O08	Therapeutic Ultrasound in Ischemic Stroke Treatment Michael Daffertshofer, Department of Neurology, University of Heidelberg, University Hospital Mannheim The only established causal therapy for acute stroke is thrombolysis (systemic application of rt-PA is approved for a 3 hour window in many countries) . Thrombolytic therapy with rt-PA demonstrated a small, although significantly reduced morbidity in a limited number of highly selected patients. As recently shown, intraarterial thrombolysis is favorable and opens the window of treatment up to 6 hours. The combination of ultrasound (US) with thrombolytic agents may further enhance the potential benefit by means of enzymatic mediated thrombolysis, which has been demonstrated in different in-vitro and in-vivo experiments for an accelerated recanalization of occluded vessels. The transcranial penetration of US is strongly frequency dependent, with optimal penetration in the lower kHz frequency ranges. Animal experiments suggested no harm to the blood brain barrier, nor systemic heating for US energies up to 2 W/cm², particularly when applicated in a pulsed design. Application of low frequency US-insonation increased rt-PA mediated thrombolysis up to 20% in a static model, meanwhile it enhanced the recanalization rate from 30 to 90% in a flow model. In-vitro results also suggest that 1 MHz US with 0.5 W/cm², established for diagnostic purposes, may already enhance rt-PA mediated thrombolysis. Moreover clinical observational studies reported a better outcome of patients having Ultrasound monitoring with 2 MHz devices during systemic thrombolysis. This combined treatment is one perspective in optimizing therapy in acute stroke within the acute phase and may be applied easily with few limitations.
O09	CLINICAL VALUE OF NEUROSONOLOGY IN ACUTE ISCHEMIC STROKE: THE AIMS OF THE NAIS STUDY G.-M. von Reutern, Asklepios Neurologische Klinik Bad Salzhausen, D-63667 Nidda, Germany Background: Doppler Ultrasound is one among several methods to be used in combination with brain tissue imaging in the first hours after ischemic stroke in order to get dynamic information concerning the pathophysiology. This information is helpful in directing further management of patients depending on the time window and the time course of neurological deficits. Methods: NAIS is an observational investigator driven study of the Research Group Neurosonology (WFN). The aim is to determine the prognostic power of different findings in 400 patients examined within 6 hour after stroke including a follow up (3h, 6h, 12 h, 7 d, 3 month). It will be differentiated whether significant lesions are located extracranially, at the level of the circle of Willis or the level of the main branches of the MCA. This last condition can be detected observing side-to-side differences (=/> 30% reduction on the pathologic side) of the MCA flow velocities. Results: Enrolment will be finished end of 2002. The frequency of intracranial pathologic results is higher in the acute than in the chronic stage due to transitory intracranial findings. Examples of typical findings will be demonstrated.
O10	CLOPIDOGREL REDUCES THROMBOEMBOLISM AFTER CAROTID ENDARTERECTOMY: A RANDOMISED TRIAL D.A. PAYNE^1, P.D. HAYES^1, C.I. JONES^2, A.H. GOODALL^2, M.T. THOMPSON^1, N.J. LONDON^1, P.R.F. BELL^1, A.R. NAYLOR^1 The Departments of Surgery^1 and Clinical Biochemistry^2, University of Leicester, UK BACKGROUND Post-operative thromboembolic stroke affects 2-3% of patients undergoing carotid endarterectomy (CEA) and is preceded by 1-2 hours of increasing embolisation. Our hypothesis was that pre-operative administration of a platelet ADP antagonist(Clopidogrel) would reduce embolisation and was based on previous studies showing that platelets of patients with the highest rates of post-operative embolisation had increased platelet reactivity to ADP. METHODS 100 CEA patients on routine aspirin therapy (75mg) were randomised to 75mg Clopidogrel (n=47) or placebo (n=53) the night before surgery. Platelet function was assessed by flow cytometry. The number of emboli detected by transcranial Doppler within 3 hours of CEA was independently quantified. Time taken from flow restoration to skin closure was used as an indirect measure of the time to secure haemostasis. RESULTS Clopidogrel significantly reduced platelet activation in response to ADP(p<0.05) whilst conferring a fourfold reduction in the number of patients with>10 emboli in the post-operative period(OR 4.4, 95% CI 1.4-14.4, p<0.008). However, the time from flow restoration to skin closure was >40 minutes in 30% of clopidogrel patients compared with 8% of controls (p<0.004). CONCLUSIONS This is the first study to show that a CEA patient’s post-operative thromboembolic potential can be significantly reduced by pre-operative pharmacotherapy. It remains to be seen whether a lower dose of Clopidogrel will confer a similar reduction in embolisation whilst reducing the time to achieve haemostasis.
O11	PATIENTS’ THROMBOEMBOLIC POTENTIAL FOLLOWING ENDOTHELIAL DISRUPTION IS RELATED TO THE PLATELETS’ SENSITIVITY TO ADP. P.D. HAYES^1,D.A. PAYNE^1, P.R.F. BELL^1, A.H. GOODALL^2 , A.R.NAYLOR^1 The Departments of Surgery^1 and Clinical Biochemistry^2, University of Leicester, UK BACKGROUND Post-operative microemboli in patients undergoing carotid endarterectomy are a significant risk factor for stroke. These emboli can be detected by TCD monitoring. They are not linked to technical error and are variable between patients. As it is known that platelets play a key role in arterial thrombosis, it was hypothesised that a patient’s risk of post-operative carotid thrombosis was linked to the individual’s platelet response to physiological agonists. METHODS Samples from 120 patients undergoing CEA were analysed prior to surgery. Platelet aggregation was measured in response to ADP (0.5 – 4 m mol/l), collagen (10 - 50 mg/ml) and arachidonic acid (3 or 6 m mol/l), and fibrinogen binding to GPIIb-IIIa, was measured by whole blood flow cytometry in response to ADP (0.1 - 10 m mol/l) and thrombin (0.02 – 0.16 u/ml). Patients underwent TCD monitoring for 3 hours after surgery and platelet functional data was compared in those who had >25 emboli in this period (n=22) with that in those with <25 emboli (n=88). RESULTS The platelet response to ADP was significantly higher in the patients with >25 emboli higher as measured both by aggregometry (p=0.0012) and by flow cytometry (p<0.0001). Platelet aggregation with collagen was also significantly higher in this group (p=0.0018) but the response to thrombin was not statistically different in the two groups. In addition there was no difference in the response to arachidonic acid between the groups. CONCLUSION The platelet response to ADP may be linked to clinical outcome, and thus specific ADP receptor inhibitors may be appropriate for this group of patients.
O12	DETECTION OF OCCLUSION AND RECANALIZATION WITH TRANSCRANIAL POWER M-MODE DOPPLER IN PATIENTS WITH ACUTE NEUROLOGICAL SYNDROMES IN THE EMERGENCY ROOM Z.Garami, S.Calleja, O.Chernyshev, J.C.Grotta, M. Malkoff, A. V.Alexandrov Department of Neurology, University of Texas-Houston, USA Background: Accurate diagnosis by imaging would improve patient selection for thrombolysis, especially intra-arterial (IA) interventions. Transcranial power motion mode Doppler (PMD, or M-mode) is a new technology that simultaneously displays flow intensity and direction over 6 cm of intracranial space. We report our experience with PMD-TCD used in the emergency department (ED) in patients with acute neurological symptoms. Method: We studied serial patients presenting with acute focal neurological symptoms referred from the ED to the Stroke Treatment Team. In addition to neurological evaluation, they were examined via conventional windows with a PMD/spectral TCD unit (100M, Spencer Technologies) at bedside. Spectral TCD data were interpreted using previously published and validated TCD criteria and compared to PMD flow tracks. TCD results were compared to clinical findings, digital subtraction angiography (DSA) and/or MRI/MRA. All patients had acute non-contrast CT scan. Results: A total of 69 patients were studied (mean age 69; 42 % women); 50 patients had ischemic stroke (PMD-TCD showed occlusion in 78%, stenosis in 6%, collateral in 4% and normal studies in 8% of patients); 8 had TIAs (PMD-TCD showed persisting occlusion despite symptom resolution in 37.5%, stenosis in 12.5%, collaterals in 12.5%, and normal studies in 37.5%); and 9 patients had etiologies other than ischemia. PMD-TCD showed suboptimal temporal windows in 4 patients (7%). TPA (0.9/mg/kg) was given in 22 stroke patients (44%), 2 (4%) received intravenous TPA 0.6 mg/kg if presented between 3-6 hours (experimental protocol) and in 9 (18%) intra-arterial thrombolysis was performed (2 pts had only IA t-PA). In all patients who underwent IA rescue, TCD had showed an initial arterial occlusion and no recanalization after IV tPA. If PMD-TCD and angiography were both performed within 720 minutes after onset, the predictive value of PMD-TCD for intracranial occlusion was100%. Overall, PMD-TCD had an accuracy of 93% for lesion location compared to angiography. Conclusions: PMD can be used as a guide for spectral Doppler examination in emergency situations. A combined use of spectral single gate TCD and PMD flow tracks yields greater sampling of vessels or segments for monitoring of acute occlusion and recanalization. At our center, PMD/TCD examination helps to confirm the ischemic nature of the neurological deficit by detection of occlusion and is also helpful in patient selection for IA therapy.
O13	Side effects of transcranial for thrombolysis used ultrasound - a rat model F. Nolle, M. Nedelmann, B.M. Eicke, O. Kempski*, B. Alessandri*, M. Dieterich Department of Neurology and *Dept. of Neurosurgical Pathophysiology Johannes Gutenberg University Mainz, Germany Background: Transcranial ultrasound for thrombolysis of the middle cerebral artery is a promising method to treat patients with ischemic stroke in the future. In previous in vitro studies we could demonstrate blood thrombus destruction by low frequency ultrasound (20 kHz). Aim of this in vivo study was to detect side effects of transcranial low frequency ultrasound in rats. Methods:. The probe was placed on top of the cranium of Wistar rats (n=18). We performed 26 measurements with different power outputs (0, 2, 4, 6, 8, 10, 12 Watt), insonation time was 20 minutes per measurement. During the insonation tympanal and rectal temperatures were monitored. Nine rats were killed immediately after somnification, nine rats were planed to survive 7 days to obtain histological data of the brain. Results: A positive correlation of power output and tympanal temperature was found (0,18°C with 2 W, 0,2°C with 4 W, 0,6°C with 6 W, 1,75°C with 8 W, 1,6°C with 10 W and 1,8°C with 12 W). In all rats the rectal temperature remained constant until the tympanal temperature reached 38,0°C. Then it rose to a maximum of 38,7°C. Five of 9 animals which were planed to survive died within 72 hours after insonation. All rats developing an increase of tympanal temperature more than 2°C died. The histological examinations showed a negative correlation between the number of surviving hippocampal and cortical cells and the power output used. Conclusion: At present time, it is not known whether the observed clinical and histological findings are only due to the increase of temperature. Thus, low frequency, high power output ultrasound is potentially hazardous. Before an application in humans can be discussed careful and extensive animal safety studies have to be performed.
O14	Outcome and their relative factors in stroke patients HY Huang, S Gao, B Wang, J Ye, WH Xu Chinese Academy of Medical Sciences, Peking Union medical College Hospital, Beijing, China Background: to evaluate the risk factors that affect the long term outcome of acute stroke patients. Method: All the ischemic stroke patients with NIHSS from 5 to 25 admitted to the ward of neurology in Peking Union Medical College Hospital (PUMC Hospital) from June, 1997 to May 2000, were screened the carotid and intracranial arteries with TCD and color coded duplex. And the relation among the modified rankin score and the age, genders, diabetics, hypertension, cardiac disorders, family history of stroke, cholesterol and triglycerin level of plasma, as well as HDL, LDL, ApoA, ApoB, LPa were accessed . Results: 189 cases aged 61.2 ±11.8 years, were collected in the study when they were admitted in PUMC Hospital. We found 123 cases (65%) with cerebral arterial stenosis. The followed-up time is 25.6±15.1months. During the follow-up, we found recurrent stroke in 38 cases (20.0%), cerebral hemorrhage in 3 cases (1.6%), and death in 23 cases (12.2%). A hundred and 2 cases (54.0%) keep in 2 or less of modified Rankin score. It is significantly associated with age, cerebral arterial stenosis, lesions in basal ganglion, in brainstem, and in cerebellum, or multiple sites involved. The Odds rate of poor outcome is 1.0549 (95% CI, 1.0244, 1.0863, p=0.0004) for age and 2.2915 ( 95% CI, 1.1979, 4.3835,p=0.0122).HDL level is significantly negative correlation with cerebral arterial stenosis(p=0.012). Conclusion: It is important that TCD screens all of acute stroke patients. The large arterial involvement had an incidence of 65% in our series. These patients had a significantly poorer outcome than those without stenosis.