Martin Bendszus

Silent embolism in diagnostic cerebral angiography and neurointerventional procedures: a prospective study

BACKGROUND Cerebral angiography is associated with a small but definite risk of neurological complications with an unknown incidence of clinically silent embolism. We assessed the neurological complication rate compared with the frequency of silent embolism after angiography METHODS We used diffusion-weighted magnetic resonance imaging (MRI) before and after angiography to assess embolic events. 100 consecutive angiographies (66 diagnostic and 34 interventional procedures) were done on 91 patients. Patients underwent neurological assessment before, immediately after, and 1 day after angiography. FINDINGS Before angiography, no abnormalities were seen on diffusion-weighted MRI. Diffusion-weighted MRI showed 42 bright lesions in 23 patients after 23 procedures (17 diagnostic, six interventional) in a pattern consistent with embolic events. There was no new neurological deficit after any angiographic procedure. After diagnostic angiography in patients with a history of vasculopathy, the frequency of lesions was significantly higher than in patients without vascular risk factors (12 [44%] of 27 vs five [13%] of 39 patients, p=0.03). In diagnostic angiography, the appearance of lesions was significantly correlated with whether vessels were difficult to probe (p=0.01), amount of contrast medium needed (p<0.01), fluoroscopy time (p<0.01), and use of additional catheters (p=0.02). INTERPRETATION After diagnostic and interventional cerebral angiography, embolic events are more frequent than the apparent neurological complication rate. In diagnostic procedures, the incidence of embolism is closely related to a vascular risk profile.

Inflammation and Atherosclerosis Novel Insights Into Plaque Formation and Destabilization

Background and Purpose— The simplistic view of atherosclerosis as a disorder of pathological lipid deposition has been redefined by the more complex concept of an ongoing inflammatory response. Summary of Review— Apolipoprotein E and low-density lipoprotein (LDL)-receptor-deficient mice develop accelerated atherosclerosis allowing in-depth pathophysiological investigations. Atherosclerotic plaques in these mice contain large numbers of T cells and macrophages. Crossbreading apolipoprotein E-deficient mice with T-cell-deficient mice and mice with impaired macrophage function (osteopetrotic op/op mice) disclosed the important impact of immune cells on atherosclerotic lesion development. In contrast to the detrimental role of T cells and macrophages, B cells appear to be atheroprotective. These basic experimental findings have partly been confirmed in studies of the human carotid artery system. Inflammation is not only instrumental in the development of human atheromatous plaques, but, importantly, plays a crucial role in the destabilization of internal carotid artery plaques, thus converting chronic atherosclerosis into an acute thrombo-embolic disorder. Humoral factors involved in internal carotid artery destabilization include cytokines, cyclooxygenase-2, matrix metalloproteinases, and tissue factor. Antibodies to oxidized LDL can reflect disease activity on one hand, but can also confer atheroprotection. Novel MRI techniques may aid in the in vivo assessment of acute plaque inflammation in humans. Conclusions— The impact of inflammation on the development of atherosclerotic plaques and their destabilization opens new avenues for treatment. The effects of statins, acetylsalicyclic acid and angiotensin-converting enzyme inhibitors on stroke prevention may partly be attributable to their profound anti-inflammatory actions. Vaccination against modified LDL and heat shock proteins halt plaque progression in experimental atherosclerosis. Their potential for prevention of human atherosclerosis is currently under investigation.

Recommendations on Angiographic Revascularization Grading Standards for Acute Ischemic Stroke A Consensus Statement

See related article, p 2509 Intra-arterial therapy (IAT) for acute ischemic stroke (AIS) has dramatically evolved during the past decade to include aspiration and stent-retriever devices. Recent randomized controlled trials have demonstrated the superior revascularization efficacy of stent-retrievers compared with the first-generation Merci device.1,2 Additionally, the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) 2, the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE), and the Interventional Management of Stroke (IMS) III trials have confirmed the importance of early revascularization for achieving better clinical outcome.3–5 Despite these data, the current heterogeneity in cerebral angiographic revascularization grading (CARG) poses a major obstacle to further advances in stroke therapy. To date, several CARG scales have been used to measure the success of IAT.6–14 Even when the same scale is used in different studies, it is applied using varying operational criteria, which further confounds the interpretation of this key metric.10 The lack of a uniform grading approach limits comparison of revascularization rates across clinical trials and hinders the translation of promising, early phase angiographic results into proven, clinically effective treatments.6–14 For these reasons, it is critical that CARG scales be standardized and end points for successful revascularization be refined.6 This will lead to a greater understanding of the aspects of revascularization that are strongly predictive of clinical response. The optimal grading scale must demonstrate (1) a strong correlation with clinical outcome, (2) simplicity and feasibility of scale interpretation while ensuring characterization of relevant angiographic findings, and (3) high inter-rater reproducibility. To address these issues, a multidisciplinary panel of neurointerventionalists, neuroradiologists, and stroke neurologists with extensive experience in neuroimaging and IAT, convened at the “Consensus Meeting on Revascularization Grading Following Endovascular Therapy” with the goal …

Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis

Formation of fibrin is critical for limiting blood loss at a site of blood vessel injury (hemostasis), but may also contribute to vascular thrombosis. Hereditary deficiency of factor XII (FXII), the protease that triggers the intrinsic pathway of coagulation in vitro, is not associated with spontaneous or excessive injury-related bleeding, indicating FXII is not required for hemostasis. We demonstrate that deficiency or inhibition of FXII protects mice from ischemic brain injury. After transient middle cerebral artery occlusion, the volume of infarcted brain in FXII-deficient and FXII inhibitor–treated mice was substantially less than in wild-type controls, without an increase in infarct-associated hemorrhage. Targeting FXII reduced fibrin formation in ischemic vessels, and reconstitution of FXII-deficient mice with human FXII restored fibrin deposition. Mice deficient in the FXII substrate factor XI were similarly protected from vessel-occluding fibrin formation, suggesting that FXII contributes to pathologic clotting through the intrinsic pathway. These data demonstrate that some processes involved in pathologic thrombus formation are distinct from those required for normal hemostasis. As FXII appears to be instrumental in pathologic fibrin formation but dispensable for hemostasis, FXII inhibition may offer a selective and safe strategy for preventing stroke and other thromboembolic diseases.

Hemostatic Therapy in Experimental Intracerebral Hemorrhage Associated With the Direct Thrombin Inhibitor Dabigatran

Background and Purpose— Dabigatran-etexilate (DE) recently has been approved for stroke prevention in atrial fibrillation. However, lack of effective antagonists represents a major concern in the event of intracerebral hemorrhage (ICH). The aims of the present study were to establish a murine model of ICH associated with dabigatran, and to test the efficacy of different hemostatic factors in preventing hematoma growth. Methods— In C57BL/6 mice receiving DE (4.5 or 9.0 mg/kg), in vivo and in vitro coagulation assays and dabigatran plasma levels were measured repeatedly. Thirty minutes after inducing ICH by striatal collagenase injection, mice received an intravenous injection of saline, prothrombin complex concentrate (PCC; 100 U/kg), murine fresh-frozen plasma (200 &mgr;L), or recombinant human factor VIIa (8.0 mg/kg). ICH volume was quantified on brain cryosections 24 hours later. Results— DE substantially prolonged tail vein bleeding time and ecarin clotting time for 4 hours corresponding to dabigatran plasma levels. Intracerebral hematoma expansion was observed mainly during the first 3 hours on serial T2* MRI. Anticoagulation with high doses of DE increased the hematoma volume significantly. PCC and, less consistently, fresh-frozen plasma prevented excess hematoma expansion caused by DE, whereas recombinant human factor VIIa was ineffective. Prevention of hematoma growth and reversal of tail vein bleeding time by PCC were dose-dependent. Conclusions— The study provides strong evidence that PCC and, less consistently, fresh-frozen plasma prevent excess intracerebral hematoma expansion in a murine ICH model associated with dabigatran. The efficacy and safety of this strategy must be further evaluated in clinical studies.

The HMGB1 Receptor RAGE Mediates Ischemic Brain Damage

In ischemic stroke, the necrotic core is surrounded by a zone of inflammation, in which delayed cell death aggravates the initial insult. Here, we provide evidence that the receptor for advanced glycation end products (RAGE) functions as a sensor of necrotic cell death and contributes to inflammation and ischemic brain damage. The RAGE ligand high mobility group box 1 (HMGB1) was elevated in serum of stroke patients and was released from ischemic brain tissue in a mouse model of cerebral ischemia. A neutralizing anti-HMGB1 antibody and HMGB1 box A, an antagonist of HMGB1 at the receptor RAGE, ameliorated ischemic brain damage. Interestingly, genetic RAGE deficiency and the decoy receptor soluble RAGE reduced the infarct size. In vitro, expression of RAGE in (micro)glial cells mediated the toxic effect of HMGB1. Addition of macrophages to neural cultures further enhanced the toxic effect of HMGB1. To test whether immigrant macrophages in the ischemic brain mediate the RAGE effect, we generated chimeric mice by transplanting RAGE−/− bone marrow to wild-type mice. RAGE deficiency in bone marrow-derived cells significantly reduced the infarct size. Thus, HMGB1–RAGE signaling links necrosis with macrophage activation and may provide a target for anti-inflammatory therapy in stroke.

Gadolinium Retention in the Dentate Nucleus and Globus Pallidus Is Dependent on the Class of Contrast Agent

PURPOSE To compare changes in signal intensity (SI) ratios of the dentate nucleus (DN) and the globus pallidus (GP) to those of other structures on unenhanced T1-weighted magnetic resonance (MR) images between linear and macrocyclic gadolinium-based contrast agents (GBCAs). MATERIALS AND METHODS The study was approved by the ethical committee of the University of Heidelberg (reference no. S-324/2014). Owing to the retrospective character of the study, the ethical committee did not require any written informed consent. Two groups of 50 patients who underwent at least six consecutive MR imaging examinations with the exclusive use of either a linear GBCA (gadopentetate dimeglumine) or a macrocyclic GBCA (gadoterate meglumine) were analyzed retrospectively. The difference in mean SI ratios of DN to pons and GP to thalamus on unenhanced T1-weighted images from the last and first examinations was calculated. One-sample and independent-sample t tests were used to assess the difference in SI ratios for both groups, and regression analysis was performed to account for potential confounders. RESULTS The SI ratio difference in the linear group was greater than 0 (mean DN difference ± standard deviation, 0.0407 ± 0.0398 [P < .001]; GP, 0.0287 ± 0.0275 [P < .001]) and significantly larger (DN, P < .001 and standardized difference of 1.16; GP, P < .001 and standardized difference of 0.81) than that in the macrocyclic group, which did not differ from 0 (DN, 0.0016 ± 0.0266 [P = .680]; GP, 0.0031 ± 0.0354 [P = .538]). The SI ratio difference between the last and first examinations for the DN remained significantly different between the two groups in the regression analysis (P < .001). CONCLUSION This study indicates that an SI increase in the DN and GP on T1-weighted images is caused by serial application of the linear GBCA gadopentetate dimeglumine but not by the macrocyclic GBCA gadoterate meglumine. Clinical implications of this observation remain unclear.

Targeting Platelets in Acute Experimental Stroke Impact of Glycoprotein Ib, VI, and IIb/IIIa Blockade on Infarct Size, Functional Outcome, and Intracranial Bleeding

Background— Ischemic stroke is a frequent and serious disease with limited treatment options. Platelets can adhere to hypoxic cerebral endothelial cells by binding of their glycoprotein (GP) Ib receptor to von Willebrand factor. Exposure of subendothelial matrix proteins further facilitates firm attachment of platelets to the vessel wall by binding of collagen to their GPVI receptor. In the present study, we addressed the pathogenic role of GPIb, GPVI, and the aggregation receptor GPIIb/IIIa in experimental stroke in mice. Methods and Results— Complete blockade of GPIb&agr; was achieved by intravenous injection of 100 &mgr;g Fab fragments of the monoclonal antibody p0p/B to mice undergoing 1 hour of transient middle cerebral artery occlusion. At 24 hours after transient middle cerebral artery occlusion, cerebral infarct volumes were assessed by 2,3,5-triphenyltetrazolium chloride staining. In mice treated with anti-GPIb&agr; Fab 1 hour before middle cerebral artery occlusion, ischemic lesions were reduced to ≈40% compared with controls (28.5±12.7 versus 73.9±17.4 mm3, respectively; P<0.001). Application of anti-GPIb&agr; Fab 1 hour after middle cerebral artery occlusion likewise reduced brain infarct volumes (24.5±7.7 mm3; P<0.001) and improved the neurological status. Similarly, depletion of GPVI significantly diminished the infarct volume but to a lesser extent (49.4±19.1 mm3; P<0.05). Importantly, the disruption of early steps of platelet activation was not accompanied by an increase in bleeding complications as revealed by serial magnetic resonance imaging. In contrast, blockade of the final common pathway of platelet aggregation with anti-GPIIb/IIIa F(ab)2 fragments had no positive effect on stroke size and functional outcome but increased the incidence of intracerebral hemorrhage and mortality after transient middle cerebral artery occlusion in a dose-dependent manner. Conclusions— Our data indicate that the selective blockade of key signaling pathways of platelet adhesion and aggregation has a different impact on stroke outcome and bleeding complications. Inhibition of early steps of platelet adhesion to the ischemic endothelium and the subendothelial matrix may offer a novel and safe treatment strategy in acute stroke.

Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature

We have recently identified T cells as important mediators of ischemic brain damage, but the contribution of the different T-cell subsets is unclear. Forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) are generally regarded as prototypic anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. In the present study, we examined the role of Tregs after experimental brain ischemia/reperfusion injury. Selective depletion of Tregs in the DEREG mouse model dramatically reduced infarct size and improved neurologic function 24 hours after stroke and this protective effect was preserved at later stages of infarct development. The specificity of this detrimental Treg effect was confirmed by adoptive transfer experiments in wild-type mice and in Rag1(-/-) mice lacking lymphocytes. Mechanistically, Tregs induced microvascular dysfunction in vivo by increased interaction with the ischemic brain endothelium via the LFA-1/ICAM-1 pathway and platelets and these findings were confirmed in vitro. Ablation of Tregs reduced microvascular thrombus formation and improved cerebral reperfusion on stroke, as revealed by ultra-high-field magnetic resonance imaging at 17.6 Tesla. In contrast, established immunoregulatory characteristics of Tregs had no functional relevance. We define herein a novel and unexpected role of Tregs in a primary nonimmunologic disease state.

Response assessment criteria for brain metastases: proposal from the RANO group

CNS metastases are the most common cause of malignant brain tumours in adults. Historically, patients with brain metastases have been excluded from most clinical trials, but their inclusion is now becoming more common. The medical literature is difficult to interpret because of substantial variation in the response and progression criteria used across clinical trials. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group is an international, multidisciplinary effort to develop standard response and progression criteria for use in clinical trials of treatment for brain metastases. Previous efforts have focused on aspects of trial design, such as patient population, variations in existing response and progression criteria, and challenges when incorporating neurological, neuro-cognitive, and quality-of-life endpoints into trials of patients with brain metastases. Here, we present our recommendations for standard response and progression criteria for the assessment of brain metastases in clinical trials. The proposed criteria will hopefully facilitate the development of novel approaches to this difficult problem by providing more uniformity in the assessment of CNS metastases across trials.