Ulrich Sliwka

Frequency of deep vein thrombosis in patients with patent foramen ovale and ischemic stroke or transient ischemic attack.

To evaluate the additional value of transesophageal (TEE) compared with transthoracic (TTE) echocardiography and the role of patent foramen ovale (PFO) and deep vein thrombosis in the work-up of embolic events, patients with presumed cardiac embolic stroke or transient ischemic attack (neurovascular etiology was excluded) were prospectively studied by transthoracic and transesophageal contrast echocardiography. If PFO was detected echocardiographically, PFO size was assessed semiquantitatively and phlebography of both legs was performed. Two hundred forty-two consecutive patients (153 men, 60 +/- 15 years) were studied. In 197 patients, neuroimaging showed evidence of embolic infarction. TEE identified 138 potential cardiac sources of embolism in 111 patients, compared with 69 by TTE (p <0.01) in 59 patients. TEE detected potential cardiac sources in 52 patients with negative TTE examination and was significantly superior compared with TTE for identifying left atrial thrombi, spontaneous echo contrast, PFO, atrial septal aneurysm, and atheroma of the ascending aorta. In patients with a positive TTE, additional diagnostic information by TEE was found in only 6 patients and did not change therapy. Phlebography was performed in 53 patients with PFO and revealed deep vein thrombosis in 5 patients (9.5%); all had medium or large PFOs. Thus, in patients with cerebral ischemia of suspected cardiogenic origin and a normal TTE examination, TEE detects potential causes of embolism in 31% of patients and is therefore of diagnostic relevance. Conversely, in the presence of a diagnostic TTE an additional TEE confers only marginal diagnostic benefit. Deep venous thrombosis was detected in nearly 10% of patients with PFO as the sole identifiable cardiac risk factor. Given that in 4 of 5 patients deep vein thrombosis was clinically silent, phlebography should be performed in patients with medium or large interatrial shunts if paradoxical embolism is suspected.

Prevalence and Time Course of Microembolic Signals in Patients With Acute Stroke A Prospective Study

BACKGROUND AND PURPOSE Cerebral emboli can be identified by the presence of typical microembolic signals (MES) in transcranial Doppler (TCD) spectral curves. The usefulness of this technique was studied by evaluating the prevalence and time course of MES in patients with acute stroke. In addition, we examined the influence of anticoagulation therapy on the occurrence of MES. Another study objective was to identify the value of MES in elucidation of the underlying pathology of cerebral ischemia in patients with acute stroke. METHODS We used bilateral TCD monitoring of the middle cerebral artery to search for microemboli in 100 patients with acute nonhemorrhagic stroke in the anterior circulation. Monitoring time was for 30 minutes at admission (examination I), after 24 hours (examination II), and again after 48 hours (examination III). RESULTS Twenty-two of the 100 patients had to be excluded from the study after examination 1 because retrospectively they did not fulfill the inclusion criterion or because they had an insufficient bone window. Forty of the patients (51%) showed MES during at least one of the three TCD examinations. In 9 of the 47 patients without MES during examination I (19%), MES could be recorded subsequently during examinations II and III. A statistically significant decrease in the prevalence of MES occurred between examinations I and III (P = .01). The frequency of MES in a single patient decreased between examinations I and II but increased again in examination III, although it did not reach the initial level. Prevalence of MES was the highest during the period up to 6 hours after the onset of symptoms. However, even at > 72 hours after the onset of symptoms, a substantial number of MES could be recorded. In 18 of the 21 patients with carotid artery stenosis or occlusion who showed MES (86%), these signals occurred ipsilateral to the affected carotid artery. In 5 of the 13 patients with MES and a potential cardiac source of embolism (38%), MES were observed bilaterally. Forty-one patients were without anticoagulation treatment at the time of examination: 19 of these patients (46%) presented with MES. In contrast, of the 37 patients receiving anticoagulation treatment at the time of the first examination, MES could be recorded in only 12 (32%). CONCLUSIONS Microemboli are a frequent phenomenon in patients with acute stroke arising from a variety of causes, both in the very early stages and several days after the onset of symptoms. The prevalence of MES decreases significantly over time. MES occur more frequently in patients with carotid artery disease than in patients with a potential cardiac source of embolism. Ipsilateral MES are frequent in patients with carotid artery disease, whereas bilateral MES are suggestive of a cardioembolic origin. Anticoagulation treatment appears to decrease the prevalence of MES, but microemboli still occur in patients receiving intravenous therapy with heparin. Because MES occur intermittently, TCD examinations should be repeated several times, even in patients without MES in the first examination, and long-term monitoring equipment is necessary.

DIAS I: Duplex-Sonographic Assessment of the Cerebrovascular Status in Acute Stroke A Useful Tool for Future Stroke Trials

Background and Purpose A number of controlled trials have evaluated the benefit of intravenous thrombolysis in acute stroke with inconsistent results. None of these studies assessed the initial vascular status or provided information regarding the recanalization rate after therapy. Further trials need to clarify whether certain subgroups might possibly benefit more than others from intravenous thrombolysis. Therefore, a fast and valid method for assessment of cerebrovascular status is needed. In this multicenter study, we evaluated the potentials and limitations of color-coded duplex sonography (TCCS) for cerebrovascular status assessment in acute stroke patients before and after therapy. Furthermore, we compared the recanalization rate for patients referred to thrombolytic and conservative medical therapy. Methods Fifty-eight patients suffering from hemispheric stroke were enrolled consecutively in 8 centers. Duplex sonography was performed on admission, 2 hours after start of therapy, and 24 hours after onset of symptoms. Therapy was started within 6 hours. Results Intravenous thrombolysis was performed in 18 patients, conservative medical therapy in 39 patients, and early thromboendarterectomy in 1 patient. The middle cerebral artery (MCA) mainstem was patent in 29 patients (53.7%), occluded in 25 (46.3%), and was not assessable in 4 patients. Recanalization of the occluded MCA after 2 and 24 hours was diagnosed in 50% and 78% of the patients treated with rtPA and in 0% and 8% in the conservatively treated patients. Conclusions Intravenous thrombolysis is highly effective in restoring blood flow after MCA occlusion. TCCS is suitable for assessment of the cerebrovascular status in acute stroke and therefore might define therapeutically relevant subgroups of patients in future stroke trials on the basis of their vascular pathology.

Effect of antenatal betamethasone treatment on microtubule‐associated proteins MAP1B and MAP2 in fetal sheep

1 Betamethasone has been used extensively to accelerate fetal lung maturation, yet little is known of its effects on neuronal morphogenesis in the developing fetus. Microtubule‐associated proteins (MAPs) are a diverse family of cytoskeletal proteins that are important for brain development and the maintenance of neuroarchitecture. 2 Vehicle (n = 7) or betamethasone (10 μg h−1, n = 7) was infused I.V. to fetal sheep over 48 h beginning at 0.87 of gestation (128 days of gestation), producing fetal plasma betamethasone concentrations resembling those to which the human fetus is exposed during antenatal glucocorticoid therapy. 3 Paraffin sections of the left hemisphere were stained with monoclonal antibodies against MAP1B and the MAP2 isoforms MAP2a,b,c and MAP2a,b. The level of the juvenile isoform MAP2c was determined by comparison of the two MAP2 immunostainings. 4 We were able to detect MAP1B and MAP2 immunoreactivity (IR) in the fetal sheep brain. MAP2c was the major MAP2, constituting 90.2 % of the total MAP2. Betamethasone exposure diminished MAP1B IR in the frontal cortex and caudate putamen (P < 0.05) but not in the hippocampus. A decrease of MAP2 IR was found in the frontal cortex, hippocampus and caudate putamen (P < 0.05). Loss of MAP2 IR was mainly due to the loss of MAP2c IR. Haematoxylin‐eosin staining did not demonstrate irreversible neuronal damage. 5 Regional cerebral blood flow determined using coloured microspheres was significantly decreased by 28 % in the frontal cortex and by 36 % in the caudate putamen but not in the hippocampus 24 h after the onset of betamethasone exposure (P < 0.05). The loss of MAP1B and MAP2a,b,c IR showed a significant correlation to the cerebral blood flow decrease only in the frontal cortex (P < 0.05). These data suggest that mechanisms other than metabolic insufficiency caused by the decreased cerebral blood flow may contribute to the loss of MAPs. 6 The results suggest that clinical doses of betamethasone may have acute effects on cytoskeletal proteins in the fetal brain.

Developmental changes in cerebral autoregulatory capacity in the fetal sheep parietal cortex.

We validated laser Doppler flowmetry (LDF) for long‐term monitoring and detection of acute changes of local cerebral blood flow (lCBF) in chronically instrumented fetal sheep. Using LDF, we estimated developmental changes of cerebral autoregulation. Single fibre laser probes (0.4 mm in diameter) were implanted in and surface probes were placed on the parietal cerebral cortex at 105 ± 2 (n= 7) and 120 ± 2 days gestational age (dGA, n= 7). Basal lCBF was monitored over 5 days followed by a hypercapnic challenge (fetal arterial partial pressure of CO2, Pa,CO2: 83 ± 3 mmHg) during which lCBF changes obtained by LDF were compared to those obtained with coloured microspheres (CMSs). Mean arterial blood pressure (MABP) was increased and decreased using phenylephrine and sodium nitroprusside at 110 ± 2 and 128 ± 2 dGA. Intracortical and cortical surface laser probes gave stable measurements over 5 days. The lCBF increase during hypercapnia obtained by LDF correlated well with flows obtained using CMS (r = 0.89, P < 0.01). The signals of intracortical and surface laser probes also correlated well (r = 0.91, P < 0.01). Gliosis of 0.35 ± 0.06 mm around the tip of intracortical probes did not affect the measurements. The range of MABP over which cerebral autoregulation was observed increased from 20–48 mmHg at 110 dGA to 35 to > 95 mmHg at 128 dGA (P < 0.05). Since MABP increased from 33 to 54 mmHg over this period (P < 0.01), the range between the lower limit of cerebral autoregulation and the MABP increased from 13 mmHg at 110 dGA to 19 mmHg at 128 dGA (P < 0.01). LDF is a reliable tool to assess dynamic changes in cerebral perfusion continuously in fetal sheep.

Long-Term Follow-Up of Patients after Intraarterial Thrombolytic Therapy of Acute Vertebrobasilar Artery Occlusion

Local thrombolysis may reduce mortality after acute vertebrobasilar artery occlusion. We focused on variables affecting recanalization, outcome and long-term prognosis. Thirty-six patients with vertebrobasilar artery occlusion were treated with local intraarterial thrombolytic therapy. Four of the survivors were among the 16 patients without recanalization. Recanalization was associated with a higher survival rate. Top-of-the-basilar-type occlusions have the highest recanalization rate. The thrombolytic medication used did not influence the recanalization frequency. One patient died due to an intracerebral bleed after thrombolysis. There was no association between the time interval (greater or less than 6 h) between the onset of symptoms and therapy initiation and survival. Relapses during follow-up (mean follow-up 3.7 years) did not occur. MRI/MRA and ultrasound studies during follow-up showed unchanged results in these patients. All survivors at the time of follow-up lived at home.

Antenatal betamethasone treatment reduces synaptophysin immunoreactivity in presynaptic terminals in the fetal sheep brain

Knowledge of morphofunctional effects on the fetal brain induced by exogenous glucocorticoids is limited. Recently, we reported alterations of both the neuronal cytoskeleton and electrocortical function in the ovine fetal brain after antenatal betamethasone treatment in doses used in perinatal medicine. In the present study we examined whether these changes are accompanied by morphological alterations of synapses. Chronically instrumented fetal sheep at 0.87 of gestation were treated either with isotonic saline (n=7) or 10 microg/h betamethasone (n=7) over 48 h administered directly to the fetal jugular vein. Paraffin sections of the frontal neocortex, caudate putamen and hippocampus were stained with a monoclonal antibody against synaptophysin, a specific membrane protein of presynaptic vesicles and quantified morphometrically. Synaptophysin-like immunoreactivity (synaptophysin-LI) showed a widespread granular pattern in the neuropil. Betamethasone exposure reduced synaptophysin-LI in the frontal neocortex, caudate putamen and hippocampus by 46.9, 41.0 and 55.4%, respectively, (P<0.05) that was not accompanied by irreversible neuronal damage. These results suggest that clinical doses of betamethasone have acute effects on presynaptic terminals in the fetal sheep brain that could contribute to the altered complexity of electrocortical function that we have shown previously to occur following fetal exposure to betamethasone.

Treatment with anticoagulants in cerebral events (TRACE)

90 patients with acute stroke and a concomitant cardiac embolism source or a symptomatic high-grade stenosis of an extra-or intracranial vessel received in a mulitcenter, randomized, controlled study either Enoxaparin 1 mg/kg BW s.c. b.i.d. or i.v. heparin aPTT-adjusted daily for 8 +/- 2 days as secondary prophylaxis. There were no significant differences between the two groups regarding cerebral and systemic embolic events, bleeding complications, length of hospital stay, number of diagnostic and therapeutic measures and outcome after three months. This suggests that Enoxaparin, which is easier to administer and monitor, is a safe drug in patients with acute cerebral events.

Conservative Medical Treatment and Intravenous Thrombolysis in Acute Stroke from Carotid T Occlusion

Background: We aimed to analyse the course of early recanalization and corresponding functional outcome in patients with an acute occlusion of the carotid T who were treated conservatively or underwent intravenous thrombolysis. Methods: Forty-two patients with an acute occlusion of the carotid T within 6 h were recruited from consecutive admissions to a neurological department participating in the Duplex Sonography in Acute Stroke study. All patients underwent a standardized admission and follow-up procedure. Colour-coded duplex sonography was performed on admission, 30 min after thrombolysis, and at 6 and 24 h after onset of symptoms. Recanalization of the carotid T was classified as complete, partial and absent. Functional outcome was rated with the modified Rankin scale (mRS) at 3 months as favourable (mRS 0–2) or poor (mRS 3–6). Results: Within 6 h, complete or partial recanalization occurred in 1 of 27 patients treated conservatively and in 6 of 15 thrombolysed patients. Intravenous thrombolysis predicted early recanalization also after adjustment for age, sex, cardioembolic stroke aetiology and time to treatment (adjusted odds ratio, OR, 39.7; 95% confidence interval, CI, 2.0–801.7; p = 0.016). An early recanalization was the only selected predictor of a favourable outcome (OR, 13.6; 95% CI, 1.0–179.0; p = 0.047) at regression analysis, and was achieved in 3 thrombolysed patients but in none with conservative medical treatment. Conclusions: In patients treated conservatively, functional outcome is poor and early recanalization rarely occurs. The latter can be achieved by intravenous thrombolysis with a rate comparable to that found at an intra-arterial approach without major intracranial bleeding complications. Early recanalization is associated with a better functional outcome.

Cerebral venous flow velocity predicts poor outcome in subarachnoid hemorrhage.

Background and Purpose— Predictors of clinical outcome in aneurysmal subarachnoid hemorrhage (SAH) vary in reliability. Measurement of cerebral venous hemodynamics by transcranial color-coded duplexsonography (TCCS) has become of increasing interest lately, and correlation with intracranial pressure (ICP) seems to be high. The aim of the presented study was to assess changes of cerebral venous hemodynamics in SAH and evaluate its relationship with clinical outcome. Methods— We performed sequential TCCS of venous peak flow velocities (vp-FVs) in the transversal sinus in 28 consecutive patients with aneurysmal SAH (Hunt and Hess scale 1 to 5). Measurement was initiated at onset of arterial vasospasm up to 5 days after SAH. All patients had a continuous ICP monitoring. Clinical outcome was evaluated with the modified ranking scale (MRS) 30 days after SAH. Patients were divided according to outcome: group I good recovery (MRS 0-III) and group II poor outcome (death or MRS IV-V). Maximum vp-FV, time-averaged vp-FV (mv-FV), and ICP were compared between groups. Results— Vp-FV and mv-FV as well as ICP of group II exceeded values of group I (P <0.001 for all 3 parameters). Vp-FV showed a positive correlation with ICP (r =0.63; P <0.001). A vp-FV exceeding 35.4 cm/s (sensitivity 100%; specificity 90.9%), an mv-FV exceeding 27.3 cm/s (sensitivity 94.1%; specificity 81.8%), and an ICP exceeding 24 mm Hg (sensitivity 87.5%; specificity 81.8%) predicted poor outcome (receiver operating characteristic analysis). Conclusions— Increased ICP values correlate with increased venous flow velocities. In SAH, increased ICP and increased venous flow velocities are associated with poor outcome. Flow velocity of the transversal sinus is a highly sensitive, reliable, and early predictor of outcome in SAH.