A retrospective multicenter study
Objective To describe neuroimaging findings and to report the epidemiologic and clinical characteristics of patients with coronavirus disease 2019 (COVID-19) with neurologic manifestations.
Methods In this retrospective multicenter study (11 hospitals), we included 64 patients with confirmed COVID-19 with neurologic manifestations who underwent a brain MRI.
Results The cohort included 43 men (67%) and 21 women (33%); their median age was 66 (range 20–92) years. Thirty-six (56%) brain MRIs were considered abnormal, possibly related to severe acute respiratory syndrome coronavirus. Ischemic strokes (27%), leptomeningeal enhancement (17%), and encephalitis (13%) were the most frequent neuroimaging findings. Confusion (53%) was the most common neurologic manifestation, followed by impaired consciousness (39%), presence of clinical signs of corticospinal tract involvement (31%), agitation (31%), and headache (16%). The profile of patients experiencing ischemic stroke was different from that of other patients with abnormal brain imaging: the former less frequently had acute respiratory distress syndrome (p = 0.006) and more frequently had corticospinal tract signs (p = 0.02). Patients with encephalitis were younger (p = 0.007), whereas agitation was more frequent for patients with leptomeningeal enhancement (p = 0.009).
Conclusions Patients with COVID-19 may develop a wide range of neurologic symptoms, which can be associated with severe and fatal complications such as ischemic stroke or encephalitis. In terms of meningoencephalitis involvement, even if a direct effect of the virus cannot be excluded, the pathophysiology seems to involve an immune or inflammatory process given the presence of signs of inflammation in both CSF and neuroimaging but the lack of virus in CSF.
ClinicalTrials.gov identifier NCT04368390.
- acute disseminated encephalomyelitis;
- acute respiratory distress syndrome;
- cytotoxic lesion of the corpus callosum;
- coronavirus disease 2019;
- fluid-attenuated inversion recovery;
- gray matter;
- human coronavirus;
- intensive care unit;
- leptomeningeal enhancement;
- multiple correspondence analysis;
- Middle East respiratory syndrome coronavirus;
- reverse transcriptase PCR;
- severe acute respiratory syndrome coronavirus
In December 2019, many unexplained pneumonia cases occurred in China.1,2 In January 2020, the causative agent was identified as a novel coronavirus, which has been called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), giving the disease the name coronavirus disease 2019 (COVID-19). Coronaviruses have neuroinvasive capacities because they are isolated in both brains and CSF of infected animals and humans.3,–,8 However, few neurologic complications with human coronaviruses (hCoVs) were documented in the past 2 decades.
The first studies that focused on clinical features of patients with COVID-191,2,11 showed neurologic manifestations such as headache, dizziness, confusion, hypogeusia, hyposmia, and more severe neurologic disorders, especially for patients hospitalized in intensive care units (ICUs). In a recent cohort of 214 patients,11 24.8% of them presented CNS manifestations, and 6 cases of strokes were diagnosed. The neurologic symptoms were more common in cases of severe respiratory infection.11 It has recently been reported12 that patients referred to ICU frequently experienced encephalopathy with agitation, confusion, and corticospinal tract signs. Brain MRI revealed in some patients leptomeningeal enhancement (LME) and cerebral blood flow abnormalities.
Despite these findings, the potential brain injuries related to COVID-19 have not been well described with neuroimaging in a large cohort. Thus, our aims were to describe the neuroimaging findings in a population of COVID-19 with neurologic manifestations who underwent brain MRI, to assess the frequency of these abnormalities, and to correlate these findings with clinical features.
This retrospective national multicenter study was initiated by the French Neuroradiology Society.
Patients with COVID-19 from 11 French centers, including 6 university hospitals and 5 general hospitals, were included from March 16, 2020, until April 9, 2020. The number of cases included from each center was as follows: 29 in Strasbourg, 11 in Colmar, 7 in Paris (Bichat), 5 in Haguenau, 4 in Nancy, 4 again in Paris (Sainte-Anne), 3 in Rennes, 2 in Dijon, 1 in Saint-Etienne, 1 in Forbach, and 1 in Antony.
The diagnosis of COVID-19 was based on the following criteria: possible exposure history, symptoms clinically compatible with COVID-19, and detection of SARS-CoV-2 by reverse transcriptase-PCR (RT-PCR) assays on the nasopharyngeal, throat, or lower respiratory tract swabs. Inclusion criteria were diagnosis of COVID-19 with neurologic manifestation and a brain MRI assessment. Exclusion criteria were missing data or noncontributory (lack of sequences, numerous artifacts) data regarding brain MRI.
The diagnosis of acute respiratory distress syndrome (ARDS) was based on Berlin criteria.14
Clinical and laboratory data were extracted from the patients’ electronic medical records in the hospital information system.
Quantitative real-time RT-PCR tests for SARS-CoV-2 nucleic acid were performed on upper or lower respiratory tract swabs and CSF. Primer and probe sequences were targeting 2 regions on the RdRp gene, which are specific to SARS-CoV-2. Assay sensitivity was ≈10 copies per reaction.
Brain MRI protocols
Imaging studies were conducted on 1.5T or 3T MRI. The multicenter nature of the study and the various clinical presentations did not allow standardization of sequences.
The most frequently sequences performed were 3D T1-weighted spin-echo with and without contrast-enhanced imaging, diffusion-weighted imaging, gradient echo T2 or susceptibility-weighted imaging, 2D or 3D fluid-attenuated inversion recovery (FLAIR) postcontrast, and 3D time-of-flight magnetic resonance angiography of the circle of Willis
Brain MRI reading
After anonymization, images were presented to readers with our GE Picture Archiving and Communication System (General Electric, Milwaukee, WI). Two neuroradiologists (S.K. and F.L., with 20 and 9 years of experience in neuroradiology, respectively) who were blinded to all patient data independently reviewed all brain MRIs. The final diagnosis was determined by consensus, and if consensus could not be reached, a third neuroradiologist (S.B., with 9 years of experience in neuroradiology) was questioned.
Neuroimaging abnormalities were divided into 3 groups: ischemic stroke, encephalitis, and LME. Ischemic strokes were classified into large artery infarctions, watershed cerebral infarctions, lacunar infarctions, and hypoxic-ischemic injuries. Encephalitis was ranked as limbic encephalitis, cytotoxic lesion of the corpus callosum (CLOCC), radiologic acute disseminated encephalomyelitis (ADEM), radiologic acute hemorrhagic necrotizing encephalopathy, and miscellaneous encephalitis.
Encephalitis was defined as brain parenchymal abnormal FLAIR hyperintensity involving gray matter (GM), white matter, or basal ganglia with variable enhancement localized mainly in medial temporal and inferior frontal lobes in case of limbic encephalitis. The term CLOCC has been proposed recently to describe a clinicoradiologic syndrome characterized by a transient mild encephalopathy and a reversible lesion of the corpus callosum, localized mainly to the central part of the splenium on MRI. CLOCCs are the consequence of numerous etiologies, the 2 most frequent being antiepileptic drug withdrawal and infections. They are related to a cytokine increase inducing glutamate elevation in the extracellular space, leading to a dysfunction of callosal neurons and microglia with intracellular water influx, resulting in cytotoxic edema.15
ADEM is an autoimmune-mediated disease occurring after viral infections and vaccinations. Multifocal demyelinating lesions involving white matter but also GM (basal ganglia) are seen with variable enhancement. Acute hemorrhagic necrotizing encephalopathy is a fulminant inflammatory demyelinating disease, which is considered the most severe form of ADEM, associated with hemorrhagic lesions.
A brain MRI without acute significative abnormalities or showing lesions unrelated to SARS-CoV-2 was considered normal.
Data were described with frequency and proportion (number, percent) for categorical variables and mean, median, and range for quantitative data. Categorical data were compared with the Fisher exact test. Quantitative data were compared with analysis of variance. Multiple correspondence analysis (MCA) was used to give a simultaneous multivariate description of clinical and radiologic characteristics of all diagnostic groups. MCA plots display results either for the subjects or for their characteristics. Those plots are to be interpreted on the basis of the proximity of the data points: 2 subjects who are close on a plot share a common pattern of symptoms, and 2 clinical symptoms that are close on a plot describe similar types of subjects. Ellipses are drawn around the mean position of each characteristic such that nonoverlapping ellipses can be considered to show a contrast between the subjects who share 1 or the other characteristic.
Computations were made with 3.5.3 through R-Studio with the readxl, and FactoMineR packages (R Foundation for Statistical Computing, Vienna, Austria). A value of p < 0.05 was considered significant.
Standard protocol approvals, registrations, and patient consents
The study was approved by the ethics standards committee on human experimentation of Strasbourg University Hospital (CE-2020-37) and was in accordance with the 1964 Declaration of Helsinki and its later amendments. Due to the emergency in the context of COVID-19 pandemic responsible for acute respiratory and neurologic manifestations pandemic, the requirement for patients’ written informed consent was waived.
We state that the data published are available and anonymized and will be shared on request by email to the corresponding author from any qualified investigator for purposes of replicating procedures and results.
A total of 68 patients with COVID-19 were included in this multicenter study. Among them, 4 were excluded because their brain MRIs were considered noncontributory.
The demographic and clinical characteristics of the 64 patients and their neurologic manifestations are summarized in tables 1 through 3. The most frequent neurologic manifestations were confusion/agitation/alteration of consciousness, corticospinal tract signs, and headache.