Brian Silver

Importance of Early Ischemic Computed Tomography Changes Using ASPECTS in NINDS rtPA Stroke Study

Background and Purpose— The importance of early ischemic change (EIC) on baseline computed tomography (CT) in the decision to thrombolyze the patient with acute ischemic stroke has been controversial. ASPECTS is a semiquantitative scale that scores the extent of EIC within the middle cerebral artery territory. We examined whether ASPECTS could be a treatment modifier by systematically reviewing the CT scans in the NINDS rtPA Stroke Study. Methods— Six hundred eight of the 624 CT scans were available and of sufficient quality. One of 2 teams (n=3 each) of expert ASPECTS readers evaluated each scan for an ASPECTS value using a consensus score approach. Each team was blind to all clinical information except symptom side and blind to follow-up imaging and outcome information. ASPECTS values were stratified before analysis. Multivariable logistic regression was used to determine if an ASPECTS by treatment interaction existed on treatment response, outcome, and intracerebral hemorrhage risk. Results— A total of 57.2% (348 of 608) of scans showed EIC with an ASPECTS <10. ASPECTS dichotomized into 8 to 10 and <8 did not have a treatment-modifying effect on good outcome but showed a trend to lower mortality at 90 days with tPA (relative risk 0.67, 95% confidence interval 0.41 to 1.06, P=0.10). ASPECTS 8 to 10 were associated with a trend to larger benefit of tPA with a number needed to treat (NNT) of 5 versus ASPECTS 3 to 7 with a NNT of 8. Conclusion— There was no evidence of treatment effect modification by the baseline ASPECTS value in the NINDS rtPA Stroke Study. Therefore, exclusion of patients for thrombolysis within 3 hours of symptom onset based on EIC is not supported by our data. There is a trend to reduced mortality and increased benefit to rtPA if the baseline CT scan is favorable (ASPECTS >7).

Is the Association of National Institutes of Health Stroke Scale Scores and Acute Magnetic Resonance Imaging Stroke Volume Equal for Patients With Right- and Left-Hemisphere Ischemic Stroke?

Background and Purpose— The National Institutes of Health Stroke Scale (NIHSS) is an established measure of neurological impairment; however, it can award more points for tests of presumed left-hemisphere function, such as language, than for tests of right-hemisphere function, such as neglect. This difference may be important if a low NIHSS score is used to exclude patients with right-hemisphere stroke from clinical trials or established treatments. The aim of this study was to investigate whether the relationship between acute NIHSS score and acute stroke volume as determined by acute diffusion- and perfusion-weighted MRI (DWI and PWI) differs between right- and left-sided stroke. Methods— This was a retrospective study of 153 patients with acute stroke seen at Beth Israel Deaconess Medical Center between January 1995 and March 2000 who underwent an MRI examination and NIHSS within 24 hours of stroke onset. NIHSS score was recorded prospectively by the admitting stroke fellow at the time of acute presentation, immediately preceding imaging. Computerized volumetric analysis of the MRI lesions was performed by investigators blinded to clinical data. Results— There were significant correlations between the acute NIHSS scores and acute DWI lesion volumes (r =0.48 right, r =0.58 left) and between acute NIHSS scores and perfusion-weight imaging hypoperfusion volumes (r =0.62 right, r =0.60 left). For patients with NIHSS scores of 0 to 5, the DWI volume of right cerebral lesions was greater than that of left-sided lesions (mean volume, 8.8 versus 3.2 cm3;P =0.04). Among patients with DWI lesions larger than the median volume (9 cm3), 8 of 37 with right-sided stroke had an NIHSS score of 0 to 5 compared with 1 of 39 patients with left-sided stroke (P =0.01). Multiple linear regression analysis revealed a significantly lower acute NIHSS on the right compared with the left side when adjusted for stroke volume on chronic T2 imaging (P =0.03). Conclusions— Patients with right-sided stroke may have a low NIHSS score despite substantial DWI lesion volume. Acute imaging information, such as that available with multimodal MRI, may be useful to identify patients for inclusion in acute stroke protocols when there is clinical uncertainty about eligibility. Prospective evaluation of criteria incorporating acute imaging data is required.

MRI detects white matter reorganization after neural progenitor cell treatment of stroke

We evaluated the effects of neural progenitor cell treatment of stroke on white matter reorganization using MRI. Male Wistar rats (n = 26) were subjected to 3 h of middle cerebral artery occlusion and were treated with neural progenitor cells (n = 17) or without treatment (n = 9) and were sacrificed at 5-7 weeks thereafter. MRI measurements revealed that grafted neural progenitor cells selectively migrated towards the ischemic boundary regions. White matter reorganization, confirmed histologically, was coincident with increases of fractional anisotropy (FA, P < 0.01) after stroke in the ischemic recovery regions compared to that in the ischemic core region in both treated and control groups. Immunoreactive staining showed axonal projections emanating from neurons and extruding from the corpus callosum into the ipsilateral striatum bounding the lesion areas after stroke. Fiber tracking (FT) maps derived from diffusion tensor imaging revealed similar orientation patterns to the immunohistological results. Complementary measurements in stroke patients indicated that FT maps exhibit an overall orientation parallel to the lesion boundary. Our data demonstrate that FA and FT identify and characterize cerebral tissue undergoing white matter reorganization after stroke and treatment with neural progenitor cells.

Tadalafil, a long-acting type 5 phosphodiesterase isoenzyme inhibitor, improves neurological functional recovery in a rat model of embolic stroke

Sildenafil, a type 5 phosphodiesterase isoenzyme (PDE5) inhibitor with a short half-life, increases brain cyclic guanosine monophosphate (cGMP) levels and improves neurological functional recovery when administered after stroke. In the present study, we investigated the effects of tadalafil (Cialis), a long acting PDE5 inhibitor, on brain cGMP levels, neurogenesis, angiogenesis, and neurological function during stroke recovery in a rat model of embolic stroke. Male Wistar rats (n=28) were subjected to embolic middle cerebral artery (MCA) occlusion. Tadalafil was orally administered every 48 h at a dose of 2 mg/kg or 10 mg/kg for 6 consecutive days starting 24 h after stroke onset. Control animals received the equivalent volume of saline at the same time points. For mitotic labeling, bromodeoxyuridine (BrdU, 100 mg/kg) was administered twice a day at 5, 6, and 7 days after stroke. ELISA assays were performed to evaluate the specificity of the effect of tadalafil on cGMP. Treatment with tadalafil at a dose of 2 or 10 mg/kg significantly improved neurological functional recovery compared with saline-treated rats. In addition, tadalafil treatment increased cerebral vascular density and the percentage of BrdU-positive endothelial cells around the ischemic boundary compared with saline-treated rats. Moreover, tadalafil-treated rats showed greater ipsilateral SVZ cell proliferation than saline-treated rats. However, treatment with tadalafil did not reduce infarct volume when compared to the saline group. Tadalafil selectively increased cGMP but not cyclic adenosine monophosphate (cAMP) in brain. Our data demonstrate that treatment of ischemic stroke with tadalafil improved functional recovery, which was associated with increases of brain cGMP levels and enhancement of angiogenesis and neurogenesis.

Importance of Leukoaraiosis on CT for Tissue Plasminogen Activator Decision Making: Evaluation of the NINDS rt-PA Stroke Study

Background: Leukoaraiosis is associated with microhemorrhages on T2*-weighted magnetic resonance imaging of the brain. Such hemorrhages have been postulated to be responsible for symptomatic intracerebral hemorrhage (ICH) after thrombolytic treatment. We examined the relationship between small-vessel ischemic disease and symptomatic ICH within the NINDS rt-PA Stroke Study. Methods: Baseline CT scans from the NINDS rt-PA Stroke Study were re-evaluated retrospectively by blinded expert CT readers using the van Swieten Score (vSS) for leukoaraiosis. The scale examined the severity of white-matter changes on 3 serial CT slices and graded separately for the 2 distinct regionsanterior and posterior to the central sulcus: 0 = no lesion, 1 = partlyinvolving the white matter, and 2 = extending up to the cortex. Results: 603 CT scans were interpreted. The risk of symptomatic ICH increased with higher vSS in both the placebo and treatment groups. The absolute risk of symptomatic hemorrhage was 7.9% in the rt-PA-treated cohort among patients with severe white-matter disease (vSS = 3–4) versus 2.9% receiving placebo. Among severe leukoaraiosis patients (vSS = 3–4), no differential treatment effect was seen with rt-PA patients achieving better outcomes than placebo, modified Rankin score 0–1 in 31.6% of rt-PA-treated versus 14.7% of placebo-treated patients. Conclusion: The results from the present study do not support the concept that leukoaraiosis present on baseline noncontrast CT scanning is critical to thrombolysis decision making in the first 3 h from symptom onset. No clear leukoaraiosis threshold was identified below which no benefit or harm could be seen from intravenous rt-PA therapy.

Medical therapy for ischemic stroke

Therapy for stroke is undergoing major changes. Many of the changes parallel the advances made in the therapy for myocardial infarction. Acute intervention with cytoprotective and thrombolytic agents is undergoing active investigation. Cytoprotective therapy includes drugs that act to prevent cell death during ischemia and reperfusion. These agents include calpain inhibitors, voltage-sensitive calcium- and sodium-channel antagonists, receptor-mediated calcium-channel antagonists [including N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) antagonists], glutamate-synthesis inhibitors, glutamate-release antagonists, gamma-aminobenzoic acid (GABA) antagonists, 5-HT (serotonin) receptor agonists, gangliosides, antioxidants, growth factors, antiapoptotic agents, and antiadhesion molecules. Thrombolysis is effective in myocardial infarction. Thrombolysis is undergoing evaluation in stroke with streptokinase, anisoylated plasminogen streptokinase activator complex (APSAC), tissue plasminogen activator (t-PA; including recombinant t-PA), urokinase, and single-chain urokinase (scu-PA). Both systemic and selective administration are being evaluated. Preventive therapy with both antiplatelet and anticoagulant drugs sheds new light on how best to stratify patients in terms of a risk-benefit ratio. Continuing public education will be essential as stroke therapy advances.

Safety of thrombolysis in acute ischemic stroke: a review of complications, risk factors, and newer technologies.

Intravenous recombinant tissue plasminogen activator (r-tPA) was approved for use in acute ischemic stroke in the United States in 1996. Approximately 2% to 5% of patients with acute ischemic stroke receive r-tPA. Complications related to intravenous r-tPA include symptomatic intracranial hemorrhage, major systemic hemorrhage, and angioedema in approximately 6%, 2%, and 5% of patients, respectively. Risk factors for symptomatic hemorrhage include age, male gender, obesity, increased stroke severity, diabetes, hyperglycemia, uncontrolled hypertension, combination antiplatelet use, large areas of early ischemic change, atrial fibrillation, congestive heart failure, and leukoariosis. A risk factor for angioedema is the use of angiotensin-converting enzyme inhibitor. Risk assessment scores, novel imaging strategies, and telemedicine may offer methods of optimizing the risk–benefit ratio.

Stroke After Coronary Artery Bypass : Incidence, Predictors, and Clinical Outcome Editorial Comment: Incidence, Predictors, and Clinical Outcome

Background and Purpose— Early postoperative stroke is a serious adverse event after coronary artery bypass grafting (CABG). This study sought to investigate risk factors, prevalence, and prognostic implications of postoperative stroke in patients undergoing CABG. Methods— We investigated the predictors of postoperative stroke (n=333, 2%) in 16 528 consecutive patients who underwent CABG between September 1989 and June 1999 in our institution. Predictors of postoperative stroke were identified by logistic regression analysis. Results— Among the preoperative and postoperative factors, significant correlates of stroke included (1) chronic renal insufficiency (P <0.001), (2) recent myocardial infarction (P =0.01), (3) previous cerebrovascular accident (P <0.001), (4) carotid artery disease (P <0.001), (5) hypertension (P <0.001), (6) diabetes (P =0.001), (7) age >75 years (P =0.008), (8) moderate/severe left ventricular dysfunction (P =0.01), (9) low cardiac output syndrome (P <0.001), and (10) atrial fibrillation (P <0.001). Postoperative stroke was associated with longer postoperative stay (11±4 versus 7±3 days for patients without stroke, P <0.001) and with higher in-hospital mortality (14% versus 2.7% for patients without stroke;P <0.001). Conclusions— Stroke after CABG is associated with high short-term morbidity and mortality. Increased stroke risk can be predicted by preoperative and postoperative clinical factors.

The Clinical and Radiographic Importance of Distinguishing Partial from Near-Complete Reperfusion Following Intra-Arterial Stroke Therapy

BACKGROUND AND PURPOSE: Reperfusion following intra-arterial stroke therapy is associated with improved clinical outcomes. However, the degree of reperfusion needed to achieve successful outcomes is unknown. The purpose of this analysis was to determine whether the degree of reperfusion has an impact on final infarct volumes and clinical outcomes. MATERIALS AND METHODS: A retrospective analysis identified 88 consecutive patients who underwent intra-arterial therapy for acute anterior circulation stroke. Reperfusion was graded by using the TICI scale into none (TICI 0 or 1), partial (TICI 2a), or near-complete (TICI 2b/3). Baseline characteristics were compared. For each of these groups, we compared discharge disposition and final infarct volumes. RESULTS: Near-complete, partial, and no reperfusion occurred in 44.3%, 26.1%, and 29.6% of patients, respectively. Baseline characteristics were similar across all 3 groups. The median NIHSS score was 15. Significant differences in discharge disposition were seen, with 41.0% of the TICI 2b/3 group discharged home versus 17.4% of TICI 2a and 7.7% of TICI 0/1. In-hospital mortality was 12.8% for TICI 2b/3 compared with 39.1% for TICI 2a and 34.6% for TICI 0/1. Patients with near-complete reperfusion were significantly more likely to have infarct volumes ≤70 mL (OR = 12.1; 95% CI, 2.7–54.2), compared with patients with partial reperfusion (OR = 2.2; 95% CI, 0.5–9.6). CONCLUSIONS: Significant differences exist in outcomes and infarct volumes between partial (TICI 2a) and near-complete (TICI 2b/3) reperfusion following intra-arterial stroke therapy. Further trials should separately report these groups to facilitate comparison among treatment paradigms.

Sildenafil Treatment of Subacute Ischemic Stroke: A Safety Study at 25-mg Daily for 2 Weeks

BACKGROUND In several animal studies of young and aged rats with ischemic stroke, treatment with sildenafil improved functional outcomes compared with placebo. We conducted a safety study of sildenafil (25 mg daily for 2 weeks) shortly after ischemic stroke onset. METHODS We recruited patients aged 18 to 80 years with ischemic stroke, National Institutes of Health stroke scale (NIHSS) score 2 to 21, between days 2 and 9 after symptom onset. Patients were treated with sildenafil for 2 weeks (25 mg daily). The primary outcome measure was the adverse occurrence of any of the following during the treatment period: stroke worsening, new stroke, myocardial infarction, vision loss, hearing loss, or death from any cause. Secondary outcome measures were NIHSS score, Barthel indices, and modified Rankin score at 90 days. RESULTS Twelve patients were recruited. Mean age was 57 years, 5 were female, and median NIHSS score at entry was 9.5 (range 2-20). The primary outcome measure occurred in one patient (sudden death). Another patient committed suicide 2 months after study entry (and 6 weeks after treatment with sildenafil had been completed). Among the 10 survivors, at 90 days, median NIHSS score was 2 (range 0-12), median Barthel index was 95 (range 15-100), and median modified Rankin score was 1.5 (range 0-5). CONCLUSIONS Sildenafil (25 mg daily for 2 weeks) appeared to be safe in this group of patients with mild to moderately severe stroke. Further studies of higher doses will be tested.