key: cord-0912980-o8quzzyg authors: Chang, Jaimie; Bulwa, Zachary; Breit, Hannah; Cherian, Laurel J.; Conners, James J.; Song, Sarah Y.; Dafer, Rima M. title: Acute Large Vessel Ischemic Stroke in Patients with COVID-19 Related Multisystem Inflammatory Syndrome date: 2021-09-25 journal: Pediatr Neurol DOI: 10.1016/j.pediatrneurol.2021.09.013 sha: 3038ce4c441012537e1441a0795adbb893c8fb0b doc_id: 912980 cord_uid: o8quzzyg BACKGROUND: Acute ischemic stroke (AIS) is rare in children and diagnosis is often delayed. Neurological involvement may occur in multisystem inflammatory syndrome in children (MIS-C), but very few cases of AIS in patients with MIS-C have been reported. CASE DESCRIPTIONS: We report two cases of AIS presenting with large vessel occlusive (LVO) disease in previously healthy adolescents recently exposed to SARS-CoV-2 infection. Both patients were subsequently diagnosed with and treated for MIS-C. Here, we discuss the course of their treatments and clinical responses. CONCLUSION: Early recognition and diagnosis of LVO in children with MIS-C is critical in order to make available all treatment options to improve clinical outcomes. clinicians are aware of the risk of stroke in MIS-C. Here, we report two cases of MIS-C-associated large vessel occlusive (LVO) AIS in previously healthy adolescents, and review the paucity of existing literature reporting similar cases. A previously healthy right-handed 15-year-old girl awoke with acute aphasia and right hemiparesis. She was last known to be in her normal state of health 10 hours prior to symptom recognition. She had no history of head trauma. One week prior, she had tested positive for SARS-CoV-2 following several days of fevers, headache, abdominal pain, and generalized weakness. The patient met CDC criteria for MIS-C based on her known recent SARS-Cov2 infection, multisystem involvement (renal, cardiac, neurologic), and elevated inflammatory markers [4] . She was treated with intravenous immunoglobulin (IVIG) 2g/kg and IV methylprednisolone 2mg/kg/day for five days, followed by a three-day oral prednisone taper, and therapeutic enoxaparin 1mg/kg twice daily for 3 months. A repeat TTE on day 6 showed improved LVEF. Upon discharge, she had subtle right hemiparesis with a Pediatric Stroke Outcome Measure (PSOM) of 1.5, which had completely resolved (PSOM 0) at 30-day follow up. A previously healthy right-handed 16-year-old girl without any history of head trauma was found obtunded and non-verbal after three days of fevers, nausea, vomiting, and diarrhea. Her family had been ill with SARS-CoV-2 about a month prior. She was diagnosed with MIS-C based on the CDC criteria [4] and was treated with a single dose of IVIG 2g/kg and IV methylprednisolone 1mg/kg/day for 5 days followed by a three-day oral prednisone taper. Her hospitalization was complicated by a catheter-associated right lower extremity DVT. Heparin drip was transitioned to enoxaparin 1mg/kg twice daily and aspirin 81 mg daily. Throughout her hospital stay, she made gradual improvement with speech and mobility. She was ultimately discharged to an acute rehabilitation facility with PSOM of 3. On day 41 outpatient follow up, she was independent in all activities of daily living with mild expressive aphasia and trace right hemiparesis with PSOM of 2. J o u r n a l P r e -p r o o f The COVID-19 pandemic has impacted millions of people globally. Over 4 million children have tested positive for SARS-CoV-2 thus far in the United States [5] . COVID-19 in children is associated with MIS-C, a debilitating multisystem syndrome that can present in children weeks after exposure to SARS-CoV-2. We report two cases of AIS due to LVO in previously healthy adolescents with MIS-C. These two cases illustrate the diverse neurological presentations of COVID-19 in children, specifically coagulopathy associated with this infection. The pathophysiology linking MIS-C to AIS is not fully understood, although emerging data from adult COVID-19-associated AIS suggest a combination of etiologies. These include venous stasis, hyper-viscosity in critically ill patients, viral endothelial injury leading to hypercoagulability, and myocardial involvement causing reduced LVEF and subsequent cardioembolism. In adults, the connection between SARS-CoV-2 and inflammation has been proposed to involve compromise of vascular integrity activating the clotting cascade, triggering platelet reactivity, cytokine storm, and immune complexes that contribute to the formation of thromboses [1, 6] . In children, especially those with delayed MIS-C relative to initial infection, a delayed immune-mediated inflammatory response stimulated by macrophages, neutrophils, and monocytes followed by the production of antibodies from plasma and B-cells, appears to be a more likely pathogenesis than direct viral invasion of tissues. In a comprehensive study of MIS-C spanning 53 pediatric health centers across the US, Feldstein et al. reported that among adolescents aged 13-20 years, the gastrointestinal, respiratory, and J o u r n a l P r e -p r o o f cardiac systems were the most commonly affected at 90%, 87%, and 80%, respectively [2] . Neurological involvement has been reported in 11-30% of children with MIS-C [2, 3] . Commonly reported neurological symptoms include fatigue, generalized weakness, confusion, headache, and loss of sense of taste or smell [7] . More severe neurologic manifestations such as seizures, encephalopathy, and cerebral edema were uncommon [7] . (Table 1) [8, [10] [11] [12] [13] Including our two cases, the ages range from 8 to 16 years, some of which were initially asymptomatic with positive PCR or IgG serology. Interestingly, though all patients had recent or proven concurrent SARS-CoV-2 infection, only three other reported patients met full diagnostic criteria for MIS-C [8, 10] . Both of our patients and the patient reported by Tiwari with LVO AIS and MIS-C were successfully treated with IVIG, steroids, and anticoagulation; the treatment for the two MIS-C cases reported by Beslow was not specified [8, 10] . Medical management of MIS-C is largely based on established treatments for Kawasaki disease including IVIG, aspirin, and corticosteroids [1] . While emerging data suggest improved cardiovascular function in patients with MIS-C initially treated with IVIG plus glucocorticoids J o u r n a l P r e -p r o o f compared to IVIG alone [14] , other studies show no difference in recovery from MIS-C after IVIG alone, IVIG plus glucocorticoids, and glucocorticoids alone [15] . Nevertheless, IVIG remains a mainstay for MIS-C treatment. Historically, IVIG has been associated with a potential increased risk of thromboembolic events including stroke, raising concerns for IVIG exacerbating a pro-thrombotic state due to MIS-C, especially in patients with AIS [16] . In Case 1, IVIG was administered according to published guidelines [1] ; Case 2 was hematologically complex as she exhibited a larger AIS, and additional signs of hypercoagulability, including lower extremity DVT and left ventricular thrombus, which warranted discontinuing IVIG and treatment with low molecular weight heparin. Pediatric AIS remains an infrequent complication of SARS-CoV-2. The two presented cases demonstrate an association between MIS-C and AIS due to LVO, thus expanding the literature on this rare condition. These cases illustrate the importance of early symptom recognition, timely diagnosis, and rapid intervention to improve clinical outcomes. 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