key: cord-1032430-wat33kpb
authors: Katal, Sanaz; Balakrishnan, Sudheer; Gholamrezanezhad, Ali
title: Neuroimaging findings in COVID-19 and other coronavirus infections: a systematic review in 116 patients
date: 2020-06-27
journal: J Neuroradiol
DOI: 10.1016/j.neurad.2020.06.007
sha: b1fbe32d947b25d3ad822f087bdcc2f415f13055
doc_id: 1032430
cord_uid: wat33kpb

Abstract Various neurologic syndromes have been described in patients with COVID-19 and other coronavirus infections. In this paper, we systematically reviewed the available imaging findings of patients diagnosed with neurological symptoms associated with coronavirus infections. Diverse radiologic results in the context of different neurologic presentations have been demonstrated using CT and MRI. While many patients have normal imaging evaluations, some patients present with intra-axial and extra-axial abnormalities. Stroke (both ischemic and hemorrhagic), encephalomyelitis, meningitis, demyelinating disorders such as acute disseminated encephalomyelitis (ADEM), and encephalopathy have been reported. Familiarity with these radiologic patterns will guide radiologists and referring clinicians to consider coronavirus infections in patients with worsening or progressive neurologic findings, particularly during the current COVID-19 pandemic. As data on this topic is very limited, further research and investigation are required.

The global novel Coronavirus disease (COVID-19) pandemic, first reported in Wuhan (China), has attracted intense attention around the world. As of June 11, 2020, more than 7.4 million COVID-19 cases with approximately 420 thousand deaths have been reported globally [1] . While the majority of infected patients present with fever and respiratory symptoms, several atypical manifestations have been reported recently, such as gastrointestinal complications, cardiac events, renal failure, and neurological deficits [2, 41] . In a case series of 214 hospitalized patients with COVID-19 from hospitals in Wuhan [3] , 36 .4% had neurological symptoms, including dizziness, headache, impaired consciousness, and acute cerebrovascular events. Moreover, in several other reports, neurologic manifestations have been reported as the initial presentation of SARS-CoV-2 infection [4] [5] [6] .

Although the literature on the typical respiratory presentation of COVID-19 has been widely reported [7] , thorough documentation of its neurologic manifestations, specifically the radiological findings, are lacking. Despite limited available data, radiologists and other healthcare providers should be aware of the spectrum of neurologic findings associated with COVID-19. This prompted us to conduct this systematic review on various radiological findings and concomitant neurologic symptoms in COVID-19 patients.

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the Middle East Respiratory syndrome (MERS-CoV), belong to the β-coronavirus family, similar to the SARS-CoV-2 strains. During the past two decades, SARS-CoV and MERS-CoV have caused epidemics affecting more than 10,000 infected patients worldwide [8, 9] . Several reports suggest that various neurologic sequelae may arise in association with respiratory coronavirus syndromes, including encephalitis, seizures, encephalopathy, Guillain-Barre syndrome (GBS), anosmia, neuromuscular disorders, and demyelinating diseases [10] [11] [12] [13] . Similarly, the neurotropism of other types of human coronaviruses (including HCoV-229E, HCoV-OC43, HCoVHKU1, and HCoV-NL63) and their possible association with neurologic diseases such as multiple sclerosis (MS) have been debated [14, 15] . The host immune response, including inflammatory cascades involving cytokine activation, has been suggested as a possible etiology for these neurologic changes. On the other hand, autopsy studies have detected viral RNA in neurons of patients who have died with SARS infection, indicating that coronaviruses might be able to infect brain cells directly [16] . Angiotensin-converting enzyme (ACE) II receptors on cerebrovascular endothelial cells may play an important role in this process.

Considering the similar viral structures and comparable post-viral neurological sequelae, we decided to analyze the available published literature on brain imaging findings associated with coronavirus strains other than COVID-19. This may provide valuable insight into coronavirus pathogenesis and guide the early detection and treatment of neurological disease associated with COVID-19 infection.

Search strategy:

Our research question was: "What are the reported neuroimaging findings in patients with coronavirus infections?" An extensive literature search was conducted for published articles describing relevant imaging findings by using Medline (assessed from PubMed), and Scopus online databases. The following search terms were used: "coronavirus" OR "SARS-CoV" OR "MERS" OR "COVID-19" OR "SARS-CoV-2" AND "neurologic" OR "brain" OR "Central Nervous System" OR "CNS" AND "computed tomography" OR "CT-scan" OR "MRI". Those studies in which title, abstract, keywords or body of manuscript contained the search terms were selected for analysis. We also searched the references of selected articles to find any possible additional studies related to brain imaging findings of COVID-19. To include relevant non-indexed reports, a hand search was also performed in Google search engine and Google scholar. The search was carried out on May 6, 2020, and was updated on June 10. No language limitation was considered. Repeated studies were excluded. Several studies that generally described neurologic manifestations of COVID-19 but did not mention brain imaging findings were also excluded.

Two reviewers searched all relevant articles independently and summarized them. All studies that described brain CT or MRI findings in COVID-19 patients were included. No search filters were applied. The search strategy and article selection process are described using a flowchart in Figure 1 , as recommended in the PRISMA statement.

Data was extracted by the authors independently: study designs, sample size, imaging methods, main results, laboratory COVID-19 confirmatory tests (using pharyngeal or CSF samples), and important notes of different cases were included in the forms. The methodological quality of the included studies was assessed based on the 9-items featured in the National Institutes of Health Quality Assessment Tool for Case Series Studies [17] .

A summary of articles and relevant findings included in this literature review is provided in Tables 2, 3a, and 3b. The electronic literature searches initially yielded 850 articles. After a manual screening of these articles based on their titles or abstracts, a total of 28 studies reporting imaging findings met the inclusion criteria for this systematic review. 21 studies were case reports, and seven were presented as case series. MR imaging was evaluated in 20 studies and CT was used in 17 reports. Sample sizes were small in most included studies, due to the rarely reported cases worldwide. The methodologic quality of the studies was generally rated as fair, indicative of scarce and low-quality data on viral neurologic findings [18] .

Twenty case reports/series with COVID-19 infection were included in this review. There were also two larger case series with neurological symptoms in COVID-19 patients, but they did not contain specific radiological findings [3, 19] . The first and largest study of neurologic manifestations in COVID-19 infection was an analysis of 214 patients of Wuhan hospitals [3] . They found that 36.4 percent of those patients showed some neurologists signs, with the most common being dizziness and headache. Moreover, fewer patients experienced more distinct neurological syndromes, such as acute stroke (5.7%), and consciousness impairment (15%). The authors mentioned that acute cerebrovascular disease (including ischemic and hemorrhagic stroke) had been diagnosed by clinical symptoms and head CT, albeit no CT findings have been specifically described. The study highlighted the importance of recognizing neurologic symptoms as an important presenting sign of COVID-19.

Amongst the available 20 studies, seven patients had CSF samples tested for SARS-CoV-2 infection [20] [21] [22] , one of which came to be positive in the presence of meningitis/encephalitis findings [21] , and the others were negative. The first case report of meningitis associated with SARS-CoV-2 [21] was a 24-year-old man with fever, and fatigue, worsening headache and sore throat. After a few days, he lost consciousness and began experiencing seizures. Diffusionweighted imaging (DWI) revealed periventricular diffusion restriction along the temporal horn of the right lateral ventricle. On Fluid-attenuated inversion recovery (FLAIR) images, hyperintense signal abnormality was noted in the right mesial temporal lobe and hippocampus, along with slight hippocampal atrophy. Contrast-enhanced imaging showed no definite abnormal intracranial enhancement. These findings indicated right lateral ventriculitis and encephalitis. The patient's nasopharyngeal swab was negative for SARS-CoV-2 RNA, but the virus was detected in a CSF sample. The authors concluded that the COVID-19 virus might be able to invade the brain directly in rare circumstances.

In terms of radiologic findings among these 20 case reports (90 patients) with COVID-19 associated neurologic signs, 37 patients (41%) with laboratory-confirmed COVID-19 infection had no acute abnormalities on brain CT or MRI [4, 6, 20, [22] [23] [24] [25] [26] . These patients presented with the following symptoms: altered mental state, headache, frequent seizures, status epilepticus, hemisensory paresthesia, and others.

In the remaining 12 articles (53 patients) with COVID-19 associated neurologic signs, abnormal brain radiologic findings have been reported, such as: hemorrhage [5, 26, 27] (seven cases), hemorrhagic posterior reversible encephalopathy syndrome [28] (PRES; two cases), vascular thrombosis (14 cases) [22, 26, [29] [30] [31] [32] 35] , Acute hemorrhagic Necrotizing Encephalopathy [33] (ANE; one case), Acute Disseminated Encephalomyelitis [34] (ADEM; one case), meningitis/encephalitis [21, 26] (two cases), cortical FLAIR signal abnormality (10 cases) [22] . In a case-series by Helms et al. [35] , bilateral frontotemporal hypoperfusion, leptomeningeal enhancement, and stroke-related findings were observed in 13 cases who had undergone brain MRI. All of the aforementioned findings have been fully described in Table 1 and 2. 

In 2004, a study was performed on a total of 183 hospitalized children with acute encephalitislike syndrome. Twenty-two children were found to have a CoV infection involving the central nervous system [15] 15 . Among these 22 patients, 16 individuals underwent MRI or CT, with 8 patients (50%) showing abnormal findings, as non-specific changes. Out of these eight patients, two cases with seizure (25%) displayed signal abnormity in the temporal lobe; two patients with headaches (25%) had periventricular signal abnormity; and four patients with fever and vomiting (50%) had signal abnormity in the basal ganglia and thalami. This study illustrates the possible association between CoV infection and CNS manifestations in these children, manifested as nonspecific radiologic changes in different brain areas.

In another case report of a child with acute disseminated encephalomyelitis (ADEM) [36] , MRI demonstrated patchy lesions in the white matter tracts, particularly in the centrum semiovale, as well as non-enhancing lesions in the spine. Subsequently, HCoV infection was detected both in pharyngeal and CSF sample of the child. These findings indicated ADEM, possibly due to the CoV infection (Table3a).

Similar studies on adults with SARS and MERS are also present. Two cases with SARS [13, 37] and one with MERS [10] who presented with neurological symptoms were reported to have a normal brain MRI. In a case series by Arabi et al. [12] , three MERS patients with severe neurological symptoms were evaluated with MRI, which displayed striking changes characterized by widespread, bilateral T2 hyperintense lesions within the white matter and subcortical areas of the frontal, temporal, and parietal lobes, the basal ganglia, and corpus callosum. None of the lesions showed enhancement. In another case series by Algahtani et al. [38] , two patients with MERS had intracerebral hemorrhage with significant edema on CT images. Similarly, another case report described intracerebral hemorrhagic changes on CT in a patient with MERS infection [39] . These findings have been fully described in Table 3b .

Various neurologic clinical manifestations have been described in patients with COVID-19 and other coronavirus infections. However, the data is sparse on this topic. When it comes to associated neuroimaging findings, available data is even more limited, as most of these studies do not include the corresponding brain imaging findings.

Previous studies have suggested that coronaviruses have neurotropic and neuroinvasive properties, even in the absence of pulmonary symptoms. Similarly, during the current COVID-19 outbreak, several new case reports again suggested a possible association between neurologic symptoms and COVID-19. A very recent review has found that myalgia, anosmia, headache, cerebrovascular disease, and encephalopathy are amongst the most common neurological manifestations associated with SARS-CoV-2 infection [42] .

Different hypotheses have been offered to explain these abnormalities. Many authors believe that a hyperimmune response secondary to cytokine storms may account for these neurologic presentations, while the others have proposed direct viral invasion of human brain cells through hematogenous, transcribrial, and neuronal retrograde dissemination pathways. In addition, the neurotropism of CoV (especially SARS-CoV-2) might be mediated by angiotensin-converting enzyme 2 (ACE2) receptors, that are expressed by brain capillary endothelial cells. Cerebral endothelial rupture then leads to irreversible brain damage, which contributes to pathophysiology of SARS-CoV-2 neurologic manifestations [40] . Furthermore, elevated levels of CRP and D-dimer due to a high inflammatory state and hypercoagulation cascade activation, may lead to cerebrovascular events in coronavirus patients. Hence, although it is still too early to know for sure, the possible mechanisms might be a combination of immune, vascular, and neuronal factors.

CNS involvement in coronavirus infection is reported to occur in more than one third of the hospitalized patients [42] , with various degrees from mild to life-threatening conditions. Therefore, it should be considered in the differential diagnosis of any patients with unexplained or worsening neurologic presentations, specifically during the current ongoing pandemic. Neurologic imaging may be helpful in these cases, as an early diagnosis is of utmost importance to minimize further neurological damage.

In Other neuroimaging abnormalities such as myelitis and encephalopathy-related changes were reported in a few cases, manifesting as parenchymal signal abnormality in different parts of the brain (Table 1-3b) .

Overall, the neurologic events associated with coronavirus infection (especially SARS-CoV-2) suggest a possible causal or synergetic relationship between cerebral ischemic/ hemorrhagic/inflammatory events and CoV infection. However, it should be noted that coincidental events, rather than casual association might explain some of these results.

Moreover, long-term neurological sequelae have not yet been explored. Thus further investigation is warranted to answer these unsolved questions.

During the current global COVID-19 pandemic, several case reports have suggested a possible association between SARS-CoV-2 virus infection and neurologic symptoms, similar to CNS findings reported during and after the previous SARS and MERS epidemics. Being aware of these patterns will ensure clinicians consider COVID-19 infection when encountering unexplained neurologic findings, particularly during the current COVID-19 pandemic. Due to limited data on this topic, further investigation is needed, including research on long-term neurologic consequences.

diagram of the study. 

The SARS-CoV-2 outbreak: what we know

Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China

Focal status epilepticus as unique clinical feature of COVID-19: a case report

Three unsuspected CT diagnoses of COVID-19

An Atypical Presentation of Novel Coronavirus Disease 2019 (COVID-19)

Coronavirus disease 2019 (COVID-19): a systematic review of imaging findings in 919 patients

World Health Organization. Summary of probable SARS cases with onset of illness from 1

Middle East respiratory syndrome coronavirus (MERS-CoV)

Neurological complications during treatment of Middle East respiratory syndrome

Neuromuscular disorders in severe acute respiratory syndrome

Severe neurologic syndrome associated with Middle East respiratory syndrome corona virus (MERS-CoV)

Possible central nervous system infection by SARS coronavirus. Emerging infectious diseases

Antibodies to coronaviruses OC43 and 229E in multiple sclerosis patients

Coronavirus infections in the central nervous system and respiratory tract show distinct features in hospitalized children

Detection of severe acute respiratory syndrome (SARS)-associated coronavirus RNA in autopsy tissues with in situ hybridization. Di 1 jun yi da xue xue bao= Academic journal of the first medical college of PLA

National Heart, Lung, and Blood Institute website. Study quality assessment tools

Central nervous system manifestations of COVID-19: A systematic review

Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in

Frequent Convulsive Seizures in an Adult Patient with COVID-19: A Case Report

A first Case of Meningitis/Encephalitis associated with SARS-Coronavirus-2

Brain MRI Findings in Patients in the Intensive Care Unit with COVID-19 Infection

Neurological complications of coronavirus disease (covid-19): encephalopathy. Cureus

Hemisensory paresthesia as the initial symptom of a SARS-Coronavirus-2 infection. A Case report

Encephalitis as a clinical manifestation of COVID-19. Brain, behavior, and immunity

Neuroradiological features in COVID-19 patients: first evidence in a complex scenario

COVID-19 and intracerebral haemorrhage: causative or coincidental? New Microbes and New Infections

Hemorrhagic Posterior Reversible Encephalopathy Syndrome as a Manifestation of COVID-19 Infection

Coronavirus Disease 2019 (COVID-19): An update on neurologic sequelae

Cerebrovascular Disease in COVID-19

Acute ischemic stroke complicating common carotid artery thrombosis during a severe COVID-19 infection

Cerebral Venous Thrombosis associated with COVID-19 infection: causality or coincidence

COVID-19-associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features

COVID-19-Associated Acute Disseminated Encephalomyelitis: A Case Report. medRxiv

Neurologic features in severe SARS-CoV-2 infection

Detection of coronavirus in the central nervous system of a child with acute disseminated encephalomyelitis

Olfactory Neuropathy in Severe Acute Respiratory Syndrome: Report of A Case

Neurological complications of Middle East respiratory syndrome coronavirus: a report of two cases and review of the literature. Case reports in neurological medicine

Spontaneous intracranial hemorrhage in a patient with Middle East respiratory syndrome corona virus. Saudi medical journal

Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms

Extrapulmonary manifestations of COVID-19: radiological and clinical overview

Neurological complications in patients with SARS-CoV-2 infection: a systematic review