key: cord-330074-5iqqgy65 authors: Patel, Smit D.; Kollar, Ryan; Troy, Patrick; Song, Xianyuan; Khaled, Mohammad; Parra, Augusto; Pervez, Mubashir title: Malignant Cerebral Ischemia in A COVID-19 Infected Patient: Case Review and Histopathological Findings date: 2020-08-05 journal: J Stroke Cerebrovasc Dis DOI: 10.1016/j.jstrokecerebrovasdis.2020.105231 sha: doc_id: 330074 cord_uid: 5iqqgy65 Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is responsible for an unprecedented worldwide pandemic that has severely impacted the United States. As the pandemic continues, a growing body of evidence suggests that infected patients may develop significant coagulopathy with resultant thromboembolic complications including deep vein thrombosis, pulmonary embolism, myocardial infarction, and ischemic stroke. However, this data is limited and comes from recent small case series and observational studies on stroke types, mechanisms, and outcomes.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 Furthermore, evidence on the role of therapeutic anticoagulation in SARS-CoV-2 infected patients with elevated inflammatory markers, such as D-dimer, is also limited. We report the case of a middle-aged patient who presented with a large vessel ischemic stroke likely resulting from an underlying inflammatory response in the setting of known novel coronavirus infection (COVID-19). Histopathologic analysis of the patient's ischemic brain tissue revealed hypoxic neurons and significant edema from the underlying ischemic insult, fibrin thrombi in small vessels, and fibroid necrosis of the vascular wall without any signs of vasculature inflammation. Brain biopsy was negative for the presence of SARS-CoV-2 RNA (RT-PCR assay). Along with a growing body of literature, our case suggests that cerebrovascular thromboembolic events in COVID-19 infection may be related to acquired hypercoagulability and coagulation cascade activation due to the release of inflammatory markers and cytokines, rather than virus-induced vasculitis. Further studies to investigate the mechanism of cerebrovascular thromboembolic events and their prevention is warranted. P a g e | 2 Ischemic stroke and COVID-19 infection mechanisms, and outcomes. 1-14 Furthermore, evidence on the role of therapeutic anticoagulation in SARS-CoV-2 infected patients with elevated inflammatory markers, such as D-dimer, is also limited. We report the case of a middle-aged patient who presented with a large vessel ischemic stroke likely resulting from an underlying inflammatory response in the setting of known novel coronavirus infection . Histopathologic analysis of the patient's ischemic brain tissue revealed hypoxic neurons and significant edema from the underlying ischemic insult, fibrin thrombi in small vessels, and fibroid necrosis of the vascular wall without any signs of vasculature inflammation. Brain biopsy was negative for the presence of SARS-CoV-2 RNA (RT-PCR assay). Along with a growing body of literature, our case suggests that cerebrovascular thromboembolic events in COVID-19 infection may be related to acquired hypercoagulability and coagulation cascade activation due to the release of inflammatory markers and cytokines, rather than virus-induced vasculitis. Further studies to investigate the mechanism of cerebrovascular thromboembolic events and their prevention is warranted. Ischemic stroke, Inflammatory conditions, COVID-19, Corona virus, SARS-CoV-2 RNA, cerebrovascular disease, hemorrhagic stroke, cerebral sinus thrombosis, vasculitis, anticoagulation, thrombotic conditions, thromboembolic conditions Introduction: The first retrospective study from China during the current COVID-19 pandemic reported a higher incidence of cerebrovascular disease and decreased functional outcomes for those admitted for COVID-19 infection. 3 A recently published article from New York reported P a g e | 3 Ischemic stroke and COVID-19 infection ischemic stroke cases in a young-to-middle-age population without apparent risk factors. 1 One theory of COVID-19 associated hypercoagulability proposes that SARS-CoV-2 facilitates recruitment of inflammatory cells in blood vessels, which leads to the release of inflammatory markers and cytokines that subsequently activate the coagulation cascade. 15 However, no causal relationship has been formally established between COVID-19 infection and cerebrovascular injury. In order to aid in the study of SARS-CoV-2 associated cerebrovascular injuries, we have reviewed the literature and compiled a series of studies reporting the incidence of cerebrovascular disease in COVID-19 infected patients (Table 1) . Further, we describe the case of a malignant ischemic stroke in a middle-aged adult admitted with COVID-19 infection with associated histopathological findings, which represents previously unreported findings. A 48-year-old right-handed male with a prior history of obesity, hypertension, hyperlipidemia, right below-the-knee amputation since childhood, history of drug abuse, and gout presented with one-week of dyspnea and cough. Two weeks prior to his presentation, he had been exposed to a COVID-19-positive patient in a skilled nursing facility where had been admitted for physical therapy following a gout flare. Upon arrival to the emergency department, he was febrile to 100.5F with a heart rate of 98 bpm, blood pressure of 124/77 mmHg, and oxygen saturation of 92% via non-rebreather mask. He was admitted to the medical intensive care unit for acute hypoxic respiratory failure without any focal Ischemic stroke and COVID-19 infection did not demonstrate evidence of vessel dissection or atherosclerotic plaques. He was not an intravenous tissue plasminogen activator (IV-tPA) candidate based on the time elapsed since last known normal and a low ASPECT score due to risk of hemorrhagic transformation. Therapeutic anticoagulation was discontinued at that time due to the risk of hemorrhage. Transthoracic echocardiography was negative for cardiac source of embolus, valvular dysfunction, regional wall motion abnormalities, or atrial septal defect. Lower extremity venous Doppler ultrasound did not demonstrate evidence of deep venous thrombosis. Urine toxicological screening for amphetamines, barbiturates, marijuana, cocaine, and phencyclidine was negative. Other tests such as Electroencephalography was not performed since there was no concerned for seizure type activities. He was initially managed with osmotherapy in the setting of significant cytotoxic edema and resultant midline shift in the setting of large territorial cerebral infarction. Surveillance stability CT scan of the head obtained on post-stroke day 2 demonstrated progressive cerebral edema with leftward midline shift increased to 1.4 cm in size and concurrent right uncal herniation with mesencephalic compression despite aggressive medical management. Given his rapid radiographic progression and concern for declining mental status, he underwent decompressive hemicraniectomy (DHC) within 72 hours of stroke symptoms. Brain biopsy of right temporal lobe infarcted tissue was obtained that showed acute cerebritis characterized by marked perivascular and parenchymal neutrophilic infiltrates, and associated acute hypoxic neurons and marked edema. Many small vessels showed fibrin thrombi, some with fibroid necrosis of the vascular wall, without any signs of vasculature inflammation. The sample also underwent RT-PCR assay for SARS-CoV-2 RNA with an eventual negative result ( figure 4) . Eventually, the P a g e | 6 Ischemic stroke and COVID-19 infection patient had worsening respiratory status and multifactorial shock. Given his grave prognosis, further goals of care were discussed with the palliative care team and family, and it was decided that he should be transitioned to comfort measures only. There have been numerous reports in the literature of an association between COVID-19 infection and thromboembolic complications, including ischemic stroke, during the current pandemic. 4, 16, 17 One recent retrospective cohort study conducted in the New York metropolitan area revealed that, while the overall rate of imaging-confirmed ischemic stroke remained low in their sample, the rate of cryptogenic stroke in those infected with COVID-19 was significantly higher than that observed in both contemporary and historical control groups. 10 While further study on etiology and management of stroke in this setting is required, there is speculation that these events may be related to acquired hypercoagulability. Our case of COVID-19 associated malignant cerebral infarct is the first to examine associated histological and biopsy findings, and Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis Neurologic Features in Severe SARS-CoV-2 Infection COVID-19 presenting as stroke Characteristics of ischaemic stroke associated with COVID-19 Stroke in patients with SARS-CoV-2 infection: case series Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. The Lancet Psychiatry SARS-CoV-2 and Stroke in a New York Healthcare System Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study Coexistence of COVID-19 and acute ischemic stroke report of four cases Incidence of thrombotic complications in critically ill ICU patients with COVID-19 Severe Acute Respiratory Syndrome Coronavirus 2 Infection and Ischemic Stroke Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Arterial thromboembolic complications in COVID-19 in lowrisk patients despite prophylaxis Thrombosis risk associated with COVID-19 infection. A scoping review Type of study Sample Size CVD cases