key: cord-308270-343r91km
authors: Sawlani, V.; Scotton, S.; Jacob, S.; Nader, K.; Jen, J. P.; Patel, M.; Gokani, K.; Denno, P.; Thaller, M.; Englezou, C.; Janjua, U.; Bowen, M.; Hoskote, C.; Veenith, T.; Hassan-Smith, G.
title: COVID-19-related intracranial imaging findings: a large single-centre experience
date: 2020-09-15
journal: Clin Radiol
DOI: 10.1016/j.crad.2020.09.002
sha: 
doc_id: 308270
cord_uid: 343r91km

Aim To describe the neuroradiological changes in patients with coronavirus disease 2019 (COVID-19). Materials and methods A retrospective review was undertaken of 3,403 patients who were confirmed positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and admitted to our institution between 1 March 2020 and 31 May 2020, and who underwent neuroimaging. Abnormal brain imaging was evaluated in detail and various imaging patterns on magnetic resonance imaging MRI were identified. Results Of the 3,403 patients with COVID-19, 167 (4.9%) had neurological signs or symptoms warranting neuroimaging. The most common indications were delirium (44/167, 26%), focal neurology (37/167, 22%), and altered consciousness (34/167, 20%). Neuroimaging showed abnormalities in 23% of patients, with MRI being abnormal in 20 patients and computed tomography (CT) in 18 patients. The most consistent neuroradiological finding was microhaemorrhage with a predilection for the splenium of the corpus callosum (12/20, 60%) followed by acute or subacute infarct (5/20, 25%), watershed white matter hyperintensities (4/20, 20%), and susceptibility changes on susceptibility-weighted imaging (SWI) in the superficial veins (3/20, 15%), acute haemorrhagic necrotising encephalopathy (2/20, 10%), large parenchymal haemorrhage (2/20, 10%), subarachnoid haemorrhage (1/20, 5%), hypoxic–ischaemic changes (1/20, 5%), and acute disseminated encephalomyelitis (ADEM)-like changes (1/20, 5%). Conclusion Various imaging patterns on MRI were observed including acute haemorrhagic necrotising encephalopathy, white matter hyperintensities, hypoxic-ischaemic changes, ADEM-like changes, and stroke. Microhaemorrhages were the most common findings. Prolonged hypoxaemia, consumption coagulopathy, and endothelial disruption are the likely pathological drivers and reflect disease severity in this patient cohort.

☒ Performed the analysis ☒ Wrote the paper Infection with the novel pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a global pandemic, which has claimed the lives of over 630,000 globally (as of 23 July 2020). Severe infection culminating in acute respiratory distress syndrome (ARDS) along with relatively high transmission rates, has led to the greatest global public health crisis in 100 years. There is predominant respiratory involvement; however, multi-organ complications have been reported.

Cerebrovascular events and altered mental status have been described as the most common neurological presentations in COVID-19 [1] . Recent studies have described abnormal brain imaging findings of microhaemorrhages, multifocal white matter hyperintense lesions with variable enhancement, infarcts, haemorrhagic lesions, acute haemorrhagic necrotising encephalopathy, inflammatory CNS syndromes including acute disseminated encephalomyelitis (ADEM), and medial temporal lobe abnormalities [2] [3] [4] . As one of the largest UK centres, the present study describes the intracranial imaging findings and likely pathogenesis of patients with COVID-19.

This retrospective observational study was approved by the institution's review board and the need for ethical approval was waived. Consecutive patients with COVID-19 and neurological manifestations who underwent brain imaging between 1 March 2020 to 31 May 2020 were assessed for inclusion. All patients had a confirmed diagnosis of COVID-19 based on detection of SARS-CoV-2 by reverse transcription polymerase chain reaction (RT-PCR) from sputum or nasopharyngeal swabs. They required hospitalisation with neurological signs or symptoms during inpatient admission, warranting brain imaging. Patients with abnormal brain imaging studies J o u r n a l P r e -p r o o f were included (Fig. 1) . Informed consent was obtained from patients or where appropriate, consent was provided by the next of kin.

Clinical, laboratory, and imaging data CT brain imaging was performed using a 64-section multidetector CT system (Siemens, Erlangen, Germany). MRI was performed using a 1.5 T system (Siemens, Erlangen, Germany) with a 32-channel phased-array head coil. The following sequences of the whole-brain were obtained: T1-weighted sagittal, axial T2- (Table 1 ). The most common indications were delirium (n=44), focal neurology (n=37), and altered consciousness (n=34). Brain MRI was abnormal in 20 patients and CT was abnormal in 18 patients.

Results of abnormal CT studies are summarised in Table 2 . Findings included subacute infarct, acute infarct, basal ganglia haemorrhage, and subarachnoid haemorrhage, with most patients presenting with focal neurology. The majority of patients presenting with altered consciousness and delirium were investigated by brain MRI. For patients who had an abnormal MRI brain study, the mean age was 59.7 (range 32-91) years, and the male-to-female ratio was approximately 2:1. Sixty percent were of White ethnicity and 25% were from an Asian background. Eighteen Outcome was variable with seven patients discharged home, six undergoing rehabilitation, four patients died, and the remaining three patients continued to remain as inpatients for at least 1 month. Patient demographic and clinical information is summarised in Table 3 .

A number of neuroradiological findings were identified in patients with abnormal MRI brain studies (n=20). MRI patterns and likely pathogenesis are described in detail in Electronic Supplementary Material Table S1 . Findings included microhaemorrhages J o u r n a l P r e -p r o o f (n=12), watershed white matter hyperintensities (n=4), susceptibility changes on SWI in superficial veins (n=3), acute infarct (n=3), subacute infarct (n=2), acute haemorrhagic necrotising encephalopathy (n=2), large parenchymal haemorrhage (n=2), subarachnoid haemorrhage (n=1), hypoxic-ischaemic changes (n=1), and ADEM-like changes (n=1). Results for MRI findings are summarised in Table 4 (Fig. 2) . Similar lesions were also seen in the corpus callosum and cerebellar white matter. In addition, microhaemorrhages were noticed in the splenium of the corpus callosum and brainstem. The other watershed pattern was of scattered DWI high signal lesions in centrum semiovale with micro-and macro-haemorrhages (Fig. 3) .

Susceptibility changes on SWI were seen in superficial veins in 15% of patients, in conjunction with microhaemorrhages, likely representing microthrombi (Fig. 4f) . All of these patients had diabetes and two of these three patients also had hypertension as a predisposing risk factor. haemorrhage. There is emerging evidence that the underlying pathogenesis for these presentations is closely linked to a combination of prolonged hypoxaemia, consumption coagulopathy, and endothelial dysfunction [5, 6] .

The spike protein of SARS-CoV-2 has a strong affinity for angiotensin-converting enzyme 2 (ACE2) receptor, which allows it to enter host cells. This protein is expressed on alveolar epithelial cells, intestinal enterocytes, and arterial and venous endothelial cells [7] . Using electron microscopy, SARS-CoV-2 viral elements have been demonstrated within endothelial cells themselves, associated with profound inflammation and tissue oedema in COVID-19 patients at autopsy [6] . A recent J o u r n a l P r e -p r o o f neuropathological series of 18 patients has shown that although the virus was detected at low levels in five patients, there was no evidence of encephalitis and the explanation for this could have been due to in situ virions or viral RNA from blood [8] .

All the patients in this neuropathological series demonstrated acute hypoxicischaemic damage. Hypoxic-ischaemic damage has been shown to cause leukoencephalopathy and white matter cytotoxic oedema in critically ill patients.

Leukoencephalopathic changes with or without cytotoxic oedema are seen in many other condition including posterior reversible encephalopathy syndrome (PRES), sepsis, ADEM, hypotension, hypoxia, prolonged ventilator support, drug therapy, and toxic metabolic diseases [9, 10] . SARS-CoV-2 infection initiates a pro-inflammatory cytokine storm led by tumour necrosis factor α (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β) [11] . This results in a downstream increase in vascular permeability, blood-brain and blood-CSF barrier dysfunction, neuroinflammation and subsequent leukoencephalopathy, thought to be due to oligodendroglial cell death and consequent demyelination predominantly in the deep watershed regions [12] . One patient, who had sustained a cardiac arrest, showed restricted diffusion in the basal ganglia bilaterally, in keeping with hypoxic-ischaemic changes. In this patient, the imaging appearances were likely secondary to hypoxia from cardiac arrest, which could have been a complication of COVID-19 infection involving the myocardium. A neuropathological study has also demonstrated similar appearances in the brain after cardiac arrest in one COVID-19 patient, thought to be secondary to hypoxia [13] .

Microvascular disruption of the endothelium in brain tissue may be responsible for extravasation of red blood cells and extensive microhaemorrhages [6, 14] .

Microhaemorrhages have been reported previously in a number of locations J o u r n a l P r e -p r o o f including lobar, subcortical, deep, corpus callosum, pontine, and cerebellar [2, 3] . A few studies have reported the splenium of corpus callosum as a predominant location for microhaemorrhages, with or without oedema [4, 15] . Microhaemorrhages in the splenium of the corpus callosum have been reported previously in severe ARDS and high-altitude cerebral oedema, thought to be due to hypoxaemia [16] . It is increasingly recognised that respiratory failure may be due to micro-emboli, and these may also affect the cerebral microcirculation resulting in microthrombosis and microvascular ischaemia. Linear structures resembling vessels were observed with susceptibility artefacts on SWI, which are probably microthrombi. This increases the risk of stroke or ischaemia amplifying the cytokine-induced injury to the brain [17] .

Ischaemic stroke was a common pattern seen on both MRI and CT. Fifteen patients presented with large vessel stroke on CT and five patients on MRI; most were severe, including bilateral MCA infarct, as noted previously [2] . Acute stroke seems to be the most common neuroradiological presentation in a large cohort of COVID-19

patients [18] . Similar findings with ischaemic changes and microhaemorrhages have also been published in isolated case reports [19] . Elevated D-dimer levels were observed in most of the present patients, probably due to a hypercoagulable environment. Four patients presented with intracerebral bleeds on CT and MRI; causes could be due to predisposing vascular risk factors (in 76% of the patient cohort) such as hypertension, anticoagulation treatment as prophylaxis from thromboembolism, and ECMO. ADEM-like presentation was seen in one patient, with evidence of haemorrhage, also reported in a previous study [2] . Although scattered white matter demyelinating lesions and perivenular tracking raises the possibility of a parainfectious ADEM-like process, the authors' impression of the overall phenotype suggested a primarily vascular insult, with secondary white matter injury. A detailed neuropathological examination of one patient has been reported recently [14] , which concluded that vascular insult was the primary driver of the neurological sequelae.

At the peak of the pandemic, although delirium and neuro-cognitive symptoms were 

Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study

The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings

Brain MRI findings in severe COVID-19: a retrospective observational study

COVID-19-associated diffuse leukoencephalopathy and microhemorrhages

COVID-19 related coagulopathy: a distinct entity?

Endothelial cell infection and endotheliitis in COVID-19

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

Neuropathological features of Covid-19

Differences of clinical manifestations according to the patterns of brain lesions in acute encephalopathy with reduced diffusion in the bilateral hemispheres

Pattern of brain injury in the acute setting of human septic shock

COVID-19: consider cytokine storm syndromes and immunosuppression

Hypoxic-ischemic leukoencephalopathy in man

Microvascular injury and J o u r n a l P r e -p r o o f hypoxic damage: emerging neuropathological signatures in COVID-19

Neuropathology of COVID-19: a spectrum of vascular and acute disseminated encephalomyelitis (ADEM)-like pathology

Unusual microbleeds in brain MRI of Covid-19 patients

The Pattern of Brain Microhemorrhages After Severe Lung Failure Resembles the One Seen in High-Altitude Cerebral Edema

COVID-19 related neuroimaging findings: a signal of thromboembolic complications and a strong prognostic marker of poor patient outcome

Evolving Neuroimaging Findings during COVID-19

COVID-19-associated Acute Hemorrhagic Necrotizing Encephalopathy: Imaging Features

Transient cortical blindness in COVID-19 pneumonia; a PRES-like syndrome: case report