Abstract
Purpose
We aimed to characterize the outcomes of patients with severe meningoencephalitis requiring intensive care.
Methods
We conducted a prospective multicenter international cohort study (2017–2020) in 68 centers across 7 countries. Eligible patients were adults admitted to the intensive care unit (ICU) with meningoencephalitis, defined by an acute onset of encephalopathy (Glasgow coma scale (GCS) score \(\le\) 13), a cerebrospinal fluid pleocytosis \(\ge\) 5 cells/mm3, and at least two of the following criteria: fever, seizures, focal neurological deficit, abnormal neuroimaging, and/or electroencephalogram. The primary endpoint was poor functional outcome at 3 months, defined by a score of three to six on the modified Rankin scale. Multivariable analyses stratified on centers investigated ICU admission variables associated with the primary endpoint.
Results
Among 599 patients enrolled, 589 (98.3%) completed the 3-month follow-up and were included. Overall, 591 etiologies were identified in those patients which were categorized into five groups: acute bacterial meningitis (n = 247, 41.9%); infectious encephalitis of viral, subacute bacterial, or fungal/parasitic origin (n = 140, 23.7%); autoimmune encephalitis (n = 38, 6.4%); neoplastic/toxic encephalitis (n = 11, 1.9%); and encephalitis of unknown origin (n = 155, 26.2%). Overall, 298 patients (50.5%, 95% CI 46.6–54.6%) had a poor functional outcome, including 152 deaths (25.8%). Variables independently associated with a poor functional outcome were age > 60 years (OR 1.75, 95% CI 1.22–2.51), immunodepression (OR 1.98, 95% CI 1.27–3.08), time between hospital and ICU admission > 1 day (OR 2.02, 95% CI 1.44–2.99), a motor component on the GCS \(\le\) 3 (OR 2.23, 95% CI 1.49–3.45), hemiparesis/hemiplegia (OR 2.48, 95% CI 1.47–4.18), respiratory failure (OR 1.76, 95% CI 1.05–2.94), and cardiovascular failure (OR 1.72, 95% CI 1.07–2.75). In contrast, administration of a third-generation cephalosporin (OR 0.54, 95% CI 0.37–0.78) and acyclovir (OR 0.55, 95% CI 0.38–0.80) on ICU admission were protective.
Conclusion
Meningoencephalitis is a severe neurologic syndrome associated with high mortality and disability rates at 3 months. Actionable factors for which improvement could be made include time from hospital to ICU admission, early antimicrobial therapy, and detection of respiratory and cardiovascular complications at admission.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The data supporting the findings of the study are available upon reasonable request after approval of a proposal from the corresponding author (RS). Related documents will also be made available, including the study protocol, and the statistical analysis plan.
References
Venkatesan A, Michael BD, Probasco JC et al (2019) Acute encephalitis in immunocompetent adults. Lancet 393:702–716. https://doi.org/10.1016/S0140-6736(18)32526-1
Venkatesan A, Tunkel AR, Bloch KC et al (2013) Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis 57:1114–1128. https://doi.org/10.1093/cid/cit458
Glaser CA, Honarmand S, Anderson LJ et al (2006) Beyond viruses: clinical profiles and etiologies associated with encephalitis. Clin Infect Dis 43:1565–1577. https://doi.org/10.1086/509330
Mailles A, Stahl J (2009) Infectious encephalitis in France in 2007: a national prospective study. Clin Infect Dis 49:1838–1847. https://doi.org/10.1086/648419
Mailles A, Argemi X, Biron C et al (2022) Changing profile of encephalitis: results of a 4-year study in France. Infect Dis Now 52:1–6. https://doi.org/10.1016/j.idnow.2021.11.007
Thakur KT, Motta M, Asemota AO et al (2013) Predictors of outcome in acute encephalitis. Neurology 81:793–800. https://doi.org/10.1212/WNL.0b013e3182a2cc6d
Singh TD, Fugate JE, Rabinstein AA (2015) The spectrum of acute encephalitis: causes, management, and predictors of outcome. Neurology 84:359–366. https://doi.org/10.1212/WNL.0000000000001190
Sonneville R, Gault N, de Montmollin E et al (2015) Clinical spectrum and outcomes of patients with encephalitis requiring intensive care. Eur J Neurol 22:6-e1. https://doi.org/10.1111/ene.12541
Sonneville R, Mariotte E, Neuville M et al (2016) Early-onset status epilepticus in patients with acute encephalitis. Medicine (Baltimore) 95:e4092. https://doi.org/10.1097/MD.0000000000004092
Granerod J, Ambrose HE, Davies NW et al (2010) Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis 10:835–844. https://doi.org/10.1016/S1473-3099(10)70222-X
Jaquet P, de Montmollin E, Dupuis C et al (2019) Functional outcomes in adult patients with herpes simplex encephalitis admitted to the ICU: a multicenter cohort study. Intensive Care Med 45:1103–1111. https://doi.org/10.1007/s00134-019-05684-0
Singh TD, Fugate JE, Hocker S et al (2016) Predictors of outcome in HSV encephalitis. J Neurol 263:277–289. https://doi.org/10.1007/s00415-015-7960-8
Auburtin M, Wolff M, Charpentier J et al (2006) Detrimental role of delayed antibiotic administration and penicillin-nonsusceptible strains in adult intensive care unit patients with pneumococcal meningitis: the PNEUMOREA prospective multicenter study. Crit Care Med 34:2758–2765. https://doi.org/10.1097/01.CCM.0000239434.26669.65
Bijlsma MW, Brouwer MC, Kasanmoentalib ES et al (2016) Community-acquired bacterial meningitis in adults in the Netherlands, 2006–14: a prospective cohort study. Lancet Infect Dis 16:339–347. https://doi.org/10.1016/S1473-3099(15)00430-2
McGill F, Griffiths MJ, Bonnett LJ et al (2018) Incidence, aetiology, and sequelae of viral meningitis in UK adults: a multicentre prospective observational cohort study. Lancet Infect Dis 18:992–1003. https://doi.org/10.1016/S1473-3099(18)30245-7
Sonneville R, Demeret S, Klein I et al (2008) Acute disseminated encephalomyelitis in the intensive care unit: clinical features and outcome of 20 adults. Intensive Care Med 34:528–532. https://doi.org/10.1007/s00134-007-0926-2
de Montmollin E, Demeret S, Brulé N et al (2017) Anti-N-methyl-d-aspartate receptor encephalitis in adult patients requiring intensive care. Am J Respir Crit Care Med 195:491–499. https://doi.org/10.1164/rccm.201603-0507OC
Sonneville R, Venkatesan A, Honnorat J (2019) Understanding auto-immune encephalitis in the ICU. Intensive Care Med 45:1795–1798. https://doi.org/10.1007/s00134-019-05773-0
Wilson MR, Sample HA, Zorn KC et al (2019) Clinical metagenomic sequencing for diagnosis of meningitis and encephalitis. N Engl J Med 380:2327–2340. https://doi.org/10.1056/NEJMoa1803396
Trujillo-Gómez J, Tsokani S, Arango-Ferreira C et al (2022) Biofire FilmArray Meningitis/Encephalitis panel for the aetiological diagnosis of central nervous system infections: a systematic review and diagnostic test accuracy meta-analysis. EClinicalMedicine 44:101275. https://doi.org/10.1016/j.eclinm.2022.101275
Teasdale G, Jennett B (1974) Assessment of coma and impaired consciousness. A practical scale. Lancet 2:81–84. https://doi.org/10.1016/s0140-6736(74)91639-0
Le Gall JR, Lemeshow S, Saulnier F (1993) A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA 270:2957–2963
Vincent JL, Moreno R, Takala J et al (1996) The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 22:707–710
Koelman DLH, Brouwer MC, Ter Horst L et al (2022) Pneumococcal meningitis in adults: a prospective nationwide cohort study over a 20-year period. Clin Infect Dis 74:657–667. https://doi.org/10.1093/cid/ciab477
Stahl JP, Azouvi P, Bruneel F et al (2017) Guidelines on the management of infectious encephalitis in adults. Medecine et Maladies Infectieuses 47:179–194. https://doi.org/10.1016/j.medmal.2017.01.005
Raschilas F, Wolff M, Delatour F et al (2002) Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study. Clin Infect Dis 35:254–260. https://doi.org/10.1086/341405
Poissy J, Wolff M, Dewilde A et al (2009) Factors associated with delay to acyclovir administration in 184 patients with herpes simplex virus encephalitis. Clin Microbiol Infect 15:560–564. https://doi.org/10.1111/j.1469-0691.2009.02735.x
Tan IL, McArthur JC, Venkatesan A, Nath A (2012) Atypical manifestations and poor outcome of herpes simplex encephalitis in the immunocompromised. Neurology 79:2125–2132. https://doi.org/10.1212/WNL.0b013e3182752ceb
Eisen DP, Hamilton E, Bodilsen J et al (2022) Longer than 2 hours to antibiotics is associated with doubling of mortality in a multinational community-acquired bacterial meningitis cohort. Sci Rep 12:672. https://doi.org/10.1038/s41598-021-04349-7
de Montmollin E, Dupuis C, Jaquet P et al (2022) Herpes simplex virus encephalitis with initial negative polymerase chain reaction in the cerebrospinal fluid: prevalence, associated factors, and clinical impact. Crit Care Med 50:e643–e648. https://doi.org/10.1097/CCM.0000000000005485
van de Beek D, Cabellos C, Dzupova O et al (2016) ESCMID guideline: diagnosis and treatment of acute bacterial meningitis. Clin Microbiol Infect 22(Suppl 3):S37-62. https://doi.org/10.1016/j.cmi.2016.01.007
Thy M, Gaudemer A, Vellieux G, Sonneville R (2022) Critical care management of meningitis and encephalitis: an update. Curr Opin Crit Care 28:486–494. https://doi.org/10.1097/MCC.0000000000000980
Sarton B, Jaquet P, Belkacemi D et al (2021) Assessment of magnetic resonance imaging changes and functional outcomes among adults with severe herpes simplex encephalitis. JAMA Netw Open 4:e2114328. https://doi.org/10.1001/jamanetworkopen.2021.14328
Jeantin L, Dupuis C, Vellieux G et al (2023) Electroencephalography for prognostication of outcome in adults with severe herpes simplex encephalitis. Ann Intensive Care 13:10. https://doi.org/10.1186/s13613-023-01110-3
Acknowledgements
The authors wish to thank the European Society of Intensive Care Medicine office for the help in the conduct of the study. RS wishes to thank Mary Pellegrin for her help in the writing of the manuscript.
EURECA investigator study group (collaborators): Manuel Santafe, Roland Smonig, Damien Roux, Guillaume Voiriot, Bertrand Souweine, Keyvan Razazi, Thibault Ducrocq, Patricia Boronat, Nadia Aissaoui, Danielle Reuter, Alain Cariou, Philippe Mateu, Barabara Balandin Moreno, Paula Vera, Estela Val Jordan, François Barbier, Mickael Landais, Jeremy Bourenne, Antoine Marchalot, Mathilde Perrin, Benjamin Sztrympf, Carole Schwebel, Shakti Bedanta Mishra, Patrick Chillet, Maelle Martin, Hugues Georges, Jean-Claude Lacherade, Romaric Larcher, Gregory Papin, David Schnell, Sulekha Saxena, Frank Chemouni, Juliette Audibert, Eric Mariotte, Shidasp Siami, Italo Calamai, Cédric Bruel, Alexandre Massri, Jesus Priego, Xavier Souloy, Pascal Beuret, Bikram Kumar Gupta, Thomas Ritzenthaler, Sami Hraiech, Aguila Radjou, and M. K. Renuka.
Funding
European Society of Intensive Care Medicine. GC was supported by the Italian MUR Dipartimenti di Eccellenza 2023-2027 (l. 232/2016, art. 1, commi 314 - 337).
Author information
Authors and Affiliations
Consortia
Contributions
RS: conception of the work (PI), funding application, enrollment of participating centers, supervision of the data collection, participation in data analysis, verification of the data and interpretation, drafting the manuscript, critical revision of the manuscript, final approval of the version. RS is the guarantor of the entire manuscript and responsible for the decision to submit the manuscript. EdM: enrollment of participating centers, drafting the manuscript, including tables and figures, participation in data interpretation, critical revision of the manuscript, final approval of the version to be published. JH, RH, IM-L, FST, JJdW, GC: participation in the definition of the protocol, critical revision of the manuscript, and final approval of the version to be published. SR, QS: data management, and statistical analysis. JFT: conception of the work, funding application, supervision of the data collection, analysis and interpretation, critical revision of the manuscript, final approval of the version. Other authors: data collection, interpretation of data, critical revision of the manuscript, final approval of the version. The EURECA investigators (listed in the EURECA investigator group), who participated in the data collection are non-author contributors.
Corresponding author
Ethics declarations
Conflicts of interest
RS reports a grant from the European Society of Intensive Care Medicine (ESICM) for the current work and grants from the French Ministry of Health, outside the submitted work. Other authors report no competing interest.
Ethical approval
The entire protocol has been reviewed and approved by the Comité de protection des personnes sud méditerranée 2 (ID RCB 2017-A00139-44). National/local approvals at the international study sites were obtained by the national coordinators and local investigators according to the local regulations. Since meningoencephalitis patients could not be informed at the time of study recruitment, each center referred to local/national law on the issue of lack of capacity. If the patients regained capacity before 3 months, they were asked either to consent to the use of the acute and follow-up data or to refuse to participate in the research.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Sonneville, R., de Montmollin, E., Contou, D. et al. Clinical features, etiologies, and outcomes in adult patients with meningoencephalitis requiring intensive care (EURECA): an international prospective multicenter cohort study. Intensive Care Med 49, 517–529 (2023). https://doi.org/10.1007/s00134-023-07032-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00134-023-07032-9