Acute seizure risk in patients with encephalitis: development and validation of clinical prediction models from two independent prospective multicentre cohorts

Greta K. Wood, Roshan Babar, Mark A. Ellul, Rhys Huw Thomas, Harriet Van Den Tooren, Ava Easton, Kukatharmini Tharmaratnam, Girvan Burnside, Ali M. Alam, Hannah Castell, Sarah Boardman, Ceryce Collie, Bethany Facer, Cordelia Dunai, Sylviane Defres, Julia Granerod, David W.G. Brown, Angela Vincent, Anthony Guy Marson, Sarosh R. IraniTom Solomon, Benedict D. Michael*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: In patients with encephalitis, the development of acute symptomatic seizures is highly variable, but when present is associated with a worse outcome. We aimed to determine the factors associated with seizures in encephalitis and develop a clinical prediction model. Methods: We analysed 203 patients from 24 English hospitals (2005-2008) (Cohort 1). Outcome measures were seizures prior to and during admission, inpatient seizures and status epilepticus. A binary logistic regression risk model was converted to a clinical score and independently validated on an additional 233 patients from 31 UK hospitals (2013-2016) (Cohort 2). Results: In Cohort 1, 121 (60%) patients had a seizure including 103 (51%) with inpatient seizures. Admission Glasgow Coma Scale (GCS) ≤8/15 was predictive of subsequent inpatient seizures (OR (95% CI) 5.55 (2.10 to 14.64), p<0.001), including in those without a history of prior seizures at presentation (OR 6.57 (95% CI 1.37 to 31.5), p=0.025). A clinical model of overall seizure risk identified admission GCS along with aetiology (autoantibody-associated OR 11.99 (95% CI 2.09 to 68.86) and Herpes simplex virus 3.58 (95% CI 1.06 to 12.12)) (area under receiver operating characteristics curve (AUROC) =0.75 (95% CI 0.701 to 0.848), p<0.001). The same model was externally validated in Cohort 2 (AUROC=0.744 (95% CI 0.677 to 0.811), p<0.001). A clinical scoring system for stratifying inpatient seizure risk by decile demonstrated good discrimination using variables available on admission; age, GCS and fever (AUROC=0.716 (95% CI 0.634 to 0.798), p<0.001) and once probable aetiology established (AUROC=0.761 (95% CI 0.6840.839), p<0.001). Conclusion: Age, GCS, fever and aetiology can effectively stratify acute seizure risk in patients with encephalitis. These findings can support the development of targeted interventions and aid clinical trial design for antiseizure medication prophylaxis.

Original languageEnglish
Article numbere000323
JournalBMJ Neurology Open
Volume4
Issue number2
DOIs
Publication statusPublished - 5 Sep 2022
Externally publishedYes

Bibliographical note

Funding Information:
Funded by the Department of Health Policy Research Programme (Enhanced Diagnostic and Management Strategies to Improve the Identification and Outcome of Individuals with Encephalitis), 047/1084. BDM is supported by the UKRI/MRC (MR/V03605X/1), the MRC/UKRI (MR/V007181//1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3).

Funding Information:
RHT has received honoraria and meeting support from Arvelle, Bial, Eisai, GW Pharma, LivaNova, Novartis, Sanofi, UCB Pharma, UNEEG, Zogenix. Conflicts of Interest. SRI is an inventor on ‘Diagnostic Strategy to improve specificity of CASPR2 antibody detection (PCT/G82019 /051257) and receives royalties on a licenced patent application for LGI1/CASPR2 testing as coapplicant (PCT/GB2009/051441) entitled ‘Neurological Autoimmune Disorders’. AV and University of Oxford hold a patent for VGKC-complex (LGI1 and CASPR2) antibody tests, licenced to Euroimmune AG. AV receives a proportion of royalties. SRI is supported by a senior clinical fellowship from the Medical Research Council (MR/V007173/1), Wellcome Trust Fellowship (104079/Z/14/Z) and 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. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. SRI has received honoraria from UCB, Immunovant, MedImmun, Roche, Cerebral therapeutics, ADC therapeutics, Brain, Medlink Neurology and research support from CSL Behring, UCB and ONO Pharma. TS was Chair/Co-Chair of the UKRI/NIHR COVID-19 Rapid Response and Rolling Funding Initiatives (from March 2020), an Advisor to the UK COVID-19 Therapeutics Advisory Panel (UK-TAP, from August 2020) and a member of the MHRA COVID-19 Vaccines Benefit Risk Expert Working Group (from August 2020). He is also a trustee of the UK Academy of Medical Sciences (December 2021). TS is President of the Encephalitis Society. TS was an advisor to the GSK Ebola Vaccine programme and chaired a Siemens Diagnostics Clinical Advisory Board. TS was on the Data Safety Monitoring Committee of the GSK Study to Evaluate the Safety and Immunogenicity of a Candidate Ebola Vaccine in Children GSK3390107A (ChAd3 EBO-Z) vaccine. TS chaired the Siemens Healthineers Clinical Advisory Board. Data safety monitoring board: Study of Ebola vaccine and ChAd3-EBO-Z - Commercial entity. BDM is supported by the UKRI/MRC (MR/V03605X/1), the MRC/UKRI (MR/V007181//1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3).

Funding Information:
Funded by the Department of Health Policy Research Programme (Enhanced Diagnostic and Management Strategies to Improve the Identification and Outcome of Individuals with Encephalitis), 047/1084. BDM is supported by the UKRI/MRC (MR/V03605X/1), the MRC/UKRI (MR/V007181//1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3).

Funding Information:
We would like to thank the patients involved in this research. UK Health Protection Agency Aetiology of Encephalitis Study Group: Helen E Ambrose, Nicholas W S Davies, Jonathan P Clewley, Amanda L Walsh, Dilys Morgan, Richard Cunningham, Mark Zuckerman, Ken J Mutton, Katherine N Ward, Michael P T Lunn, Natasha S Crowcroft, Craig Ford, Emily Rothwell, William Tong, Jean-Pierre Lin, Ming Lim, Nicholas Price, Javeed Ahmed, David Cubitt, Sarah Benton, Cheryl Hemingway, David Muir, Hermione Lyall, Ed Thompson, Geoff Keir, Viki Worthington, Paul Griffiths, Susan Bennett, Rachel Kneen, Paul Klapper. ENCEPH-UK Study Group: Ruth Backman, Gus Baker, Nicholas J Beeching, Rachel Breen, Chris Cheyne, Enitan D Carrol, Nicholas W S Davies, Martin Eccles, Robbie Foy, Marta Garcia-Finana, Julia Griem, Michael Griffiths, Alison Gummery, Lara Harris, Helen Hickey, Helen Hill, Ann Jacoby, Hayley Hardwick, Ciara Kierans, Michael Kopelman, Rachel Kneen, Gill Lancaster, Michael Levin, Rebecca McDonald, Antonieta Medina-Lara, Esse Menson, Natalie Martin, Andrew Pennington, Andrew Pollard, Julie Riley, Manish Sadarangani, Anne Salter, Maria Thornton, Charles Warlow. AGM is a National Institute for Health Research (NIHR) Senior Investigator and also part funded by NIHR ARC North West Coast.

Publisher Copyright:
© 2022 Author(s) (or their employer(s)).

Keywords

  • AUTOIMMUNE ENCEPHALITIS
  • CLINICAL NEUROLOGY
  • INFECTIOUS DISEASES

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