Angioplasty in asymptomatic carotid artery stenosis vs. endarterectomy compared to best medical treatment: One-year interim results of SPACE-2.

BACKGROUND: Treatment of individuals with asymptomatic carotid artery stenosis is still handled controversially. Recommendations for treatment of asymptomatic carotid stenosis with carotid endarterectomy (CEA) are based on trials having recruited patients more than 15 years ago. Registry data indicate that advances in best medical treatment (BMT) may lead to a markedly decreasing risk of stroke in asymptomatic carotid stenosis. The aim of the SPACE-2 trial (ISRCTN78592017) was to compare the stroke preventive effects of BMT alone with that of BMT in combination with CEA or carotid artery stenting (CAS), respectively, in patients with asymptomatic carotid artery stenosis of ≥70% European Carotid Surgery Trial (ECST) criteria. METHODS: SPACE-2 is a randomized, controlled, multicenter, open study. A major secondary endpoint was the cumulative rate of any stroke (ischemic or hemorrhagic) or death from any cause within 30 days plus an ipsilateral ischemic stroke within one year of follow-up. Safety was assessed as the rate of any stroke and death from any cause within 30 days after CEA or CAS. Protocol changes had to be implemented. The results on the one-year period after treatment are reported. FINDINGS: It was planned to enroll 3550 patients. Due to low recruitment, the enrollment of patients was stopped prematurely after randomization of 513 patients in 36 centers to CEA (n = 203), CAS (n = 197), or BMT (n = 113). The one-year rate of the major secondary endpoint did not significantly differ between groups (CEA 2.5%, CAS 3.0%, BMT 0.9%; p = 0.530) as well as rates of any stroke (CEA 3.9%, CAS 4.1%, BMT 0.9%; p = 0.256) and all-cause mortality (CEA 2.5%, CAS 1.0%, BMT 3.5%; p = 0.304). About half of all strokes occurred in the peri-interventional period. Higher albeit statistically non-significant rates of restenosis occurred in the stenting group (CEA 2.0% vs. CAS 5.6%; p = 0.068) without evidence of increased stroke rates. INTERPRETATION: The low sample size of this prematurely stopped trial of 513 patients implies that its power is not sufficient to show that CEA or CAS is superior to a modern medical therapy (BMT) in the primary prevention of ischemic stroke in patients with an asymptomatic carotid stenosis up to one year after treatment. Also, no evidence for differences in safety between CAS and CEA during the first year after treatment could be derived. Follow-up will be performed up to five years. Data may be used for pooled analysis with ongoing trials.

Saturation of hemoglobin in intracranial arteries is similar in patients with hemodynamically relevant and irrelevant stenosis of the internal carotid artery.

The aim of this study was to establish if patients with hemodynamically relevant or irrelevant stenoses of the extracranial internal carotid artery have different intracranial arterial oxygen saturation as measured by transcranial pulse oximetry using near infrared spectroscopy. Patients with unilateral stenosis > 70% according to North American Symptomatic Carotid Endarterectomy Trial (NASCET) were included. Hemodynamic relevance was assessed using ultrasound criteria. Transcranial spectroscopy recordings were taken before and after surgical or interventional treatment of the stenosis. Optodes were placed bilaterally on the intact frontoparietal aspect of the skull. Oxygen saturation and diversion angle alpha from the hemoglobin plane were measured. There were no significant differences regarding arterial oxygen saturation between the two groups. Oxygen saturation ranged from 0.910 +/- 0.08 to 0.957 +/- 0.028 in the subgroups (all values as mean +/- S.E.). These values are consistent with previous studies and theoretical values. In smokers we found a significantly shifted diversion angle from the hemoglobin plane to the negative side. This indicates the presence of an absorber other than oxy- and desoxyhemoglobin in the optical field. We conclude that transcranial pulse oximetry cannot distinguish between patients with hemodynamically relevant and irrelevant stenosis of the internal carotid artery. However it seems to be capable of distinguishing smokers from non-smokers.

30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial.

BACKGROUND: Carotid endarterectomy is effective in stroke prevention for patients with severe symptomatic carotid-artery stenosis, and carotid-artery stenting has been widely used as alternative treatment. Since equivalence or superiority has not been convincingly shown for either treatment, we aimed to compare the two. METHODS: 1200 patients with symptomatic carotid-artery stenosis were randomly assigned within 180 days of transient ischaemic attack or moderate stroke (modified Rankin scale score of < or =3) carotid-artery stenting (n=605) or carotid endarterectomy (n=595). The primary endpoint of this hospital-based study was ipsilateral ischaemic stroke or death from time of randomisation to 30 days after the procedure. The non-inferiority margin was defined as less than 2.5% on the basis of an expected event rate of 5%. Analyses were on an intention-to-treat basis. This trial is registered at Current Controlled Trials with the international standard randomised controlled trial number ISRCTN57874028. FINDINGS: 1183 patients were included in the analysis. The rate of death or ipsilateral ischaemic stroke from randomisation to 30 days after the procedure was 6.84% with carotid-artery stenting and 6.34% with carotid endarterectomy (absolute difference 0.51%, 90% CI -1.89% to 2.91%). The one-sided p value for non-inferiority is 0.09. INTERPRETATION: SPACE failed to prove non-inferiority of carotid-artery stenting compared with carotid endarterectomy for the periprocedural complication rate. The results of this trial do not justify the widespread use in the short-term of carotid-artery stenting for treatment of carotid-artery stenoses. Results at 6-24 months are awaited.

Reversibility of venous sinus obstruction in idiopathic intracranial hypertension.

Elevated intracranial intravenous pressure seems to be of importance in pseudotumor cerebri syndromes, either as a cause (secondary intracranial hypertension) or as a consequence (idiopathic intracranial hypertension) of increased intracranial pressure. We present 3 case reports in which diagnostic imaging before and after CSF diversion provided evidence that narrowing of the transverse sinuses is a secondary phenomenon. Stent angioplasty of the venous sinuses should not be considered a therapeutic approach in these cases.

Selective affection of hippocampal CA-1 neurons in patients with transient global amnesia without long-term sequelae.

The aetiology, pathomechanisms and anatomical correlates of transient global amnesia (TGA) still remain obscure. Recently, focal MR-signal diffusion-weighted imaging (DWI) changes in the hippocampus have been described in patients with TGA, but the exact localization, long term outcome and pathophysiological nature of these lesions still remain unknown. The topography and time course of hippocampal DWI lesions in 41 TGA patients was studied using serial 3 T high-resolution MR-imaging and correlated to clinical and neuropsychometric results. Of these, 29 patients showed 36 DWI lesions with corresponding T(2) lesions in the hippocampus within a time window of 48 h after onset. Almost all lesions (94%; 34/36) were selectively found in the CA-1 sector (Sommer sector) of the hippocampal cornu ammonis. Most DWI lesions (8/10) were already detectable in the peri-acute phase <6 h after onset of symptoms. A follow-up study 4-6 months after the episode did not show evidence for residual structural sequelae of these lesions (n = 20/20). A venous MR angiography of the intracranial dural sinus showed an asymmetric venous drainage in 21/24 (88%) patients. In 11/16 (69%) patients with unilateral lesions, the asymmetry corresponded to the side of the DWI lesion. Significant episodic verbal memory deficits in the acute phase (n = 14/18) were associated with lesions of the dominant hemisphere while impairment of visuospatial memory was associated with lesions of the non-dominant hemisphere. Persistent neuropsychological sequelae were not detected 4-6 months after the episode (n = 16). This is the first prospective study combining high-resolution imaging and neuropsychometry analysing the detailed functional anatomy and outcome of hippocampal DWI/T(2) lesions in TGA supporting the view the TGA being a benign transient disorder. The TGA can be considered a model for a focal transient perturbation of memory circuits in the temporo-mesial region.

[Treatment of carotid artery aneurysms with covered stents]. / Aneurysmabehandlung der Arteria carotis interna mit gecoverten Stents.

PURPOSE: Evaluation of the use of covered stents in treating pseudoaneurysms of the cervical and intracranial/extradural carotid artery and determination of the periprocedural and short- to mid-term complication rate. MATERIALS AND METHODS: 8 patients with 9 spontaneous dissecting aneurysms of the cervical carotid artery--5 of which were symptomatic--plus one patient with ofthalmoplegia due to an aneurysm of the cavernous carotid artery were studied. While the latter was treated with a PTFE-covered balloon-mounted stainless steel stent (Jostent/Graftmaster), a self-expanding PTFE-covered Nitonol Stent (Symbiot) was used in all other cases. Intervention was performed with local anesthesia. Aspirin and Clopidogrel were both used as antiplatelet drugs. Clinical signs and symptoms and vascular imaging with DS, MR, CT angiography and ultrasound were recorded during patient follow-up, with a mean follow-up period of 14.6 months (4 - 30). RESULTS: We were able to treat 8 out of 10 aneurysms (80%) using covered stents. The aneurysms were immediately occluded and the associated stenoses of the parent vessel were eliminated. No clinically relevant complications occurred during the procedure or in the follow-up interval. In two cases, elongation of the carotid artery prevented the stent from being positioned over the aneurysm neck. These cases were shown to be stable with the use of antiplatelet drugs. CONCLUSION: Covered stents can be used in the treatment of pseudoaneurysms of the carotid artery as an alternative to long-term antithrombotic medication or surgery. In our study treatment was effective (80%) and free of complications in the short- and mid-term follow-up. Possible indications, technique and the use of imaging modalities for patient follow-up are discussed.

[Stroke: causes and classification]. / Schlaganfall: Ursachen und Klassifikation.

Cerebrovascular disease is caused by ischaemic stroke, intracerebral haemorrhage, subarachnoidal haemorrhage or cerebral vein and sinus thrombosis. Approximately 80% of all cerebrovascular accidents are caused by ischaemic stroke, whereas 20% are due to primary haemorrhage. This article summarizes the typical causes of each of the four main groups of cerebrovascular disease and points out clinical differences. Special attention is given to transitory ischemic attacks since new reports underline the necessity of early diagnostic and therapeutic intervention. Useful diagnostic and clinical scales are presented and discussed.

[Coagulation disorders and stroke]. / Gerinnungsstörungen und Schlaganfall.

Hereditary and acquired coagulation disorders may play an important role in the pathophysiology of acute ischaemic stroke. Because of the low prevalence of these disorders and the considerable costs of unmindful diagnostic effort, a custom-tailored approach is desirable. Suggestive in favour of a possible prothrombotic clotting disorder are young patients, repeated episodes of thrombosis in the patient's history, inappropriate atherosclerotic vascular changes, previous repeated miscarriages in stroke patients, or structural cardiac abnormalities as a patent foramen ovale. Disorders affecting antithrombin III, protein C und S, APC-resistance, the prothrombin mutation, homocysteinaemia, antiphospholipid antibodies, and procoagulatory cellular interaction are discussed.

[Therapy of acute stroke]. / Akuttherapie des Schlaganfalls.

Current therapeutic concepts for acute cerebral ischaemia and cerebral haemorrhage are summarized. Patient selection for thrombolysis, the role of stroke MRI and the choice of recanalization techniques are discussed. The treatment of intracerebral haemorrhage with particular emphasis on evacuation of haematoma and acute haemostatic therapy are discussed.

Thrombectomy vs. Systemic Thrombolysis in Acute Embolic Stroke with High Clot Burden: A Retrospective Analysis.

PURPOSE: The efficacy of i. v. thrombolysis in acute stroke with high clot burden is limited. Successful recanalization is very unlikely if the thrombus length exceeds 7 mm. Thus this retrospective controlled study evaluated the efficacy and safety of neurothrombectomy in the treatment of acute embolic stroke in patients selected by a thrombus length of ≥ 8 mm using the stent retriever Trevo(®) device. MATERIALS AND METHODS: 40 patients with acute occlusion of the anterior intracranial arteries with a thrombus length of ≥ 8 mm were treated with neurothrombectomy. We compared the outcome with a historical cohort of 42 patients with a thrombus length of ≥ 8 mm that received i. v. thrombolysis only. Clinical outcome was assessed by modified Rankin scale in both groups at discharge and on day 90. RESULTS: Patients did not differ in age, mRS on admission, thrombus length or time from symptom onset to i. v. thrombolysis, but the thrombectomy group had higher NIHSS on admission. Successful recanalization was achieved in 33/40 patients (83 %) with neurothrombectomy. 15 patients received i. v. thrombolysis prior to neurothrombectomy. Median mRS at discharge was 3.5 (1.25 - 5) vs. 5 (4 - 6; p < 0.01) and on day 90 3 (1 - 4) vs. 5 (4 - 6; p < 0.01). Symptomatic hemorrhage occurred in 3 vs. 7 patients. 3 vs. 17 patients died within 90 days (thrombectomy vs. control each). There were only a few intervention-related complications. CONCLUSION: Thrombectomy in acute stroke with high clot burden using the Trevo(®) device has a low risk and improved clinical outcome compared to i. v. thrombolysis alone. Treatment selection by a clot length of ≥ 8 mm might be a powerful approach to improve the outcome of mechanical thrombectomy. KEY POINTS: • Clot length of ≥ 8 mm might be a valuable criterion for indicating neurothrombectomy. • Thrombolysis only in high clot burden is associated with poor clinical outcome. • Thrombectomy using the Trevo(®) stent retriever is safe and effective.

Independent HIV replication in paired CSF and blood viral isolates during antiretroviral therapy.

BACKGROUND: The goal of highly active antiretroviral therapy in HIV-infected patients is to reduce plasma viral load (VL) below quantifiable levels. Mutations associated with drug resistance within the HIV-1 genome can limit therapeutic success. Low VL implicates a low risk of emergence of resistant mutants. Whether there is divergent development of HIV strains in different biologic compartments is not understood. METHODS: The authors studied VL and the occurrence of mutations conferring resistance in viral genomes isolated from blood and CSF samples of 23 HIV-infected patients. They determined sequences of HIV-1 RNA by reverse transcriptase PCR amplification and direct sequencing. They measured resistance to antiretroviral drugs genotypically by detection of drug-related point mutations and VL by a branched-DNA assay. RESULTS: Amplification of HIV was successful even in patients with plasma or CSF VL below detection limit. VL was considerably lower in CSF as compared with blood (p < 0.0001). There was no correlation between CSF and plasma VL. The mutational pattern in viral copies derived from blood and CSF was not identical. Ten (9%) of the total number of 118 mutations associated with drug resistance occurred in blood isolates only; 14 (11%) were detected exclusively in CSF strains. CONCLUSION: There is evidence for viral replication at HIV RNA levels less than 50/mL. The results suggest divergent evolution of HIV-1 in different biologic compartments. The presence of resistant mutants in the CSF may escape regular diagnostic in blood. Therapeutic success may fail after adapting therapy to genotypic resistance patterns detected in one compartment only.

Update in thrombolytic therapy.

Several studies have proven the usefulness of thrombolytic agents in the therapy of ischemic stroke. Data from open and small placebo-controlled trials show a relationship between recanalization and an improved clinical outcome. Three large scaled studies have examine the effect of streptokinase treatment. Because of an increasing mortality the results of these studies were negative, and so streptokinase should not be used to treat acute ischemic stroke. In contrast, three rt-PA studies with together more than 2000 patients showed a significant benefit. Recent meta-analyses including data of all these trials show an odds ratio for death and disability of 0.67 (95 p. 100 CI 0.56; 0.8). The number needed to treat to prevent one death or disability is 11 in a 6 hour time window and 7 in a 3 hour time window. These are impressive numbers that are rarely found in other areas of internal or neurological medicine. The most important risk of thrombolytic therapy is the occurrence of intracerebral hemorrhage, which is reported as between 0-18 p. 100, but which is not associated with increased morbidity or mortality. At present, thrombolytic therapy cannot be recommended for all patients with acute stroke. Careful selection and experiences with this therapy and its risks are necessary.

[How did the results of ECASS II influence clinical practice of treatment of acute stroke]. / Cómo han influido los resultados del estudio ECASS II en la práctica clínica del tratamiento de la enfermedad cerebrovascular aguda?

INTRODUCTION AND DEVELOPMENT: There appears to be a rationale for the use of thrombolysis in ischemic stroke. Streptokinase should no longer be used to treat acute ischemic stroke. However, thrombolytic treatment with recombinant tissue plasminogen activator (rt-PA) may have an important role in the management of acute stroke. The studies to-date highlight the importance of early intervention and careful patient selection. In the National Institute of Neurological Disorders and Stroke (NINDS) trial, treatment within three hours was associated with an improved functional outcome without an increase in mortality. In the European Cooperative Acute Stroke Study (ECASS), treatment of eligible patients resulted in improved neurologic and functional out come. In the Multicentre Acute Stroke Trial Europe (MAST-E) and Australian Streptokinase Trial (ASK) trials, later intervention was associated with an increased risk of cerebral hemorrhage and poor outcome. CONCLUSIONS: Successful use of thrombolytic therapy with rt-PA, therefore, depends on rapid assessment to exclude patients with hemorrhagic stroke or those at risk of hemorrhagic complications. It has been shown to be beneficial in patients treated within three hours who conform to the strict inclusion and exclusion criteria of the NINDS trial. Moreover, after the results of ECASS II, and the recent metaanalyses of all three major rt-PA trials, it seems that with strict selection criteria, expert CT-reading, adherence to the protocols and a stroke unit type approach, the time window for thrombolysis may be as long as six hours in selected patients.

Contrast-enhanced magnetic resonance angiography in stroke diagnostics: additional information compared with time-of-flight magnetic resonance angiography?

PURPOSE: The aim of this study was a comparison of the diagnostic value of time-of-flight magnetic resonance angiography (TOF-MRA) and contrast-enhanced (CE) MRA in the setting of acute stroke MRI. The hypothesis was that CE-MRA has at least the same diagnostic value as the commonly used TOF-MRA. MATERIALS AND METHODS: A total of 66 stroke patients underwent MRI up to 24 h after symptom onset and again after 3­6 days. Primary slices and maximum intensity projections (MIP) of both techniques were evaluated separately and in combination by two readers in consensus. The quality of imaging and degree of vascular pathologies were evaluated. RESULTS: Out of 109 examinations 105 could be evaluated. There were no significant differences in imaging quality in normal vascular segments. For arterial segments distal to an occlusion CE-MRA allowed better visualization of vessels than TOF-MRA. A combined evaluation of both techniques allowed a significantly better assessment than evaluation of images by one technique alone. In contrast to TOF-MRA, CE-MRA included extracranial segments. CONCLUSION: CE-MRA and TOF-MRA do not differ regarding the evaluation of normal intracranial vessels. CE-MRA provides the advantage of good visualization of vessels distal to occluded segments. Furthermore CE-MRA allows visualization of extracranial vessels and faster image acquisition. TOF-MRA can be equivalently used if the administration of contrast agents is not possible.

Stent-protected angioplasty in asymptomatic carotid artery stenosis vs. endarterectomy: SPACE2 - a three-arm randomised-controlled clinical trial.

Moderate to severe (> or =70%) asymptomatic stenosis of the extracranial carotid artery leads to an increased rate of stroke of approximately 11% in 5 years. Patients with asymptomatic carotid stenosis, however, are also at a higher risk of nonstroke vascular events. The estimated annual risks of such events in patients with asymptomatic stenosis are 7% for a coronary ischaemic event and 4-7% for overall mortality. The superiority of carotid endarterectomy compared with medical treatment in symptomatic carotid disease is established, provided that the surgical procedure can be performed with a perioperative morbidity and mortality of <6%. The advantage of carotid endarterectomy for asymptomatic patients is less established. An alternative treatment, carotid artery stenting, has been developed. This treatment is used frequently in both symptomatic and asymptomatic patients. In the last decade, major advantages in medical primary prevention of cerebrovascular and cardiovascular disease have been accomplished. The control groups in the large trials for asymptomatic carotid artery disease (ACAS and ACST) originate from more than a decade ago and, for the most part, have not received a medical primary prevention strategy that would now be considered the standard according to current national and international guidelines. For this reason, a three-arm trial (SPACE2; http://www.space-2.de) with a hierarchical design and a recruitment target of 3640 patients is chosen. Firstly, a superior trial of intervention (carotid artery stenting or carotid endarterectomy) vs. state-of-the-art conservative treatment is designed. In case of superiority of the interventions, a noninferiority end-point will be tested between carotid artery stenting and carotid endarterectomy. This trial is registered at Current Controlled Trials ISRCTN 78592017.

Bootstrap statistics of ECASS II data: just another post hoc analysis of a negative stroke trial?

UNLABELLED: The results of the Second European-Australasian Acute Stroke Study (ECASS II) were negative with respect to the primary endpoint. This post hoc analysis of ECASS II data was designed to make the least number of a priori assumptions. This is accomplished by a bootstrap-based hypothesis test on a non-parametric test statistic. No assumptions are made on shape or variance of population distributions and the method does not suffer from the disadvantages of dichotomization. By reducing the number of a priori assumptions, the possibilities to modify the test result by adjusting the test procedure are minimized. RESULTS: If rt-PA does not improve the outcome (null hypothesis), the probability of observing a difference of modified ranking scale equal or larger than the one observed in ECASS II is 0.047. We therefore rejected the null hypothesis.

Laser Doppler flowmetry of focal ischaemia and reperfusion in deep brain structures in rats.

Monitoring cerebral blood flow during focal ischaemia and reperfusion with established techniques such as hydrogen clearance and autoradiography is difficult. Laser Doppler flowmetry is a new technique, it allows one to continuously measure blood flow in small tissue samples. The objective of this study was to compare laser Doppler flowmetry with hydrogen clearance using a new single fiber probe to obtain measurements in deep brain structures and then to show the temporal profile of cerebral blood flow during focal ischaemia and after reperfusion. First, the single fiber laser Doppler method was compared with the hydrogen clearance method in ten Wistar rats. Second, focal cerebral ischaemia was induced in fifteen Wistar rats using a model of middle cerebral artery occlusion based on the intravascular insertion of a nylon suture; reperfusion occurred after withdrawal of the suture. The laser Doppler probe was placed in the lateral caudatoputamen, and local cerebral blood flow was measured continuously before and during occlusion as well as after reperfusion. The relative blood flow values obtained by the laser Doppler method and the hydrogen clearance method showed a good correlation (r = 0.76) and a linear relationship. A rapid decrease in laser Doppler flowmetry to 42 +/- 16% of former baseline values was seen with occlusion of the middle cerebral artery; during occlusion cerebral blood flow remained at this level. Reperfusion resulted in a heterogeneous pattern of cerebral blood flow as laser Doppler flowmetry values ranged from 25% to 134% of baseline values. The effects of middle cerebral artery occlusion and reperfusion on cerebral blood flow can be monitored on-line with laser Doppler flowmetry.(ABSTRACT TRUNCATED AT 250 WORDS)