key: cord-353628-f6ew980g authors: Zayet, Souheil; Ben Abdallah, Yousri; Royer, Pierre‐Yves; Toko‐Tchiundzie, Lynda; Gendrin, Vincent; Klopfenstein, Timothee title: Encephalopathy in patients with COVID‐19: ‘Causality or coincidence?’ date: 2020-05-19 journal: J Med Virol DOI: 10.1002/jmv.26027 sha: doc_id: 353628 cord_uid: f6ew980g The main tropism of the novel coronavirus disease 2019 (COVID‐19) is respiratory. Increasing evidences show that SARS‐CoV‐2 is not always confined to the respiratory tract but can also invade the central nervous system (CNS) and induce neurological diseases. We report two cases illustrating this phenomenon. This article is protected by copyright. All rights reserved. Since its discovery in December 2019, the novel coronavirus disease 2019 (COVID-19) has caused several clinical presentations: mainly respiratory, rarely gastrointestinal, and exceptionally neurological. The neuroinvasive mechanism of this virus is poorly described. We report two recent observations of altered mental status that inaugurate an infection with SARS-CoV-2. On March 8 th , a 68-year-old male patient with no significant medical history (except obesity) presented to emergency department with altered consciousness since few days. Physical examination revealed blood pressure at 140/80 mmHg, regular heartbeat at 86/min. The patient was afebrile with normal pulmonary auscultation, neurological examination showed a patient with a confused verbal response and a Glasgow Coma Scale score of 14/15 (E=4, M=5, V=4). The patient didn't complain about headache, vomiting or seizure. He was drowsy without neck stiffness or focal abnormalities. Serology for HIV, Syphilis and Borrelia burgdorferi were negative. Chest X-ray was normal. Brain magnetic resonance imaging (MRI) with angio-MRI was normal. Treatment with high dose of ceftriaxone and aciclovir was empirically initiated, stopped after the receipt of the results of lumbar puncture (LP) ( Table 1) . On March 11 th , he presented fever measured at 39.5C° with cough and bilateral crackling sounds on pulmonary auscultation. Chest X-ray showed a bilateral interstitial infiltrates. Urinary Legionella pneumophila antigen, serology for Legionella pneumophila, Mycoplasma pneumonia, Chlamydophila pneumoniae and Coxiella burnetii were negatives. Real-Time Polymerase Chain Reaction (RT-PCR) on nasopharyngeal swab and sputum confirmed the diagnosis of infection with SARS-CoV-2. On March 13 th , the patient was admitted in intensive care unit (ICU) for acute respiratory failure to be mechanically ventilated. In addition to that, the patient was treated with antibiotics and lopinavir/ritonavir. The clinical course was favorable with successful extubation, on April 2 nd . On March 15 th , a 39-year-old male patient with no significant medical history had frontal headache and fever followed by anosmia and dysgeusia 4 days after. He had just come back few days ago from a cruise on the Caribbean Sea. On March 24 th , he presented cough with dyspnea, diarrhea. He developed also dysarthria, inattention, progressive drowsiness and decreased consciousness. On admission, he was he was febrile at 38.8C°, neurological examination showed a Glasgow Coma Scale score of 12/15 (E=4, M=5, V=3) with non-fluent aphasia. There was no neck stiffness or other neurological physical sign. Altered consciousness still remains at emergency department during the period without fever. Routine laboratory findings showed elevated CRP (102mg/l). The brain MRI and the LP were normal (Table 1 ). In the epidemic context of COVID-19, the patient was isolated immediately and a thoracic Computed Tomography (CT) scan was performed, revealing bilateral ground-glass opacities ( Figure A) . COVID-19 was diagnosed based on RT-PCR microbiologic (positive RT-PCR on nasopharyngeal swab) and CT thoracic imaging results. It has not been possible to perform a test for the presence of SARS-CoV-2 in the cerebrospinal fluid, for this patient. The initial treatment was supportive, associated to hydroxychloroquine for 10 days. The clinical course was rapidly favorable with resolution of neurological symptoms after 3 days and all symptoms on 29 th March. The patient was discharged on 30 th March. The description of our two cases suggests several hypotheses in the potential neuro-invasive mechanism of COVID-19. In addition to the usual symptoms (general, respiratory and otorhinolaryngological) of the infection with SARS-CoV-2, several authors have described neurological manifestations as headache, nausea, and vomiting. It is known that the entry of SARS-CoV-2 into human host cells is mediated mainly by a cellular receptor: angiotensin-converting enzyme 2 (ACE2), which is expressed in human airways epithelia, lung parenchyma, but also in small intestine cells, which explains this clinical features 1-3 . In our opinion, nausea and vomiting are more often related to gastrointestinal than CNS invasion by SARS-CoV-2. Encephalopathy occurs frequently with severe infections, and since here there is no other culprit than COVID-19, this infection is indeed the most likely. On the other hand, some experts describe disseminated intravascular coagulation and venous thromboembolism induced by this virus 4 . This coagulation dysfunction may probably explain cerebrovascular manifestations of COVID-19 like cerebral venous thrombosis or intra cerebral hemorrhage 5,6 . In our cases, cerebral MRI with vascular sequences has been performed, the normality of MRI doesn't sustain this hypothesis. Eventually, the neuro-invasive propensity has been demonstrated as a common feature of coronaviruses (CoVs) that can cause nerve damage via diverse pathways 7 It is known that CoVs may enter the CNS through two distinct routes: hematogenous dissemination or neuronal retrograde dissemination 8 . Some CoVs have been demonstrated to be able to spread via a synapse-connected route to the medullary cardiorespiratory center from the mechanoreceptors and chemoreceptors in the lungs and lower respiratory airways. These viruses can invade brainstem via a synapse-connected route from the lungs and airways 9 .Considering the high similarity between SARS-CoV-2 and others CoVs 10 , it is still not clearly known whether the potential neuro-invasion of SARS-CoV2 is partially responsible for respiratory failure in patients with COVID-19 9,11,12 . We don't know the exact physiopathology of the neurological signs in our 2 patients. No thrombosis, bleeding, sign of cerebral edema or inflammation was found on brain MRIs. LP was normal with negative RT-PCR COVID-19 in CSF. There is no sufficient proof that the symptoms of the patients described are caused by direct CNS involvement. To our knowledge, only one case of meningitis/encephalitis associated with SARS-CoV-2 has been described in the literature, with detection of SARS-CoV-2 RNA in CSF (10) . In our patients, the LP was performed the second week after the onset of symptoms, which could explain viral load (VL) decreasing in the CSF and its non-detection. As the second patient initially described anosmia and dysgeusia, we wonder if there was invasion of the olfactory receptors of the first cranial nerves in the nasal cavity cell membrane, as described with other viruses [13] [14] [15] [16] [17] [18] . Our final assumption is that there is a possibility of correlation between the VL level in respiratory samples and these neurological features. In the literature, it has been shown that viral load in respiratory samples is higher during the first week of symptoms or during the second week in severe cases with acute respiratory distress syndrome 19 . In our two patients we notice that the mean VL was clearly higher (7.1 log copies/ml) than the mean VL of our COVID population without neurological symptoms (5.5 log copies/ml). Finally, no other treatment (as Immunoglobulin therapy, anti-IL6-R or steroids) than lopinavir/ritonavir and hydroxychloroquine has been administrated to our patients. No recommendations to date have been published to our knowledge for the treatment of COVID-19 with neurologic manifestations. The neuro-invasive potential of COVID-19 remains uncertain but possible. Therefore, in the context of COVID pandemic, it would be reasonable to perform a thoracic CT and a RT-PCR for SARS-CoV-2 in case of encephalopathy with normal lumbar puncture and brain imaging. This will help to prevent the transmission of the virus in hospital settings, especially to health care workers and to not delay the management of patients with neurological presentation. Table Table I : Demographic characteristics, laboratory findings and imaging features of the two patients infected by COVID-19 with a presentation of encephalopathy. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis Aldosterone System Inhibitors in Patients with Covid-19 In silico studies on the comparative characterization of the interactions of SARS-CoV-2 spike glycoprotein with ACE-2 receptor homologs and human TLRs Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy COVID-19-associated Acute Hemorrhagic Necrotizing Encephalopathy: CT and MRI Features COVID 19 and Intra cerebral hemorrhage: Causative or Coincidental. New Microbes and New Infections Nervous system involvement after infection with COVID-19 and other coronaviruses Sars-Cov-2: Underestimated damage to nervous system The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China The neuroinvasive potential of SARS-CoV-2 may play a role in the respiratory failure of COVID-19 patients An alteration of the dopamine synthetic pathway is possibly involved in the pathophysiology of COVID-19 Identification of viruses in patients with postviral olfactory dysfunction Coronavirus disease 2019: new things to know On admission All authors declare no competing interests. We thank especially Dr Zahra Hajer for her help.