Stephan Behrens

LOW-FREQUENCY, LOW-INTENSITY ULTRASOUND ACCELERATES THROMBOLYSIS THROUGH THE SKULL

Systemic thrombolysis of acute ischemic stroke with recombinant tissue plasminogen activator (rt-PA) has been established recently. Whereas the delay to and the rate of vessel recanalization are unknown, they are likely slower and smaller than for local application of rt-PA. This may contribute to the small benefits of recovery reported and stimulate further investigations to improve clot lysis. Pilot studies indicate that continuous-wave low-frequency ultrasound (US) can accelerate rt-PA-mediated recanalization of peripheral thrombotic vessel occlusion. For the hypothesized therapeutical purpose in stroke treatment, we measured the attenuation of ultrasound through the skull at different frequencies and intensities (33.3 and 71.4 kHz; 0.5 and 3.4 W/cm2), and investigated thrombolysis in vitro (n = 125 clots). Attenuation was lowest by transtemporal insonation of 33.3 kHz, 0.1 dB (0.9). Thrombolysis (artificial fibrin-rich clots) was significantly increased after 1 h (p < 0.025) and after 3 h (p < 0.01) for US treatment in combination with rt-PA vs. rt-PA alone. Results suggest that US increases rt-PA-mediated thrombolysis through the skull and may improve benefits of thrombolytic stroke treatment in vivo.

Transcranial ultrasound-improved thrombolysis: diagnostic vs. therapeutic ultrasound.

Success of stroke treatment with rt-PA depends on rapid vessel recanalization. Enzymatic thrombolysis may be enhanced by additional transcranial application of ultrasound (US). We investigated this novel technique using a 185-kHz probe and compared it to standard diagnostic US. In vitro studies were performed in a continuous pressure tubing system. Clots were placed in a postmortem skull and treated with rt-PA together with or without transtemporal 185-kHz US insonation (2W/cm(2)) and in comparison to 1-MHz diagnostic US (0.5 W/cm(2)). Recanalization time was significantly (p < 0.01) shorter in the 185-kHz (14.1 min) and 1-MHz (17.1 min) US rt-PA treatment group compared to rt-PA treatment alone (29.3 min.). Flow rate was significantly higher (p < 0.025) and increased faster in the combined treatment group with rt-PA + 185-kHz US compared to rt-PA + 1-MHz US. We investigated the blood-brain barrier in rats after 90-min exposure time of the brain with 185-kHz US, but no damage was observed. Results suggest efficacy and safety of the 185-kHz transducer, which is superior to diagnostic US. Such a novel US probe may be able to optimize thrombolytic stroke treatment.

Acceleration of thrombolysis with ultrasound through the cranium in a flow model

Thrombolysis is an efficient therapy for hyperacute stroke within a limited time window. Neurological outcome depends on the recanalization time of the occluded vessel. Nonthermal effects of low-frequency ultrasound (US) accelerate enzymatic fibrinolysis in vitro. We examined the effects of transcranially applied US on recombinant tissue plasminogen activator (rt-PA)-mediated thrombolysis in a flow model in vitro. Pure fibrin clots were placed in a continuous-pressure flow model and treated with rt-PA during 1-MHz US exposure (0.5 W/cm(2); spatial peak, temporal peak intensity). Transcranial and direct US application in combination with rt-PA significantly (p<0.001) shortened recanalization time, increased perfusion flow and reperfusion rate in comparison with rt-PA-mediated thrombolysis alone. Recanalization rate within 30 min was 90-100% in the US-exposed clots vs. 30% in the clots treated only with rt-PA. Our results suggest that transcranial application of 1-MHz US may accelerate reperfusion and recanalization rate of occluded intracerebral vessels by enhancing rt-PA-mediated thrombolysis. Shortening of recanalization time could contribute to optimizing effects of acute thrombolytic stroke therapy.

Long-term follow-up and outcome in patients treated for spinal dural arteriovenous fistula

Abstract Clinical outcome was examined in 21 patients treated for spinal dural arteriovenous fistula after 5–50 months. We compared the neurological condition (motor function, pain, sensory disturbance, vegetative dysfunction) and Barthel index before and after fistula occlusion. Neurological impairment was assessed as improved, unchanged, or deteriorated. All patients initially showed paraparesis of varying degree, and a sensory loss with a defined level in 81% before treatment. The greatest postoperative change that we measured was in motor activity (67% improved), and the most important deterioration was in male potency (28% deteriorated). We observed unchanged or absent symptoms in pain in 71% of our patients. We were thus able not only to stop but even to reverse the progression of symptoms and the degree of disability. On average, neurological symptoms stabilized within 1 year. The results of this study confirm that spinal dural arteriovenous fistula should be treated as early as possible after diagnosis.

Improvement in Stroke Quality Management by an Educational Programme

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

Early Motor Evoked Potentials in Acute Stroke: Adjunctive Measure to MRI for Assessment of Prognosis in Acute Stroke within 6 Hours

Background: In acute stroke, a magnetic resonance (MR) perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) mismatch (PWI>DWI mismatch) may indicate tissue at risk for infarction and poor prognosis. However, different to early enthusiasm about this surrogate marker, its validity has shown several drawbacks in individual patients. Rather than relying on imaging, we evaluated motor evoked potentials (MEP) as a measure of cerebral function in the acute stroke setting. Methods: Thirteen patients with acute hemiparetic stroke underwent time to peak PWI and DWI within 6 h after onset as well as recordings of early MEP of first dorsal interosseous muscles. Outcome was assessed by the Unified Neurological Stroke Scale and Barthel Index at day 42. Results: Of 8 patients with PWI>DWI mismatch, 4 patients with normal MEP had a good clinical outcome and 4 patients with absent or pathological MEP had an unfavourable outcome (p < 0.05, Fisher’s exact test). In all patients without PWI>DWI mismatch, MEP findings predicted clinical outcome. Normal MEP at day 0 – but not PWI/DWI findings – significantly correlated with a good clinical outcome. Conclusions: Early MEP recordings in acute stroke patients provide valid prognostic information; they may become more useful for specific treatment decisions than presently available MRI surrogate parameters.

Acceleration of Cerebral Blood Flow Velocity in a Patient with Sleep Apnea and Intracranial Arterial Stenosis

Sleep apnea (SA) syndromes of different etiologies are known to induce complications including cardiovascular diseases and stroke. However, the exact mechanisms involved in cerebral ischemia remain obscure. We measured the cerebral blood flow velocities (CBFV) by means of transcranial Doppler sonography in an 81-year-old patient who presented with an acute ischemic stroke caused by an intracranial middle cerebral artery (MCA) stenosis in the presence of SA syndrome. During apnea episodes simultaneous recordings revealed reduced intra-arterial oxygen but increased carbon dioxide saturation. This resulted in an increased CBFV (220 to 320 cm/s) and suggested intermittent hemodynamic relevance of a structurally only moderate MCA stenosis. Intracranial artery stenosis can become hemodynamically significant due to episodic hypercapnia in patients with SA. This may cause ischemic infarction in the periphery of the related cerebral vascular territories.

Stroke Treatment Guided by Transcranial Doppler Monitoring in a Patient Unresponsive to Standard Regimens

Today secondary prevention of stroke is based on large clinical trials with the disadvantage of a lack of individual pathophysiological aspects. This is mainly due to the difficulty in identifying the source of stroke reliably and rapidly in these patients. Recurrent microembolic events detected by transcranial Doppler monitoring (TCM) has been suggested to individualize treatment. We describe a patient with recurrent ischemic events in the posterior circulation. Repeated TCM of the PCA disclosed microembolic events in the course of an acute embolic lesion pattern demonstrated by MRI. Detection of high-intensity transient signals by TCM provided a useful guidance of pathophysiologically oriented treatment in this patient.

Cerebrovascular Anatomy: Special Considerations

The brain-supplying arteries can be divided into two communicating circulatory systems: the anterior and the posterior circulation. The anterior circulation originates in both internal carotid arteries (ICA) and in part from both external carotid arteries (ECA) if a high-grade stenosis of the ipsilater-al ICA is present. The posterior circulation arises from both vertebral arteries and the unpaired basilar artery. The posterior and anterior circulation is connected via the circle of Willis, which is known to have a very heterogeneous anatomical structure. The circle of Willis is a vascular polygon with ten components: both ICAs, both posterior communicating arteries (PCoAs), the single anterior communicating artery (ACoA), the anterior cerebral arteries (ACAs), the posterior cerebral arteries (PCAs), and the basilar artery (BA). Circle of Willis is an inefficient collateral in 50% of subjects due to insufficient communication between the anterior and the posterior circulation, and between the left-sided and the right-sided circulation secondary to the hypoplasia of the PCoA and ACoA respectively.