Multicentre comparison of a diagnostic assay: aquaporin-4 antibodies in neuromyelitis optica

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Abstract

Objective

Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD).

Methods

Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1).

Results

Results of tests on 92 controls identified 12assays as highly specific (0–1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5–100%) of all 21 assays. The specificities (85.8–100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples.

Conclusions

The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology.

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Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia

Sarosh R. Irani, Sian Alexander, Patrick Waters … (2010)

Antibodies that immunoprecipitate 125I-α-dendrotoxin-labelled voltage-gated potassium channels extracted from mammalian brain tissue have been identified in patients with neuromyotonia, Morvan’s syndrome, limbic encephalitis and a few cases of adult-onset epilepsy. These conditions often improve following immunomodulatory therapies. However, the proportions of the different syndromes, the numbers with associated tumours and the relationships with potassium channel subunit antibody specificities have been unclear. We documented the clinical phenotype and tumour associations in 96 potassium channel antibody positive patients (titres >400 pM). Five had thymomas and one had an endometrial adenocarcinoma. To define the antibody specificities, we looked for binding of serum antibodies and their effects on potassium channel currents using human embryonic kidney cells expressing the potassium channel subunits. Surprisingly, only three of the patients had antibodies directed against the potassium channel subunits. By contrast, we found antibodies to three proteins that are complexed with 125I-α-dendrotoxin-labelled potassium channels in brain extracts: (i) contactin-associated protein-2 that is localized at the juxtaparanodes in myelinated axons; (ii) leucine-rich, glioma inactivated 1 protein that is most strongly expressed in the hippocampus; and (iii) Tag-1/contactin-2 that associates with contactin-associated protein-2. Antibodies to Kv1 subunits were found in three sera, to contactin-associated protein-2 in 19 sera, to leucine-rich, glioma inactivated 1 protein in 55 sera and to contactin-2 in five sera, four of which were also positive for the other antibodies. The remaining 18 sera were negative for potassium channel subunits and associated proteins by the methods employed. Of the 19 patients with contactin-associated protein-antibody-2, 10 had neuromyotonia or Morvan’s syndrome, compared with only 3 of the 55 leucine-rich, glioma inactivated 1 protein-antibody positive patients (P < 0.0001), who predominantly had limbic encephalitis. The responses to immunomodulatory therapies, defined by changes in modified Rankin scores, were good except in the patients with tumours, who all had contactin-associated-2 protein antibodies. This study confirms that the majority of patients with high potassium channel antibodies have limbic encephalitis without tumours. The identification of leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 as the major targets of potassium channel antibodies, and their associations with different clinical features, begins to explain the diversity of these syndromes; furthermore, detection of contactin-associated protein-2 antibodies should help identify the risk of an underlying tumour and a poor prognosis in future patients.

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Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series.

Meizan Lai, Maartje GM Huijbers, Eric Lancaster … (2010)

Voltage-gated potassium channels are thought to be the target of antibodies associated with limbic encephalitis. However, antibody testing using cells expressing voltage-gated potassium channels is negative; hence, we aimed to identify the real autoantigen associated with limbic encephalitis. We analysed sera and CSF of 57 patients with limbic encephalitis and antibodies attributed to voltage-gated potassium channels and 148 control individuals who had other disorders with or without antibodies against voltage-gated potassium channels. Immunohistochemistry, immunoprecipitation, and mass spectrometry were used to characterise the antigen. An assay with HEK293 cells transfected with leucine-rich, glioma-inactivated 1 (LGI1) and disintegrin and metalloproteinase domain-containing protein 22 (ADAM22) or ADAM23 was used as a serological test. The identity of the autoantigen was confirmed by immunoabsorption studies and immunostaining of Lgi1-null mice. Immunoprecipitation and mass spectrometry analyses showed that antibodies from patients with limbic encephalitis previously attributed to voltage-gated potassium channels recognise LGI1, a neuronal secreted protein that interacts with presynaptic ADAM23 and postsynaptic ADAM22. Immunostaining of HEK293 cells transfected with LGI1 showed that sera or CSF from patients, but not those from control individuals, recognised LGI1. Co-transfection of LGI1 with its receptors, ADAM22 or ADAM23, changed the pattern of reactivity and improved detection. LGI1 was confirmed as the autoantigen by specific abrogation of reactivity of sera and CSF from patients after immunoabsorption with LGI1-expressing cells and by comparative immunostaining of wild-type and Lgi1-null mice, which showed selective lack of reactivity in brains of Lgi1-null mice. One patient with limbic encephalitis and antibodies against LGI1 also had antibodies against CASPR2, an autoantigen we identified in some patients with encephalitis and seizures, Morvan's syndrome, and neuromyotonia. LGI1 is the autoantigen associated with limbic encephalitis previously attributed to voltage-gated potassium channels. The term limbic encephalitis associated with antibodies against voltage-gated potassium channels should be changed to limbic encephalitis associated with LGI1 antibodies, and this disorder should be classed as an autoimmune synaptic encephalopathy. National Institutes of Health, National Cancer Institute, and Euroimmun. Copyright 2010 Elsevier Ltd. All rights reserved.

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Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents.

Nicole R Florance, Rebecca L. Davis, Christopher Lam … (2009)

To report the clinical features of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in patients 18 years old, 31% in girls < or =18 years old (p = 0.05), and 9% in girls < or =14 years old (p = 0.008). None of the male patients had tumors. Of 32 patients < or =18 years old, 87.5% presented with behavioral or personality change, sometimes associated with seizures and frequent sleep dysfunction; 9.5% with dyskinesias or dystonia; and 3% with speech reduction. On admission, 53% had severe speech deficits. Eventually, 77% developed seizures, 84% stereotyped movements, 86% autonomic instability, and 23% hypoventilation. Responses to immunotherapy were slow and variable. Overall, 74% had full or substantial recovery after immunotherapy or tumor removal. Neurological relapses occurred in 25%. At the last follow-up, full recovery occurred more frequently in patients who had a teratoma that was removed (5/8) than in those without a teratoma (4/23; p = 0.03). Anti-NMDAR encephalitis is increasingly recognized in children, comprising 40% of all cases. Younger patients are less likely to have tumors. Behavioral and speech problems, seizures, and abnormal movements are common early symptoms. The phenotype resembles that of the adults, although dysautonomia and hypoventilation are less frequent or severe in children. Ann Neurol 2009;66:11-18.

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Author and article information

Journal

Journal ID (nlm-ta): J Neurol Neurosurg Psychiatry

Journal ID (iso-abbrev): J. Neurol. Neurosurg. Psychiatr

Journal ID (hwp): jnnp

Journal ID (publisher-id): jnnp

Title: Journal of Neurology, Neurosurgery, and Psychiatry

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Print): 0022-3050

ISSN (Electronic): 1468-330X

Publication date (Print): September 2016

Publication date (Electronic): 25 April 2016

Volume: 87

Issue: 9

Pages: 1005-1015

Affiliations

[1 ]Nuffield Department of Clinical Neurosciences, University of Oxford , Oxford, UK

[2 ]Clinical Department of Neurology, Medical University of Innsbruck , Innsbruck, Austria

[3 ]Neuroimmunology Program, Hospital Clinic and Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Universitat de Barcelona , Barcelona, Spain

[4 ]Zdravotni ustav se sidlem v Usti nad Labem, Centrum imunologie a mikrobiologie , Usti nad Labem, Czech Republic

[5 ]Department of Neurology, Center of Clinical Neuroscience First Faculty of Medicine, General University Hospital and First Faculty of Medicine, Charles University in Prague , Prague, Czech Republic

[6 ]Laboratory for CSF and Neuroimmunology, Topelex Ltd , Prague, Czech Republic

[7 ]Department of Clinical Immunology, Odense University Hospital , Odense, Denmark

[8 ]Institute of Clinical Research, University of Southern Denmark , Odense, Denmark

[9 ]Department of Neurology, University of Pécs , Pécs, Hungary

[10 ]Euroimmun AG , Lübeck, Germany

[11 ]Klinikum rechts der Isar der TU München, Klinik für Neurologie , Munich, Germany

[12 ]Department of Immunology and Biotechnology, University of Pécs , Pécs, Hungary

[13 ]Clinical Neurobiology Unit, Neuroscience Institute Cavalieri Ottolenghi (NICO), University Hospital San Luigi Gonzaga, Regional Referring Multiple Sclerosis Centre , Orbassano, Italy

[14 ]Department of Neurology, Azienda ULSS 9 Treviso , Treviso, Italy

[15 ]Sanquin Diagnostic Services, Department of Immunopathology and Blood Coagulation, Amsterdam, The Netherlands

[16 ]Department of Neurology, MS Centre ErasMS, Erasmus MC , Rotterdam, The Netherlands

[17 ]Institute of Neurology , Medical University of Vienna , Vienna, Austria

[18 ]Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona , Barcelona, Spain

[19 ]Neurology Department, Istanbul University, Cerrahpasa Medical School , Istanbul, Turkey

[20 ]Department of Immunology, Istanbul University, Institute of Experimental Medicine , Istanbul, Turkey

[21 ]NeuroCure Clinical Research Center (NCRC), Charité Universitätsmedizin Berlin , Berlin, Germany

[22 ]Medical Faculty, Department of Neurology, Heinrich–Heine–University Düsseldorf , Düsseldorf, Germany

[23 ]Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg , Germany

[24 ]Department of Clinical Medicine, University of Bergen , Bergen, Norway

[25 ]Department of Neurology, Haukeland University Hospital , Bergen, Norway

[26 ]Faculty of Medecine RTH Laennec, Lyon Neurosciences Research Centre, Neuro–inflammation and Neuro–oncology Team , Lyon, France

[27 ]Department of Neurology, University Hospital of Schleswig-Holstein, Campus Lübeck , Lübeck, Germany

[28 ]Institute for Quality Assurance , Lübeck, Germany

Author notes

[Correspondence to ] Dr Patrick Waters, Nuffield Department of Clinical Neurosciences, Level 5/6 West wing, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK; paddy.waters@ 123456ndcn.ox.ac.uk

PW and MR are joint first authors

AV is a senior author

Article

Publisher ID: jnnp-2015-312601

DOI: 10.1136/jnnp-2015-312601

PMC ID: 5013123

PubMed ID: 27113605

SO-VID: e2473420-ab64-4c2d-81dd-1262ff32af45

Copyright © 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/

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This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

History

Date received : 30 October 2015

Date revision received : 19 January 2016

Date accepted : 6 February 2016

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Multicentre comparison of a diagnostic assay: aquaporin-4 antibodies in neuromyelitis optica

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Most cited references 14

Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia

Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents.

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