key: cord-0887122-0tzd7ydc authors: Meppiel, Elodie; Peiffer-Smadja, Nathan; Maury, Alexandra; Bekri, Imen; Delorme, Cécile; Desestret, Virginie; Gorza, Lucas; Hautecloque-Raysz, Geoffroy; Landre, Sophie; Lannuzel, Annie; Moulin, Solène; Perrin, Peggy; Petitgas, Paul; Sellal, François; Wang, Adrien; Tattevin, Pierre; de Broucker, Thomas title: Neurological manifestations associated with COVID-19: a multicentric registry date: 2020-11-13 journal: Clin Microbiol Infect DOI: 10.1016/j.cmi.2020.11.005 sha: 8792b51de0f614f9883d6b4635e445b7d8ed8163 doc_id: 887122 cord_uid: 0tzd7ydc OBJECTIVE: This study aims to provide an overview of the spectrum, characteristics and outcomes of neurological manifestations associated with SARS-CoV-2 infection. METHODS: We conducted a multicentric, retrospective study during the French COVID-19 epidemic in March-April 2020. All COVID-19 patients with de novo neurological manifestations were eligible. RESULTS: We included 222 COVID-19 patients with neurological manifestations from 46 centers in France. Median age was 65 years (IQR 53-72), and 136 patients (61.3%) were male. COVID-19 was severe or critical in 102 patients (45.2%). The most common neurological diseases were COVID-19 associated encephalopathy (67/222, 30.2%), acute ischemic cerebrovascular syndrome (57/222, 25.7%), encephalitis (21/222, 9.5%), and Guillain-Barré Syndrome (15/222, 6.8%). Neurological manifestations appeared after first COVID-19 symptoms with a median (IQR) delay of 6 (3-8) days in COVID-19 associated encephalopathy, 7 (5-10) days in encephalitis, 12 (7-18) days in acute ischemic cerebrovascular syndrome and 18 (15-28) days in Guillain-Barré Syndrome. Brain imaging was performed in 192 patients (86.5%), including 157 MRI (70.7%). Among patients with acute ischemic cerebrovascular syndrome, 13/57 (22.8%) had multi territory ischemic strokes, with large vessel thrombosis in 16/57 (28.1%). Brain MRI of encephalitis patients showed heterogeneous acute non vascular lesion in 14/21 patients (66.7%). Cerebrospinal fluid was analyzed in 97 patients (43.7%), with pleocytosis in 18 patients (18.6%) and a positive SARS-CoV-2 PCR in 2 patients with encephalitis. The median (IQR) follow-up was 24 (17-34) days with a high short-term mortality rate (28/222, 12.6%). CONCLUSION: Clinical spectrum and outcomes of neurological manifestations associated with SARS-CoV-2 infection were broad and heterogeneous, suggesting different underlying pathogenic processes. COVID-19, the disease linked to the SARS-CoV-2 coronavirus, is an emerging infectious disease with first cases reported in China in December 2019. Since then, the virus has continued to spread and on March 11 , 2020 the World Health Organization (WHO) characterized COVID-19 as a pandemic. Common manifestations of the disease include respiratory tract and associated systemic manifestations but neurological manifestations including headaches, dizziness, anosmia, encephalopathy and strokes have been reported in cohort studies 3, 4 . However, the potential pathogenesis of SARS-CoV-2 in the central nervous system remains unclear 5 , and the range of neurological disorders associated with COVID-19 is not fully defined. The present study aims to provide a comprehensive overview of neurological manifestations associated with SARS-CoV-2 infection and to describe the clinical course and outcomes of COVID-19 patients with neurological manifestations. We conducted a retrospective, multicentric, observational study to collect neurological manifestations associated with COVID-19 in 46 hospitals in France. A case report form (CRF) was sent from March 16 to April 27, 2020 to French neurologists, infectious diseases specialists and intensivists. The study complied with French Commission Nationale de l'Informatique et des Libertés (CNIL, number 2217844) and ethics committee (RCB 2020-A01300-39) requirements. The IRB n°2020-0602 COVID approved the study. We included adult COVID-19 patients with any neurological manifestations occurring 5 days before to 35 days after the first symptoms of COVID-19. A confirmed case of COVID-19 was defined as a J o u r n a l P r e -p r o o f patient with a positive SARS-CoV-2 RT-PCR assay on a nasopharyngeal sample or a positive SARS-CoV-2 serology. As RT-PCR analysis and serology were unavailable in some centers, some cases were considered COVID-19 if the clinical history and the chest CT-scan were typical according to referent clinicians. We excluded patients with no diagnosis of COVID-19, patients with neurological signs that were not time-related with COVID-19, patients with incomplete CRF and patients with exacerbations of chronic neurological diseases. We defined the severity of COVID-19 illness as mild, moderate, severe and critical according to NIH 6 . The follow-up for each patient was recorded up to the completion of the CRF by clinicians. Neurological manifestations were split into Central Nervous System (CNS) and Peripheral Nervous System (PNS) manifestations and then classified into the following categories: -Stroke was considered in patients with sudden neurological deficit related to an acute vascular lesion on cerebral MRI or CT scan, in patients with transient focal deficit and normal MRI (transient ischemic attack), or in patients with cerebral venous thrombosis. -Encephalitis was defined as altered mental status lasting ≥ 24 hours and one of the following criteria: white blood count cells (WBCs) in cerebrospinal fluid (CSF) > 5/mm 3 ; presence of compatible acute lesion on brain MRI. All the patients with encephalitis had a CSF examination. 7, 8 -Encephalopathy was defined by altered mental status lasting ≥ 24 hours, and could be associated to seizure and/or focal neurological sign, in the absence of criteria for encephalitis criteria. 8 We defined COVID-associated encephalopathy (CAE) if encephalopathy could not be accounted for by another cause such as toxic or metabolic factor according to the reporting clinician. -Guillain-Barré Syndrome (GBS) was defined according to standard diagnosis criteria 9 . -Acute meningitis was defined as meningeal syndrome (head stiffness, headache, fever) without encephalitic course, and CSF WBC counts > 5/mm 3 . The population study was 259 patients among whom 222 hospitalized COVID-19 patients with neurological manifestations from 46 centers in all the regions of continental France and overseas were included ( Figure 1, Supplementary appendix 2 Median age was 65 years (IQR 53-72), and 136 (61.3%) were male (Table 1) . Forty-seven patients (21.2%) had a past neurological history, mostly prior stroke (20, 9 .0%) and neurodegenerative disease (17, 7 .7%). The diagnosis of COVID-19 was confirmed by a positive SARS-CoV-2 PCR in 192 patients (86.5%) patients and by serology in 4 patients (1.8%). Twenty-six patients (11.7%) had a diagnosis on the basis of a typical clinical course and imaging. COVID-19 severity was severe or critical in 102 patients (45.2%). The most common neurological symptom was altered mental status (117, 52.4%). Neurological work-up mostly included brain MRI (157, 70.7%) and CSF examination (97, 43.7%). SARS-CoV-2 PCR was performed in the CSF for 75 patients (33.8%) and was negative in 73/75 cases (97.3%). The median follow-up was 24 days (IQR 17-34). Twenty-eight patients (12.6%) died, mostly following acute respiratory distress syndrome (ARDS, n=17, 7.7%) or stroke (2.3%). One hundred eighty-nine patients (85.1%) had CNS manifestations, mostly encephalopathy (85/222, Twenty-nine patients (13.1%) had PNS manifestations, mostly Guillain-Barré syndrome (GBS, 15/222, 6.8%). Ten other patients had peripheral complications of ICU management, either critical illness neuropathy (8/222, 3.6%) or Tapia Syndrome: hypoglossal and pneumogastric nerves palsy following oro-tracheal intubation (2/222, 0.9%). The remaining PNS manifestations were cranial neuropathy (3/222, 1.4%) including two oculomotor nerve palsy and one facial peripheral nerve palsy, and bilateral fibular nerve palsy (1/222, 0.5%). Eleven patients (5.9%) had both CNS and PNS manifestations ( Figure 1 ). Fifteen patients (6.8%) had mixed manifestations of undetermined mechanisms, including headache, dizziness, anosmia, auditory symptoms and subjective sensitive symptoms. The mortality rate was 15.8%. Median age was 67 years (IQR 51-70). More than half patients ( Table 3 ). Ten patients (47.6%) fully recovered, 3 of whom received corticosteroids (CS). The mortality rate was 4.8%. We described 67 patients with CAE who had severe forms of COVID-19, as previously shown 3, 10 . A high proportion of patients with encephalopathy had pre-existing neurodegenerative disorders which may the reflect the fact that chronic cognitive impairment is a known risk factor for delirium in patients with an acute illness. 26 CAE patients had a clinical presentation suggestive of septicassociated encephalopathy (SAE) 27 : advanced age, previous cognitive impairment, illness severity, focal deficit and seizures, tremor, myoclonus and acute vascular lesion on brain MRI 28 . The release of pro-inflammatory cytokines is a key pathogenic pathway suggested in SAE, and is thought to play a central role in COVID-19 29 . AICS was reported in 57 patients (26%). Although 75% of AICS patients had vascular comorbidities, our study highlighted some features already described in published articles: high prevalence of large vessels stroke 30, 31 , multi-territory involvement 31 , undetermined J o u r n a l P r e -p r o o f etiology 32 , and high mortality rate 32 . Several cases of GBS are currently reported in the literature [33] [34] [35] [36] [37] [38] and a study has demonstrated an increased incidence of GBS during the COVID-19 epidemics compared with the three previous years 39 . GBS cases reported in this study can be considered as probably associated with COVID-19 as defined by Ellul et al. 8 Our study has several limitations. First, this is a retrospective registry with inherent reporting biases, which should lead us to interpret with caution the different proportions of neurological manifestations. Small vessel infarct 6 (11.5) 2 (9.5) 6 (9) 1 (6.7) Microhemorrhages 0 (0) 2 (9. 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