Imaging Findings of Ischemic Stroke Associated with COVID-19

Amac: Inme ile COVID-19 arasindaki iliskiyi, inme tipleri ve goruntuleme bulgulari sunmayi amacladik. Gerec ve Yontem: Mart-Kasim 2020 arasinda, inmesi olan (n = 10) COVID-19 teshisi konulan hastalar retrospektif olarak calismaya dahil edildi. Intrakraniyal kanamayi ortadan kaldirmak icin tum hastalara kontrastsiz bilgisayarli tomografi (BT) yapildi. Daha sonra manyetik rezonans goruntuleme (MRI) ve Difuzyon Agirlikli MR (DAG) elde edildi. BT anjiyografisi kontrendike olan hastalara manyetik rezonans anjiyografi yapildi. Klinik bilgiler, inme risk faktorleri ve goruntuleme sonuclari kaydedildi. Inme suresi, boyutu, konumu (kortikal, derin lakuner ve beyaz cevher) ve vaskuler bolge alani degerlendirildi. Bulgular: Calismaya alinan 10 hastanin ortalama yasi 62±15.10 idi. Tum hastalarda iskemik inme vardi. Toplamda 4 vakada (%40) serebral vaskuler hastalik icin herhangi bir risk faktoru yoktu. DAG sonuclarina gore yedi vaka akut inme (%70) ve uc vaka subakut inme (%30) olarak degerlendirildi. Inme boyutu 21.80±15.83 mm idi. 4 olguda genis kortikal, 3 olgu kortikal, 5 olguda lakuner, 2 olguda kortikal ve lakuner enfarktus vardi. 6 olgu arka serebral arter bolgesinde ve 4 olgu on serebral bolgede idi. Sonuc: COVID-19 tedavisi sirasinda veya tedaviden hemen sonra inmeli hastalarin ortaya cikmasi, ozellikle risk faktorlerinin eslik ettigi durumlarda virusun iskemik inmeye yol actigi COVID-19 tedavisi sirasinda veya tedaviden hemen sonra inmeli hastalarin ortaya cikmasi, ozellikle risk faktorlerinin eslik ettigi durumlarda virusun iskemik inmeye yol actigi hipotezini dusundurmektedir.


INTRODUCTION
Coronavirus disease , which began in Wuhan, China in December 2019 and spread rapidly worldwide, is an infectious disease that often causes acute respiratory distress syndrome. However, it has been found to cause numerous diseases of the system in addition to pulmonary diseases (1). It increases daily at the same time as cerebrovascular presentations (2). The relationship between the renin-angiotensin-aldosterone system and the pathogenic potency of SARS-CoV-1 and the pathogenic potency of COVID-19 is very complex. The virus enters host cells by the receptor of the angiotensin 2 conversion enzyme (ACE2) expressed in its various organs. It can cause damage to many organs in COVID-19 with the imbalance between the regulation of ACE2 and the renin-angiotensin system in infected cells (3,4). Vasoconstriction, fluid and salt retention, proinflammatory, pro-coagulation effect, and increased blood pressure occur with enzymatic activation (5). Direct damage to vascular structures of the brain and heart, the tendency to thrombosis due to cytokine storm triggered by inflammation, and hyper viscosity are reported as the main pathogenesis and pathogenesis and predisposing factors of stroke in COVID-19 patients (6,7). However, the lack of information on the genetics behind COVID-19 remains today (8). It has been reported in the literature that infected COVID-19 patients who were previously healthy and had no risk factors for a cerebrovascular disease may be affected for ischemic strokes after COVID-19 infection or during the treatment. Endothelial damages and possible hypoxia may have triggered partial or full vessel embolic events (9). Our knowledge of cerebral vascular events related to COVID-19 today is based on case reports. There are very limited studies in the literature, no comprehensive study. In this article, we aimed to present the relationship between stroke and COVID-19, stroke types, and imaging findings in COVID-19 with stroke in our pandemic hospital.

MATERIAL AND METHOD Study Design:
Approval was obtained from the ethics committee of S.B.U. Haseki Education Research Hospital (2021/08). Informed consent was obtained from all patients. Following the declaration of COVID-19 as a global pandemic, our hospital became a pandemic hospital in March 2020. From March to November 2020, COVID-19 diagnosed in patients with stroke (n= 10) was included in the study retrospectively. COVID-19 has been diagnosed based on positivity with PCR and clinicallaboratory-radiological findings. Although the PCR test of 2 patients was negative, the imaging findings of the thorax and the laboratory tests were accepted as positive COVID-19 because their results supported COVID-19 infection and the treatment was arranged as of COVID-19 infection. Transient ischemic attacks and patients with ischemia without imaging findings were excluded from the study. Imaging Techniques: First of all, to eliminate intracranial hemorrhage, a non-contrast brain computed tomography (CT) scan was performed for all patients (PHILIPS Ingenuity, Nederland). The following CT parameters were used: collimation, 16 × 1.5mm; tube current, 150 mA; tube potential, 120 kVp; gantry rotation time, 0.5s; pitch value, 0.93. All images were reconstructed with an image matrix of 512 × 512 pixels, an image thickness of 1mm. Then, magnetic resonance imaging (MRI) and Diffusionweighted MRI (DWI) (n= 10) were obtained with a 1.5T MR Scanner (GEM flex LG full, USA). The cranial MRI scan included axial, coronal, sagittal non-en-hanced T1weighted images; axial and sagittal T2-weighted images, axial fluid-attenuated inversion recovery (FLAIR) images. The contrast-enhanced examination was added for MR angiography. Our routine MRI stroke protocol included the following sequences acquired in the axial plane: spin-echo DWI (b = 0-1,000 s/mm 2 ), FLAIR, and gradi-ent-echo T2weighted imaging. The presence of lesions was defined by areas of high signal intensity on DWI. Apparent diffusion coefficient (ADC) maps from each slice were generated from the DWI for each slice. All films were reported by 5 years experienced neuroradiologist. MRI examination could not be performed in 2 patients. Magnetic resonance angiography (MRA) was performed in patients (n=2) whose CT angiography (n=3) was contraindicated.
CT and MRA could not be performed on one of our patients due to high creatine and claustrophobia. Clinical information, stroke risk factors, and case imaging results were recorded. Patients with risk factors are summarized in Table 1.
While categorizing types of strokes, all of our cases are classified as ischemic strokes. Stroke time, size (the largest size was considered mainly), location (cortical, deep lacunar, and white matter), and vascular territory area (anterior cerebral artery territory, posterior cerebral artery territory, and watershed area) were evaluated. Statistical Analysis: The Statistical Package for Social Sciences 15.0 (SPSS, Inc, Chicago, IL, USA) for Windows was used for statistical analyses. Results were presented in number (n) and percent (%) due to the small number of patients in the study.

RESULTS
The age range of the 10 patients included in the study was 30-77, and the mean age was 62±15.10 years. All patients had an ischemic stroke. In total, 4 cases (40%) did not have any risk factors for cerebral vascular disease. 6 cases (60%) had risk factors for cerebrovascular disease (hypertension, diabetes mellitus, atrial fibrillation, congestive heart failure, atherosclerosis). Based on DWI results, seven cases were assessed as acute strokes (70%) and three cases as sub-acute strokes (30%). The size of the stroke was 21.80±15.83mm. In 4 cases, the size was extended cortical areas. 3 cases were cortical (Figure 1a,b), 5 cases had a lacunar infarction (Figure 2a-d,  3a,b), 2 cases had cortical and lacunar infarctions. 6 cases were in the posterior cerebral artery territory and 4 cases were in the anterior cerebral artery territory.
32 Gocgun et al.  A watershed stroke had not been seen. Our patients were discharged after they finished treatment for COVID-19 and stroke, and none of them died. Imaging findings, according to stroke types, age, and demographic characteristics are summarized in Table-2.

DISCUSSION
The virus, which reaches the central system through the neighboring or hematogenous way from the nasal olfactory nerve cells, leads to microthrombus and dissection with direct endothelial damage and causes or facilitates ischemic strokes or cortical small vessel occlusions (5).  In the literature, this mechanism is highlighted in stroke cases associated with COVID-19. The stenosis of large vessels and cardiogenic causes are implicated in the etiologies of cortical infarct (10). In our study, 3 patients with cortical infarction had cardiogenic risk factors such as pacemaker and atrial fibrillation, while not have large vessel stenosis. However, the fact that our cases are receiving corona treatment or after a few days of COVID-19 suggests the existence of an interaction between the COVID-19 virus and cardiac-related strokes. In the study conducted by the global COVID-19 stroke center in 174 patients with COVID-positive stroke, they mentioned that both direct vascular injury, various reactions caused by inflammatory agents, and infections may cause a stroke by triggering cardiac arrhythmia (11,12). One of our two patients with both cortical and lacunar stroke had hemodynamically significant stenosis in Basillary Artery, and it was a possible source of thrombus for Posterior Cerebral Artery occlusion. The other patient had an ischemic stroke while is receiving treatment for COVID-19 pneumonia. In his angiography, ipsilateral Internal Carotid Artery (ICA) was occluded, there was no plaque or stenosis in vascular structures except wall calcifications, but there were chronic ischemic gliotic signals in the left centrum semiovale on FLAIR sequence, which may indicate the presence of ICA hemodynamically significant stenosis. As a known mechanism in the literature, it is stated that infection may accelerate atherosclerosis, occlusion, and cause stroke (13). COVID-19 virus is reported to reach the central system, which is the cause of lacunar infarction. In our case series, most of our cases were types of small-vessel occlusion. We detected less large vessel occlusion. However, risk factors for stroke were also present.The lacunar infarct is a type of stroke that means a maximum diameter of 20 mm, localized in the basal ganglia, brainstem, deep white matter, and occurs due to the occlusion of short perforating vessels. It is mainly associated with uncontrolled hypertension and diabetes mellitus (14). In our study, 7 patients had lacunar infarction. Only one of our patients has been diagnosed with hypertension. In the study of Baudin et al. 89  and therefore it is estimated that the actual number is higher than we recorded (18)(19)(20).
Limitations; the small number of cases is the biggest limitation of the study. Besides the small number of cases, there was no homogeneous distribution. There were no previous imaging findings of the cases and angiography could not be performed in all cases. The RT-PCR test of 2 cases was negative, they were diagnosed with COVID-19 pneumonia according to thorax findings. There may be a case who came to the hospital due to stroke and was coincidentally diagnosed with COVID-19. As a result, the presentation of patients with stroke during corona disease therapy or after therapy might be considered the hypothesis that the virus led to a stroke, especially in cases accompanied by risk factors. Largescale multicenter studies will be more informative in this regard.
In the study by Ntaios et al. lacunar infarction was reported in a total of 17.8% (11). In our study, the rate of total lacunar infarction was 70%, and the rate was very high compared to the literature. One reason is the relatively high rate associated with a low number of cases. Although common carotid artery and ICA were total thrombosed in one of the patients in the lacunar infarct group, less diffusion restriction than we expected was observed in the acute period on diffusion imaging. This case referred to interventional radiology for thrombectomy but thrombectomy was not successful. In the subacute period, the diffusion restriction of this patient progressed to the entire Middle Cerebral Artery. It has been reported in the literature that large vessel occlusion and strokes associated with COVID-19 may even be one of the clinical presentation forms (16,17). Another reason; according to Hernandez-Fernandez et al.'s research, cases with lacunar infarction present less to hospitals due to the pandemic,