Thomas Postert

S-100 Protein: Serum Marker of Focal Brain Damage After Ischemic Territorial MCA Infarction

BACKGROUND AND PURPOSE Elevations of protein S-100 (S-100) in cerebrospinal fluid and serum have been reported after cerebral infarctions. The aim of our study was to evaluate the time course of serum S-100 concentrations after territorial middle cerebral artery (MCA) infarctions in correlation with clinical data and prognosis. METHODS S-100 serum levels were serially determined in 26 patients with an acute infarction in the territory of the MCA at day 0 (within 12 hours after onset of symptoms), day 1 (24 hours after stroke onset), and days 2, 3, 4, 5, 7 or 8, and 10 after stroke and in 26 age- and sex-matched control subjects. S-100 assays were performed using a two-site radioimmunoassay technique. The clinical status was documented using the Scandinavian Stroke Scale. The functional deficit 4 weeks after stroke onset was scored by use of the modified Rankin scale. A cranial computed tomography (CCT) was performed initially and at day 4 or 5. RESULTS Elevated concentrations of S-100 (> 0.2 microgram/L) were observed in 21 of 26 patients with MCA infarction but in none of the control subjects. S-100 levels peaked at days 2 and 3 after stroke. The S-100 concentrations in serum were significantly higher in patients with severe neurological deficits at admission, with extensive infarctions and a space-occupying effect of ischemic edema as compared with the rest of the population. S-100 values were not significantly correlated with the functional prognosis. CONCLUSIONS Presence of S-100 in serum after ischemic stroke may be due to combined leakage out of necrotic glial cells and passage through an impaired brain-blood barrier, indicating severe ischemic cell injury. Therefore, S-100 in serum can be used as a peripheral marker of ischemic focal brain damage and may be helpful for therapeutic decisions in acute ischemic stroke.

Feasibility and validity of transcranial duplex sonography in patients with acute stroke

Objectives: To evaluate in a prospective multicentre setting the feasibility of transcranial colour coded duplex sonography (TCCS) for examination of the middle cerebral artery (MCA) in patients with acute hemispheric stroke, and to assess the validity of sonographic findings in a subgroup of patients who also had a correlative angiographic examination. Methods: TCCS was performed in 58 consecutive patients within six hours of the onset of a moderate to severe hemispheric stroke. Ultrasound contrast agent (Levovist) was applied if necessary. Thirty two patients also had computed tomography angiography (n=13), magnetic resonance angiography (n=18), or digital subtraction angiography (n=1). In 14 of these patients, both the sonographic and corresponding angiographic examination were performed within six hours of stroke onset (mean time difference between TCCS and angiography 0.8 hours). Eighteen patients, in whom angiography was carried out more than 24 hours after stroke onset, had a follow up TCCS for method comparison (mean time difference 6.1 hours). Results: Initial unenhanced TCCS performed 3.4 (SD 1.2) hours after the onset of symptoms depicted the symptomatic MCA mainstem in 32 patients (55%) (13 occlusions, one stenosis, 18 patent arteries). After signal enhancement, MCA status could be determined in 54 patients (93%) (p<0.05), showing an occlusion in 25, a stenosis in two, and a patent artery in 27 patients. In 31 of the 32 patients who had correlative angiography, TCCS and angiography produced the same diagnosis of the symptomatic MCA (10 occlusions, three stenoses, 18 patent arteries); TCCS was inconclusive in the remaining one. Conclusion: TCCS is a feasible, fast, and valid non-invasive bedside method for evaluating the MCA in an acute stroke setting, particularly when contrast enhancement is applied. It may be a valuable and cost effective alternative to computed tomography and magnetic resonance angiography in future stroke trials.

Autonomic neurocardiac function in patients with major depression and effects of antidepressive treatment with nefazodone

BACKGROUND Major depression (MD) is associated with an augmented risk of cardiovascular mortality. One possible explanation for this association is that MD influences autonomic neurocardiac regulation (ANR). However, previous studies on this subject revealed conflicting results. METHODS Using an autonomic test battery, which consisted of standardised measurements of heart rate variability (HRV) and blood pressure, we (1) compared ANR between 25 patients with DSM-III-R diagnosed MD and 60 healthy controls, and (2) investigated the autonomic effects of antidepressive treatment with nefazodone. RESULTS Following multivariate analysis of all tests a significant reduction in HRV could only be shown for the Valsalva ratio amongst the depressives compared to controls. There was a significant inverse correlation between the HRV during deep respiration and both the severity of depression and the duration of the depressive episode. Serial HRV recordings revealed that both the mean resting heart rate and systolic blood pressure significantly decreased after 21 days of nefazodone treatment (average dosage 413 mg/day), whereas after 10 days (average dosage 270.8 mg/day) there were no striking changes compared to the pre-treatment values. During nefazodone treatment no significant changes in parasympathetic tone occurred. LIMITATIONS ANR was not assessed in a randomised, placebo-controlled fashion. CONCLUSIONS (1) Patients with MD may suffer from functional disturbances in the interaction between the sympathetic and parasympathetic autonomic tree. (2) The pattern of autonomic changes during treatment suggests that nefazodone induced a dose dependent, serotonergically-mediated down-regulation of the sympathetic tone. This mechanism might be responsible for nefazodones properties of reducing anxiety.

Contrast-Enhanced Transcranial Color-Coded Sonography in Acute Hemispheric Brain Infarction

PURPOSE The aim of the present study was to investigate the diagnostic potential of contrast-enhanced transcranial color-coded real-time sonography (CE-TCCS) in otherwise ultrasound-refractory acute stroke patients with an ischemia in the territory of the middle cerebral artery (MCA). Furthermore, correlations of CE-TCCS findings with clinical, angiographic, and CT results were investigated. METHODS In 90 acute stroke patients with inadequate insonation conditions in unenhanced transcranial color-coded real-time sonography (TCCS) examinations, CE-TCCS, clinical, angiographic, and CT examinations were performed within 12 hours, 36 hours (CE-TCCS only), and 1 week after onset of clinical symptoms. A CT angiography (CTA) as reference method was available in 39 individuals. After application of a galactose-based echo-enhancing agent, the portion of conclusive ultrasound examinations of the MCA, as manifested by an MCA occlusion, decreased or increased flow velocity (FV), and symmetrical MCA FV, was evaluated. CE-TCCS findings on admission and during follow-up were correlated with infarction size as demonstrated on follow-up CT, and clinical findings were assessed by use of the European Stroke Scale. RESULTS Adequate diagnosis was achieved in 74 of 90 patients (82%) by the use of echo contrast agents. MCA occlusion or reduction of MCA FV was found in 20 and 27 patients, respectively. MCA occlusion was confirmed by CTA in 17 cases. In one individual, false-positive diagnosis of MCA occlusion was made according to ultrasound criteria. In 5 patients with MCA occlusion, vessel recanalization was observed during follow-up; 15 of 27 patients with decreased flow velocities showed normalization after the third examination that was associated with a significantly better clinical outcome (P<0.0001). Furthermore, MCA occlusion or decreased FV in the first 12 hours were associated with significantly larger infarctions in the MCA territory compared with normal CE-TCCS findings (P<0.0001). CONCLUSIONS CE-TCCS enables adequate diagnosis in approximately 80% of acute hemispheric stroke patients with insufficient unenhanced TCCS examinations. It is a reliable diagnostic tool regarding MCA mainstem and branch occlusions. Because this method conveys useful information concerning cerebral tissue and clinical prognosis, it may be useful to identify those patients who benefit most from local or intra-arterial thrombolytic therapy.

Transient Response Harmonic Imaging An Ultrasound Technique Related to Brain Perfusion

BACKGROUND AND PURPOSE Gray-scale harmonic imaging is the first method to visualize blood perfusion and capillary blood flow with ultrasound after intravenous contrast agent application. The purpose of the present study was to evaluate the potential of transient response second harmonic imaging (TRsHI) to assess normal echo contrast characteristics in different brain areas by transcranial ultrasound. METHODS In 18 patients without cerebrovascular diseases, TRsHI examinations were performed bilaterally with the use of the transtemporal approach after application of 6.5 mL of a galactose-based microbubble suspension (400 mg/mL). The transmission rate was once every 4 cardiac cycles. Regional cerebral contrast was visually assessed and then quantified off-line with the use of time-intensity curves. In 4 different regions of interest (ROI) (posterior part of the thalamus [ROIa], anterior part of the thalamus [ROIb], lentiform nucleus [ROIc], and white matter [ROId]), the following parameters were evaluated: peak intensity, area under the curve (AUC), and time to peak intensity. AUC ratios for ROIc/a, d/a, c/b, and d/b were calculated. RESULTS In all patients parenchymal contrast enhancement was visually detectable. One hundred thirty-one characteristic time-intensity curves (baseline phase, peak contrast intensity, slow washout phase) were demonstrable in 144 ROIs. In ROIc and ROId, characteristic contrast curves could be observed most frequently (68/72 examinations), whereas time-intensity curves in ROIa and ROIb could not be evaluated because of inadequate contrast enhancement in 9 of 72 examinations. Time to peak intensity varied between 20 and 52 cardiac cycles; in 1 patient it was 88 cardiac cycles. In all individuals AUCs and in 16 of 18 subjects peak intensity in ROIc and ROId showed a 2- to 10-fold increase compared with ROIa and ROIb. In no examination did AUC ratios show a >2-fold side difference irrespective of the ROI. CONCLUSIONS The present study demonstrates for the first time that TRsHI produces accurate contrast in different brain areas and represents an ultrasonic tool related to brain perfusion. Absolute values of quantitative parameters show high variations caused by different temporal bone thicknesses and a complex relationship between echo contrast concentrations and measurements of optic intensities. Ratios between different ROIs help to compare contrast enhancement in different brain areas. Furthermore, because of the fact that attenuation of contrast enhancement in TRsHI depends strictly on the insonation depth, harmonic imaging studies of brain perfusion cannot be compared directly with other imaging techniques such as positron emission tomography.

Insufficient and absent acoustic temporal bone window: potential and limitations of transcranial contrast-enhanced color-coded sonography and contrast-enhanced power-based sonography.

The aim of this study was to investigate the diagnostic potential of contrast-enhanced transcranial color-coded sonography (CE-TCCS) and contrast-enhanced transcranial power-based sonography (CE-TPS) in patients with insufficient or absent acoustic bone windows (IABW). Due to temporal bone thickness, the basal cerebral circulation could not be insonated in 21 of 172 patients using unenhanced transcranial color-coded real-time sonography (TCCS) and transcranial power-based sonography. Additional CE-TCCS and CE-TPS were performed after application of 400 mg/ml galactose microbubble suspension. In both modalities, the use of echo-contrast agents allowed visualisation of the first segment of the middle cerebral artery (MCA) in all patients. The A1 segment of the anterior cerebral artery (67% in CE-TCCS; 81% in CE-TPS), P1 segment of the posterior cerebral artery (71% in CE-TCCS; 76% in CE-TPS) and the basilar artery (48% in CE-TCCS; 67% in CE-TPS) were depictable in the majority of the examinations. The M3 (5% in CE-TCCS; 33% in CE-TPS; p < 0.05), P2 (24% in CE-TCCS; 71% in CE-TPS; p < 0.005), P3 segments (0% in CE-TCCS; 43% in CE-TPS; p < 0.005) and the posterior communicating artery (5% in CE-TCCS; 33% in CE-TPS; p < 0.05) were detected in a significantly greater proportion of subjects using power Doppler. In conclusion, CE-TCCS and CE-TPS appear to be sensitive ultrasonic tools that provide reliable data regarding the basal cerebral circulation in patients with IABW. Furthermore, CE-TPS offers advantages over CE-TSSC in the identification of small-caliber arteries and vessels that run at unfavorable angels to the ultrasound beam. Both methods can overcome hyperostosis of the skull that is a major hindrance in transcranial ultrasonography, and may be helpful in the diagnosis of occlusive diseases of intracranial vessels.

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.

Contrast agent specific imaging modes for the ultrasonic assessment of parenchymal cerebral echo contrast enhancement.

Previous work has demonstrated that cerebral echo contrast enhancement can be assessed by means of transcranial ultrasound using transient response second harmonic imaging (HI). The current study was designed to explore possible advantages of two new contrast agent specific imaging modes, contrast burst imaging (CBI) and time variance imaging (TVI), that are based on the detection of destruction or splitting of microbubbles caused by ultrasound in comparison with contrast harmonic imaging (CHI), which is a broadband phase-inversion—based implementation of HI. Nine healthy individuals with adequate acoustic temporal bone windows were included in the study. Contrast harmonic imaging, CBI, and TVI examinations were performed in an axial diencephalic plane of section after an intravenous bolus injection of 4 g galactose-based microbubble suspension in a concentration of 400 mg/mL. Using time-intensity curves, peak intensities and times-to peak-intensity (TPIs) were calculated off-line in anterior and posterior parts of the thalamus, in the region of the lentiform nucleus, and in the white matter. The potential of the different techniques to visualize cerebral contrast enhancement in different brain areas was compared. All techniques produced accurate cerebral contrast enhancement in the majority of investigated brain areas. Contrast harmonic imaging visualized signal increase in 28 of 36 regions of interest (ROIs). In comparison, TVI and CBI examinations were successful in 32 and 35 investigations, respectively. In CHI examinations, contrast enhancement was most difficult to visualize in posterior parts of the thalamus (6 of 9) and the lentiform nucleus (6 of 9). In TVI examinations, anterior parts of the thalamus showed signal increase in only 6 of 9 examinations. For all investigated imaging modes, PIs and TPIs in different ROIs did not differ significantly, except that TVI demonstrated significantly higher PIs in the lentiform nucleus as compared with the thalamus and the white matter (P < 0.05). The current study demonstrates for the first time that CBI and TVI represent new ultrasonic tools that allow noninvasive assessment of focal cerebral contrast enhancement and that CBI and TVI improve diagnostic sensitivity as compared with CHI.

Serum levels of neuron-specific enolase and s-100 protein after single tonic-clonic seizures

Abstract Serum neuron-specific enolase (s-NSE) and s-100 protein (s-100) are sensitive markers of various brain diseases. We investigated both of these markers in nine patients within 5 min, 6 h, 12 h, and 48 h after a single tonic-clonic seizure. The mean peak s-NSE level was significantly higher after 5 min (11.97 ± 8.56 μg/l) and 48 h (10.31 ± 8.92 μg/l, P < 0.05) than the levels of seizure-free, age-matched controls. Five patients had increased s-NSE levels regarding the upper limit of normal as mean + 3 SD. s-100 was not detected either in controls or epileptic patients. These data indicate that s-NSE in contrast to s-100 may be an in vivo marker after generalized seizures in some patients.

Contrast Burst Depletion Imaging (CODIM) A New Imaging Procedure and Analysis Method for Semiquantitative Ultrasonic Perfusion Imaging

Background and Purpose— Established methods of ultrasonic perfusion imaging using a bolus application of echo contrast agent provide only qualitative data because of various physical phenomena. This study was intended to investigate whether a new ultrasound perfusion imaging method termed contrast burst depletion imaging (CODIM) may provide semiquantitative measures of parenchymal perfusion independent of examination depth and acoustic energy distribution. Methods— In a system with a constant concentration of contrast agent, analyzing the decrease in image intensity that occurs with microbubble-destructive imaging modes yields parameters that are considered to correlate with tissue perfusion. This method was first evaluated with a perfusion model that showed that the main resulting parameter “perfusion coefficient” (PC) is a monotonic nonlinear function of flow velocity. Seventeen human volunteers were then scanned according to this method with the use of 2 different contrast agents. Results were correlated with those from perfusion-weighted MRI examinations. Results— The PC did not show significant differences in gray matter areas (ranging from 1.466×10−2 s−1 to 1.641×10−2 s−1) of the brain despite different insonation depths (eg, ipsilateral and contralateral thalamus). In contrast, white matter exhibited significantly lower perfusion values in both imaging modes (PC: 0.604×10−2 s−1 to 0.745×10−2 s−1;P <0.05). Conclusions— CODIM is a promising new tool of imaging parenchymal (brain) perfusion in healthy persons. The method provides semiquantitative and depth-independent perfusion parameters and in this way overcomes the limitations of the perfusion methods using a bolus kinetic. Further investigations must be done to evaluate the potential of the method in patients with perfusion deficits.