New recommendations on cerebral venous and dural sinus thrombosis from the German consensus-based (S2k) guideline.

Over the last years, new evidence has accumulated on multiple aspects of diagnosis and management of cerebral venous and dural sinus thrombosis (CVT) including identification of new risk factors, studies on interventional treatment as well as treatment with direct oral anticoagulants. Based on the GRADE questions of the European Stroke Organization guideline on this topic, the new German guideline on CVT is a consensus between expert representatives of Austria, Germany and Switzerland. New recommendations include:• CVT occurring in the first weeks after SARS-CoV-2 vaccination with vector vaccines may be associated with severe thrombocytopenia, indicating the presence of a prothrombotic immunogenic cause (Vaccine-induced immune thrombotic thrombocytopenia; VITT).• D-dimer testing to rule out CVT cannot be recommended and should therefore not be routinely performed.• Thrombophilia screening is not generally recommended in patients with CVT. It should be considered in young patients, in spontaneous CVT, in recurrent thrombosis and/or in case of a positive family history of venous thromboembolism, and if a change in therapy results from a positive finding.• Patients with CVT should preferably be treated with low molecular weight heparine (LMWH) instead of unfractionated heparine in the acute phase.• On an individual basis, endovascular recanalization in a neurointerventional center may be considered for patients who deteriorate under adequate anticoagulation.• Despite the overall low level of evidence, surgical decompression should be performed in patients with CVT, parenchymal lesions (congestive edema and/or hemorrhage) and impending incarceration to prevent death.• Following the acute phase, oral anticoagulation with direct oral anticoagulants instead of vitamin K antagonists should be given for 3 to 12 months to enhance recanalization and prevent recurrent CVT as well as extracerebral venous thrombosis.• Women with previous CVT in connection with the use of combined hormonal contraceptives or pregnancy shall refrain from continuing or restarting contraception with oestrogen-progestagen combinations due to an increased risk of recurrence if anticoagulation is no longer used.• Women with previous CVT and without contraindications should receive LMWH prophylaxis during pregnancy and for at least 6 weeks post partum.Although the level of evidence supporting these recommendations is mostly low, evidence from deep venous thrombosis as well as current clinical experience can justify the new recommendations.This article is an abridged translation of the German guideline, which is available online.

Endovascular therapy outcome in isolated posterior cerebral artery occlusion strokes: A multicenter analysis of the Swiss Stroke Registry.

PURPOSE: There is little data on the safety and efficacy of endovascular treatment (EVT) in comparison with intravenous thrombolysis (IVT) in acute ischemic stroke due to isolated posterior cerebral artery occlusion (IPCAO). We aimed to investigate the functional and safety outcomes of stroke patients with acute IPCAO treated with EVT (with or without prior bridging IVT) compared to IVT alone. METHODS: We did a multicenter retrospective analysis of data from the Swiss Stroke Registry. The primary endpoint was overall functional outcome at 3 months in patients undergoing EVT alone or as part of bridging, compared with IVT alone (shift analysis). Safety endpoints were mortality and symptomatic intracranial hemorrhage. EVT and IVT patients were matched 1:1 using propensity scores. Differences in outcomes were examined using ordinal and logistic regression models. FINDINGS: Out of 17,968 patients, 268 met the inclusion criteria and 136 were matched by propensity scores. The overall functional outcome at 3 months was comparable between the two groups (EVT vs IVT as reference category: OR = 1.42 for higher mRS, 95% CI = 0.78-2.57, p = 0.254). The proportion of patients independent at 3 months was 63.2% in EVT and 72.1% in IVT (OR = 0.67, 95% CI = 0.32-1.37, p = 0.272). Symptomatic intracranial hemorrhages were overall rare and present only in the IVT group (IVT = 5.9% vs EVT = 0%). Mortality at 3 months was also similar between the two groups (IVT = 0% vs EVT = 1.5%). CONCLUSION: In this multicenter nested analysis, EVT and IVT in patients with acute ischemic stroke due to IPCAO were associated with similar overall good functional outcome and safety. Randomized studies are warranted.

Impact of intravenous thrombolysis on recanalization rates in patients with stroke treated with bridging therapy.

BACKGROUND AND PURPOSE: Randomized controlled trials have shown that bridging endovascular therapy (EVT) after intravenous thrombolysis (IVT) therapy improves outcome in patients with stroke with large-artery anterior circulation stroke compared with IVT alone. It remains unknown whether IVT adds any benefit to EVT in these patients. The aim of this study was to assess recanalization rates and thrombus dislocation before initiation of EVT in patients receiving bridging therapy. METHODS: All patients in the Bernese stroke registry (2008-2015) in whom bridging therapy was considered were included in this analysis. Relevant recanalization before EVT, thrombus dislocation and increase in thrombus load between initial and control imaging were assessed retrospectively. RESULTS: A total of 319 patients were included. Relevant recanalization before EVT occurred in 8.8% and thrombus dislocation in 7.2% of patients before EVT. Recanalization rates were significantly higher in distal compared with large and more proximal vessel occlusions of the anterior circulation (occlusion of internal carotid artery, 5.4%; middle cerebral artery segment M1, 8.1%; middle cerebral artery segment M2, 17.6%) and in drip-and-ship patients compared with mother-ship patients. In multivariable regression analysis the occlusion site was the only independent predictor of relevant recanalization before EVT (P = 0.046). CONCLUSIONS: Relevant recanalization after IVT and prior to EVT in patients receiving bridging therapy was highly dependent on the occlusion site. These findings suggest that future randomized controlled trials should consider occlusion site and treatment paradigm to specify patients who benefit most from bridging therapy in comparison to EVT or IVT alone.

Impact of Anesthesia on the Outcome of Acute Ischemic Stroke after Endovascular Treatment with the Solitaire Stent Retriever.

BACKGROUND AND PURPOSE: General anesthesia during endovascular treatment of acute ischemic stroke may have an adverse effect on outcome compared with conscious sedation. The aim of this study was to examine the impact of the type of anesthesia on the outcome of patients with acute ischemic stroke treated with the Solitaire stent retriever, accounting for confounding factors. MATERIALS AND METHODS: Four-hundred one patients with consecutive acute anterior circulation stroke treated with a Solitaire stent retriever were included in this prospective analysis. Outcome was assessed after 3 months by the modified Rankin Scale. RESULTS: One-hundred thirty-five patients (31%) underwent endovascular treatment with conscious sedation, and 266 patients (69%), with general anesthesia. Patients under general anesthesia had higher NIHSS scores on admission (17 versus 13, P < .001) and more internal carotid artery occlusions (44.6% versus 14.8%, P < .001) than patients under conscious sedation. Other baseline characteristics such as time from symptom onset to the start of endovascular treatment did not differ. Favorable outcome (mRS 0-2) was more frequent with conscious sedation (47.4% versus 32%; OR, 0.773; 95% CI, 0.646-0.925; P = .002) in univariable but not multivariable logistic regression analysis (P = .629). Mortality did not differ (P = .077). Independent predictors of outcome were age (OR, 0.95; 95% CI, 0.933-0.969; P < .001), NIHSS score (OR, 0.894; 95% CI, 0.855-0.933; P < .001), time from symptom onset to the start of endovascular treatment (OR, 0.998; 95% CI, 0.996-0.999; P = .011), diabetes mellitus (OR, 0.544; 95% CI, 0.305-0.927; P = .04), and symptomatic intracerebral hemorrhage (OR, 0.109; 95% CI, 0.028-0.428; P = .002). CONCLUSIONS: In this single-center study, the anesthetic management during stent retriever thrombectomy with general anesthesia or conscious sedation had no impact on the outcome of patients with large-vessel occlusion in the anterior circulation.

Thrombolysis in patients with prior stroke within the last 3 months.

BACKGROUND AND PURPOSE: Patients with prior stroke within 3 months have been mostly excluded from randomized thrombolysis trials mainly because of the fear of an increased rate of symptomatic intracerebral hemorrhage (sICH). The aim of this study was to compare baseline characteristics and clinical outcome of thrombolyzed patients who had a previous stroke within the last 3 months with those not fulfilling this criterion (comparison group). METHODS: In all, 1217 patients were included in our analysis (42.2% women, mean age 68.8 ± 14.4 years). RESULTS: Patients with previous stroke within the last 3 months (17/1.4%) had more often a basilar artery occlusion (41.2% vs. 10.8%) and less frequently a modified Rankin scale (mRS) score 0-1 prior to index stroke (88.2% vs. 97.3%) and a higher mean time lapse from symptom onset to thrombolysis (321 min vs. 262 min) than those in the comparison group. Stroke severity was not different between the two groups. Rates of sICH were 11.8% vs. 6%. None of the sICHs and only one asymptomatic intracerebral hemorrhage occurred in the region of the former infarct. At 3 months, favorable outcome (mRS ≤ 2) in patients with previous stroke within 3 months was 29.4% (vs. 48.9%) and mortality 41.2% (vs. 22.7%). CONCLUSIONS: In patients with prior stroke within the last 3 months, none of the sICHs and only one asymptomatic intracerebral hemorrhage occurred in the region of the former infarct. The high mortality was influenced by four patients, who died until discharge due to acute major index stroke. It is reasonable to include these patients in randomized clinical trials and registries to assess further their thrombolysis benefit-risk ratio.

Endovascular therapy in 201 patients with acute symptomatic occlusion of the internal carotid artery.

BACKGROUND AND PURPOSE: Endovascular therapy is used increasingly for treatment of acute symptomatic internal carotid artery (ICA) occlusion, although randomized trials are lacking. Predictors of outcome are therefore of special interest. METHODS: From 1992 to 2010 we treated 201 patients with acute ICA occlusion with intra-arterial pharmacological thrombolysis (32), endovascular mechanical therapy (78) or a combination of both (91). All data were assessed prospectively. RESULTS: There were 76/38% patients with tandem occlusions [ICA plus middle (MCA) or anterior cerebral arteries (ACA)], 18/9% without concomitant occlusions of major intracranial arteries (ICA plus branch occlusion) and 107/53% with functional ICA-T occlusions (ICA plus MCA and ACA). Median baseline National Institute of Health Stroke Scale (NIHSS) score was 17. Good recanalization (Thrombolysis in Myocardial Infarction 2-3) was achieved in (157/201) 78% patients and good reperfusion (Thrombolysis in Cerebral Infarction 2-3) in (151/182) 83%. Better recanalization rates were obtained with mechanical approaches, with/without thrombolytics (78/91 = 86% and 64/78 = 82%) compared with pharmacological thrombolysis only (15/32 = 47%; P < 0.001). Twelve patients (6%) suffered symptomatic intracranial haemorrhages. The 3-month outcome was favourable [modified Rankin score (mRS) 0-2] in 54/28% patients and moderate (mRS 0-3) in 90/46%; 60/31% patients died. Only 17/16% patients with functional ICA-T occlusions had favourable outcomes compared with 32/44% with tandem occlusions and 5/31% with ICA plus cerebral branch occlusions (P = 0.001). In multivariate analysis age [odds ratio (OR) = 0.96, 95% confidence interval (CI) = 0.93-0.98], NIHSS on admission (OR = 0.9, 95% CI = 0.83-0.98) and functional ICA-T occlusion (OR = 0.35, 95% CI = 0.16-0.77) were non-modifiable predictors, and vessel recanalization was the only modifiable predictor of outcome (OR = 9.30, 95% CI = 2.03-42.63). CONCLUSIONS: The outcome of acute symptomatic ICA occlusion is poor. However, recanalization is associated with better outcome, and recanalization rates with mechanical techniques were superior to merely pharmacological recanalization attempts.

Safety of endovascular treatment beyond the 6-h time window in 205 patients.

BACKGROUND AND PURPOSE: Intra-arterial treatment (IAT) is effective when performed within 6 h of symptom onset in selected stroke patients ('T < 6H'). Its safety and efficacy is unclear when the patient has had symptoms for more than 6 h ('T > 6H') or for an unknown time (unclear-onset stroke, UOS), or woke up with a stroke (wake-up stroke, WUS). In this study we compared the safety of IAT in these four patient groups. METHODS: Eight-hundred and fifty-nine patients treated with IAT were enrolled. The main outcome parameters were clinical outcome [excellent: modified Rankin Scale (mRS) 0 or 1; or favorable: mRS 0-2] or mortality 3 months after treatment. Further outcome parameters were the rates of vessel recanalization, and cerebral and systemic hemorrhage. RESULTS: Six-hundred and fifty-four patients were treated before (T < 6H) and 205 after 6 h or an unknown time (128 T > 6H, 55 WUS and 22 UOS). NIHSS scores were higher in UOS patients than in T < 6H patients, vertebrobasilar occlusion was more common in T > 6H and UOS patients, and middle cerebral artery occlusions less common in T > 6H than in T < 6H patients. Other baseline characteristics were similar. There was no significant difference in clinical outcome and the rate of hemorrhage in multivariable regression analysis. CONCLUSIONS: Clinical outcome of our four groups of patients was similar with no increase of hemorrhage rates in patients treated after awakening, after an unknown time or more than 6 h. Our preliminary data suggest that treatment of such patients may be performed safely. If confirmed in randomized trials, this would have major clinical implications.

Impact of retrievable stents on acute ischemic stroke treatment.

BACKGROUND AND PURPOSE: Retrievable stents combine the high recanalization rate of stents and the capability of removing the thrombus offered by mechanical thrombectomy devices. We hypothesized that retrievable stents shorten time to recanalization in the multimodal approach for endovascular stroke treatment. MATERIALS AND METHODS: Forty consecutive patients with acute ischemic stroke and undergoing endovascular therapy were included. Treatment included thromboaspiration, thrombus disruption, thrombolysis, PTA, and stent placement. In 17 patients, a retrievable stent was used (group A) in addition to multimodal therapy. The remaining 23 patients constituted group B. Baseline characteristics, occlusion sites, urokinase dose, recanalization rate, and time to recanalization were compared between the groups. RESULTS: Median NIHSS scores were higher in group A compared with group B on admission (19 versus 12.5; P = .018) but were not significantly different at day 1 (14 versus 10; P = .6). Intra-arterial thrombolysis was used in significantly fewer patients of group A than group B (53% versus 87%, respectively; P = .017), and median urokinase dose was lower in group A than in group B (250,000 IU versus 700,000 IU; P = .006). Time to recanalization was significantly shorter in group A compared with group B (median time to recanalization 52.5 minutes versus 90 minutes, respectively; P = .001). Recanalization rate was higher in group A than group B (94% versus 78%; P = .17). CONCLUSIONS: Addition of retrievable stents to the multimodal endovascular approach for acute ischemic stroke treatment significantly reduces time to recanalization and further increases the recanalization rate.

G protein-coupled receptor-induced sensitization of phospholipase C stimulation by receptor tyrosine kinases.

Activation of stably expressed M(2) and M(3) muscarinic acetylcholine receptors (mAChRs) as well as of endogenously expressed lysophosphatidic acid and purinergic receptors in HEK-293 cells can induce a long lasting potentiation of phospholipase C (PLC) stimulation by these and other G protein-coupled receptors (GPCRs). Here, we report that GPCRs can induce an up-regulation of PLC stimulation by receptor tyrosine kinases (RTKs) as well and provide essential mechanistic characteristics of this sensitization process. Pretreatment of HEK-293 cells for 2 min with carbachol, a mAChR agonist, lysophosphatidic acid, or ATP, followed by agonist washout, strongly increased (by 2-3-fold) maximal PLC stimulation (measured >/=40 min later) by epidermal growth factor and platelet-derived growth factor, but not insulin, and largely enhanced PLC sensitivity to these RTK agonists. The up-regulation of RTK-induced PLC stimulation was cycloheximide-insensitive and was observed for up to approximately 90 min after removal of the GPCR agonist. Sensitization of receptor-induced PLC stimulation caused by prior M(2) mAChR activation was fully prevented by pertussis toxin and strongly reduced by expression of Gbetagamma scavengers. Furthermore, inhibition of conventional protein kinase C (PKC) isoenzymes and chelation of intracellular Ca(2+) suppressed the sensitization process, while overexpression of PKC-alpha, but not PKC-betaI, further enhanced the M(2) mAChR-induced sensitization of PLC stimulation. None of these treatments affected acute PLC stimulation by either GPCR or RTK agonists. Taken together, short term activation of GPCRs can induce a strong and long lasting sensitization of PLC stimulation by RTKs, a process apparently involving G(i)-derived Gbetagammas as well as increases in intracellular Ca(2+) and activation of a PKC isoenzyme, most likely PKC-alpha.