Frequency and Patterns of Brain Infarction in Patients With Embolic Stroke of Undetermined Source: NAVIGATE ESUS Trial.

BACKGROUND AND PURPOSE: The spectrum of brain infarction in patients with embolic stroke of undetermined source (ESUS) has not been well characterized. Our objective was to define the frequency and pattern of brain infarcts detected by magnetic resonance imaging (MRI) among patients with recent ESUS participating in a clinical trial. METHODS: In the NAVIGATE ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source), an MRI substudy was carried out at 87 sites in 15 countries. Participants underwent an MRI using a specified protocol near randomization. Images were interpreted centrally by those unaware of clinical characteristics. RESULTS: Among the 918 substudy cohort participants, the mean age was 67 years and 60% were men with a median (interquartile range) of 64 (26-115) days between the qualifying ischemic stroke and MRI. On MRI, 855 (93%) had recent or chronic brain infarcts that were multiple in 646 (70%) and involved multiple arterial territories in 62% (401/646). Multiple brain infarcts were present in 68% (510/755) of those without a history of stroke or transient ischemic attack before the qualifying ESUS. Prior stroke/transient ischemic attack (P<0.001), modified Rankin Scale score >0 (P<0.001), and current tobacco use (P=0.01) were associated with multiple infarcts. Topographically, large and/or cortical infarcts were present in 89% (757/855) of patients with infarcts, while in 11% (98/855) infarcts were exclusively small and subcortical. Among those with multiple large and/or cortical infarcts, 57% (251/437) had one or more involving a different vascular territory from the qualifying ESUS. CONCLUSIONS: Most patients with ESUS, including those without prior clinical stroke or transient ischemic attack, had multiple large and/or cortical brain infarcts detected by MRI, reflecting a substantial burden of clinical stroke and covert brain infarction. Infarcts most frequently involved multiple vascular territories. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02313909.

Air embolism during lumbar surgery in the prone position.

Only a few clinical cases of cerebral arterial gas embolism during spinal surgery are published. It seems important not to overlook this diagnosis in order to initiate rapid appropriate treatment. This was a suspected case of paradoxical gas embolism revealed postoperatively by neurological deficits and whose recovery was noted during hyperbaric oxygen treatment. Unfortunately, no complementary examination showed gas embolism and only the context, the clinical picture and the case evolution evoke this diagnosis. The diagnostic difficulty in the immediate postoperative period is highlighted.

Cerebral arterial gas embolism in a patient with hypoplastic left heart syndrome treated with emergent hyperbaric oxygen: case report.

A 30-year-old female with a history of seizure disorder and hypoplastic left heart syndrome treated with a Norwood procedure in 1986 followed by a modified non-fenestrated Fontan (Left SVC to IVC to pulmonary arteries) with a known baffle leak presented to the emergency department. On day of presentation, the patient became unresponsive, with perioral cyanosis, rightward gaze and a left facial droop near the end of a platelet transfusion. An emergent non-contrast head CT revealed intracranial air in the right MCA distribution. She was taken to the hyperbaric chamber and was treated with a U.S. Navy Table 6 in a multiplace chamber with no extensions. Ten minutes into the treatment patient became more alert and spontaneously asked questions. The following day she was treated with a U.S. Navy Table 5. Patient had repeat CT of the head, which showed resolution of intracerebral gas and small areas of ischemia in right frontal lobe and right caudate. On hospital day five neurologic exam was normal, with 5/5 strength and no residual deficits. Treating the patient was a concern because patient has a single ventricle, in which the pulmonary artery is connected directly to the vena cava. There is very little data regarding the effects of hyperbaric oxygen (HBO2)therapy on single-ventricle physiology. Only two case reports of three pediatric patients treated with HBO2 for CAGE in a similar setting are known. In these cases the patients had improvements in their symptoms following HBO2. These cases and ours indicate HBO2 is feasible and indicated for CAGE in patients with cyanotic congenital heart disease.

Intracranial and systemic atherosclerosis in the NAVIGATE ESUS trial: Recurrent stroke risk and response to antithrombotic therapy.

BACKGROUND: Non-stenotic intracranial and systemic atherosclerosis are associated with ischemic stroke. We report frequency and response to anticoagulant vs. antiplatelet prophylaxis of patients with embolic stroke of undetermined source (ESUS) who have non-stenotic intracranial atherosclerosis and/or systemic atherosclerosis. METHODS: Exploratory analysis of the international NAVIGATE ESUS randomized trial comparing rivaroxaban 15mg daily with aspirin 100mg daily in 7213 patients with recent ESUS. Among participants with results of intracranial arterial imaging with either computed tomographic angiography (CTA) or magnetic resonance angiography (MRA), the frequency and predictors of non-stenotic intracranial and systemic atherosclerosis and responses to antithrombotic therapy were assessed. RESULTS: Among 4723 participants with available intracranial CTA or MRA results (65% of the trial cohort), the prevalence of intracranial atherosclerosis was 16% (n=739). Patient features independently associated with intracranial atherosclerosis included East Asian region (odds ratio 2.7, 95%CI 2.2,3.3) and cervical carotid plaque (odds ratio 2.3, 95%CI 1.9,2.7), among others. The rate of recurrent ischemic stroke averaged 4.8%/year among those with intracranial atherosclerosis vs. 5.0.%/year for those without (HR 0.95, 95%CI 0.65, 1.4). Among those with intracranial atherosclerosis, the recurrent ischemic stroke rate was higher if assigned to rivaroxaban (5.8%/year) vs. aspirin (3.7%/year), but the difference was not statistically significant (HR 1.6, 95%CI 0.78, 3.3). There was trend for the effect of antithrombotic treatments to be different according to the presence or absence of intracranial atherosclerosis (pinteraction=0.09). Among participants with evidence of systemic atherosclerosis by either history or imaging (n=3820), recurrent ischemic stroke rates were similar among those assigned to rivaroxaban (5.5%/year) vs. aspirin (4.9%/year)(HR 1.1, 95%CI 0.84, 1.5). CONCLUSIONS: East Asia region was the strongest factor associated with intracranial atherosclerosis. There were no statistically significant differences between rivaroxaban and aspirin prophylaxis for recurrent ischemic stroke in patients with non-stenotic intracranial atherosclerosis and/or systemic atherosclerosis.

Efficacy and Safety of Rivaroxaban Versus Aspirin in Embolic Stroke of Undetermined Source and Carotid Atherosclerosis.

Background and Purpose- The sources of emboli in patients with embolic stroke of undetermined source (ESUS) are multiple and may not respond uniformly to anticoagulation. In this exploratory subgroup analysis of patients with carotid atherosclerosis in the NAVIGATE (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism)-ESUS trial, we assessed whether the treatment effect in this subgroup is consistent with the overall trial population and investigated the association of carotid atherosclerosis with recurrent ischemic stroke. Methods- Carotid atherosclerosis was analyzed either as the presence of mild (ie, 20%-49%) atherosclerotic stenosis or, separately, as the presence of carotid plaque. Primary efficacy outcome was ischemic stroke recurrence. Safety outcomes were major bleeding and symptomatic intracerebral bleeding. Results- Carotid plaque was present in 40% of participants and mild carotid stenosis in 11%. There was no significant difference in ischemic stroke recurrence between rivaroxaban- and aspirin-treated patients among 490 patients with carotid stenosis (5.0 versus 5.9/100 patient-years, respectively, hazard ratio [HR], 0.85; 95% CI, 0.39-1.87; P for interaction of treatment effect with patients without carotid stenosis 0.78) and among 2905 patients with carotid plaques (5.9 versus 4.9/100 patient-years, respectively, HR, 1.20; 95% CI, 0.86-1.68; P for interaction of treatment effect with patients without carotid stenosis 0.2). Among patients with carotid plaque, major bleeding was more frequent in rivaroxaban-treated patients compared with aspirin-treated (2.0 versus 0.5/100 patient-years, HR, 3.75; 95% CI, 1.63-8.65). Patients with carotid stenosis had similar rate of ischemic stroke recurrence compared with those without (5.4 versus 4.9/100 patient-years, respectively, HR, 1.11; 95% CI, 0.73-1.69), but there was a strong trend of higher rate of ischemic stroke recurrence in patients with carotid plaque compared with those without (5.4 versus 4.3/100 patient-years, respectively, HR, 1.23; 95% CI, 0.99-1.54). Conclusions- In ESUS patients with carotid atherosclerosis, we found no difference in efficacy between rivaroxaban and aspirin for prevention of recurrent stroke, but aspirin was safer, consistent with the overall trial results. Carotid plaque was much more often present ipsilateral to the qualifying ischemic stroke than contralateral, supporting an important etiological role of nonstenotic carotid disease in ESUS. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

Branch atheromatous disease diagnosed as embolic stroke of undetermined source: A sub-analysis of NAVIGATE ESUS.

BACKGROUND: Branch atheromatous disease (BAD) is distinctive from large and small arterial diseases, which is single subcortical infarction larger than lacunar stroke in the territories of deep perforators without relevant arterial stenosis. BAD meets the current criteria of embolic stroke of undetermined source. We performed an exploratory analysis of BAD in patients recruited to NAVIGATE embolic stroke of undetermined source, a randomized controlled trial to compare rivaroxaban and aspirin in embolic stroke of undetermined source patients. METHODS AND RESULTS: Among 3972 stroke patients in cerebral hemispheres with intracranial arterial imaging, 502 (12.6%) patients met the criteria for BAD. BAD was associated with younger age (years; OR: 0.97, 95% CI: 0.96-0.98), race (Asian; OR: 1.78, 95% CI: 1.44-2.21), region (Eastern Europe; OR: 2.49, 95% CI: 1.87-3.32), and higher National Institute of Health Stroke Scale (OR: 1.17, 95% CI: 1.12-1.22) at randomization. During follow-up, stroke or systemic embolism (2.5%/year vs. 6.2%/year, p = 0.0022), stroke (2.1%/year vs. 6.2%/year, p = 0.0008), and ischemic stroke (2.1%/year vs. 5.9%/year, p = 0.0013) occurred less frequently in BAD than non-BAD patients. There were no differences in annual rates of stroke or systemic embolism (2.5%/year vs. 2.5%/year, HR: 1.01, 95% CI: 0.33-3.14) or major bleeding (1.3%/year vs. 0.8%/year, HR: 1.51, 95% CI: 0.25-9.05) between rivaroxaban and aspirin groups among BAD patients. CONCLUSIONS: BAD was relatively common, especially in Asian and from Eastern Europe among embolic stroke of undetermined source patients. Stroke severity was higher at randomization but recurrence of stroke was fewer in BAD than non-BAD patients. The efficacy and safety of rivaroxaban and aspirin did not differ among BAD patients.

A Rare Case of Cerebral Air Embolism Caused by Pulmonary Arteriovenous Malformation After Removal of a Central Venous Catheter.

Cerebral air embolism following central venous catheter (CVC) removal is extremely rare. We report a case of cerebral air embolism with loss of consciousness after removal of CVC caused by pulmonary arteriovenous malformation (PAVM). Computed tomography revealed air bubbles in the internal carotid arteries along the sulci in the cerebral hemispheres, as well as a PAVM. The cerebral air embolism was treated with hyperbaric oxygen and intravenous thrombolytic therapy, and transcatheter embolization of the PAVM was performed. When inserting/removing CVC in a patient with a small PAVM, treatment of the PAVM, irrespective of its size, could prevent the type of complication that occurred in our present case.

Devastating cerebral Lipiodol® embolization related to therapeutic lymphangiography for refractory chylothorax in a patient with Behçet's disease.

Onset of neurological symptoms early after intranodal lymphangiography can occur due to Lipiodol droplet migration through intrapulmonary lymphovenous communication. Patients with Behçet's disease may be at higher risk of developing this devastating complication.

Ultradense Middle Cerebral Artery: Specific Sign of Cerebral Lipiodol Embolization.

Cerebral lipiodol embolization is a rare but known complication of lymphatic embolization for plastic bronchitis. The classic imaging finding on a noncontrast head computed tomography is multiple small areas of hyperdensity within the cerebral hemispheres, which represent lipiodol deposition in the brain. We report a case of lipiodol deposition in the middle cerebral artery following lymphatic embolization, producing an "ultradense" vessel sign on noncontrast computed tomography.

Complex neurological symptoms in bilateral thalamic stroke due to Percheron artery occlusion.

The artery of Percheron is a rare anatomical variant where a single thalamic perforating artery arises from the proximal posterior cerebral artery (P1 segment) between the basilar artery and the posterior communicating artery and supplies the rostral mesencephalon and both paramedian territories of the thalami. Almost one-third of human brains present this variant. Occlusion of the artery of Percheron mostly results in a bilateral medial thalamic infarction, which usually manifests with altered consciousness (including coma), vertical gaze paresis, and cognitive disturbance. The presentation is similar to the "top of the basilar syndrome", and early recognition should be prompted. We describe the case of a young female with this vessel variant who experienced a bilateral thalamic stroke. Magnetic resonance angiography demonstrated bilateral thalamic infarcts and a truncated artery of Percheron. Occlusion of the vessel was presumably due to embolism from a patent foramen ovale. Thrombolysis was performed, with incomplete symptom remission, cognitive impairment, and persistence of speech disorders. Early recognition and treatment of posterior circulation strokes is mandatory, and further investigation for underlying stroke etiologies is needed.

Prognosis of cerebral lipiodol embolism caused by transarterial chemoembolization.

OBJECTIVES: Transarterial chemoembolization (TACE) plays an essential role in the management of unresectable hepatocellular cell carcinoma and other hepatic neoplasms. Cerebral lipiodol embolism (CLE) is a rare complication of TACE and its prognostic factors have not been well studied. The aim of this paper was to elucidate the prognostic factors of CLE based on clinical data obtained from our patients and cases published since 2004. METHODS: We present two patients with CLE, analyze the clinical data, and review all CLE cases published since 2004. A poor outcome was defined as stupor, coma, quadriplegia, or death within 45 days. Patients who had other neurological conditions within 45 days were considered as having a good outcome. RESULTS: The rate of poor outcome was 25.7% (9/35). Compared with the patients with good outcome, those with poor outcome were older (mean age 68.3 ± 7.3 vs. 58.3 ± 10.6 years, p = 0.03), more often female (76.9% vs. male 33.3%, p = 0.02), and more likely chemoembolized via both the right hepatic and right inferior phrenic arteries (44.4 vs. 8.7%, p = 0.02). DISCUSSION: The prognosis of CLE was related to age, gender, and the arteries selected for injection.

Early Rivaroxaban Use After Cardioembolic Stroke May Not Result in Hemorrhagic Transformation: A Prospective Magnetic Resonance Imaging Study.

BACKGROUND AND PURPOSE: Early anticoagulation after cardioembolic stroke remains controversial because of the potential for hemorrhagic transformation (HT). We tested the safety and feasibility of initiating rivaroxaban ≤14 days after cardioembolic stroke/transient ischemic attack. METHODS: A prospective, open-label study of patients with atrial fibrillation treated with rivaroxaban ≤14 days of transient ischemic attack or ischemic stroke (National Institute of Health Stroke Scale <9). All patients underwent magnetic resonance imaging <24 hours of rivaroxaban initiation and day 7. The primary end point was symptomatic HT at day 7. RESULTS: Sixty patients (mean±SD age 71±19 years, 82% stroke/18% transient ischemic attack) were enrolled. Median (interquartile range) time from onset to rivaroxaban was 3 (5) days. At treatment initiation, median National Institute of Health Stroke Scale was 2 (4), and median diffusion-weighted imaging volume was 7.9 (13.7) mL. At baseline, HT was present in 25 (42%) patients (hemorrhagic infarct [HI]1=19, HI2=6). On follow-up magnetic resonance imaging, no patients developed symptomatic HT. New asymptomatic HI1 developed in 3 patients, and asymptomatic progression from HI1 to HI2 occurred in 5 patients; otherwise, HT remained unchanged at day 7. CONCLUSIONS: These data support the safety of rivaroxaban initiation ≤14 days of mild-moderate cardioembolic stroke/transient ischemic attack. Magnetic resonance imaging evidence of petechial HT, which is common, does not appear to increase the risk of symptomatic HT.

A favorable outcome despite a 39-hour treatment delay for arterial gas embolism: case report.

Cerebral arterial gas embolism (CAGE) occurs when gas enters the cerebral arterial vasculature. CAGE can occur during sitting craniotomies, cranial trauma or secondary to gas embolism from the heart. A far less common cause of CAGE is vascular entrainment of gas during endoscopic procedures. We present the case of a 49-year-old male who developed a CAGE following an esophagoduodenoscopy (EGD) biopsy. Due to a delay in diagnosis, the patient was not treated with hyperbaric oxygen (HBO2) therapy until 39 hours after the inciting event. Despite presenting to our institution non-responsive and with decorticate posturing, the patient was eventually discharged to a rehabilitation facility, with only mild left upper extremity weakness. This delay in HBO2 treatment represents the longest delay in treatment to our knowledge for a patient suffering from CAGE secondary to EGD. In addition to the clinical case report, we discuss the etiology of CAGE and the evidence supporting early HBO2 treatment, as well as the data demonstrating efficacy even after considerable treatment delay.

Cerebral Lipiodol Embolism in Hepatocellular Carcinoma Patients Treated with Transarterial Embolization/Chemoembolization.

BACKGROUND AND PURPOSE: Liver cancer is the third leading cause of cancer mortality worldwide. The aim of this study was to investigate the frequency and characteristics of cerebral lipiodol embolism (CLE) in patients with hepatocellular carcinoma (HCC) receiving transarterial embolization/chemoembolization (TAE/TACE). METHODS: We reviewed all HCC patients who received TAE/TACE during the period of 2007 and 2013 at a university medical center. The frequency of CLE per procedure and the clinical manifestations of CLE, including the review of previous reported cases (n = 24), were analyzed. RESULTS: During the study period, a total of 7855 TAE/TACE procedures were conducted on 3277 patients. There were 8 patients (mean age 59±11 years; 5 males and 3 females) who developed CLE. The frequency of TAE/TACE-related CLE was 1.02 (95% CI, 0.44-2.01) per 1000 procedures. Acute disturbance of consciousness and respiratory distress after TAE/TACE were the most common presentations of CLE. All patients had disseminated infarcts involving both the anterior and posterior cerebral circulations. For 3 patients with shunting between the tumor feeding artery and the pulmonary vein, a specific imaging pattern of coexisting scattered hyperdense spots was found. Furthermore, combined with our 8 cases, the total of 32 cases indicated that old age and female sex were the two risk factors for poor outcome after CLE. CONCLUSIONS: CLE is a rare but potentially serious complication in HCC patients receiving TAE/TACE. The clinical characteristics of CLE summarized in our study would help facilitate the ability of clinicians to provide timely diagnosis and management.

High-intensity focused ultrasound (HIFU) for dissolution of clots in a rabbit model of embolic stroke.

It is estimated that only 2-6% of patients receive thrombolytic therapy for acute ischemic stroke suggesting that alternative therapies are necessary. In this study, we investigate the potential for high intensity focused ultrasound (HIFU) to initiate thrombolysis in an embolic model of stroke. Iron-loaded blood clots were injected into the middle cerebral artery (MCA) of New Zealand White rabbits, through the internal carotid artery and blockages were confirmed by angiography. MRI was used to localize the iron-loaded clot and target the HIFU beam for treatment. HIFU pulses (1.5 MHz, 1 ms bursts, 1 Hz pulse repetition frequency, 20 s duration) were applied to initiate thrombolysis. Repeat angiograms and histology were used to assess reperfusion and vessel damage. Using 275 W of acoustic power, there was no evidence of reperfusion in post-treatment angiograms of 3 rabbits tested. In a separate group of animals, 415 W of acoustic power was applied and reperfusion was observed in 2 of the 4 (50%) animals treated. In the last group of animals, acoustic power was further increased to 550 W, which led to the reperfusion in 5 of 7 (∼70%) animals tested. Histological analysis confirmed that the sonicated vessels remained intact after HIFU treatment. Hemorrhage was detected outside of the sonication site, likely due to the proximity of the target vessel with the base of the rabbit skull. These results demonstrate the feasibility of using HIFU, as a stand-alone method, to cause effective thrombolysis without immediate damage to the targeted vessels. HIFU, combined with imaging modalities used to identify and assess stroke patients, could dramatically reduce the time to achieve flow restoration in patients thereby significantly increasing the number of patients which benefit from thrombolysis treatments.

Cerebral venous air embolism treated with hyperbaric oxygen: a case report.

We present a case of cerebral venous gas embolism. Our patient made a complete neurological recovery after hyperbaric oxygen therapy (HBOT). The principles of HBOT, compressing and eliminating air bubbles and decreasing Β-2 integrin function, thus improving microcirculation, can only be beneficial in a situation where neurological damage is likely. Retrograde cerebral venous gas embolism is a less well recognised variant of gas embolism than the arterial variant. Its existence as a different entity is better recognised in the forensic medicine and radiology literature than in other disciplines. There is evidence in the literature of patients dying from this complication and others seemingly experiencing very little effect. This case report highlights this condition, to encourage others to look out for it and report outcomes, and to serve as a reminder that peripheral lines may be a potential cause of gas embolism, although the portal of air entry in our case remains uncertain.

Cerebral lipiodol embolism proven by dual-energy computed tomography: a case report.

We report a case of cerebral lipiodol embolism after transarterial chemoembolization of hepatocellular carcinoma, which was confirmed by dual-energy computed tomography (CT). A 44-year-old male patient developed left leg weakness after transarterial chemoembolization for hepatocellular carcinoma. The noncontrast CT scan of his brain revealed multiple high-attenuating lesions scattered along the gyral surface of the both cerebral hemispheres; meanwhile, the lesions disappeared on the iodine-removed virtual noncontrast images generated from dual-energy CT.

[Cerebral lipiodol embolism after transcatheter arterial chemoembolization of hepatocellular carcinoma].

Transcatheter arterial chemoembolization (TACE) is the mainstay of treatment for unresectable hepatocellular carcinoma (HCC). Although various complications of TACE have been reported, cerebral lipiodol embolism after TACE is rare. We report a 67-year-old man, who had patent foramen ovale and developed cerebral lipiodol embolism after TACE via the inferior phrenic artery. At 20 months after third TACE of 3 cm sized HCC in the left hepatic lobe, computed tomography (CT) revealed about 1.6 cm newly developed HCC in the anterior superior segment of right hepatic lobe. The angiogram revealed the HCC was supplied from the right inferior phrenic artery. Toward the end of TACE, there were accumulations of the iodized oil in the pulmonary vasculature. Immediately after TACE, he complained of weakness in right upper and lower limbs and sensory decrease in right limbs and right hemitrunk. Magnetic resonance imaging revealed a cerebral lipiodol embolism. Transesophageal echocardiography revealed no visible thrombi but contrast-echocardiography using hand agitated saline revealed an intracardiac right to left shunt consistent with patent foramen ovale. Motor weakness and sensory decrease were gradually improved, and all neurological symptoms disappeared over 4 weeks.