P A Barber

Why are stroke patients excluded from tPA therapy? An analysis of patient eligibility.

Background: Thrombolytic therapy for acute stroke (<3 hours) will not have a major impact on death and dependency unless it is accessible to more patients. Objective: To determine why patients with ischemic stroke did not receive IV TPA and assess the availability of this therapy to patients with ischemic stroke. Methods: Consecutive patients with acute ischemic stroke were prospectively identified at a university teaching hospital between October 1996 and December 1999. Additional patients with ischemic stroke were identified that were admitted to one of three other hospitals in the Calgary region during the study period. The Oxford Community Stroke Programme Classification was used to record type and side of stroke. Results: Of 2165 stroke patients presenting to the university hospital, 1168 (53.9%) were diagnosed with ischemic stroke, 31.8% with intracranial hemorrhage (intracerebral, subarachnoid, or subdural), and 13.9% with TIA. Delay in presentation to emergency department beyond 3 hours excluded 73.1% (854/1168). Major reasons for delay included uncertain time of onset (24.2%), patients waited to see if symptoms would improve (29%), delay caused by transfer from an outlying hospital (8.9%), and inaccessibility of treating hospital (5.7%). Twenty-seven percent of patients with ischemic stroke (314/1168) were admitted within 3 hours of sympton onset and of these 84 (26.7%) patients received IV TPA. The major reasons for exclusion in this group of patients (<3 hours) were mild stroke (13.1%), clinical improvement (18.2%), perceived protocol exclusions (13.6%), emergency department referral delay (8.9%), and significant comorbidity (8.3%). Of those patients who were considered too mild or were documented to have had significant improvement, 32% either remained dependent at hospital discharge or died during hospital admission. Throughout the region there was a total of 1806 ischemic stroke patients (admitted to all four Calgary hospitals). During this study period, 4.7% received IV TPA. Conclusions: The majority of patients are unable to receive TPA for acute ischemic stroke because they do no not reach the hospital soon enough. Of those patients presenting within 3 hours, 27% received the therapy but a further 31% were excluded because their symptoms were either considered too mild or were rapidly improving. Subsequently, a third of these patients were left either dependent or dead, bringing into question the initial decision not to treat.

Imaging of the brain in acute ischaemic stroke: comparison of computed tomography and magnetic resonance diffusion-weighted imaging.

Background and objectives: Controversy exists about the optimal imaging technique in acute stroke. It was hypothesised that CT is comparable with DWI, when both are read systematically using quantitative scoring. Methods: Ischaemic stroke patients who had CT within six hours and DWI within seven hours of onset were included. Five readers used a quantitative scoring system (ASPECTS) to read the baseline (b) and follow up CT and DWI. Use of MRI in acute stroke was also assessed in patients treated with tissue plasminogen activator (tPA) by prospectively recording reasons for exclusion. Patients were followed clinically at three months. Results: bDWI and bCT were available for 100 consecutive patients (admission median NIHSS = 9). The mean bDWI and bCT ASPECTS were positively related (p<0.001). The level of interrater agreement ranged from good to excellent across all modalities and time periods. Bland–Altman plots showed more variability between bCT and bDWI than at 24 hours. The difference between bCT and bDWI was ⩽2 ASPECTS points. Of bCT scans with ASPECTS 8–10, 81% had DWI ASPECTS 8–10. Patients with bCT ASPECTS of 8–10 were 1.9 times more likely to have a favourable outcome at 90 days than those with a score of 0–7 (95% CI 1.1 to 3.1, p = 0.002). The relative likelihood of favourable outcome with a bDWI ASPECTS 8–10 was 1.4 (95% CI 1.0 to 1.9, p = 0.10). Of patients receiving tPA 45% had contraindications to urgent MRI. Conclusion: The differences between CT and DWI in visualising early infarction are small when using ASPECTS. CT is faster and more accessible than MRI, and therefore is the better neuroimaging modality for the treatment of acute stroke.

The Rise and Fall of NMDA Antagonists for Ischemic Stroke

It has long been accepted that high concentrations of glutamate can destroy neurons, and this is the basis of the theory of excitotoxicity during brain injury such as stroke. Glutamate N-methyl-D-aspartate (NMDA) receptor antagonists such as Selfotel, Aptiganel, Gavestinel and others failed to show neuroprotective efficacy in human clinical trials or produced intolerable central nervous system adverse effects. The failure of these agents has been attributed to poor studies in animal models and to poorly designed clinical trials. We also speculate that NMDA receptor antagonism may have hindered endogenous mechanisms for neuronal survival and neuroregeneration. It remains to be proven in human stroke whether NMDA receptor antagonism can be neuroprotective.

Kir6.2-containing ATP-sensitive potassium channels protect cortical neurons from ischemic/anoxic injury in vitro and in vivo.

ATP-sensitive potassium (K(ATP)) channels are weak inward rectifiers that appear to play an important role in protecting neurons against ischemic damage. Cerebral stroke is a major health issue, and vulnerability to stroke damage is regional within the brain. Thus, we set out to determine whether K(ATP) channels protect cortical neurons against ischemic insults. Experiments were performed using Kir6.2(-/-) K(ATP) channel knockout and Kir6.2(+/+) wildtype mice. We compared results obtained in Kir6.2(-/-) and wildtype mice to evaluate the protective role of K(ATP) channels against focal ischemia in vivo, and, using cortical slices, against anoxic stress in vitro. Immunohistochemistry confirmed the presence of K(ATP) channels in the cortex of wildtype, but not Kir6.2(-/-), mice. Results from in vivo and in vitro experimental models indicate that Kir6.2-containing K(ATP) channels in the cortex provide protection from neuronal death. Briefly, in vivo focal ischemia (15 min) induced severe neurological deficits and large cortical infarcts in Kir6.2(-/-) mice, but not in wildtype mice. Imaging analyses of cortical slices exposed briefly to oxygen and glucose deprivation (OGD) revealed a substantial number of damaged cells (propidium iodide-labeled) in the Kir6.2(-/-) OGD group, but few degenerating neurons in the wildtype OGD group, or in the wildtype and Kir6.2(-/-) control groups. Slices from the three control groups had far more surviving cells (anti-NeuN antibody-labeled) than slices from the Kir6.2(-/-) OGD group. These findings suggest that stimulation of endogenous cortical K(ATP) channels may provide a useful strategy for limiting the damage that results from cerebral ischemic stroke.

The probability of middle cerebral artery MRA flow signal abnormality with quantified CT ischaemic change: targets for future therapeutic studies

Objectives: In this study we define the probability of vascular abnormality in the middle cerebral artery (MCA) territory according to the extent of ischaemic change seen using computed tomography (CT). We assessed the sensitivity and specificity of the hyperdense middle cerebral artery (HMCA) and the “dot” sign using magnetic resonance angiography (MRA). Methods: Patients presenting with ischaemic stroke had a CT scan (<6 h) prior to MRI (<7 h). A quantitative CT scoring system (ASPECTS) was applied to CT and diffusion weighted images (DWI) at baseline and follow up (24 h) by five independent observers. The presence of HMCA and the MCA “dot” sign was also evaluated. An expert reader assessed the 3D time of flight (TOF) MRA in the anterior circulation for areas of decreased vascular signal in the MCA territory, with an absent signal taken to represent severely reduced or absent flow. Results: A total of 100 consecutive patients had baseline CT and MR scans. The median NIHSS was 9. The median CT ASPECTS was 8 and equalled the median DWI ASPECTS. There were a total of 10 HMCA and 19 MCA “dot” signs, with four patients having both HMCA and “dot” signs. A total of 47 MRA flow signal abnormalities were observed in the anterior circulation. Conclusions: In the absence of accessible neurovascular imaging, the extent of CT ischaemia (ASPECTS) is a strong predictor of vascular occlusion. The CT hyperdense artery signs have a high positive predictive value but low negative predictive value.

Combined full‐dose IV and endovascular thrombolysis in acute ischaemic stroke

Background There is an increasing trend to treating proximal vessel occlusions with intravenous–inter-arterial (IV-IA) thrombolysis. The best dose of IV tissue plasminogen activator (tPA) remains undetermined. We compared the combination of full-dose IV recombinant tissue plasminogen activator (rtPA) and IA thrombolytic therapy to IA therapy. Methods Between 2002 and 2009, we reviewed our computed tomographic angiography database for patients who received full-dose intravenous rtPA and endovascular therapy or endovascular therapy alone for acute ischaemic stroke treatment. Details of demographics, risk factors, endovascular procedure, and symptomatic intracranial haemorrhage were noted. Modified Rankin Scale ≤2 at three-months was used as good outcome. Recanalization was defined as Thrombolysis in Myocardial Ischaemia 2–3 flow on angiography. Results Among 157 patients, 104 patients received IV-IA treatment and 53 patients underwent direct IA therapy. There was a higher recanalization rate with IV-IA therapy compared with IA alone (71% vs. 60%, P < 0·21) which was driven by early recanalization after IV rtPA. Mortality and independent outcome were comparable between the two groups. Symptomatic intracranial haemorrhage occurred in 8% of patients (12% in the IA group, 7% in the IV-IA group) but was more frequent as the intensity of intervention increased from device alone to thrombolytic drug alone to device plus thrombolytic drug(s). Recanalization was a strong predictor of reduced mortality risk ratio (RR) 0·48 confidence interval95 0·27–0·84) and favourable outcome (RR 2·14 confidence interval95 1·3–3·5). Conclusions Combined IV-IA therapy with full-dose intravenous rtPA was safe and results in good recanalization rates without excess symptomatic intracranial haemorrhage. Testing of full-dose IV tPA followed by endovascular treatment in the IMS3 trial is justified.

Quantified T1 as an adjunct to apparent diffusion coefficient for early infarct detection: a high-field magnetic resonance study in a rat stroke model

Background Thrombolytic treatment for acute stroke has focused attention on accurate identification of injured vs. salvageable brain tissue, particularly if reperfusion occurs. However, our knowledge of differences in acute magnetic resonance imaging changes between transient and permanent ischemia and how they reflect permanently damaged tissue remain incomplete. Aims and/or hypothesis Magnetic resonance imaging characteristics vary widely following ischemia and, at acute times, T1, T2 or apparent diffusion coefficient quantification may differentiate viable tissue from that destined to infarct. Methods High-resolution magnetic resonance imaging was performed at 9·4T following permanent or transient (90 min) middle cerebral artery occlusion in spontaneously hypertensive male rats or Wistar rats. Within 30 min, quantified maps of the apparent diffusion coefficient, T1, and T2 were performed and measures determined for sequences in the infarct and compared with that in the contralateral region. Lesion area for each magnetic resonance imaging sequence (T1, T2, apparent diffusion coefficient, and perfusion maps) was delineated for different time points using quantitative threshold measures and compared with final histological damage. Results Early extensive changes in T1 following both transient and permanent middle cerebral artery occlusion provided a sensitive early indicator of the final infarct area. Following reperfusion, small but measurable early T2 changes indicative of early development of vasogenic edema occurred in the transient but not permanent groups. In transient middle cerebral artery occlusion, at 70 min apparent diffusion coefficient decreased (P<0·001) and then pseudonormalized at 150 min. In permanent middle cerebral artery occlusion, apparent diffusion coefficient declined over time. Lesion area detected using T1 maps exceeded that with T2 and apparent diffusion coefficient at 70 and 150 min in both groups (P<0·001). Conclusions The results indicate that, independent of reperfusion, quantified T1 is superior for detecting early ischemic changes that are not necessarily detected with T2 or apparent diffusion coefficient.

Unexpected posthemorrhagic hydrocephalus in patients treated with rFVIIa

When a new drug is tried, it is important to identify adverse and serious adverse events. The data reported in the article by Subramaniam et al. require follow-up in the analyses of larger trials.1 Their data are not comprehensive enough to allow for definite conclusions and the analysis of the data should also be considered. The authors report only nine cases. They also estimated the expected risk of hydrocephalus based on the modified Graeb criteria and compared it to the observed rate.2 Furthermore, the original criteria were not validated, the population in the study was heterogeneous, …

Insular cortical ischaemia does not independently predict acute hypertension or hyperglycaemia within 3 h of onset

Objectives: To test the hypothesis that insular cortical ischaemia is associated with acute hypertension and hyperglycaemia. Methods: From the Canadian Activase for Stroke Effectiveness Study, which included only patients treated with thrombolysis hyperacutely (ie, within 3 h of onset of stroke), 966 patients were identified with ischaemia affecting (n = 685), or sparing (n = 281), the insular cortex. Demographic and clinical data, pretreatment indices of blood pressure, blood glucose, atrial fibrillation, and clinical imaging and outcome measures were compared between the two groups. Multivariable linear regression was used to assess predictors of systolic blood pressure and glucose levels before thrombolysis. Results: Pretreatment hypertension (p = 0.009), but not hyperglycaemia (p = 0.32), was predicted by insular ischaemia in univariable linear regression analyses. After adjusting for other factors, however, insular cortical ischaemia was not found to be an independent predictor for acute hypertension or hyperglycaemia. Conclusions: Raised blood pressure or serum glucose levels in hyperacute (<3 h) cerebral ischaemia is not independently predicted by insular involvement. Several hours are required for sympathetic manifestations of insular ischaemia to evolve.

Experimental neuroprotection: Translation to human stroke trials

For a drug to be effectivein vivo in-vitroprotection must be translated to studies of both global (transient forebrain ischemia) to discern “cellular” neuroprotection (cytoprotection) and focal ischemia to evaluate “parenchymal” neuroprotection (infarct reduction). Drug concentrations that suggest that the mechanism is activein vitromust translate to drug levels that achieve cytoprotection and infarct volume reductions which are not only significant but sustained (indefatigable). Initiation of experimental therapy should be delayed in order to have clinical relevance. Most importantly, the “effective dose” plasma level reached in rodents to achieve a neuroprotective effect must be matched in humans, in the absence of overt toxicity.