Accepted Abstracts  

Abstracts

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POSTERS

(01) Contrast-enhanced TDC monitoring pre and after transcatheter closure of patent foramen ovale: 100 cases

Anzola G.P. ¹ M.D., Morandi E. ² M.D., Casilli F. ³ M.D., Onorato E. ³ M.D.

¹ Service of Neurology, S. Orsola Hospital, Brescia, ITALY

² Neurology Clinic, Spedali Civili, Brescia, ITALY

³ Division of Cardiology, Humanitas Gavazzeni, Bergamo, ITALY

Introduction: the role of patent foramen ovale in cryptogenic stroke remains still debated even if several studies have estabilished the association of PFO and cerbrovascular events in selected patients. Therapeutic options for stroke preventions in patiens with PFO include lifelong medical treatment with antitrombotics and more invasive treatments such as surgical or minor invasive percutaneus trancatheter closure of the defect. The aim of this study is to assess the efficacy, and safety of transcatheter closure of PFO using contrast-enhanced transcranial doppler during normal breathing and Valvalva manouvre to quantify the amount of right-to-left shunt.

Patients and methods: a total of 100  consecutive patients (mean age= 48 years; man= 59; woman= 41) with PFO were referred to an Interventional Cardiology Department for transcatheter closure of PFO using two different devices (Helex =1; Amplatzer=99). Fifty patients suffered from a stroke, twenty-two patients suffered from a TIA, one patient had everlasting TGA, two patients were scuba divers, and twenty-five suffered from arrhythmia, serious dyspnoea and syncope. A contrast-enhanced transcranial doppler was done before transcatheter closure in 75 patients; and during follow-up visit: after one month of the procedure in all  the patients; after three months in 78 patients; after six months in 47 patients and one year after the procedure in 26 patients.

Results: the implantation was succesfull in all patients. During the first follow-up a residual shunt was still detectable in 11 patients (11%) during normal breathing  (3 significant shunts) and in 49 (49%) patients during Valsalva (19 significant shunts). The average of bubbles counts was 9 and 13 respectively. At the second follow-up visit we saw  a shunt in 6 patients (7%) during normal breathing (none with significant shunt) and in 33 (42%) patients during Valsalva (14 significant shunts). The average of  bubbles counts was 5 in the first group and 14 in the second one. After six months following  the procedure a  shunt was still detectable in 5 patients (10%) during normal breathing and in 14 (29%) during Valsalva (5 significant shunt) with an average load of 2 and 7 bubbles. We found 1 shunt (3%) during normal breathing and 10 shunt (38%) during Valsalva (2 significant shunts) on 1-year follw-up visit. The average of bubbles was 2 and 7 respectively.

Conclusions: closure of PFO can be atteined to a high degree of completeness. Most part of the patients exhibit a progressive closure after six months of the procedure with an improvement during the following months. Follow up TCD should be pursued  at regular intervals up to one year postoperatively.

Hemodynamics before and after the transposition of the right vertebral artery on the common carotid artery in a patient with a symptomatic proximal vertebral artery stenosis

(02) P. Erban, B. Vatankhah, M. Horn, G. Ickenstein

Department of Neurology, University of Regensburg, Germany

Background: The patient selection for the transposition of the vertebral artery (VA) on the common carotid artery (CCA) in case of a proximal stenosis of the VA is difficult.

Methods: We used the duplex ultrasound (DU) for the examination of hemodynamics before and after the transposition of the right VA on the right CCA in a 68 year old male patient with a diffuse, long distance stenosis of the left VA and a proximal short distance stenosis of the right VA on the MRA, who presented with recurrent episodes of vertigo, diplopia and dysarthria.

Results: On DU there was a spectrum of low frequency in the V2-segment of the left VA (V4-segment being of normal frequency) and a pseudovenous spectrum in the V2- and V4-segments of the right VA as well as in the basilar artery (BA). Few days after surgery the flow spectrum in the right VA (V4-segment) and in the BA completely normalised. Three months after surgery the the patient did not complain of any of the previous symptoms of the vertebrobasilar TIAs.

Conclusions: The evaluation of the hemodynamics of the vertebrobasilar circulation with DU helps to select symptomatic patients who may benefit from a transposition of the VA on the CCA. Especially in patients with pathological doppler spectrum in the BA the procedure seems to be indicated. 

Hemodynamics and cerebral perfusion before and after the placement of a left to right common artery cross-over bypass in a patient with an isolated occlusion of the brachiocephalic trunc

(03) P. Erban, B. Vatankhah, M. Horn, U. Bogdahn, G. Ickenstein
Department of Neurology, University of Regensburg, Germany

Background: The patient selection for the placement of a venous graft between the common carotid arteries (CCA) in case of an occluded brachiocephalic trunc is difficult and the time window, in which postoperative changes of hemodynamics occur unclear.

Methods: We examined the hemodynamics and the cerebral perfusion before and after the placement of a CCA-CCA venous graft in a 34 year old female patient with a posttraumatic occlusion of the brachiocephalic trunc, who presented with a first time dysaesthesia of the left eye lid. Duplex ultrasound (DU), conventional angiography (DSA) and the MR-perfusion (MRP) were employed for diagnosis and follow up.

Results: The initial DU showed a bidirectional flow in the right internal carotid artery (r-ICA), a retrograde flow in the right vertebral artery (r-VA) and the right anterior cerebral artery (r-ACA), as well as a pseudovenous spectrum in the right middle cerebral artery. On the DSA the r-ICA was receiving blood from the retrograd perfundated r-VA. Ten days after the surgery the only abnormalities on the DU were a bidirectional flow in all segments of the r-VA and in the r-ACA. There were no signs of the initial perfusion deficit on the follow up MRP scan. Nine weeks after surgery there was still a bidirectional flow in the right V4-segment, but only a systolic deceleration in the V2-segment and in the r-ACA.

Conclusions: The evaluation of the hemodynamics and of the cerebral perfusion with DU and MRP helps to select symptomatic patients who may benefit from the placement of a venous graft in case of an isolated occlusion of the brachiocephalic trunc. The noninvasive follow up with these methods shows a normalisation of hemodynamics within several weeks to months. 

(04) Cervical ultrasonography of carotid and vertebral arteries as a preoperative examination

T.Terasaki, Y. Matsuura, M.Naganuma, Y. Hashimoto

Kumamoto City Hospital, Kumamoto, Japan

Introduction: The significance of carotid ultrasonography as a preoperative examination for the cases of cardiac surgery is widely recognized. The objective of this study was to determine whether carotid ultrasonography has a potential to identify patients at risk for brain infarction following operations other than open-heart surgery.

Patients and methods: The subjects included 88 patients (M/F ratio 56/32; mean age 69.4yrs) who underwent carotid and vertebral ultrasonography as preoperative examinations. They were divided into 3 groups (cardioaortic disease 61, arteriosclerosis obliterans: ASO 17, others 10). Age, sex, risk factors (hypertension, diabetes mellitus, hyperlipidemia), carotid and vertebral ultrasonographic findings (max intima-media thickness of CCA: IMT-Cmax, stenosis or occlusion of the carotid artery, abnormality of the artery flow pattern) and brain infarction following operation were compared among these groups.

Results: No difference in age, sex, risk factors and IMT-Cmax was found among these groups. Internal carotid artery stenosis in 2 cases and reverse flow in the vertebral artery in one case were found in the cardioaortic disease group. Three cases of common carotid artery occlusion and one case of internal artery stenosis were found in the ASO group. One case of elevated end diastolic velocity rate (ED-ratio) of CCA was found in the group of other diseases. Two cases suffered from brain infarction following operations. Both of them had abnormal findings on ultrasonography and one of them had a history of TIA.  

(05) Correlation between internal carotid resistance index and volume of cerebral ischemic damage

Lepic T, Raicevic R, Veljancic D, Radulovic M, Miskovic M, Cirkovic S.

Dpt. of Neurology, Dpt. of Radiology** Military Medical Academy, Belgrade, Serbia

Introduction: Resistance index (RI) as relationship between systolic and diastolic blood flow velocity reflects peripheral vascular resistance. It is increased not only in vascular occlusive changes, but in increased intracranial pressure, too. Our hypothesis is that large cerebral ishemic infarctions with perifocal brain edema as space-occupying processes correlate with increased RI in both internal carotid and vertebral arteries.

Methods: Duplex sonography examination of neck arteries was performed with the use of a 7.0-MHz transducer of a computed sonography system. We analyzed relationship between RI and volume of brain ishemic lesion based on computed tomographic examination.

Results: Study was performed in 221 consecutive patients with ishemic stroke, aged 20 to 85 years, 121 men and 100 women.  Average RI value was 0,65. Older patients had significant higher RI then younger. Increased RI at least in one of arteries had 65% of patients, 64% in vertebral and 37% in carotid arteries. Increased RI in both carotid and vertebral arteries was in 10% of patients. Unilateral increased RI in internal carotid artery correlates with site of infarction in 35%. Patients with increased RI in all neck arteries had massive ishemic lesions with perifocal edema in 88%.

Conclusions: Our results suggest significant correlation of the increased RI, with space-occupying ishemic brain lesions and brain edema after acute stroke.

(06) Ultrasound perfusion imaging and densitometric curves in a patient with acute ischemic stroke

Sanguigni S., *Malferrari G., **Accorsi F.

Neurology Department. San Benedetto del Tronto(Italy)

*Neurology Dept. Reggio Emilia

**Medicine Dept. Bologna

Pet  and RMN represent "gold-standard " metods for the study of the cerebral perfusion areas. However their availability in acute stroke is surely limited,the running costs are high and their use within the first few hours in ischemic stroke is surely limited(non collaboration of patient ecc).On the other hand ,the ultrasonology represents a rapid and easily applicable examination technique and can be performed even at bedside.It is also possible to perform densitometric curves of "IN and OUT" which enable us to have a semiquantitative index of cerebral microcirculation in the interested "ROI" in a few seconds.

We have studied,within 6 hours from the beginning of symptoms ,a 73 years-old patient who had arrived at our department for rigth hemiparesis with aphasia.

Equipment used : HP Sonos 5500 and Esaote-Esatune.

After carrying out a cerebral TAC ,we gave 2.5 cc of "Sonovue" immediately followed by bolus of 5 cc of saline solution. The acquisition of the images has occurred using a Mechanical-Index between 0,2 and 0,4. The perfusional study has pointed-out a clear circular non perfusion area in the territory of the  left middle cerebral artery. Normal perfusional reports  on the rigth.The following performance of densitometric curves of "IN and Wash-OUT" by ROI centred on paraventricular regions,bilaterally,has confirmed the absence of perfusion in the area of the lefth MCA.(curve flat) with normal curve of IN and OUT on the rigth.Finally a further encephalic Tac examen ,carried out four days later ,has clearly pointed out the presence of circular ischemic area in the territory of the left MCA. In conclusion  the ultrasound perfusional study,together with IN and OUT densitometric curves,can enable us to have irreplaceable informations about the conditions of parenchyma in the course of ischemic stroke.

(07) Hypoperfusion ischemic stroke - As a result of atrial fibrillation.

Z. Metreveli MD, G. Imnadze MD

P. Sarajishvili Institute of Neurology and Neurosurgery,Tbilisi,Georgia

Introduction; The objective of this study was to identify the influence of atrial fibrillation onset on the cerebral hemodynamic and  development of cerebral ischemia.

Patients and Methods: We studied 36 patients (m/f-10/26; mean age -48years) presenting with TIA and arrhythmia episodes in anamnesis. One month follow-up had been performed extra-transcranial Doppler,ECG and TA monitoring, echocardiography, routine blood analysis, coagulation-aggregation tests.  12 patients needed CT and 7 - MRI investigation. From the final group  were excluded the persons with the heart,  blood, vessels and somatic probably  source of cerebral embolic or hemodynamic ischemia. The selected group (12) were investigated by transoesophagal atrial pasing (TAS), as a  diagnostic facility while TCD monitoring. TCD data before TAS in all the cases were in normal value. TAS investigation needs 15 min.   Maximal duration of arrhythmia after TAS was 2 hours.

Results: TAS induced arrhythmia exposed:

I-At the least 15% of systoles registered on ECG were not detected on intracranial vessels.

II-Mean flow velocity had diminished on  average by 32%.(p<0.01)

III-Blood flow obstruction was not seen while and after investigation in any of cases.s

IV-4 of 12 patients demonstrate cerebral discirculation symptoms (3-posterior circulation, 1- left MCA circulation).

V- MCA basin ischemia’s clinical manifestation lasted one week regardless of the fact that arrhythmia duration was not longer then 1,5 hour. CT  ischemic data was positive in appropriate area.

VI-There was not found the strong correlation between the mean velocity reduction level and cerebral discyrculation manifestation.

VII-TCD monitoring detected one microembolus while TAS investigation, without clinical manifestation.

Conclusion: Atrial fibrillation may course cerebral hemodynamics reduction, hypoperfusion in intracranial vessels and lead to TIA or stroke.

(08) Transcranial monitoring in acute stroke – initial experience from Chennai.

Dr. M.R. Sivakumar, Stroke Neurologist,

Cerebrovascular and Vasculitis Center,  Chennai – 600 010, India.

Email: sivakumar25@yahoo.com

Background: Transcranial Doppler (TCD) has been documented to be useful in acute ischemic stroke, monitoring vasospasm after subarachnoid hemorrhage, detecting intracranial stenosis and has a role in carotid endarterectomy (CEA) and angioplasty. TCD can be used to select patients for CEA and can reliably identify the patency of middle cerebral and basilar arteries, high resistance flow patterns due to increased intracranial pressure and progression to cerebral circulatory arrest. TCD also can monitor spontaneous or induced arterial recanalization.

Aim:To examine the role of transcranial Doppler ultrasound (TCD), in Acute Stroke.

Methods: The records of  100 randomly selected patients undergoing serial TCD monitoring following  acute ischemic strokes and subarachnoid hemorrhage (SAH) were reviewed. Dates and results of TCDs and cerebral angiograms when performed and the development of new neurological deficits were recorded. TCD was performed immediately after the stroke and serially whenever indicated. The results of TCD examination were correlated with MR Angiograms and invasive 4 vessel Digital Substraction Angiograms.

Results: The Mean age was 58.4 years. The Men : Women ratio was 6.5: 3.5. Right middle cerebral stenosis/occlusions were seen in 16 %, left middle cerebral narrowing in 22% and Basilar stenosis in 4%. Poor temporal windows were seen in 17%. Mild or moderate TCD-defined vasospasm developed in  30%  and 20% developed severe TCD-defined vasospasm after 7-8 days. TCD abnormalities preceding the focal neurological deficits by 3 days  in 30%.

Conclusions: A high incidence of intracranial stenosis were present. TCD may be helpful in selecting patients for intra-arterial thrombolysis. Since TCD-defined vasospasm preceded the neurological deficit in patients with SAH, early intervention might reduce the incidence of vasospasm-related stroke.

(09) TCCD study the symptomatic stenoses of the middle cerebral artery

G. Malferrari , F.Casoni , °F.Accorsi ,^ S.Sanguigni , *G.Meneghetti

Arcispedale S.Maria Nuova , Reggio Emilia ;°Ospedale Maggiore , Bologna ;^Ospedale Civile , S.benedetto del Tronto ;*University Hospital ; Padova , Italy

Introduction:Our first aim was to investigate the presence of intracranial stenoses in patients with stroke or TIA by TCCD .Second aim was to individuate different types of stenoses and a correlation between therapy and stenoses .

Patients and methods:We have studied both intracranial and extracranial vessels with ultrasound ( Sonos 5500 – Philips ).Morover  in the patients with intracranial stenoses we have used contrast agent and back scattering method .We enrolled 100 patients from April 2002 to April 2003:

fourty of them presented stroke and sixty presented only TIAs

18 patients presented MCA occlusion and were treated with rtPA ;40 patients presented MCA stenoses

42 patients had normal intracranial flow pattern.

In the patients treated with rtPA we have seen : -1-complete reperfusion in 12 patients ;-2-two patient with only one stenosis with compensatory dilatation in the distal part ;-3-four patients with many stenoses in the same vessel .By analogy with the other 40 patients we have seen:

-a-26 patients with MCA stenosis presented atherosclerotic lesions in several sites of the vessel ;-b-14 patients presented a single stenosis .The MCA stenosis were confirmed by Angio MRI in all patients .We have seen a strong correlation with diabetes and then with hypertension .

Conclusion: We think that the routinary use of TCCD is necessary to distinguish the intracranial stenoses in single or multiple stenoses . Moreover patients with multiple MCA stenosis had benefits from anticoagulant therapy. 

(10) Detection of occlusion with transcranial Power M-mode Doppler in patients with acute neurological Syndromes in the emergency room

Z. Garami, S. Calleja, J.C. Grotta, A.V. Alexandrov,

Stroke Team, The University of Texas-Houston Medical School

Background: Accurate diagnosis by imaging would improve patient selection for thrombolysis, especially intra-arterial (IA) interventions. We report our experience with PMD-TCD used in the emergency department (ED) in patients (pts) with acute neurological symptoms. 

Method: We studied serial pts 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 at bedside. TCD results were compared to clinical findings, digital subtraction angiography (DSA) and MRA. 

Results: 69 pts were studied (mean age 69; 42%w); 50 pts had ischemic stroke (occlusion in 78%,stenosis in 6%,collateral in 4% and normal in 8% of pts); 8 had TIAs (occlusion in 37%, stenosis in 13%, collaterals in 13%, and normal studies in 37%); and 9 pts had etiologies other than ischemia. PMD-TCD showed suboptimal temporal windows in 4 pts (7%). TPA (0.9/mg/kg) was given in 22 stroke pts (44%), 2 (4%) received intravenous TPA 0.6 mg/kg if presented between 3-6 hours (experimental protocol) and in 9 (18%) IA thrombolysis was performed. In all pts who underwent IA rescue, TCD had showed an initial arterial occlusion. If PMD-TCD and angiography were both performed within 720 minutes after onset, the predictive value of PMD-TCD for intracranial occlusion was100%. 

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.

(11) Yield of urgent carotid scanning in acute cerebral ischemia

Garami Z, Alexandrov AV.

Stroke Team, University of Texas-Houston Medical School, USA

Background: Noninvasive detection of a severe carotid stenosis impacts management of patients with cerebral ischemia, and hand-held ultrasound technology now makes it possible to perform scanning in the Emergency Department.

Methods: We studied consecutive patients with acute cerebral ischemia using a Sonosite 180 Plus (B-mode, power-mode, angle-corrected spectral Doppler) who were possible candidates for thrombolytic therapy.

Results: A total of 135 patients were evaluated: 79 men, 56 women, mean age 64 yrs, range from symptom onset 50 – 2880 min.Of these, 29 were treated with 0.9 mg/kg IV TPA or intra-arterial thrombolysis (median NIHSS15, range 6-25) and carotid duplex was performed at mean time 116 min. from stroke onset, and no delay in TPA administration was experienced. 75 had ischemic strokes outside thrombolysis window, and 31 had minor or resolved symptoms. Internal carotid artery was normal in 38, 69 and 74 (%) patients, > 70% stenosed in 14, 7 and 16 (%) patients and near-occlusion/ occlusion was detected in 48, 24 and 10(%) of these patient groups (p=0.004).

Compared to invasive urgent angiography ultrasound scanning had the following accuracy parameters: ( Sensitivity, Specificity, PPV, NPV)

I.                     Normal or less than 70% stenosis:            100%, 90%, 82%, 100%,

II.                     70-95% stenosis:                                         87%, 97%,87%, 97%,

III.                    Near occlusion or occlusion:                      81%, 100%, 100%, 72%.

Serial extracranial carotid examinations of patients with initial ICA occlusions yield partial proximal ICA recanalization during intravenous TPA infusion in 14(%), and proximal ICA re-occlusion in 7(%).

(12) Morphological study of intracranial stenoses with transcranial backscattering technique

G. Malferrari

Arcispedale S.Maria Nuova , Reggio Emilia , Italy

Introduction : TCCD  studies  more accurately the morphology of the artery and detects the intracranial stenosis .In particular it is very important to know whether the stenoses are single or multiple, and to localise them more accurately (i.e. M1, M2 or C1).

Patients and Methods : We used a last generation ultrasound machines , Sonos 5500-Philips, together with ultrasound contrast agents ( sonovue ) to detect intracranial stenosis in 40 stroke patients and we applied a peculiar imaging technique called “backscatter”, currently used for echocardiographic applications.The backscatter technique is based on the interaction between ultrasound waves and objects much smaller than the ultrasound wave length, i.e. microbubbles of ultrasound contrast agents.

The acoustic pressure used during the scan is another important parameter.

In fact, if we use acoustic pressure (i.e. Mechanical Index) higher than 1 MPa, ultrasound contrast agent will be destroyed (explosion of microbubble) will generate a highly non-linear signal wich can be read by the ultrasound equipment.

If we use intermediate acoustic pressure i.e. around 150 KPa, the contrast agent microbubble will resonate without breaking and generate a high harmonic response which can be read by the ultrasound scanner.

Results : -a-26 patients with MCA stenosis presented atherosclerotic lesions in several sites of the vessel without a significant velocity increment ;-b-14 patients presented a single stenosis with significant increment

The MCA stenosis were confirmed by Angio MRI in all patients .

Conclusions: we adopted the backscatter technique together with ultrasound contrast agents with low acoustic pressure, in order to obtain a better morphological appearance of the intracranial vessels. 

(13) Color Doppler patterns of craniocervical artery dissection – Diagnosis and Monitoring

Lovrenčić Huzjan A, Zavoreo I, Vuković V, Kesić MJ, Demarin V.

Department of  Neurology, UH Sestre milosrdnice, Zagreb, Croatia

Background: The localization of craniocervical dissection determines symptomatology. Besides headache, stroke, cranial nerve paralysis, patients may present with other clinical symptoms.

Methods: Color Doppler Flow Imaging was applied in a variety of neurological clinical settings as a result of craniocervical artery dissection. The symptoms varied from fluctuating lower limb paraplegia, left arm fluctuating paresis, unexplained loss of consciousness up to usual clinical presentations of dissections like headache, stroke and cranial nerve palsies.

Results: Dissections arising from aortic arch presented with different symptoms depending of its localization. In patients with headache, or stroke, usual site of the dissection was the distal portion of the internal carotid or vertebral artery. While in the first group of patients Color Doppler enabled visualisation of the double lumen, with no changes during time, in the second group color Doppler enabled visualisation of the hemathoma, localization of the occlusion, redistribution of the hemodynamic and activation of the collateral pathways. During time, in this group the regression of the hemathoma was visible.

(15) Recanalization and short-term-outcome after systemic thrombolysis in relation to site of occlusion as determined by transcranial Doppler sonography (TCD)

C. Fritzsch, J.-P. Garczarek, G.M. v. Reutern

Background: Pathophysiological concepts and MR-Angiography studies suggest, that the (short-term) prognosis of systemic thrombolysis of ischaemic stroke depends on the time of onset and the localisation of the arterial occlusion. Dopplersonographic results before and immediately after systemic thrombolysis were compared to the clinical development during the first hours.

Methods: In all patients of the stroke unit Bad Salzhausen treated with systemic thrombolysis after acute ischaemic stroke (N=53) the dopplersonographic status and clinical scores were evaluated before, 3 and 6 hours after treatment. Frequency, localisation and recanalisation time of the differend types of occlusion were analyzed. An increase of the NIHSS for at least 4 points 10-30 min. after start of systemic thrombolysis was defined as a thrombolysis-associated improvement.

Results: Occlusions in the carotid circulation were detected in 38 patients, among them 16 occlusions of the distal ACM, 9 of them recanalized after treatment. All recanalisations were detected 3 hours post stroke, 8 of them with a thrombolysis-associated improvement. 3 of 16 occlusions of the proximal ACM recanalized in 6 hours- none in 3 hours- and only one of them showed improvement. 3 of 5 T-occlusions recanalized, 2 within 3 hours. None of the proximal ACI-occlusions recanalized. In the 38 patients 11 recanalisations within 3 hours were noticed, 10 (90,9%) of them were followed by improvement. In one (25%) of 4 recanalisations within 6 hours improvement was noticed. Only 4 (18,1%) of improvements were detected in the 23 patients without any recanalisation.

Discussion: Distal occlusions recanalized more frequently and earlier after systemic thrombolysis then proximal occlusions. A recanalisation as shown by Doppler sonography within 3 hours post stroke was mostly seen with a thrombolysis-associated clinical improvement in contrast to recanalisation within 6 hours and persistent occlusion. This is a result which is conform with data from MRA studies in acute stroke. Dopplersonography seems to be a appropriate in acute hemispheric stroke in order to estimate the probability of recanalisation of arterial occlusions and the early clinical outcome.

(16) Results of early Doppler/Duplex-sonography in ischemic posterior circulation stroke

Garczarek JP, Fritzsch C, von Reutern, GM

Asklepios Neurologische Klinik Bad Salzhausen, D 63667 Nidda, Germany

Background: Data of Doppler/ Duplex sonography in the early phase of ischemic stroke of the posterior circulation is limited and often reserved to special cases. In contrast to basilaris thrombosis relatively little is known about single vertebral occlusions (frequency and prognostic relevance).

Methods: We reviewed retrospectively all patients who were admitted to our stroke unit since 1998 within 6 hours of stroke onset presenting with persisting symptoms clearly defined as ischemic posterior circulation stroke by symptoms or computer tomography. We noted initial sonographic vascular status, type and localisation of ischemia, clinical scores (admission and after 7 days) and length of stay (acute and rehabilitation).

Results: 26 of the 71 patients showed an occlusion/ high-grade stenosis of one vertebral artery (VA), 6 of them proximal, 20 distal; 12 patients had a basilar thrombosis/ occlusion of both vertebral arteries (BA). Microvascular stroke was more frequent in patients without vertebral/basilar pathology. Most patients in the BA-group had multilocular infarctions; whereas cerebellar (esp. PICA-) infarctions were dominant in the VA-group. Patients with VA and BA were significantly more severely disabled on admission, after 7 days the disability was similar in those with VA and those without. However length of stay in patients with VA was significantly longer.

PLATFORM PRESENTATION

Treatment strategies

Extended concept of thrombolysis

M. Siebler, St. Straub, U. Junghans

Universitätsklinikum Düsseldorf, Dept. of Neurology, D-40225 Düsseldorf, Germany

Background: Fast recanalization is the best way to prevent the transition of ischemic tissue into the infarct proper. Current concepts to accomplish recanalization are based on the systemic or local administration of thrombolytic agents and the use of mechanical/ultrasonic devices. Early studies demonstrated that potent fibrinolytic agents like urokinase and streptokinase facilitate thrombolysis but the recanalisation was accompanied by severe cerebral bleedings in stroke patients. In contrast, the introduction of rtPA achieved a more acceptable benefit-risk ratio but vessel reocclusions associated with secondary neurological deterioration have often been observed. As known from cardiovascular studies, intrinsic and extrinsic activation of thrombolysis concomitantly activates circulating platelets with the consequence of vessel reocclusions. Here we report on the extended application of fibrinolytic substances with the highly selective, short acting non-peptide platelet GPIIb/IIIa receptor antagonist tirofiban.

Patients and methods: Acute ischemic stroke patients (n=150) received tirofiban for 48 hours. Nineteen patients presenting with an MCA occlusion within 3 hours after symptom onset were treated with a combination of rtPA (20 mg bolus injection) and tirofiban. The recanalization rate and the size of the resulting ischemic lesions were evaluated by repetitive MR imaging.

Results: In none of the cases  a symptomatic cerebral bleeding occurred. In patients with acute MCA occlusion the recanalization rate was approx. 70%, exceeding the respective rates reported for systemic rtPA lysis.

Discussion: The combination of GPIIb/IIIa antagonists with fibrinolytic agents may facilitate thrombolysis, prevent vessel reocclusion and attenuate microcirculatory disturbances. Thus, extended concepts of thrombolysis have the potential to improve the treatment in acute ischemic stroke. 

Systemic thrombolysis in patients with acute basilar artery thrombosis

U. Junghans

Universitätsklinikum Düsseldorf, Dept. of Neurology, D-40225 Düsseldorf, Germany

Background: Acute basilar artery thrombosis has a very poor prognosis. Even after immediate intraarterial thrombolysis case fatality rates of up to 70% have been reported. Thrombolytic agents concomitantly activate of the coagulatory system leading to incomplete or delayed reperfusion, microcirculatory disturbances, or even repeated vessel occlusions. We introduce a new therapeutic concept for the systemic thrombolysis in patients with acute basilar artery thrombosis.

Patients and methods: Patients presenting with a severe brainstem syndrome due to acute basilar artery thrombosis received a systemic thrombolysis with low-dose rtPA and tirofiban, a selective platelet glycoprotein IIb/IIIa receptor antagonist, within a median of 150 (range: 100 to 240) minutes after symptom onset. Basilar artery occlusion and recanalization was documented by intraarterial angiography or repeated multimodal magnetic resonance imaging.

Results: All patients (median age 60, range 59 to 75 years) presenting with acute basilar artery thrombosis were clinically severely affected (median NIHSS 23, range 13 to 32; GCS 6, 4 to 11). After systemic thrombolysis complete arterial recanalization and good neurological outcome (NIHSS 1, 0 to 2, p=0,042; BI 100; mRS 1; p=0,041) were achieved in all cases. In no cases cerebral or extracerebral hemorrhagic complications were observed.

Discussion: Combining fibrinolytic agents and glycoprotein IIb/IIIa inhibitors may have a high potential in the treatment of acute basilar artery thrombosis. A prospective multi-center trial is needed to compare the safety, efficacy and feasibility between intraarterial thrombolysis and this new therapeutic concept. 

A pilot study of a novel tissue plasminogen activator (HTUPA) in patients with acute ischemic stroke - A preliminary report

W.J. Wong, *H.L. Shieh, Y.O. Luk, C.M. Chern, L.C. Hsu, H.H. Hu

Section of Neurovascular Disease, Neurological Institute, Veterans General Hospital-Taipei, Taiwan, *Global Biotech Inc., Taiwan

Introduction: Human Tissue Urokinase Type Plasminogen Activator (HTUPA)-a novel thrombolytic agents, is constructed by inserting the single kringle region of urokinase into the beginning of the double kringle region of tissue plasminogen activator. The objective of this study is to evaluate the safety and explore the preliminary efficacy of HTUPA administered within 5 hours after onset of ischemic stroke.

Patients and methods: Patients with NIHSS ³9 and £ 20 (for brain stem stroke, patients with NIHSS>20 were enrolled at the discretion of investigators) followed by brain-computed tomography were evaluated and treated with HTUPA (IV bolus) under a dose-finding and open-labeled design within 5 hours after the symptom onset. The study endpoints included hemorrhage manifestations and neurological outcomes. 

Results: Nineteen acute ischemic stroke patients (Male: 12; Female 7) with average age of 65.3±9.3 y were enrolled so far. Fifteen patients received 0.3 mg/kg, 2 patients, 0.35 mg/kg and 1 patient, 0.4 mg/kg; 1 patient withdrew from the study before giving HTUPA. The mean time from stroke onset to administration of HTUPA was 3.4±1.0 hr. The total dose given ranged from 15.8mg to 29mg per patient. Intracranial hemorrhage associated with neurological deterioration was only observed in the patient who received 0.4mg/kg. Favorable outcome (Modified Rankin scale £1 at 90 days) occurred in 7/14 (50%) patients who received 0.3 mg/kg. 

Conclusion: These observations suggested that the novel thrombolytic agent-HTUPA at dose of 0.3 mg/kg to treat acute ischemic stroke within 5 hours after the symptom onset has the potential clinical benefits and justifies further investigation.

Clopidogrel plus Aspirin for infarct reduction in acute stroke/TIA patients with large artery stenosis and microembolic signal (CLAIR): a multi-center randomized control study in Asia

KS Wong, HM Chang, KC Chang, J Navarro, YN Huang, CZ Lu, KS Tan, N Suwanwela, H Markus

Chinese University of Hong Kong; Singapore General Hospital; Chang Gung Memorial Hospital, Taiwan; St. Luke Hospital, Manila; Peking Union Medical College Hospital, Beijing; Fudan University Huashan Hospital; University of Malaya, Kuala Lumpur; Chulalongkorn University, Bangkok; Shanghai.

Microembolic signal (MES) predicts the number of acute infarcts and early recurrent stroke in Asian acute stroke patients with intracranial large artery stenosis. We aim to use MES as a surrogate marker to test the hypothesis that clopidogrel plus aspirin is superior to aspirin alone in reducing the number of MES for acute stroke patients with large artery stenosis in Asia. Patients with acute stroke (i) within 48 hours of symptom onset and (ii) with large artery occlusive disease and (iii) MES during 30 minutes monitoring will be randomized to receive either clopidogrel+ aspirin or aspirin alone. MES monitoring will be repeated after 24 hours and also 7 days. Diffusion-weighted MRI will be done on Day 1 and 7 to document of the number of acute infarct. Primary outcome is the proportion of patients with at least one MES as interpreted independently in the Clopidogrel +Aspirin group compared with the Aspirin alone group at Day 2. Secondary outcomes include: number of new acute infarcts as defined by recent infarct(s) shown on DWI on Day 7 but not on Day 1; number of MES on Day 7; number of acute infarcts on DWI; NIHSS at Day 7 ; difference of NIHSS between baseline and Day 7; modified Rankin Scale at Day 7; overall mortality at Day 7; thrombo-embolic events during the study period: recurrent stroke, coronary syndrome, deep vein thrombosis, pulmonary embolus. This study will start in July 2003 and should be completed in 12 months.

Imaging in acute stroke

Integrated diagnostic concept of CT perfusion and ultrasound modalities in acute stroke

Darius G Nabavi, MD

Department of Neurology, University of Münster, Germany

With the introduction of thrombolysis in acute stroke, patient stratification within the hyperacute stage of disease has become of increasing importance. Since amount and severity of cerebral ischemia is the most decisive parameter for tissue viability, measurement of the brain perfusion has become a focus of stroke research during the last decades. The ultimate goal of perfusion imaging in acute stroke is to discriminate tissue already destined to infarction (= ischemic core) from potentially salvageable tissue-at-risk (= penumbra). The idea of this derived “mismatch-concept” is to individualize and - in selective cases - expand the window for thrombolytic therapy. Although MRI has clearly become the goldstandard for this purpose, still only a limited number of centres can offer this technology “around-the-clock” for emergency cases. Neurovascular ultrasound (US) and computed tomography (CT) still represent first-line diagnostic techniques for acute stroke management in most hospitals. By means of multimodal CT technology, information about cerebral anatomy and infarcted tissue (native scan), intracranial vessel status (CT-Angiography) and tissue perfusion (Perfusion-CT) can be acquired within 20 minutes. Evidence is accumulating that mismatch-imaging is also provided by Perfusion-CT. US is a portable bed-side technique that enables to monitor the extra- and intracranial vessel status noninvasively before, during, and after thrombolysis. Thereby, individually “tailored” thrombolysis guided by the vessel status may be established. Furthermore, due to the phenomenon of sonothrombolysis, US also constitutes an attractive therapeutic tool for the near future. Therefore, the combined use of CT and US in acute stroke provides neurovascular informations comparable to MRI. Low costs and rapid availability underscores the potential of CT and US to improve acute stroke management on a much broader basis. 

Functional impact of DWI and PWI in acute stroke

Neumann-Haefelin T, Singer O, Sitzer M, du Mesnil de Rochemont R

Klinik für Neurologie und Institut für Neuroradiologie, JW v. Goethe – Universität, Frankfurt a. Main

Introduction: Multimodal magnetic resonance imaging (MRI) techniques including diffusion- and perfusion-weighted imaging (DWI, PWI) have become available in many centers in the past years. In this update, the diagnostic impact of these techniques we will be reviewed based on pathophysiological considerations.

Results: The time course of DWI lesion evolution will be discussed as well as the (rare) conditions where DWI lesions may be reversible. In most cases the DWI lesion may be safely viewed as a good surrogate for the ischemic core, indicating severe and often irreversible tissue damage. The ischemic penumbra, on the other hand, is mainly located within the DWI- / PWI-mismatch, i.e. in the region with a perfusion deficit, but no diffusion abnormality. Typically, a substantial DWI-/PWI-mismatch indicates that the patient is at risk of lesion enlargement, although early reperfusion may stop this process. Several PWI methods have been developed with the aim to semiquantita­tively differentiate between severe (critical) ischemia and oligemia, but absolute quantification of PWI remains difficult due to methodological problems. DWI and PWI are supplemented by MR angiography of the circle of Willis providing reliable information on the status of the proximal intracranial vessels.

Conclusion: In summary, with multimodal MRI acute stroke patients can be imaged resulting in a high yield of pathophysiologically relevant information. The main limitations are scanner availability and restrictions in monitoring vital parameters.

Power M-mode Doppler and Brain Perfusion

Power M-mode Doppler: Technical features for application in acute stroke

M.A. Moehring, M.P. Spencer

Spencer Technologies, Seattle, USA

Introduction:  The use of TCD in the acute stroke setting requires rapid location of temporal bone windows and exploration of the entire length of the MCA, and unambiguous detection of microemboli.  A power M-mode Doppler (PMD) was explored to meet these demands.  PMD shows depth on the vertical axis, time on the horizontal, and power as intensity colored red or blue according to mean velocity. PMD for acute stroke necessitates a high dynamic range digital receiver, enabling sensitive and rapid recognition of blood flow and emboli.

Methods: A 2 MHz PMD system (Spencer Technologies PMD100M) having a receiver dynamic range of 84 dB and 33 sample gates deployed at 2 mm intervals was used with sample volume sizes (SV) of 3 or 9mm.  Transmit amplitude was adjusted depending on sample volume size to maintain a constant temporal average acoustic intensity.  PMD signals from the MCA were acquired with different sample volume sizes, and reviewed to compare sensitivity to blood and emboli in a subject with prosthetic heart valves. 

Results:  PMD shortened window acquisition time by displaying blood flow signals at all depths from 22 to 86mm along the beam path and allowed easy exploration of flow velocities along the MCA and ACA.  PMD with 3mm SV has sensitivity to localized blood flow which meets or exceeds that for 9mm SV.  PMD high dynamic range eliminates saturation due to high amplitude embolic tracks and tissue motion signals.

Parameters of normal and pathological brain perfusion imaging with phase inversion harmonic imaging (PIHI) - two case reports-

  J. Eyding, A. Muhs, C. Büschleb, G. Schmid, T. Postert

St. Josef Hospital, Ruhr-Universität, Bochum, Germany

St. Vincenz Hospital, Paderborn, Germany

Background: In a series of 14 cerebro-vascular healthy patients we have been able to show, that phase inversion harmonic imaging (PIHI) in combination with 2^nd generation echo contrast agents is able to display semi-quantitative perfusion parameters of both hemispheres of the brain in only one examination (“bilateral approach”). Hereby, time of examination of acute stroke patients can be halved and also evaluation of cortical structures becomes possible for the first time in neurosonology. Two patients are presented to indicate the possible potential of the method.

Case 1

82 years old E.K. presented a MTT delay in p-MRI behind a medium MCA stenosis without clinical features. In bilateral PIHI, time-to-peak intensity (TPI) was the only pathological parameter with 31.9s in the affected area and a mean of 29.4s in not affected gray matter areas.

Case 2

81 years old S.W. presented with a major MCA infarction with signs of distal M1 occlusion (initial cCT: hyperdense MCA sign, obscuration of anterior lentiform nucleus). Three hours after symptom onset and just before systemic rt-PA lysis, bilateral PIHI showed TPI delay and shortening of peak width (PW) in a region ranging from anterior parts of the lentiform nucleus up to cortical regions. In the center of this region, corresponding to the eventual infarcted region in follow up cCT, the PIHI algorithm could not extract any sensible data.

Conclusions :Both cases suggest, that PIHI in combination with the model function used is able to detect perfusion abnormalities. Case 1 displayed a sole perfusion abnormality in accordance to p-MRI, in which only a MTT delay was seen. Case 2 displayed different regions of perfusion abnormalities, i.e. a “core” region, in which no curve following the model function could be extracted and a “surrounding” region, in which a curve could be extracted but both TPI and PW were pathological. Follow-up cCT displayed the final infarction in the a.m. “core” region and survived tissue after recanalisation of the MCA-occlusion in the region where initial PIHI could display hypoperfusion. Further evaluation of acute patients in comparison to p-/d-MRI with follow up is needed to evaluate the potential of the method.

Optimal transcranial perfusion images for acute ischemic stroke: Comparison between ultraharmonic, second harmonic and power harmonic imaging

  T. Shiogai¹⁾, A. Morisaka¹⁾, N. Takayasu²⁾, T. Mizuno²⁾, M. Nakagawa²⁾, H. Furuhata³⁾

Department of Clinical Neurosciences, Kyoto Takeda Hospital¹⁾, Department of Neurology, Kyoto Prefectural University of Medicine²⁾, Medical Engineering Laboratory, Tokyo Jikei University School of Medicine³⁾

To clarify optimal brain tissue perfusion images for acute ischemic stroke visualized by transcranial harmonic imaging, we compared between gray-scale integrated backscatter (IBS) images of ultraharmonic imaging (UHI) and conventional second harmonic imaging (SHI), and power harmonic imaging (PHI) in 10 patients with and 4 without a temporal skull.

Methods: Utilizing a SONOS 5500, transient response images taken after a bolus Levovist injection were evaluated at a horizontal diencephalic plane via temporal windows. Based on transmitting/ receiving frequencies (MHz), 4 imaging procedures utilizing an S3 transducer [SHI2.6 (1.3/2.6), UHI (1.3/3.6), PHI2.6 (1.3/2.6), and PHI3.2 (1.6/3.2)], and 2 imaging procedures utilizing an S4 transducer [SHI3.6 (1.8/3.6) and PHI3.6 (1.8/3.6)] were compared in terms of size and location, peak intensity (PI), and contrast image demarcation.

Results: a) Intact skull cases: Gray-scale imaging tended to have larger contrast areas than PHI. A large contrast area was most frequently observed in SHI2.6 images. The contrast area was defined in all PHI2.6 cases. No contrast area was observed in SHI2.6, UHI, and PHI3.2 in a few cases. b) Craniectomized cases: All images, especially in PHI3.6, tended to have large, high PI, and defined contrast areas.

Conclusions: Gray-scale SHI utilizing low receiving frequency of 2.6 MHz is the superior method for visualizing transcranial brain tissue perfusion images. However, color-coded imaging with B-mode, such as PHI, is easier and quicker to identify the contrast area localization rather than gray-scale imaging, would be suitable for acute ischemic stroke cases.

Clinical aspects of diagnostic ultrasound in acute stroke

Ultrasound pattern of occlusion and recanalization in acute stroke

Carlos A. Molina, MD

Brain Hemodynamic Research Laboratory. Neurovascular Unit

Hospital Vall d´Hebron. Barcelona

Transcranial Doppler (TCD) is a non-invasive tool that provides a unique opportunity to evaluate, in real-time, the presence and location of arterial occlusion and the occurrence of spontaneous or tPA-induced recanalization. Ultrasonic patterns of intracranial occlusions and recanalization have been correlated with angiography with high sensitivity and specificity values. These patterns initially defined to evaluate spontaneous recanalization in patients with acute MCA stroke, were further refined to be applied in the setting of thrombolysis. The resulting Thrombolysis In Brain Ischemia (TIBI) flow grading system accurately reflects the dynamic nature of the recanalization process.

In the last few years, several studies of TCD monitoring of recanalization during thrombolysis provided valuable information regarding the frequency, temporal profile and degree of recanalization, the speed of clot lysis during tPA infusion and the persistence of recanalization over time. Early recanalization (<6h) occurs in 66%-70% of tPA treated patients as compared with only 13% of controls. Thrombolytic therapy increases in 8- and 3- fold the rate of complete and partial recanalization, respectively. Sudden (lasting seconds) recanalization shortly after tPA infusion associates with a better short-term clinical outcome than stepwise  (< 30 minutes) or slow (> 30minutes) patterns of recanalization. While early complete recanalization achieved < 300 minutes of stroke onset strongly predicts full neurological recovery at 24 hours, delayed recanalization (>6 hours) associates with an increased risk of symptomatic intracranial hemorrhage.

In conclusion, TCD represent a powerful tool to assess recanalization particularly in the setting of thrombolysis, providing valuable prognostic information and improving the selection of patients for more aggressive reperfusion strategies.

Influence of the time of parameter assessment for outcome prediction after ischemic stroke on the predictive value of chosen parameters

H. Lotze, K. Haupt, T. Blaser, C.-W. Wallesch, M. Goertler

Department of Neurology, University of Magdeburg

Introduction: Several parameters have been suggested to predict outcome after ischemic stroke. We investigated whether the time when outcome is predicted after a stroke influences the predictive value of a parameter.

Patients and Methods: 162 consecutive patients (89 men, mean age 64+/-15 years) with symptoms of an anterior circulation ischemia were admitted within 48 hours. Outcome after 3 months was dichotomised into a maximally mild disability with independence from help in the activities of daily living (modified Rankin Scale 0 to 2) and dependence or death (mRS 3 to 6). Admission parameters investigated for their outcome prediction were patients’ age and sex, side of the affected hemisphere, ischemic CT-findings (</> 1/3 of the middle cerebral artery (MCA) area), occlusion/flow diminution (< 40 cm/s) in the MCA, NIH Stroke Scale score, blood pressure, body temperature, CRP and blood glucose level. Relevance of parameters was tested by multiple logistic regression with forward stepwise entry (p < 0.05) and removal selection (p > 0.10) based on the likelihood-ratios.

Results: Within 3 hours, sonographic finding of the MCA was the only selected parameter (OR 4.8, 95%CI 1.1 to 20.3, p=0.032). Within 6 hours, MCA finding (OR 3.8, 95%CI 1.1 to 13.1, p=0.038) and NIH-SS score (OR 1.2, 95%CI 1.1 to 1.3, p=0.002) were predictive. Predictive factors in patients admitted within 12 hours were MCA-finding, NIH-SS score, side of the affected hemisphere and blood glucose level. Age was an additional factor for admission within 48 hours. If only patients were evaluated admitted >12 hours after the onset of stroke symptoms, NIH-SS score was the only predictive factor selected.

Discussion: Relevance of parameter to predict outcome depends on the time of the examination after stroke onset. 

Likelihood of early arterial recanalization with intravenous TPA and ITS predictors: A multicenter transcranial Doppler study

Zsolt Garami, Ken Uchino, Carlos A. Molina, Andrei V. Alexandrov for Clotbust Investigators

University of Texas-Houston, Hospital Vall d'Hebron, Barcelona,

Background: Intravenous tissue plasminogen activator (IV tPA) treatment of acute ischemic stroke can result in early arterial recanalization, which is predictive of better outcome. We aimed to determine likelihood of recanalization at various occlusion sites and its predictors.

Methods: Subjects of this study were patients with acute ischemic stroke who received IV tPA at 4 academic centers. A nested case-control design was used to determine the odds of complete recanalization based on occlusion site. Stepwise logistic regression was used to determine predictors of complete and partial recanalization. All patients had occlusions on pre-bolus transcranial Doppler by previously validated Thrombolysis in Brain Ischemica (TIBI) system and were monitored for two hours. Variables analyzed were age, gender, pre-treatment NIH Stroke Scale (NIHSS) scores, early ischemic changes on CT, ASPECTS score, residual flow signals on Doppler, occlusion site, time to TPA bolus, and stroke subtypes.

Results: 250 patients received IV tPA (127 men, mean age 68±14 years, median NIHSS 17 points, 88% with scores >10 points, tPA bolus at median 135 min after onset). The likelihood of complete recanalization of the distal (presumed M2) MCA occlusion (34/77) was 44% (OR 2.12, 1.21-3.71 95% CI), proximal MCA occlusion (38/132) 29% (0.71, 0.41-1.2), tandem ICA/MCA including "T"-type (3/28) 11%, (0.22, 0.07- 0.76), other sites n=13, n/a. The only factor that independently predicted partial or complete recanalization after IV tPA was the presence of detectable residual flow signals before tPA bolus (p=0.032). Only the pre-tPA NIHSS score independently predicted complete recanalization at any occlusion site (median 14 points in those who recanalized completely vs 18 points in those with persisting occlusions, p=0.009).

Conclusions: A more distal occlusion in the anterior circulation is associated with greater likelihood of early arterial recanalization. Tandem lesions are least likely to recanalize with IV tPA alone. However, lower pre-tPA NIHSS scores appear to be  stronger predictors of complete recanalization at any occlusion  location. 

In vivo realtime hemodynamic changes caused by microembolism detected by transcranial Doppler monitoring of the middle cerebral artery stenosis

KS Wong, S Gao

Devision of Neurology, Chinese University of Hong Kong, Hong Kong SAR

Background: Monitoring the hemodynamic changes of ongoing in vivo thromboembolism from an atherosclerotic artery is feasible by using transcranial Doppler (TCD) in the cerebral circulation. We described the hemodynamic changes caused by microembolism by the transcranial Doppler in the middle cerebral artery (MCA) stenosis among acute stroke patients. 

Methods and Results: We performed microembolic signal (MES) monitoring on symptomatic MCA stenoses (mean of peak systolic flow velocity Vs=284, range 200-300 cm/s on TCD and severe stenoses on magnetic resonance angiography) with a 2MHz bi-gate transducer for 30 minutes. MES monitoring were performed on every day after onset of symptoms until no further MES were detected. Patients with severe internal carotid artery stenosis or atrial fibrillation were excluded. The number of MES in every monitoring and the maximum flow velocity of insonated MCA were recorded. The value of flow velocity before and after MES was also recorded. Results- The flow velocities fluctuated widely in the early stage of stroke along with decreasing of the number of MES in all patients. In 20 episodes of MES, there were flow velocity changes after the dislodgement of MES. Most (19/20) were associated with an decreased velocities. The reduction in velocities ranged from 12 to 37%. In some, turbulent flow pattern disappeared after the MES. 

Conclusion: It is feasible to monitor ongoing thromboembolism arising from an atherosclerotic stenosis. The occurrence of microembolic signals is associated with improved hemodynamic changes. 

TCCD is essential in thrombolysis eligible patients with stroke

G. Malferrari , D.Guidetti , N.Marcello

Arcispedale S.Maria Nuova , Reggio Emilia , Italy

Introduction: The primary aim  is to define with ultrasound wich patient with internal carotid artery occlusion and or with middle cerebral artery occlusion may benefit from the rtPA therapy .

Patients and methods: Between March 2002 and April 2003 , 26 patients ( age 40-79 years ) with ischemic acute stroke were token to our stroke unit .Extracranial color doppler and TCCD were performed using Philips SONOS 5500 at the admission and 12 , 24 and 48 hours after therapy .TCCD was even performed using contrast agents ( sonovue ) .We have distinguished four group with TCCD

-1- five patients with stroke in evolution due to  ICA plus + MCA occlusion ; we have performed thromboendoarterctomy in emergency with the reperfusion of the ICA and MCA vessels .

-2-16 patients presented the occlusion of MCA ( with rtPA  ) .10 patients had the MCA occlusion at M1 ;6 patients had the occlusion at M2 .A dramatic recovery was observed in 10  patients with atrial fibrillation .

-3-Fourth patients presented  Tocclusion ( MCA + siphon + cerebral anterior artery ).In the two patients with atrial fibrillation we have a dramatic recovery , after rtPA; in the other we don’t have  a reperfusion .

-4-In one patient we observed a intracranial stenosis .

Results:first group -( rtPA ) MCA recanalization was observed before 12 hours in 13 patients and after 24 hours in the others 5 . MCA recanalization in the other patients was obtained in longer times . In two patient with T occlusion of the siphon we don’t observed reperfusion. Second Group - ( thromboendoartectomy ) All patients have a total reperfusion of the middle cerebral artery than two patients in wich we have seen stenosis of the siphon .

Conclusions:TCCD  is a rapid test to select patients for thromolysis and to monitor the artery recanalization. 

Ultrasound enhanced thrombolysis: Basic research

Efficacy and safety aspects of low-frequency therapeutic ultrasound

M. Nedelmann¹, F. Nolle¹, T. Gerriets², O. Kempski¹, M. Kaps², M. Dieterich¹, B.M. Eicke¹

Johannes Gutenberg-University, Mainz¹ and Justus-Liebig-University,Gießen², Germany

Background : Acceleration of clot lysis to restore circulation may limit the extent of brain injury and improve clinical outcome after stroke. Recent findings suggest that use of ultrasound alone and in combination with rt-PA has a thrombolytic potential. Identification of the optimal frequency and intensity will be critical in developing externally applied ultrasound for therapeutic application.

Methods : We performed efficacy studies of low frequency ultrasound in an in vitro flow model and compared different frequencies from 20.5 to 60.7 kHz (KLN, Germany) as to their potential as a “stand alone” therapy. The acoustic field of the different ultrasound probes was calibrated in a water tank by use of a needle-type hydrophone (Reson^TM, Germany). Using 20 kHz cw ultrasound (non-invasive, transcranial), a safety study was performed in wistar rats. In different study groups, the brain was insonated for 20 minutes, with intensities ranging from 0.5 to 3.2 W/cm²). Side effects were evaluated by MRI and in histology.

Results : The use of ultrasound at 20.5 kHz resulted in a significant thrombolytic effect at both intensity levels (mean weight loss of the blood clots was 53.0% at 0.2 W/cm² and 28.5% at 0.12 W/cm²) as compared to a control group (20.7%). At both intensity levels, thrombolytic efficacy decreased with increasing frequencies, with the least effect at 60.7 kHz (25.6% at 0.2 W/cm²; p<0.0001 compared to 20.5 kHz; no significant effect compared to control). On MRI, ultrasound induced brain damage was seen with intensities of 2.6 W/cm².

Discussion :These data show that thrombolytic efficacy of ultrasound is frequency dependent with best results at low frequencies. There are safety concerns of low frequency ultrasound. However, in our study, critical side effects were seen at intensities above the ones that showed efficacy in our flow model. Animal studies in cerebral artery occlusion models within these intensity limits seem appropriate.

Experimental evaluation of transcranial ultrasonic thrombolysis in the acute ischemic stroke

H. Furuhata, T. Saguchi

ME Lab. RCMS Jikei Univ. School of Med. Tokyo Japan

Introduction: The effect of transcranial ultrasonic thrombolysis (TUT) with low frequency and low intensity and tissue plasminogen activator (tPA) has been already verified by in vivo experiments by Ishibashi et al. The effect of the neurological improvement and the pathological safety of TUT were evaluated in the rat acute ischemic model with thrombo-embolism under the similar ultrasonic condition.

Method: Thirty male Wistar rats were used for the MCA occlusion model with hemiparasis by autologous thrombus put through a catheter injected from the external carotid artery. Animals were classified into three group: 1) no therapy: NT group (n=8), 2) an intravenous administration of 1.2mg tPA; monteplase at three hours after embolization: TPA group (n=11), and 3) 2) with TUT: TUT group (n=11). TUT conditions were 488.2KHz, 0.8W/cm² with a 60-minute intermittent application. Twenty hours after the treatment, neurological examination was re-evaluated and the removed brain was examined pathologically.

Results: The recanalization ratio and the neurological improvement of TUT group were significantly higher than those of NT and TPA groups. The pathological deficit by ultrasound could not found in all cases in TUT group. Despite of that tPA was administered after three hours after the MCAO onset, the neurological improvement was obviously observed without any damages by the ultrasound. Remarkably, the reperfusion injury was found in several cases.

Conclusion: It was suggested from this in vivo animal experiments that TUT using about 500KHz, 0.8W/cm² and intermittent sonication has a great advantage for the neurological improvement of the acute ischemic stroke without any ultrasonic damages.

In vivo trial of a newly developed combination 500kHz/2MHz therapy/Power
M-mode Doppler probe for ultrasound enhancement of t-PA thrombolysis

J. Shimizu^1,2, M. Nakano¹, H. Matsuyama¹, T. Saguchi^1,2, T. Abe², H. Furuhata^1,
M.A. Moehring³, A.H. Voie³, M.P. Spencer³

ME Lab.¹, Dept. of Neurosurg.² Jikei Univ. School of Medicine, Spencer Technologies, Inc.³

Introduction: We examined the change of Power M-mode Doppler (PMD) waveforms during the process of thrombolysis in the rabbit femoral thrombo-embolic model using a newly developed 500kHz/2MHz combination probe.

Methods:  A new type of probe has two functions, providing therapeutic ultrasound (US) for enhancement of thrombolysis at 500kHz and PMD monitoring of residual blood flow at 2MHz US. US modes were alternated by an automatic switching circuit.  Threrapeutic US was applied in 2-minute intervals with 30-second pauses four times, followed by a 5 minute pause. These 10-minute cycles, followed by 5-minute pauses, were repeated four times. All timed pauses were used for monitoring the blood flow using PMD.

An occlusion model of a rabbit femoral artery was produced with thrombin after establishment of stenotic flow and endothelial damage. After stable occlusion was confirmed, moteplase(mtPA) and echo contrast agent (Levovist) were administered intravenously, and thrombolytic US (500kHz,0.3W/cm²) was applied through an acoustic stand off model AC-4(ATS laboratories,Inc) .

Results:  The PMD waveforms after occlusion and at the beginning of thrombolysis changed from the normal systolic flow signals to a spike pattern synchronized to the heart beat. The waveform changed to two beat spike pattern during thrombolysis. These pattern changes were explained by increased vascular wall motion during thrombolysis.  At the end of recanalization, the waveform showed a blood flow pattern depicting stenosis.

Conclusions:  The study suggested that the newly developed 500kHz/2MHz combined probe is advantageous in that it is capable of US therapy and PMD US monitoring from the same footprint.  This is anticipated to be an important combination in acute stroke therapy.

Ultrasound enhanced thrombolysis: Clinical application

Ultrasound enhanced thrombolysis: CLOTBUST trial design and preliminary results

Andrei V. Alexandrov* for CLOTBUST Collaborators: Carlos A. Molina, Barcelona, Spain, Maher Saqqur, Edmonton, and Andrew M. Demchuk, Calgary, Canada.

*The University of Texas Stroke Treatment Team, Houston, TX

Background: Tissue plasminogen activator (TPA) activity can be enhanced with ultrasound, potentially 2 MHz transcranial Doppler (TCD). We obtained Phase I non-randomized data on recanalization rates when TPA was infused with TCD monitoring and designed the CLOTBUST (Combined Lysis of Thrombus in Brain ischemia using transcranial Ultrasound and Systemic TPA) trial. Phase I data was used for end-point selection.

Subjects and Methods: Non-randomized stroke patients with proximal arterial occlusion on a pre-bolus TCD receiving intravenous 0.9 mg/kg TPA within 3 hours after stroke onset were monitored with portable diagnostic TCD equipment and a standard headframe. Complete recanalization was defined as Thrombolysis in Brain Ischemia (TIBI) flow grades 4-5.

Phase I Results: 55 patients (mean age 69+15 years, median baseline NIH Stroke Scale (NIHSS) 18, range 4 – 29, 90% with > 9 points) were treated at 125+36 minutes from symptom onset. TCD monitoring began at 117+39 min. Complete recanalization on TCD within 2 hours after bolus was found in 20 patients (36%). Dramatic recovery (NIHSS score < 3) occurred in 20% at 2 hours and in 24% at 24 hours. Overall improvement by > 4 NIHSS points was found in 49% at 24 hours. Improvement was associated with recanalization during or shortly after TPA infusion (F r²=0.5, p=0.03), however in 6/20 patients with complete recanalization (30%) no immediate clinical change was noticed within 2 hours.

CLOTBUST Design and Update: Dramatic recovery and complete recanalization shortly after TPA bolus are feasible goals for thrombolysis given with TCD monitoring. The Phase II CLOTBUST is underway at centers in Houston, Barcelona, Edmonton, and Calgary. All patients are treated with 0.9 mg/kg TPA and randomized to either 2 hours of TCD monitoring or placebo monitoring. Potential enhancement of TPA therapy with diagnostic ultrasound will be determined using the combined primary end-points of complete recanalization on TCD, dramatic recovery (total NIHSS < 3), or decline in the NIHSS by > 10 points repeatedly measured within 2 hours after TPA bolus, at 24 hours and at 90 days. As of June 12, 2003 CLOTBUST collaborators randomized 106 of projected minimum sample of 120 patients. Continuous TCD insonation for up to 2 hours at maximum intensities allowed by current bio-safety guidelines is safe with symptomatic intracerebral hemorrhage rate of 3.8% (2/53) vs 5.7% (3/53) among controls (NS).

Continuous transcranial ultrasound application in patients with acute stroke due to middle cerebral artery occlusion improves outcome

G. Seidel, J. Eggers , B. Koch, K. Meyer-Wiethe

Dept. of Neurology, University of Schleswig-Holstein, Campus Luebeck, Germany

Introduction: The accelerating effect of ultrasound (US) on thrombolysis has been shown previously in several in vitro and animal models. In a randomized study we examined the effect of transcranial pulsed-wave (p/w)-US on the course of recanalization and the clinical outcome in stroke patients with acute occlusion of the middle cerebral artery (MCA).

Patients and methods: Stroke patients with acute occlusion of the MCA admitted within the first 3 hours after symptom onset were randomized for continuous and discontinuous ultrasound monitoring of the occluded vessel for 1 hour by p/w-US during TPA-treatment (0.9 mg/kg BW rt-PA). US was applied by a diagnostic device used for transcranial color coded sonography (TCCS). Outcome was measured after 4 days using the National Institute of Health Stroke Scale (NIHSS ) and after 3 months using modified Rankin Score (mRS) and the Barthel Index (BI). Grade of recanalization of the MCA after 1 hour was determined by TCCS.

Results: 25 consecutive patients (NIHSS median 17.9±3.8, mean age 61.3±9.1 years) were included. The group monitored continuously with US (n = 11) showed a higher peak systolic blood flow velocity (cm/s) of the MCA at the end of TPA treatment (p=0.024), a better outcome after 4 days (NIHSS improvement ³ 4, p= 0.37) and after 3 months (BI: p= 0.037; mRS: p=0.16). Mortality and symptomatic intracranial hemorrhage were not significant different in both groups.

Conclusions: Transcranial US can accelerate recanalization of occluded vessels and improves the outcome in stroke patients. Possible mechanisms are acceleration of thrombolysis and improving of capillary perfusion of ischemic brain parenchyma by US.

Safety and efficacy of thrombotripsy - Acceleration of thrombolysis by TCCS

D. Skoloudik, M. Bar, P. Hradilek, D. Vaclavik, O. Skoda

Dept. of Neurology, University Hospital Ostrava-Poruba, BMA Hospital Ostrava, Hospital Pelhrimov, Czech Republic

Effect of ultrasound (US) in acceleration of spontaneous thrombolysis was demonstrated by in vitro studies with low US frequencies and by in vivo studies with low and diagnostic US frequencies. The aim of this study was to document safety and efficacy of acceleration of thrombolysis by US (thrombotripsy) in stroke patients using 2 MHz probe.

Methods: In period of 26 months 71 patients with acute occlusion of MCA (M1-, M2-) were repeatedly examined by TCCS. Thrombotripsy up to 6 hours from the stroke onset was used in 21 patients, systemic thrombolysis (ST) up to 3 hours in 15 patients, 35 patients had only aspirin. We examined by TCCS partial or complete recanalisation of MCA at 6^th and at 24^th hour in all patients. In all patients we recorded all adverse events, especially brain haemorhage and oedema.

Results: Patients treated by US had complete recanalisation of MCA at 6^th hour in 60%, partial recanalization in 30%. At 24^th hour we detected complete recanalization of MCA in all patients (100%). In patients treated with systemic thrombolysis we detected recalization of MCA in 6^th hour in 40%, at 24^th hour in 60%, in aspirin group it was 0% / 25%. This difference was statistically significant (p=0.01). 1 patient treated by US died (4.7%) - intracranial haematoma after 24 hours from stroke onset. 2 patients (13%) treated with ST had malignant intracranial haematoma too.

3 patients were treated by thrombotripsy 6-12 hours after stroke onset. 2 patients had severe brain oedema, 1 patient had late recanalization of MCA 24 hours after thrombotripsy.

Conclusion: Thrombotripsy seems to be a safe method in patients with MCA occlusion within 6 hours after stroke onset and is efficient in early MCA recanalisation.

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Last update: 12. Oktober 2003