Cerebrovascular complications in patients with SARS-CoV-2 infection: Case series


 Background: Italy is one of the most affected countries by the Coronavirus disease 2019 (COVID-19). The responsible pathogen is named Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). The clinical spectrum ranges from asymptomatic infection to severe pneumonia leading to intensive care unit admission. Evidence of cerebrovascular complications associated with SARS-CoV-2 is limited. We herein report 6 patients who developed acute stroke during COVID-19 infection. Methods: Retrospective case series of patients diagnosed with COVID-19 using reverse-transcriptase–polymerase-chain-reaction (RT-PCR) on nasopharyngeal swabs, who developed clinical and neuroimaging evidence of acute stroke during SARS-CoV-2 infection.Results: Six patients were identified (5 men); median age was 69 years (range: 57-82). Stroke subtypes were ischemic (4, 67%) and hemorrhagic (2, 33%). All patients but 1 had pre-existing vascular risk factors. One patient developed encephalopathy prior to stroke, characterized by focal seizures and behavioral abnormalities. COVID-19-related pneumonia was severe (i.e. requiring critical care support) in 5/6 cases (83%). Liver enzyme alteration and lactate dehydrogenase (LDH) elevation was registered in all cases. Four patients (67%) manifested acute kidney failure prior to stroke. Four patients (67%) had abnormal coagulation tests. Outcome was poor in the majority of the patients: 4 died (67%), 1 is still in coma (20%) and the remaining 1 remains severely neurologically affected (mRS: 4).Conclusions: Acute stroke can complicate the course of COVI-19 infection. In our series, stroke developed mostly in patients with severe pneumonia and multi organ failure, liver enzymes and LDH were markedly increased in all cases, and the outcome was poor.


Introduction
Italy was the first country in Europe to witness an outbreak of the Coronavirus disease 2019 (COVID- 19), which, as of April 6, has infected 1,277,196 people worldwide [1]. The responsible pathogen is named Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). The clinical spectrum associated with COVID-19 ranges from asymptomatic infection to severe pneumonia leading to intensive care unit (ICU) admission [2][3][4]. Evidence of cerebrovascular complications associated with SARS-CoV-2 is limited, but previous reports from the SARS epidemic in Asia in 2003 suggested a higher incidence of thromboembolic complications, including stroke [5]. Management of acute stroke in the setting of this pandemic disease poses unique challenges, including the need to maintain high quality stroke care with limited resources, while at the same time preventing infection spread to patients and physicians [6]. A better characterization of cerebrovascular complications associated with COVID-19 infection is important to guide decision making.
We herein report clinical spectrum, neuroimaging findings, and outcome of 6 patients developing acute stroke during COVID-19 infection.

Methods
This is a retrospective observational case series of patients developing clinical and neuroimaging evidence of acute stroke during COVID-19 infection. We included only patients with laboratoryconfirmed COVID-19 infection who were admitted to the Fondazione Poliambulanza Hospital, Brescia, Italy or the Udine University Hospital, Udine, Italy, between March 16 and April 5, 2020. A confirmed case of COVID-19 was defined by a positive result on a reverse-transcriptase-polymerase-chainreaction (RT-PCR) assay on nasopharyngeal swabs. Demographic data, information on clinical presentation and evolution, and laboratory and radiologic results were recorded. The severity of acute respiratory distress syndrome (ARDS) was rated using the PaO 2 /FiO 2 ratio (partial pressure of arterial oxygen over the fraction of inspired oxygen) which was indicated whenever this data was available.
Acute lung injury is present if PaO 2 /FiO 2 ratio is ≤ 300 [7]. Each diagnosis of stroke was confirmed by brain computed tomography (CT)/CT angiography (CTA), and/or magnetic resonance imaging (MRI).
All exams were reviewed by 2 experienced neuroradiologists (DB, MM). Neurological presentations were reviewed by 1 experienced neurologist (AV). Descriptive analysis is presented as frequencies and percentages for categorical variables and as the median and range for continuous variables. All procedures were performed in accordance with the institutional ethics committee and the Declaration of Helsinki.
Outcome was poor in the majority of the patients: 4 died (67%), 1 is still in coma (20%) and the remaining 1 remains severely neurologically affected (mRS: 4). Clinical and laboratory data for all patients are summarized in the table.    [5,8]. Additionally, a recent report from Wuhan, China, showed that acute cerebrovascular disease is not uncommon in COVID-19, and it represents a negative prognostic factor. Among 221 infected patients, 11 (5%) developed ischemic stroke, 1 (0.5%) cerebral venous thrombosis, and 1 (0,5%) brain hemorrhage [9]. In agreement with the finding of the present study, it was also observed that cardiovascular risk factors were common, while the patients demonstrated increased biomarkers of inflammatory response as well as a hypercoagulable state [9].
The relationship between acute infection and stroke is complex and it was demonstrated for many types of bacterial and viral infections. Importantly, an increased risk of stroke was documented after respiratory infections, including influenza, and the risk was highest within the first week [10].
Accordingly, measures to prevent viral illnesses (e.g. influenza vaccination) were shown to be protective for the development of cerebrovascular disease [11]. Intriguingly, the association between infection and stroke is also relevant for patients with preexistent risk factors. In this group, the vulnerability of atherosclerotic plaques to rupture appears to be increased in the presence of systemic inflammation and sepsis [10]. The mechanisms by which viral infections can trigger stroke are multiple and depend on the associated pathogen and host characteristics. For example, varicella zoster virus (VZV) is responsible for a distinctive vasculopathy involving both large and small arteries, which can result in ischemic infarction of the brain and spinal cord, as well as subarachnoid and cerebral hemorrhage [12]. At autopsy, the cerebral arteries showed disruption of the internal elastic lamina and multinucleated giant cells, while the presence of VZV DNA was demonstrated in the posterior cerebral and basilar arteries [13]. Similarly, human immunodeficiency virus (HIV) is a known cause of large vessel vasculopathy (mainly aneurysmal), that can also involve the brain [14]. A vasculitic-like mechanism can also apply in the context of COVID-19, since localized fibrinoid necrosis as well as infiltration of monocytes, lymphocytes, and plasma cells into vessel walls were demonstrated in 3 cases of the 2003 SARS disease [15]. Interestingly enough, another type of Coronavirus (New Haven CoV) was associated with the development of systemic vasculitis of childhood (Kawasaki disease) in a case-control study [16]. An alternative mechanism leading to stroke during the course of an infection is the presence of a pro-thrombotic state. Numerous reports have documented various coagulation abnormalities (in particular raised D-dimer, thrombocytopenia and isolated prolonged aPTT) in patients with SARS-CoV, nearly two decades ago [17,18] infarctions of the heart, kidneys, spleen, and occipital lobe [18].Similarly, an underlying thrombophilic state can also be also hypothesized in SARS-CoV-2 infection, as suggested by report of pulmonary embolism in patients from Wuhan [19] and in Patient 1 of the present series who also presented brain and spleen lesions suggestive for embolization.
We observed a marked elevation of a ubiquitous cell enzyme (LDH) in all patients of the present series. Elevated serum LDH is associated with numerous clinical conditions, including hemolysis, cancer, and sepsis [20]. In the setting of COVID-19, it is possible that the very high LDH levels reflect the underlying respiratory failure and systemic shock. Its role as a potential prognostic factor in COVID-19-associated stroke should be further investigated.
No patient with ischemic stroke was treated with thrombolysis or thrombectomy in the present series.
This could be related to the fact that the patients were critically ill, and the detection of changes in neurological status is highly complex in ICU patients, where lightening of sedation and frequent neurological follow-up is needed. All these measures can be less prompt in the presence of restricted resources and limited medical personnel, as in a catastrophic medical emergency like COVID-19.