Investigation of the presence of specific neural antibodies in dogs with epilepsy or dyskinesia using murine and human assays

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Abstract

Background

Autoimmune mechanisms represent a novel category for causes of seizures and epilepsies in humans, and LGI1‐antibody associated limbic encephalitis occurs in cats.

Hypothesis/Objectives

To investigate the presence of neural antibodies in dogs with epilepsy or dyskinesia of unknown cause using human and murine assays modified for use in dogs.

Animals

Fifty‐eight dogs with epilepsy of unknown cause or suspected dyskinesia and 57 control dogs.

Methods

Serum and CSF samples were collected prospectively as part of the diagnostic work‐up. Clinical data including onset and seizure/episode type were retrieved from the medical records. Screening for neural antibodies was done with cell‐based assays transfected with human genes for typical autoimmune encephalitis antigens and tissue‐based immunofluorescence assays on mouse hippocampus slices in serum and CSF samples from affected dogs and controls. The commercial human und murine assays were modified with canine‐specific secondary antibody. Positive controls were from human samples.

Results

The commercial assays used in this study did not provide unequivocal evidence for presence of neural antibodies in dogs including one dog with histopathologically proven limbic encephalitis. Low titer IgLON5 antibodies were present in serum from one dog from the epilepsy/dyskinesia group and in one dog from the control group.

Conclusion and Clinical Importance

Specific neural antibodies were not detected using mouse and human target antigens in dogs with epilepsy and dyskinesia of unknown origin. These findings emphasize the need for canine‐specific assays and the importance of control groups.

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Most cited references 49

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ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology

Ingrid Scheffer, Samuel Berkovic, Giuseppe Capovilla … (2017)

The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world. The new classification originates from a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It presents three levels, starting with seizure type, where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification. After diagnosis of the seizure type, the next step is diagnosis of epilepsy type, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and also an unknown epilepsy group. The third level is that of epilepsy syndrome, where a specific syndromic diagnosis can be made. The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences. New terminology is introduced such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self-limited and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the 21st century.

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A clinical approach to diagnosis of autoimmune encephalitis.

Francesc Graus, Maarten J. Titulaer, Ramani Balu … (2016)

Encephalitis is a severe inflammatory disorder of the brain with many possible causes and a complex differential diagnosis. Advances in autoimmune encephalitis research in the past 10 years have led to the identification of new syndromes and biomarkers that have transformed the diagnostic approach to these disorders. However, existing criteria for autoimmune encephalitis are too reliant on antibody testing and response to immunotherapy, which might delay the diagnosis. We reviewed the literature and gathered the experience of a team of experts with the aims of developing a practical, syndrome-based diagnostic approach to autoimmune encephalitis and providing guidelines to navigate through the differential diagnosis. Because autoantibody test results and response to therapy are not available at disease onset, we based the initial diagnostic approach on neurological assessment and conventional tests that are accessible to most clinicians. Through logical differential diagnosis, levels of evidence for autoimmune encephalitis (possible, probable, or definite) are achieved, which can lead to prompt immunotherapy.

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Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study.

Maarten J. Titulaer, Lindsey McCracken, Iñigo Gabilondo … (2013)

Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disorder in which the use of immunotherapy and the long-term outcome have not been defined. We aimed to assess the presentation of the disease, the spectrum of symptoms, immunotherapies used, timing of improvement, and long-term outcome. In this multi-institutional observational study, we tested for the presence of NMDAR antibodies in serum or CSF samples of patients with encephalitis between Jan 1, 2007, and Jan 1, 2012. All patients who tested positive for NMDAR antibodies were included in the study; patients were assessed at symptom onset and at months 4, 8, 12, 18, and 24, by use of the modified Rankin scale (mRS). Treatment included first-line immunotherapy (steroids, intravenous immunoglobulin, plasmapheresis), second-line immunotherapy (rituximab, cyclophosphamide), and tumour removal. Predictors of outcome were determined at the Universities of Pennsylvania (PA, USA) and Barcelona (Spain) by use of a generalised linear mixed model with binary distribution. We enrolled 577 patients (median age 21 years, range 8 months to 85 years), 211 of whom were children (<18 years). Treatment effects and outcome were assessable in 501 (median follow-up 24 months, range 4-186): 472 (94%) underwent first-line immunotherapy or tumour removal, resulting in improvement within 4 weeks in 251 (53%). Of 221 patients who did not improve with first-line treatment, 125 (57%) received second-line immunotherapy that resulted in a better outcome (mRS 0-2) than those who did not (odds ratio [OR] 2·69, CI 1·24-5·80; p=0·012). During the first 24 months, 394 of 501 patients achieved a good outcome (mRS 0-2; median 6 months, IQR 2-12) and 30 died. At 24 months' follow-up, 203 (81%) of 252 patients had good outcome. Outcomes continued to improve for up to 18 months after symptom onset. Predictors of good outcome were early treatment (0·62, 0·50-0·76; p<0·0001) and no admission to an intensive care unit (0·12, 0·06-0·22; p<0·0001). 45 patients had one or multiple relapses (representing a 12% risk within 2 years); 46 (67%) of 69 relapses were less severe than initial episodes (p<0·0001). In 177 children, predictors of good outcome and the magnitude of effect of second-line immunotherapy were similar to those of the entire cohort. Most patients with anti-NMDAR encephalitis respond to immunotherapy. Second-line immunotherapy is usually effective when first-line treatments fail. In this cohort, the recovery of some patients took up to 18 months. The Dutch Cancer Society, the National Institutes of Health, the McKnight Neuroscience of Brain Disorders award, The Fondo de Investigaciones Sanitarias, and Fundació la Marató de TV3. Copyright © 2013 Elsevier Ltd. All rights reserved.

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Author and article information

Contributors

Andrea Fischer:

ORCID: https://orcid.org/0000-0001-7094-1947

andreafischer@lmu.de

Journal

Journal ID (nlm-ta): J Vet Intern Med

Journal ID (iso-abbrev): J Vet Intern Med

Journal ID (doi): 10.1111/(ISSN)1939-1676

Journal ID (publisher-id): JVIM

Title: Journal of Veterinary Internal Medicine

Publisher: John Wiley & Sons, Inc. (Hoboken, USA )

ISSN (Print): 0891-6640

ISSN (Electronic): 1939-1676

Publication date (Electronic): 26 May 2023

Publication date Collection: Jul-Aug 2023

Volume: 37

Issue: 4 ( doiID: 10.1111/jvim.v37.4 )

Pages: 1409-1417

Affiliations

[ ¹ ] Section of Neurology, Centre for Clinical Veterinary Medicine LMU Munich Munich Germany

[ ² ] Department of Epileptology (Krankenhaus Mara) Bielefeld University, Medical School Bielefeld Germany

[ ³ ] Laboratory Krone Bad Salzuflen Germany

[ ⁴ ] Department of Small Animal Medicine and Surgery University of Veterinary Medicine Hannover Foundation Hannover Germany

[ ⁵ ] Tierarztpraxis, Dr A. Bathen‐Nöthen Cologne Germany

[ ⁶ ] Section of Clinical & Comparative Neuropathology, Centre for Clinical Veterinary Medicine LMU Munich Munich Germany

[ ⁷ ] Institute of In Vivo and In Vitro Models, University of Veterinary Medicine Vienna Vienna Austria

[ ⁸ ] Fitzpatrick Referrals, Halfway Lane Surrey UK

[ ⁹ ] School of Veterinary Medicine, Faculty of Health & Medical Sciences University of Surrey Surrey UK

[ ¹⁰ ] Tierärztliche Praxis für Neurologie Dettelbach Germany

Author notes

[*] [* ] Correspondence

Andrea Fischer, Centre for Clinical Veterinary Medicine, LMU Munich, Veterinärstr. 13, 80539 Munich, Germany.

Email: andreafischer@ 123456lmu.de

Author information

Andrea Tipold https://orcid.org/0000-0002-9421-942X

Jasmin Neßler https://orcid.org/0000-0002-1427-2555

Clare Rusbridge https://orcid.org/0000-0002-3366-2110

Holger A. Volk https://orcid.org/0000-0002-7312-638X

Andrea Fischer https://orcid.org/0000-0001-7094-1947

Article

Publisher ID: JVIM16744

DOI: 10.1111/jvim.16744

PMC ID: 10365065

PubMed ID: 37232512

SO-VID: 2d4b139b-197f-41de-bb11-82f38f334cdd

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date received : 15 September 2022

Date accepted : 07 May 2023

Page count

Figures: 1, Tables: 2, Pages: 9, Words: 7101

Funding

Funded by: GKF ‐ Gesellschaft zur Förderung Kynologischer Forschung e.V.

Custom metadata

source-schema-version-number 2.0

cover-date July/August 2023

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.3.2 mode:remove_FC converted:24.07.2023

ScienceOpen disciplines: Veterinary medicine

Keywords: animal model,autoimmune epilepsy,dyskinesia,epileptic seizure,idiopathic epilepsy,movement disorder,neural antibodies,neuroinflammation,sleep disorder

Data availability:

ScienceOpen disciplines: Veterinary medicine

Keywords: animal model, autoimmune epilepsy, dyskinesia, epileptic seizure, idiopathic epilepsy, movement disorder, neural antibodies, neuroinflammation, sleep disorder

Investigation of the presence of specific neural antibodies in dogs with epilepsy or dyskinesia using murine and human assays

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Abstract

Background

Hypothesis/Objectives

Animals

Methods

Results

Conclusion and Clinical Importance

Related collections

Horses and Humans Research Foundation

Most cited references 49

ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology

A clinical approach to diagnosis of autoimmune encephalitis.

Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study.

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