Faculty Bibliography

BACKGROUND:In A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA), randomisation was halted at a mean follow-up of 33·3 months after a prespecified interim analysis showed that medical management alone was superior to the combination of medical management and interventional therapy in preventing symptomatic stroke or death. We aimed to study whether these differences persisted through 5-years' follow-up. METHODS:ARUBA was a non-blinded, randomised trial done at 39 clinical centres in nine countries. Adults (age ≥18 years) diagnosed with an unruptured brain arteriovenous malformation, who had never undergone interventional therapy, and were considered by participating clinical centres to be suitable for intervention to eradicate the lesion, were eligible for inclusion. Patients were randomly assigned (1:1) by a web-based data collection system, stratified by clinical centre in a random permuted block design with block sizes of two, four, and six, to medical management alone or with interventional therapy (neurosurgery, embolisation, or stereotactic radiotherapy, alone or in any combination, sequence, or number). Although patients and investigators at a given centre were not masked to treatment assignment, investigators at other centres and those in the clinical coordinating centre were not informed of assignment or outcomes at any of the centres. The primary outcome was time to death or symptomatic stroke confirmed by imaging, assessed by a neurologist at each centre not involved in the management of participants' care, and monitored by an independent committee using an adaptive approach with interim analyses. Enrolment began on April 4, 2007, and was halted on April 15, 2013, after which follow-up continued until July 15, 2015. All analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00389181. FINDINGS:Of 1740 patients screened, 226 were randomly assigned to medical management alone (n=110) or medical management plus interventional therapy (n=116). During a mean follow-up of 50·4 months (SD 22·9), the incidence of death or symptomatic stroke was lower with medical management alone (15 of 110, 3·39 per 100 patient-years) than with medical management with interventional therapy (41 of 116, 12·32 per 100 patient-years; hazard ratio 0·31, 95% CI 0·17 to 0·56). Two patients in the medical management group and four in the interventional therapy group (two attributed to intervention) died during follow-up. Adverse events were observed less often in patients allocated to medical management compared with interventional therapy (283 vs 369; 58·97 vs 78·73 per 100 patient-years; risk difference -19·76, 95% CI -30·33 to -9·19). INTERPRETATION:After extended follow-up, ARUBA showed that medical management alone remained superior to interventional therapy for the prevention of death or symptomatic stroke in patients with an unruptured brain arteriovenous malformation. The data concerning the disparity in outcomes should affect standard specialist practice and the information presented to patients. The even longer-term risks and differences between the two therapeutic approaches remains uncertain. FUNDING:National Institute of Neurological Disorders and Stroke for the randomisation phase and Vital Projects Fund for the follow-up phase.

In acute ischemic stroke, early recanalization of the occluded artery is crucial for best outcome to be achieved. Recanalization aims at restoring blood flow to the ischemic tissue (reperfusion) and is achieved with pharmacological thrombolytic drugs, endovascular thrombectomy (EVT) devices, or both. The introduction of modern endovascular devices has led to tremendous anatomical and clinical success with rates of substantial reperfusion exceeding 80% and proven clinical benefit in patients with anterior circulation large vessel occlusions (LVOs). However, not every successful reperfusion procedure leads to the desired clinical outcome. In fact, the rate of non-disabled outcome at 3 months with current EVT treatment is ~1 out of 4. A constraint upon better outcomes is that reperfusion, though resolving ischemic stress, may not restore the anatomic structures and metabolic functions of ischemic tissue to their baseline states. In fact, ischemia triggers a complex cascade of destructive mechanisms that can sometimes be exacerbated rather than alleviated by reperfusion therapy. Such reperfusion injury may cause infarct progression, intracranial hemorrhage, and unfavorable outcome. Therapeutic hypothermia has been shown to have a favorable impact on the molecular elaboration of ischemic injury, but systemic hypothermia is limited by slow speed of attaining target temperatures and clinical complications. A novel approach is endovascular delivery of hypothermia to cool the affected brain tissue selectively and rapidly with tight local temperature control, features not available with systemic hypothermia devices. In this perspective article, we discuss the possible benefits of adjunctive selective endovascular brain hypothermia during interventional stroke treatment.

Reperfusion is the first line of care in a growing number of eligible acute ischemic stroke patients. Early reperfusion with thrombolytic drugs and endovascular mechanical devices is associated with improved outcome and lower mortality rates compared with natural history. Reperfusion is not without risk, however, and may result in reperfusion injury, which manifests in hemorrhagic transformation, brain edema, infarct progression, and neurologic worsening. In this article, the functional and structural changes and underlying molecular mechanisms of ischemia and reperfusion are reviewed. The pathways that lead to reperfusion injury and novel neuroprotective strategies with endogenous properties are discussed.

Selective brain hypothermia is a powerful concept for neuroprotection that has been successfully investigated in a variety of animal models of global and focal ischemia. Its major advantages over systemic hypothermia include rapid induction of cooling, ability to achieve profound target brain temperatures, organ-selective cooling, and temperature control. Clinical systems and devices are available or are currently under development that utilize conductive (surface-cooling pads, closed-loop catheters), convective (transnasal coolant delivery), or mass and energy transport (cold intra-arterial infusion) methods to achieve and maintain selective brain hypothermia. The "ideal" brain-cooling system that is characterized by rapid cooling to profound hypothermia, its ability to maintain selective cooling over several days, and is noninvasive in nature, remains unrealistic. Instead, systems may be identified by their distinct advantages to meet a specific need in the care of a patient. This involves the consideration of the timing of ischemic injury (preischemic, intraischemic, postischemic), extent of ischemic damage (excitotoxicity, inflammation, necrosis, edema), and type and setting of therapeutic intervention (intensive care, interventional therapy, surgery). The successful translation of these systems into clinical practice will depend on smart engineering, safety and efficacy, and usability in current clinical work flow.

OBJECTIVE:To investigate the effects of medical vs interventional management on functional outcome in A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA). METHODS:We used the initial results of a nonblinded, randomized, controlled, parallel-group trial involving adults ≥18 years of age with an unruptured brain arteriovenous malformation (AVM) to compare the effects of medical management (MM) with or without interventional therapy (IT) on functional impairment, defined by a primary outcome of death or symptomatic stroke causing modified Rankin Scale (mRS) score ≥2. ARUBA closed recruitment on April 15, 2013. RESULTS:< 0.001). CONCLUSION/CONCLUSIONS:Death or stroke with functional impairment in ARUBA after a median follow-up of 33 months was significantly lower for those in the MM arm both as randomized and as treated compared with those with IT. Functional severity of outcomes was lower in the MM arm, regardless of Spetzler-Martin grades. CLINICALTRIALSGOV IDENTIFIER/UNASSIGNED:NCT00389181. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class II evidence that for adults with unruptured brain AVMs, interventional management compared to MM increases the risk of disability and death over ≈3 years.

BACKGROUND:The choice of an animal model for cerebrovascular research is often determined by the disease subtype to be studied (e.g. ischemic stroke, hemorrhage, trauma), as well as the nature of the intervention to be tested (i.e. medical device or pharmaceutical). Many initial studies are performed in smaller animals, as they are cost-effective and their encephalic vasculature closely models that of humans. Non-human primates are also utilized when confirmation or validation is required on higher levels and to test larger devices. However, working with primates is complex and expensive. Intermediate sized animal models, such as swine and sheep, may represent a valuable compromise. Their cerebrovascular anatomy, however, comes with challenges because of the natural higher external carotid artery perfusion and the existence of a rete mirabile. We describe a modification to the traditional swine cerebrovascular model that significantly enhances selective brain hemispheric perfusion, limiting external carotid perfusion and dilution. RESULTS:We investigated whether unilateral endovascular coil-embolization of external carotid artery branches in swine would lead to increased brain perfusion, altering cerebral circulation so that it more closely models human cerebral circulation. Equal amounts of approximately 4 °C cold saline were injected in 6 Yorkshire pigs into the ipsilateral common carotid artery before and after embolization. Hemispheric temperature changes from pre- and post-embolization were obtained as a measure of brain perfusion and averaged and compared using non-parametric statistical tests (Wilcoxon signed rank test, Mann-Whitney U Test). Graphs were plotted with absolute changes in hemispheric temperature over time to determine peak temperature drop (PTD) and corresponding time to peak (TTP) following the cold bolus injection. There was a 288 ± 90% increase in ipsilateral brain cooling after embolization indicating improved selective blood flow to the brain due to this vascular modification. CONCLUSION/CONCLUSIONS:We have developed an effective, selective vascular brain model in swine that may be useful as a practical and cost-reducing intermediate step for evaluating target dose-responses for central nervous system drugs and brain selective interventions, such as local hypothermia.

Dural arteriovenous fistulas (DAVFs) may occur anywhere there is a dural or meningeal covering around the brain or spinal cord. Clinical manifestations are mostly related to venous hypertension, and may be protean, acute or chronic, ranging from minor to severe, from non-disabling tinnitus to focal neurological deficits, seizures, hydrocephalus, psychiatric disturbances, and developmental delay in pediatric patients. Although low-grade lesions may have a benign course and spontaneous involution may occasionally occur (i.e. cavernous sinus DAVFs), the risk of hemorrhage is considerable in high grade lesions. Angiographic features of DAVFs have been clarified since the 1970s when venous drainage pattern was clearly identified as the most significant risk predictor and as a major determinant of success or failure of treatment. The mainstay of therapy is interruption of arteriovenous shunting, which has traditionally been accomplished surgically. Currently, endovascular therapy is generally considered the first line of treatment, allowing elimination of the lesion in most patients, with surgery and stereotactic radiosurgery reserved for complex situations. This review discusses major aspects of DAVFs, including grading systems, clinical presentation, diagnostic evaluation, various issues impacting endovascular therapy, and pathophysiology.

OBJECTIVES/OBJECTIVE:The goals of the study were to assess US nationwide trends in hospital outcome following carotid endarterectomy (CEA) and carotid angioplasty and stenting (CAS) and to determine potential predictors of outcome. METHODS:The Nationwide Inpatient Sample, constituting a 20% representative and stratified sample of non-federal US hospitals, was analyzed retrospectively from years 1998 to 2007. RESULTS:The annual number of CEA decreased (137,877-111,658) and increased for CAS (2318-14,415). Inhospital mortality following CEA decreased from 0.4% to 0.3% (P < 0.001), whereas long-term facility (LTF) discharge increased from 8.2% to 10.5% (P < 0.001). Discharge outcome improved for CAS in both categories (mortality 2-0.5%; LTF discharge 10.7-8.3%; both P < 0.001). The trend analysis revealed an increase in patient age and a worsening comorbid profile over time. Age, women, length of stay, atrial fibrillation, and carotid stenosis with infarction were important determinants of unfavorable hospital outcome. CONCLUSION/CONCLUSIONS:From a nationwide practice perspective, the number of carotid revascularizations fell by 10%. CEA has resulted in stable hospital mortality rates. Meanwhile, CAS has been increasingly utilized with overall improvement in short-term outcome. Our results further suggest a decrease in the number of patients with treatment-eligible carotid disease over time. However, the increasing prevalence of high-risk comorbidity in the aging population may pose a challenge to revascularization strategies.

OBJECTIVES/OBJECTIVE:Nationwide practice patterns during the implementation of novel technology, such as carotid angioplasty and stenting (CAS) and embolic protection devices (EPD), and the clinical impact thereof have received less attention. METHODS:The Nationwide Inpatient Sample, constituting a 20% representative sample of non-federal US hospitals, was analyzed from years 1998 to 2007. Hospital outcome was stratified into in-hospital mortality (IHM), long-term facility discharge, and home/ short-term facility discharge (HSF). RESULTS:Discharge outcome improved for CAS over the decade. However, this improvement occurred in two phases with a period of worsening (2003-2005) in between. During this transition period, the risk of IHM following CAS was increased (RR 1.29-2.43) and was lower for good outcome (HSF: RR 0.97-0.99) when compared with 2002/2003. During the same transition period, carotid endarterectomy (CEA) was associated with a lower risk of IHM (RR 0.75-1.00), but also a lower risk of HSF (RR 0.98-0.99). CONCLUSIONS:The results lead to the hypothesis that the nationwide introduction of CAS-EPD may have been associated with temporary increases in in-hospital mortality and discharge morbidity. If such 'clinical opportunity costs' exist with the widespread introduction and adoption of new medical technology with proven efficacy in randomized trials, effective mechanisms are needed for mitigation or prevention during the transition period.

The feasibility of rapid cerebral hypothermia induction in humans with intracarotid cold saline infusion (ICSI) was investigated using a hybrid approach of jugular venous bulb temperature (JVBT) sampling and mathematical modeling of transient and steady state brain temperature distribution. This study utilized both forward mathematical modeling, in which brain temperatures were predicted based on input saline temperatures, and inverse modeling, where brain temperatures were inferred based on JVBT. Changes in ipsilateral anterior circulation territory temperature (IACT) were estimated in eight patients as a result of 10 min of a cold saline infusion of 33 ml/min. During ICSI, the measured JVBT dropped by 0.76±0.18°C while the modeled JVBT decreased by 0.86±0.18°C. The modeled IACT decreased by 2.1±0.23°C. In the inverse model, IACT decreased by 1.9±0.23°C. The results of this study suggest that mild cerebral hypothermia can be induced rapidly and safely with ICSI in the neuroangiographical setting. The JVBT corrected mathematical model can be used as a non-invasive estimate of transient and steady state cerebral temperature changes.