Michael Daffertshofer

Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia: Increased Risk of Hemorrhage With Combined Ultrasound and Tissue Plasminogen Activator: Results of a Phase II Clinical Trial

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

Proinflammatory cytokines in serum of patients with acute cerebral ischemia : kinetics of secretion and relation to the extent of brain damage and outcome of disease

The release of the proinflammatory cytokines IL-1 beta, IL-6, TNF-alpha and soluble TNF-receptors p55 and p75 in peripheral blood was serially determined in 19 patients with acute cerebral ischemia. Only patients admitted within 4 h following onset of symptoms were studied. In contrast to serum levels of IL-1 beta, TNF-alpha and TNF-receptors, which did not exhibit a significant response, IL-6 showed a significant increase of serum levels already within the first hours following onset of disease and reached a plateau at 10 h until day 3 and returned to baseline by day 7. The increase of levels of this cytokine was significantly (P < 0.05) correlated with increasing volumes of brain lesion and was also significantly (P < 0.005) associated with poor functional and neurological outcome. The increase of levels of IL-6 despite a considerable dilution in peripheral blood shown in this preliminary study suggests an early inflammatory response in ischemic brain lesion.

Cohort study of multiple brain lesions in sport divers: role of a patent foramen ovale

Abstract Objective: To investigate the role of a patent foramen ovale in the pathogenesis of multiple brain lesions acquired by sport divers in the absence of reported decompression symptoms. Design: Prospective double blind cohort study. Setting: Diving clubs around Heidelberg and departments of neuroradiology and neurology. Subjects: 87 sport divers with a minimum of 160 scuba dives (dives with self contained underwater breathing apparatus). Main outcome measures: Presence of multiple brain lesions visualised by cranial magnetic resonance imaging and presence and size of patent foramen ovale as documented by echocontrast transcranial Doppler ultrasonography. Results: 25 subjects were found to have a right-to-left shunt, 13 with a patent foramen ovale of high haemodynamic relevance. A total of 41 brain lesions were detected in 11 divers. There were seven brain lesions in seven divers without a right-to-left shunt and 34 lesions in four divers with a right-to-left shunt. Multiple brain lesions occurred exclusively in three divers with a large patent foramen ovale (P=0.004). Conclusions: Multiple brain lesions in sport divers were associated with presence of a large patent foramen ovale. This association suggests paradoxical gas embolism as the pathological mechanism. A patent foramen ovale of high haemodynamic relevance seems to be an important risk factor for developing multiple brain lesions in sport divers. Key messages An increased prevalence of multiple brain lesions has been reported in scuba divers compared with non-diving controls It has been suggested that the brain lesions were due to arterial gas embolism and that the gas emboli could have entered the arterial circulation via a patent foramen ovale We investigated this hypothesis in volunteer sport divers who had made at least 160 scuba dives Brain lesions occurred in divers even in the absence of reported decompression sickness Multiple brain lesions occurred exclusively in divers with a large patent foramen ovale The association of multiple brain lesions with a large patent foramen ovale suggests paradoxical gas embolism as the pathological mechanism

Pattern of activation of the hypothalamic-pituitary-adrenal axis in acute stroke. Relation to acute confusional state, extent of brain damage, and clinical outcome.

Background and Purpose The aim of this study was to characterize the response of the hypothalamic-pituitary-adre-nal system in the first hours of ischemic stroke and to relate its extent to the occurrence of acute confusional state, volume of brain damage, and clinical outcome. Methods The secretion of corticotropin (adrenocorticotropic hormone [ACTH]) and cortisol was studied in 23 patients by determinations at hours 4, 6, 8, 10, and 14 and days 1, 3, 5, and 7 after onset of symptoms. Acute confusional state (DSM-III-R criteria), extent of lesion (volumetry of computed tomographic scans), and neurological and functional outcome (Scandinavian Stroke Scale, Barthel Index scores) were assessed. Results The massive neuroendocrine response observed consisted of an initial phase with concomitantly increased levels of ACTH and cortisol and a second phase with decreased levels of ACTH while high concentrations of cortisol persisted. Initial levels of ACTH but not cortisol were significantly increased in patients with acute confusional state and significantly correlated with volume of brain lesion and neurological and functional outcome. Conclusions An early and persisting activation of the hypothalamic-pituitary-adrenal axis was observed in relation to severity of disease. Its characteristic biphasic pattern suggests an initial central stimulation of release of ACTH followed by feedback suppression concomitant with an increased susceptibility of the adrenal gland. Because these hormones are known to exacerbate hypoxic injury to neurons, their massive release in hyperacute stroke may increase the extent of brain damage.

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.

Leakage of brain-originated proteins in peripheral blood: temporal profile and diagnostic value in early ischemic stroke

The clinical value of determination of CNS-specific proteins in peripheral blood at the acute phase of ischemic stroke is unclear. S-100 protein and neurone specific enolase were serially quantified in peripheral blood at the acute and subacute phase of ischemic stroke (hours 4, 8, 10, 24 and 72 after onset of symptoms). Whereas S-100 protein was detected in none of the matched control subjects. this protein was observed in 17/24 of the stroke patients. Patients with detectable S-100 protein had significantly larger infarctions. Cortical infarctions had already significantly increased S-100 concentrations at days 1 and 3 compared to subcortical or brainstem infarctions. Patients with volumes of brain lesion of >5 ccm exhibited significantly increased serum levels of S-100 at hours 10, 24 and 72 compared to those with lesion volumes of <5 ccm. At hours 10, 24 and 72, concentrations of S-100 correlated with scores of neurological outcome. Although kinetics of release of neurone specific enolase showed a similar pattern of release in blood, no significant association to outcome or extent of brain damage was observed. These results suggest that S-100 protein and not NSE may represent a useful serum marker of brain damage in acute stroke.

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.

Stroke recurrences in patients with symptomatic vs asymptomatic middle cerebral artery disease

Background: Although the natural history of extracranial carotid artery disease has been investigated systematically, limited data are available on the course of middle cerebral artery (MCA) disease. Methods: The authors observed 102 consecutive patients (67 men, 35 women; mean age 61.9 years) with significant MCA stenosis or occlusion as demonstrated by transcranial Doppler and transcranial color-coded duplex ultrasonography. Forty-six patients entered the study after TIA (n = 17) or stroke (n = 29); 56 patients were asymptomatic. Neurologic and ultrasound investigations were performed at regular intervals with a mean follow-up of 31 (range 6 to 117) months. Patients were continuously treated with either platelet inhibitors (n = 75) or anticoagulation (n = 27). Results: Nineteen cerebral ischemic events (11 strokes, 8 TIAs) occurred during follow-up, resulting in an overall annual rate of 7.3%. Thirteen events (8 strokes, 5 TIAs) were attributable to the vascular territory ipsilateral to MCA disease. Patients with symptomatic MCA disease at study entry had an overall stroke risk of 12.5% per year (ipsilateral: 9.1%), whereas the annual incidence in primarily asymptomatic MCA disease was only 2.8% (ipsilateral: 1.4%; p < 0.01). Symptomatic MCA disease was an independent predictor for overall (hazard ratio [HR] 7.91, 95% CI 2.03 to 30.79; p < 0.01) and ipsilateral (HR 9.66, 95% CI 1.5 to 62.25; p = 0.02) cerebrovascular events. Conclusions: Compared with asymptomatic middle cerebral artery disease, there was a high and continuous recurrence rate of ischemic events in symptomatic patients, which was even higher than in patients with symptomatic extracranial carotid artery disease.

Transient Ischemic Attacks Are More Than “Ministrokes”

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

Ultrasound in the treatment of ischaemic stroke.

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