Effect of Intra-arterial Alteplase vs Placebo Following Successful Thrombectomy on Functional Outcomes in Patients With Large Vessel Occlusion Acute Ischemic Stroke: The CHOICE Randomized Clinical Trial.

Importance: It is estimated that only 27% of patients with acute ischemic stroke and large vessel occlusion who undergo successful reperfusion after mechanical thrombectomy are disability free at 90 days. An incomplete microcirculatory reperfusion might contribute to these suboptimal clinical benefits. Objective: To investigate whether treatment with adjunct intra-arterial alteplase after thrombectomy improves outcomes following reperfusion. Design, Setting, and Participants: Phase 2b randomized, double-blind, placebo-controlled trial performed from December 2018 through May 2021 in 7 stroke centers in Catalonia, Spain. The study included 121 patients with large vessel occlusion acute ischemic stroke treated with thrombectomy within 24 hours after stroke onset and with an expanded Treatment in Cerebral Ischemia angiographic score of 2b50 to 3. Interventions: Participants were randomized to receive intra-arterial alteplase (0.225 mg/kg; maximum dose, 22.5 mg) infused over 15 to 30 minutes (n = 61) or placebo (n = 52). Main Outcomes and Measures: The primary outcome was the difference in proportion of patients achieving a score of 0 or 1 on the 90-day modified Rankin Scale (range, 0 [no symptoms] to 6 [death]) in all patients treated as randomized. Safety outcomes included rate of symptomatic intracranial hemorrhage and death. Results: The study was terminated early for inability to maintain placebo availability and enrollment rate because of the COVID-19 pandemic. Of 1825 patients with acute ischemic stroke treated with thrombectomy at the 7 study sites, 748 (41%) patients fulfilled the angiographic criteria, 121 (7%) patients were randomized (mean age, 70.6 [SD, 13.7] years; 57 women [47%]), and 113 (6%) were treated as randomized. The proportion of participants with a modified Rankin Scale score of 0 or 1 at 90 days was 59.0% (36/61) with alteplase and 40.4% (21/52) with placebo (adjusted risk difference, 18.4%; 95% CI, 0.3%-36.4%; P = .047). The proportion of patients with symptomatic intracranial hemorrhage within 24 hours was 0% with alteplase and 3.8% with placebo (risk difference, -3.8%; 95% CI, -13.2% to 2.5%). Ninety-day mortality was 8% with alteplase and 15% with placebo (risk difference, -7.2%; 95% CI, -19.2% to 4.8%). Conclusions and Relevance: Among patients with large vessel occlusion acute ischemic stroke and successful reperfusion following thrombectomy, the use of adjunct intra-arterial alteplase compared with placebo resulted in a greater likelihood of excellent neurological outcome at 90 days. However, because of study limitations, these findings should be interpreted as preliminary and require replication. Trial Registration: ClinicalTrials.gov Identifier: NCT03876119; EudraCT Number: 2018-002195-40.

Reversible Cerebral Vasoconstriction Syndrome in Patients with Coronavirus Disease: A Multicenter Case Series.

BACKGROUND AND OBJECTIVES: RCVS (Reversible Cerebral Vasoconstrictive Syndrome) is a condition associated with vasoactive agents that alter endothelial function. There is growing evidence that endothelial inflammation contributes to cerebrovascular disease in patients with coronavirus disease 2019 (COVID-19). In our study, we describe the clinical features, risk factors, and outcomes of RCVS in a multicenter case series of patients with COVID-19. MATERIALS AND METHODS: Multicenter retrospective case series. We collected clinical characteristics, imaging, and outcomes of patients with RCVS and COVID-19 identified at each participating site. RESULTS: Ten patients were identified, 7 women, ages 21 - 62 years. Risk factors included use of vasoconstrictive agents in 7 and history of migraine in 2. Presenting symptoms included thunderclap headache in 5 patients with recurrent headaches in 4. Eight were hypertensive on arrival to the hospital. Symptoms of COVID-19 included fever in 2, respiratory symptoms in 8, and gastrointestinal symptoms in 1. One patient did not have systemic COVID-19 symptoms. MRI showed subarachnoid hemorrhage in 3 cases, intraparenchymal hemorrhage in 2, acute ischemic stroke in 4, FLAIR hyperintensities in 2, and no abnormalities in 1 case. Neurovascular imaging showed focal segment irregularity and narrowing concerning for vasospasm of the left MCA in 4 cases and diffuse, multifocal narrowing of the intracranial vasculature in 6 cases. Outcomes varied, with 2 deaths, 2 remaining in the ICU, and 6 surviving to discharge with modified Rankin scale (mRS) scores of 0 (n=3), 2 (n=2), and 3 (n=1). CONCLUSIONS: Our series suggests that patients with COVID-19 may be at risk for RCVS, particularly in the setting of additional risk factors such as exposure to vasoactive agents. There was variability in the symptoms and severity of COVID-19, clinical characteristics, abnormalities on imaging, and mRS scores. However, a larger study is needed to validate a causal relationship between RCVS and COVID-19.

COVID-19 Associated Reversible Cerebral Vasoconstriction Syndrome Successfully Treated with Nimodipine and Aspirin.

There have been limited cases linking SARS-CoV-2 infection with the development of reversible cerebral vasoconstriction syndrome (RCVS). We hereby report a rare case of RCVS in the setting of mild SARS-CoV-2 respiratory infection successfully treated with nimodipine and aspirin. SARS-CoV-2 attacks the ACE2-receptors, which are expressed in various body organs including the lungs, kidneys, and blood vessels. Vasoconstriction can result from down-regulation of the ACE2-receptors that can lead to sympathetic hypertonia of the cerebral blood vessel walls and/or over-activation of the renin-angiotensin axis.

Large and Small Cerebral Vessel Involvement in Severe COVID-19: Detailed Clinical Workup of a Case Series.

BACKGROUND AND PURPOSE: Case series indicating cerebrovascular disorders in coronavirus disease 2019 (COVID-19) have been published. Comprehensive workups, including clinical characteristics, laboratory, electroencephalography, neuroimaging, and cerebrospinal fluid findings, are needed to understand the mechanisms. METHODS: We evaluated 32 consecutive critically ill patients with COVID-19 treated at a tertiary care center from March 9 to April 3, 2020, for concomitant severe central nervous system involvement. Patients identified underwent computed tomography, magnetic resonance imaging, electroencephalography, cerebrospinal fluid analysis, and autopsy in case of death. RESULTS: Of 32 critically ill patients with COVID-19, 8 (25%) had severe central nervous system involvement. Two presented with lacunar ischemic stroke in the early phase and 6 with prolonged impaired consciousness after termination of analgosedation. In all but one with delayed wake-up, neuroimaging or autopsy showed multiple cerebral microbleeds, in 3 with additional subarachnoid hemorrhage and in 2 with additional small ischemic lesions. In 3 patients, intracranial vessel wall sequence magnetic resonance imaging was performed for the first time to our knowledge. All showed contrast enhancement of vessel walls in large cerebral arteries, suggesting vascular wall pathologies with an inflammatory component. Reverse transcription-polymerase chain reactions for SARS-CoV-2 in cerebrospinal fluid were all negative. No intrathecal SARS-CoV-2-specific IgG synthesis was detectable. CONCLUSIONS: Different mechanisms of cerebrovascular disorders might be involved in COVID-19. Acute ischemic stroke might occur early. In a later phase, microinfarctions and vessel wall contrast enhancement occur, indicating small and large cerebral vessels involvement. Central nervous system disorders associated with COVID-19 may lead to long-term disabilities. Mechanisms should be urgently investigated to develop neuroprotective strategies.

Reversible cerebral vasoconstriction syndrome and dissection in the setting of COVID-19 infection.

The current COVID-19 pandemic has recently brought to attention the myriad of neuro- logic sequelae associated with Coronavirus infection including the predilection for stroke, particularly in young patients. Reversible cerebral vasoconstriction syndrome (RCVS) is a well-described clinical syndrome leading to vasoconstriction in the intracra- nial vessels, and has been associated with convexity subarachnoid hemorrhage and oc- casionally cervical artery dissection. It is usually reported in the context of a trigger such as medications, recreational drugs, or the postpartum state; however, it has not been described in COVID-19 infection. We report a case of both cervical vertebral ar- tery dissection as well as convexity subarachnoid hemorrhage due to RCVS, in a pa- tient with COVID-19 infection and no other triggers.

Treatment of Acute Ischemic Stroke due to Large Vessel Occlusion With COVID-19: Experience From Paris.

BACKGROUND AND PURPOSE: Higher rates of strokes have been observed in patients with coronavirus disease 2019 (COVID-19), but data regarding the outcomes of COVID-19 patients suffering from acute ischemic stroke due to large vessel occlusion (LVO) are lacking. We report our initial experience in the treatment of acute ischemic stroke with LVO in patients with COVID-19. METHODS: All consecutive patients with COVID-19 with acute ischemic stroke due to LVO treated in our institution during the 6 first weeks of the COVID-19 outbreak were included. Baseline clinical and radiological findings, treatment, and short-term outcomes are reported. RESULTS: We identified 10 patients with confirmed COVID-19 treated for an acute ischemic stroke due to LVO. Eight were men, with a median age of 59.5 years. Seven had none or mild symptoms of COVID-19 at stroke onset. Median time from COVID-19 symptoms to stroke onset was 6 days. All patients had brain imaging within 3 hours from symptoms onset. Five patients had multi-territory LVO. Five received intravenous alteplase. All patients had mechanical thrombectomy. Nine patients achieved successful recanalization (mTICI2B-3), none experienced early neurological improvement, 4 had early cerebral reocclusion, and a total of 6 patients (60%) died in the hospital. CONCLUSIONS: Best medical care including early intravenous thrombolysis, and successful and prompt recanalization achieved with mechanical thrombectomy, resulted in poor outcomes in patients with COVID-19. Although our results require further confirmation, a different pharmacological approach (antiplatelet or other) should be investigated to take in account inflammatory and coagulation disorders associated with COVID-19.