R. von Kummer

Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke

BACKGROUND We aimed to assess the safety and efficacy of thrombectomy for the treatment of stroke in a trial embedded within a population-based stroke reperfusion registry. METHODS During a 2-year period at four centers in Catalonia, Spain, we randomly assigned 206 patients who could be treated within 8 hours after the onset of symptoms of acute ischemic stroke to receive either medical therapy (including intravenous alteplase when eligible) and endovascular therapy with the Solitaire stent retriever (thrombectomy group) or medical therapy alone (control group). All patients had confirmed proximal anterior circulation occlusion and the absence of a large infarct on neuroimaging. In all study patients, the use of alteplase either did not achieve revascularization or was contraindicated. The primary outcome was the severity of global disability at 90 days, as measured on the modified Rankin scale (ranging from 0 [no symptoms] to 6 [death]). Although the maximum planned sample size was 690, enrollment was halted early because of loss of equipoise after positive results for thrombectomy were reported from other similar trials. RESULTS Thrombectomy reduced the severity of disability over the range of the modified Rankin scale (adjusted odds ratio for improvement of 1 point, 1.7; 95% confidence interval [CI], 1.05 to 2.8) and led to higher rates of functional independence (a score of 0 to 2) at 90 days (43.7% vs. 28.2%; adjusted odds ratio, 2.1; 95% CI, 1.1 to 4.0). At 90 days, the rates of symptomatic intracranial hemorrhage were 1.9% in both the thrombectomy group and the control group (P=1.00), and rates of death were 18.4% and 15.5%, respectively (P=0.60). Registry data indicated that only eight patients who met the eligibility criteria were treated outside the trial at participating hospitals. CONCLUSIONS Among patients with anterior circulation stroke who could be treated within 8 hours after symptom onset, stent retriever thrombectomy reduced the severity of post-stroke disability and increased the rate of functional independence. (Funded by Fundació Ictus Malaltia Vascular through an unrestricted grant from Covidien and others; REVASCAT ClinicalTrials.gov number, NCT01692379.).

Safety and efficacy of intravenous tissue plasminogen activator and heparin in acute middle cerebral artery stroke.

Background and Purpose There is little reported of the safety and efficacy of high-dose intravenous recombinant tissue plasminogen activator (alteplase) in combination with heparin anticoagulation in patients presenting with acute ischemic stroke. Methods Thirty-two patients with severe hemispheric stroke syndrome caused by angiographically proven middle cerebral artery and/or intracranial internal carotid artery occlusion were treated with 100 mg alteplase by intravenous infusion over 90 minutes within a mean±SD of 226±68 minutes after symptom onset Recanalization was assessed by digital subtraction angiography in all patients immediately after treatment and by transcranial Doppler monitoring (n=30) and/or a third angiogram (n=5) 12-24 hours later. Results Complete or partial reperfusion was observed in 11 patients (34%) 90 minutes after the initiation of alteplase infusion and in 17 patients (53%) within 12–24 hours. Hemorrhagic infarction without clinical deterioration was detected by follow-up computed tomography in nine patients (28%). Fatal parenchymal hemorrhage occurred in three patients (9%) with huge middle cerebral artery infarcts. Serious hemorrhage from the puncture site occurred in two patients (6%). Good clinical outcome correlated with reperfusion (p<0.05) and the presence of grade 2 collateral blood flow (p<0.01). Conclusions When 100 mg of recombinant tissue plasminogen activator was given within the first 6 hours of acute stroke together with heparin the incidence of deleterious hemorrhage was <10%. Reperfusion and effective collateral blood flow seem to be two important factors associated with a small infarct volume and good clinical outcome.

Treatment of Acute Ischemic Stroke Challenging the Concept of a Rigid and Universal Time Window

Acute stroke treatment has recently become a major area for clinical trials. Each year, thousands of patients with first-ever middle cerebral artery (MCA) territory stroke are enrolled in therapeutic trials, testing the hypothesis that the investigational treatment might improve functional outcome. In addition to trials of therapeutic thrombolysis, other classes of agents such as glutamate antagonists, free radical scavengers, anticytokines, and calcium channel blockers are presently being tested for therapeutic efficacy. Whereas most trials in the 1970s and 1980s enrolled patients within 24 or even 48 hours after stroke onset, at the present time it would be almost unthinkable to extend the time of inclusion beyond the “magic limit” of 6 hours. There are four reasons for this: First, experiments conducted in the nonhuman primate that led to the concept of the ischemic penumbra clearly documented that “time is brain,” with apparently only little penumbra remaining beyond 3 hours.1 2 Second, thus far many clinical trials have reported negative, only marginally significant, and/or positive but poorly reproducible findings; late inclusion of patients was considered to be responsible for treatment failure.3 4 Third, recent studies have demonstrated that it is possible to have stroke patients seen in the hospital within 3 to 6 hours after onset.5 6 Fourth, the success of intravenous therapeutic thrombolysis in less than 6 hours after myocardial infarction stimulated a similar design for acute stroke.7 For organizational reasons it has been operationally justified to apply a rigid time window for screened patients in multicenter, international trials. Furthermore, it is reasonable to consider that a cohort of stroke patients recruited within certain time limits may be more homogeneous. We would like to examine this view and call into question that therapy in individual patients within the 6-hour time limit would necessarily …

Ischaemic damage of brain microvessels: inherent risks for thrombolytic treatment in stroke

Recent trials of plasminogen activators in acute ischaemic stroke underscore the delicate balance between promise of benefit and risk. Attempts to manage clinical outcome by systemic infusion of recombinant tissue plasminogen activator (rt-PA) have so far had mixed success.1 2 The benefits seen in the National Institutes of Neurological Diseases and Stroke (NINDS) trial of rt-PA in acute ischaemic stroke were a significant absolute improvement in disability outcome.2 3 However, the risks in that study and in the European Cooperative Acute Stroke Study (ECASS)1 included further disability and mortality associated with haemorrhagic consequences of the plasminogen activator (PA).1 2 Three recent studies of streptokinase in acute ischaemic stroke were terminated because of safety concerns.4-9 In all five trials, the risk of symptomatic haemorrhage associated with the PA was significantly increased over placebo (table 1). In addition, approaches which effect recanalisation of documented cerebral arterial thrombotic occlusions by intravenous or intra-arterial PA infusion have yet to be rigorously shown to promote overall benefit, although anecdotal evidence suggests that individual patients may improve clinically.10-24 The reasons are practical. The perceived risks, those of angiography and the interventional procedures required for intra-arterial PA delivery, have not been fully evaluated,25 although the relative risks of diagnostic angiography are low.26-28 Clearly, this assessment hides many important differences in PA behaviour, study design and conduct, patient populations, diagnostic and therapeutic procedures, disease severity, comorbidity, and a host of other potential contributors. None the less, concerns which may erode the promise of benefit of thrombolytic agents in acute ischaemic stroke include the accentuation of innate risks associated with the evolution of ischaemic injury after the stroke event itself.29-34 These include early mortality caused by severe brain oedema and the development of haemorrhagic transformation which causes clinical deterioration or …

Detectability of cerebral hemisphere ischaemic infarcts by CT within 6 h of stroke

To determine how early and how reliably ischaemic brain infarcts can be detected on CT within 6 h of the onset of cerebral hemisphere strokes, 44 such studies were interpreted by an experienced neuroradiologist blinded to clinical signs, but aware that the cohort was a stroke population. He was asked to detect and localise an area of parenchymal low density and/or focal brain swelling. A follow-up study showing the definite infarct served as a reference in each case. In 38 patients areas of slightly low density were seen, and in 36 follow-up CT confirmed infarcts in the locations indicated. In 2 patients the reading was false positive. In 6 patients no low density focus could be detected. In these 8 patients examined by CT within 180 min of the stroke, no low density could be identified, even in retrospect with the knowledge of the findings on follow-up. Thus, 42 readings (95%) were true positive or true negative; 2 were false positive; and none was a false negative. CT within 6 h of the onset of symptoms has a mean sensitivity of 82% (36/44) for ischaemic cerebral hemisphere infarcts. By contrast, its sensitivity to ischaemic parenchymal low density is low during the initial 2 h. The early development of hemispheric infarcts can be detected reliably if the radiologist is familiar with the signs.

Endovascular therapy of arteriovenous fistulae with electrolytically detachable coils.

Abstract We report our experience in using Guglielmi electrolytically detachable coils (GDC) alone or in combination with other materials in the treatment of intracranial or cervical high-flow fistulae. We treated 14 patients with arteriovenous fistulae on brain-supplying vessels – three involving the external carotid or the vertebral artery, five the cavernous sinus and six the dural sinuses – by endovascular occlusion using electrolytically detachable platinum coils. The fistula was caused by trauma in six cases. In one case Ehlers-Danlos syndrome was the underlying disease, and in the remaining seven cases no aetiology could be found. Fistulae of the external carotid and vertebral arteries and caroticocavernous fistulae were reached via the transarterial route, while in all dural fistulae a combined transarterial-transvenous approach was chosen. All fistulae were treated using electrolytically detachable coils. While small fistulae could be occluded with electrolytically detachable coils alone, large fistulae were treated by using coils to build a stable basket for other types of coil or balloons. In 11 of the 14 patients, endovascular treatment resulted in complete occlusion of the fistula; in the remaining three occlusion was subtotal. Symptoms and signs were completely abolished by this treatment in 12 patients and reduced in 2. On clinical and neuroradiological follow-up (mean 16 months) no reappearance of symptoms was recorded.

Disappearing hyperdense middle cerebral artery sign in ischaemic stroke patients treated with intravenous thrombolysis: clinical course and prognostic significance.

Background and purpose: Hyperdense middle cerebral artery sign (HMCAS) on CT is a well known indication of thromboembolic arterial occlusion. Its disappearance after thrombolytic therapy is poorly described. Taking the rate of HMCAS disappearance as a surrogate for MCA recanalisation, its prognostic value after intravenous thrombolysis was examined. Methods: 1905 stroke patients with HMCAS on admission CT scan in the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Register (SITS-ISTR) were studied. On follow-up CT scans 22–36 h after thrombolysis, HMCAS disappeared in 831 cases, persisted in 788 and was uncertain in 122; follow-up CT was not done in 164 cases. Results: Patients whose HMCAS disappeared were younger (median age 67 years vs 69 years for persistent; p = 0.03), with milder stroke (admission National Institute of Health Stroke Scale (NIHSS) score was 16 vs 17; p<0.005) and were less likely to have early infarct signs on admission CT (26% vs 33%; p<0.005). Patients with disappearing HMCAS were more likely to have early improvement in NIHSS score (median improvement 2 vs 0 at 2 h; 4 vs 1 at 24 h), be independent at 3 months (42% vs 19%), with fewer deaths (15% vs 30%) than those with persistent HMCAS. In multivariate analysis, HMCAS disappearance independently predicted functional independence and survival. Early NIHSS improvement independently predicted HMCAS disappearance. Conclusions: HMCAS disappeared after intravenous thrombolysis in about half of cases and these patients had twice as good outcomes compared with those with persistent HMCAS. The prognosis in patients with MCA occlusion that persists after intravenous thrombolysis is poor, which may indicate the need for an alternative treatment approach to this subgroup.

Early X-Ray Hypoattenuation of Brain Parenchyma Indicates Extended Critical Hypoperfusion in Acute Stroke

BACKGROUND AND PURPOSE The presence of early x-ray hypoattenuation is an important selection criterion for thrombolytic therapy. However, knowledge about the pathophysiological constellation reflected by this hypoattenuation is lacking. Our objective was to study the relationship between the presence of early CT hypoattenuation and the volumes of critical cortical hypoperfusion. METHODS In 32 patients with acute ischemic stroke, CT was performed 20 to 170 minutes (mean, 94 minutes) after symptom onset, and [(15)O]H(2)O-PET 20 to 120 minutes (mean, 67 minutes) later. CTs were scrutinized for the presence of hypoattenuation. On the PET scans, the volumes of critical cortical hypoperfusion were assessed. RESULTS CT hypoattenuation was present in 18 patients (56%), all of whom had critical cortical hypoperfusion and developed infarction. Of the 14 patients with normal CTs, critical hypoperfusion was found in 6, and 7 developed infarction. The mean volumes of critically hypoperfused tissue differed significantly (P=0.0001, Wilcoxon test) between the CT normal (mean 13.9 cm(3), range 0 to 71 cm(3)) and the CT abnormal (mean 116.3 cm(3), range 4 to 389 cm(3)) groups. CONCLUSIONS Early presence of hypoattenuation is indicative of extended volumes of critically hypoperfused cortical tissue. The extent of hypoperfusion may exceed that of hypoattenuation, and some of that tissue might still be salvageable.

Cerebrovascular CO2 reactivity in migraine: assessment by transcranial Doppler ultrasound.

SummaryCerebrovascular reactivity to CO2 inhalation was studied by transcranial Doppler sonography in 30 patients with classic or common migraine and 39 healthy controls without clinical or ultrasonic signs of arteriosclerosis. Systolic and diastolic Doppler frequencies of the middle cerebral artery were plotted against end-tidal CO2 partial pressure; the reactivity index (I×R) was defined as relative frequency change during a PCO2 increase of 5 mm Hg. In the normal subjects, I×R was 20.0±6.3 for systolic velocities, and 26.0±8.2 for diastolic values. Migraineurs during their headache-free interval had significantly higher I×R values on the affected side (mean: 41.6 systolic, 61.2 diastolic), compared with either controls (P<0.01) or the contralateral side (mean: 28.3 systolic, 30.8 diastolic; P<0.01). During the headache attack, CO2 reactivity was significantly lower than normal only for systolic velocities (mean: 8.3; P<0.05). Increased CO2 reactivity is thought to be one phenomenon of migraine. Transcranial Doppler CO2 testing of cerebrovascular reactivity is a reliable method that may be of interest for the diagnostic evaluation and management of migraine patients.

Autoregulatory capacity and the effect of isovolemic hemodilution on local cerebral blood flow.

The effect of isovolemic hemodilution with dextran 40 on local cerebral blood flow was measured in eight cats by means of the hydrogen clearance technique. Under normotension the decrease of hematocrit from 35% to 25% causes a sudden increase of up to 30% in local cerebral blood flow. After lowering the mean arterial blood pressure from 140 to 80 mm Hg, hemodilution did not alter cerebral blood flow significantly. From this observation it is concluded that the increase of cerebral blood flow following hemodilution is caused by compensatory vasodilatation and not by reduction of blood viscosity. This could imply that hemodilution cannot improve blood flow in areas of impaired autoregulation.