Abstract

Background

Brain MRI parenchymal signal abnormalities have been in association with SARS-CoV-2.

Purpose

Describe the neuroimaging findings (excluding ischemic infarcts) in patients with severe COVID-19 infection.

Methods

This was a retrospective study of patients evaluated from March 23th, 2020 to April 27th, 2020 at 16 hospitals. Inclusion criteria were: (i) positive nasopharyngeal or lower respiratory tract reverse transcriptase-polymerase chain reaction assays; (ii) severe COVID infection defined as requirement for hospitalization and oxygen therapy; (iii) neurologic manifestations; (iv) abnormal brain MRI. Exclusion criteria were patients with missing or non-contributory data regarding brain MRI or a brain MRI showing ischemic infarcts, cerebral venous thrombosis, or chronic lesions unrelated to the current event. Categorical data were compared using Fisher exact test. Quantitative data were compared using Student’s t-test or Wilcoxon test. A p-value lower than 0.05 was considered significant.

Results

Thirty men (81%) and 7 women (19%) met inclusion criteria, with a mean age of 61+/- 12 years (range: 8-78). The most common neurologic manifestations were alteration of consciousness (27/37, 73%), pathological wakefulness when the sedation was stopped (15/37, 41%), confusion (12/37, 32%), and agitation (7/37, 19%). The most frequent MRI findings were: signal abnormalities located in the medial temporal lobe in 16/37 (43%, 95% CI 27-59%) patients, non-confluent multifocal white matter hyperintense lesions on FLAIR and diffusion sequences, with variable enhancement, with associated hemorrhagic lesions in 11/37 patients (30%, 95% CI 15-45%), and extensive and isolated white matter microhemorrhages in 9/37 patients (24%, 95% CI 10-38%). A majority of patients (20/37, 54%) had intracerebral hemorrhagic lesions with a more severe clinical presentation: higher admission rate in intensive care units, 20/20 patients, 100% versus 12/17 patients, 71%, p=0.01; development of the acute respiratory distress syndrome in 20/20 patients, 100% versus 11/17 patients, 65%, p=0.005. Only one patient was positive for SARS-CoV-2 RNA in the cerebrospinal fluid.

Conclusion

Patients with severe COVID-19 and without ischemic infarcts had a wide range of neurologic manifestations that were be associated with abnormal brain MRIs. Eight distinctive neuroradiological patterns were described.

Summary

Eight distinctive neuroradiologic patterns (excluding ischemic infarcts) were identified in patients with severe COVID-19 infection with abnormal brain MRIs.

Key Results

  • 1. In patients with COVID-19, the most frequent neuroimaging features were: involvement of the medial temporal lobe, non-confluent multifocal white matter hyperintense lesions on FLAIR with variable enhancement and hemorrhagic lesions, and extensive and isolated white matter microhemorrhages.

  • 2. A majority of our patients presented intracerebral hemorrhagic lesions, which were associated with worse clinical status.

  • 3. Of 37 patients, only one was positive for SARS-CoV-2 RNA in the cerebrospinal fluid.

Introduction

SARS-CoV-2 is the seventh member of the family of coronaviruses (CoVs) that infect humans (1) and induces COVID-19 disease. Human CoVs (HCoVs) have neuroinvasive capacities and may be neurovirulent by two main mechanisms (24): viral replication into glial or neuronal cells of the brain, or autoimmune reaction with a misdirected host immune response (5). Thus, a few cases of acute encephalitis-like syndromes with hCoVs were reported in the past two decades (58). Concerning COVID-19, current data on central nervous system (CNS) involvement is uncommon but growing (917), demonstrating the high frequency of neurological symptoms.

However, the delineation of a large cohort of confirmed brain MRI parenchymal signal abnormalities (excluding ischemic infarcts) related to COVID-19 has never been performed, and the underlying pathophysiological mechanisms remain unknown. The purpose of this current study was to describe the neuroimaging findings (excluding ischemic infarcts) in patients with severe COVID-19 and report the clinico-biological profile of these patients.

Material & Methods

This retrospective observational national multicenter study was initiated by the French Society of Neuroradiology (SFNR) in collaboration with neurologists, intensivists, and infectious disease specialists, and brought together 16 hospitals. The study was approved by the ethical committee of Strasbourg University Hospital (CE-2020-37) and was in accordance with the 1964 Helsinki Declaration and its later amendments. Due to the emergency in the context of COVID-19 pandemic responsible for acute respiratory and neurological manifestations pandemic, the requirement for patients’ written informed consent was waived.

Patient cohort

Consecutive patients with COVID-19 infection and neurologic manifestations who underwent brain MRI were included from March 23th, 2020, to April 27th, 2020, in 16 French centers, including 11 university hospitals and 5 general hospitals. Inclusion criteria were: (i) diagnosis of COVID-19 based on possible exposure history or symptoms clinically compatible, validated with a detection of SARS-CoV-2 by reverse transcriptase-polymerase chain reaction (RT-PCR) assays on the nasopharyngeal, throat or lower respiratory tract swabs; (ii) severe COVID-19 infection defined as requirement for hospitalization and oxygen therapy; (iii) neurologic manifestations; (iv) abnormal brain MRI with acute/subacute abnormalities. Exclusion criteria were: (i) patients with missing or non-contributory data (lack of sequences, numerous artifacts) regarding brain MRI; (ii) a brain MRI showing ischemic infarcts, cerebral venous thrombosis, or chronic lesions unrelated to the current event.

Clinical and laboratory data were extracted from the patients’ electronic medical records in the Hospital Information System. Only laboratory analysis within three days before the brain MRI were considered. In the case of redundancy of the tests, the worst value has been kept. Clinical and biological data were reviewed by two neurologists (J.D.S., and M.A. with 25 and 15 years of clinical expertise on neurology, respectively), and by one virologist (S.F-K). They participated to the elaboration of the study design, the interpretation of the data, and to manuscript editing. When available, all electroencephalogram (EEG) were reviewed by one expert neurologist (C.B.) and classified into five groups (normal, under sedation, nonspecific, encephalopathy or seizures).

Virological assessment

Quantitative real-time RT-PCR tests for SARS-CoV-2 nucleic acid were performed on nasopharyngeal or lower respiratory tract swabs, and cerebrospinal fluid (CSF). Primer and probe sequences target two regions on the RdRp gene and are specific to SARS-CoV-2. Assay sensitivity is around 10 copies/reaction (in house-method, Institut Pasteur, Paris, France) (18).

Brain MRI protocols

Imaging studies were conducted either on 1.5- or 3-Tesla MRI. The multicenter nature of the study and the various clinical setups did not allow standardization of sequences. The most frequently sequences performed were 3D T1 weighted spin-echo MRI with and without contrast enhancement, diffusion-weighted imaging (DWI), gradient-echo T2 or Susceptibility-weighted imaging, and 2D or 3D FLAIR after administration of gadolinium-based contrast agent.

MRI interpretation

After anonymization, images were presented to readers with our GE Picture Archiving and Communication System (General Electric, Milwaukee, WI, USA). After review of MRI studies by three neuroradiologists (S.K., F.C., and F.L. with 20, 25, and 9 years of experience in neuroradiology, respectively) who were blinded to all patient data, brain MRI findings were divided by consensus into eight groups: (a) unilateral FLAIR and/or diffusion hyperintensities located in medial temporal lobe; (b) FLAIR and diffusion ovoid hyperintense lesion located in the central part of the splenium of the corpus callosum; (c) non-confluent multifocal white matter (WM) hyperintense lesions on FLAIR and diffusion, with variable enhancement; (d) non-confluent multifocal WM hyperintense lesions on FLAIR and diffusion, with variable enhancement, associated with hemorrhagic lesions; (e) acute necrotizing encephalopathy (ANE) (9) when symmetric thalamic lesions (edema, petechial hemorrhage, and necrosis), with variable involvement of the brainstem, internal capsule, putamen, cerebral and cerebellar WM; (f) extensive and isolated WM microhemorrhages; (g) extensive and confluent supratentorial WM FLAIR hyperintensities; (h) FLAIR hyperintense lesions involving both middle cerebellar peduncles. Patients could have had more than one pattern.

Statistical analysis

Data were described using frequency and proportion (n, %) for categorical variables, using mean, median, interquartile range, and range for quantitative data. In a second step, patients with hemorrhagic lesions were gathered into a single group called « patients with hemorrhagic complications », to look for clinico-biological differences between the two populations. Categorical data were compared using Fisher exact test. Quantitative data were compared using Student’s t-test or Wilcoxon test. A p-value lower than 0.05 was considered significant.

Results

Between March 23th, 2020, and April 27th, 2020, 190 consecutive patients with COVID-19 infection and neurologic manifestations, performed a brain MRI in 16 hospitals. Among them, were excluded all patients with normal brain MRI, ischemic infarcts, cerebral venous thrombosis or chronic lesions unrelated to the current event. A total of 37 patients with COVID-19 infection were finally included in this study. The average age of the patients was 61 +/- 12 years with 30 men and 7 women included. The majority of our patients (32/37, 87%) were admitted to Intensive Care Units (ICUs) because of acute respiratory failure. The most frequent neurologic manifestations were alteration of consciousness (27/37, 73%), pathological wakefulness after sedation (15/37, 41%), confusion (12/37, 32%), and agitation (7/37, 19%).

Read more: https://pubs.rsna.org/doi/10.1148/radiol.2020202222