Stephen Meairs

Mannheim carotid intima-media thickness consensus (2004-2006). An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, 2006.

Intima-media thickness (IMT) is increasingly used as a surrogate end point of vascular outcomes in clinical trials aimed at determining the success of interventions that lower risk factors for atherosclerosis and associated diseases (stroke, myocardial infarction and peripheral artery diseases). The necessity to promote further criteria to distinguish early atherosclerotic plaque formation from thickening of IMT and to standardize IMT measurements is expressed through this updated consensus. Plaque is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness >1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. Standard use of IMT measurements is based on physics, technical and disease-related principles as well as agreements on how to perform, interpret and document study results. Harmonization of carotid image acquisition and analysis is needed for the comparison of the IMT results obtained from epidemiological and interventional studies around the world. The consensus concludes that there is no need to ‘treat IMT values’ nor to monitor IMT values in individual patients apart from exceptions named, which emphasize that inside randomized clinical trials should be performed. Although IMT has been suggested to represent an important risk marker, according to the current evidence it does not fulfill the characteristics of an accepted risk factor. Standardized methods recommended in this consensus statement will foster homogenous data collection and analysis. This will help to improve the power of randomized clinical trials incorporating IMT measurements and to facilitate the merging of large databases for meta-analyses.

MANNHEIM CAROTID INTIMA-MEDIA THICKNESS AND PLAQUE CONSENSUS (2004–2006–2011)

Intima-media thickness (IMT) provides a surrogate end point of cardiovascular outcomes in clinical trials evaluating the efficacy of cardiovascular risk factor modification. Carotid artery plaque further adds to the cardiovascular risk assessment. It is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness >1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. The scientific basis for use of IMT in clinical trials and practice includes ultrasound physics, technical and disease-related principles as well as best practice on the performance, interpretation and documentation of study results. Comparison of IMT results obtained from epidemiological and interventional studies around the world relies on harmonization on approaches to carotid image acquisition and analysis. This updated consensus document delineates further criteria to distinguish early atherosclerotic plaque formation from thickening of IMT. Standardized methods will foster homogenous data collection and analysis, improve the power of randomized clinical trials incorporating IMT and plaque measurements and facilitate the merging of large databases for meta-analyses. IMT results are applied to individual patients as an integrated assessment of cardiovascular risk factors. However, this document recommends against serial monitoring in individual patients.

Mannheim intima-media thickness consensus.

Intima-media thickness (IMT) is increasingly used in clinical trials as a surrogate end point for determining the success of interventions that lower risk factors for atherosclerosis. The necessity for unified criteria to distinguish early atherosclerotic plaque formation from thickening of IMT and to standardize IMT measurements is addressed in this consensus statement. Plaque is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness of ≧1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. Standard use of IMT measurements is recommended in all epidemiological and interventional trials dealing with vascular diseases to improve characterization of the population investigated. The consensus concludes that there is no need to ‘treat IMT values’ nor to monitor IMT values in individual patients apart from few exceptions. Although IMT has been suggested to represent an important risk marker, it does not fulfill the characteristics of an accepted risk factor. Standardized methods recommended in this consensus statement will foster homogenous data collection and analysis. This will help to improve the power of studies incorporating IMT measurements and to facilitate the merging of large databases for meta-analyses.

Improving Outcome after Stroke: Overcoming the Translational Roadblock

Stroke poses a massive burden of disease, yet we have few effective therapies. The paucity of therapeutic options stands contrary to intensive research efforts. The failure of these past investments demands a thorough re-examination of the pathophysiology of ischaemic brain injury. Several critical areas hold the key to overcoming the translational roadblock: (1) vascular occlusion: current recanalization strategies have limited effectiveness and may have serious side effects; (2) complexity of stroke pathobiology: therapy must acknowledge the ‘Janus-faced’ nature of many stroke targets and must identify endogenous neuroprotective and repair mechanisms; (3) inflammation and brain-immune-system interaction: inflammation contributes to lesion expansion, but is also instrumental in lesion containment and repair; stroke outcome is modulated by the interaction of the injured brain with the immune system; (4) regeneration: the potential of the brain for reorganization, plasticity and repair after injury is much greater than previously thought; (5) confounding factors, long-term outcome and predictive modelling. These 5 areas are linked on all levels and therefore need to be tackled by an integrative approach and innovative therapeutic strategies.

Molecular Imaging of Human Thrombus With Novel Abciximab Immunobubbles and Ultrasound

Background and Purpose— Molecular imaging of therapeutic interventions with targeted agents that simultaneously carry drugs or genes for local delivery is appealing. We investigated the ability of a novel microbubble carrier (immunobubble) for abciximab, a glycoprotein IIb/IIIa receptor inhibitor, for ultrasonographic molecular imaging of human clots. Methods— Human thrombi were incubated with immunobubbles conjugated with abciximab. Control clots were incubated in either saline or with immunobubbles conjugated with nonspecific antibody. We evaluated immunobubble suspensions with variable concentrations of encapsulated gas and measured mean acoustic intensity of the incubated clots. In vivo molecular imaging of human thrombi with abciximab immunobubbles was evaluated in a rat model of carotid artery occlusion. Results— Mean acoustic intensity was significantly higher for abciximab immunobubbles as compared with control immunobubbles under all conditions tested with maximum difference in intensity at a gas volume of 0.2 &mgr;L (P=0.0013 for mechanical index 0.05, P=0.0001 for mechanical index 0.7). Binding of abciximab immunobubbles to clots in vitro led to enhanced echogenicity dependent on bubble concentration. In vivo ultrasonic detectability of carotid thrombi was significantly higher for clots targeted with abciximab immunobubbles (P<0.05). Quantification of in vivo contrast enhancement displayed a highly significant increment for abciximab immunobubble-targeted clots compared with nonspecific immunobubble-targeted clots (P<0.0001) and to native clots (P<0.0001). Conclusions— This study demonstrates the feasibility of using a therapeutic agent for selective targeting in vascular imaging. Abciximab immunobubbles improve visualization of human clots both in vitro and in an in vivo model of acute arterial thrombotic occlusion.

Four-Dimensional Ultrasonographic Characterization of Plaque Surface Motion in Patients With Symptomatic and Asymptomatic Carotid Artery Stenosis

BACKGROUND AND PURPOSE In vitro studies of atherosclerotic plaque fracture mechanics suggest that analysis of local variations in surface deformability may provide information on relative vulnerability to plaque fissuring or rupture. We investigated plaque surface deformations in patients with symptomatic and asymptomatic carotid artery disease using 4-dimensional ultrasonography and techniques for measuring optical flow. METHODS Four-dimensional ultrasound examinations of carotid artery plaques were performed in 23 asymptomatic and 22 symptomatic patients with 50% to 90% stenosis of the internal carotid artery. Plaque surface motion during 1 cardiac cycle was computed with a hierarchical model-based motion estimator. Results were compared with plaque echogenicity and surface structure. RESULTS Of the 45 patients examined, plaque surface motion estimates were obtained for 18 asymptomatic and 13 symptomatic patients. There were no significant differences in echogenicity or surface structure of asymptomatic and symptomatic plaques (P>0.05). Results of motion estimation showed that asymptomatic plaques had surface motion vectors of equal orientation and magnitude to those of the internal carotid artery, whereas symptomatic plaques demonstrated evidence of inherent plaque movement. There was no significant difference in maximal plaque velocity between symptomatic and asymptomatic plaques (P<0.14). Maximal discrepant surface velocity (MDSV) in symptomatic plaques was 3.85+/-1.26 mm/s (mean+/-SD), which was significantly higher (P<0.001) than MDSV of asymptomatic plaques with 0.58+/-0.42 mm/s (mean+/-SD). CONCLUSIONS ++MDSV of carotid artery plaques is significantly different in asymptomatic and symptomatic disease. Further studies are warranted to determine whether plaque surface motion patterns can identify vulnerable plaques in patients with carotid artery stenosis.

Self-assembled liposome-loaded microbubbles: the missing link for safe and efficient ultrasound triggered drug-delivery

Liposome-loaded microbubbles have been recently introduced as a promising drug delivery platform for ultrasound guided drug delivery. In this paper we design liposome-loaded (lipid-shelled) microbubbles through the simple self-assembly of the involved compounds in a single step process. We thoroughly characterized the liposome-loading of the microbubbles and evaluated the cell killing efficiency of this material using doxorubicin (DOX) as a model drug. Importantly, we observed that the DOX liposome-loaded microbubbles allowed killing of melanoma cells even at very low doses of DOX. These findings clearly prove the potential of liposome-loaded microbubbles for ultrasound targeted drug delivery to cancer tissues.

Effects of Prophylactic Antibiotic Therapy With Mezlocillin Plus Sulbactam on the Incidence and Height of Fever After Severe Acute Ischemic Stroke The Mannheim Infection in Stroke Study (MISS)

Background and Purpose— Fever after stroke is a strong predictor for a negative outcome with infections as the most common cause. The aim of this pilot study was to evaluate the effects of prophylactic antibiotic therapy on the incidence and height of fever after acute ischemic stroke. Methods— This is a randomized, controlled study of antibiotic prophylaxis in patients with ischemic stroke enrolled within 24 hours from clinical onset who presented bedridden (modified Rankin score >3) with no significant infection. Interventions included prophylactic mezlocillin plus sulbactam (3×2 g/1 g for 4 days) or conventional management. Over 10 days, body temperature was continuously monitored, and the presence of infection was daily assessed. Primary end points were incidence and height of fever; secondary end points included rate of infection and clinical outcome. Results— Sixty patients were included (mean, 75 years; median National Institutes of Health Stroke Scale score, 16). Over the first 3 days, patients in the intervention group showed lower mean body temperatures as well as lower daily peak temperatures (P<0.05). Throughout the observation period, 15 of 30 patients in the intervention group but 27 of 30 patients in the conventionally treated group developed an infection (P<0.05). Mean interval until the diagnosis of infection was 5.1 days in the intervention group and 3.3 days in the control group (P<0.05). Clinical outcome was more favorable in patients with prophylactic therapy (P=0.01). Conclusions— In patients with acute severe stroke, prophylactic administration of mezlocillin plus sulbactam over 4 days decreases body temperature, lowers the rate of infection, and may be associated with a better clinical outcome.

Sonographic Assessment of Carotid Artery Stenosis Comparison of Power Doppler Imaging and Color Doppler Flow Imaging

BACKGROUND AND PURPOSE Power Doppler imaging (PDI) is a new ultrasound technique that, in contrast to color Doppler flow imaging (CDFI), generates intravascular color signals from the reflected echo amplitude depending mainly on the density of red blood cells. We evaluated the diagnostic significance of PDI compared with CDFI for the measurement of carotid stenosis and characterization of plaque surface. METHODS In 25 internal carotid artery stenoses, reduction of the intrastenotic lumen contrasted by blood density signals and color Doppler signals on longitudinal and transverse views was assessed for correlative evaluation. In addition, the peak systolic flow velocity of the Doppler spectrum was correlated with PDI and CDFI measurements. RESULTS PDI provided good visualization of the residual lumen in all stenoses, whereas displays on CDFI were inadequate in two calcified plaques. PDI revealed two ulcerative stenoses classified as smooth on CDFI. The correlation between PDI and CDFI was high for measurement of area stenosis (r = .93) and moderate for diameter stenosis (r = .73). Similarly, cross-sectional reduction on both imaging methods correlated more significantly with peak systolic flow velocity than diameter reduction. CONCLUSIONS This pilot study suggests that PDI provides additional information for luminal measurement and characterization of plaque surface in complicated high-grade carotid stenosis. Because of the absent visualization of hemodynamics, PDI should be used in combination with CDFI.

Characterization of Carotid Artery Plaques Using Real-time Compound B-mode Ultrasound

Background and Purpose— Real-time compound ultrasound imaging is a new technique for improving the image quality of B-mode scanning. We investigated the value of this method for the characterization of atherosclerotic plaques in the internal carotid artery. Methods— Thirty-two patients (22 men, 10 women; mean age, 75 years) with plaques of the internal carotid artery as identified by high-resolution B-mode scanning were investigated with real-time compound ultrasound imaging with the use of a 5- to 12-MHz dynamic range linear transducer on a duplex scanner. Two independent observers rated plaque morphology according to a standardized protocol. Results— The majority of plaques was classified as predominantly echogenic and as plaques of irregular surface, whereas ulcerated plaques were rarely observed. The interobserver agreement for plaque surface characterization was good for both compound ultrasound (&kgr;=0.72) and conventional B-mode (&kgr;=0.65). For the determination of plaque echogenicity, the reproducibility of compound ultrasound (&kgr;w=0.83) was even higher than that of conventional B-mode ultrasound (&kgr;w=0.74). According to a semiquantitative analysis, real-time compound ultrasound was rated superior in the categories plaque texture resolution, plaque surface definition, and vessel wall demarcation. Furthermore, there was a significant reduction of acoustic shadowing and reverberations. Conclusions— Real-time compound ultrasound is a suitable technique for the characterization of atherosclerotic plaques, showing good general agreement with high-resolution B-mode imaging. This advanced technique allows reduction of ultrasound artifacts and improves the assessment of plaque texture and surface for enhanced evaluation of carotid plaque morphology.