Cerebral embolic ischemia in rats: correlation of stroke severity and functional deficit as important outcome parameter.

The embolic MCA occlusion model in rats is used for recanalisation studies in acute stroke. In addition to the determination of lesion size, the assessment of functional outcome may improve the value of this model. Male Wistar rats were submitted to MCA clot embolism or sham surgery. In order to achieve a larger variety of lesion volume, 2 subgroups (each 7 animals) were subjected to differently sized emboli (30 and 40 mm). Follow-up period was 6 days. Outcome assessment consisted of a test battery including parallel bar crossing, observation of behaviour in an open field and an 8-arm maze and a neurological score with ten different sensorimotor and coordinative items. Animals were perfusion-fixed on day 7 (blinded examination). For both subgroups, there were significant impairments with regard to performance on the Neuro score, parallel bar crossing and maze exploration. Improvement was only partial during the follow-up period. On follow-up day 6, there was still a significant correlation between total infarct volume and functional outcome on the Neuro score (R=0.80, p=0.0006) and the exploration behaviour in the maze (R=0.66, p=0.01). Application of emboli with a length of 40 mm caused more functional impairment and a more extended lesion volume compared with 30 mm. We present outcome tests that provide quantitative and objective tools to test functional impairment in rats following embolic stroke.

Increased incidence of jugular valve insufficiency in patients with transient global amnesia.

OBJECTIVE: While transient global amnesia (TGA) is a clinically well defined disorder, its etiology is poorly understood. Cerebral venous hypertension and subsequent damage to hippocampal and diencephalic structures are among the discussed hypothetical causes. Using a direct method for the study of retrograde flow during a Valsalva maneuver, we determined whether jugular valve insufficiency contributes to cerebral venous hypertension in patients with TGA. METHODS: Jugular valve closure was assessed by duplex sonography in 20 patients with TGA and 20 age and gender matched controls. The diagnosis of valvular insufficiency was made on the basis of recently established criteria. RESULTS: Valvular insufficiency (either left or right-sided, or bilateral) was identified in 85% of patients with TGA,and in 45% of controls (p = 0.008). All patients with involuntary Valsalva episodes immediately prior to TGA developed valvular insufficiency (n = 8; p = 0.13 compared with patients who did not recall such an event). The mean duration of the insufficiency jet did not differ significantly between patients with TGA (3.26 s) and controls (2.78 s; p = 0.315). However, patients with TGA who experienced a trigger event were characterized by significantly longer insufficiency reflux times (3.84 s) than those without (2.55 s; p = 0.03). CONCLUSIONS: TGA is associated with an increase in the prevalence of jugular insufficiency. Valvular insufficiency may lead to increased venous pressure transmission during a Valsalva maneuver and thus contribute to venous ischemia in TGA. The association of valvular insufficiency and longer reflux times with the occurrence of a trigger event further suggests that cerebral venous congestion is an important etiological factor in transient global amnesia.

Ultrasound-induced blood clot dissolution without a thrombolytic drug is more effective with lower frequencies.

BACKGROUND AND PURPOSE: Therapeutic ultrasound as stand-alone therapy or in combination with rt-PA has proven to be an effective measure for recanalisation of acute vessel occlusion in different in vitro and in vivo studies. Uncertainty still exists concerning the optimal frequency and intensity with regard to the thrombolytic efficacy of ultrasound. The purpose of this study was a direct comparison of different ultrasound frequencies, when otherwise using identical measurement settings and parameters. METHODS: Ultrasound-induced dissolution of fresh human blood clots was studied in a flow system using low-frequency continuous wave ultrasound of 20, 40 and 60 kHz. After calibration of each ultrasound probe, blood clots were exposed to local time average intensities of either 0.12 or 0.2 W/cm2. Exposure time of the clots to ultrasound was 10 min, the number of treated clots in each experimental group was 12. RESULTS: As tested with 0.2 W/cm2, we found the most pronounced thrombolytic effect with the 20-kHz probe (weight loss of blood clots: 52.4%) and the 40-kHz probe (49.4%), as compared to the 60-kHz probe (21.4%) and the control group (18.5%). The difference between the 20- and 60-kHz probes was statistically significant (p < 0.001). The treatment effect was clearly intensity dependent with a less pronounced, but still significant treatment effect at 0.12 W/cm2 (24.5% at 20 kHz; p < 0.001 compared to 0.2 W/cm2; p = 0.045 compared to controls). CONCLUSIONS: These data show that therapeutic efficacy of ultrasound, in absence of a thrombolytic drug, is frequency and intensity dependent with best results at low frequencies. With continuous wave transmission, the benefit may be limited to the very low frequency range. The results are a basis for further evaluation in animal models.

Functional and morphological criteria of internal jugular valve insufficiency as assessed by ultrasound.

BACKGROUND AND PURPOSE: Jugular venous valve insufficiency may play a role in different neurological diseases. This study describes the methodology to detect internal jugular valve insufficiency and establishes functional and morphological criteria to discriminate retrograde flow during valve closure from retro grade insufficiency flow. METHODS: Valve closure was assessed in 100 valves (50 healthy volunteers). The valves were visualized in B-mode. During a pressure-controlled Valsalva maneuver, valve closure was monitored by color duplex. The duration and the peak velocity of retrograde flow were determined. RESULTS: Backward flow during valve closure in competent valves was visually clearly discernible from a retrograde flow jet through insufficient valves. Insufficiency was found in 29% of valves. The duration of backward flow in competent valves was between 0.22 and 0.78 seconds (mean = 0.46 +/- 0.14 seconds on Doppler measurements) and in insufficient valves between 1.23 and 6.15 seconds (mean = 2.66 +/- 1.28; P < .0001). Peak velocity of retrograde flow in competent valves was between 12 and 65 cm/s (mean = 26.2 +/- 11.1 cm/s) and between 25 and 160 cm/s (mean = 89.5 +/- 39.3 cm/s; P < .0001) in insufficient valves. On B-mode imaging, the "typical" aspect of an immobile, frozen valve was seen only in 5 cases of insufficient valves; 21 insufficient valves did not display this aspect. CONCLUSION: The duration of retrograde flow clearly discriminates competent and incompetent valves. On the basis of our results, we provide cut off values that help differentiate between physiological and insufficiency reflux. The differences in peak velocity and morphology criteria are helpful but not reliable to predict insufficiency of the valve.

Volume flow rate evaluation in patients with obstructive arteriosclerotic disease.

This study was performed to quantify the volumetric impact of extracranial arteriosclerotic lesions. We investigated patients with different degrees of carotid stenosis as defined by conventional velocity-based duplex criteria and different patterns of collateralization. We studied the volume flow rate (color duplex M-mode device) in 37 patients with symmetrical internal carotid artery (ICA) plaques (<50% stenosis) and compared these data to 43 patients with a unilateral 50-74% stenosis, 75-99% stenosis (n = 73) and occlusion of the ICA (n = 37). A 75-99% stenosis caused an ipsilateral flow reduction of 36% with a wide interindividual variability, and an occlusion of 51%. Collateralization via the ophthalmic artery only caused a nonsignificant ipsilateral volume flow increase, whereas the contralateral volume flow was significantly higher in patients with a patent anterior communicating artery. The increase was more pronounced in patients with an occluded vessel. Our data demonstrate a wide diversity of the hemodynamic impact of carotid stenosis as defined by 'classical' Doppler criteria. Collateral flow reflects a dynamic quantitative process.

Low-frequency ultrasound induces nonenzymatic thrombolysis in vitro.

OBJECTIVE: To evaluate whether ultrasound, applied over a distance of several centimeters and in the absence of thrombolytic agents, may have a thrombolytic effect on blood clots. METHODS: Low-frequency (20 kHz) continuous wave ultrasound at different intensity levels (0.15-1.2 W/cm2) and exposure times (5, 10, and 20 minutes) was assessed for its potential to induce thrombolysis of fresh human blood clots. The ultrasound effect was also studied in combination with recombinant tissue-type plasminogen activator-mediated thrombolysis. Experiments were carried out in a flow model in degassed sodium phosphate buffer at 37 degrees C at a distance of 3 cm from the ultrasonic probe to the blood clots. Regardless of ultrasound exposure times, blood clots in all experimental groups and the control group were left in the flow system for 20 minutes. RESULTS: The use of ultrasound alone showed a significant thrombolytic effect compared with the control group, with a statistically significant effect at 0.15 W/cm2 and exposure of 10 minutes (P = .02). There was a clear correlation between the extent of weight loss and the chosen intensity level and exposure time. Complete disruption in 8 of 10 blood clots occurred at 1.2 W/cm2 within 10 min. Addition of ultrasound to recombinant tissue-type plasminogen activator-mediated thrombolysis significantly enhanced thrombolysis compared with application of recombinant tissue-type plasminogen activator or ultrasound alone (P = .0001), with the results pointing toward a purely additive, nonsynergistic effect of the 2 treatment modalities. Lysis was more effective in fresh thrombi. CONCLUSIONS: The use of low-frequency ultrasound alone, without addition of a thrombolytic drug, has the potential to induce thrombolysis over a distance. Combination of ultrasound with recombinant tissue-type plasminogen activator is superior to either treatment alone. Ultrasound is a promising tool for developing an alternative or additional treatment modality for acute cerebral vessel occlusion.

[The ultrasound contrast medium levovist increases the thrombolytic effect of low frequency ultrasound]. / Ultraschallkontrastmittel Levovist steigert den thrombolytischen Effekt von niederfrequentem Ultraschall.

BACKGROUND: Therapeutic application of ultrasound is a promising tool to develop an alternative or additional treatment modality of acute vessel occlusion. It has previously been shown that ultrasound enhances the effect of pharmacologic thrombolytic agents and has a thrombolytic potential in "stand-alone" therapy. The purpose of this study was to determine, whether the presence of the echo contrast agent Levovist further increases the thrombolytic efficacy of ultrasound. MATERIAL AND METHODS: Thrombolytic efficacy of low-frequency (20.5 kHz) continuous-wave ultrasound was evaluated. Fresh human blood clots (age 3-6 h) were sonicated for 10 min at an intensity of 0.35 W/cm2. The thrombolytic effect of ultrasound alone and in combination with rt-PA (3 micrograms/ml) was assessed with and without addition of Levovist (2 mg/ml). Loss in weight of each blood clot was used to measure the extent of thrombolysis. The number of thrombi in each group was between ten and 18. Experiments were carried out in sodium phosphate buffer, at a temperature of 37 degrees C, in a flow system with a flow rate of 15 ml/min. RESULTS: The use of ultrasound alone showed a significant thrombolytic effect (41.8% weight loss), as compared to a control group (24.2%). The addition of Levovist further increased thrombolysis to 44.7%, which was not significant. However, in combination with rt-PA, ultrasound-mediated thrombolysis could be significantly increased from 65.8% to 74.2%, when Levovist was added (p < 0.05). CONCLUSION: These data show that the thrombolytic efficacy of low-frequency continuous-wave ultrasound in combination with rt-PA is augmented in the presence of Levovist.

Extracranial internal carotid artery occlusion: the role of common carotid artery volume flow.

BACKGROUND AND PURPOSE: Quantitative measurement of blood flow volume in the common carotid artery (CCA) is now possible using the color velocity imaging quantification (CVI-Q) ultrasound technique. The aim of this study was to evaluate the cerebral hemodynamic effects of unilateral internal carotid artery (ICA) occlusion on CCA blood flow volumes (FVs) using CVI-Q. METHODS: Records of ultrasound studies in our neurosonology laboratory were retrospectively reviewed to identify patients with unilateral ICA occlusions who at a minimum received both a routine color duplex carotid ultrasound examination and quantitative measurement of FV in the CCA, bilaterally, using the CVI-Q method. A total of 71 patients met criteria and were included in the cohort. A side to side comparison was performed for FV, peak systolic velocities (PSV), end-diastolic velocities (EDV), and resistance indices (RIs) in the CCA. Results correlated with any other available data such as flow direction in the ophthalmic artery and the presence of intracranial collateralization. RESULTS: The FV, PSV, and EDV were significantly reduced, and the RI was significantly increased in the CCA on the side of the occlusion. A subgroup analysis in patients who also had an examination of the ophthalmic (n = 61) and the intracranial arteries of the Circle of Willis (n = 50), showed significantly higher FV in the CCA on the side of the occlusion if there was also reversed flow in the ophthalmic artery on the side of the occlusion (344 +/- 144 ml/min versus 169 +/- 53 ml/min). CONCLUSION: Quantitative FV measurement using CVI-Q ultrasound can identify clear alterations in volume flow, collateral pathways, and cerebral hemodynamics in patients with unilateral ICA occlusion. It is a complementary tool, providing additional objective information about the cerebral hemodynamic effects of ICA occlusion that goes beyond what is available using routine flow velocity data.