key: cord-1036865-nq3esjyb
authors: Uginet, Marjolaine; Breville, Gautier; Assal, Frédéric; Lövblad, Karl‐Olof; Vargas, Maria Isabel; Pugin, Jérôme; Serratrice, Jacques; Herrmann, Francois R.; Lalive, Patrice H.; Allali, Gilles
title: COVID‐19 encephalopathy: Clinical and neurobiological features
date: 2021-04-23
journal: J Med Virol
DOI: 10.1002/jmv.26973
sha: 411cd12d2f2cb60d29af8c8a2f137495623ef833
doc_id: 1036865
cord_uid: nq3esjyb

Severe acute respiratory coronavirus 2 (SARS‐CoV‐2) has been associated with neurological complications, including acute encephalopathy. To better understand the neuropathogenesis of this acute encephalopathy, we describe a series of patients with coronavirus disease 2019 (COVID‐19) encephalopathy, highlighting its phenomenology and its neurobiological features. On May 10, 2020, 707 patients infected by SARS‐CoV‐2 were hospitalized at the Geneva University Hospitals; 31 (4.4%) consecutive patients with an acute encephalopathy (64.6 ± 12.1 years; 6.5% female) were included in this series, after exclusion of comorbid neurological conditions, such as stroke or meningitis. The severity of the COVID‐19 encephalopathy was divided into severe and mild based on the Richmond Agitation Sedation Scale (RASS): severe cases (n = 14, 45.2%) were defined on a RASS < −3 at worst presentation. The severe form of this so‐called COVID‐19 encephalopathy presented more often a headache. The severity of the pneumonia was not associated with the severity of the COVID‐19 encephalopathy: 28 of 31 (90%) patients did develop an acute respiratory distress syndrome, without any difference between groups (p = .665). Magnetic resonance imaging abnormalities were found in 92.0% (23 of 25 patients) with an intracranial vessel gadolinium enhancement in 85.0% (17 of 20 patients), while an increased cerebrospinal fluid/serum quotient of albumin suggestive of blood‐brain barrier disruption was reported in 85.7% (6 of 7 patients). Reverse transcription‐polymerase chain reaction for SARS‐CoV‐2 was negative for all patients in the cerebrospinal fluid. Although different pathophysiological mechanisms may contribute to this acute encephalopathy, our findings suggest the hypothesis of disturbed brain homeostasis and vascular dysfunction consistent with a SARS‐CoV‐2‐induced endotheliitis.

Coronavirus disease-2019 (COVID-19) has been associated with an increased prevalence of acute encephalopathy 1 referred to as COVID-19 encephalopathy. By definition, 2 its clinical and radiological spectrum is heterogeneous. 1, 3, 4 The severe acute respiratory coronavirus 2 (SARS-CoV-2) may enter into the brain via a hematogenous or a direct trans-nasal route through the olfactory nerve. 5 The physiopathology of this encephalopathy is poorly understood: external factors including intubation and sedative medication, or isolation imposed by the social distancing strategy, as well as specific SARS-CoV-2 related factors may contribute to the encephalopathy. 3 Early recognition of this acute condition, especially in the intensive care unit (ICU), is key as it has been associated with increased hospital length of stay and higher mortality. 6 We recently reported five patients with a severe form of COVID-19 encephalopathy clinically responsive to steroid suggestive of an inflammatory-mediated mechanism. 7 To better understand its neuropathogenesis, we describe a series of patients with COVID-19 encephalopathy, highlighting its phenomenology and its neurobiological features. at worst presentation (meaning deep sedationno response to voice but possible movement or eye-opening to physical stimulation). Following our inclusion criteria, all patients at the time of the neurological evaluation were not comatose but presented a delirium or a subsyndromal delirium that was quantified by the confusion assessment method (CAM). 

Baseline characteristics were summarized using means and standard deviations or frequencies and percentages, as appropriate. The normality of data distribution was checked using the Shapiro-Francia test. Between-group comparisons (severe vs. mild COVID-19 encephalopathy) were performed using unpaired t test, Mann-Whitney U test or Fisher exact test, as appropriate.

We performed stepwise forward logistic regression models to identify which combination of neurological symptoms was associated with severe COVID-19 encephalopathy. The proportion of the variance explained by the models was estimated by the pseudo-R 2 . All analyses were conducted using SPSS version 25 (SPSS Inc.).

Clinical characteristics of the 31 patients were compared in Table 1 between the 14 patients with a severe form of COVID-19 encephalopathy and the 17 with a mild form.

The mean age of patients was 64.6 ± 12.1 years with a vast majority of males (93.5%). All females with COVID-19 encephalopathy were severely affected. COVID-19 encephalopathy was present at admission before other symptoms in 6% of patients and started 20.9 ± 8.1 days after COVID-19 symptom onset. The mean duration before clinical improvement of COVID-19 encephalopathy was 12.1 ± 11.3 days. The most common symptoms at admission were fatigue (96.6%), fever (93.5%), and cough (72.4%).

The severity of the pneumonia was not associated with severity of the COVID-19 encephalopathy: 28 of 31 (90%) patients did develop an acute respiratory distress syndrome; the mean O2 request Neurological symptoms and signs are presented in Table 2 . enhancement presented an increased concentration of C-reactive protein in comparison to those without gadolinium enhancement (63.6 ± 54.6 vs. 6.9 ± 9.5 mg/L; p = .012) (Figure 3) . We also measured serum concentration of interleukin-6 (IL-6) in a subsample of patients with post-contrast fat saturated T1-weighted black blood VISTA sequence: 14 in the group with intracranial gadolinium vessel enhancement and 3 in the group without intracranial gadolinium vessel enhancement. Although IL-6 was higher in the group of patients with signs of intracranial gadolinium vessel enhancement than in the group without signs of intracranial gadolinium vessel enhancement, the difference was not significant (766.2 ± 799.7 vs. 161.7 ± 60.7 pg/ml, respectively; p-value = .432). CSF white blood cell count was normal in 8 of 8 patients, whereas CSF/serum quotient of albumin (QAlb-measured in 7 of 8 patients) was increased in 85.7% (mean QAlb = 11.6 ± 5.5). RT-PCR for SARS-CoV-2 was negative for all patients in the CSF (measured in 7 of 8).

Among the 31 patients, 2 patients were treated by high-dose steroid (methylprednisolone 0.5 g/d iv for 5 days) due to a prolonged delirium without any improvement. Following steroid initiation, both patients presented a clinical improvement with resolution of delirium. Although the neuropathogenesis of COVID-19 encephalopathy is still unknown, this observation suggests the hypothesis of disturbed brain homeostasis and vascular dysfunction consistent with the recent description of a SARS-CoV-2-induced endotheliitis in autopsy. 15 However, we should acknowledge that in the current series, we did not have any histological evidence of endotheliitis or vasculitis in other organs, as reported by others. 10, 15 Finally, the patients included in this cohort did not have any clinical evidence of vasculitis in other organs, explaining why we did not perform a standardized screening for autoimmune vasculitis.

Others and our group 16, 17 suggested that the phenomenon of "happy or silent hypoxemia"-hypoxemia without dyspnea-reported in many patients with severe COVID-19 pneumonia could be the consequence of inappropriate cortical processing of interoceptive information from the respiratory system. Dyspnea perception involves the activation of various cortical regions, especially the insula, 18 and the presence of COVID-19 encephalopathy may interfere with such a physiological complex mechanism of dyspnea perception. In the current series, the prevalence of dyspnea was similar between severe and mild encephalopathy. Therefore, we are not able to support the hypothesis suggesting that severe COVID-19 encephalopathy may be associated with the phenomenon of "happy or silent hypoxemia." Future studies should investigate this hypothesis by quantifying the severity of the dyspnea with appropriate questionnaires.

This retrospective study has some limitations. Although we followed strict inclusion criteria for COVID-19 encephalopathy (delirium or subsyndromal delirium without cause), only subgroups of patients underwent a different evaluation: MRI in 81%, EEG in 74%, and CSF analysis in 26% of patients. Although we could not definitively rule out encephalitis in the 23 patients without CSF analyses, the clinical decision to exclude the CSF analyses was done after a diagnostic conference involving neurologists and internal medicine physicians based on the follow-up and common medical knowledge at the time of the pandemic, namely that SARS-CoV-2 rarely produces encephalitis. 1 An MRI and an EEG were not available for 3 patients; however, the clinical presentation (delirium at a distance of pneumonia) and follow-up of these patients were highly suggestive of COVID-19 encephalopathy. Finally, we should acknowledge that none of the patients died during their hospitalization; this may suggest that the patients with the most severe COVID-19 pneumonia (those who eventually died) were not referred for a neurological consult and consecutively not included in this series; that would restrict the generalization of the study findings to patients with COVID-19 encephalopathy, who survive during their hospitalization.

At this time of the pandemic, recognition of COVID-19 encephalopathy and appropriate treatment are needed, as the long-term neuropsychiatric consequences of this encephalopathy are not yet established, and that the evolution of the pandemic depends on various unknown scenarios.

COVID-19: a global threat to the nervous system

Updated nomenclature of delirium and acute encephalopathy: statement of ten societies

COVID-19: ICU delirium management during SARS-CoV-2 pandemic

Neurologic and neuroimaging findings in patients with COVID-19: A retrospective multicenter study

The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients

Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit

COVID-19-related encephalopathy responsive to high doses glucocorticoids

The use and pitfalls of intracranial vessel wall imaging: how we do it

Frequent neurologic manifestations and encephalopathy-associated morbidity in COVID-19 patients

Cerebrovascular disease in patients with COVID-19: neuroimaging, histological and clinical description

Report of EEG finding on critically ill patients with COVID-19

Guillain-Barre syndrome and COVID-19: an observational multicentre study from two Italian hotspot regions

A case of limbic encephalitis associated with asymptomatic COVID-19 infection

Steroidresponsive encephalitis in COVID-19 disease

Endothelial cell infection and endotheliitis in COVID-19

Dyspnea: the vanished warning symptom of COVID-19 pneumonia

The mystery of the pandemic's 'happy hypoxia'

Mechanisms of dyspnea

This study has been performed in the Geneva University Hospitals. This study was funded by a donor from the Private Foundation of the Geneva University Hospitals.

The authors declare that there are no conflict of interests.

Conception and design of the study: Frédéric Assal, Patrice H. 

The study was approved by the institutional review board of the Geneva University Hospitals (protocol #2020-01206approved May 25, 2020).

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

http://orcid.org/0000-0002-4455-6719