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.

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.

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.

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).

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.

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.

Modular organization of cognitive systems masked by interhemispheric integration.

After resection of the corpus callosum, V.J., a left-handed woman with left-hemisphere dominance for spoken language, demonstrated a dissociation between spoken and written language. In the key experiment, words flashed to V.J.'s dominant left hemisphere were easily spoken out loud, but could not be written. However, when the words were flashed to her right hemisphere, she could not speak them out loud, but could write them with her left hand. This marked dissociation supports the view that spoken and written language output can be controlled by independent hemispheres, even though before her hemispheric disconnection, they appeared as inseparable cognitive entities.

Clinical utility of diffusion-weighted magnetic resonance imaging in the assessment of ischemic stroke.

Diffusion-weighted imaging (DWI) detects small changes in water diffusion that occur in ischemic brain. This study evaluated the clinical usefulness of a phase-navigated spin-echo DWI sequence compared with T2-weighted magnetic resonance imaging (T2W MRI) in patients with cerebral ischemia and assessed apparent diffusion coefficient (ADC) and T2-weighted imaging (T2WI) changes over time. ADC values and T2 ratios of image intensity were measured from the region of ischemia and from the corresponding contralateral brain region. The clinical histories of patients with DWI scans obtained over the course of 1 year were reviewed to ascertain whether DWI aided in clinical diagnosis or management. Of 103 scans obtained a mean of 10.4 days after symptom onset, DWI detected six lesions not seen on T2WI and discriminated two new infarcts from old lesions. DWI was most useful within 48 hours of the ictus. The evolution of ADC values and T2 ratios was evaluated in 26 cases with known symptom onset times. ADC values were low at less than 1 week after stroke onset and became elevated at chronic time points. T2 ratios were near normal acutely, increasing thereafter. DWI was superior to T2W MRI in detecting acute stroke, whereas both techniques assisted in determining lesion age.

The therapeutic potential of anti-cytokine strategies 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, including the cytokines interleukin-1 (IL-1) and TNF-alpha. These trigger the production of additional cytokines, including IL-6, and activate leukocytes which infiltrate the CNS. IL-6 appears to play a central role in modulating this response, exhibiting both pro-inflammatory and anti-inflammatory activities. Preliminary clinical studies suggest that plasma levels of IL-6 are correlated with stroke size and functional recovery. Conversely, brain levels of cytokines have been demonstrated to increase following experimental ischaemia. Although there are at present no clinical ;anti-cytokine' treatment studies, experimental studies modulating cytokines have shown neuroprotection.

Cerebral and callosal organisation in a right hemisphere dominant "split brain" patient.

Patients described in previous reports who have undergone corpus callostomy for control of seizures have been left hemisphere dominant for language. To determine the hemispheric localisation (and possible coexistence) of language and traditional right hemisphere skills in reversed dominance, the first right hemisphere dominant corpus callostomy patient was studied. Localisation of callosal functions was also investigated, as MRI showed 1.5 cm of spared callosal body. The patient, KO, a 15 year old girl with familial left handedness, underwent two stage callosotomy in 1988. Lateralised visually presented stimuli requiring same or different comparisons between visual fields showed chance performance. Oral naming and reading showed better performance by the right hemisphere than the left, whereas both hemispheres were proficient in auditory comprehension. Active voice syntax was above chance only in the right hemisphere. Face recognition was significantly better in the right hemisphere than in the left. Tasks requiring tactile comparisons between hands showed above chance performance except in the instance in which the non-dominant right hand was stimulated first in a point localisation task between hands. This case showed hemispheric coexistence of language and traditional right hemispheric skills in a corpus callosotomy patient with reversed language dominance. Tactile transfer was localised to the mid-posterior callosal body.

Ultrastructural, morphometric, and immunocytochemical study of anterior horn cells in mice with "wasted" mutation.

Mice with the autosomal recessive gene "wasted" (wst/wst) manifest hindlimb paralysis and tremulousness, develop reduced secretory immune responses, and have abnormal DNA repair mechanisms. There is prominent vacuolar degeneration of neurons within anterior horns of the spinal cord and motor nuclei of the brainstem. A morphometric analysis of motor neurons in the spinal cord was performed on 2-hydroxyethyl methacrylate-embedded tissue from ten wst/wst mice, ten littermates (wst/+, +/+) without clinical deficits, and ten parental (+/+) control mice. Vacuolated neurons were present only in wst/wst mice (p = 0.0008). Fibrillary neurons were more numerous in the wst/wst mice than in littermates (p = 0.01) or controls (p = 0.007). The number of total or normal neurons did not differ significantly among the three groups. Volume measurements for normal, fibrillary, vacuolated, and total neurons were greater in wst/wst mice (p less than 0.008). Electron microscopic studies revealed vacuolar degeneration exclusively within neurons of wst/wst mice with the prominent accumulation of neurofilaments. Immunocytochemical staining of Araldite-embedded sections with monoclonal antibodies (MAb) to 68 kDa, 160 kDa, and 200 kDa neurofilament proteins showed prominent staining of vacuolated and fibrillary neurons in wst/wst mice exclusively with the MAb to 200 kDa neurofilaments. Dephosphorylation of tissue reduced the staining of 200 kDa neurofilaments in wst/wst mice. These studies suggest that phosphorylated neurofilaments may be important in events producing neuronal dysfunction. Therefore the "wasted" mutation may be an excellent model for the study of motor neuron disease.