Distinctive seizure signature in the first video case-control study of a naturally-occurring feline autoimmune encephalitis model

S N M Binks¹, A H Crawford², E Ives³, L J Davison⁴, A Fower⁵, H Fox⁵, A Kaczmarska⁶, M Woodhall⁵, P Waters⁵, A E Handel⁵, S R Irani⁷, R Gutierrez Quintana⁶, F A Chowdhury⁸, S H Eriksson⁹, A Pakozdy⁹

Affiliations

¹ Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK; Department of Neurology, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK. Electronic address: sophie.binks@ndcn.ox.ac.uk.
² The Royal Veterinary College, Hertfordshire AL9 7TA, UK.
³ Anderson Moores Veterinary Specialists, Winchester, Hampshire SO21 2LL, UK.
⁴ The Royal Veterinary College, Hertfordshire AL9 7TA, UK; Department of Anatomy, Physiology and Genetics, University of Oxford, Sherrington Building, Sherrington Rd, Oxford OX1 3PT, UK.
⁵ Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
⁶ University of Glasgow, School of Biodiversity, One Health and Veterinary Medicine, Small Animal Hospital, 464 Bearsden Rd, Glasgow G61 1QH, UK.
⁷ Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK; Departments of Neurology and Neurosciences, Mayo Clinic, Jacksonville, FL, USA.
⁸ Neurology, National Hospital for Neurology and Neurosurgery, London, UK; Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, London, UK.
⁹ University Clinic for Small Animals, University of Veterinary Medicine, Vienna, Austria.

PMID: 39984138
PMCID: PMC12037459
DOI: 10.1016/j.bbi.2025.02.018

Distinctive seizure signature in the first video case-control study of a naturally-occurring feline autoimmune encephalitis model

S N M Binks et al. Brain Behav Immun. 2025 May.

. 2025 May:126:289-296.

doi: 10.1016/j.bbi.2025.02.018. Epub 2025 Feb 19.

Authors

Affiliations

¹ Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK; Department of Neurology, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK. Electronic address: sophie.binks@ndcn.ox.ac.uk.
² The Royal Veterinary College, Hertfordshire AL9 7TA, UK.
³ Anderson Moores Veterinary Specialists, Winchester, Hampshire SO21 2LL, UK.
⁴ The Royal Veterinary College, Hertfordshire AL9 7TA, UK; Department of Anatomy, Physiology and Genetics, University of Oxford, Sherrington Building, Sherrington Rd, Oxford OX1 3PT, UK.
⁵ Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
⁶ University of Glasgow, School of Biodiversity, One Health and Veterinary Medicine, Small Animal Hospital, 464 Bearsden Rd, Glasgow G61 1QH, UK.
⁷ Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK; Departments of Neurology and Neurosciences, Mayo Clinic, Jacksonville, FL, USA.
⁸ Neurology, National Hospital for Neurology and Neurosurgery, London, UK; Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, London, UK.
⁹ University Clinic for Small Animals, University of Veterinary Medicine, Vienna, Austria.

PMID: 39984138
PMCID: PMC12037459
DOI: 10.1016/j.bbi.2025.02.018

Abstract

Background and objective: Autoimmune encephalitis (AE) is a form of brain inflammation where pathogenic autoantibodies bind surface proteins. In humans, AE is at least as common as infective encephalitis, and seizures are a prominent manifestation. The most common adult human AE is associated with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E). AE in non-human mammals is also recognised, notably the polar bear 'Knut', diagnosed with N-methyl D-aspartate receptor antibody encephalitis. LGI1-Ab-E is an emerging cause of spontaneously-arising AE in domestic cats. Our objective was to phenotype the seizure profile of feline LGI1-Ab-E and probe parallels to its human counterpart.

Methods: We characterised seizures in naturally-occurring feline LGI1-Ab-E. Three veterinary and two human neurologists independently blind-rated 35 LGI1-antibody positive and negative feline seizure videos from 24 cats (16 LGI1-Ab-E positive, 8 negative). Data analysed included seizure frequency, semiologies and their co-occurrence, localisation, inter-rater agreement, and predictive factors.

Results: The mean number of daily seizures at peak was significantly higher in LGI1-antibody positive compared to LGI1-antibody-negative cats (12.6 vs. 1.9/day, pcorr = 0.011). Semiologies statistically significantly enriched in LGI1-Ab-E observations included orofacial automatisms (88/120, 73 % vs. 26/55, 47 %, pcorr = 0.024), salivation (87/120, 73 % vs. 23/55, 42 %, pcorr = 0.004); and mydriasis (79/120, 66 % vs 19/55, 35 %, pcorr = 0.004), and almost exclusively seen in LGI1-Ab-E were circling (39/120, 33 % vs. 1/55, 2 %, pcorr=<0.001) and aggression (14/120, 12 % vs. 0/55, 0 %, non significant after correction). A temporal lobe onset was proposed in 67 % (80/120) of seropositive ratings, compared to 28 % (15/55) LGI1-Ab-E negative (p < 0.0001). Network analysis depicted complex and overlapping relationships between features, akin to the frequent and multifaceted seizures of human LGI1-Ab-E. Orofacial automatisms, mydriasis and temporal lobe localisation were predictive semiological features of feline LGI1-Ab-E.

Significance: Feline LGI1-Ab-E represents a clinically distinctive seizure disorder. Our findings highlight the value of studying naturally-occurring, biologically representative animal models which closely mimic human diseases. This bidirectional translational approach confers benefits across species and unites human and veterinary neurology.

Keywords: Autoimmune; Cats; Encephalitis; Leucine-rich glioma-inactivated 1 (LGI1); Orofacial; Seizures.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Binks has received an honorarium from Vetmeduni Wien and is named on a patent application entitled “Diagnostic Strategy to improve specificity of CASPR2 antibody detection” (TBA / BB Ref. JA94536P.GBA). Dr Handel has received research funding from UCB-Pharma. Dr Waters 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, UCB, F. Hoffmann La-Roche, MIAC and Alexion; travel grants from the Guthy-Jackson Charitable Foundation; and research funding from Euroimmun AG. His work in the Autoimmune Neurology Diagnostic Laboratory is supported by the NHS Commissioning service for NMOSD. Professor Irani has received honoraria/research support from UCB, Argenx, Immunovant, MedImmun, Roche, Janssen, Cerebral therapeutics, ADC therapeutics, Brain, CSL Behring, and ONO Pharma, and receives licensed royalties on patent application WO/2010/046716 entitled 'Neurological Autoimmune Disorders', and has filed two other patents entitled “Diagnostic method and therapy” (WO2019211633 and US-2021-0071249-A1; PCT application WO202189788A1) and “Biomarkers” (PCT/GB2022/050614 and WO202189788A1). Dr Eriksson has received honoraria for educational activities from Eisai, Fidia, Lincoln and UCB pharma, nonrelevant for the current study. Dr Crawford, Dr Ives, Professor Davison, Mr Fower, Dr Fox, Dr Kaczmarska, Dr Woodhall, Dr Gutierrez Quintana, Dr Chowdhury, and Dr Pakozdy declare no competing interests.

Figures

**Fig. 1**
**Experimental plan and results of the first video study of a naturally-occurring feline autoimmune encephalitis model. [A]** Study design **[B]** Cell based assay from a LGI1-antibody-positive cat (top row; Cat 1- titre 1:40) in the study, and a representative negative control cat (bottom row). Left-Right: HEK cells transfected with a feline LGI1 construct tagged with EGFP, with a feline anti-Fc gamma receptor antibody applied after incubation with patient serum at 1:20 dilution, and images merged with the addition of nuclei stained with DAPI (4′,6-diamidino-2-phenylindole). All images taken on a fluorescent microscope at 100 x magnification. Scale bar represents 10 μm **[C]** Bar chart depicting mean peak daily seizure number at onset in LGI1-Ab-E positive (dark purple) compared to LGI1-antibody-negative (light purple) cats. Error bar shows upper limit of standard deviation **[D, E]** Lollipop diagrams showing percent of observations of localisation based on top-level **[D]** and second-level ILAE **[E]** classifications in LGI1-antibody-positive (top, total observations = 120) and −negative (bottom, total observations = 55) clips **[F]** Video stills from study clips showing key features of orofacial automatisms, mydriasis, salivation, aggression, and circling in study cats **[G]** Circos plot delineating connectivity between top 10 observed features in LGI1-Ab-E cats. Each colour segment proportionally represents a semiology, and its co-occurrence with other semiologies is also proportionally represented through incoming or outgoing projections. **Abbreviations:** HEK, human embryonic kidney cells; ILAE, International League Against Epilepsy; LGI1, leucine-rich glioma-inactivated 1; LGI1-Ab-E, LGI1-antibody encephalitis.

See this image and copyright information in PMC

References

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Distinctive seizure signature in the first video case-control study of a naturally-occurring feline autoimmune encephalitis model

Affiliations

Distinctive seizure signature in the first video case-control study of a naturally-occurring feline autoimmune encephalitis model

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Substances

Supplementary concepts

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous