Outcome of endovascular stroke therapy in a large mandatory stroke-registry.

BACKGROUND: Endovascular stroke treatment (EST) has become the standard treatment for patients with stroke due to large vessel occlusion, especially in earlier time windows. Only few data from population-based registries on effectiveness of EST have been published. METHODS: Baden-Wuerttemberg is the third largest state in Germany in terms of area and population and has a structured stroke concept since 1998 which includes mandatory collection of quality assurance data. In 2018 and 2019, 3820 of 39,168 ischemic stroke patients (9.8%) were treated by EST (age median 78 y, NIHSS median 14). We analyzed the clinical outcome of these patients determined with the modified Rankin Scale (mRS) at discharge from the hospital or with the initiation of palliative therapy using logistic regression analysis with adjustment for the mRS at admission, additive IVT, age, and NIHSS. RESULTS: The probability of an excellent clinical outcome (mRS 0 or 1 at discharge) and for a good clinical outcome (mRS 0-2) were significantly higher in EST-patients (odds-ratio (OR) 1.27; 95% confidence interval (95% CI) 1.13-1.43, and OR of 1.15 (95% CI 1.04-1.28). Also, the regression model showed an advantage for EST-patients with less frequent 'decision for palliative care' (OR 0.87; 95% CI 0.78-0.98). Sensitivity analysis adjusting for intracranial vessel occlusion as further factor showed similar results. CONCLUSION: Our data suggest that EST can be of benefit also for an area-wide unselected stroke population, in a large German federal state with sometimes long distance to the next thrombectomy center.

Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany-Updated series of 120 cases.

BACKGROUND: Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran reversing its anticoagulant effects within minutes. Thereby, patients with acute ischemic stroke who are on dabigatran treatment may become eligible for thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). In patients on dabigatran with intracerebral hemorrhage idarucizumab could prevent lesion growth. AIMS: To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of acute ischemic stroke or intracranial hemorrhage. METHODS: Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January 2016 to August 2018 were used. RESULTS: One-hundred and twenty stroke patients received idarucizumab in 61 stroke centers. Eighty patients treated with dabigatran presented with ischemic stroke and 40 patients suffered intracranial bleeding (intracerebral hemorrhage (ICH) in n = 27). In patients receiving intravenous thrombolysis with rt-PA following idarucizumab, 78% showed a median improvement of 7 points in National Institutes of Health Stroke Scale. No bleeding complications were reported. Hematoma growth was observed in 3 out of 27 patients with ICH. Outcome was favorable with a median National Institutes of Health Stroke Scale improvement of 4 points and modified Rankin score 0-3 in 61%. Six out of 40 individuals (15%) with intracranial bleeding died during hospital stay. CONCLUSION: Administration of rt-PA after reversal of dabigatran activity with idarucizumab in case of acute ischemic stroke seems feasible, effective, and safe. In dabigatran-associated intracranial hemorrhage, idarucizumab appears to prevent hematoma growth and to improve outcome.

Outcomes of patients with stroke treated with thrombolysis according to prestroke Rankin Scale scores.

BACKGROUND: It is common practice to withhold IV thrombolysis (IVT) for acute ischemic stroke in patients with preexisting disabilities. To test the hypothesis of an association of IVT and good clinical outcome also in patients with preexisting disabilities without an increase in mortality, we analyzed data from 52,741 patients (15,317 treated with IVT) depending on prestroke Rankin Scale (pRS) score. METHODS: We performed an observational study based on a consecutive stroke registry covering 10.8 million inhabitants. The outcome at discharge of patients with stroke admitted in the time window of potential eligibility for IVT (<4.5 hours after stroke onset) was compared between patients treated and those not treated with thrombolysis, stratified by pRS score. Logistic regression analysis was used to estimate adjusted odds ratios (ORs) along with 95% confidence intervals (CIs) for favorable clinical outcome, defined as returning to the baseline pRS score or a score of 0 or 1 and mortality. Sensitivity analyses for subgroups of mildly and severely affected patients with stroke were performed, and the influence of treatment duration was assessed. RESULTS: Among included patients, IVT rates were 32% for patients with pRS scores of 0 to 1 and 20% for patients with pRS scores of 2 to 5. IVT in patients with pRS scores of 0 to 4 was associated with a higher chance of returning to the baseline pRS score (or a modified Rankin Scale score of 0/1), with ORs ranging between 1.42 (pRS score 2; 95% CI 1.16-1.73) and 1.73 (pRS score 0; 95% CI 1.61-1). The OR observed in patients with a pRS score of 5 was 0.65 (95% CI 0.25-1.70). Observed associations remained consistent in sensitivity analyses. Subgroup analyses revealed no evidence of bias due to potential floor and ceiling effects. No evidence of elevated in-hospital mortality of patients treated with thrombolysis was observed. CONCLUSIONS: Our study suggests that IVT can be effective even in patients with severe preexisting disabilities, provided that they were not bedridden before stroke onset. Withholding IVT on the sole ground of prestroke disabilities may not be justified.

Early spontaneous recanalization following acute carotid occlusion.

BACKGROUND AND PURPOSE: Occlusion of the internal carotid artery (ICA) and stroke may be the consequence of either local thrombosis due to atherosclerosis or massive embolism. Up to date, there are only few reports of subsequent recanalization. METHODS: We report 12/76 cases of acute ICA occlusion leading to ischemic stroke, in which early recanalization was identified. Ultrasound and stroke MRI findings, therapeutic options, and outcome are described. RESULTS: 10/12 patients showed an- or hypoechogenic morphology of occlusion. While in 7/12 cases complete recanalization was seen, in 5/12 patients partial recanalization with filiform flow (4) or residual high-grade stenosis (1) was detected. 10/12 patients had territorial or subcortical infarction, while two showed small cortical lesions only. In 7/12 cases, a potential cardiac source of embolism was found. Five patients received tPA; four patients underwent early carotid endarterectomy of the partially recanalized ICA within 48 hours. In the 10-day follow-up examination 10/12 patients showed clinical improvement as measured by the NIHSS. CONCLUSIONS: Spontaneous recanalization after occlusion of the ICA may occur and might be more frequent than hitherto assumed. Echogenicity analysis and serial examinations of symptomatic ICA occlusion is useful for identifying a patient subgroup that might benefit from further therapy.

Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany - A national case collection.

Background Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran that reverses its anticoagulant effects within minutes. It may exhibit the potential for patients under dabigatran therapy suffering ischemic stroke to regain eligibility for thrombolysis with rt-PA and may inhibit lesion growth in patients with intracerebral hemorrhage on dabigatran. Aims To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of ischemic stroke or intracranial hemorrhage. Methods Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January to August 2016 were used. Results Thirty-one patients presenting with signs of stroke received idarucizumab in 22 stroke centers. Nineteen patients treated with dabigatran presented with ischemic stroke and 12 patients suffered from intracranial bleeding. In patients receiving rt-PA thrombolysis following idarucizumab, 79% benefitted from i.v. thrombolysis with a median improvement of five points in NIHSS. No bleeding complications occurred. Hematoma growth was observed in 2 out of 12 patients with intracranial hemorrhage. The outcome was favorable with a median NIHSS improvement of 5.5 points and mRS 0-3 in 67%. Overall, mortality was low with 6.5% (one patient in each group). Conclusion Administration of rt-PA after reversing dabigatran activity with idarucizumab in case of ischemic stroke is feasible, easy to manage, effective, and appears to be safe. In dabigatran-associated intracranial hemorrhage, idarucizumab has the potential to prevent hematoma growth and improve outcome. Idarucizumab represents a new therapeutic option for patients under dabigatran treatment presenting with ischemic stroke or intracranial hemorrhage.

Brain temperature during 340-kHz pulsed ultrasound insonation: a safety study for sonothrombolysis.

BACKGROUND AND PURPOSE: Because ultrasound is used for improving thrombolysis of cerebral infarction but continuous ultrasound insonation also has significant thermal effects, we evaluated brain temperature increase and tissue destruction during pulsed ultrasound emission. METHODS: We examined 340-kHz pulsed ultrasound effects in male Wistar rats. Ultrasound was applied transcranially for 30 minutes on different power levels (1 to 7 W/cm2). Temperature was measured at different locations (brain, in the focus of ultrasound beam, inner ear, temporalis muscle, and rectum). The cooling time after 30-minute insonation for every power level was recorded, and animals were examined by postmortem brain histology (TUNEL and hematoxylin/eosin). RESULTS: Brain temperature increased within 2 to 5 minutes of insonation. Brain temperature increase and cooling time were in proportion to power level, and even with the highest intensity of 7 W/cm2 for 30 minutes, the maximum elevation of mean brain temperature was 0.9 degrees C, with the highest cooling time of 40 minutes. No deleterious side effects of this treatment could be found in histological examination. CONCLUSIONS: Using a pulsed ultrasound design, only a moderate temperature increase could be observed with no histopathological abnormalities. Deleterious side effects of mid-kilohertz ultrasound (eg, intracerebral hemorrhage) are therefore not a consequence of local brain temperature increase.

Restriction of therapy mainly explains lower thrombolysis rates in reduced stroke service levels.

OBJECTIVE: To assess the influence of preexisting disabilities, age, and stroke service level on standardized IV thrombolysis (IVT) rates in acute ischemic stroke (AIS). METHODS: We investigated standardized IVT rates in a retrospective registry-based study in 36,901 patients with AIS from the federal German state Baden-Wuerttemberg over a 5-year period. Patients admitted within 4.5 hours after stroke onset were selected. Factors associated with IVT rates (patient-level factors and stroke service level) were assessed using robust Poisson regression modeling. Interactions between factors were considered to estimate risk-adjusted mortality rates and potential IVT rates by service level (with stroke centers as benchmark). RESULTS: Overall, 10,499 patients (28.5%) received IVT. The IVT rate declined with service level from 44.0% (stroke center) to 13.1% (hospitals without stroke unit [SU]). Especially patients >80 years of age and with preexisting disabilities had a lower chance of being treated with IVT at lower stroke service levels. Interactions between stroke service level and age group, preexisting disabilities, and stroke severity (all p < 0.0001) were observed. High IVT rates seemed not to increase mortality. Estimated potential IVT rates ranged between 41.9% and 44.6% depending on stroke service level. CONCLUSIONS: Differences in IVT rates among stroke service levels were mainly explained by differences administering IVT to older patients and patients with preexisting disabilities. This indicates considerable further potential to increase IVT rates. Our findings support guideline recommendations to admit acute stroke patients to SUs.

Supratentorial age-related white matter changes predict outcome in cerebellar stroke.

BACKGROUND AND PURPOSE: Little is known about the relevance of age related white matter lesions (WMLs) concerning outcome after first-ever territorial stroke. Based on an index patient, we hypothesized that age and pre-existent WMLs rather than infarct volume and topography determine outcome. PATIENTS AND METHODS: Thirty-four consecutive patients with magnetic resonance diffusion-weighted imaging-proven isolated acute cerebellar infarction were prospectively entered on our stroke data registry. Patients with pre-existent neurological deficits, hemorrhagic, or malignant cerebellar infarction were excluded. Patients were stratified using Rankin and Barthel disability scales into groups: I complete recovery, II moderate, and III significant disability 14 days after stroke onset. RESULTS: Initial neurological and functional scores were similar among all the groups with vertigo, nausea, unsteadiness, and limb ataxia being the most common. Infarct volume, vascular territories, and comorbidity did not predict clinical outcome. In contrast, presence and severity of supratentorial WMLs and age significantly determined outcome by functional tests. CONCLUSIONS: In patients with isolated cerebellar infarction functional outcome correlated with the coexistence of age-related WMLs rather than stroke volume and topography. This reflects the loss of compensatory network integrity as the equivalent of functional incapacity beyond local lesion disturbances.

Transcranial low-frequency ultrasound-mediated thrombolysis in brain ischemia: increased risk of hemorrhage with combined ultrasound and tissue plasminogen activator: results of a phase II clinical trial.

BACKGROUND: Clinical studies using ultrasound at diagnostic frequencies in transcranial Doppler devices provided encouraging results in enhancing thrombolysis with tissue plasminogen activator (tPA) in acute stroke. Low-frequency ultrasound does not require complex positioning procedures, penetrates through the skull better, and has been demonstrated to accelerate thrombolysis with tPA in animal experiments in wide cerebrovascular territories without hemorrhagic side effects. We therefore conducted the first multicenter clinical trial to investigate safety of tPA plus low-frequency ultrasound (300 kHz). METHODS: Acute stroke patients within a 6-hour time window were included (National Institutes of Health Stroke Scale scores >4). Magnetic resonance imaging (MRI) was used to document vascular occlusion and to rule out cerebral hemorrhage. Patients were allocated to combination therapy alternately; the first patient received tPA only, the second patient received tPA plus ultrasound, etc. Follow-up included serial MRI directly thereafter and 24 hours later to confirm recanalization and tissue imaging. Clinical recovery was measured after treatment and 3 months later. RESULTS: 26 patients (70.4+/-9.7 years) entered the trial (12 tPA, 14 tPA plus ultrasound). The study was prematurely stopped because 5 of 12 patients from the tPA only group but 13 of 14 patients treated with the tPA plus ultrasound showed signs of bleeding in MRI (P<0.01). Within 3 days of treatment, 5 symptomatic hemorrhages occurred within the tPA plus ultrasound group. At 3 months, neither morbidity nor treatment-related mortality or recanalization rates differed between both groups. CONCLUSIONS: This study demonstrated bioeffects from low-frequency ultrasound that caused an increased rate of cerebral hemorrhages in patients concomitantly treated with intravenous tPA.

Transient ischemic attacks are more than "ministrokes".

BACKGROUND AND PURPOSE: Transient ischemic attacks (TIAs) are warning signs of stroke. Recently, the hypothesis was raised that TIA bears a significant risk for death and dependence and requires the same complex diagnostic workup as a complete stroke. METHODS: We prospectively collected pre- and in-hospital procedures, symptoms, outcome, complications, and therapies from a representative sample of all stroke-treating hospitals (n=82) in southwest Germany. Follow-up was attempted 6 months after discharge. End points were death or dependence in activities of daily living (Barthel Index <95, modified Rankin Scale (mRS) of 3 to 6, or institutionalization in a nursing home). RESULTS: 1380 TIA patients and 3855 stroke patients entered the database. During hospital stay, stroke incidence was 8% for TIA patients and another 5% within the first half-year. Similarly, for ischemic stroke (IS) patients these figures were 7% and 6% (P>0.05), respectively. Two percent of TIA patients died in hospital (5% afterward) compared with 9% of stroke patients (10% afterward, P<0.001). Seventeen percent TIA compared with 38% IS patients (P<0.05) were dependent at follow-up. Whereas an estimated preexisting deficit (mRS >2) was the strongest predictor for death or disability (baseline mRS odds ratio, 4.1; 95% CI, 2.3 to 7.2), admission to a stroke unit was a valid predictor for survival and independence (odds ratio, 0.4; 95% CI, 0.2 to 0.9). CONCLUSIONS: These data from a large, multicenter, nonselected, observational study underscore the "not so benign" prognosis for TIA patients. There is a relevant individual risk of early stroke, death, or disability in TIA patients. Management and treatment strategies are similar for both TIA and acute stroke.

Ultrasound in the treatment of ischaemic stroke.

Intravenous alteplase (recombinant tissue plasminogen activator) has been shown to be beneficial within a short 3 h window after stroke. Ultrasound has a thrombolytic capacity that can be used for pure mechanical thrombolysis or improvement of enzyme-mediated thrombolysis. Mechanical thrombolysis with ultrasound needs high intensities at the clot (>2 W/cm2) that may have unwanted side-effects, whereas improvement of enzymatic thrombolysis can be done at the safer energy levels used in diagnostic ultrasound. Methods of improving enzymatic thrombolysis with ultrasound include intra-arterial delivery of thrombolytic agents with an ultrasound-emitting catheter and targeted and non-targeted non-invasive transcranial ultra sound delivery during intravenous thrombolytic infusion. Animal and clinical studies of sonothrombolysis have shown clot lysis and accelerated recanalisation of arterial occlusion has been seen in in vitro flow models, occluded peripheral and coronary arteries, and intracerebral arteries. Controlled clinical trials to test safety management and effectiveness of both strategies are in progress.

Infrared spectroscopy: a new diagnostic tool in Alzheimer disease.

Biological markers play an evolving role in the diagnosis of Alzheimer disease (AD). We compare conventional measurements of cerebrospinal fluid (CSF) tau and beta-amyloid(1-42) proteins to a novel approach - Fourier transformed infrared (FT-IR) spectroscopy - a simple technique derived from chemical and physical sciences that characterizes intramolecular bonds. For automatic diagnostic analysis, we developed an artificial neural network (ANN). We examined 71 patients with a clinical diagnosis of AD and 66 controls. beta-Amyloid(1-42) was decreased (sensitivity 80% and specificity 78%); tau was elevated (sensitivity 76% and specificity 88%) in CSF of AD patients. The combined tau/beta-amyloid(1-42) quotient was able to distinguish healthy from diseased subjects with 99% sensitivity and 86% specificity. The ANN could separate FT-IR spectroscopy data with 88.5% sensitivity and 80% specificity. FT-IR spectroscopy proved to be cost-effective and simple to perform. Diagnostic sensitivity and specificity is in the range of CSF tau and beta-amyloid(1-42) protein analysis. Larger sample numbers for ANN training and validation could increase diagnostic accuracy and thus prove to be a useful screening tool.

Sonothrombolysis: experimental evidence.

Reopening of the occluded artery is the primary therapeutic goal in hyperacute ischemic stroke. Systemic treatment with tissue recombinant plasminogen activator (tPA) has been shown to be beneficial at least in a 3-hour door to needle window. Intra-arterial thrombolysis is favorable and opens the window of treatment up to at least 6 h but consequences invasive intra-arterial angiography in a high number of patients, of whom a significant number do not finally receive thrombolysis. The combination of ultrasound with thrombolytic agents may enhance the potential benefit by means of enzyme-mediated thrombolysis. When ultrasound is applied externally through skin or chest, attenuation will be very low. Attenuation, however, is significantly higher if penetration through the skull is required. Attenuation is frequency dependent, with ultrasound intensity being <10% of the output intensity for diagnostic frequencies (>1 MHz). This ratio nearly reverses in the kiloHertz range (>500 kHz). Ultrasound insonation is efficient for accelerating enzymatic thrombolysis within a wide range of intensities, from 0.5W/cm2 (MI approximately 0.3) to several watts per square centimeter, particularly in the nonfocused ultrasound field. Insonation with ultrasound increased tPA-mediated thrombolysis up to 20% in a static model, while it enhanced the recanalization rate from 30 to 90% in a flow model. Results from embolic rat models suggest that low-frequency ultrasound with 0.6W/cm2 significantly reduces infarct volume compared to pure tPA treatment. Safety of ultrasound exposure of the brain for therapeutic purposes has to address hemorrhage, heating, and direct tissue damage. Since animal studies suggested no increase of bleeding rate or harm to the blood-brain barrier, a clinical phase II study applying low-frequency ultrasound at approximately 300 kHz found a high number of secondary hemorrhages. Heating depends critically on the characteristics of the ultrasound. The most significant heating of the brain tissue itself is >1 degrees C per hour using a 2W/cm2 probe; however, no significant heating could be found when using an emission protocol pulsing the ultrasound. The current experimental data helps to identify the optimal ultrasound characteristics for sonothrombolysis and supports the hypothesis combined treatment being a perspective in optimizing thrombolytic therapy in acute stroke.

Tirofiban for the treatment of ischaemic stroke.

Tirofiban is one of three glycoprotein IIb/IIIa receptor antagonists approved by the US FDA, beside abciximab and eptifibatide. The approval of tirofiban covers conservative treatment of myocardial infarction and unstable angina, as well as percutaneous coronary intervention, for which treatment with tirofiban is recommended in moderate-to-high-risk patients. The efficacy of glycoprotein IIb/IIIa antagonists in myocardial infarction indicated that these agents may also be helpful in the treatment of acute ischaemic stroke. Although experimental data are lacking, observational studies are promising. In recent years, increasing effort in studying glycoprotein IIb/IIIa antagonists has been made, mostly for treatment with abciximab. However, there is one Phase II trial that investigated treatment with tirofiban.

Improvement of sensitivity and interrater reliability to detect acute stroke by dynamic perfusion computed tomography and computed tomography angiography.

OBJECTIVE: To assess the benefits of additional computed tomography perfusion (CTP) and computed tomography angiography (CTA) on the detection of early stroke, vessel occlusion, estimated infarct size, and interrater reliability. METHODS: Sixty-seven consecutive patients underwent nonenhanced computed tomography (CT) imaging, CTA, and CTP. The final diagnosis of stroke was made from follow-up neuroimaging. A first diagnosis was made on-site by the physician on duty. Three experienced neuroradiologists blinded to follow-up findings analyzed the data set off-line, evaluated CT for signs of acute stroke, and subsequently evaluated CTP and CTA for infarction-related perfusion deficits and vessel abnormalities. RESULTS: Computed tomography perfusion and CTA increased the time from CT start to diagnosis from 2 minutes to 10 minutes. Sensitivity to detect acute stroke increased significantly in all investigators from 0.46-0.58 to 0.79-0.90 compared with CT (<0.005). The interrater weighted kappa value increased from 0.35 to 0.64. Estimation of infarct size was not improved. CONCLUSION: Computed tomography perfusion and CTA provide an effective add-on to standard CT in acute stroke imaging by significantly increasing the sensitivity and reliability of infarct detection.

Hemodynamic reserve and high-intensity transient signals in moyamoya disease.

BACKGROUND: Moyamoya disease (MMD) as a rare obstructive cerebrovascular disease is assumed to present with ischemic symptoms due to hemodynamic compromise. However, alternative mechanisms, such as cerebral embolism in low-flow territories, may also contribute to clinical symptoms. The incidence of high-intensity transient signals (HITS) and the degree of hemodynamic compromise were studied in symptomatic patients with MMD. METHODS: Twenty-four patients (17 female, 7 male; mean age 33 +/- 13 years) with clinical symptoms attributable to cerebral ischemia and the angiographic features of MMD (21 definite form, 3 probable MMD; 22 patients 'late stage' MMD, 2 patients 'early stage' MMD) in 45 affected hemispheres were enrolled in the present study. Patients underwent parallel estimation of hemodynamic compromise by means of functional blood flow (rCBF) studies using SPECT, PET or xenon-CT and HITS detection by TCD. RESULTS: Hemodynamic compromise was observed in 37/40 (92%) hemispheres studied. During TCD monitoring, HITS were detected in 3 patients (12.5%), with a total frequency of 3 (6.6%) in the 45 hemispheres investigated. All patients with HITS showed hemodynamic compromise in functional rCBF studies. In these patients, HITS were recorded ipsilateral to the symptomatic hemisphere. HITS occurred in late stage MMD patients only once, while both cases with early stage MMD demonstrated multiple HITS. CONCLUSIONS: The incidence of HITS in patients with MMD appears to be lower compared to patients with atherosclerotic or atherothrombotic arterial obstructions. In addition, ischemia-related symptoms in 'late stage' MMD seem to be caused by hemodynamic compromise in the majority of these patients.

Therapeutic ultrasound in ischemic stroke treatment: experimental evidence.

Re-opening of the occluded artery is the primary therapeutic goal in hyper-acute ischemic stroke. Systemic treatment with IV rt-PA has been shown to be beneficial at least in a 3 h 'door to needle' window and is approved within that interval in many countries. Trials of thrombolytic therapy with rt-PA demonstrated a small, but significant improvement in neurological outcome in selected patients. As recently shown, intra-arterial application of rt-PA is effective and opens the therapeutical window to 6 h, but requires invasive intra-arterial angiographic intervention in a high number of patients, who do not finally achieve thrombolysis. Ultrasound (US) is known to have several biological effects depending on the emission characteristics. At higher energy levels US alone has a thrombolytic effect. That effect is already used for clinical purposes in interventional therapy using US catheters. Recently, there is growing evidence that US at lower energy levels (<2 W/cm(2)) facilitates enzymatic mediated thrombolysis, most probably by breaking molecular linkages of fibrin polymers and therefore, increasing the working surface for the thrombolytic drug. Different in-vitro and in-vivo experiments have shown increased clot lysis as well as accelerated recanalization of occluded peripheral, coronary vessels and most recently also intracerebral arteries. Sonothrombolysis at low energy levels, however, is of great interest because of the low risk for collateral tissue damage, enabling external insonation without the need for local catheterization. Whereas little or no attenuation of US can be expected through skin and chest, intensity will be significantly attenuated if penetration of bones, particularly the skull, is required. That effect, however, is frequency dependent. Whereas >90% of intracerebral US intensity is lost (of the output power) in frequencies currently used for diagnostic purposes (mostly 2 MHz and up), that ratio is nearly reversed in the lower KHz range (<300 kHz). US at these low frequencies, however, is efficient for accelerating enzymatic thrombolysis in-vitro as well as in vivo within a wide range of intensities, from 0.5 W/cm(2) (MI approximately 0.3) to several W/cm(2). Since the emitted US beam widens with decreasing frequency, low-frequency US can insonate the entire intracerebral vasculature. That may overcome the limitation of US in the MHz range being restricted to insonation of the MCA mainstem. There are no reports in the preclinical literature about intracerebral bleeding or relevant cerebral cellular damage (either signs of necrosis or apoptosis) for US energy levels up to 1 W/cm(2). Moreover, recent investigations showed no break-down of the blood brain barrier. Safety of US exposure of the brain for therapeutic purposes has to address heating. Heating depends critically on the characteristics of the US. The most significant heating of the brain tissue itself is >1 degrees C/h using a continuous wave (CW) 2 W/cm(2) probe, whereas no significant heating could be found when using an intermittent (pulsed) emission protocol. The experimental data so far help to characterize the optimal US settings for sonothrombolysis and support the hypothesis that this combined treatment is a prospective advance in optimizing thrombolytic therapy in acute stroke.

Ultrasound and arterial wall disease.

Rapid progress in non-invasive ultrasound techniques has resulted in a wide variety of clinical applications for the assessment of cerebrovascular diseases. Recent highlights in ultrasound research include the evaluation of vascular ageing as a degenerative process, the demonstration of plaque development, motion and vulnerability in atherosclerosis and multi-dimensional as well as innovative imaging techniques (e.g., compound imaging) to depict early and small vascular lesions. In addition, echo-contrast agents have been used to compensate for difficulties in visualising late, severe or subtotal obstructive plaques, but failed to be really superior to conventional techniques as evidenced in a prospective, multi-centre trial (Contrast Enhanced Duplex sonography versus Arteriography Studies - CEDAS). With increasing sophistication of ultrasound methodology, it becomes essential to establish standards for data acquisition and interpretation: three consensus meetings have provided detailed recommendations on quantification of carotid atherosclerosis, characterisation of carotid artery plaques and detection of microembolism by transcranial Doppler as a potential indicator of stroke risk.

Improvement in stroke quality management by an educational programme.

Time after symptom onset in ischaemic stroke has to be as short as possible to increase success of treatment. We prospectively analysed latencies from symptom onset until the start of therapy and the rate of thrombolysis in 196 patients with suspected stroke sequentially admitted to the hospital before (6 weeks prior, n = 83) and after (n = 113) initiating an educational stroke programme (EP). A total of 345 dispatchers, paramedics, and emergency staff were trained, each person for at least 2 h. The mean pre-hospital time interval from symptom onset until admission was significantly decreased by nearly 2 h (p < 0.05). Thrombolytic therapy frequencies increased from 2 to 10.5% (p < 0.01) because the overall mean time interval from admission to the start of therapy significantly decreased (p < 0.01) by 69 min after the EP, with increasing numbers of patients suitable for acute stroke therapies within a 0- to 3-hour treatment window.