18 results on '"Irani, SR"'
Search Results
2. CLINICAL FEATURES AND FOLLOW-UP OF 13 PATIENTS WITH ANTIBODIES AGAINST NMDA RECEPTORS
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Irani, SR, Maxwell, S, Zandi, M, Cossins, J, Beeson, D, and Vincent, A
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- 2009
Catalog
3. Clinical value of cell-based assays in the characterisation of seronegative myasthenia gravis.
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Damato V, Spagni G, Monte G, Woodhall M, Jacobson L, Falso S, Smith T, Iorio R, Waters P, Irani SR, Vincent A, and Evoli A
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- Adult, Autoantibodies, Cohort Studies, Humans, Receptors, Cholinergic, Myasthenia Gravis diagnosis, Receptor Protein-Tyrosine Kinases
- Abstract
Objective: Patients with myasthenia gravis without acetylcholine receptor (AChR) or muscle-specific kinase (MuSK) antibodies detected by radioimmunoprecipitation assays (RIAs) are classified as seronegative myasthenia gravis (SNMG). Live cell-based assays (l-CBAs) can detect additional antibodies to clustered AChR, MuSK and low-density lipoprotein receptor-related protein 4 (LRP4), but positivity rates are variable and both clinical relevance and utility of CBA platforms remain unclear., Methods: Sera from 82 patients with SNMG were tested by l-CBAs. Human embryonic kidney cells were transfected to individually express clustered AChR, MuSK or LRP4; or transfected to jointly express both clustered adult AChR and MuSK. Sera from 30 and 20 patients positive by RIA for AChR or MuSK antibodies were used as comparators., Results: 53 of 82 (72%) patients with SNMG had generalised and 29 (28%) had ocular disease. The clustered AChR CBA detected antibodies in 16 of 82 patients (19.5%; including 4 patients with solely fetal AChR antibodies), while 7 of 82 (8.5%) patients had MuSK antibodies. A novel exploratory combined adult AChR-MuSK l-CBA efficiently detected all these antibodies in a subset of the SNMG cohort. No LRP4 antibodies were identified. Overall, patients with SNMG with clustered AChR antibodies, CBA-positive MuSK-MG or triple seronegative were younger, had less severe disease than patients with RIA-positive MG and had a better clinical outcome when immunotherapy was started soon after disease onset, although the time interval from onset to immunotherapy was not different when compared with patients with RIA-positive MG., Conclusion: Around one-third of patients with SNMG had AChR or MuSK antibodies by l-CBAs, which were efficiently detected with a combined l-CBA. The results in this large and unselected cohort of patients with MG demonstrate the diagnostic usefulness of performing CBAs and the importance of making these tests more widely available., Competing Interests: Competing interests: AV and the University of Oxford held a patent for detection of MuSK antibody assays (expired 2020), licensed to Athena Diagnostics; AV received a proportion of royalties. SRI and PW are co-applicants and receive royalties on patent application WO/2010/046716 entitled ‘Neurological Autoimmune Disorders’ (the patent has been licensed for the development of assays for LGI1 and other VGKC-complex antibodies) and have filed two other patents regarding autoantibody diagnostic algorithms., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.) more...
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- 2022
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4. Naïve B cells followed by aquaporin-4 antibodies characterise the onset of neuromyelitis optica: evidence from stem cell transplantation.
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McNaughton P, Payne R, Michael S, Leahy T, Nicols A, Fower A, Hambleton S, Pang K, Gennery A, and Irani SR
- Abstract
Competing Interests: Competing interests: SRI is a co-applicant and receives royalties on patent application WO/2010/046716 (UK patent no. PCT/GB2009/051441) entitled ‘Neurological Autoimmune Disorders’. The patent has been licensed commercially for the development of assays for LGI1 and other VGKC-complex antibodies. SRI is an inventor on a patent application entitled Diagnostic Strategy to improve specificity of CASPR2 antibody detection (PCT/GB2019/051257, publication number WO/2019/211633 and UK1807410.4). SRI has received honoraria from UCB, MedImmun, ADC therapeutics and Medlink Neurology, and research support from CSL Behring, UCB and ONO Pharma. PM, RP, SM, TL, AN, AF, SH, KP and AG have no conflicts of interest to declare. more...
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- 2022
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5. Frequency of MOG-IgG in cerebrospinal fluid versus serum.
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Pace S, Orrell M, Woodhall M, Palace J, Leite MI, Irani SR, Waters P, and Handel AE
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- Aged, Databases, Factual, Female, Humans, Immunoglobulin G blood, Immunoglobulin G cerebrospinal fluid, Myelitis, Transverse blood, Myelitis, Transverse cerebrospinal fluid, Optic Neuritis blood, Optic Neuritis cerebrospinal fluid, Young Adult, Immunoglobulin G metabolism, Myelin-Oligodendrocyte Glycoprotein immunology, Myelitis, Transverse metabolism, Optic Neuritis metabolism
- Abstract
Competing Interests: Competing interests: PW is a named inventor on patents for antibody assays and has received royalties. He has received honoraria from Biogen Idec, Mereo Biopharma, Retrogenix, UBC, Euroimmun AG and Alexion; travel grants from the Guthy-Jackson Charitable Foundation; and research funding from Euroimmun AG. more...
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- 2022
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6. Improving clinical practice with an old friend from the neuroimmunology toolkit: acute corticosteroids in LGI1 antibody encephalitis.
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Irani SR
- Subjects
- Adrenal Cortex Hormones, Friends, Humans, Intracellular Signaling Peptides and Proteins, Encephalitis immunology, Limbic Encephalitis immunology
- Abstract
Competing Interests: Competing interests: SRI is a co-applicant and receive royalties on patent application WO/2010/046716 entitled ‘Neurological Autoimmune Disorders’. The patent has been licensed to Euroimmun AG for the development of assays for LGI1 and other VGKC-complex antibodies. SRI is inventor on ‘A Diagnostic Strategy to improve specificity of CASPR2 antibody detection.’ Ref. JA94536P. SRI has received honoraria from UCB, Immunovant, Roche, Cerebral Therapeutics, MedImmun, ADC therapeutics, Medlink Neurology and research support from CSL Behring, UCB and ONO Pharma. more...
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- 2022
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7. Clinical features which predict neuronal surface autoantibodies in new-onset focal epilepsy: implications for immunotherapies.
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McGinty RN, Handel A, Moloney T, Ramesh A, Fower A, Torzillo E, Kramer H, Howell S, Waters P, Adcock J, Sen A, Lang B, and Irani SR
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- Adolescent, Adult, Aged, Cohort Studies, Encephalitis blood, Encephalitis etiology, Epilepsies, Partial therapy, Female, Humans, Male, Middle Aged, Predictive Value of Tests, ROC Curve, Young Adult, Autoantibodies blood, Epilepsies, Partial blood, Epilepsies, Partial immunology, Immunotherapy, Nerve Tissue Proteins immunology
- Abstract
Objective: To generate a score which clinically identifies surface-directed autoantibodies in adults with new-onset focal epilepsy, and evaluate the value of immunotherapy in this clinical setting., Methods: Prospective clinical and autoantibody evaluations in a cohort of 219 consecutive patients with new-onset focal epilepsy., Results: 10.5% (23/219) of people with new-onset focal epilepsy had detectable serum autoantibodies to known or novel cell surface antigenic targets. 9/23 with autoantibodies were diagnosed with encephalitis, by contrast to 0/196 without autoantibodies (p<0.0001). Multivariate analysis identified six features which predicted autoantibody positivity (area under the curve=0.83): age ≥54 years, ictal piloerection, lowered self-reported mood, reduced attention, MRI limbic system changes and the absence of conventional epilepsy risk factors. 11/14 (79%) patients with detectable autoantibodies, but without encephalitis, showed excellent long-term outcomes (modified Rankin Score=0) despite no immunotherapy. These outcomes were superior to those of immunotherapy-treated patients with confirmed autoantibody-mediated encephalitis (p<0.05)., Conclusions: Seizure semiology, cognitive and mood phenotypes, alongside inflammatory investigation findings, aid the identification of surface autoantibodies among unselected people with new-onset focal epilepsy. The excellent immunotherapy-independent outcomes of autoantibody-positive patients without encephalitis suggests immunotherapy administration should be guided by clinical features of encephalitis, rather than autoantibody positivity. Our findings suggest that, in this cohort, immunotherapy-responsive seizure syndromes with autoantibodies largely fall under the umbrella of autoimmune encephalitis., Competing Interests: Competing interests: SRI and PW are coapplicants and receive royalties on patent application WO/210/046716 (UK patent no. PCT/GB2009/051441) entitled ‘Neurological Autoimmune Disorders’. The patent has been licensed for the development of assays for LGI1 and other VGKC-complex antibodies., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.) more...
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- 2021
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8. Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management.
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Abboud H, Probasco J, Irani SR, Ances B, Benavides DR, Bradshaw M, Christo PP, Dale RC, Fernandez-Fournier M, Flanagan EP, Gadoth A, George P, Grebenciucova E, Jammoul A, Lee ST, Li Y, Matiello M, Morse AM, Rae-Grant A, Rojas G, Rossman I, Schmitt S, Venkatesan A, Vernino S, Pittock SJ, and Titulaer M more...
- Abstract
The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. The most popular bridging therapy was oral prednisone taper chosen by 38% of responders while rituximab was the most popular maintenance therapy chosen by 46%. Most responders considered maintenance immunosuppression after a second relapse in patients with neuronal surface antibodies (70%) or seronegative autoimmune encephalitis (61%) as opposed to those with onconeuronal antibodies (29%). Most responders opted to cancer screening for 4 years in patients with neuronal surface antibodies (49%) or limbic encephalitis (46%) as opposed to non-limbic seronegative autoimmune encephalitis (36%). Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion., Competing Interests: Competing interests: HA is a consultant for Roche/Genentech, which manufactures rituximab and tocilizumab that were discussed in this paper. HA is a consultant for Bristol-Myers Squibb, which manufactures cyclophosphamide that is discussed in this paper. SRI is a coapplicant and receives royalties on patent application WO/210/046716 (UK patent No. PCT/GB2009/051441) licensed to Euroimmun for the development of assays for leucine-rich glioma inactivated protein 1 and other voltage-gated potassium channel complex antibodies discussed in this paper. SRI is supported by the BMA Research Grants- Vera Down grant (2013) and Margaret Temple (2017), Epilepsy Research UK (P1201), the Fulbright UK-US commission (MS-Society research award) and by the NIHR Oxford Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. AG has a patent for MAP1B autoantibodies as biomarkers of neurological autoimmunity and small cell lung cancer. S-TL is a consultant for GC Pharma, which manufactures IVIg that was discussed in this paper and for Advanced Neural Technologies which operates several neuronal autoantibody panels. SV receives research support from Quest Laboratories Diagnostics, which offers several commercial neuronal autoantibody panels, and from Genentech (rituximab) and Grifols (IVIG). SJP has a patent Patent# 8,889,102 (Application#12-678350)—Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia issued, and a patent Patent# 9891219B2 (Application#12-573942)—SJP has a patent pending for GFAP, Septin-5, Kelch11 and MAP1B autoantibodies as biomarkers of neurological autoimmunity. Some of these antibodies are discussed in this paper. MJT has filed a patent for methods for typing neurological disorders and cancer, and devices for use therein, and has received an unrestricted research grant from Euroimmun AG., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.) more...
- Published
- 2021
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9. Combining clinical and molecular heterogeneity within CASPR2-antibody mediated diseases: towards the underlying disease biology.
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Binks S and Irani SR
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- Biology, Humans, Phenotype, Membrane Proteins genetics, Nerve Tissue Proteins genetics
- Abstract
Competing Interests: Competing interests: SRI is a co-applicant and receives royalties on patent application WO/2010/046716 entitled ‘Neurological Autoimmune Disorders’. The patent has been licensed to Euroimmun AG for the development of assays for LGI1 and other VGKC-complex antibodies. SRI and SB are coinventors on ‘A Diagnostic Strategy to improve specificity of CASPR2 antibody detection.’ Ref. JA94536P. more...
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- 2020
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10. Pain and the immune system: emerging concepts of IgG-mediated autoimmune pain and immunotherapies.
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Xu M, Bennett DLH, Querol LA, Wu LJ, Irani SR, Watson JC, Pittock SJ, and Klein CJ
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- Animals, Humans, Pain drug therapy, Immune System immunology, Immunoglobulin G immunology, Immunotherapy methods, Pain immunology, Synaptic Transmission immunology
- Abstract
The immune system has long been recognised important in pain regulation through inflammatory cytokine modulation of peripheral nociceptive fibres. Recently, cytokine interactions in brain and spinal cord glia as well as dorsal root ganglia satellite glia have been identified important- in pain modulation. The result of these interactions is central and peripheral sensitisation of nociceptive processing. Additionally, new insights and the term 'autoimmune pain' have emerged through discovery of specific IgGs targeting the extracellular domains of antigens at nodal and synaptic structures, causing pain directly without inflammation by enhancing neuronal excitability. Other discovered IgGs heighten pain indirectly by T-cell-mediated inflammation or destruction of targets within the nociceptive pathways. Notable identified IgGs in pain include those against the components of channels and receptors involved in inhibitory or excitatory somatosensory synapses or their pathways: nodal and paranodal proteins (LGI1, CASPR1, CASPR2); glutamate detection (AMPA-R); GABA regulation and release (GAD65, amphiphysin); glycine receptors (GLY-R); water channels (AQP4). These disorders have other neurological manifestations of central/peripheral hyperexcitabability including seizures, encephalopathy, myoclonus, tremor and spasticity, with immunotherapy responsiveness. Other pain disorders, like complex regional pain disorder, have been associated with IgGs against β2-adrenergic receptor, muscarinic-2 receptors, AChR-nicotinic ganglionic α-3 receptors and calcium channels (N and P/Q types), but less consistently with immune treatment response. Here, we outline how the immune system contributes to development and regulation of pain, review specific IgG-mediated pain disorders and summarise recent development in therapy approaches. Biological agents to treat pain (anti-calcitonin gene-related peptide and anti-nerve growth factor) are also discussed., Competing Interests: Competing interests: DLHB reports that he has acted as a consultant on behalf of Oxford Innovation for Abide, Biogen, GSK, Lilly, Mitsubishi Tanabe, Mundipharma and TEVA over the last 3 years. LAQ reports that he has provided expert testimony for Grifols and CSL Behring and received research funds from Novartis Spain and Grifols. SRI reports that he is a coapplicant and receives royalties on patent application WO/2010/046716 (UK patent no. PCT/GB2009/051441) entitled ‘Neurological Autoimmune Disorders’. The patent has been licensed to Euroimmun AG for the development of assays for LGI1 and other VGKC-complex antibodies. The remaining authors report no relevant disclosures to this work., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.) more...
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- 2020
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11. Hippocampal network abnormalities explain amnesia after VGKCC-Ab related autoimmune limbic encephalitis.
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Loane C, Argyropoulos GPD, Roca-Fernández A, Lage C, Sheerin F, Ahmed S, Zamboni G, Mackay C, Irani SR, and Butler CR
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- Adult, Aged, Amnesia diagnostic imaging, Amnesia pathology, Autoimmune Diseases diagnostic imaging, Autoimmune Diseases immunology, Autoimmune Diseases pathology, Case-Control Studies, Cross-Sectional Studies, Female, Hippocampus diagnostic imaging, Humans, Limbic Encephalitis diagnostic imaging, Limbic Encephalitis immunology, Limbic Encephalitis pathology, Magnetic Resonance Imaging, Male, Memory Disorders etiology, Memory Disorders pathology, Middle Aged, Neuroimaging, Amnesia etiology, Autoantibodies immunology, Autoimmune Diseases complications, Hippocampus pathology, Limbic Encephalitis complications, Potassium Channels, Voltage-Gated immunology
- Abstract
Objective: Limbic encephalitis associated with antibodies to components of the voltage-gated potassium channel complex (VGKCC-Ab-LE) often leads to hippocampal atrophy and persistent memory impairment. Its long-term impact on regions beyond the hippocampus, and the relationship between brain damage and cognitive outcome, are poorly understood. We investigated the nature of structural and functional brain abnormalities following VGKCC-Ab-LE and its role in residual memory impairment., Method: A cross-sectional group study was conducted. Twenty-four VGKCC-Ab-LE patients (20 male, 4 female; mean (SD) age 63.86 (11.31) years) were recruited post-acutely along with age- and sex-matched healthy controls for neuropsychological assessment, structural MRI and resting-state functional MRI (rs-fMRI). Structural abnormalities were determined using volumetry and voxel-based morphometry; rs-fMRI data were analysed to investigate hippocampal functional connectivity (FC). Associations of memory performance with neuroimaging measures were examined., Results: Patients showed selective memory impairment. Structural analyses revealed focal hippocampal atrophy within the medial temporal lobes, correlative atrophy in the mediodorsal thalamus, and additional volume reduction in the posteromedial cortex. There was no association between regional volumes and memory performance. Instead, patients demonstrated reduced posteromedial cortico-hippocampal and inter-hippocampal FC, which correlated with memory scores (r = 0.553; r = 0.582, respectively). The latter declined as a function of time since the acute illness (r = -0.531)., Conclusion: VGKCC-Ab-LE results in persistent isolated memory impairment. Patients have hippocampal atrophy with further reduced mediodorsal thalamic and posteromedial cortical volumes. Crucially, reduced FC of remaining hippocampal tissue correlates more closely with memory function than does regional atrophy., Competing Interests: Competing interests: SRI is a co-applicant and receives royalties on patent application WO/2010/046716 (UK patent no, PCT/GB2009/051441) entitled ‘Neurological Autoimmune Disorders’. The patent has been licensed to Euroimmun AG for the development of assays for LGI1 and other VGKC-complex antibodies., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.) more...
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- 2019
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12. The Movement disorder associated with NMDAR antibody-encephalitis is complex and characteristic: an expert video-rating study.
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Varley JA, Webb AJS, Balint B, Fung VSC, Sethi KD, Tijssen MAJ, Lynch T, Mohammad SS, Britton F, Evans M, Hacohen Y, Lin JP, Nardocci N, Granata T, Dale RC, Lim MJ, Bhatia KP, Lang AE, and Irani SR
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- Adolescent, Adult, Anti-N-Methyl-D-Aspartate Receptor Encephalitis diagnosis, Anti-N-Methyl-D-Aspartate Receptor Encephalitis physiopathology, Child, Child, Preschool, Female, Humans, Infant, Male, Young Adult, Anti-N-Methyl-D-Aspartate Receptor Encephalitis complications, Movement Disorders diagnosis, Movement Disorders etiology
- Abstract
Competing Interests: Competing interests: SRI is a co-applicant and receives royalties on patent application WO/2010/046716 entitled ‘Neurological Autoimmune Disorders’. The patent has been licensed to Euroimmun AG for the development of assays for LGI1 and other VGKC-complex antibodies. more...
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- 2019
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13. LGI1, CASPR2 and related antibodies: a molecular evolution of the phenotypes.
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Binks SNM, Klein CJ, Waters P, Pittock SJ, and Irani SR
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- Humans, Intracellular Signaling Peptides and Proteins, Potassium Channels, Voltage-Gated immunology, Autoantibodies adverse effects, Autoantibodies immunology, Evolution, Molecular, Membrane Proteins immunology, Nerve Tissue Proteins immunology, Proteins immunology
- Abstract
Recent biochemical observations have helped redefine antigenic components within the voltage-gated potassium channel (VGKC) complex. The related autoantibodies may be now divided into likely pathogenic entities, which target the extracellular domains of leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2), and species that target intracellular neuronal components and are likely non-pathogenic. This distinction has enhanced clinical practice as direct determination of LGI1 and CASPR2 antibodies offers optimal sensitivity and specificity. In this review, we describe and compare the clinical features associated with pathogenic LGI1 and CASPR2 antibodies, illustrate emerging laboratory techniques for antibody determination and describe the immunological mechanisms that may mediate antibody-induced pathology. We highlight marked clinical overlaps between patients with either LGI1 or CASPR2 antibodies that include frequent focal seizures, prominent amnesia, dysautonomia, neuromyotonia and neuropathic pain. Although occurring at differing rates, these commonalities are striking and only faciobrachial dystonic seizures reliably differentiate these two conditions. Furthermore, the coexistence of both LGI1 and CASPR2 antibodies in an individual occurs surprisingly frequently. Patients with either antibody respond well to immunotherapies, although systematic studies are required to determine the magnitude of the effect beyond placebo. Finally, data have suggested that CASPR2 and LGI1 modulation via genetic or autoimmune mechanisms may share common intermediate molecules. Taken together, the biochemical distinction of antigenic targets has led to important clinical advances for patient care. However, the striking syndrome similarities, coexistence of two otherwise rare antibodies and molecular insights suggest the VGKC complex may yet be a common functional effector of antibody action. Hence, we argue for a molecular evolution alongside a clinical and phenotypic re-evaluation., Competing Interests: Competing interests: SRI and PW are coapplicants and receive royalties on patent application WO/2010/046716 (UK patent no.: PCT/GB2009/051441) entitled ’Neurological Autoimmune Disorders'. The patent has been licenced to Euroimmun AG for the development of assays for LGI1 and other VGKC complex antibodies., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.) more...
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- 2018
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14. Longitudinal analysis of myelin oligodendrocyte glycoprotein antibodies in CNS inflammatory diseases.
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Hyun JW, Woodhall MR, Kim SH, Jeong IH, Kong B, Kim G, Kim Y, Park MS, Irani SR, Waters P, and Kim HJ
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- Aquaporin 4 immunology, Autoantibodies immunology, Humans, Immunoglobulin G blood, Longitudinal Studies, Magnetic Resonance Imaging, Demyelinating Autoimmune Diseases, CNS blood, Myelin-Oligodendrocyte Glycoprotein immunology, Seroepidemiologic Studies
- Abstract
Background: We evaluated the seroprevalence of myelin oligodendrocyte glycoprotein immunoglobulin G1 (MOG-IgG) and associated clinical features of patients from a large adult-dominant unselected cohort with mainly relapsing central nervous system (CNS) inflammatory diseases. We also investigate the clinical relevance of MOG-IgG through a longitudinal analysis of serological status over a 2-year follow-up period., Methods: Serum samples from 505 patients with CNS inflammatory diseases at the National Cancer Center were analysed using cell-based assays for MOG-IgG and aquaporin-4 immunoglobulin G (AQP4-IgG). MOG-IgG serostatus was longitudinally assessed in seropositive patients with available serum samples and at least 2 years follow-up., Results: Twenty-two of 505 (4.4%) patients with CNS inflammatory diseases were positive for MOG-IgG. Patients with MOG-IgG had neuromyelitis optica spectrum disorder (NMOSD, n=10), idiopathic AQP4-IgG-negative myelitis (n=4), idiopathic AQP4-IgG-negative optic neuritis (n=4), other demyelinating syndromes (n=3) and multiple sclerosis (n=1). No relapses were seen in patients when they became MOG-IgG seronegative, whereas a persistent positive serological status was observed in patients with clinical relapses despite immunotherapy., Conclusions: In a large adult-predominant unselected cohort of mainly relapsing CNS inflammatory diseases, we confirmed that NMOSD phenotype was most commonly observed in patients with MOG-IgG. A longitudinal analysis with 2-year follow-up suggested that persistence of MOG-IgG is associated with relapses., Competing Interests: Competing interests: JWH, MRW, SHK, IHJ, BSK, GYK, YSK report no disclosures. SRI is supported by the Wellcome Trust, British Medical Association Research grant, Vera Down grant and Epilepsy Research UK. PW has received honoraria from Biogen Idec Japan, Euroimmun AG, Germany and Mereo Biopharma, UK; SRI and PW are named coinventors and receive royalties for assays for the detection of antibodies. HJK has lectured, consulted and received honoraria from Bayer Schering Pharma, Biogen, Genzyme, HanAll BioPharma, MedImmune, Merck Serono, Novartis, Teva-Handok and UCB; received a grant from the Ministry of Science, ICT & Future Planning; accepted research funding from Genzyme, Kael-GemVax, Merck Serono, Teva-Handok and UCB; serves on a steering committee for MedImmune; is a coeditor for the Multiple Sclerosis Journal—Experimental, Translational and Clinical, and an associated editor for the Journal of Clinical Neurology., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.) more...
- Published
- 2017
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15. Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies.
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Lang B, Makuch M, Moloney T, Dettmann I, Mindorf S, Probst C, Stoecker W, Buckley C, Newton CR, Leite MI, Maddison P, Komorowski L, Adcock J, Vincent A, Waters P, and Irani SR
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- Brain immunology, Brain Diseases diagnosis, Cohort Studies, Cytosol immunology, Elapid Venoms immunology, Epitopes immunology, HEK293 Cells immunology, Hippocampus immunology, Humans, Intracellular Signaling Peptides and Proteins, Intracellular Space immunology, Iodine Radioisotopes, Membrane Proteins immunology, Nerve Tissue Proteins immunology, Neurons immunology, Proteins immunology, Shaker Superfamily of Potassium Channels immunology, Autoantibodies blood, Autoimmune Diseases of the Nervous System immunology, Brain Diseases immunology, Neuromuscular Diseases immunology, Potassium Channels, Voltage-Gated immunology
- Abstract
Objectives: Autoantibodies against the extracellular domains of the voltage-gated potassium channel (VGKC) complex proteins, leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-2 (CASPR2), are found in patients with limbic encephalitis, faciobrachial dystonic seizures, Morvan's syndrome and neuromyotonia. However, in routine testing, VGKC complex antibodies without LGI1 or CASPR2 reactivities (double-negative) are more common than LGI1 or CASPR2 specificities. Therefore, the target(s) and clinical associations of double-negative antibodies need to be determined., Methods: Sera (n=1131) from several clinically defined cohorts were tested for IgG radioimmunoprecipitation of radioiodinated α-dendrotoxin (
125 I-αDTX)-labelled VGKC complexes from mammalian brain extracts. Positive samples were systematically tested for live hippocampal neuron reactivity, IgG precipitation of125 I-αDTX and125 I-αDTX-labelled Kv1 subunits, and by cell-based assays which expressed Kv1 subunits, LGI1 and CASPR2., Results: VGKC complex antibodies were found in 162 of 1131 (14%) sera. 90 of these (56%) had antibodies targeting the extracellular domains of LGI1 or CASPR2. Of the remaining 72 double-negative sera, 10 (14%) immunoprecipitated125 I-αDTX itself, and 27 (38%) bound to solubilised co-expressed Kv1.1/1.2/1.6 subunits and/or Kv1.2 subunits alone, at levels proportionate to VGKC complex antibody levels (r=0.57, p=0.0017). The sera with LGI1 and CASPR2 antibodies immunoprecipitated neither preparation. None of the 27 Kv1-precipitating samples bound live hippocampal neurons or Kv1 extracellular domains, but 16 (59%) bound to permeabilised Kv1-expressing human embryonic kidney 293T cells. These intracellular Kv1 antibodies mainly associated with non-immune disease aetiologies, poor longitudinal clinical-serological correlations and a limited immunotherapy response., Conclusions: Double-negative VGKC complex antibodies are often directed against cytosolic epitopes of Kv1 subunits and occasionally against non-mammalian αDTX. These antibodies should no longer be classified as neuronal-surface antibodies. They consequently lack pathogenic potential and do not in themselves support the use of immunotherapies., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.) more...- Published
- 2017
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16. FDG-PET hyperactivity in basal ganglia correlating with clinical course in anti-NDMA-R antibodies encephalitis.
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Maeder-Ingvar M, Prior JO, Irani SR, Rey V, Vincent A, and Rossetti AO
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- Adult, Anticonvulsants therapeutic use, Brain diagnostic imaging, Electroencephalography, Encephalitis drug therapy, Encephalitis immunology, Epilepsy, Complex Partial complications, Epilepsy, Complex Partial diagnostic imaging, Female, Fluorodeoxyglucose F18, Humans, Language Disorders complications, Language Disorders diagnostic imaging, Positron-Emission Tomography, Radiopharmaceuticals, Basal Ganglia diagnostic imaging, Encephalitis diagnostic imaging, Receptors, N-Methyl-D-Aspartate immunology
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- 2011
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17. Immunotherapy: responsive autoimmune encephalopathy associated with bullous pemphigoid.
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Soni A, Irani SR, Lang B, Taghipour K, Mann R, Vincent A, and Collins D
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- Anti-Inflammatory Agents therapeutic use, Autoimmune Diseases of the Nervous System drug therapy, Encephalitis drug therapy, Encephalitis immunology, Female, Humans, Methylprednisolone therapeutic use, Middle Aged, Pemphigoid, Bullous drug therapy, Autoimmune Diseases of the Nervous System complications, Encephalitis complications, Pemphigoid, Bullous complications
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- 2009
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18. Hypothermia in VGKC antibody-associated limbic encephalitis.
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Jacob S, Irani SR, Rajabally YA, Grubneac A, Walters RJ, Yazaki M, Clover L, and Vincent A
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- Aged, Atrophy, Azathioprine adverse effects, Azathioprine therapeutic use, Cyclosporine adverse effects, Cyclosporine therapeutic use, Dominance, Cerebral physiology, Epilepsy, Temporal Lobe etiology, Epilepsy, Temporal Lobe immunology, Female, Hippocampus pathology, Humans, Hypothalamus pathology, Hypothermia etiology, Immunization, Passive, Immunosuppressive Agents adverse effects, Immunosuppressive Agents therapeutic use, Limbic Encephalitis diagnosis, Limbic Encephalitis drug therapy, Low Back Pain immunology, Magnetic Resonance Imaging, Male, Middle Aged, Plasma Exchange, Prednisolone adverse effects, Prednisolone therapeutic use, Recurrence, Retreatment, Temporal Lobe pathology, Thymoma diagnosis, Thymoma immunology, Thymus Neoplasms diagnosis, Thymus Neoplasms immunology, Autoantibodies blood, Hypothermia immunology, Limbic Encephalitis immunology, Potassium Channels, Voltage-Gated immunology
- Abstract
Voltage-gated potassium channel antibody (VGKC-Ab)-associated limbic encephalitis (LE) is a recently described syndrome that broadens the spectrum of immunotherapy-responsive central nervous system disorders. Limbic encephalitis is typically characterised by a sub-acute onset of disorientation, amnesia and seizures, but the clinical spectrum is not yet fully defined and the syndrome could be under-diagnosed. We here describe the clinical profile of four patients with VGKC-Ab-associated LE who had intermittent, episodic hypothermia. One of the patients also described a prodrome of severe neuropathic pain preceding the development of limbic symptoms. Both of these novel symptoms responded well to immunosuppressive therapy, with concurrent amelioration of amnesia/seizures. more...
- Published
- 2008
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