Severe COVID-19-related encephalitis can respond to immunotherapy

doi:10.1093/brain/awaa337 BRAIN 2020: 143; 1–6 | e102 LETTER TO THE EDITOR Severe COVID-19-related encephalitis can respond to immunotherapy † These authors contributed equally to this work. ‡ Appendix 1. 1 AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, site Pitié-Salpêtrière, Department of Neurology, Neuro-ICU, Paris, France 2 Sorbonne Université, Paris, France 3 Brain institute - ICM, Sorbonne Université, Inserm U1127, CNRS UMR 7225, F-75013, Paris, France 4 Department of Neurology, Columbia University, New York, NY, USA 5 AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, site Pitié-Salpêtrière, Department of Hemobiotherapy, Paris, France 6 AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, site Pitié-Salpêtrière, Service de Pneumologie, Médecine Intensive et Réanimation (Département R3S) and Sorbonne Université, INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, F-75005 Paris, France 7 AP-HP, Department of Critical Care, Hôpital Avicenne, AP-HP GHU-93, Bobigny, France 8 AP-HP, Department of Critical Care, Hôpital Louis Mourier, AP-HP, Université de Paris, Colombes, France 9 Medical and Surgical Intensive Care Unit, Groupe Hospitalier Paris Saint Joseph, Paris, France 10 AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, site Pitié-Salpêtrière, Department of Infectious and Tropical Diseases, AP-HP, Paris, France 11 AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, site Pitié-Salpêtrière, Department of Anesthesiology and Critical Care, AP-HP, Paris, France 12 Sorbonne Université, Brain Liver Pitié-Salpêtrière Study group, INSERM UMR_S 938, Centre de Recherche Saint-Antoine and Institute of Cardiometabolism and Nutrition (ICAN), Paris, France Correspondence to: Dr Benjamin Rohaut MD, PhD Hôpital Pitié-Salpêtrière Département de Neurologie, Unité de Médecine Intensive Réanimation Neurologique, 47-83 Bd de l’Hôpital PARIS 75013, France E-mail: benjamin.rohaut@sorbonne.universite.fr We read with great interest the article of Ross W. Paterson and colleagues in Brain (Paterson et al., 2020), in which they describe the emerging spectrum of coronavirus disease2019 (COVID-19) neurological syndromes. This article provides major categories of COVID-19-related neurological syndromes, including patients with encephalitis, and reports corticosteroids and intravenous immunoglobulin response in some patients. Indeed, various COVID-19-related neurological syndromes have been reported since December 2019 (Filatov et al., 2020; Helms et al., 2020; Khoo et al., 2020; Mao et al., 2020; Moriguchi et al., 2020; Oxley et al., 2020; Poyiadji et al., 2020). However, encephalitis has seldom been reported and the potential benefit of immunotherapy remains unclear (one of two patients improved in Paterson et al., 2020). Herein, we report a case series of five patients (from an observational cohort: the CoCo Neurosciences Study) with severe COVID-19-related encephalitis (impaired consciousness/unresponsive and mechanically ventilated) treated by therapeutic plasma exchanges (TPE) and corticosteroids. The dramatic improvement in three of five patients reinforces the hypothesis of an immune-related mechanism, as evoked by Paterson and colleagues. Neurologists and Advance access publication December 2, 2020 C The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. V For permissions, please email: journals.permissions@oup.com Downloaded from https://academic.oup.com/brain/article/143/12/e102/5926056 by guest on 22 January 2023 Albert Cao,1,† Benjamin Rohaut,1,2,3,4,† Loic Le Guennec,1,2 Samir Saheb,1,5 Clémence Marois,1 Victor Altmayer,1 Vincent T. Carpentier,1 Safaa Nemlaghi,2,6 Marie Soulie,7 Quentin Morlon,8 Bryan Berthet-Delteil,9 Alexandre Bleibtreu,10 Mathieu Raux,2,11 Nicolas Weiss1,2,12 and Sophie Demeret and on behalf of the CoCo-Neurosciences study group‡ e102 | BRAIN 2020: 143; 1–6 Relation between immunotherapy and clinical improvement Although a neuro-invasive potential of SARS-CoV-2 is suspected—as for others coronaviruses—there are surprisingly few reports of COVID-19-associated encephalitis (Hanna Huang et al., 2020; Le Guennec et al., 2020; Moriguchi et al., 2020; Paterson et al., 2020). An immune-mediated mechanism has been proposed to explain coronavirusesassociated encephalitis (Weyhern et al., 2020), and TPE has shown promising results in a recent case series of COVID19 mild meningoencephalitis (Dogan et al., 2020). Reports on patients with positive SARS-CoV-2 RT-PCR assay in the CSF are scarce (Hanna Huang et al., 2020; Moriguchi et al., 2020) and most patients had moderate acute cognitive impairment without pleocytosis (Helms et al., 2020) or mildly elevated CSF cell counts (BernardValnet et al., 2020). Likewise, Guillain-Barré and Miller Fisher syndromes, acute necrotizing haemorrhagic encephalopathy, and acute disseminated encephalomyelitis have also been described in COVID-19 patients, suggesting a host-immune response mechanism rather than a direct neuro-invasion of the SARS-CoV-2 (Gutiérrez-Ortiz et al., 2020; Novi et al., 2020; Toscano et al., 2020). In the Paterson cohort, 10 patients were treated with corticosteroids, and three of these patients also received intravenous immunoglobulin; one made a full recovery, 10 of 12 made a partial recovery, and one patient died (Paterson et al., 2020). In our cases, the secondary neurological involvement (no prior neurological initial symptoms), associated with the MRI abnormalities and the absence of SARS-CoV-2 in the CSFs point towards a post-infectious antibody or cell-mediated immune mechanism rather than a direct viral neuro-invasion, as suggested by Weyhern et al. (2020), although no oligoclonal bands and low interleukin-6 were found in the CSF. The rapid clinical improvement (i.e. 6, 2 and 7 days for Cases 1, 2 and 3, respectively) after immunotherapy was in striking contrast with the protracted persistence of neurological impairment (24, 30 and 31 days, respectively, after sedation withdrawal) before treatment initiation. Such a feature supports an inflammatory or immune process. In the instance of critical illness, delayed awakening and cognitive impairment, such as delirium, may result from many factors, such as hypoxic encephalopathy, metabolic disturbances, or side effects of sedation in the case of ICU patients (Mazeraud et al., 2018). However, ICU-related brain injuries had never been reported to be responsive to immunotherapy. Although we cannot rule out a spontaneous recovery (Fischer et al., 2020), the rapid improvement observed after immunotherapy initiation in the present case series seems to point towards a therapeutic effect of immunotherapy. Differences between responders and non-responders TPE and corticosteroid responders (Cases 1–3) and non-responders (Cases 4 and 5) shared similar disease courses (severe COVID-19-related ARDS, mechanical ventilation and sedation for several weeks, severe consciousness impairment, Downloaded from https://academic.oup.com/brain/article/143/12/e102/5926056 by guest on 22 January 2023 intensivists should be aware that this life-threatening COVID-19 neurological syndrome has a potentially favourable outcome after immunotherapy, and should not motivate systematic limitation in active patient care. Patients were aged between 37 and 77 years with COVID19-related encephalitis presenting with altered consciousness, and were treated by TPE and corticosteroids. They all fulfilled diagnosis criteria for possible immune encephalitis according to Graus et al. (2016). The clinical presentation and the time-course of the disease are summarized in Table 1, and complementary explorations findings are summarized in Table 2 (a detailed history is available for each patient in the Supplementary material). Patients had no prior history of neurological disease. They were intubated and mechanically ventilated for COVID-19related acute respiratory distress syndrome (ARDS). After sedation withdrawal (ranging from Day 12–30 from initiation), they presented severe and persistent consciousness disorder (comatose state or unresponsive wakefulness syndrome), three had oculomotor disturbances (Cases 1–3) and one had peripheral symptoms attributed to Guillain-Barré syndrome (Case 3). CSF examinations were unremarkable except in one patient with albuminocytologic dissociation (Case 3), and one with mild pleocytosis (Case 4). Reverse transcription polymerase chain reaction (RT-PCR) assays of the CSF were negative for severe acute respiratory syndrome-coronavirus 2 (SARSCoV-2), as common viruses for all patients (Supplementary material). Onconeural antibodies were negative in serum and CSF. None of the patients had signs of thrombotic microangiopathy (no haemolysis, normal levels of ADAMTS13 activity and antigen). When performed, somatosensory evoked potentials showed bilateral presence of N20 (Cases 2–4). EEGs showed unspecific slow-wave activity. Brain MRIs mostly showed bilateral hyperintense lesions in the deep and periventricular supratentorial white matter, either punctiform and slightly diffuse (Cases 1–3) or diffuse and confluent (Cases 4 and 5), associated with lesions in the pons for two patients (Cases 1 and 2) (Supplementary Fig. 1). All patients received immunotherapy combining corticosteroids infusions (1 g/day intravenous methylprednisolone for 5–10 days) and TPE with albumin (5 to 10 sessions). It is worth noting that neurological impairment remained unchanged in all patients with severe consciousness disorder despite cessation of sedation for 9–33 days. Three patients (Cases 1–3) showed dramatic neurological improvement few days after immunotherapy initiation (6, 2, and 7 days, respectively), with consciousness improvement allowing functional communication. Two patients (Cases 4 and 5) showed no signs of consciousness improvement and died after discontinuation of life-sustaining therapies. Letter to the Editor Age (years) /sex Past medical history Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 49 /M Kidney transplant (rheumatoid purpura) 56 /M High blood pressure 61 /M Pulmonary sarcoidosis Heparin-induced thrombocytopenia 37 /M Obesity 77 /F Obesity High blood pressure Asthma Fever, fatigue, shortness of breath Fever, fatigue, shortness of breath, gait disturbances, doubt about a paresis of the right hand 6 Dry cough, odynophagia, headache 10 Fever, fatigue, cough, shortness of breath, headache, anosmia 10 83 (still ongoing at time of writing) 65 No Yes Yes 60 65 50 Yes Yes Yes 41 Yes No Yes 23 Unresponsive wakefulness syndrome 12 Unresponsive wakefulness syndrome 10 / 10 5/5 Clinical features at admission in ICU COVID-19 symptoms Fever, cough, shortness of breath Delay between COVID-19 10 onset and mechanical ventilation (days) Duration of mechanical ventila59 tion (days) SAPS II 38 Prone positioning sessions Yes Renal replacement therapy Yes Yes Catecholaminesa Clinical features at sedation withdrawal and treatments Duration of sedation (days) 18 Neurological symptoms after Unresponsive wakefulness sedation withdrawal syndrome Brainstem impairment Movement disorders 93 58 Yes Yes Yes 30 Coma Brainstem impairment 10 / 5 5/5 17 Unresponsive wakefulness syndrome Brainstem impairment Movement disorders Dysautonomia 5 / 10 52 / 57 66 / 69 49 / 48 42 / 45 40 / 50 24 / 29 30 / 33 32 / 31 9 / 12 18 / 28 6 2 7 No improvement No improvement | e102 COVID-19 = coronavirus disease 2019; ICU= intensive care unit; NP = not performed; SAPS II = simplified acute physiology score 2; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; TPE = therapeutic plasma exchange. a Epinephrine 4 0.1 lg/kg/min OR norepinephrine 4 0.1 lg/kg/min. BRAIN 2020: 143; 1–6 Corticosteroid injections (n) / TPE sessions (n) COVID-19 symptoms onset to intravenous corticosteroids / TPE (days) Sedation withdrawal to intravenous corticosteroids / TPE (days) First TPE to neurological improvement (verbal commands following, days) 6 Letter to the Editor Table 1 Clinical presentation and time course of the disease Downloaded from https://academic.oup.com/brain/article/143/12/e102/5926056 by guest on 22 January 2023 e102 Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 0 0.32 Absence 52.5 Negative Negative 1 0.26 Absence 4 Negative Negative 4 1.54 Absence 8 Negative Negative 10 0.18 Absence NP Negative Negative 0 0.18 Absence 5 2.5 Negative Negative 59.7 Negative Non-specific frontal and temporal slow activity 6 Negative Non-specific slow-wave activity, poorly reactive, without any epileptic patterns 71.7 Negative Non-specific diffuse slow-wave activity, unreactive, without any epileptic patterns Brain MRI results (see Supplementary Fig. 1) Deep hemispherical bilateral white matter lesions on T2/FLAIR with gadolinium enhancement on T1 Left posterolateral lesions of the pons on T2/FLAIR Pontine tegmentum lesion on T2/FLAIR Small haemorrhagic lesion of the left parietal lobe on SWAN Multiple pontine microhaemorrhages within the tegmentum on SWAN 181.3 Negative Non-specific slow-wave activity, reactive to auditory stimuli, without any epileptic patterns Bilateral diffuse lesions of the deep subcortical white matter on T2/FLAIR Multiple microhemorrhages of the corpus callosum on SWAN 33.6 Negative Non-specific diffuse slow-wave activity, inconstantly reactive, without any epileptic patterns Several confluent periventricular and deep supratentorial white matter lesions on FLAIR, mostly with necrotic centers and slight peripheral gadolinium enhancement on T1 Spinal cord MRI Somatosensory evoked potential Normal NP Electroneuromyography NP Normal Bilateral presence of N20 Signs of critical illness polyneuropathy CSF testing Cellularity, cells/mm3 Protein levels, g/l Oligoclonal bands IL-6 levels in CSF, pg/ml (reference value 56.5 pg/ml) SARS-CoV-2 RT-PCR Onconeural antibodies Other complementary explorations IL-6 levels in serum, pg/ml (reference value 56.5 pg/ml) Onconeural antibodies EEG results Normal NP NP COVID-19 = coronavirus disease 2019; FLAIR = fluid-attenuated inversion recovery; IL-6 = interleukin-6; NP = not performed; RT-PCR = reverse transcription polymerase chain reaction; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SWAN = susceptibility weighted magnetic resonance sequences. Letter to the Editor NP Bilateral presence of N20 Complete abolition of sensory and motor potential in four limbs Several confluent periventricular and deep supratentorial white matter lesions on T2/ FLAIR Gadolinium-enhanced symmetrical bilateral focal lesions of centrum semiovale, pallidum and periventricular white matter on T1 Normal Bilateral presence of N20 NP | BRAIN 2020: 143; 1–6 Table 2 Complementary explorations findings Downloaded from https://academic.oup.com/brain/article/143/12/e102/5926056 by guest on 22 January 2023 Letter to the Editor Data availability Detailed data are available upon request to the corresponding author. Acknowledgements The authors thank the investigators of the Cohort COVID19 Neurosciences (CoCo Neurosciences, see member list in Appendix 1 and full details in the Supplementary material) sponsored by Assistance Publique - Hôpitaux de Paris (APHP) and, funded by the "Fédération Internationale de l’Automobile" (FIA) and the Paris Brain Institute – ICM. The authors also thank Prof. Didier Dreyfus (Department of Critical Care, Hôpital Louis Mourier, AP-HP.Université de Paris. Colombes, France) for his thorough review of the manuscript. We thank the tele-expertise plateform www.neu rocovid.fr for its assistance during the pandemic. Finally we thank all the caregivers of the Neuro-ICU and the residents of neurology who came to help the Neuro-ICU team during the epidemic outbreak (Jean-Baptiste Brunet de Courssou, Adam Celier, Gregoire Demoulin, Julia Devianne, Anceline Dong and Thomas Rambaud). Funding The research leading to these results received funding from the program “Investissements d’Avenir” ANR-10-IAIHU-06. | e102 Competing interests The authors report no competing interests. Supplementary material Supplementary material is available at Brain online. Appendix 1 CoCo-Neurosciences Study Group For full details, see the Supplementary material. Cecile Delorme, Jean-Christophe Corvol, Jean-Yves Delattre, Stephanie Carvalho, Sandrine Sagnes, Bruno Dubois, Vincent Navarro, Celine Louapre, Tanya Stojkovic, Ahmed Idbaih, Charlotte Rosso, David Grabli, Ana Zenovia Gales, Bruno Millet, Benjamin Rohaut, Eleonore Bayen, Sophie Dupont, Gaelle Bruneteau, Stephane Lehericy, Danielle Seilhean, Alexandra Durr, Aurelie Kas, Foudil Lamari, Marion Houot, Vanessa Batista Brochard, Catherine Lubetzki, Pascale Pradat-Diehl, Khe Hoang-Xuan, Bertrand Fontaine, Lionel Naccache, Philippe Fossati, Isabelle Arnulf, Alexandre Carpentier, Yves Edel, Anna Luisa Di Stefano, Gilberte Robain, Philippe Thoumie, Bertrand Degos, Tarek Sharshar, Sonia Alamowitch, Emmanuelle Apartis-Bourdieu, Charles-Siegried Peretti, Renata Ursu, Nathalie Dzierzynski, Kiyoka Kinugawa Bourron, Joel Belmin, Bruno Oquendo, Eric Pautas, Marc Verny, Yves Samson, Sara Leder, Anne Leger, Sandrine Deltour, Flore Baronnet, Stephanie Bombois, Mehdi Touat, Marc Sanson, Caroline Dehais, Caroline Houillier, Florence Laigle-Donadey, Dimitri Psimaras, Agusti Alenton, Nadia Younan, Nicolas Villain, Maria del Mar Amador, LouiseLaure Mariani, Nicolas Mezouar, Graziella Mangone, Aurelie Meneret, Andreas Hartmann, Clement Tarrano, David Bendetowicz, Pierre-François Pradat, Michel Baulac, Sara Sambin, François Salachas, Nadine Le Forestier, Phintip Pichit, Florence Chochon, Adele Hesters, Bastien Herlin, An Hung Nguyen, Valerie Procher, Alexandre Demoule, Elise Morawiec, Julien Mayaux, Morgan Faure, Claire Ewenczyk, Giulia Coarelli, Anna Heinzmann, Perrine Charles, Marion Masingue, Guillaume Bassez, Isabelle An, Yulia Worbe, Virginie Lambrecq, Rabab Debs, Esteban Munoz Musat, Timothee Lenglet, Aurelie Hanin, Lydia Chougar, Nathalia Shor, Nadya Pyatigorskaya, Damien Galanaud, Delphine Leclercq, Sophie Demeret, Albert Cao, Clemence Marois, Nicolas Weiss, Salimata Gassama, Loic Le Guennec, Vincent Degos, Alice Jacquens, Thomas Similowski, Capucine Morelot-Panzini, Jean-Yves Rotge, Bertrand Saudreau, Victor Pitron, Nassim Sarni, Nathalie Girault, Redwan Maatoug, Smaranda Leu, Lionel Thivard, Karima Mokhtari, Isabelle Plu, Bruno Gonçalves, Laure Bottin, Marion Yger, Gaelle Ouvrard, Rebecca Haddad, Flora Ketz, Carmelo Downloaded from https://academic.oup.com/brain/article/143/12/e102/5926056 by guest on 22 January 2023 which persisted several weeks after sedation withdrawal, unremarkable CSF findings). Differences in treatment response may be related to lesion intensity observed on MRI between the two groups. The responders mainly had small deep white matter lesions while non-responders had more diffuse confluent lesions of the deep white matter. Time of treatment from diagnosis does not seem to be a relevant factor since non-responders received immunotherapy earlier compared to responders (40 and 42 days after COVID-19 symptoms onset for the nonresponders, versus 48, 52 and 66 days for the responders). Another cause of treatment failure can also be related to the underlying mechanism: non-responders may have had irreversible necrotic lesions related to vasculopathy and coagulopathy as often seen after COVID-19 infection, especially in the lungs (Helms et al., 2020). Taken together, our findings support the hypothesis that immunotherapy combining TPE and corticosteroids can be effective in the treatment of severe COVID-19-related encephalitis. 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