Neurologic safety event rates in the SENTIS trial control population.

BACKGROUND: Adverse event (AE) rates for interventional stroke trials are not well established. AIMS: We prospectively evaluated control arm AEs from a randomized stroke trial to establish expected rates of neurologic AEs. METHODS: Control data from the Safety and Efficacy of NeuroFlo Technology in Ischemic Stroke (SENTIS) Trial were evaluated. Patients were ≥ 18 years with National Institutes of Health Stroke Scale (NIHSS) scores 5-18 within 14 h of stroke onset. Follow-up was 90 days. Neurological AEs and serious AEs (SAEs) were adjudicated and the following defined times used to determine treatment relatedness: 24-h imaging for intracranial hemorrhage (ICnH) including hemorrhagic transformation, 7 days each for cerebral edema and neurologic worsening/stroke progression, and 30 days for new ischemic strokes. RESULTS: The control group included 257 patients, 49.4% female, mean age of 68.3 years, and median NIHSS of 10. Neurologic AEs occurred at the following rates: ICnH 27.6%, cerebral edema 6.6%, neurologic worsening 18.3%, and new stroke 4.7%. Most of these events occurred within the defined times: ICnH 74.6%, cerebral edema 94.1%, neurologic worsening 87.2%, and new stroke 83.3%. CONCLUSIONS: SENTIS Trial control arm neurologic events provide estimates of expected AE rates and defined times that can be used for future stroke trial's safety assessments.

Endovascular mechanical thrombectomy for the treatment of acute ischemic stroke due to arterial dissection.

Arterial dissections account for 2% of strokes in all age groups, and up to 25% in patients aged 45 years or younger. The safety of endovascular intervention in this patient population is not well characterized. We identified all patients in the Merci registry - a prospective, multi-center post-market database enrolling patients treated with the Merci Retriever thrombectomy device - with arterial dissection as the most likely stroke etiology. Stroke presentation and procedural details were obtained prospectively; data regarding procedural complications, intracerebral hemorrhage (ICH), and the use of stenting of the dissected artery were obtained retrospectively. Of 980 patients in the registry, ten were identified with arterial dissection (8/10 ICA; 2/10 vertebrobasilar). The median age was 48 years with a baseline NIH stroke scale score of 16 and median time to treatment of 4.9 h. The procedure resulted in thrombolysis in cerebral ischemia (TICI) scores of 2a or better in eight out of ten and TICI 2b or better in six out of ten patients. Stenting of the dissection was performed in four of nine (44%). The single complication (1/9; 11%) - extension of a dissected carotid artery - was treated effectively with stenting. No symptomatic ICH or stroke in a previously unaffected territory occurred. A favorable functional outcome was observed in eight out of ten patients. Despite severe strokes on presentation, high rates of recanalization (8/10) and favorable functional outcomes (8/10) were observed. These results suggest that mechanical thrombectomy in patients with acute stroke resulting from arterial dissection is feasible, safe, and may be associated with favorable functional outcomes.

Higher degrees of recanalization after mechanical thrombectomy for acute stroke are associated with improved outcome and decreased mortality: pooled analysis of the MERCI and Multi MERCI trials.

BACKGROUND AND PURPOSE: Although the combined end point of partial and complete recanalization is a well-established predictor of good outcome following acute stroke intervention, few investigations have evaluated the effect of the degree of recanalization. We hypothesized that greater degrees of recanalization would be associated with a higher likelihood of favorable functional outcomes. MATERIALS AND METHODS: Data from MERCI and Multi MERCI-prospective single-arm trials of endovascular mechanical thrombectomy for acute stroke-were pooled. The TIMI score was used to define the degree of recanalization, and a favorable outcome was defined as an mRS score of 0-2 at 90 days. RESULTS: A total of 305 patients were included. Age, stroke severity, and site of arterial occlusion did not differ among groups stratified by the TIMI score. The unadjusted OR for a favorable outcome increased significantly as the TIMI score increased from 0 to 1 (OR, 5.9; 95% CI, 1.7-20.0; P = .007) and from 2 to 3 (OR. 2.3; 95% CI, 1.2-4.5; P = .01) and the likelihood of death decreased significantly as the TIMI score increased from 2 to 3 (OR, 2.2; 95% CI, 1.1-4.3; P = .05). In multivariate analysis, each increase in TIMI grade increased the odds of a good outcome 2.6-fold (95% CI, 1.9-3.4, P < .0001). CONCLUSIONS: Increases in the TIMI score were highly associated with improved outcomes. This finding not only provides additional evidence that restoration of blood flow improves clinical outcomes in ischemic stroke but also suggests that interventionalists should strive for complete revascularization when they provide endovascular treatment for acute ischemic stroke.

Drug eluting stents for symptomatic intracranial and vertebral artery stenosis.

The use of bare metal stents (BMS) to prevent recurrent stroke due to stenosis of the cerebral vasculature is associated with high rates of restenosis. Drug-eluting stents (DES) may decrease this risk. We evaluated the performance of DES in a cohort of patients treated at our institution.Consecutive patients treated with DES were identified by a case log and billing records; data regarding procedural details, clinical outcome and angiographic follow-up was obtained by retrospective chart review.Twenty-six patients (27 vessels; 14 vertebral origin (VO); 13 intracranial) were treated. Stenosis was reduced from mean 81% to 8% at the VO and 80% to 2% intracranially. No strokes occurred in the first 24 hours after stenting or at any time point in the VO group during a mean follow-up period of nine months. Among patients with intracranial stents, stroke with permanent disability occurred within 30 days in 1/12 (8%) and after 30 days in 1/11 (9%) with clinical follow-up (mean follow-up, 14 months). Follow-up catheter angiography was obtained in 14/14 (100%) in the VO group at mean eight months and in 8/11 surviving patients (73%) at a mean of ten months after stenting in the intracranial group. The restenosis rate was 21% at the VO (3/14) and 38% (3/8) for intracranial stents. Restenosis at the VO was less frequent than might have been expected from reports utilizing BMS, however, overall restenosis rates appeared higher than previously reported for patients with intracranial DES and comparable with restenosis rates for intracranial BMS.

Risk factors associated with major cerebrovascular complications after intracranial stenting.

BACKGROUND: There are limited data on the relationship between patient and site characteristics and clinical outcomes after intracranial stenting. METHODS: We performed a multivariable analysis that correlated patient and site characteristics with the occurrence of the primary endpoint (any stroke or death within 30 days of stenting or stroke in the territory of the stented artery beyond 30 days) in 160 patients enrolled in this stenting registry. All patients presented with an ischemic stroke, TIA, or other cerebral ischemic event (e.g., vertebrobasilar insufficiency) in the territory of a suspected 50-99% stenosis of a major intracranial artery while on antithrombotic therapy. RESULTS: Cerebral angiography confirmed that 99% (158/160) of patients had a 50-99% stenosis. In multivariable analysis, the primary endpoint was associated with posterior circulation stenosis (vs anterior circulation) (hazard ratio [HR] 3.4, 95% confidence interval [CI] 1.2-9.3, p = 0.018), stenting at low enrollment sites (< 10 patients each) (vs high enrollment site) (HR 2.8, 95% CI 1.1-7.6, p = 0.038), < or = 10 days from qualifying event to stenting (vs > or = 10 days) (HR 2.7, 95% CI 1.0-7.8, p = 0.058), and stroke as a qualifying event (vs TIA/other) (HR 3.2, 95% CI 0.9-11.2, p = 0.064). There was no significant difference in the primary endpoint based on age, gender, race, or percent stenosis (50-69% vs 70-99%). CONCLUSIONS: Major cerebrovascular complications after intracranial stenting may be associated with posterior circulation stenosis, low volume sites, stenting soon after a qualifying event, and stroke as the qualifying event. These factors will need to be monitored in future trials of intracranial stenting.

The NIH registry on use of the Wingspan stent for symptomatic 70-99% intracranial arterial stenosis.

BACKGROUND: The Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial showed that patients with symptomatic 70% to 99% intracranial arterial stenosis are at particularly high risk of ipsilateral stroke on medical therapy: 18% at 1 year (95% CI = 3% to 24%). The Wingspan intracranial stent is another therapeutic option but there are limited data on the technical success of stenting and outcome of patients with 70% to 99% stenosis treated with a Wingspan stent. METHODS: Sixteen medical centers enrolled consecutive patients treated with a Wingspan stent in this registry between November 2005 and October 2006. Data on stenting indication, severity of stenosis, technical success (stent placement across the target lesion with <50% residual stenosis), follow-up angiography, and outcome were collected. RESULTS: A total of 129 patients with symptomatic 70% to 99% intracranial stenosis were enrolled. The technical success rate was 96.7%. The mean pre and post-stent stenoses were 82% and 20%. The frequency of any stroke, intracerebral hemorrhage, or death within 30 days or ipsilateral stroke beyond 30 days was 14.0% at 6 months (95% CI = 8.7% to 22.1%). The frequency of >or=50% restenosis on follow-up angiography was 13/52 (25%). CONCLUSION: The use of a Wingspan stent in patients with severe intracranial stenosis is relatively safe with high rate of technical success with moderately high rate of restenosis. Comparison of the event rates in high-risk patients in Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) vs this registry do not rule out either that stenting could be associated with a substantial relative risk reduction (e.g., 50%) or has no advantage compared with medical therapy. A randomized trial comparing stenting with medical therapy is needed.

Potential of anticytokine therapies in central nervous system ischaemia.

Central nervous system (CNS) ischaemia is associated with an acute inflammatory response which appears to potentiate CNS injury, especially following reperfusion. This response includes the release of inflammatory mediators called cytokines including IL-1 and TNF-alpha, which triggers the production of additional cytokines including IL-6 and activates leukocytes which infiltrate into the CNS. Increased expression of cytokines has been demonstrated to occur in the first few hours after CNS ischaemia. Preliminary clinical studies suggest that plasma levels of IL-6 are correlated with functional recovery while brain levels of cytokines have been demonstrated to increase following experimental ischaemia. Although there are no current clinical 'anti-cytokine' treatment studies for stroke, experimental studies modulating IL-1 and TNF-alpha have shown neuroprotection.

Localizing acute stroke-related EEG changes: assessing the effects of spatial undersampling.

Because of its sensitivity to metabolic and ionic disturbances related to ischemia, the EEG can be a potentially useful tool for acute stroke detection and for monitoring affected tissue. However, the clinical use of the EEG in detecting stroke is determined in part by how accurately the spatial information is characterized. The purpose of the current study was to determine the effects of spatial undersampling on the distribution and interpretation of the stroke-related topographic EEG. Using a 128-channel sensor montage, EEG was recorded from six stroke patients acutely (between 8 and 36 hours) after symptom onset. The EEG was submitted to a spectral analysis and was compared with patient symptoms and MRI and computed tomographic findings. To determine loss of spatial and clinical information resulting from spatial undersampling, the average-referenced data from the original 128-channel recording montage were subsampled into 64-, 32-, and 19-channel arrays. Furthermore, the analytical findings were compared with a board-certified electroencephalographer's review of the raw EEG using a conventional clinical montage. As predicted, the results showed that accurate description of stroke-related topographic EEG changes is dependent on adequate spatial sampling density. Accurate description of the spatial distribution of the stroke-related EEG was achieved only with the 64- and 128-channel EEG. As the recording density decreases to 32 channels, the distribution of the scalp EEG spectra is distorted, potentially resulting in mislocalization of the affected region. Results of the clinical review by an expert electroencephalographer corroborated the quantitative analyses, and the results also demonstrated the shortcomings of the conventional 10-20 recording density for capturing focal EEG abnormalities in several cases. The EEG provides useful information about the localization of acute cerebral ischemia, but recording densities of 64 channels or higher are required for accurate spatial characterization of focal stroke-related EEG changes.

Does reversal of ischemia on diffusion-weighted imaging reflect higher apparent diffusion coefficient values?

This study investigated whether ischemia on diffusion-weighted imaging (DWI) that reverses has higher apparent diffusion coefficients (ADCs). A patient treated with thrombolytics was evaluated with serial magnetic resonance imaging studies before treatment, at 3 and 14 days and at 4 weeks. A 100.01-cm3 left frontoparietal stroke on baseline DWI was only 18.11 cm3 (18%) on 4-week fluid attenuated inversion recovery. The mean ADC was 7.43 x 10(-3) mm2/s in the 6 regions that reversed and 7.31 x 10(-3) mm2/s in the 6 regions that persisted (P < .036). With thrombolytic treatment, large ischemic lesions on DWI may reverse, and these areas display higher mean ADCs.

Current status of neuroprotective agents in the treatment of acute ischemic stroke.

To keep ischemic brain cells alive, neuroprotective agents target events in the ischemic cascade that might be injurious to the cells. They can be divided broadly into groups that restore ion balance, block receptors, prevent reperfusion injury, or promote neuronal healing. To date, neuroprotective agents have either shown a lack of efficacy in clinical stroke trials or been limited by side effects. Ongoing clinical trials with novel agents are trying to enroll a more homogeneous population of stroke patients in an effort to demonstrate treatment benefit.

An update of neuroprotectants in clinical development for acute stroke.

Neuroprotectants are drugs designed to treat stroke by preserving ischemic neurons in the penumbra. Despite numerous studies over the past ten years, no such drug has yet shown clinical efficacy. This article reviews those trials completed since 1999, including assessments of drugs that modify receptors or ion flow, block leukocyte adhesion receptors or stabilize membranes. In addition, ongoing trials and early trials using novel mechanisms of action, such as hypothermia and antioxidants, are discussed.

Association of intracranial stenosis with cortical symptoms or signs.

The association of the presence of cortical symptoms or signs and anterior circulation intracranial stenosis in patients with anterior circulation ischemia and no known extracranial carotid or cardiac etiology was studied. Fifteen percent (5/33) of patients with cortical symptoms or signs had symptomatic intracranial stenosis of 50% or more by MR angiography or angiography, compared with 0% (0/15) of those without such findings (p < 0.005).

Emergi-paths and stroke teams: an emergency department approach to acute ischemic stroke.

In patients with early acute ischemic stroke (AIS), studies have shown improved recovery rates when thrombolytic therapy is appropriately initiated. However, in clinical practice, there are several barriers to rapid patient evaluation and drug administration. To facilitate the management of this population, an AIS clinical pathway, Emergi-path, was developed. Initiated at the time of the patients' arrival to the emergency department, Emergi-path provides a step-by-step guide for early care of AIS patients. A citywide stroke team plays an integral role in this process by responding to stroke codes. Implementation of an AIS pathway and activation of an organized team of stroke specialists can facilitate rapid evaluation and treatment of this high-risk population.

Benign angioedema after thrombolysis for acute stroke.

We present a case of acute angioedema after administration of recombinant tissue plasminogen activator (t-PA) for acute ischemic stroke. Our patient was treated with t-PA in accordance with the National Institute of Neurological Disorders and Stroke (NINDS) protocol, and subsequently developed angioedema of the lower lip that subsided within 2 hours. Five patients who required upper airway control after the use of t-PA for ischemic stroke have been reported in the literature. Although the outcome in our case was excellent, development of angioedema after t-PA administration is a potential complication of which treating physicians need to be aware.

Neuroprotection in acute ischaemic stroke. Current status and future potential.

Acute ischaemic strokes can potentially be treated by 2 different mechanisms: lysing the thrombus to enhance brain perfusion or salvaging brain tissue directly. Neuroprotective agents are designed to try to salvage brain tissue. They work either during acute ischaemia or during reperfusion, when additional brain injury may occur. Despite the completion of a number of clinical trials investigating neuroprotective agents that have various mechanisms of action, as yet no effective agent has been identified. Some drugs, such as N-methyl-D-aspartate (NMDA) receptor antagonists and anti-leucocyte adhesion agents, have been limited by adverse effects and drug reactions. However, the development of other agents in these classes that have better risk to benefit ratios may lead to an effective neuroprotective drug. Other drugs, including citicoline, clomethiazole and nalmefene, have more efficacy in certain patient subgroups than in the stroke population as a whole. Therefore, targeting these agents toward the groups in which they are most likely to work, such as patients with a certain size of stroke, may uncover efficacy. Encouragingly, a number of drugs that are in the early stages of development, such as YM 872, Bay X 3702 and BMS 204352, appear to offer new hope for neuroprotection.

Clinical acute stroke evaluation.

This article outlines the evaluation and management of acute stroke patients in the emergency room and during the acute stroke period. Although a few neurologic and metabolic processes can mimic stroke, a stroke can often be diagnosed and localized from the history and examination. The availability of a treatment that must be given within 3 hours of symptom onset, tissue plasminogen activator (tPA), necessitates that the initial evaluation be streamlined. The assessment of the potential tPA candidate requires specific attention to bleeding risks. All stroke patients benefit from interventions to limit complications in the acute period although in the thrombolytic-treated patient, blood pressures are managed more aggressively to prevent intracranial hemorrhage.

Medical treatment strategies: intravenous thrombolysis, neuronal protection, and anti-reperfusion injury agents.

This article reviews and critiques the use of intravenous tPA for acute stroke. Guidelines on which patients should receive tPA are proposed with a particular emphasis placed on onset time. The current status of other potential stroke therapies are also reviewed, including neuroprotective trials and agents designed to limit reperfusion injury.

Efficacy of intraarterial thrombolysis of basilar artery stroke.

BACKGROUND: Stroke from basilar artery (BA) occlusion is a devastating neurological event with reported mortality rates of up to 90%. This series reports our experience in 15 cases using intraarterial (IA) thrombolysis to treat basilar artery stroke at the Oregon Stroke Center. METHODS: Over a 4-year period, consecutive cases of basilar artery stroke were treated with IA urokinase (UK) if they met the following criteria: had a baseline National Institutes of Health Stroke Scale (NIHSS) score greater than 6; symptoms began within 48 hours; had no or minimal early infarct signs on computed tomography (CT) scan; and angiogram confirmed basilar occlusion. Patients were treated with UK infused via a microcatheter directly into the clot. Angiographic efficacy was assessed by a repeat angiogram at the end of infusion and clinical efficacy was determined by NIHSS evaluation at 48 hours and 3 months. RESULTS: Fifteen patients, mean age 59 (16 to 78) and baseline NIHSS of 30 (7 to 40), were treated at a mean of 12 hours (4 to 48). An average dose of 500,000 (150,000 to 1,250,000) units of UK was given over 1 to 2 hours. Excellent vessel recanalization occurred in 12 of 15 (80%) patients. All three cases without recanalization died within 48 hours (100%). Of the 12 patients with recanalization, 2 died (16.7%), whereas the 9 of 10 remaining had mild or moderate neurological deficits (mean NIHSS of 5) at 3 months. CONCLUSION: IA thrombolysis has the potential to decrease mortality and improve outcome in cases with severe basilar artery stroke even when administered after 6 hours.

Open label tissue plasminogen activator for stroke: the Oregon experience.

BACKGROUND: Tissue plasminogen activator (t-PA) is the first effective treatment for stroke. This study sought to explore the outcome of patients treated with t-PA in the community after approval of its use in the treatment of stroke in June, 1996. METHODS: All patients with acute stroke within the 6-hospital Oregon Stroke Center network were screened for potential t-PA treatment. Baseline and 24-hour outcome assessments were performed with the use of the National Institutes of Health Stroke Scale (NIHSS) and computed tomography (CT); 3-month outcome was evaluated by using the Modified Rankin scale. RESULTS: Thirty-three patients who met the criteria for t-PA therapy were treated within 3 hours of symptom onset. All but 2 strokes were in the anterior circulation; 48.5% were cardioembolic. The NIHSS scores at 24 hours after administration of t-PA (mean, 14.7) showed modest gains from baseline NIHSS scores (mean, 16.6). Twelve patients (36%) had minimal or no deficits at 3 months. Three patients (9%), all of whom had baseline NIHSS scores of 20 or more, had symptomatic intracranial hemorrhages, 2 of which were fatal (6%). CONCLUSION: This study shows the feasibility of treating acute stroke with t-PA in the community. The percentage of fully recovered patients at 3 months mirrored those in the National Institute of Neurologic Disorders and Stroke (NINDS) trial.