–5.863, p after correction [pc] = 0.0045), HLA-B*08 (61.9% vs 25.6%, OR 4.66, 95% CI, 2.513–8.643, pc < 0.0001), and HLA-DRB1*03 (51.2% vs 27.6%, OR 2.75, 95% CI, 1.495–5.042, pc = 0.0199) compared with controls. Conclusions The present study demonstrates differences in the immunogenetic background of MOGAD and AQP4-IgG–positive NMOSD. The strong positive association with HLA-A*01, -B*08, and -DRB1*03 is suggestive of a role of this haplotype in the etiology of AQP4-IgG–positive NMOSD in patients with European ancestry, whereas in MOGAD no evidence was found for any HLA association in these disorders. Glossary ADEM=acute disseminated encephalomyelitis; AQP4=aquaporin-4; CBA=cell-based assay; HLA=human leukocyte antigen; LETM=longitudinally extensive transverse myelitis; MOG=myelin oligodendrocyte glycoprotein; MOGAD=myelin oligodendrocyte glycoprotein–associated disease; NMDAR=NMDA receptor; NMOSD=neuromyelitis optica spectrum disorder; ON=optic neuritis; pc=p after correction; SSO=sequence-specific oligonucleotide; TM=transverse myelitis Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) are related to a spectrum of demyelinating syndromes of the CNS, both in adult and pediatric patients. These are currently known as MOG-IgG–associated diseases (MOGADs) and predominantly include acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), and/or transverse myelitis (TM).1,–,4 A subset of these patients seropositive for MOG-IgG fulfill the criteria for neuromyelitis optica spectrum disorder (NMOSD),5 whereas the majority of NMOSDs are associated with aquaporin-4 antibodies (AQP4-IgG).6,–,9 This partial clinical overlap between patients seropositive for MOG-IgG and AQP4-IgG is interesting because the underlying disease mechanism is thought to be different, with autoantibodies targeting oligodendrocytes and astrocytes, respectively.10,–,12 The existence of these IgG autoantibodies, however, is indicative for a key role for B and CD4+ T cells in the disease process of both disorders and, consequently, for a potential role for human leukocyte antigen (HLA). Possible HLA associations could further elucidate similarity or difference between MOG-IgG– and AQP4-IgG–related disorders based on their immunogenetic background. Previous studies have described different HLA associations in NMOSD including subgroups of AQP4-IgG–seropositive patients. Of interest, so far, a possible HLA association has never been studied in MOGAD. Furthermore, HLA associations vary between ethnic backgrounds, and the Dutch AQP4-IgG-seropositive patients with European ancestry have never been studied before. The aim of this study was to investigate the possible HLA association of both MOGAD and AQP4-IgG–positive NMOSD in the Dutch population with European ancestry to clarify the contribution of HLA to the pathophysiology in both of these diseases. Methods Study participants and definitions This study was conducted at the Dutch national center for acquired demyelinating syndromes, which includes the NMOSD expert clinic (Erasmus MC) and Pediatric MS center (Erasmus MC-Sophia Children's Hospital) in Rotterdam, the Netherlands, and Sanquin Diagnostic Services in Amsterdam, the Netherlands. Serum samples from all patients who either presented primarily at our hospitals or were referred by other (non)academic hospitals were sent in for routine MOG-IgG and AQP4-IgG diagnostics as part of standard clinical care. Patients from all ages were included if they were (1) seropositive for either MOG-IgG or AQP4-IgG and (2) of European descent. Included patients presented with a demyelinating event within the acquired demyelinating syndromes spectrum, i.e., ON and/or (longitudinally extensive) transverse myelitis ([LE]TM), area postrema syndrome, or ADEM. Diagnosis at last follow-up was determined as NMOSD if fulfilling the Wingerchuk 2015 diagnostic criteria.5 Patients who had 1 or more ON following initial presentation with ADEM were diagnosed with ADEM-ON.13 Patients with a possible diagnosis of MS (clinically and radiologically) were excluded. HLA allele frequencies of MOG-IgG– and AQP4-IgG–seropositive patients were compared with the HLA allele frequencies of 5,604 healthy Dutch blood donors from the Leiden area in the Netherlands. Standard protocol approvals, registrations, and patient consents The Medical Ethical Committee of Erasmus Medical Center in Rotterdam approved this study. All patients signed informed consent to store their blood samples and clinical characteristics in our Biobank. Cell culture and cell-based assays All serum samples were tested blindly, centrally, and in duplicate at Sanquin Diagnostics with the cell-based assay (CBA) as previously described.1,8 Briefly, patient serum was incubated with HEK293 cells transiently transfected with AQP4-M23 (final serum dilution 1:20) or LN18 cells stably transfected with full-length MOG (final serum dilution 1:200). After washing, cells were incubated with goat anti-human IgG allophycocyanin-conjugated secondary antibody (Jackson ImmunoResearch Laboratories, Brunschwig Chemie B.V., Amsterdam, the Netherlands [specific for human IgG]) and analyzed using fluorescence-activated cell sorter. The cutoff was determined in every assay as average Delta MFI +10 SDs of 8 individual sera of negative controls. Our assay comprises an anti–IgG-specific detection antibody, and thus, no IgM anti-MOG or IgM anti-AQP4 is detected. HLA analysis HLA Class I and II genotyping was performed at the National Reference Center for Histocompatibility Testing at the Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, the Netherlands. DNA for HLA analysis was isolated from peripheral blood samples. HLA Class I typing (HLA-A*, -B*, -Cw*) was performed by the reverse sequence–specific oligonucleotide (SSO) method on a suspension array platform using microspheres as a solid support to immobilize oligonucleotide probes (Luminex bead technology; Immucor Transplant Diagnostics, Stamford, CT). HLA Class II (HLA-DRB1*, DQB1*, DRB3*/4*/5*) was genotyped using the PCR SSO probe technique,14 which results in medium-low resolution subtyping. Statistical analysis For patient characteristic group comparisons, the χ2 or Fisher exact test and the Mann-Whitney U test were used when appropriate. HLA allele frequencies were analyzed using the Fisher exact probability test. p Values were corrected with Sidak method for multiple testing. A corrected p value (pc) below 0.05 was considered significant. ORs were calculated using the Woolf method with Haldane modifications (Woolf-Haldane). Data availability The raw data used in this article are available at the Erasmus University Medical Center and could be shared by request from a qualified investigator, maintaining anonymization of the individual patients. Results In total, 85 Dutch patients with European ancestry were analyzed, including 43 MOG-IgG– and 42 AQP4-IgG–seropositive patients. Patient characteristics are shown in table 1. View inline View popup Table 1 Patient characteristics of MOG-IgG– and AQP4-IgG–seropositive patients Patient characteristics of MOG-IgG–seropositive patients MOG-IgG–seropositive patients were predominantly male (63%), and almost half of the MOG-IgG–seropositive patients (49%) had their onset of disease during childhood (<18 years) (table 1). Table 1 also gives a separate overview of included children and adults. Except for age at onset of disease, patient characteristics were not significantly different between children and adults. As described above, the clinical phenotype of MOGAD consists of a spectrum of demyelinating disorders. In total, 12 MOG-IgG–seropositive patients (28%) presented with ON, of which 42% were bilateral, and 10 (23%) with TM, of which 60% showed an longitudinally extensive lesion on MRI. In addition, of the 7 patients (16%) presenting with a combination of ON and TM, 71% had a bilateral ON, and 67% an LETM on MRI. Figure 1 shows an overview of diagnosis at last follow-up of the included MOG-IgG–seropositive patients, separated for children and adults. Within a median follow-up of 55 months (range: 1–463 months), in total, 28% of MOG-IgG–seropositive patients (including 4 children and 8 adults) were finally diagnosed with a combination of ON and MT. Of these, only 6 patients fulfilled the Wingerchuk 2015 criteria for NMOSD diagnosis (50%). Only pediatric patients were diagnosed with ADEM (62% of children vs 0% of adults, p < 0.001). Adults were more often diagnosed with a TM compared with pediatric patients (5% of children vs 32% of adults, p = 0.046). Figure 1 Diagnosis at last follow-up of included MOG-IgG–seropositive children and adults *6/12 patients fulfilling Wingerchuk 2015 diagnostic criteria for NMOSD. **Relapsing ADEM group only consists of patients with ADEM-ON (ADEM followed by (recurrent) optic neuritis). ***Including 1 adult with a relapsing encephalitis (double syndrome MOG-IgG/NMDA-R) and 1 child with a progressive ‘leukodystrophy-like’ disease. ADEM = acute disseminated encephalomyelitis; MOG-IgG = myelin oligodendrocyte glycoprotein antibody; MOGAD = MOG-IgG-associated disease; ON = optic neuritis; TM = transverse myelitis. Furthermore, among the MOG-IgG–seropositive patients, 1 patient was diagnosed with a progressive leukodystrophy-like disorder with a severe regression of cognitive functions (figure 1). This patient deceased 6 years after the start of first symptoms. Another MOG-IgG–seropositive patient presented with a recurrent encephalitis. In this patient, NMDA receptor (NMDAR) antibodies were found additionally to the positive MOG-IgG. This patient was diagnosed with a double syndrome (figure 1) because besides typical anti-NMDAR encephalitis features, this patients also had clinical and radiologic findings compatible with a demyelinating disorder, including diplopia, visual impairment, urge incontinence, and demyelinating lesions on MRI. Finally, 1 MOG-IgG–seropositive patient diagnosed with monophasic ADEM also had transient AQP4-IgG; he twice had a weak positive CBA test result for AQP4-IgG, i.e., during onset of disease and in the first follow-up sample 5 years later. In the following sample, 1 year later, he became AQP4-IgG seronegative. Because the MOG-IgG remained detectable and because of his clinical phenotype, which was more compatible with MOGAD than AQP4-IgG–seropositive NMOSD, this patient was only included in the MOG-IgG–seropositive patient group. Patient characteristics AQP4-IgG–seropositive patients The majority of AQP4-IgG–seropositive patients were female (86%), and 67% of patients had a relapsing disease course (table 1). Within a median follow-up of 65 months (range: 6–312 months), all AQP4-IgG–seropositive patients were diagnosed with NMOSD (all fulfilling the Wingerchuk 2015 diagnostic criteria). HLA association in MOG-IgG–seropositive patients In MOG-IgG–seropositive patients, a lower proportion of HLA-A*68 (0.0% vs 9.2%, OR 0.11, 95% CI, 0.007–1.838, p = 0.0299) and a higher proportion of HLA-B*08 (41.9% vs 25.6%, OR 2.11, 95% CI, 1.154–3.842, p = 0.0217) were observed compared with controls. However, these results did not remain significant after statistical correction for multiple testing (table 2). No significant HLA-A, -B, -C, -DR, and -DQ associations were found in MOG-IgG–seropositive patients (table e-1, links.lww.com/NXI/A214). View inline View popup Table 2 HLA allele frequencies in MOG-IgG–seropositive patients and controlsa Because of the heterogeneity in the MOG-IgG–seropositive patient group, different subanalyses were performed. A subanalysis with exclusion of MOG-IgG–seropositive patients with above described rare MOGAD presentations (n = 3; progressive leukodystrophy-like disorder, double syndrome with NMDAR encephalitis, and ADEM with coexisting transient weak positive AQP4-IgG) showed comparable results, with, in addition, an increased frequency of HLA-DRB1*15 (40.0% vs 24.2%, OR 2.11, 95% CI, 1.127–3.949, p = 0.0260). However, this association did not remain significant after statistical correction for multiple testing. A subanalysis on age group, comparing MOG-IgG–seropositive children (n = 21) with MOG-IgG–seropositive adults (n = 22), showed no significant differences nor tendencies. Further subanalyses in MOG-IgG–seropositive patients on disease onset phenotype (opticospinal, n = 28 vs non-opticospinal, n = 15), disease course (monophasic, n = 27 vs multiphasic, n = 16), and final diagnosis (ADEM, n = 13 vs non-ADEM, n = 30) showed no significant differences nor tendencies for the HLA-A*01, -B*08, -DRB1*03 haplotype, which is the most relevant haplotype in the European population (see below). HLA association in AQP4-IgG–seropositive patients Table 3 shows significant HLA associations in the AQP4-IgG–seropositive patients compared with controls. After correction for multiple testing, a strong positive association for HLA-A*01 (61.9% vs 33.7%, OR 3.16, 95% CI, 1.707–5.863, pc = 0.0045), HLA-B*08 (61.9% vs 25.6%, OR 4.66, 95% CI, 2.513–8.643, pc < 0.0001), and HLA-DRB1*03 (51.2% vs 27.6%, OR 2.75, 95% CI, 1.495–5.042, pc = 0.0199) remained significant (figure 2), suggestive of a role of this conserved HLA-A*01, -B*08, -DRB1*03 haplotype. In 16/42 (38%) of patients, this haplotype was present. All HLA allelic frequencies of AQP4-IgG–seropositive patients are displayed in table e-2 (links.lww.com/NXI/A214). View inline View popup Table 3 HLA allele frequencies in AQP4-IgG–seropositive patients and controlsa Figure 2 Forest plot of significant HLA associations in AQP4-IgG–seropositive patients* *After correction for multiple testing (Sidak method). Discussion We found clear differences in HLA Class I and II alleles in Dutch MOG-IgG– and AQP4-IgG–seropositive patients with European ancestry. In AQP4-IgG–seropositive patients, we found a strong positive association with HLA-A*01, -B*08, and -DRB1*03. In contrast, we did not find any evidence for a particular HLA association in MOG-IgG–seropositive patients. These findings are relevant for a further distinction between MOGAD from AQP4-IgG–positive NMOSD. Where MOG-IgG was first found to represent a subset of patients with AQP4-IgG–negative NMOSD, nowadays MOG-IgG is consistently identified in a broad spectrum of acquired demyelinating syndromes, which extend beyond the NMOSD phenotype.1,–,4,12 Previous studies have identified some clinical and imaging features that can distinguish MOGAD from AQP4-IgG–positive NMOSD; however, in several patients, the clinical and radiologic phenotype still overlaps.12,15,–,18 Nevertheless, the immunopathogenic differences in these diseases, i.e., an astrocytopathy in AQP4-IgG–positive NMOSD and an oligodendrocytopathy in MOGAD, suggest 2 distinctive autoimmune disorders.12 The present findings further support these differences on the basis of the immunogenetic features and therefore once again emphasize the probable pathophysiologic difference between MOG-IgG– and AQP4-IgG–related diseases. Although HLA associations in AQP4-IgG–mediated NMOSD have previously been studied in a few ethnic populations worldwide, this study was the first investigating the Dutch population with European ancestry. Our finding of HLA-DRB1*03 as risk allele in AQP4-IgG–mediated disorders confirms and extends the results previously obtained in patients with NMOSD from different non-Asian populations.19,–,24 Also, the recent large genome-wide association study from Estrada et al.25 found HLA-DRB1*03:01 as the most significant HLA allele in patients with NMOSD from Texas compared with controls of European ancestry, which was driven by the presence of AQP4-IgG. HLA-DRB1*03 has not been found as risk allele in 2 studies with European26 and Arabic27 patients with NMOSD. However, these 2 studies had smaller proportions of AQP4-IgG–seropositive patients among their included patients with NMOSD (respectively, 61% and 49%, compared with 73–100% in the other mentioned cohorts), what could explain the absence of a significant association with HLA-DRB1*03. An association with HLA-DPB1*0501 has previously been described only in Asian patients with AQP4-IgG–positive NMOSD28,–,30 and was not found in our Dutch patients with European ancestry. In addition, we found a strong correlation with HLA-A*01 (OR 3.16) and HLA-B*08 (OR 4.66): 2 HLA Class I genes. These associations have never been described in the previous literature, possibly as most previous studies only focused on the HLA Class II alleles. AQP4-IgG has been established as pathogenic autoantigen, directly targeting the AQP4 water channel on the foot of the astrocytes and causing complement-mediated necrosis, secondary demyelination, inflammation, and subsequently neuronal death.9,10,31 Therefore, the expectation of HLA Class II associations in this presumed primary B cell–mediated disorder is imaginable. However, also HLA Class I genes can play a key or additional role in initiating or maintaining autoimmune responses, primarily by triggering a CD8+ cytotoxic T-cell response.32 Our found associations with HLA Class I alleles could indicate involvement of such T-cell responses in the pathogenesis of AQP4-IgG–mediated NMOSD. Nonetheless, HLA-A*01 and HLA-B*08 are also known to form an ancestral European haplotype together with (among others) HLA-DRB1*03 due to linkage.33 Whether there is an independent contribution of HLA-A*01 and HLA-B*08 in AQP4-IgG–mediated NMOSD or whether these HLA Class I associations are only a result of linkage with DRB1*03 remains to be established. Of interest, this ancestral European haplotype including HLA-DRB1*03 has also been linked to several other autoimmune diseases, such as SLE, Sjögren syndrome, myasthenia gravis, Graves disease, and celiac disease.32,33 This is in accordance with the clinical observation in AQP4-IgG–seropositive patients that around 25% of these patients have coexisting autoimmune disorders as listed above.34,–,38 In our AQP4-IgG–seropositive patients 19% also had an accompanying autoimmune disease. To our best knowledge, this was the first study worldwide investigating HLA associations in MOGAD. Of interest, we found no evidence for particular HLA associations in our MOG-IgG–seropositive patients. This finding is striking because one could expect a contribution of HLA in the pathophysiology of MOGAD due to the presence of the autoantibodies. However, in contrast to AQP4-IgG, the pathogenicity of MOG-IgG has not fully been elucidated.15,39 MOG-IgG targets the CNS-specific MOG protein, which is expressed on the outer surface of the myelin sheaths and plasma membrane of oligodendrocytes.4,40,41 Although the MOG protein only represents a minor component of myelin (0.05%),41 its location makes it highly immunogenic4 and is an imaginable target for autoantibodies in a demyelinating disease. However, although in vitro studies have demonstrated that human MOG-IgG activates complement and cellular-dependent cytotoxicity, in vivo rodent models could not confirm the human MOG-IgG to cause demyelination in these animals.15,42,–,45 Nevertheless, there are various possible explanations for the human MOG-IgG not being pathogenic in rodents, most importantly because human MOG-IgG simply does not recognize the rodent MOG protein.39 Additionally to these immunologic studies, histopathologic findings from MOG-IgG–seropositive patients show activated complement at sites of ongoing demyelinating.39,46,47 This again supports a humoral immune pathogenesis and a potential pathogenic activity of human MOG-IgG. Importantly, our negative result for HLA associations in MOGAD does not directly reject the assumption that these disorders are primary B cell-mediated due to the potential T cell-independent B cell activation by antibody-inducing signals from, for example, dendritic cells, macrophages, and granulocytes.48 An alternative explanation may be that many different HLA Class II/peptide complexes are able to trigger CD4+ T cells to provide help to the B cells resulting in IgG antibodies in all patients irrespective of their HLA-DR type. One could hypothesize that the distinctive clinical phenotypes within the MOGAD could have a different underlying pathogenesis with potentially a different immunogenetic background. The broad spectrum of MOGAD is also variable with age at onset. In children, ADEM is more prevalent compared with adults. In adults, most patients have ON, (LE)TM, or both (either simultaneously or subsequently).49 Despite these apparent phenotypical differences, we did not find differences in HLA allele frequencies when comparing subgroups regarding age (child vs adult), disease course (mono- vs multiphasic), and clinical presentation (opticospinal vs non-opticospinal and ADEM vs non-ADEM), neither after exclusion of rare MOGAD presentations. This again supports our main finding regarding the absence of HLA association in MOGAD, with also the absence of HLA association in distinctive MOGAD subgroups. In general, confounding due to linkage with neighboring HLA and non-HLA genes is a possible limitation when studying HLA associations. Furthermore, as described before, we should be reminiscent of the ethnic variation of HLA associations within the same disease. We therefore only included patients with European ancestry in our study. A specific limitation of our study is the relatively small sample size, which is inherent to the rarity of both antibody-mediated diseases. However, our AQP4-IgG–seropositive patient group was very homogeneous, and therefore, we do not expect that the relatively low number has influenced the results in this patient group. In contrast, our MOG-IgG–seropositive patient group was more heterogeneous regarding clinical phenotype and age at onset, as a result of the broad spectrum in MOGAD. Because of the small sample size, only limited subanalyses were possible to overcome this issue. In conclusion, we show no evidence for HLA association in MOGAD in the Dutch population with European ancestry. Whereas in AQP4-IgG–seropositive patients, the newly found association with HLA-A*01 and HLA-B*08, together with the confirmation of the earlier described association with HLA-DRB1*03, is suggestive of a role of this haplotype in the etiology of these AQP4-IgG–mediated diseases in patients with European ancestry. These findings are suggestive of a different immunogenetic background and therefore once again emphasize MOGAD and AQP4-IgG–positive NMOSD to be distinctive demyelinating disorders of the CNS. Similar studies need to be conducted in MOGAD, preferably with international collaboration for larger sample sizes. Furthermore, it would be interesting to investigate the independent risk of the found HLA Class I and II alleles to AQP4-IgG–positive NMOSD. Study funding The study was supported by the Dutch MS research Foundation. This study was not industry sponsored. Disclosure A.L. Bruijstens, Y.Y.M. Wong, D.E. van Pelt, P.J.E. van der Linden, G.W. Haasnoot, R.Q. Hintzen, F.H.J. Claas, R.F. Neuteboom, and B.H.A. Wokke report no disclosures relevant to the manuscript. Go to Neurology.org/NN for full disclosures. Acknowledgment The authors thank the patients and their families for their participation in this study. Rogier Q. Hintzen is deceased. Appendix Authors Footnotes Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article. The Article Processing Charge was funded by the authors. ↵* These authors are shared last authors. Received November 18, 2019. Accepted in final form February 7, 2020. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. 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Is neuromyelitis optica associated with human leukocyte antigen?. Mult Scler 2009;15:571–579.OpenUrlCrossRefPubMed 21.↵Deschamps R, Paturel L, Jeannin S, et al. Different HLA class II (DRB1 and DQB1) alleles determine either susceptibility or resistance to NMO and multiple sclerosis among the French Afro-Caribbean population. Mult Scler 2011;17:24–31.OpenUrlCrossRefPubMed 22.↵Brum DG, Barreira AA, dos Santos AC, et al. HLA-DRB association in neuromyelitis optica is different from that observed in multiple sclerosis. Mult Scler 2010;16:21–29.OpenUrlCrossRefPubMed 23.↵Alvarenga MP, Fernandez O, Leyva L, et al. The HLA DRB1*03:01 allele is associated with NMO regardless of the NMO-IgG status in Brazilian patients from Rio de Janeiro. J Neuroimmunol 2017;310:1–7.OpenUrl 24.↵Alonso VR, de Jesus Flores Rivera J, Garci YR, et al. Neuromyelitis optica (NMO IgG+) and genetic susceptibility, potential ethnic influences. Cent Nerv Syst Agents Med Chem 2018;18:4–7.OpenUrl 25.↵Estrada K, Whelan CW, Zhao F, et al. A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica. Nat Commun 2018;9:1929.OpenUrl 26.↵Asgari N, Nielsen C, Stenager E, Kyvik KO, Lillevang ST. HLA, PTPN22 and PD-1 associations as markers of autoimmunity in neuromyelitis optica. Mult Scler 2012;18:23–30.OpenUrlCrossRefPubMed 27.↵Brill L, Mandel M, Karussis D, et al. Increased occurrence of anti-AQP4 seropositivity and unique HLA Class II associations with neuromyelitis optica (NMO), among Muslim Arabs in Israel. J Neuroimmunol 2016;293:65–70.OpenUrl 28.↵Matsushita T, Matsuoka T, Isobe N, et al. Association of the HLA-DPB1*0501 allele with anti-aquaporin-4 antibody positivity in Japanese patients with idiopathic central nervous system demyelinating disorders. Tissue Antigens 2009;73:171–176.OpenUrlCrossRefPubMed 29.↵Wang H, Dai Y, Qiu W, et al. HLA-DPB1 0501 is associated with susceptibility to anti-aquaporin-4 antibodies positive neuromyelitis optica in southern Han Chinese. J Neuroimmunol 2011;233:181–184.OpenUrlCrossRefPubMed 30.↵Yoshimura S, Isobe N, Matsushita T, et al. Distinct genetic and infectious profiles in Japanese neuromyelitis optica patients according to anti-aquaporin 4 antibody status. J Neurol Neurosurg Psychiatry 2013;84:29–34. 31.↵Lucchinetti CF, Guo Y, Popescu BF, Fujihara K, Itoyama Y, Misu T. The pathology of an autoimmune astrocytopathy: lessons learned from neuromyelitis optica. Brain Pathol 2014;24:83–97.OpenUrlCrossRefPubMed 32.↵Gough SC, Simmonds MJ. The HLA region and autoimmune disease: associations and mechanisms of action. Curr Genomics 2007;8:453–465.OpenUrlCrossRefPubMed 33.↵Gambino CM, Aiello A, Accardi G, Caruso C, Candore G. Autoimmune diseases and 8.1 ancestral haplotype: an update. HLA 2018;92:137–143.OpenUrl 34.↵Pittock SJ, Lennon VA, de Seze J, et al. Neuromyelitis optica and non organ-specific autoimmunity. Arch Neurol 2008;65:78–83.OpenUrlCrossRefPubMed 35.↵Jarius S, Ruprecht K, Wildemann B, et al. Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: a multicentre study of 175 patients. J Neuroinflammation 2012;9:14.OpenUrlCrossRefPubMed 36.↵Wandinger KP, Stangel M, Witte T, et al. Autoantibodies against aquaporin-4 in patients with neuropsychiatric systemic lupus erythematosus and primary Sjogren's syndrome. Arthritis Rheum 2010;62:1198–1200.OpenUrlCrossRefPubMed 37.↵Jarius S, Jacob S, Waters P, Jacob A, Littleton E, Vincent A. Neuromyelitis optica in patients with gluten sensitivity associated with antibodies to aquaporin-4. J Neurol Neurosurg Psychiatry 2008;79:1084.OpenUrlFREE Full Text 38.↵Jarius S, Paul F, Franciotta D, et al. Neuromyelitis optica spectrum disorders in patients with myasthenia gravis: ten new aquaporin-4 antibody positive cases and a review of the literature. Mult Scler 2012;18:1135–1143.OpenUrlCrossRefPubMed 39.↵Peschl P, Bradl M, Hoftberger R, Berger T, Reindl M. Myelin oligodendrocyte glycoprotein: deciphering a target in inflammatory demyelinating diseases. Front Immunol 2017;8:529.OpenUrlCrossRefPubMed 40.↵Brunner C, Lassmann H, Waehneldt TV, Matthieu JM, Linington C. Differential ultrastructural localization of myelin basic protein, myelin/oligodendroglial glycoprotein, and 2',3'-cyclic nucleotide 3'-phosphodiesterase in the CNS of adult rats. J Neurochem 1989;52:296–304.OpenUrlCrossRefPubMed 41.↵Hemmer B, Archelos JJ, Hartung HP. New concepts in the immunopathogenesis of multiple sclerosis. Nat Rev Neurosci 2002;3:291–301.OpenUrlCrossRefPubMed 42.↵Peschl P, Schanda K, Zeka B, et al. Human antibodies against the myelin oligodendrocyte glycoprotein can cause complement-dependent demyelination. J Neuroinflammation 2017;14:208.OpenUrl 43.↵Zhou D, Srivastava R, Nessler S, et al. Identification of a pathogenic antibody response to native myelin oligodendrocyte glycoprotein in multiple sclerosis. Proc Natl Acad Sci U S A 2006;103:19057–19062. 44.↵Mader S, Gredler V, Schanda K, et al. Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders. J Neuroinflammation 2011;8:184.OpenUrlCrossRefPubMed 45.↵Bettelli E, Baeten D, Jager A, Sobel RA, Kuchroo VK. Myelin oligodendrocyte glycoprotein-specific T and B cells cooperate to induce a Devic-like disease in mice. J Clin Invest 2006;116:2393–2402.OpenUrlCrossRefPubMed 46.↵Spadaro M, Gerdes LA, Mayer MC, et al. Histopathology and clinical course of MOG-antibody-associated encephalomyelitis. Ann Clin Transl Neurol 2015;2:295–301.OpenUrl 47.↵Wang JJ, Jaunmuktane Z, Mummery C, Brandner S, Leary S, Trip SA. Inflammatory demyelination without astrocyte loss in MOG antibody-positive NMOSD. Neurology 2016;87:229–231.OpenUrl 48.↵Cerutti A, Puga I, Cols M. New helping friends for B cells. Eur J Immunol 2012;42:1956–1968.OpenUrlCrossRefPubMed 49.↵Chen L, Chen C, Zhong X, et al. Different features between pediatric-onset and adult-onset patients who are seropositive for MOG-IgG: a multicenter study in South China. J Neuroimmunol 2018;321:83–91.OpenUrl
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Neural Antibody Testing in Patients with Suspected Autoimmune Encephalitis | Clinical Chemistry | Oxford Academic

Neural Antibody Testing in Patients with Suspected Autoimmune Encephalitis | Clinical Chemistry | Oxford Academic | AntiNMDA | Scoop.it
AbstractBackground. Autoimmunity is an increasingly recognized cause of encephalitis with a similar prevalence to that of infectious etiologies. Over the past d
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Pathophysiology of paraneoplastic and autoimmune encephalitis: genes, infections, and checkpoint inhibitors - Alberto Vogrig, Sergio Muñiz-Castrillo, Virginie Desestret, Bastien Joubert, Jérôme Hon...

Pathophysiology of paraneoplastic and autoimmune encephalitis: genes, infections, and checkpoint inhibitors - Alberto Vogrig, Sergio Muñiz-Castrillo, Virginie Desestret, Bastien Joubert, Jérôme Hon... | AntiNMDA | Scoop.it
Paraneoplastic neurological syndromes (PNSs) are rare complications of systemic cancers that can affect all parts of the central and/or peripheral nervous system. A body of experimental and clinica...
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Relationship between serum NMDA receptor antibodies and response to antipsychotic treatment in first episode psychosis

Relationship between serum NMDA receptor antibodies and response to antipsychotic treatment in first episode psychosis | AntiNMDA | Scoop.it
When psychosis develops in NMDAR antibody encephalitis it usually has an acute or
subacute onset, and antipsychotic treatment may be ineffective and associated with
adverse effects. Serum NMDAR antibodies have been reported in a minority of patients with first episode psychosis (FEP), but their...
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https://www.researchgate.net/publication/343817904_Anti-N-methyl-D-Aspartate_NMDA_Receptor_Encephalitis_A_Case_Report

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Defying the odds, U of T's Carisse Samuel to graduate after spending five months in a coma

Defying the odds, U of T's Carisse Samuel to graduate after spending five months in a coma | AntiNMDA | Scoop.it
When Carisse Samuel joins her fellow graduates at the University of Toronto’s virtual convocation this Saturday, the celebration will be both an academic and personal victory.
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Clinical features which predict neuronal surface autoantibodies in new-onset focal epilepsy: implications for immunotherapies | Journal of Neurology, Neurosurgery & Psychiatry

Introduction Neuronal surface-directed antibodies (NSAbs) are considered pathogenic in patients with autoimmune encephalitis (AE). AE commonly presents with prominent seizures and neuropsychiatric features and shows a preferential response to immunotherapies versus anti-seizure medications (ASMs).1–4 This has prompted the introduction of ‘epilepsy of immune aetiology’ within the International League Against Epilepsy (ILAE) 2017 classification.5 The same NSAbs, as well as high levels of antibodies to intraneuronal glutamic acid decarboxylase-65 (GAD65), are also described in the serum of people with more isolated forms of epilepsy, without core features of encephalitis.6–8 In this context, their clinical, aetiological and therapeutic relevance is unclear, but of major potential importance to all neurologists who manage new-onset epilepsy. In our large, prospective, real-world study of new-onset focal epilepsy, we predicted that formes frustes of AE would help identify clinical features suggesting the presence of NSAbs and asked whether detection of these NSAbs should alter patient management. Materials and methods Between 9 December 2011 and 4 November 2015, consecutive adult patients (≥18 years) with a diagnosis of new-onset focal epilepsy and their first seizure within the previous 12 months were prospectively recruited from the routine practice of two epileptologists at the Oxford University Hospitals NHS Foundation Trust. Written informed consent and sera were obtained (Ethical approvals: Oxfordshire RECA 07/Q160X/28 and REC16/YH/0013). Clinical data gathered at onset (online supplemental table 1) included detailed phenotype and investigation results, Quality of Life in Epilepsy-31, Hospital Anxiety and Depression Score, Addenbrooke’s Cognitive Examination (ACE) and modified Rankin Score (mRS); as well as information to inform the Antibody Prevalence in Epilepsy and Encephalopathy (APE2) score (online supplemental table 2)9 10 and diagnostic criteria for possible or definite AE.11 Subsequently, 1-year and 3-year mRS were ascertained from patients with NSAbs. Supplemental material For NSAbs, sera were tested against autoantigen-expressing live HEK293 cells (live cell-based assay; online supplemental table 3), and for reactivity with the surface of live cultured hippocampal neurons, using sensitive protocols.12 13 Autoantibodies to GAD65 were determined using a commercial radioimmunoprecipitation assay. Statistical analysis was conducted in R (V.3.6.1). Dimensionality reduction was performed using Multiple Factor Analysis in ‘FactoMineR’ with up to 10% missing data imputed using missForest. Stepwise Bayesian general linear modelling analysis was undertaken using ‘arm’. Wilson 95% CIs with continuity correction were calculated using ‘DescTools’. Results NSAb findings Of 241 recruited patients, 22 were excluded (online supplemental table 4). Of the remaining 219, median age was 49 years (range 16–91) and 109 (49.8%) were female. In 23/219 (10.5%) patients, serum NSAbs were detected across candidate and novel autoantigens (table 1) including roughly equal frequencies against leucine-rich glioma inactivated-1 (LGI1), contactin-associated protein-like 2 (CASPR2), plus the N-methyl-d-aspartate receptor (NMDAR) and γ-aminobutyric acid A/B receptors (GABAAR and GABABR). An additional five patients had antibodies to the surface of live neurons, without an established autoantigen. Autoantibodies to contactin-2, the glycine receptor and the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) were each found in one patient. No dipeptidyl-peptidase-like protein 6 (DPPX) or high-titre GAD65 antibodies were detected. Overall, from the 23 people with NSAbs, 9 had a clinical diagnosis of AE (7/9 fulfilling published criteria).11 By contrast, none of the 196 without NSAbs had a clinical diagnosis of AE (p<0.0001; Fisher’s exact test). VIEW INLINE VIEW POPUP Table 1 Clinical and laboratory features of patients with epilepsy and positive neuronal surface autoantibodies Factors associated with the presence of NSAbs and AE Dimensionality reduction with multiple factor analysis showed that patients were highly heterogeneous and the modest clustering of those with NSAbs was largely driven by a clinical diagnosis of AE (figure 1A,B). Univariate analysis identified 11 clinical parameters that differed significantly between patients with and without NSAbs: age (p=0.04), ictal piloerection (p=0.02), lesional MRI (p=0.04), self-reported mood disturbance (p=0.007), ACE attention domain (p=0.01), ACE total score (p=0.04), QOLIE-31 score (p=0.02), self-reported neuropsychiatric features (p=0.03), epilepsy risk factors (p=0.05), inflammatory cerebrospinal fluid (CSF; p=0.004) and limbic system lesions on MRI (p=0.0002). A multivariate stepwise regression model allocated weighted scores to six of these: age ≥54 years=+1, self-reported mood disturbance=+1, limbic system lesions on MRI=+2, ictal piloerection=+2.5, ACE attention score ≥16=−1.5 and epilepsy risk factors=−1.5 (figure 1C). The probability of NSAb positivity increased with higher scores (Spearman’s ρ=0.99, p<0.0001; figure 1C) and receiver operating characteristic (ROC) analysis confirmed these features strongly predicted NSAb status (area under the curve (AUC)=0.83; total score ≥0; sensitivity=66.7%, specificity=84.9%; figure 1D). By contrast, the APE2 score performed less well in predicting NSAb status (sensitivity 43.5%, specificity 79.1%, AUC=0.68) and more accurately predicted criteria-defined AE, particularly if associated with NSAbs (sensitivity 85.7%, specificity 78.8%, AUC=0.94; figure 1E). Figure 1 Clinical phenotypes associated with NSAb status in new-onset focal epilepsy. The first two dimensions are shown, highlighting: (A) NSAb-positive (red) or NSAb-negative (grey) status and (B) NSAb-positive (pale red) or NSAb-negative (grey) without encephalitis (dots), or NSAb-positive (dark red) with clinically diagnosed autoimmune encephalitis (triangles). (C) The proportion of patients by total model score. Error bars show 95% CIs. The inset shows the weighting and SE of each factor within the regression model. (D) Receiver operator characteristic (ROC) curve of the total model score for predicting NSAb status across all patients. (E) ROC curve of the APE2 score for predicting NSAb status across all patients (black), patients not meeting the criteria for autoimmune encephalitis (blue), patients meeting the criteria for autoimmune encephalitis (red) and predicting NSAb-positive criteria-confirmed autoimmune encephalitis across all patients. (F) Scatter plot of modified Rankin score in NSAb-positive patients by immunotherapy status over time (Mann-Whitney U test p values<0.05). AE, autoimmune encephalitis; APE2, Antibody Prevalence in Epilepsy and Encephalopathy; epilepsy RF, epilepsy risk factors; MRI limbic Δ, changes within the limbic system on MRI. Comparisons of those with and without AE From 23 patients with NSAbs (table 1), a comparison of those with (n=9) and without (n=14) a clinical diagnosis of AE revealed several differences in the AE cohort: more ASMs (median of 3 vs 1; p=0.0073), more frequent immunotherapies (7/9 vs 0/14, p=0.0001), higher APE2 scores (median of 6 vs 2; p<0.0001), more frequent MRI limbic inflammation (6/9 vs 0/14; p=0.0008) and a trend towards greater positivity of serum IgGs targeting the surface of live neurons (7/9 vs 5/14, p=0.09). Compared with the seven patients administered immunotherapy, those with NSAbs who were not administered immunotherapy showed lower disability after 1 and 3 years (both p<0.05), and 11/16 (68.8%) were asymptomatic at 3-year follow-up (mRS=0 ; figure 1F). Hence, despite no immunotherapy, patients with NSAbs, but without AE, generally showed good outcomes. Discussion In this prospective study of 219 consecutive adults with new-onset focal epilepsy, NSAb status was best predicted by a combination of clinical parameters which closely resemble features observed in AE. Almost half of our patients with NSAbs were diagnosed with AE, and ~30% fulfilled stringent criteria for AE.11 Of those with NSAbs and more isolated forms of epilepsy, without individual features of AE, almost all were treated with ASMs alone and typically remained asymptomatic at long-term follow-up. Overall, these findings suggest that detection of NSAbs in patients with new-onset seizures, but without features of AE, should not alter current clinical management. Our observations should help guide the frequent clinical dilemma of which patients with new-onset seizures to test for autoantibodies and subsequently treat with immunotherapy. Taken together, our data suggest the clinical phenotype is paramount in guiding the relevance of autoantibody results, and provide data to address an outstanding question from a recent ILAE consensus statement.7 This ILAE statement also highlighted controversy over the term ‘autoimmune epilepsy’.7 In routine clinical practice, this nomenclature acts as a valuable signpost and aide memoire when seeing patients with seizures.2 14 However, ‘epilepsy’ carries several social stigmata and is defined by an enduring tendency to seizures. In AE, this lifelong risk is refuted by a recent study,4 despite several forms of AE commonly leading to hippocampal atrophy.2–4 7 10 The alternative concept of acute symptomatic seizures may more accurately capture the nature of seizures in patients with AE. Data-driven modifications to nomenclature will benefit from longer-term follow-up studies. Ictal piloerection, low mood and attention and MRI limbic system changes are recognised features of late-onset AE, particularly in association with LGI1 antibodies.2 4 14 15 The absence of movement disorders or more diffuse cognitive impairment as predictive factors in our model suggests the overall syndrome may reflect a formes frustes of AE. This contrasts with APE2 score parameters,9 which appear to largely reflect more florid features seen in classical AE. Our observational study has several limitations. These include limited CSF autoantibody measurements, which reflected UK practice particularly at the start of the study period. Yet,w ithout this valuable parameter, a diagnosis of NMDAR-antibody encephalitis is still possible.11 Yet, two of our four patients with serum NMDAR antibodies did not have features consistent with encephalitis, likely suggesting detection of clinically unrelated serum antibodies in these cases. In addition, our series in total only identified nine AE cases, although this may be considered substantial given the largely outpatient-based recruitment. This, and the high (~10%) seroprevalence rate, may reflect a referral bias given Oxford’s interest in AE, but is well aligned with other available estimates.6 9 10 Our serological data identified some samples with NSAbs proven by live cell-based assays, but without concomitant cell surface neuronal reactivities. This was especially evident in the cohort without a clinical diagnosis of AE, and perhaps these antibodies reflect low-affinity or low-titre autoantibodies which are not disease relevant. Their specificity, however, remains reassuring given their typical selectivity for just one of eight surface-expressed autoantigens. In the future, our prediction model will benefit from validation in independent, larger studies which may compare the risk of enduring seizures in the NSAb-positive versus NSAb-negative populations, with and without AE, something which we did not survey at follow-up. Hence, we cannot comment on long-term seizure status in the 5/16 patients (31%) who had NSAbs, no diagnosis of AE and 3-year mRS >0. In these patients, it remains possible that immunotherapy would have led to a greater benefit. However, in our view, this finding is more likely to be consistent with the predicted ~30% of all people with epilepsy who are known to become ASM resistant: this provides a testable hypothesis for a future randomised controlled trial. Overall, our observations support the concept that, in patients who present with new-onset focal seizures, clinical features which are consistent with a ‘mild encephalitis’ helps identify those with NSAbs which should alter patient management. This clinico-serological syndrome appeared characteristic and its recognition will improve detection and treatment of these patients. These findings should discourage widespread screening strategies to identify patients with autoantibodies among unselected seizure cohorts. References ↵Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol 2011;69:892–900.doi:10.1002/ana.22307 ↵Thompson J, Bi M, Murchison AG, et al. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain 2018;141:348–56.doi:10.1093/brain/awx323OpenUrlCrossRef ↵Geis C, Planagumà J, Carreño M, et al. Autoimmune seizures and epilepsy. J Clin Invest 2019;129:926–40.doi:10.1172/JCI125178OpenUrlPubMed ↵de Bruijn MAAM, van Sonderen A, van Coevorden-Hameete MH, et al. Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis. Neurology 2019;92:e2185–96.doi:10.1212/WNL.0000000000007475pmid:30979857OpenUrlPubMed ↵Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017;58:512–21.doi:10.1111/epi.13709pmid:http://www.ncbi.nlm.nih.gov/pubmed/28276062OpenUrlPubMed ↵Brenner T, Sills GJ, Hart Y, et al. Prevalence of neurologic autoantibodies in cohorts of patients with new and established epilepsy. Epilepsia 2013;54:1028–35.doi:10.1111/epi.12127pmid:http://www.ncbi.nlm.nih.gov/pubmed/23464826OpenUrlCrossRefPubMed ↵Steriade C, Britton J, Dale RC, et al. Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions. Epilepsia 2020;61:1341–51.doi:10.1111/epi.16571pmid:http://www.ncbi.nlm.nih.gov/pubmed/32544279OpenUrlPubMed ↵von Podewils F, Suesse M, Geithner J, et al. Prevalence and outcome of late-onset seizures due to autoimmune etiology: a prospective observational population-based cohort study. Epilepsia 2017;58:1542–50.doi:10.1111/epi.13834pmid:http://www.ncbi.nlm.nih.gov/pubmed/28681401OpenUrlPubMed ↵Dubey D, Alqallaf A, Hays R, et al. Neurological autoantibody prevalence in epilepsy of unknown etiology. JAMA Neurol 2017;74:397–402.doi:10.1001/jamaneurol.2016.5429pmid:http://www.ncbi.nlm.nih.gov/pubmed/28166327OpenUrlPubMed ↵Dubey D, Kothapalli N, McKeon A, et al. Predictors of neural-specific autoantibodies and immunotherapy response in patients with cognitive dysfunction. J Neuroimmunol 2018;323:62–72.doi:10.1016/j.jneuroim.2018.07.009pmid:http://www.ncbi.nlm.nih.gov/pubmed/30196836OpenUrlPubMed ↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.doi:10.1016/S1474-4422(15)00401-9pmid:http://www.ncbi.nlm.nih.gov/pubmed/26906964OpenUrlCrossRefPubMed ↵Makuch M, Wilson R, Al-Diwani A, et al. N-Methyl-D-aspartate receptor antibody production from germinal center reactions: therapeutic implications. Ann Neurol 2018;83:553–61.doi:10.1002/ana.25173pmid:http://www.ncbi.nlm.nih.gov/pubmed/29406578OpenUrlPubMed ↵Ramberger M, Berretta A, Tan JMM, et al. Distinctive binding properties of human monoclonal LGI1 autoantibodies determine pathogenic mechanisms. Brain 2020;143:1731–45.doi:10.1093/brain/awaa104pmid:http://www.ncbi.nlm.nih.gov/pubmed/32437528OpenUrlPubMed ↵Quek AML, Britton JW, McKeon A, et al. Autoimmune epilepsy: clinical characteristics and response to immunotherapy. Arch Neurol 2012;69:582–93.doi:10.1001/archneurol.2011.2985pmid:http://www.ncbi.nlm.nih.gov/pubmed/22451162OpenUrlCrossRefPubMed ↵Rocamora R, Becerra JL, Fossas P, et al. Pilomotor seizures: an autonomic semiology of limbic encephalitis? Seizure 2014;23:670–3.doi:10.1016/j.seizure.2014.04.013pmid:http://www.ncbi.nlm.nih.gov/pubmed/24890932OpenUrlCrossRefPubMed
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Sleep disorders in autoimmune encephalitis

Sleep disorders in autoimmune encephalitis | AntiNMDA | Scoop.it
Sleep disorders in people with autoimmune encephalitis have received little attention,
probably overshadowed by the presence of other neurological and psychiatric symptoms
in this group of conditions.
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Cerebrospinal fluid CD20 positive B-cell expansion in a case of anti-NMDAR encephalitis - ScienceDirect

Cerebrospinal fluid CD20 positive B-cell expansion in a case of anti-NMDAR encephalitis - ScienceDirect | AntiNMDA | Scoop.it
Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a potentially fatal autoimmune encephalitis with a strong B-cell response. We measured the …
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Clinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis

Clinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis | AntiNMDA | Scoop.it
Serum neuronal autoantibodies, such as those to the NMDA receptor (NMDAR), are detectable in a subgroup of patients with psychotic disorders. It is not known if they are present before the onset of psychosis or whether they are associated with particular clinical features or outcomes. In a case–control study, sera from 254 subjects at clinical high risk (CHR) for psychosis and 116 healthy volunteers were tested for antibodies against multiple neuronal antigens implicated in CNS autoimmune disorders, using fixed and live cell-based assays (CBAs). Within the CHR group, the relationship between NMDAR antibodies and symptoms, cognitive function and clinical outcomes over 24 month follow-up was examined. CHR subjects were not more frequently seropositive for neuronal autoantibodies than controls (8.3% vs. 5.2%; OR = 1.50; 95% CI: 0.58–3.90). The NMDAR was the most common target antigen and NMDAR IgGs were more sensitively detected with live versus fixed CBAs (p < 0.001). Preliminary phenotypic analyses revealed that within the CHR sample, the NMDAR antibody seropositive subjects had higher levels of current depression, performed worse on the Rey Auditory Verbal Learning Task (p < 0.05), and had a markedly lower IQ (p < 0.01). NMDAR IgGs were not more frequent in subjects who later became psychotic than those who did not. NMDAR antibody serostatus and titre was associated with poorer levels of functioning at follow-up (p < 0.05) and the presence of a neuronal autoantibody was associated with larger amygdala volumes (p < 0.05). Altogether, these findings demonstrate that NMDAR autoantibodies are detectable in a subgroup of CHR subjects at equal rates to controls. In the CHR group, they are associated with affective psychopathology, impairments in verbal memory, and overall cognitive function: these findings are qualitatively and individually similar to core features of autoimmune encephalitis and/or animal models of NMDAR antibody-mediated CNS disease. Overall the current work supports further evaluation of NMDAR autoantibodies as a possible prognostic biomarker and aetiological factor in a subset of people already meeting CHR criteria.
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Longitudinal measurement of CSF neurofilament light in anti‐NMDAR encephalitis - Macher - - European Journal of Neurology

Longitudinal measurement of CSF neurofilament light in anti‐NMDAR encephalitis - Macher - - European Journal of Neurology | AntiNMDA | Scoop.it
Abstract Background Biomarkers reflecting the course of patients suffering from anti‐NMDAR encephalitis (anti‐NMDARE) are urgently needed. Neurofilament light chains (NfL) have been studied as a po...
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Brain researcher: It’s difficult to separate the physical and mental when it comes to our brains

Brain researcher: It’s difficult to separate the physical and mental when it comes to our brains | AntiNMDA | Scoop.it
Emotions, mental ailments, brain diseases: Everything happens in the brain. Technological advances have given us new perspectives on how the brain works, according to Norwegian brain researchers.
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Specialists and Care Centers for Autoimmune Encephalitis

Specialists and Care Centers for Autoimmune Encephalitis | AntiNMDA | Scoop.it
The Northwestern Medicine Autoimmune Encephalitis and Paraneoplastic Disorders clinic takes a multidiscplinary approach to the diagnosis and care of patients affected by these disorders.
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Neurologic Emergencies at the Extremes of Age

Neurologic Emergencies at the Extremes of Age | AntiNMDA | Scoop.it
The diagnosis and management of neurologic conditions are more complex at the extremes
of age than in the average adult. In the pediatric population, neurologic emergencies
are somewhat rare and some may require emergent consultation.
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(PDF) Anti-N-methyl-D-Aspartate (NMDA) Receptor Encephalitis: A Case Report

(PDF) Anti-N-methyl-D-Aspartate (NMDA) Receptor Encephalitis: A Case Report | AntiNMDA | Scoop.it
PDF | We report case of a 42 years old female who came with a constellation of behavioral symptoms, delirium, body stiffness, and fever for one week....| Find, read and cite all the research you need on ResearchGate...
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RACGP - Old doc, new disease: Anti-NMDA receptor encephalitis

RACGP - Old doc, new disease: Anti-NMDA receptor encephalitis | AntiNMDA | Scoop.it
Dr Casey Parker reflects on an intriguing presentation that made him ask: What else do I not know?
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Cost-Effectiveness of Routine Screening for Autoimmune Encephalitis in Patients With First-Episode Psychosis in the United States |J Clin Psychiatry

Autoimmune encephalitis (AE) is a highly treatable neurologic condition that can cause psychosis. This study estimated the cost-effectiveness of routine screening for AE compared with clinically targeted screening in first-episode psychosis patients.
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Unremitting diarrhoea in a girl diagnosed anti-N-methyl-D-aspartate-receptor encephalitis: A case report | Read by QxMD

Unremitting diarrhoea in a girl diagnosed anti-N-methyl-D-aspartate-receptor encephalitis: A case report | Read by QxMD | AntiNMDA | Scoop.it
Create a free QxMD account to take advantage of the features offered by Read like saving your papers and creating collections. Get Started Unremitting diarrhoea in a girl diagnosed anti-N-methyl-D-aspartate-receptor encephalitis: A case report Norrapat Onpoaree, Montida Veeravigrom, Anapat Sanpavat, Narissara Suratannon, Palittiya Sintusek World Journal of Clinical Cases 2020 October 26, 8 (20): 4866-4875 BACKGROUND: Asymptomatic cytomegalovirus (CMV) infection is common in children; in contrast, in children with a weakened immune system, invasive CMV can occur. This is the first case report of a severe manifestation of CMV esophago-enterocolitis in a girl diagnosed with anti-N-methyl-D-aspartate-receptor (anti-NMDAR) encephalitis who received only a moderate dose of corticosteroid therapy. CASE SUMMARY: A 12-year-old-Thai girl presented with acute behavioural change and headache for 6 d. Electroencephalogram and positivity for NMDAR autoantibodies were compatible with anti-NMDAR encephalitis. Hence, she received pulse methylprednisolone 10 mg/kg per day for 4 d and continued with prednisolone 1.2 mg/kg per day. On day 42 of corticosteroid therapy, she developed unremitting vomiting and diarrhoea. Endoscopy showed multiple ulcers and erythaematous mucosa along the gastrointestinal tract. Tissue CMV viral load and viral-infected cells confirmed CMV esophago-enterocolitis. Therefore, the patient received ganciclovir 5 mg/kg per dose every 12 h for 3 wk and then 5 mg/kg per dose once daily for 3 wk. Unremitting diarrhoea slowly improved from stool output 1-4 L per day to 1-2 L per day after 3 wk of treatment. Pulse methylprednisolone 20 mg/kg for 5 d was initiated and continued with prednisolone 1 mg/kg per day. After this repeated pulse methylprednisolone treatment, surprisingly, diarrhoea subsided. Immunologic work-up was performed to rule out underlying immune deficiency with unremarkable results. CONCLUSION: Unremitting diarrhoea from CMV esophago-enterocolitis subsided with antiviral and methylprednisolone therapy, implying the immune and NMDAR dysregulation in anti-NMDAR encephalitis. Full Text Links We have located links that may give you full text access. Additional links Discussion You are not logged in. Sign Up or Log In to join the discussion. Trending Papers Colchicine in Patients with Chronic Coronary Disease. Stefan M Nidorf, Aernoud T L Fiolet, Arend Mosterd, John W Eikelboom, Astrid Schut, Tjerk S J Opstal, Salem H K The, Xiao-Fang Xu, Mark A Ireland, Timo Lenderink, Donald Latchem, Pieter Hoogslag, Anastazia Jerzewski, Peter Nierop, Alan Whelan, Randall Hendriks, Henk Swart, Jeroen Schaap, Aaf F M Kuijper, Maarten W J van Hessen, Pradyot Saklani, Isabel Tan, Angus G Thompson, Allison Morton, Chris Judkins, Willem A Bax, Maurits Dirksen, Marco M W Alings, Graeme J Hankey, Charley A Budgeon, Jan G P Tijssen, Jan H Cornel, Peter L Thompson New England Journal of Medicine 2020 August 31 Extracorporeal life support for adults with acute respiratory distress syndrome. Alain Combes, Matthieu Schmidt, Carol L Hodgson, Eddy Fan, Niall D Ferguson, John F Fraser, Samir Jaber, Antonio Pesenti, Marco Ranieri, Kathryn Rowan, Kiran Shekar, Arthur S Slutsky, Daniel Brodie Intensive Care Medicine 2020 November 2 Clinical strategies for implementing lung and diaphragm-protective ventilation: avoiding insufficient and excessive effort. Ewan C Goligher, Annemijn H Jonkman, Jose Dianti, Katerina Vaporidi, Jeremy R Beitler, Bhakti K Patel, Takeshi Yoshida, Samir Jaber, Martin Dres, Tommaso Mauri, Giacomo Bellani, Alexandre Demoule, Laurent Brochard, Leo Heunks Intensive Care Medicine 2020 November 2 Emergency Department Management of COVID-19: An Evidence-Based Approach. Nicholas M McManus, Ryan Offman, Jason D Oetman Western Journal of Emergency Medicine 2020 September 25 Glucocorticoids: surprising new findings on their mechanisms of actions. Frank Buttgereit Annals of the Rheumatic Diseases 2020 November 8 Prone position in ARDS patients: why, when, how and for whom. Claude Guérin, Richard K Albert, Jeremy Beitler, Luciano Gattinoni, Samir Jaber, John J Marini, Laveena Munshi, Laurent Papazian, Antonio Pesenti, Antoine Vieillard-Baron, Jordi Mancebo Intensive Care Medicine 2020 November 10 Severe organising pneumonia following COVID-19. István Vadász, Faeq Husain-Syed, Peter Dorfmüller, Fritz C Roller, Khodr Tello, Matthias Hecker, Rory E Morty, Stefan Gattenlöhner, Hans-Dieter Walmrath, Friedrich Grimminger, Susanne Herold, Werner Seeger Thorax 2020 November 11 Analgesia and sedation in patients with ARDS. Gerald Chanques, Jean-Michel Constantin, John W Devlin, E Wesley Ely, Gilles L Fraser, Céline Gélinas, Timothy D Girard, Claude Guérin, Matthieu Jabaudon, Samir Jaber, Sangeeta Mehta, Thomas Langer, Michael J Murray, Pratik Pandharipande, Bhakti Patel, Jean-François Payen, Kathleen Puntillo, Bram Rochwerg, Yahya Shehabi, Thomas Strøm, Hanne Tanghus Olsen, John P Kress Intensive Care Medicine 2020 November 10
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Possible coexistence of MOG-IgG-associated disease and anti-Caspr2 antibody-associated autoimmune encephalitis: a first case report

Possible coexistence of MOG-IgG-associated disease and anti-Caspr2 antibody-associated autoimmune encephalitis: a first case report | AntiNMDA | Scoop.it
Myelin oligodendrocyte glycoprotein antibody-associated disease has been proposed as a separate inflammatory demyelinating disease of the central nervous system (CNS) since the discovery of pathogenic antibodies against myelin oligodendrocyte glycoprotein ...
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The Anti-NMDA Receptor Encephalitis Foundation Newsletter

The Anti-NMDA Receptor Encephalitis Foundation Newsletter | AntiNMDA | Scoop.it
On your Marks, Get Set, Register for the WORLD ENCEPHALITIS DAY CONFERENCE 2021 From...
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Autoimmune encephalitis: When your body attacks your brain, and people think you’re going mad

Autoimmune encephalitis: When your body attacks your brain, and people think you’re going mad | AntiNMDA | Scoop.it
Four PhD candidates from Monash University, who are already Doctors of the medical kind, are conducting research on a rare and debilitating neurological illness affecting the Australian population. It’s described as feeling like your brain is on fire.
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Characteristics of internalization of NMDA-type GluRs with antibodies to GluN1 and GluN2B - ScienceDirect

Characteristics of internalization of NMDA-type GluRs with antibodies to GluN1 and GluN2B - ScienceDirect | AntiNMDA | Scoop.it
To characterize internalization of NMDA-type glutamate receptors (GluRs) by antibodies to NMDA-type GluRs, we produced rabbit antibodies to N-terminal…
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Seizure-related 6 homolog like 2 autoimmunity | Neurology Neuroimmunology & Neuroinflammation

Seizure-related 6 homolog like 2 autoimmunity | Neurology Neuroimmunology & Neuroinflammation | AntiNMDA | Scoop.it
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Early clinical suspicion and treatment in a patient with anti-NMDA receptor encephalitis

Early clinical suspicion and treatment in a patient with anti-NMDA receptor encephalitis | AntiNMDA | Scoop.it
Anti-NMDA receptor encephalitis is a complicated disease associated with paraneoplastic syndromes and autoimmune conditions.This case report highlights the importance of early identification and reviews the common clinical manifestations, diagnostic studies, and treatment modalities for this potent...
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